ISSN 1866-8836
Клеточная терапия и трансплантация
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Introduction

Gale-fig01.jpg

Figure 1. Numbers of hematopoietic cell transplants in CML reported to the CIBMTR (1976-2022) [2]

The question I want to address is whether we abandoned haematopoietic cells transplants too soon in people with chronic phase chronic myeloid leukaemia (CML)? I think so. The idea of re-addressing transplants was suggested by the late CML expert Prof. Michele Baccarani to whom I dedicate this typescript [1].

Figure 1 displays numbers of transplants for CML 1976-2022 reported to the Centre for Blood and Marrow Research (CIBMTR). These data indicate that whilst CML was once the most common transplant indication, the introduction of imatinib, a tyrosine kinase-inhibitor (TKI), in 2001 markedly reduced numbers of transplants done. The reason, of course, is the remarkable improvement in survival of persons with chronic-phase CML receiving TKIs reaching an adjusted 10-year survival of about 90 percent.

To define the efficacy of a therapy, we first need to define the goal. Is it cure defined as normal sex- and age-adjusted survival with a normal quality-of-life off therapy, or is it operational cure defined as near-normal sex- and age-adjusted survival off or on therapy with a near normal quality of life. When operational cure is achieved off therapy, it is termed therapy-free remission (TFR). Therapy goals in CML are displayed in Fig. 2.

Unfortunately, very few persons with chronic-phase CML achieve operational cure and even few, if any, are cured with TKI therapy. Figure 3 is a cartoon of endpoints starting with 100 people with chronic-phase CML starting TKI-therapy. Only about 15 percent achieve therapy-free remission (TFR). Also controversial is the issue whether TKI, if any, is best to achieve TFR.

Gale-fig02-03.jpg

Results of transplants for chronic-phase CML from diverse donor types are indicated in Fig. 4 and 5. Quite similar survival curves are observed when using different types of donor grafts including those from haploidentical donors.

Gale-fig04.jpg

Figure 4. Survival after transplants from HLA-matched relatives and HLA-matched unrelated donors (A), as well as HLA-haplotype- matched relatives and HLA-mismatched unrelated donors (B) reported to the CIBMTR [2]

Overall substantial decrease in early deaths after allo-HSCT was registered in 2013-2017 compared to early 2000’s (Fig. 5A). Moreover, the 15-year probability of survival of transplant recipients alive at 5 years as displayed in Fig. 5B.

Gale-fig05.jpg

Figure 5. Reduction in early transplant-related death (A) [3], 15-year probability of survival of transplant recipients alive at 5 years (B) [4]

There are several issues which impact the metric for considering transplants in persons with chronic-phase CML. The 1st is median age of CML diagnosis is 60 years in the West and 50 years in Asia making > one-half potential transplant recipients. Second, the reduced-intensity conditioning (RIC) transplants are being done in older persons, albeit with a higher relapse rate compared with conventional conditioning. Third, usage of HLA-haplotype-matched relatives as donors with posttransplant cyclophosphamide means almost everyone has a suitable donor. Lastly, as indicated, early transplant-related deaths have decreased substantially. However, an early death rate of up to 20 percent must be acknowledged in this population. We also need to consider we can predict relatively early and accurately people unlikely to achieve TFR on TKI-therapy.

Table 1. Persons and conditions where a transplant in chronic phase might be considered

Gale-tab01.jpg

These considerations raise the question who is a reasonable candidate to receive a transplant in chronic phase. I suggest the following answers in Table 1.

Returning to the question, whether we have abandoned transplants in chronic phase CML too soon I suggest why this question deserves reconsidered as shown below. I also consider some concerns of using transplants in an era of TKI-therapy, as follows:
• Few people receiving TKI therapy achieve therapy-free remission, and even fewer are cured.
• Most people likely to fail TKI-therapy can be identified relatively early.
• However, there are few recent transplants limiting our prediction models.
• Subject selection biases arise for transplants.
• 20% 1-year deaths and risk of chronic GvHD.
• Randomized trial will never be done.

There is not and cannot be a universal answer to who should receive a transplant. For example, the metric of an otherwise healthy 30-year-old person facing potentially 50 years of TKI-therapy is rather different than that of a 70 year-old with other health problems more likely to kill him than CML. Helping people decide is our responsibility as physicians, a difficult challenge. As Sir William Osler, the great Canadian, British, American physician said: Medicine is a science of uncertainty and an art of probability.

Acknowledgement

Support from the UK National Institute of Health Research (NIHR) Biomedical Research Centre funding scheme.

Conflict of interest

Consultant to NexImmune Inc. and Ananexa Pharma Ascentage Pharm Group, Antengene Biotech LLC, Medical Director, FFF Enterprises Inc.; partner, AZAC Inc.; Board of Directors, Russian Foundation for Cancer Research Support; and Scientific Advisory Board: StemRad Ltd.

References

  1. Baccarani M, Bonifazi F, Soverini S, Castagnetti F, Gugliotta G, Saber W, Estrada-Merly N, Rosti G, and Gale RP. Questions concerning tyrosine kinase-inhibitor therapy and transplants in chronic phase chronic myeloid leukaemia. Leukemia. 2022; 36, 1227–1236. https://doi.org/10.1038/s41375-022-01522-3
  2. Auletta JJ, Kou J, Chen M, Shaw BE. Current use and outcome of hematopoietic stem cell transplantation: CIBMTR US summary slides, 2021. In: https://www.cibmtr.org/ReferenceCenter/SlidesReports/SummarySlides/pages/
  3. McDonald GB, Sandmaier BM, Mielcarek M, Sorror M, Pergam SA, Cheng GS, Hingorani S, Boeckh M, Flowers MD, Lee SJ, Appelbaum FR, Storb R, Martin PJ, Deeg HJ, Schoch G, and Gooley TA. Survival, nonrelapse mortality, and relapse-related mortality after allogeneic hematopoietic cell transplantation: Comparing 2003-2007 versus 2013-2017 cohorts. Ann Intern Med. 2020; 172(4):229-239. doi: 10.7326/M19-2936
  4. Goldman JM, Majhail NS, Klein JP, Wang Z, Sobocinski KA, Arora M, Horowitz MM, and Rizzo JD. Relapse and late mortality in 5-year survivors of myeloablative allogeneic hematopoietic cell transplantation for chronic myeloid leukemia in first chronic phase. J Clin Oncol. 2010;28(11):1888-1895. doi: 10.1200/JCO.2009.26.7757

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Introduction

Gale-fig01.jpg

Figure 1. Numbers of hematopoietic cell transplants in CML reported to the CIBMTR (1976-2022) [2]

The question I want to address is whether we abandoned haematopoietic cells transplants too soon in people with chronic phase chronic myeloid leukaemia (CML)? I think so. The idea of re-addressing transplants was suggested by the late CML expert Prof. Michele Baccarani to whom I dedicate this typescript [1].

Figure 1 displays numbers of transplants for CML 1976-2022 reported to the Centre for Blood and Marrow Research (CIBMTR). These data indicate that whilst CML was once the most common transplant indication, the introduction of imatinib, a tyrosine kinase-inhibitor (TKI), in 2001 markedly reduced numbers of transplants done. The reason, of course, is the remarkable improvement in survival of persons with chronic-phase CML receiving TKIs reaching an adjusted 10-year survival of about 90 percent.

To define the efficacy of a therapy, we first need to define the goal. Is it cure defined as normal sex- and age-adjusted survival with a normal quality-of-life off therapy, or is it operational cure defined as near-normal sex- and age-adjusted survival off or on therapy with a near normal quality of life. When operational cure is achieved off therapy, it is termed therapy-free remission (TFR). Therapy goals in CML are displayed in Fig. 2.

Unfortunately, very few persons with chronic-phase CML achieve operational cure and even few, if any, are cured with TKI therapy. Figure 3 is a cartoon of endpoints starting with 100 people with chronic-phase CML starting TKI-therapy. Only about 15 percent achieve therapy-free remission (TFR). Also controversial is the issue whether TKI, if any, is best to achieve TFR.

Gale-fig02-03.jpg

Results of transplants for chronic-phase CML from diverse donor types are indicated in Fig. 4 and 5. Quite similar survival curves are observed when using different types of donor grafts including those from haploidentical donors.

Gale-fig04.jpg

Figure 4. Survival after transplants from HLA-matched relatives and HLA-matched unrelated donors (A), as well as HLA-haplotype- matched relatives and HLA-mismatched unrelated donors (B) reported to the CIBMTR [2]

Overall substantial decrease in early deaths after allo-HSCT was registered in 2013-2017 compared to early 2000’s (Fig. 5A). Moreover, the 15-year probability of survival of transplant recipients alive at 5 years as displayed in Fig. 5B.

Gale-fig05.jpg

Figure 5. Reduction in early transplant-related death (A) [3], 15-year probability of survival of transplant recipients alive at 5 years (B) [4]

There are several issues which impact the metric for considering transplants in persons with chronic-phase CML. The 1st is median age of CML diagnosis is 60 years in the West and 50 years in Asia making > one-half potential transplant recipients. Second, the reduced-intensity conditioning (RIC) transplants are being done in older persons, albeit with a higher relapse rate compared with conventional conditioning. Third, usage of HLA-haplotype-matched relatives as donors with posttransplant cyclophosphamide means almost everyone has a suitable donor. Lastly, as indicated, early transplant-related deaths have decreased substantially. However, an early death rate of up to 20 percent must be acknowledged in this population. We also need to consider we can predict relatively early and accurately people unlikely to achieve TFR on TKI-therapy.

Table 1. Persons and conditions where a transplant in chronic phase might be considered

Gale-tab01.jpg

These considerations raise the question who is a reasonable candidate to receive a transplant in chronic phase. I suggest the following answers in Table 1.

Returning to the question, whether we have abandoned transplants in chronic phase CML too soon I suggest why this question deserves reconsidered as shown below. I also consider some concerns of using transplants in an era of TKI-therapy, as follows:
• Few people receiving TKI therapy achieve therapy-free remission, and even fewer are cured.
• Most people likely to fail TKI-therapy can be identified relatively early.
• However, there are few recent transplants limiting our prediction models.
• Subject selection biases arise for transplants.
• 20% 1-year deaths and risk of chronic GvHD.
• Randomized trial will never be done.

There is not and cannot be a universal answer to who should receive a transplant. For example, the metric of an otherwise healthy 30-year-old person facing potentially 50 years of TKI-therapy is rather different than that of a 70 year-old with other health problems more likely to kill him than CML. Helping people decide is our responsibility as physicians, a difficult challenge. As Sir William Osler, the great Canadian, British, American physician said: Medicine is a science of uncertainty and an art of probability.

Acknowledgement

Support from the UK National Institute of Health Research (NIHR) Biomedical Research Centre funding scheme.

Conflict of interest

Consultant to NexImmune Inc. and Ananexa Pharma Ascentage Pharm Group, Antengene Biotech LLC, Medical Director, FFF Enterprises Inc.; partner, AZAC Inc.; Board of Directors, Russian Foundation for Cancer Research Support; and Scientific Advisory Board: StemRad Ltd.

References

  1. Baccarani M, Bonifazi F, Soverini S, Castagnetti F, Gugliotta G, Saber W, Estrada-Merly N, Rosti G, and Gale RP. Questions concerning tyrosine kinase-inhibitor therapy and transplants in chronic phase chronic myeloid leukaemia. Leukemia. 2022; 36, 1227–1236. https://doi.org/10.1038/s41375-022-01522-3
  2. Auletta JJ, Kou J, Chen M, Shaw BE. Current use and outcome of hematopoietic stem cell transplantation: CIBMTR US summary slides, 2021. In: https://www.cibmtr.org/ReferenceCenter/SlidesReports/SummarySlides/pages/
  3. McDonald GB, Sandmaier BM, Mielcarek M, Sorror M, Pergam SA, Cheng GS, Hingorani S, Boeckh M, Flowers MD, Lee SJ, Appelbaum FR, Storb R, Martin PJ, Deeg HJ, Schoch G, and Gooley TA. Survival, nonrelapse mortality, and relapse-related mortality after allogeneic hematopoietic cell transplantation: Comparing 2003-2007 versus 2013-2017 cohorts. Ann Intern Med. 2020; 172(4):229-239. doi: 10.7326/M19-2936
  4. Goldman JM, Majhail NS, Klein JP, Wang Z, Sobocinski KA, Arora M, Horowitz MM, and Rizzo JD. Relapse and late mortality in 5-year survivors of myeloablative allogeneic hematopoietic cell transplantation for chronic myeloid leukemia in first chronic phase. J Clin Oncol. 2010;28(11):1888-1895. doi: 10.1200/JCO.2009.26.7757

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Роберт Питер Гэйл

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Имперский Колледж науки, технологии и медицины, Лондон, Великобритания; Университетский онкологический центр им. Сун-Ятсена, Гуанчжоу, Китай

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В статье затрагивается вопрос: нужно ли нам пересматривать применение трансплантации гемопоэтических клеток в качестве адекватной терапии у некоторых пациентов с хроническим миелоидным лейкозом в хронической фазе? Ответ может быть положительным для некоторых больных, которые не отвечают на лечение ингибиторами тирозинкиназы или вряд ли достигнут ремиссии без дальнейшей терапии.

Ключевые слова

Хронический миелоидный лейкоз, иматиниб, трансплантация гемопоэтических стволовых клеток, стратегия лечения.

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Robert Peter Gale

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Imperial College of Science, Technology and Medicine, London, UK; Sun Yat-sen Univ. Cancer Centre, Guangzhou, China


Correspondence:
Robert Peter Gale, MD, PhD DSc(hc), FACP, FRCP, FRSPI(hon), FRSM, Centre for Haematology Research, Department of Immunology and Inflammation, Imperial College of Science, Technology and Medicine, London, UK SW7 2BX


Citation: Robert Peter Gale. Time to reconsider haematopoietic cell transplants in chronic myeloid leukaemia? Cell Ther Transplant 2022; 11(3-4): 6-9.

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The article concerns whether we need to reconsider whether haematopoietic cell transplants are an appropriate therapy in some persons with chronic phase chronic myeloid leukaemia. The answer may be yes in some persons failing tyrosine kinase-inhibitor therapy or unlikely to achieve therapy-free remission. 

Keywords

Сhronic myeloid leukemia, imatinib, hematopoietic stem cell transplantation, treatment strategy.

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Robert Peter Gale

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Robert Peter Gale

" } ["SUMMARY_EN"]=> array(37) { ["ID"]=> string(2) "39" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:02:59" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(21) "Description / Summary" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(10) "SUMMARY_EN" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "39" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "29484" ["VALUE"]=> array(2) { ["TEXT"]=> string(554) "<p style="text-align: justify;">The article concerns whether we need to reconsider whether haematopoietic cell transplants are an appropriate therapy in some persons with chronic phase chronic myeloid leukaemia. The answer may be yes in some persons failing tyrosine kinase-inhibitor therapy or unlikely to achieve therapy-free remission. </p> <h2>Keywords</h2> <p style="text-align: justify;">Сhronic myeloid leukemia, imatinib, hematopoietic stem cell transplantation, treatment strategy.</p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(498) "

The article concerns whether we need to reconsider whether haematopoietic cell transplants are an appropriate therapy in some persons with chronic phase chronic myeloid leukaemia. The answer may be yes in some persons failing tyrosine kinase-inhibitor therapy or unlikely to achieve therapy-free remission. 

Keywords

Сhronic myeloid leukemia, imatinib, hematopoietic stem cell transplantation, treatment strategy.

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The article concerns whether we need to reconsider whether haematopoietic cell transplants are an appropriate therapy in some persons with chronic phase chronic myeloid leukaemia. The answer may be yes in some persons failing tyrosine kinase-inhibitor therapy or unlikely to achieve therapy-free remission. 

Keywords

Сhronic myeloid leukemia, imatinib, hematopoietic stem cell transplantation, treatment strategy.

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Imperial College of Science, Technology and Medicine, London, UK; Sun Yat-sen Univ. Cancer Centre, Guangzhou, China


Correspondence:
Robert Peter Gale, MD, PhD DSc(hc), FACP, FRCP, FRSPI(hon), FRSM, Centre for Haematology Research, Department of Immunology and Inflammation, Imperial College of Science, Technology and Medicine, London, UK SW7 2BX


Citation: Robert Peter Gale. Time to reconsider haematopoietic cell transplants in chronic myeloid leukaemia? Cell Ther Transplant 2022; 11(3-4): 6-9.

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Imperial College of Science, Technology and Medicine, London, UK; Sun Yat-sen Univ. Cancer Centre, Guangzhou, China


Correspondence:
Robert Peter Gale, MD, PhD DSc(hc), FACP, FRCP, FRSPI(hon), FRSM, Centre for Haematology Research, Department of Immunology and Inflammation, Imperial College of Science, Technology and Medicine, London, UK SW7 2BX


Citation: Robert Peter Gale. Time to reconsider haematopoietic cell transplants in chronic myeloid leukaemia? Cell Ther Transplant 2022; 11(3-4): 6-9.

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Роберт Питер Гэйл

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Роберт Питер Гэйл

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В статье затрагивается вопрос: нужно ли нам пересматривать применение трансплантации гемопоэтических клеток в качестве адекватной терапии у некоторых пациентов с хроническим миелоидным лейкозом в хронической фазе? Ответ может быть положительным для некоторых больных, которые не отвечают на лечение ингибиторами тирозинкиназы или вряд ли достигнут ремиссии без дальнейшей терапии.

Ключевые слова

Хронический миелоидный лейкоз, иматиниб, трансплантация гемопоэтических стволовых клеток, стратегия лечения.

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В статье затрагивается вопрос: нужно ли нам пересматривать применение трансплантации гемопоэтических клеток в качестве адекватной терапии у некоторых пациентов с хроническим миелоидным лейкозом в хронической фазе? Ответ может быть положительным для некоторых больных, которые не отвечают на лечение ингибиторами тирозинкиназы или вряд ли достигнут ремиссии без дальнейшей терапии.

Ключевые слова

Хронический миелоидный лейкоз, иматиниб, трансплантация гемопоэтических стволовых клеток, стратегия лечения.

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Имперский Колледж науки, технологии и медицины, Лондон, Великобритания; Университетский онкологический центр им. Сун-Ятсена, Гуанчжоу, Китай

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Имперский Колледж науки, технологии и медицины, Лондон, Великобритания; Университетский онкологический центр им. Сун-Ятсена, Гуанчжоу, Китай

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Introduction

Long-term experience in usage of high-dose immunosuppressive therapy (HDIT) followed by autologous hematopoietic stem cell transplantation (AHSCT) has shown its efficiency in achieving clinical stabilization of multiple sclerosis (MS), thus potentially exceeding the results of highly effective drug immunotherapy [1-5]. However, due to usage of high doses of cytostatics, the safety issues of HDIT-AHSCT still remain relevant. At the same time, frequency and severity of complications in HDIT-AHSCT depends not only on the intensity of conditioning regimens (CR, chemotherapy protocol using cytotoxic drugs) [1; 6-8]. Analysis of data from the Registry of the European Society for Blood and Marrow Transplantation (EBMT) and the Center for International Blood and Marrow Transplant Research (CIBMTR) presumes a dependence of favorable outcomes in HDIT-AHSCT on the quality of patients’ selection and clinical expertise of the transplant center [9-12].

Analysis of research publications concerning the choice of optimal conditions and criteria for administering HDIT-AHSCT in multiple sclerosis, as well as a description of the main stages of the method, was presented earlier [13].

The purpose of this review is to analyze the clinical research data about complications of HDIT-AHSCT in MS, as well as potential factors that may reduce the risk of their occurrence.

Materials and methods

Literature search

We have searched scientific publications in the "Pubmed" and "Scopus" databases. The search algorithm included articles and review articles with the following queries: "stem cells" and "multiple sclerosis". The literature data were analyzed and summarized for the following items: 1) variants of conditioning regimens in HDIT-AHSCT; 2) early complications of HDIT-AHSCT; 3) late complications of HDIT-AHSCT in MS; 4) risk factors for complications of HDIT-AHSCT associated with clinical profile of the HSCT recipient.

Conditioning regimens (CR)

Currently, the most common HDIT regimens in MS treatment today are the protocols of medium-intensity (Table 1). High-intensity protocols may potentially cause a broader range of side effects, whereas low-intensity CR, in turn, may be less effective. At the same time, it should be emphasized that HDIT-AHSCT can only be performed in hematological transplant clinics with aseptic wards and a skilled multidisciplinary team.

Table 1. Average-intensity conditioning regimens in MS therapy

Polushin-tab01.jpg

Notes: 1. In addition to HDIT, the protocol includes supportive therapy at all stages of the procedure; 2. D, day pre- and posttransplant with transfusion of thawed autograft on D0; ATG, Antithymocyte globulin.

Absence of a generally accepted conditioning regimen, and the use of several CR variants, even within the same transplant centers, reflect a number of issues that need to be addressed in the course of treatment. The choice of CR is determined by: a) the predominant mechanisms of action on cells of the applied scheme; b) expected positive and negative effects; c) safety issues for the given patient, taking into account his clinical and demographic features and comorbidity, as well as characteristics of the underlying disease. It is the CR schedule that largely determines the safety issues of HDIT-AHSCT.

HDIT-AHSCT is associated with undesirable effects which may occur early (expected effects, due to profound immunosuppression), or may be observed at later terms.

Early complications of HDIT-AHSCT develop, mainly, due to conditioning treatment, with period of cytopenia, and during the post-transplantation period (up to D+100). Infectious complications of immunosuppressive therapy are expected, being observed in almost all cases, and are often caused by reactivation of pathogens persisting in the body. Among early infectious complications, neutropenic fever, septicemia, urinary tract infections, mucositis, gastrointestinal infections, chronic latent infections (e.g., reactivation/reinfection of cytomegalovirus and Epstein-Barr virus) may be observed. In most cases, they are prevented with antibacterial, antimycotic and antiviral therapy according to the algorithm adopted at each HSCT center. Nevertheless, according to the recent publications, infectious mortality during HDIT-AHSCT in MS can reach 0.2-1% [3; 5; 14-16]. Of particular importance may be organ toxicity associated with CR, in particular, impairment of heart, liver, kidney and lung functions.

Among the early side effects of HDIT-AHSCT, transient neurological disorders may be present, which are nonspecific in most cases, reflecting constitutional or cerebral symptoms, associated with fever or allergic reactions to injected colony stimulating factor (CSF) or ATG, e.g., headache, dizziness, asthenia. The list of expected complications occurring at the early stage of HDIT-AHSCT when using the recently recommended conditioning in MS therapy [5] is presented in Table 2 [1-4; 17-21; own data].

Table 2. Early complications of HDIT-AHSCT observed in patients with multiple sclerosis (classified by CTCAE 5.0)

Polushin-tab02.jpg

Note: *, all complications are potentially expected and treatable at the inpatient stage; **, complications observed only with cyclophosphamide-induced mobilization of hematopoietic stem cells (not used in most transplant centers); VZV, varicella zoster virus/herpes zoster; EBV, Epstein-Barr virus; AID, autoimmune diseases; UT, urinary tract.

Intensity of the conditioning regimen directly correlates with both hematological toxicity (anemia, leukopenia, neutropenia, thrombocytopenia) and systemic/organ damage (hepatitis, cystitis, diarrhea, encephalopathy, alopecia). During the period of neutropenia, episodes of febrile fever are frequent, both in presence of the current infectious process, and without signs of infection. High-intensity conditioning regimens are characterized by longer pancytopenia, which seems to be are associated with adverse outcomes. Low-intensity conditioning regimens produce milder side effects and absence of transplant-associated mortality.

Late complications, as well as therapeutic effects of HDIT, may develop due to the dynamic process of immunosuppression which accompany the posttransplant reconstitution, mainly, following myeloablative treatment. On the background of complications (especially "Blood and immune system disorders"), an imbalance in the functioning of the immune system leads to a violation of immunological surveillance, which may result into bacterial infections, including opportunistic pathogens, as well as development of oncological disorders, secondary autoimmune, and allergic conditions.

The risks of long-term opportunistic infections after medium- and low-intensity conditioning are, generally, low. A possible increase in the reactivation of herpesviruses mainly concerns herpes simplex (HSV 1, 2) and Varicella Zoster (VZV). It refers to events that are significant but could be canceled by standard antiviral drug therapy regimens, and occurs more often in the early post-transplant period. The probability and severity of late complications may depend on the intensity of CR and is inversely proportional to the duration of antiviral therapy after HDIT-AHSCT [4].

Progressive multifocal leukoencephalopathy (PML) caused by the transformation of latent infection with JC virus occurs rarely when using modern CRs. According to the EBMT registry, no PML cases were reported, including the patients previously treated with natalizumab, and those with high JCV titers [22].

HDIT may cause damage to the ovaries and reproductive function, thus leading to impaired fertility in females, early menopause caused by chemotherapy, and longitudinal consequences of estrogen deficiency [23-25]. Restoration of the menstrual cycle after HDIT in women under 32 years old was recorded in all cases and occurred within 5 to 12 months. From our experience (Pavlov University, St. Petersburg), the median recovery time of the menstrual cycle occurs after 3±2.56 months (1 to 12 months after HDIT-AHSCT) in the group of respondents (57 women at 36±5.6 y.o. were questioned since 2018). Restoration of the menstrual cycle is much less common in the women >41 y.o., i.e., only in 38% of cases [21, 26]. Meanwhile, despite the risk of secondary infertility, the known cases of childbirth in patients with MS after HDIT-AHSCT proceeded, without complications for the mother or child. According to the EBMT registry, the postpartum women with MS, in contrast to the group with systemic sclerosis or rheumatoid arthritis, did not experience exacerbations [27, 28]. There have been no studies evaluating the effect of disease modifying therapies (DMT) on reproductive function [29], thus precluding comparisons with the risks of HDIT option.

Secondary autoimmune diseases (AID) comprise another group of late complications of HDIT-AHSCT, described at a frequency of 4-10% in MS patients [3, 5, 30]. The most expected complications are hypothyroidism, hyperthyroidism, autoimmune thrombocytopenic purpura.

According to the scarce literature data, the probability of developing endocrinopathies after chemotherapy is reported for 4-17% of cases when using medium-intensity regimens, thus being significantly lower than their frequency with high-intensity conditioning regimens (up to 26%) [3, 21].

In general, when using medium-intensity CR, the severity of HDIT complications according to the Common Terminology Criteria for Adverse Events (CTCAE 5.0) is mostly considered mild and moderate (Grade 0-3). Table 3 presents a list of potential late complications of HDIT-AHSCT when using the recommended protocols for MS [1, 4, 5, 13, 19-21, 30-32].

Table 3. Possible late complications of HDIT-AHSCT in patients with multiple sclerosis (according to CTCAE 5.0)

Polushin-tab03.jpg

Potential neurotoxicity of HDIT

High doses of cytostatic therapy are associated with a wider range, frequency, and severity of complications, with neurodegenerative component of MS being the potential feature of HDIT neurotoxicity [34-38]. Chemotherapeutic drugs used for immunoablation in MS are administered selectively, taking into account their ability to penetrate the blood-brain barrier [39], which seems to be especially relevant in progressive forms of MS, when autoimmune inflammation is "compartmentalized" with its predominance within central nervous system.

There are no data on the relevance of clinically significant neurotoxicity of chemotherapy drugs used in the protocols in the available literature. It has been proven that neurotoxicity associated with busulfan usage is transient and does not extend to the post-transplant recovery period [40]. Petzold A. et al. have shown that the blood concentration of heavy neurofilament chains of (NfH) correlating with axonal damage increased by 79% of patients with MS, and in 49% of patients with hematological malignancies after total body irradiation (TBI) and ATG treatment. However, this protocol (with TBI) is not used for treatment of MS due to high risks of adverse events [36, 41].

The potential neurotoxicity of HDIT-AHSCT is associated with MRI markers commonly used in clinical studies, e.g., dynamics of changing volumes for the distinct brain structures. The ratio of atrophy, "pseudoatrophy" and slowing down of the atrophy of the medulla is still a controversial issue in HDIT-AHSCT. After 6-24 months of HDIT-AHSCT, according to MRI data, an increased loss of brain matter can be detected [44], and without additional biomarkers that may be interpreted in two ways. On the one hand, the acceleration of atrophy associated with the neurotoxic effects of chemotherapy cannot be ruled out. On the other hand, a well-studied MRI phenomenon in the pharmacotherapy of MS is "pseudoatrophy" – a faster decrease in brain volume compared to the initial rate in the first year of treatment with DMTs, which quickly suppress autoimmune inflammation and eliminate the accompanying tissue edema. According to some researchers, it is precisely in line with the effect of inflammation on the volume of brain tissue before HDIT-AHSCT (brain enlargement due to inflammatory infiltration and edema). Therefore, that the optimal assessment of brain volume is possible as late as 2 years after HDIT-AHSCT [42]. According to Roccatagliata L. et al. and Atkins H. et al., the usage of HDIT-AHSCT in aggressive forms of MS (RRMS and SPMS) having been observed during 5-year period, is followed by a slowdown in the rate of brain volume atrophy from 50% to the pathophysiological level recorded in the general population free of MS [40, 43, 44]. These data prompted the workers to suggest a long-lasting anti-inflammatory effect of immune reconstitution after HDIT-AHSCT, which is confirmed by the almost complete absence of MR activity for 5 years, or more in 70-94% of patients [19, 44-46].

Mortality

Polushin-fig01.jpg

Figure 1. EBMT Registry data on usage of different CRs for HSCT in MS (1995-2021) (adopted from [3; 11; 50 and data of EBMT register])

Notes: *, the analysis on differentiation of CRs was not carried out; **, HSCT restrictions during COVID-19; 1-3, number of transplant-related mortality (TRM) cases.

Polushin-fig02.jpg

Figure 2. The ratio of patients with different types of multiple sclerosis selected for HDIT-AHSCT, %

Notes: RRMS, relapsing-remitting multiple sclerosis; PMS, progressive multiple sclerosis. Comment: malignant multiple sclerosis (aggressive) MS is characterized by an abrupt onset with several consecutive exacerbations within a short period of time, resulting into severe disability and extensive MRI lesions [5].

Since 1997, there has been a consensus elaborated by the European League Against Rheumatism (EULAR) with the European Group for Blood and Bone Marrow Transplantation (EBMT), that allogeneic (related/unrelated) HSCT is unacceptable in autoimmune diseases due to transplant-related mortality (TRM). The TRM rates reached 15-35% and in most cases was due to graft-versus-host disease [47]. In contrast to allogeneic transplants, the EBMT reports for 2002 and 2006 reported much lower mortality associated with autologous HSCT (6% and 5.3%, respectively), as seen in Fig. 1 [1, 6]. According to the EBMT report of 2005, it was noted that therapy-associated mortality following high-intensity CR in all autoimmune diseases, was higher than in the moderate-intensity CR group. Protocols with the maximal available doses of busulfan were associated with higher risk of therapy-associated mortality (p=0.001) in the patients with progressive forms of MS [1]. Lower risk of mortality with busulfan-containing protocols was shown in the patients with shorter duration of MS [48]. However, when comparing CRs with busulfan (high intensity) and cyclophosphamide CRs (medium/low intensity) in the group of patients with MS (unlike SLE and scleroderma), the difference was not significant [49].

Fig. 1 shows growing rates of transplantation activity with CR using cyclophosphamide (Cy-ATG), and decreased usage of BEAM-ATG regimen. In accordance with reduced CR intensity, there is a decrease in TRM.

According to EBMT reports, a significant decrease in TRM (from 7.3% to 1.3%) occurred since 2002-2005 [51]. The improvement in this important index was achieved primarily due to rejection of high-intensity CR (protocols with busulfan and total body irradiation), as well as selection of younger patients with less pronounced neurological deficit [52]. The dynamics of the paradigm shift in the patients’ selection for HDIT-AHSCT is presented in Fig. 2.

Fig. 2 shows a paradigm shift in priority of HDIT-AHSCT usage in relapsing-remitting MS, which is generally characterized by a shorter duration of the disease, lesser severity of neurological deficit, and predominance of inflammatory processes over neurodegeneration.

It should be emphasized that the most dramatic effect exhibiting clinical improvement and long-term stabilization of the condition after timely HDIT-AHSCT may be observed in patients with malignant forms of MS in presence of a rapid progression of neurological deficit [16, 53-55]. Moreover, preserved quality of life is expected with the use of HDIT-AHSCT in all the MS phenotypes [56].

On the basis of data from research publications reflecting modern approaches to the treatment of MS, and results of studies using the HDIT-AHSCT, one may proposed a patient profile which is the optimal candidate for HDIT-AHSCT with a potential positive therapeutic effect from treatment (Table 4).

Table 4. Expected effect from HDIT-AHSCT on the basis of clinical and demographic characteristics of the patient

Polushin-tab04.jpg

Note: a decrease in the EDSS score by 0.5 or more is considered a positive effect, however, patients with PMS also include stopping of further progression (stabilization).

Transplantation centers with a long history of AID treatment take into account the optimal characteristics of a patient with MS for HDIT-AHSCT, i.e., younger age, short duration of the disease, type of clinical course, e.g., RRMS or early stages of transition to SPMS, mild or moderate neurological deficit, the presence of MRI activity (appearance of gadolinium-positive lesions in central nervous system).

As mentioned above, expectations for efficiency of HDIT-AHSCT should be based on the timely implication of the method, taking into account the disease evolution pattern in a particular patient. The types of HDIT-AHSCT by goals and time frames are presented in Tab. 5.

Table 5. Types of HDIT-AHSCT in multiple sclerosis [12, 33, 57-61, adapted]

Polushin-tab05.jpg

To date, the HDIT-AHSCT is not performed at later terms (in cases of long duration of the disease, with PPMS, EDSS >6.5 points), despite proven efficiency of canceling MS progression, with respect to potential risks and benefits of the method. This approach should be recommended to patients with similar characteristics who are motivated to carry out this treatment method, as well as to physicians involved into the decision.

Pre-requisites for the potential success of HDIT-AHSCT in multiple sclerosis are as follows:
- optimal selection of patients, taking into account their demographic and clinical characteristics;
- choice of the conditioning regimen intensity depending on activity and severity of MS, as well as patient risk factors, including comorbidities;
- clinical activity of the transplant center must comply with the criteria of the Joint Accreditation Committee ISCT- Europe & EBMT (JACIE);
- the main activity of the transplant center should be centered on treatment of hematological patients, thus providing organizational basis for quick coping with problems of therapy and prevention of adverse events;
- involvement of a multidisciplinary team (hematologist, transfusiologist, neurologist), radiologist). The specialists should have experience in treating the appropriate cohorts of patients and participate in decision-making not only at HSCT, but also at the pre-transplant stage and during long-term observation;
- dynamic follow-up of the patient’s condition with clinical examination, monitoring of immune functions, neuroimaging should be carried out in order to prevent exacerbations in patients with refractory/malignant forms of MS;
- implementation of effective specialized measures for physical rehabilitation at all stages of HDIT-AHSCT, including physical therapy before admission to the transplant center (preparation regimens for long-term hospitalization and physical rehabilitation);
- obligatory keeping of the therapeutic window between the last course of DMT and the scheduled HDIT (Table 6).

Table 6. “Therapeutic window” between the last administration of DMT and the start of HDIT

Polushin-tab06.jpg

Conclusion

According to current literature data, HDIT-AHSCT may produce a wide range of significant complications. However, a trend for usage of reduced (medium) intensity conditioning regimens and better (more careful) selection of patients led to minimization of adverse events. The moderate-intensity HDIT (conditioning regimens for HSCT) may be less effective than high-intensity protocols, but their use at early stages of the disease may be of maximum benefit to individuals with MS refractory to standard therapy.

HDIT-AHSCT cannot be the method of choice for all categories of patients with multiple sclerosis, since the expected clinical effect may be not justified, due to risks of complications, in particular in cases with a long duration of the disease, severe neurological deficit and lack of activity (no new lesions or gadolinium enhancement) of the process. The maximal effect can be expected in the case of early HDIT-AHSCT, and in aggressive forms of MS, where the efficiency can be considered life-determining. If such a category of patients does not meet the criteria that preclude HDIT-AHSCT, their chances for clinical improvement and/or long-term stabilization of clinical state are very high, with minimal probability of adverse events.

The costs of this treatment option are relatively high. However, taking into account the expected effectiveness, i.e., long-term relapse-free course of the disease and improved quality of life, especially in young people of working age, its inclusion into the list of standard methods of therapy for MS patients is extremely important and potentially cost-effective after the prospective comparative studies.

Acknowledgements

We are acknowledged to the Autoimmune Diseases Working Party (ADWP) of the European Society for Blood and Marrow Transplantation (EBMT) for its support in providing updated Registry data, and all EBMT member centers and their clinicians, data managers and patients for their valuable contributions to the EBMT registry.

Conflict of interest

The study had no sponsorship. Authors declare no conflict of interest. The authors are fully responsible for submitting the final version of the manuscript. All the authors took part in the development of the concept of the article and the writing of the manuscript. The final version of the manuscript was approved by all authors.

Compliance with ethical principles

The authors confirm that they respect the rights of the people participated in the study, including obtaining informed consent when it is necessary, and the rules of treatment of animals when they are used in the study. Author Guidelines contains the detailed information.

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  44. Atkins HL, Bowman M, Allan D, Anstee G, Arnold DL, Bar-Or A, et al. Immunoablation and autologous haemopoietic stem-cell transplantation for aggressive multiple sclerosis: a multicentre single-group phase 2 trial. Lancet. 2016; 388(10044):576-585.
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Introduction

Long-term experience in usage of high-dose immunosuppressive therapy (HDIT) followed by autologous hematopoietic stem cell transplantation (AHSCT) has shown its efficiency in achieving clinical stabilization of multiple sclerosis (MS), thus potentially exceeding the results of highly effective drug immunotherapy [1-5]. However, due to usage of high doses of cytostatics, the safety issues of HDIT-AHSCT still remain relevant. At the same time, frequency and severity of complications in HDIT-AHSCT depends not only on the intensity of conditioning regimens (CR, chemotherapy protocol using cytotoxic drugs) [1; 6-8]. Analysis of data from the Registry of the European Society for Blood and Marrow Transplantation (EBMT) and the Center for International Blood and Marrow Transplant Research (CIBMTR) presumes a dependence of favorable outcomes in HDIT-AHSCT on the quality of patients’ selection and clinical expertise of the transplant center [9-12].

Analysis of research publications concerning the choice of optimal conditions and criteria for administering HDIT-AHSCT in multiple sclerosis, as well as a description of the main stages of the method, was presented earlier [13].

The purpose of this review is to analyze the clinical research data about complications of HDIT-AHSCT in MS, as well as potential factors that may reduce the risk of their occurrence.

Materials and methods

Literature search

We have searched scientific publications in the "Pubmed" and "Scopus" databases. The search algorithm included articles and review articles with the following queries: "stem cells" and "multiple sclerosis". The literature data were analyzed and summarized for the following items: 1) variants of conditioning regimens in HDIT-AHSCT; 2) early complications of HDIT-AHSCT; 3) late complications of HDIT-AHSCT in MS; 4) risk factors for complications of HDIT-AHSCT associated with clinical profile of the HSCT recipient.

Conditioning regimens (CR)

Currently, the most common HDIT regimens in MS treatment today are the protocols of medium-intensity (Table 1). High-intensity protocols may potentially cause a broader range of side effects, whereas low-intensity CR, in turn, may be less effective. At the same time, it should be emphasized that HDIT-AHSCT can only be performed in hematological transplant clinics with aseptic wards and a skilled multidisciplinary team.

Table 1. Average-intensity conditioning regimens in MS therapy

Polushin-tab01.jpg

Notes: 1. In addition to HDIT, the protocol includes supportive therapy at all stages of the procedure; 2. D, day pre- and posttransplant with transfusion of thawed autograft on D0; ATG, Antithymocyte globulin.

Absence of a generally accepted conditioning regimen, and the use of several CR variants, even within the same transplant centers, reflect a number of issues that need to be addressed in the course of treatment. The choice of CR is determined by: a) the predominant mechanisms of action on cells of the applied scheme; b) expected positive and negative effects; c) safety issues for the given patient, taking into account his clinical and demographic features and comorbidity, as well as characteristics of the underlying disease. It is the CR schedule that largely determines the safety issues of HDIT-AHSCT.

HDIT-AHSCT is associated with undesirable effects which may occur early (expected effects, due to profound immunosuppression), or may be observed at later terms.

Early complications of HDIT-AHSCT develop, mainly, due to conditioning treatment, with period of cytopenia, and during the post-transplantation period (up to D+100). Infectious complications of immunosuppressive therapy are expected, being observed in almost all cases, and are often caused by reactivation of pathogens persisting in the body. Among early infectious complications, neutropenic fever, septicemia, urinary tract infections, mucositis, gastrointestinal infections, chronic latent infections (e.g., reactivation/reinfection of cytomegalovirus and Epstein-Barr virus) may be observed. In most cases, they are prevented with antibacterial, antimycotic and antiviral therapy according to the algorithm adopted at each HSCT center. Nevertheless, according to the recent publications, infectious mortality during HDIT-AHSCT in MS can reach 0.2-1% [3; 5; 14-16]. Of particular importance may be organ toxicity associated with CR, in particular, impairment of heart, liver, kidney and lung functions.

Among the early side effects of HDIT-AHSCT, transient neurological disorders may be present, which are nonspecific in most cases, reflecting constitutional or cerebral symptoms, associated with fever or allergic reactions to injected colony stimulating factor (CSF) or ATG, e.g., headache, dizziness, asthenia. The list of expected complications occurring at the early stage of HDIT-AHSCT when using the recently recommended conditioning in MS therapy [5] is presented in Table 2 [1-4; 17-21; own data].

Table 2. Early complications of HDIT-AHSCT observed in patients with multiple sclerosis (classified by CTCAE 5.0)

Polushin-tab02.jpg

Note: *, all complications are potentially expected and treatable at the inpatient stage; **, complications observed only with cyclophosphamide-induced mobilization of hematopoietic stem cells (not used in most transplant centers); VZV, varicella zoster virus/herpes zoster; EBV, Epstein-Barr virus; AID, autoimmune diseases; UT, urinary tract.

Intensity of the conditioning regimen directly correlates with both hematological toxicity (anemia, leukopenia, neutropenia, thrombocytopenia) and systemic/organ damage (hepatitis, cystitis, diarrhea, encephalopathy, alopecia). During the period of neutropenia, episodes of febrile fever are frequent, both in presence of the current infectious process, and without signs of infection. High-intensity conditioning regimens are characterized by longer pancytopenia, which seems to be are associated with adverse outcomes. Low-intensity conditioning regimens produce milder side effects and absence of transplant-associated mortality.

Late complications, as well as therapeutic effects of HDIT, may develop due to the dynamic process of immunosuppression which accompany the posttransplant reconstitution, mainly, following myeloablative treatment. On the background of complications (especially "Blood and immune system disorders"), an imbalance in the functioning of the immune system leads to a violation of immunological surveillance, which may result into bacterial infections, including opportunistic pathogens, as well as development of oncological disorders, secondary autoimmune, and allergic conditions.

The risks of long-term opportunistic infections after medium- and low-intensity conditioning are, generally, low. A possible increase in the reactivation of herpesviruses mainly concerns herpes simplex (HSV 1, 2) and Varicella Zoster (VZV). It refers to events that are significant but could be canceled by standard antiviral drug therapy regimens, and occurs more often in the early post-transplant period. The probability and severity of late complications may depend on the intensity of CR and is inversely proportional to the duration of antiviral therapy after HDIT-AHSCT [4].

Progressive multifocal leukoencephalopathy (PML) caused by the transformation of latent infection with JC virus occurs rarely when using modern CRs. According to the EBMT registry, no PML cases were reported, including the patients previously treated with natalizumab, and those with high JCV titers [22].

HDIT may cause damage to the ovaries and reproductive function, thus leading to impaired fertility in females, early menopause caused by chemotherapy, and longitudinal consequences of estrogen deficiency [23-25]. Restoration of the menstrual cycle after HDIT in women under 32 years old was recorded in all cases and occurred within 5 to 12 months. From our experience (Pavlov University, St. Petersburg), the median recovery time of the menstrual cycle occurs after 3±2.56 months (1 to 12 months after HDIT-AHSCT) in the group of respondents (57 women at 36±5.6 y.o. were questioned since 2018). Restoration of the menstrual cycle is much less common in the women >41 y.o., i.e., only in 38% of cases [21, 26]. Meanwhile, despite the risk of secondary infertility, the known cases of childbirth in patients with MS after HDIT-AHSCT proceeded, without complications for the mother or child. According to the EBMT registry, the postpartum women with MS, in contrast to the group with systemic sclerosis or rheumatoid arthritis, did not experience exacerbations [27, 28]. There have been no studies evaluating the effect of disease modifying therapies (DMT) on reproductive function [29], thus precluding comparisons with the risks of HDIT option.

Secondary autoimmune diseases (AID) comprise another group of late complications of HDIT-AHSCT, described at a frequency of 4-10% in MS patients [3, 5, 30]. The most expected complications are hypothyroidism, hyperthyroidism, autoimmune thrombocytopenic purpura.

According to the scarce literature data, the probability of developing endocrinopathies after chemotherapy is reported for 4-17% of cases when using medium-intensity regimens, thus being significantly lower than their frequency with high-intensity conditioning regimens (up to 26%) [3, 21].

In general, when using medium-intensity CR, the severity of HDIT complications according to the Common Terminology Criteria for Adverse Events (CTCAE 5.0) is mostly considered mild and moderate (Grade 0-3). Table 3 presents a list of potential late complications of HDIT-AHSCT when using the recommended protocols for MS [1, 4, 5, 13, 19-21, 30-32].

Table 3. Possible late complications of HDIT-AHSCT in patients with multiple sclerosis (according to CTCAE 5.0)

Polushin-tab03.jpg

Potential neurotoxicity of HDIT

High doses of cytostatic therapy are associated with a wider range, frequency, and severity of complications, with neurodegenerative component of MS being the potential feature of HDIT neurotoxicity [34-38]. Chemotherapeutic drugs used for immunoablation in MS are administered selectively, taking into account their ability to penetrate the blood-brain barrier [39], which seems to be especially relevant in progressive forms of MS, when autoimmune inflammation is "compartmentalized" with its predominance within central nervous system.

There are no data on the relevance of clinically significant neurotoxicity of chemotherapy drugs used in the protocols in the available literature. It has been proven that neurotoxicity associated with busulfan usage is transient and does not extend to the post-transplant recovery period [40]. Petzold A. et al. have shown that the blood concentration of heavy neurofilament chains of (NfH) correlating with axonal damage increased by 79% of patients with MS, and in 49% of patients with hematological malignancies after total body irradiation (TBI) and ATG treatment. However, this protocol (with TBI) is not used for treatment of MS due to high risks of adverse events [36, 41].

The potential neurotoxicity of HDIT-AHSCT is associated with MRI markers commonly used in clinical studies, e.g., dynamics of changing volumes for the distinct brain structures. The ratio of atrophy, "pseudoatrophy" and slowing down of the atrophy of the medulla is still a controversial issue in HDIT-AHSCT. After 6-24 months of HDIT-AHSCT, according to MRI data, an increased loss of brain matter can be detected [44], and without additional biomarkers that may be interpreted in two ways. On the one hand, the acceleration of atrophy associated with the neurotoxic effects of chemotherapy cannot be ruled out. On the other hand, a well-studied MRI phenomenon in the pharmacotherapy of MS is "pseudoatrophy" – a faster decrease in brain volume compared to the initial rate in the first year of treatment with DMTs, which quickly suppress autoimmune inflammation and eliminate the accompanying tissue edema. According to some researchers, it is precisely in line with the effect of inflammation on the volume of brain tissue before HDIT-AHSCT (brain enlargement due to inflammatory infiltration and edema). Therefore, that the optimal assessment of brain volume is possible as late as 2 years after HDIT-AHSCT [42]. According to Roccatagliata L. et al. and Atkins H. et al., the usage of HDIT-AHSCT in aggressive forms of MS (RRMS and SPMS) having been observed during 5-year period, is followed by a slowdown in the rate of brain volume atrophy from 50% to the pathophysiological level recorded in the general population free of MS [40, 43, 44]. These data prompted the workers to suggest a long-lasting anti-inflammatory effect of immune reconstitution after HDIT-AHSCT, which is confirmed by the almost complete absence of MR activity for 5 years, or more in 70-94% of patients [19, 44-46].

Mortality

Polushin-fig01.jpg

Figure 1. EBMT Registry data on usage of different CRs for HSCT in MS (1995-2021) (adopted from [3; 11; 50 and data of EBMT register])

Notes: *, the analysis on differentiation of CRs was not carried out; **, HSCT restrictions during COVID-19; 1-3, number of transplant-related mortality (TRM) cases.

Polushin-fig02.jpg

Figure 2. The ratio of patients with different types of multiple sclerosis selected for HDIT-AHSCT, %

Notes: RRMS, relapsing-remitting multiple sclerosis; PMS, progressive multiple sclerosis. Comment: malignant multiple sclerosis (aggressive) MS is characterized by an abrupt onset with several consecutive exacerbations within a short period of time, resulting into severe disability and extensive MRI lesions [5].

Since 1997, there has been a consensus elaborated by the European League Against Rheumatism (EULAR) with the European Group for Blood and Bone Marrow Transplantation (EBMT), that allogeneic (related/unrelated) HSCT is unacceptable in autoimmune diseases due to transplant-related mortality (TRM). The TRM rates reached 15-35% and in most cases was due to graft-versus-host disease [47]. In contrast to allogeneic transplants, the EBMT reports for 2002 and 2006 reported much lower mortality associated with autologous HSCT (6% and 5.3%, respectively), as seen in Fig. 1 [1, 6]. According to the EBMT report of 2005, it was noted that therapy-associated mortality following high-intensity CR in all autoimmune diseases, was higher than in the moderate-intensity CR group. Protocols with the maximal available doses of busulfan were associated with higher risk of therapy-associated mortality (p=0.001) in the patients with progressive forms of MS [1]. Lower risk of mortality with busulfan-containing protocols was shown in the patients with shorter duration of MS [48]. However, when comparing CRs with busulfan (high intensity) and cyclophosphamide CRs (medium/low intensity) in the group of patients with MS (unlike SLE and scleroderma), the difference was not significant [49].

Fig. 1 shows growing rates of transplantation activity with CR using cyclophosphamide (Cy-ATG), and decreased usage of BEAM-ATG regimen. In accordance with reduced CR intensity, there is a decrease in TRM.

According to EBMT reports, a significant decrease in TRM (from 7.3% to 1.3%) occurred since 2002-2005 [51]. The improvement in this important index was achieved primarily due to rejection of high-intensity CR (protocols with busulfan and total body irradiation), as well as selection of younger patients with less pronounced neurological deficit [52]. The dynamics of the paradigm shift in the patients’ selection for HDIT-AHSCT is presented in Fig. 2.

Fig. 2 shows a paradigm shift in priority of HDIT-AHSCT usage in relapsing-remitting MS, which is generally characterized by a shorter duration of the disease, lesser severity of neurological deficit, and predominance of inflammatory processes over neurodegeneration.

It should be emphasized that the most dramatic effect exhibiting clinical improvement and long-term stabilization of the condition after timely HDIT-AHSCT may be observed in patients with malignant forms of MS in presence of a rapid progression of neurological deficit [16, 53-55]. Moreover, preserved quality of life is expected with the use of HDIT-AHSCT in all the MS phenotypes [56].

On the basis of data from research publications reflecting modern approaches to the treatment of MS, and results of studies using the HDIT-AHSCT, one may proposed a patient profile which is the optimal candidate for HDIT-AHSCT with a potential positive therapeutic effect from treatment (Table 4).

Table 4. Expected effect from HDIT-AHSCT on the basis of clinical and demographic characteristics of the patient

Polushin-tab04.jpg

Note: a decrease in the EDSS score by 0.5 or more is considered a positive effect, however, patients with PMS also include stopping of further progression (stabilization).

Transplantation centers with a long history of AID treatment take into account the optimal characteristics of a patient with MS for HDIT-AHSCT, i.e., younger age, short duration of the disease, type of clinical course, e.g., RRMS or early stages of transition to SPMS, mild or moderate neurological deficit, the presence of MRI activity (appearance of gadolinium-positive lesions in central nervous system).

As mentioned above, expectations for efficiency of HDIT-AHSCT should be based on the timely implication of the method, taking into account the disease evolution pattern in a particular patient. The types of HDIT-AHSCT by goals and time frames are presented in Tab. 5.

Table 5. Types of HDIT-AHSCT in multiple sclerosis [12, 33, 57-61, adapted]

Polushin-tab05.jpg

To date, the HDIT-AHSCT is not performed at later terms (in cases of long duration of the disease, with PPMS, EDSS >6.5 points), despite proven efficiency of canceling MS progression, with respect to potential risks and benefits of the method. This approach should be recommended to patients with similar characteristics who are motivated to carry out this treatment method, as well as to physicians involved into the decision.

Pre-requisites for the potential success of HDIT-AHSCT in multiple sclerosis are as follows:
- optimal selection of patients, taking into account their demographic and clinical characteristics;
- choice of the conditioning regimen intensity depending on activity and severity of MS, as well as patient risk factors, including comorbidities;
- clinical activity of the transplant center must comply with the criteria of the Joint Accreditation Committee ISCT- Europe & EBMT (JACIE);
- the main activity of the transplant center should be centered on treatment of hematological patients, thus providing organizational basis for quick coping with problems of therapy and prevention of adverse events;
- involvement of a multidisciplinary team (hematologist, transfusiologist, neurologist), radiologist). The specialists should have experience in treating the appropriate cohorts of patients and participate in decision-making not only at HSCT, but also at the pre-transplant stage and during long-term observation;
- dynamic follow-up of the patient’s condition with clinical examination, monitoring of immune functions, neuroimaging should be carried out in order to prevent exacerbations in patients with refractory/malignant forms of MS;
- implementation of effective specialized measures for physical rehabilitation at all stages of HDIT-AHSCT, including physical therapy before admission to the transplant center (preparation regimens for long-term hospitalization and physical rehabilitation);
- obligatory keeping of the therapeutic window between the last course of DMT and the scheduled HDIT (Table 6).

Table 6. “Therapeutic window” between the last administration of DMT and the start of HDIT

Polushin-tab06.jpg

Conclusion

According to current literature data, HDIT-AHSCT may produce a wide range of significant complications. However, a trend for usage of reduced (medium) intensity conditioning regimens and better (more careful) selection of patients led to minimization of adverse events. The moderate-intensity HDIT (conditioning regimens for HSCT) may be less effective than high-intensity protocols, but their use at early stages of the disease may be of maximum benefit to individuals with MS refractory to standard therapy.

HDIT-AHSCT cannot be the method of choice for all categories of patients with multiple sclerosis, since the expected clinical effect may be not justified, due to risks of complications, in particular in cases with a long duration of the disease, severe neurological deficit and lack of activity (no new lesions or gadolinium enhancement) of the process. The maximal effect can be expected in the case of early HDIT-AHSCT, and in aggressive forms of MS, where the efficiency can be considered life-determining. If such a category of patients does not meet the criteria that preclude HDIT-AHSCT, their chances for clinical improvement and/or long-term stabilization of clinical state are very high, with minimal probability of adverse events.

The costs of this treatment option are relatively high. However, taking into account the expected effectiveness, i.e., long-term relapse-free course of the disease and improved quality of life, especially in young people of working age, its inclusion into the list of standard methods of therapy for MS patients is extremely important and potentially cost-effective after the prospective comparative studies.

Acknowledgements

We are acknowledged to the Autoimmune Diseases Working Party (ADWP) of the European Society for Blood and Marrow Transplantation (EBMT) for its support in providing updated Registry data, and all EBMT member centers and their clinicians, data managers and patients for their valuable contributions to the EBMT registry.

Conflict of interest

The study had no sponsorship. Authors declare no conflict of interest. The authors are fully responsible for submitting the final version of the manuscript. All the authors took part in the development of the concept of the article and the writing of the manuscript. The final version of the manuscript was approved by all authors.

Compliance with ethical principles

The authors confirm that they respect the rights of the people participated in the study, including obtaining informed consent when it is necessary, and the rules of treatment of animals when they are used in the study. Author Guidelines contains the detailed information.

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За последние 20 лет значимо уменьшена частота и выраженность нежелательных явлений терапии за счет накопления опыта трансплантационных центров, изменения принципов отбора пациентов и снижения интенсивности режимов кондиционирования. Однако терапевтические протоколы средней интенсивности также могут приводить к нежелательным последствиям. В работе проанализированы данные литературы и собственный опыт по ранним и отсроченным осложнениям ВИСТ-АТГСК. Также представлен профиль вероятного кандидата на ВИСТ-АТГСК исходя из характеристик пациента и течения заболевания. 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побочные эффекты и способы их ослабления" ["SECTION_META_TITLE"]=> string(320) "Высокодозная иммуносупрессивная терапия с аутологичной трансплантацией гемопоэтических стволовых клеток при рассеянном склерозе: побочные эффекты и способы их ослабления" ["SECTION_META_KEYWORDS"]=> string(320) "Высокодозная иммуносупрессивная терапия с аутологичной трансплантацией гемопоэтических стволовых клеток при рассеянном склерозе: побочные эффекты и способы их ослабления" ["SECTION_META_DESCRIPTION"]=> string(320) "Высокодозная иммуносупрессивная терапия с аутологичной трансплантацией гемопоэтических стволовых клеток при рассеянном склерозе: побочные эффекты и способы их ослабления" ["SECTION_PICTURE_FILE_ALT"]=> string(320) "Высокодозная иммуносупрессивная терапия с аутологичной трансплантацией гемопоэтических стволовых клеток при рассеянном склерозе: побочные эффекты и способы их ослабления" ["SECTION_PICTURE_FILE_TITLE"]=> string(320) "Высокодозная иммуносупрессивная терапия с аутологичной трансплантацией гемопоэтических стволовых клеток при рассеянном склерозе: побочные эффекты и способы их ослабления" ["SECTION_PICTURE_FILE_NAME"]=> string(100) "vysokodoznaya-immunosupressivnaya-terapiya-s-autologichnoy-transplantatsiey-gemopoeticheskikh-stvolo" ["SECTION_DETAIL_PICTURE_FILE_ALT"]=> string(320) "Высокодозная иммуносупрессивная терапия с аутологичной трансплантацией гемопоэтических стволовых клеток при рассеянном склерозе: побочные эффекты и способы их ослабления" ["SECTION_DETAIL_PICTURE_FILE_TITLE"]=> string(320) "Высокодозная иммуносупрессивная терапия с аутологичной трансплантацией гемопоэтических стволовых клеток при рассеянном склерозе: побочные эффекты и способы их ослабления" ["SECTION_DETAIL_PICTURE_FILE_NAME"]=> string(100) "vysokodoznaya-immunosupressivnaya-terapiya-s-autologichnoy-transplantatsiey-gemopoeticheskikh-stvolo" ["ELEMENT_PREVIEW_PICTURE_FILE_NAME"]=> string(100) 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["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "3" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "Y" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(13) "EAutocomplete" ["USER_TYPE_SETTINGS"]=> array(9) { ["VIEW"]=> string(1) "E" ["SHOW_ADD"]=> string(1) "Y" ["MAX_WIDTH"]=> int(0) ["MIN_HEIGHT"]=> int(24) ["MAX_HEIGHT"]=> int(1000) ["BAN_SYM"]=> string(2) ",;" ["REP_SYM"]=> string(1) " " ["OTHER_REP_SYM"]=> string(0) "" ["IBLOCK_MESS"]=> string(1) "N" } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> bool(false) ["VALUE"]=> bool(false) ["DESCRIPTION"]=> bool(false) ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> bool(false) ["~DESCRIPTION"]=> bool(false) ["~NAME"]=> string(12) "Авторы" ["~DEFAULT_VALUE"]=> string(0) "" } ["AUTHOR_RU"]=> array(36) { ["ID"]=> string(2) "25" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:01:20" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(12) "Авторы" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(9) "AUTHOR_RU" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "25" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "29502" ["VALUE"]=> array(2) { ["TEXT"]=> string(238) "<p> Алексей Ю. Полушин, Александр А. Цынченко, Юрий Р. Залялов, Евгения И. Лопатина, Наталья А. Тотолян, Александр Д. Кулагин </p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(226) "

Алексей Ю. Полушин, Александр А. Цынченко, Юрий Р. Залялов, Евгения И. Лопатина, Наталья А. Тотолян, Александр Д. Кулагин

" ["TYPE"]=> string(4) "HTML" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(12) "Авторы" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } } ["ORGANIZATION_RU"]=> array(36) { ["ID"]=> string(2) "26" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:01:20" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(22) "Организации" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(15) "ORGANIZATION_RU" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "26" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "29503" ["VALUE"]=> array(2) { ["TEXT"]=> string(235) "<p> Первый Санкт-Петербургский государственный медицинский университет им. акад. И. П. Павлова, Санкт-Петербург, Россия </p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(223) "

Первый Санкт-Петербургский государственный медицинский университет им. акад. И. П. Павлова, Санкт-Петербург, Россия

" ["TYPE"]=> string(4) "HTML" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(22) "Организации" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } } ["SUMMARY_RU"]=> array(36) { ["ID"]=> string(2) "27" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:01:20" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(29) "Описание/Резюме" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(10) "SUMMARY_RU" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "27" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "29504" ["VALUE"]=> array(2) { ["TEXT"]=> string(2233) "<p style="text-align: justify;"> Высокодозная иммуносупрессивная терапия с аутологичной трансплантацией гемопоэтических стволовых клеток (ВИСТ-АТГСК) является перспективным и эффективным методом лечения аутоиммунных заболеваний, в том числе, рассеянного склероза. За последние 20 лет значимо уменьшена частота и выраженность нежелательных явлений терапии за счет накопления опыта трансплантационных центров, изменения принципов отбора пациентов и снижения интенсивности режимов кондиционирования. Однако терапевтические протоколы средней интенсивности также могут приводить к нежелательным последствиям. В работе проанализированы данные литературы и собственный опыт по ранним и отсроченным осложнениям ВИСТ-АТГСК. Также представлен профиль вероятного кандидата на ВИСТ-АТГСК исходя из характеристик пациента и течения заболевания. Сформулированы виды ВИСТ-АТГСК исходя из целей и ожиданий от проводимого метода лечения. </p> <h2>Ключевые слова</h2> <p style="text-align: justify;"> Рассеянный склероз, высокодозная иммуносупрессивная терапия, гемопоэтические стволовые клетки, аутологичная трансплантация, побочные эффекты, ранние осложнения, отсроченные осложнения, показания к трансплантации. </p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(2177) "

Высокодозная иммуносупрессивная терапия с аутологичной трансплантацией гемопоэтических стволовых клеток (ВИСТ-АТГСК) является перспективным и эффективным методом лечения аутоиммунных заболеваний, в том числе, рассеянного склероза. За последние 20 лет значимо уменьшена частота и выраженность нежелательных явлений терапии за счет накопления опыта трансплантационных центров, изменения принципов отбора пациентов и снижения интенсивности режимов кондиционирования. Однако терапевтические протоколы средней интенсивности также могут приводить к нежелательным последствиям. В работе проанализированы данные литературы и собственный опыт по ранним и отсроченным осложнениям ВИСТ-АТГСК. Также представлен профиль вероятного кандидата на ВИСТ-АТГСК исходя из характеристик пациента и течения заболевания. Сформулированы виды ВИСТ-АТГСК исходя из целей и ожиданий от проводимого метода лечения.

Ключевые слова

Рассеянный склероз, высокодозная иммуносупрессивная терапия, гемопоэтические стволовые клетки, аутологичная трансплантация, побочные эффекты, ранние осложнения, отсроченные осложнения, показания к трансплантации.

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Alexey Yu. Polushin, Alexander A. Tsynchenko, Yuri R. Zalyalov, Evgenia I. Lopatina, Natalia A. Totolyan, Alexander D. Kulagin

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Pavlov University, St. Petersburg, Russia


Correspondence:
Dr. Alexey Yu. Polushin, First St. Petersburg State I. Pavlov Medical University, 6-8 L.Tolstoy St, 197022, St. Petersburg, Russia
Phone: +7 (911) 816-75-59
E-mail: alexpolushin@yandex.ru


Citation: Polushin AY, Tsynchenko AA, Zalyalov YR et al. High-dose immunosuppressive therapy with autologous hematopoietic stem cell transplantation in multiple sclerosis: side effects and the tools of their reduction. Cell Ther Transplant 2022; 11(3-4): 25-35.

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High-dose immunosuppressive therapy with autologous hematopoietic stem cell transplantation (HDIT-AHSCT) is a promising and effective method of treatment of autoimmune diseases, including multiple sclerosis. Over the past 20 years, the frequency and severity of side effects of therapy have been significantly reduced due to the accumulation of experience of transplant centers, changing principles of patient selection and decreased intensity of conditioning regimens. However, the medium-intensity therapeutic protocols may also be accompanied by complications. We have analyzed the literature data and our own experience on early and late side effects of HDIT-AHSCT. The profile of an appropriate schedule of HDIT-AHSCT is also presented, as determined by characteristics of the patients and the clinical course of multiple sclerosis. The types of HDIT-AHSCT are formulated, as based on the goals and expectations of the treatment approach.

Keywords

Multiple sclerosis, high-dose immunosuppressive therapy, hematopoietic stem cells, autologous transplantation, side effects, early complications, late complications, indications for transplantation.

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Polushin, Alexander A. Tsynchenko, Yuri R. Zalyalov, Evgenia I. Lopatina, Natalia A. Totolyan, Alexander D. Kulagin </p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(138) "

Alexey Yu. Polushin, Alexander A. Tsynchenko, Yuri R. Zalyalov, Evgenia I. Lopatina, Natalia A. Totolyan, Alexander D. Kulagin

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Alexey Yu. Polushin, Alexander A. Tsynchenko, Yuri R. Zalyalov, Evgenia I. Lopatina, Natalia A. Totolyan, Alexander D. Kulagin

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High-dose immunosuppressive therapy with autologous hematopoietic stem cell transplantation (HDIT-AHSCT) is a promising and effective method of treatment of autoimmune diseases, including multiple sclerosis. Over the past 20 years, the frequency and severity of side effects of therapy have been significantly reduced due to the accumulation of experience of transplant centers, changing principles of patient selection and decreased intensity of conditioning regimens. However, the medium-intensity therapeutic protocols may also be accompanied by complications. We have analyzed the literature data and our own experience on early and late side effects of HDIT-AHSCT. The profile of an appropriate schedule of HDIT-AHSCT is also presented, as determined by characteristics of the patients and the clinical course of multiple sclerosis. The types of HDIT-AHSCT are formulated, as based on the goals and expectations of the treatment approach.

Keywords

Multiple sclerosis, high-dose immunosuppressive therapy, hematopoietic stem cells, autologous transplantation, side effects, early complications, late complications, indications for transplantation.

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High-dose immunosuppressive therapy with autologous hematopoietic stem cell transplantation (HDIT-AHSCT) is a promising and effective method of treatment of autoimmune diseases, including multiple sclerosis. Over the past 20 years, the frequency and severity of side effects of therapy have been significantly reduced due to the accumulation of experience of transplant centers, changing principles of patient selection and decreased intensity of conditioning regimens. However, the medium-intensity therapeutic protocols may also be accompanied by complications. We have analyzed the literature data and our own experience on early and late side effects of HDIT-AHSCT. The profile of an appropriate schedule of HDIT-AHSCT is also presented, as determined by characteristics of the patients and the clinical course of multiple sclerosis. The types of HDIT-AHSCT are formulated, as based on the goals and expectations of the treatment approach.

Keywords

Multiple sclerosis, high-dose immunosuppressive therapy, hematopoietic stem cells, autologous transplantation, side effects, early complications, late complications, indications for transplantation.

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Pavlov University, St. Petersburg, Russia


Correspondence:
Dr. Alexey Yu. Polushin, First St. Petersburg State I. Pavlov Medical University, 6-8 L.Tolstoy St, 197022, St. Petersburg, Russia
Phone: +7 (911) 816-75-59
E-mail: alexpolushin@yandex.ru


Citation: Polushin AY, Tsynchenko AA, Zalyalov YR et al. High-dose immunosuppressive therapy with autologous hematopoietic stem cell transplantation in multiple sclerosis: side effects and the tools of their reduction. Cell Ther Transplant 2022; 11(3-4): 25-35.

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Pavlov University, St. Petersburg, Russia


Correspondence:
Dr. Alexey Yu. Polushin, First St. Petersburg State I. Pavlov Medical University, 6-8 L.Tolstoy St, 197022, St. Petersburg, Russia
Phone: +7 (911) 816-75-59
E-mail: alexpolushin@yandex.ru


Citation: Polushin AY, Tsynchenko AA, Zalyalov YR et al. High-dose immunosuppressive therapy with autologous hematopoietic stem cell transplantation in multiple sclerosis: side effects and the tools of their reduction. Cell Ther Transplant 2022; 11(3-4): 25-35.

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Алексей Ю. Полушин, Александр А. Цынченко, Юрий Р. Залялов, Евгения И. Лопатина, Наталья А. Тотолян, Александр Д. Кулагин

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Высокодозная иммуносупрессивная терапия с аутологичной трансплантацией гемопоэтических стволовых клеток (ВИСТ-АТГСК) является перспективным и эффективным методом лечения аутоиммунных заболеваний, в том числе, рассеянного склероза. За последние 20 лет значимо уменьшена частота и выраженность нежелательных явлений терапии за счет накопления опыта трансплантационных центров, изменения принципов отбора пациентов и снижения интенсивности режимов кондиционирования. Однако терапевтические протоколы средней интенсивности также могут приводить к нежелательным последствиям. В работе проанализированы данные литературы и собственный опыт по ранним и отсроченным осложнениям ВИСТ-АТГСК. Также представлен профиль вероятного кандидата на ВИСТ-АТГСК исходя из характеристик пациента и течения заболевания. Сформулированы виды ВИСТ-АТГСК исходя из целей и ожиданий от проводимого метода лечения.

Ключевые слова

Рассеянный склероз, высокодозная иммуносупрессивная терапия, гемопоэтические стволовые клетки, аутологичная трансплантация, побочные эффекты, ранние осложнения, отсроченные осложнения, показания к трансплантации.

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Высокодозная иммуносупрессивная терапия с аутологичной трансплантацией гемопоэтических стволовых клеток (ВИСТ-АТГСК) является перспективным и эффективным методом лечения аутоиммунных заболеваний, в том числе, рассеянного склероза. За последние 20 лет значимо уменьшена частота и выраженность нежелательных явлений терапии за счет накопления опыта трансплантационных центров, изменения принципов отбора пациентов и снижения интенсивности режимов кондиционирования. Однако терапевтические протоколы средней интенсивности также могут приводить к нежелательным последствиям. В работе проанализированы данные литературы и собственный опыт по ранним и отсроченным осложнениям ВИСТ-АТГСК. Также представлен профиль вероятного кандидата на ВИСТ-АТГСК исходя из характеристик пациента и течения заболевания. Сформулированы виды ВИСТ-АТГСК исходя из целей и ожиданий от проводимого метода лечения.

Ключевые слова

Рассеянный склероз, высокодозная иммуносупрессивная терапия, гемопоэтические стволовые клетки, аутологичная трансплантация, побочные эффекты, ранние осложнения, отсроченные осложнения, показания к трансплантации.

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Первый Санкт-Петербургский государственный медицинский университет им. акад. И. П. Павлова, Санкт-Петербург, Россия

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Первый Санкт-Петербургский государственный медицинский университет им. акад. И. П. Павлова, Санкт-Петербург, Россия

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Introduction

Cancer is a broad term for a series of diseases characterized by irregular cell development with the ability to infiltrate and disseminate to other body parts [1]. It’s one of the most common causes of death worldwide and a significant public health issue. In 2020, 19.3 million new cases of cancer and over ten million deaths from cancer were registered, globally [2].

Cancer is featuring by the aggregation of many genetic and non-genetic alterations in the cancer cell genome, which lead to carcinogenesis and malignant growth [3]. These alterations may include inactivated tumor suppression, oncogene activation, epigenetic factor mutations, and chemoresistance mutations [4].

Despite the significant advancements in cancer treatment, such as irradiation, chemotherapy, and surgery, the high likelihood of rejection and primary or acquired chemo-radiation tolerance usually leads to inadequate treatment [5]. As a result, the ability to repair or destroy certain DNA regions of a cancer cells which can be achieved by genome editing, can provide an important method for cancer therapy [5].

Genome editing is a kind of genetic modification in which artificially modified nucleases or molecular scissors are used to insert, substitute, or delete DNA from a genome [6]. However, the gene editing technologies are divided into three methodological generations: zinc-finger nucleases (ZFNs), transcription activator-like effector nucleases (TALENs), and the clustered regulatory interspaced short palindromic repeat (CRISPR) system [7].

CRISPR is an adaptive immune system in bacteria that comprises a bank of foreign genetic information and a process for identifying and killing the invading foreign agents like plasmids and viruses [8]. The CRISPR systems are found in 70% of bacteria and 90% of Archaea, and some contain several CRISPR areas on their chromosomes. However, following discovery of CRISPR system as a natural defensive mechanism in bacteria, the researchers tried to modify it to make it a useful tool for gene editing [9]. The CRISPR system comprises a single guide RNA (sgRNA) that targets the specific gene and the Cas9 protein, which is now the most widely used gene editing tool [9]. Moreover, the CRISPR technology has been used in oncology testing and cancer therapy trials since it allows for accurate and effective genome engineering [10, 11].

CRISPR Background

In 1987, CRISPR was first discovered in Escherichia coli when researchers were looking for the gene that controls alkaline phosphatase isozyme conversion [12]. Also, CRISPRs were discovered in Archaea, especially Haloferax mediterranei, in 1993, and have subsequently been found in multiple bacterial and archaeal genomes [13].

In the mid-2000s, the discovery of similarities between the spacer regions of CRISPRs and the succession of archaea, plasmids, and bacteriophages provided an insight that CRISPRs could play an essential role, e.g., in immune system [14]. Later, in 2002, Cas (CRISPR-Linked) genes were assigned to genes that were predicted to encode DNA repair proteins for hyperthermophilic Archaea and were found to be strongly associated with CRISPR [15]. Meanwhile, CRISPR is a term has been universally launched. Similarly, in the eukaryotic RNA interference (RNAi) system, comparative genomic studies have suggested that CRISPR and its proteins function together, forming a supposed immunity mechanism to protect prokaryotic cells from invading pathogens and plasmids [16]. Spacer repeats are transcribed into CRISPR RNAs (crRNAs) that lead the Cas enzyme to the invader's target DNA [17]. In 2012, Jennifer Doudna and Emmanuelle Charpentier proved that the CRISPR-Cas9 can be programmed with RNA in order to edit genomic DNA [18]. However, the use of CRISPR/Cas9 in the modification of human genomes was then declared, thus paving the way for CRISPR use in medicine [19]. Moreover, in 2016, CRISPR/Cas9 modified immune cells were utilized in order to treat people with lung cancer in the first human clinical study using CRISPR [20]. In 2020, for their development of CRISPR/Cas9 technology, the Nobel Prize in Chemistry was given to Emmanuelle Charpentier and Jennifer Doudna. Figure 1 shows, in brief, the time course of CRISPR technology evolution.

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Figure 1. Timeline of the CRISPR technology evolution

CRISPR/Cas system classification

There are two classes of CRISPR systems that are divided into six different types and several subtypes. Class 1 includes I, III, and IV types. While class 2 includes II, V, and VI types, being classified according to structural and functional properties [Table 1]. Also, the CRISPR system contains many associated proteins with distinct type of CRISPR [Table 2]. The CRISPR/Cas class 1 system employs a mixture of many Cas proteins, while the class 2 system only employs one Cas protein with several domains. Therefore, the class 2 CRISPR/Cas system is preferable for gene engineering due to its easiness and simplicity. The type II CRISPR/Cas9 system is the most commonly used and studied among the different types of CRISPR class 2 systems [8, 21].

Table 1. Classes of CRISPR system [8, 21]

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Abbreviation: PAM: Protospacer adjacent motif, crRNA: CRISPR RNAs, tracrRNA: Trans-activating crisper RNA.

Table 2. Proteins in CRISPR system [8, 21]

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CRISPR/Cas9 as an editorial tool

Cas9 is a CRISPR protein type II, class 2, targets DNA molecular. It is a crRNA-guided endonuclease with HNH and RuvC nuclease regions that cleaves the genomic dsDNA [18]. The HNH nuclease region splits the strand of DNA complementary to the gRNA array, whereas the RuvC nuclease region splits the strand of DNA [18]. The most frequently used type of CRISPR/Cas9, Streptococcus pyogenes Cas9 (SpCas9), targets DNA by recognizing the protospacer adjacent motif (PAM) [22]. The Cas9 protein size is variable for different bacterial species, with 1053 amino acid residues (a.a) in Streptococcus aureus and 1368 a.a in Streptococcus pyogenes [23]. The CRISPR/Cas9 system is composed of crRNA, tracrRNA, and Cas9. Artificially, tracrRNA and crRNA can be turned into sgRNA, which guides Cas9 to the target region [24].

Mechanism of CRISPR/Cas9 system action

CRISPR is a natural defense mechanism that helps bacteria and Archaea to resist viral or exogenous plasmid invasion [25]. When a virus infects bacteria, remnants of the viral DNA are embedded into the bacterial CRISPR gene, thus serving as a memory. I.e., when the same virus infects the bacterium again, it can recognize the virus by using this marker. Moreover, bacteria use the Cas9 endonuclease to trigger a double-strand break (DSB) in the viral DNA, which can result in viral inactivation [26]. At the molecular level, the mechanism of CRISPR-Cas9 action can be presented into three major phases: Adaptation, Biogenesis, and Interference, as illustrated in Table 3.

Table 3. The three phases of CRISPR/Cas9 mechanism [27, 28, 29]

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At the technical level, the CRISPR type II system is made up of the Cas9 protein and single guide RNA (sgRNA). Cas9 acts as a nuclease that triggers DSBs in the DNA molecule, while sgRNA can identify the target site, particularly through homologous recombination of the 20-bp DNA sequence [30, 31]. Thus, when the CRISPR/Cas9 system is introduced into a cell, the gRNAs direct the Cas9 nuclease to a particular DNA site with a protospacer adjacent motif (PAM) that corresponds to the gRNA. Then, the Cas9 nuclease breaks the DNA double strands and produces a DSB [32]. As shown in Figure 2, an endogenous repair mechanism, e.g., non-homologous end joining (NHEJ) and homology directed repair (HDR) can mostly repair the DSBs caused by Cas9 nuclease [33]. NHEJ is effective but not precise and could cause genetic mutations such as deletions or insertions [34]. Meanwhile the HDR path is ineffective and proceeds through mitosis only. However, HDR allows for precise DNA repair based on homologous sequences [35]. Notably, the CRISPR/Cas9 system is used to edit genes in a variety of cells, and successful transfer of the CRISPR-Cas9 system into cells is still a major challenge.

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Figure 2. Endogenous repair mechanisms; non-homologous end joining (NHEJ) and homology directed repair (HDR)

Delivery systems of CRISPR/Cas9

There are several CRISPR/Cas9 genome editing strategies: sgRNA and Cas9-mRNA, sgRNA and Cas9 protein, and a plasmid-based CRISPR-Cas9 system [36]. The benefits and disadvantages of these strategies are illustrated in Table 4. However, the efficient distribution of the CRISPR/Cas9 system to cancer cells is essential for the CRISPR/Cas9 system to be successful in treating cancer. Therefore, the CRISPR/Cas9 system for cancer gene treatment has been studied using three delivery approaches: physical approaches, non- viral vectors, and viral vectors.

Table 4. Features of various CRISPR/Cas9 genome editing strategies

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Physical methods of gene transduction

Physical methods do not depend on the utilization of vectors, but rather on making pores in the cell membrane [38]. However, the physical method provides a delivery process that is unaffected by the type of cell or package size [39]. Electroporation is a common physical method used to deliver CRISPR/Cas9 with great efficiency. It employs electrical current pulses to promote transient holes in plasma membranes, allowing the cargo to be delivered into cells [40]. On the other hand, in vitro electroporation has successfully delivered a CRISPR/Cas9 plasmid into cancer cells [41, 42]. Despite the benefits of electroporation, cell damage induced by electroporation may be a major concern for in vitro experiments [40]. Moreover, the delivery of CRISPR/Cas9 may be performed by other common physical methods, e.g., microinjection, membrane deformation, and hydrodynamic injection [43, 44]. Herein, Table 5 shows some studies that used physical methods to deliver CRISPR/Cas9.

Table 5. CRISPR/Cas9 delivery by means of physical methods

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Viral vectors

Viral vectors are broadly utilized as gene delivery tools because of their great effectiveness and potentially, long-term effects due to their integration with the host DNA [50]. However, there are various viral types for CRISPR/Cas9 delivery, i.e., adenovirus (AdV), retroviruses (RV), adeno-associated virus (AAV), lentivirus (LV), Epstein-Barr virus, Sendai virus, and baculovirus. The loading capacity of viruses is variable (4.7-38 kb), thus defining the package of genes encoding the CRISPR/Cas systems enzyme [39]. However, AAVs have mostly been employed for CRISPR genome editing in vivo due to their unique features, e.g., being less immunogenic, having low toxicity, and having many AAV serotypes [51]. On the other hand, lentivirus (LV) is often used to deliver CRISPR/Cas9 in vitro because of its capacity to permeate the nuclear membrane without causing cell division [39]. Table 6 depicts some trials that used viral vectors to deliver CRISPR/Cas9.

Table 6. Different viral vectors used for the in vitro CRISPR/Cas9 delivery

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Non-viral vectors

CRISPR/Cas9 may also be introduced to the cells using non-viral vectors. These approaches provide lower immune response, are not restricted by packaging limits, are simpler to synthesize, and can deliver many sgRNAs at once [50]. Furthermore, compared to viral vectors, non-viral vectors have fewer off-target effects [58]. Non-viral vectors, on the other hand, have limited in vivo applications due to their low transduction efficiency, despite their safety and ease of use [51]. Table 7 shows some trials that used non-viral delivery systems to introduce CRISPR/Cas9.

Table 7. CRISPR/Cas9 delivery via non-viral vectors

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CRISPR/Cas9 Applications

CRISPR/Cas9 technology has paved the way for novel opportunities in human gene editing. Recently, it has been used in a variety of areas, including the treatment of genetic diseases, detection of disease- related gene and diagnosis, tumor therapy, genetic engineering of plants and animals, and the suppression and management of harmful bacteria [65].

CRISPR/Cas9 Application in cancer therapy

Despite been some advances in recent years, the rate of deaths due to cancer continues to rise, demonstrating the essential need for new and more effective treatment approaches. CRISPR/Cas9 technology seems to be a potential tool for cancer treatment. Due to its multiple applications in targeting cancer cells, such as cancer immunotherapy, oncolytic virotherapy, stromal-targeting therapies, etc. The CRISPR/Cas9 technology could be a promising tool of cancer treatment [66]. By using a variety of CRISPR/Cas9 strategies such as base editing and gene knockout/in, CRISPR/Cas9 can be utilized to replace, remove, or correct undesirable genes that cause genetic diseases [32]. Moreover, CRISPR/Cas9 is used in the treatment of different types of cancer such as lung, breast, liver, and others malignancies.

1. Lung cancer
Lung cancer is the major cause of fatality-related cancer in both men and women [2]. Various genes like EGFR, CD38, FAK, RSF1, and others are thought to be proto-oncogenes linked to lung cancer. Likewise, GOT1, MFN2, miR-1304, and others are recognized as suppressor genes in this malignancy [67]. The overexpression of oncogenes and suppressor gene mutations may promote the tumor development. In this respect, the CRISPR/Cas9 technology has the potential to effectively eradicate lung cancer [68]. By targeting the oncogenes CD38 and KRAS, CRISPR/Cas9 knockout/down decreased cell proliferation and tumor growth in vivo [69, 70]. Moreover, the knockout of the MFN2 suppressor gene enhances cell activity and colony formation by activating the mTORC2/Akt pathway [71]. Another study found that knockout of the suppressor gene Plakophilin 1 (PKP1) in the A549 cell line increased cell dissemination while decreasing their reproduction [72].

2. Breast cancer
Breast cancer is the most common cause of mortality in women worldwide. Over 2 million new cases of breast cancer are reported globally [73]. The genetic profile of breast cancer shows high clinical heterogeneity and presence of various molecular subtypes [74]. The complexity of breast cancer is represented by the fact that it comprises a variety of cells, including stem and progenitor cells, instead of a single cell population [75]. Relying on estrogen receptor (ER) expression, the breast epithelial cancer is divided into four subtypes: luminal A, B, triple-negative breast cancer (TNBC), and Her2-positive [76]. Simultaneously, the luminal subtypes are the more fatal and common forms of breast cancer, accounting for around 70% of cases, with 30% of patients resistant to endocrine treatments [77]. Therefore, cytoreductive therapy is critical in the malignancy treatment. In this regard, CRISPR/Cas9 has emerged as a novel and efficient therapeutic tool in the therapy of breast cancer [33]. The knockout of APOBEC3G and CDK4 oncogenes by CRISPR/Cas9 in MCF10A and MDA-MB-231 cell lines, respectively, leads to the inhibition of growth and proliferation of breast cancer cells [78, 79]. On the contrary, knocking down the RLIP and PSMD12 oncogenes in BC and MDA-MB-231 cell lines resulted in decreased breast cell reproduction and development, both in vitro and in vivo [80, 81].

3. Colorectal cancer
Colorectal cancer (CRC) is a cancer that arises in the rectum and colon, being is the world's ninth most common cancer [73]. Over 90% of all colorectal carcinomas are adenocarcinomas (ADC). Nevertheless, squamous cell, spindle-cell, adenosquamous, and neuroendocrine carcinomas account for the remaining 10% of carcinomas [82]. Mutations in many oncogenes and suppressor genes, including ATF3, NAT1, RBX2, DRD2, and AMPKa1, contribute to colorectal cancer. Thus, the knockout of these genes in the HCT116 cell line by CRISPR/Cas9 could be a promising therapeutic target, and inhibiting them could be useful in the patients with advanced colorectal cancer [83, 84].

4. Liver cancer
Liver cancer is the world's fifth most prevalent cancer and the second leading cause of cancer death, and it is more common in males [73]. Hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC) are the two major types of liver cancer. HCC and ICC represent 75% and 12-15% of all cases, respectively [85]. However, liver cancer patients have a poor diagnosis and few therapy choices [86]. Therefore, CRISPR/Cas9 technology may be a useful way to find novel therapeutic tools for this malignancy. Various oncogenes, like NCOA5 and Sphk1, were targeted in human HCC cell lines by CRISPR/Cas9 knockout, resulting in decreased cell proliferation, growth, and dissemination, thus reducing tumor development [87, 88]. In contrast, targeting the phosphatase and tension homolog (PTEN) gene in vitro by knocking it out promoted the invasion capacity of HCC cells [89]. Hence, with more experiments, CRISPR/Cas9 could have a promising future in fighting hepatocellular cancer.

5. Prostate and bladder cancer
Prostate cancer is the fourth most common cancer-related cause of mortality among males [73]. The prevalence and death rates in PC patients are significantly linked to age, with the peak incidence reported in the elderly (> 65 years) [90]. Prostate cancer is detected by relying on levels of prostate-specific antigen (PSA more than 4 ng/mL), a glycoprotein usually secreted by prostate cells. Albeit, patients without cancer are also found to have high PSA levels. Therefore, tissue biopsy is still the standard method for confirming this type of cancer [90]. Usage of CRISPR/Cas9 to fix the mutations caused by genomic changes might be a promising direction for PC treatment. In particular, it has been found that the knockout of the PTEN gene in PC by CRISPR/Cas9 mobilizes many critical genes for the survival of tumor cells. Moreover, the PTEN cell line showed increased cell proliferation and colony formation [91]. Deficiency of PTEN, a tumor suppressor gene, is associated with the progression, development, and metastasis of prostate cancer. Hence, PTEN knockout by CRISPR/Cas9 in vivo could explain the role of many genes with altered expression in PTEN-deficient cells in the development of prostate cancer [91].

On the contrary, bladder cancer accounts for 4.4% of all cancer incidence worldwide, and it is more common in males than in females [73]. Urothelial cell carcinoma causes 90% of all cases, while squamous cells cause the remaining 10% of bladder cancer cases [92]. However, lncRNA UCA1 has an important role in promoting bladder cancer as an oncogene [93]. In fact, the roles of the UCA1 gene in bladder cancer include increased cell cycle, apoptosis repression, and increased MMP [94]. Therefore, UCA1 knockdown by CRISPR/Cas9 in T24 and 5637 cell lines was shown to reduced cell reproduction, migration, and invasion in vivo and in vitro. As a result, the cell cycle was arrested at G1 phase, along with significant increase in apoptosis, and decreased MMP activity [93].

6. Cervical and ovarian cancer
Cervical cancer is another common cancer in women, being the third most prevalent cancer among women with a mortality rate of 7.7% [73]. Human papillomavirus (HPV) is among the most common causes of cervical cancer. The HPV produces cervical malignant cells by oncoprotein E7, which inhibits the activity of retinoblastoma family proteins (pRB), and oncoprotein E6, which destructs the tumor suppressor protein p53 [95]. However, the CRISPR/Cas9 technology can destroy HPV E6 and E7, by employing CRISPR-sgRNA to target E7 and E6 in vitro. This resulted in reduction in E7 and E6 mRNA and protein expression and accumulation of p21 and p53 proteins. Furthermore, cell growth has slowed and apoptosis has increased, particularly in vitro [96].

On the contrary, ovarian cancer is the ninth most frequent malignancy in women and the eighth most fatal among women [73]. About 95% of ovarian cancers are epithelial ovarian malignancies cancers, whereas non-epithelial cancers account for up to 5% of ovarian cancers [97]. In ovarian cancer, the epithelial to mesenchymal transition (EMT) pathway is linked to tumor metastasis, treatment resistance, and a low patient survival rate [98]. Moreover, high expression of the baculoviral IAP repeat containing 5 (BIRC5) gene leads to changes in EMT and tumor growth. Therefore, CRISPR/Cas9-mediated knockout of the BIRC5 gene in SKOV3 and OVCAR3 ovarian cells inhibited EMT, dramatically decreased cell proliferation, and their invasion, prompting cell apoptosis. Hence, in tumors, targeting the overexpressed BIRC5 gene could be an effective anti-cancer therapy [99].

A number of in vitro and in vivo experimental trials that used the CRISPR/Cas9-based gene knockout technologies in the therapy of various cancers, including lung, breast, colorectal, prostate, liver, and other malignancies are listed in Table 8.

Table 8. Some relevant works on CRISPR applications in potential cancer treatment

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Abbreviations: AV: Adenovirus, CD8: Cluster of differentiation 38, CDK4: Cyclin-dependent kinase 4, LV: Lentivirus, TS: Tumor suppressor, OG: Oncogene, NV: Not available.

Benefits and disadvantages

In terms of simplicity, flexibility, and low price, the CRISPR/Cas9 system has many benefits over other gene editing technologies like ZFN and TALENs. However, the most significant distinction is that the CRISPR method depends on DNA-RNA recognition instead of DNA-protein interaction [18]. Thus, constructing a customized CRISPR/Cas9 system by simply modifying the guide-RNA (gRNA) sequence rather than designing a novel protein is more feasible and simpler than designing a novel protein [19, 113]. Nevertheless, the huge size of the Cas9 protein is one of the disadvantages of CRISPR-Cas9. Because of Cas9's large size (4-7 kb), it's difficult to pack the protein into low immunogenic AVV vectors used for gene delivery in vivo and in vitro [114]. Thus, to resolve this issue, the delivery method must be redesigned with a larger cargo capacity, or smaller Cas9 types can be used [115]. Furthermore, clinical trials have shown that Cas9 from S. aureus and S. pyogenes may cause an immune response within the body [116]. One probable way to override this problem is to upgrade Cas9 or use another bacterial protein that can evade the host's immune system. Another issue with the CRISPR system are the off-target effects that makes it hard to focus on a specific genomic locus [117]. Thus, one of the strategies that may include selection of an appropriate delivery tool that will help to reduce off-target effects while still increasing target performance, such as RNP delivery [118].

Conclusion and future directions

The emergence of the CRISPR/Cas9 system as a bacterial defense response against pathogens, as well as its use as a potent tool for generating selective genomic modifications, has opened new avenues for molecular biology. As an effective editing tool, CRISPR-Cas9 technology has considerable therapeutic potential for improving anticancer approaches, although with certain challenges. Moreover, CRISPR-Cas9 has a wide range of possible applications, including combating oncogenic diseases, modulating gene expression, and immunotherapy. As such, because of CRISPR's medicinal potential, it is regarded as a critical tool in combatting severe cancer disorders. CRISPR is only capable of correcting a single human mutation. However, by driving the technique to its extremes, many genes may be fixed, deleted, substituted, or implanted in vivo concurrently with one single strike. Moreover, the development of cas9 forms with no or minimal off-target effects must be considered for future CRISPR uses. Finally, the improvement of non-viral and viral delivery systems will be required to enhance CRISPR/Cas9 in vivo application, providing a basis for CRISPR therapeutic use.

Conflict of interest

None declared.

Abbreviations

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Introduction

Cancer is a broad term for a series of diseases characterized by irregular cell development with the ability to infiltrate and disseminate to other body parts [1]. It’s one of the most common causes of death worldwide and a significant public health issue. In 2020, 19.3 million new cases of cancer and over ten million deaths from cancer were registered, globally [2].

Cancer is featuring by the aggregation of many genetic and non-genetic alterations in the cancer cell genome, which lead to carcinogenesis and malignant growth [3]. These alterations may include inactivated tumor suppression, oncogene activation, epigenetic factor mutations, and chemoresistance mutations [4].

Despite the significant advancements in cancer treatment, such as irradiation, chemotherapy, and surgery, the high likelihood of rejection and primary or acquired chemo-radiation tolerance usually leads to inadequate treatment [5]. As a result, the ability to repair or destroy certain DNA regions of a cancer cells which can be achieved by genome editing, can provide an important method for cancer therapy [5].

Genome editing is a kind of genetic modification in which artificially modified nucleases or molecular scissors are used to insert, substitute, or delete DNA from a genome [6]. However, the gene editing technologies are divided into three methodological generations: zinc-finger nucleases (ZFNs), transcription activator-like effector nucleases (TALENs), and the clustered regulatory interspaced short palindromic repeat (CRISPR) system [7].

CRISPR is an adaptive immune system in bacteria that comprises a bank of foreign genetic information and a process for identifying and killing the invading foreign agents like plasmids and viruses [8]. The CRISPR systems are found in 70% of bacteria and 90% of Archaea, and some contain several CRISPR areas on their chromosomes. However, following discovery of CRISPR system as a natural defensive mechanism in bacteria, the researchers tried to modify it to make it a useful tool for gene editing [9]. The CRISPR system comprises a single guide RNA (sgRNA) that targets the specific gene and the Cas9 protein, which is now the most widely used gene editing tool [9]. Moreover, the CRISPR technology has been used in oncology testing and cancer therapy trials since it allows for accurate and effective genome engineering [10, 11].

CRISPR Background

In 1987, CRISPR was first discovered in Escherichia coli when researchers were looking for the gene that controls alkaline phosphatase isozyme conversion [12]. Also, CRISPRs were discovered in Archaea, especially Haloferax mediterranei, in 1993, and have subsequently been found in multiple bacterial and archaeal genomes [13].

In the mid-2000s, the discovery of similarities between the spacer regions of CRISPRs and the succession of archaea, plasmids, and bacteriophages provided an insight that CRISPRs could play an essential role, e.g., in immune system [14]. Later, in 2002, Cas (CRISPR-Linked) genes were assigned to genes that were predicted to encode DNA repair proteins for hyperthermophilic Archaea and were found to be strongly associated with CRISPR [15]. Meanwhile, CRISPR is a term has been universally launched. Similarly, in the eukaryotic RNA interference (RNAi) system, comparative genomic studies have suggested that CRISPR and its proteins function together, forming a supposed immunity mechanism to protect prokaryotic cells from invading pathogens and plasmids [16]. Spacer repeats are transcribed into CRISPR RNAs (crRNAs) that lead the Cas enzyme to the invader's target DNA [17]. In 2012, Jennifer Doudna and Emmanuelle Charpentier proved that the CRISPR-Cas9 can be programmed with RNA in order to edit genomic DNA [18]. However, the use of CRISPR/Cas9 in the modification of human genomes was then declared, thus paving the way for CRISPR use in medicine [19]. Moreover, in 2016, CRISPR/Cas9 modified immune cells were utilized in order to treat people with lung cancer in the first human clinical study using CRISPR [20]. In 2020, for their development of CRISPR/Cas9 technology, the Nobel Prize in Chemistry was given to Emmanuelle Charpentier and Jennifer Doudna. Figure 1 shows, in brief, the time course of CRISPR technology evolution.

Saleem-fig01.jpg

Figure 1. Timeline of the CRISPR technology evolution

CRISPR/Cas system classification

There are two classes of CRISPR systems that are divided into six different types and several subtypes. Class 1 includes I, III, and IV types. While class 2 includes II, V, and VI types, being classified according to structural and functional properties [Table 1]. Also, the CRISPR system contains many associated proteins with distinct type of CRISPR [Table 2]. The CRISPR/Cas class 1 system employs a mixture of many Cas proteins, while the class 2 system only employs one Cas protein with several domains. Therefore, the class 2 CRISPR/Cas system is preferable for gene engineering due to its easiness and simplicity. The type II CRISPR/Cas9 system is the most commonly used and studied among the different types of CRISPR class 2 systems [8, 21].

Table 1. Classes of CRISPR system [8, 21]

Saleem-tab01.jpg

Abbreviation: PAM: Protospacer adjacent motif, crRNA: CRISPR RNAs, tracrRNA: Trans-activating crisper RNA.

Table 2. Proteins in CRISPR system [8, 21]

Saleem-tab02.jpg

CRISPR/Cas9 as an editorial tool

Cas9 is a CRISPR protein type II, class 2, targets DNA molecular. It is a crRNA-guided endonuclease with HNH and RuvC nuclease regions that cleaves the genomic dsDNA [18]. The HNH nuclease region splits the strand of DNA complementary to the gRNA array, whereas the RuvC nuclease region splits the strand of DNA [18]. The most frequently used type of CRISPR/Cas9, Streptococcus pyogenes Cas9 (SpCas9), targets DNA by recognizing the protospacer adjacent motif (PAM) [22]. The Cas9 protein size is variable for different bacterial species, with 1053 amino acid residues (a.a) in Streptococcus aureus and 1368 a.a in Streptococcus pyogenes [23]. The CRISPR/Cas9 system is composed of crRNA, tracrRNA, and Cas9. Artificially, tracrRNA and crRNA can be turned into sgRNA, which guides Cas9 to the target region [24].

Mechanism of CRISPR/Cas9 system action

CRISPR is a natural defense mechanism that helps bacteria and Archaea to resist viral or exogenous plasmid invasion [25]. When a virus infects bacteria, remnants of the viral DNA are embedded into the bacterial CRISPR gene, thus serving as a memory. I.e., when the same virus infects the bacterium again, it can recognize the virus by using this marker. Moreover, bacteria use the Cas9 endonuclease to trigger a double-strand break (DSB) in the viral DNA, which can result in viral inactivation [26]. At the molecular level, the mechanism of CRISPR-Cas9 action can be presented into three major phases: Adaptation, Biogenesis, and Interference, as illustrated in Table 3.

Table 3. The three phases of CRISPR/Cas9 mechanism [27, 28, 29]

Saleem-tab03.jpg

At the technical level, the CRISPR type II system is made up of the Cas9 protein and single guide RNA (sgRNA). Cas9 acts as a nuclease that triggers DSBs in the DNA molecule, while sgRNA can identify the target site, particularly through homologous recombination of the 20-bp DNA sequence [30, 31]. Thus, when the CRISPR/Cas9 system is introduced into a cell, the gRNAs direct the Cas9 nuclease to a particular DNA site with a protospacer adjacent motif (PAM) that corresponds to the gRNA. Then, the Cas9 nuclease breaks the DNA double strands and produces a DSB [32]. As shown in Figure 2, an endogenous repair mechanism, e.g., non-homologous end joining (NHEJ) and homology directed repair (HDR) can mostly repair the DSBs caused by Cas9 nuclease [33]. NHEJ is effective but not precise and could cause genetic mutations such as deletions or insertions [34]. Meanwhile the HDR path is ineffective and proceeds through mitosis only. However, HDR allows for precise DNA repair based on homologous sequences [35]. Notably, the CRISPR/Cas9 system is used to edit genes in a variety of cells, and successful transfer of the CRISPR-Cas9 system into cells is still a major challenge.

Saleem-fig02.jpg

Figure 2. Endogenous repair mechanisms; non-homologous end joining (NHEJ) and homology directed repair (HDR)

Delivery systems of CRISPR/Cas9

There are several CRISPR/Cas9 genome editing strategies: sgRNA and Cas9-mRNA, sgRNA and Cas9 protein, and a plasmid-based CRISPR-Cas9 system [36]. The benefits and disadvantages of these strategies are illustrated in Table 4. However, the efficient distribution of the CRISPR/Cas9 system to cancer cells is essential for the CRISPR/Cas9 system to be successful in treating cancer. Therefore, the CRISPR/Cas9 system for cancer gene treatment has been studied using three delivery approaches: physical approaches, non- viral vectors, and viral vectors.

Table 4. Features of various CRISPR/Cas9 genome editing strategies

Saleem-tab04.jpg

Physical methods of gene transduction

Physical methods do not depend on the utilization of vectors, but rather on making pores in the cell membrane [38]. However, the physical method provides a delivery process that is unaffected by the type of cell or package size [39]. Electroporation is a common physical method used to deliver CRISPR/Cas9 with great efficiency. It employs electrical current pulses to promote transient holes in plasma membranes, allowing the cargo to be delivered into cells [40]. On the other hand, in vitro electroporation has successfully delivered a CRISPR/Cas9 plasmid into cancer cells [41, 42]. Despite the benefits of electroporation, cell damage induced by electroporation may be a major concern for in vitro experiments [40]. Moreover, the delivery of CRISPR/Cas9 may be performed by other common physical methods, e.g., microinjection, membrane deformation, and hydrodynamic injection [43, 44]. Herein, Table 5 shows some studies that used physical methods to deliver CRISPR/Cas9.

Table 5. CRISPR/Cas9 delivery by means of physical methods

Saleem-tab05.jpg

Viral vectors

Viral vectors are broadly utilized as gene delivery tools because of their great effectiveness and potentially, long-term effects due to their integration with the host DNA [50]. However, there are various viral types for CRISPR/Cas9 delivery, i.e., adenovirus (AdV), retroviruses (RV), adeno-associated virus (AAV), lentivirus (LV), Epstein-Barr virus, Sendai virus, and baculovirus. The loading capacity of viruses is variable (4.7-38 kb), thus defining the package of genes encoding the CRISPR/Cas systems enzyme [39]. However, AAVs have mostly been employed for CRISPR genome editing in vivo due to their unique features, e.g., being less immunogenic, having low toxicity, and having many AAV serotypes [51]. On the other hand, lentivirus (LV) is often used to deliver CRISPR/Cas9 in vitro because of its capacity to permeate the nuclear membrane without causing cell division [39]. Table 6 depicts some trials that used viral vectors to deliver CRISPR/Cas9.

Table 6. Different viral vectors used for the in vitro CRISPR/Cas9 delivery

Saleem-tab06.jpg

Non-viral vectors

CRISPR/Cas9 may also be introduced to the cells using non-viral vectors. These approaches provide lower immune response, are not restricted by packaging limits, are simpler to synthesize, and can deliver many sgRNAs at once [50]. Furthermore, compared to viral vectors, non-viral vectors have fewer off-target effects [58]. Non-viral vectors, on the other hand, have limited in vivo applications due to their low transduction efficiency, despite their safety and ease of use [51]. Table 7 shows some trials that used non-viral delivery systems to introduce CRISPR/Cas9.

Table 7. CRISPR/Cas9 delivery via non-viral vectors

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CRISPR/Cas9 Applications

CRISPR/Cas9 technology has paved the way for novel opportunities in human gene editing. Recently, it has been used in a variety of areas, including the treatment of genetic diseases, detection of disease- related gene and diagnosis, tumor therapy, genetic engineering of plants and animals, and the suppression and management of harmful bacteria [65].

CRISPR/Cas9 Application in cancer therapy

Despite been some advances in recent years, the rate of deaths due to cancer continues to rise, demonstrating the essential need for new and more effective treatment approaches. CRISPR/Cas9 technology seems to be a potential tool for cancer treatment. Due to its multiple applications in targeting cancer cells, such as cancer immunotherapy, oncolytic virotherapy, stromal-targeting therapies, etc. The CRISPR/Cas9 technology could be a promising tool of cancer treatment [66]. By using a variety of CRISPR/Cas9 strategies such as base editing and gene knockout/in, CRISPR/Cas9 can be utilized to replace, remove, or correct undesirable genes that cause genetic diseases [32]. Moreover, CRISPR/Cas9 is used in the treatment of different types of cancer such as lung, breast, liver, and others malignancies.

1. Lung cancer
Lung cancer is the major cause of fatality-related cancer in both men and women [2]. Various genes like EGFR, CD38, FAK, RSF1, and others are thought to be proto-oncogenes linked to lung cancer. Likewise, GOT1, MFN2, miR-1304, and others are recognized as suppressor genes in this malignancy [67]. The overexpression of oncogenes and suppressor gene mutations may promote the tumor development. In this respect, the CRISPR/Cas9 technology has the potential to effectively eradicate lung cancer [68]. By targeting the oncogenes CD38 and KRAS, CRISPR/Cas9 knockout/down decreased cell proliferation and tumor growth in vivo [69, 70]. Moreover, the knockout of the MFN2 suppressor gene enhances cell activity and colony formation by activating the mTORC2/Akt pathway [71]. Another study found that knockout of the suppressor gene Plakophilin 1 (PKP1) in the A549 cell line increased cell dissemination while decreasing their reproduction [72].

2. Breast cancer
Breast cancer is the most common cause of mortality in women worldwide. Over 2 million new cases of breast cancer are reported globally [73]. The genetic profile of breast cancer shows high clinical heterogeneity and presence of various molecular subtypes [74]. The complexity of breast cancer is represented by the fact that it comprises a variety of cells, including stem and progenitor cells, instead of a single cell population [75]. Relying on estrogen receptor (ER) expression, the breast epithelial cancer is divided into four subtypes: luminal A, B, triple-negative breast cancer (TNBC), and Her2-positive [76]. Simultaneously, the luminal subtypes are the more fatal and common forms of breast cancer, accounting for around 70% of cases, with 30% of patients resistant to endocrine treatments [77]. Therefore, cytoreductive therapy is critical in the malignancy treatment. In this regard, CRISPR/Cas9 has emerged as a novel and efficient therapeutic tool in the therapy of breast cancer [33]. The knockout of APOBEC3G and CDK4 oncogenes by CRISPR/Cas9 in MCF10A and MDA-MB-231 cell lines, respectively, leads to the inhibition of growth and proliferation of breast cancer cells [78, 79]. On the contrary, knocking down the RLIP and PSMD12 oncogenes in BC and MDA-MB-231 cell lines resulted in decreased breast cell reproduction and development, both in vitro and in vivo [80, 81].

3. Colorectal cancer
Colorectal cancer (CRC) is a cancer that arises in the rectum and colon, being is the world's ninth most common cancer [73]. Over 90% of all colorectal carcinomas are adenocarcinomas (ADC). Nevertheless, squamous cell, spindle-cell, adenosquamous, and neuroendocrine carcinomas account for the remaining 10% of carcinomas [82]. Mutations in many oncogenes and suppressor genes, including ATF3, NAT1, RBX2, DRD2, and AMPKa1, contribute to colorectal cancer. Thus, the knockout of these genes in the HCT116 cell line by CRISPR/Cas9 could be a promising therapeutic target, and inhibiting them could be useful in the patients with advanced colorectal cancer [83, 84].

4. Liver cancer
Liver cancer is the world's fifth most prevalent cancer and the second leading cause of cancer death, and it is more common in males [73]. Hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC) are the two major types of liver cancer. HCC and ICC represent 75% and 12-15% of all cases, respectively [85]. However, liver cancer patients have a poor diagnosis and few therapy choices [86]. Therefore, CRISPR/Cas9 technology may be a useful way to find novel therapeutic tools for this malignancy. Various oncogenes, like NCOA5 and Sphk1, were targeted in human HCC cell lines by CRISPR/Cas9 knockout, resulting in decreased cell proliferation, growth, and dissemination, thus reducing tumor development [87, 88]. In contrast, targeting the phosphatase and tension homolog (PTEN) gene in vitro by knocking it out promoted the invasion capacity of HCC cells [89]. Hence, with more experiments, CRISPR/Cas9 could have a promising future in fighting hepatocellular cancer.

5. Prostate and bladder cancer
Prostate cancer is the fourth most common cancer-related cause of mortality among males [73]. The prevalence and death rates in PC patients are significantly linked to age, with the peak incidence reported in the elderly (> 65 years) [90]. Prostate cancer is detected by relying on levels of prostate-specific antigen (PSA more than 4 ng/mL), a glycoprotein usually secreted by prostate cells. Albeit, patients without cancer are also found to have high PSA levels. Therefore, tissue biopsy is still the standard method for confirming this type of cancer [90]. Usage of CRISPR/Cas9 to fix the mutations caused by genomic changes might be a promising direction for PC treatment. In particular, it has been found that the knockout of the PTEN gene in PC by CRISPR/Cas9 mobilizes many critical genes for the survival of tumor cells. Moreover, the PTEN cell line showed increased cell proliferation and colony formation [91]. Deficiency of PTEN, a tumor suppressor gene, is associated with the progression, development, and metastasis of prostate cancer. Hence, PTEN knockout by CRISPR/Cas9 in vivo could explain the role of many genes with altered expression in PTEN-deficient cells in the development of prostate cancer [91].

On the contrary, bladder cancer accounts for 4.4% of all cancer incidence worldwide, and it is more common in males than in females [73]. Urothelial cell carcinoma causes 90% of all cases, while squamous cells cause the remaining 10% of bladder cancer cases [92]. However, lncRNA UCA1 has an important role in promoting bladder cancer as an oncogene [93]. In fact, the roles of the UCA1 gene in bladder cancer include increased cell cycle, apoptosis repression, and increased MMP [94]. Therefore, UCA1 knockdown by CRISPR/Cas9 in T24 and 5637 cell lines was shown to reduced cell reproduction, migration, and invasion in vivo and in vitro. As a result, the cell cycle was arrested at G1 phase, along with significant increase in apoptosis, and decreased MMP activity [93].

6. Cervical and ovarian cancer
Cervical cancer is another common cancer in women, being the third most prevalent cancer among women with a mortality rate of 7.7% [73]. Human papillomavirus (HPV) is among the most common causes of cervical cancer. The HPV produces cervical malignant cells by oncoprotein E7, which inhibits the activity of retinoblastoma family proteins (pRB), and oncoprotein E6, which destructs the tumor suppressor protein p53 [95]. However, the CRISPR/Cas9 technology can destroy HPV E6 and E7, by employing CRISPR-sgRNA to target E7 and E6 in vitro. This resulted in reduction in E7 and E6 mRNA and protein expression and accumulation of p21 and p53 proteins. Furthermore, cell growth has slowed and apoptosis has increased, particularly in vitro [96].

On the contrary, ovarian cancer is the ninth most frequent malignancy in women and the eighth most fatal among women [73]. About 95% of ovarian cancers are epithelial ovarian malignancies cancers, whereas non-epithelial cancers account for up to 5% of ovarian cancers [97]. In ovarian cancer, the epithelial to mesenchymal transition (EMT) pathway is linked to tumor metastasis, treatment resistance, and a low patient survival rate [98]. Moreover, high expression of the baculoviral IAP repeat containing 5 (BIRC5) gene leads to changes in EMT and tumor growth. Therefore, CRISPR/Cas9-mediated knockout of the BIRC5 gene in SKOV3 and OVCAR3 ovarian cells inhibited EMT, dramatically decreased cell proliferation, and their invasion, prompting cell apoptosis. Hence, in tumors, targeting the overexpressed BIRC5 gene could be an effective anti-cancer therapy [99].

A number of in vitro and in vivo experimental trials that used the CRISPR/Cas9-based gene knockout technologies in the therapy of various cancers, including lung, breast, colorectal, prostate, liver, and other malignancies are listed in Table 8.

Table 8. Some relevant works on CRISPR applications in potential cancer treatment

Saleem-tab08-01.jpgSaleem-tab08-02.jpg

Abbreviations: AV: Adenovirus, CD8: Cluster of differentiation 38, CDK4: Cyclin-dependent kinase 4, LV: Lentivirus, TS: Tumor suppressor, OG: Oncogene, NV: Not available.

Benefits and disadvantages

In terms of simplicity, flexibility, and low price, the CRISPR/Cas9 system has many benefits over other gene editing technologies like ZFN and TALENs. However, the most significant distinction is that the CRISPR method depends on DNA-RNA recognition instead of DNA-protein interaction [18]. Thus, constructing a customized CRISPR/Cas9 system by simply modifying the guide-RNA (gRNA) sequence rather than designing a novel protein is more feasible and simpler than designing a novel protein [19, 113]. Nevertheless, the huge size of the Cas9 protein is one of the disadvantages of CRISPR-Cas9. Because of Cas9's large size (4-7 kb), it's difficult to pack the protein into low immunogenic AVV vectors used for gene delivery in vivo and in vitro [114]. Thus, to resolve this issue, the delivery method must be redesigned with a larger cargo capacity, or smaller Cas9 types can be used [115]. Furthermore, clinical trials have shown that Cas9 from S. aureus and S. pyogenes may cause an immune response within the body [116]. One probable way to override this problem is to upgrade Cas9 or use another bacterial protein that can evade the host's immune system. Another issue with the CRISPR system are the off-target effects that makes it hard to focus on a specific genomic locus [117]. Thus, one of the strategies that may include selection of an appropriate delivery tool that will help to reduce off-target effects while still increasing target performance, such as RNP delivery [118].

Conclusion and future directions

The emergence of the CRISPR/Cas9 system as a bacterial defense response against pathogens, as well as its use as a potent tool for generating selective genomic modifications, has opened new avenues for molecular biology. As an effective editing tool, CRISPR-Cas9 technology has considerable therapeutic potential for improving anticancer approaches, although with certain challenges. Moreover, CRISPR-Cas9 has a wide range of possible applications, including combating oncogenic diseases, modulating gene expression, and immunotherapy. As such, because of CRISPR's medicinal potential, it is regarded as a critical tool in combatting severe cancer disorders. CRISPR is only capable of correcting a single human mutation. However, by driving the technique to its extremes, many genes may be fixed, deleted, substituted, or implanted in vivo concurrently with one single strike. Moreover, the development of cas9 forms with no or minimal off-target effects must be considered for future CRISPR uses. Finally, the improvement of non-viral and viral delivery systems will be required to enhance CRISPR/Cas9 in vivo application, providing a basis for CRISPR therapeutic use.

Conflict of interest

None declared.

Abbreviations

Saleem-abbr.jpg

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Эти заболевания – одна из ведущих причин смерти в мире и представляет собой крупную социальную и экономическую проблему. Согласно статистическим данным, более 10 миллионов человек погибают от злокачественных опухолей, и ожидается 50%-ное повышение частоты их возникновения в следующие 10 лет, приводя к 15 миллионам смертельных исходов. Единичные или множественные генные мутации, хромосомные аберрации могут вызывать раковые заболевания. Хотя для лечения рака используют многочисленные варианты лечения, они все же недостаточны против этих заболеваний. Поэтому изучается ряд новых стратегий ранней терапии злокачественных опухолей. Одной из наиболее современных и потенциально эффективных технологий, применяемых в последние годы для генных модификаций и онкотерапии является система Clustered Regularly Interspaced Short Palindromic Repeat (CRISPR)- ассоциированного протеина-9 (Cas9) – уникальная технология геномной инженерии, основанная на применении уникальной РНК-содержащей эндонуклеазы. Исходно, CRISPR/Cas9 возникла из противовирусного механизма защиты бактерий от вирусных инфекций. В настоящее время этот подход оказался полезным в лечении рака и генном редактировании. В целом, это сообщение является обзором этой ключевой технологии и ее компонентов. В частности, в этой работе мы касаемся возможных перспективных приложений и нынешних прорывов в технологии CRISPR/Cas9 для лечения рака, а также тех проблем, которые могут возникнуть при клинических исследованиях. 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Салем<sup>1</sup>, Халида К. Аль-Келаби<sup>2</sup></p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(90) "

Али А. Салем1, Халида К. Аль-Келаби2

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1 Лаборатория медицинских технологий и патологического анализа, Госпиталь Аль-Хаким, Наджаф, Ирак
2 Департамент клинических и лабораторных исследований, Факультет фармации, Университет Куфа, Наджаф, Ирак

" ["TYPE"]=> string(4) "HTML" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(22) "Организации" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } } ["SUMMARY_RU"]=> array(36) { ["ID"]=> string(2) "27" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:01:20" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(29) "Описание/Резюме" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(10) "SUMMARY_RU" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "27" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "29492" ["VALUE"]=> array(2) { ["TEXT"]=> string(3359) "<p style="text-align: justify;">Рак является заболеванием, обусловленным в основном, генетическими и эпигенетическими нарушениями. Эти заболевания – одна из ведущих причин смерти в мире и представляет собой крупную социальную и экономическую проблему. Согласно статистическим данным, более 10 миллионов человек погибают от злокачественных опухолей, и ожидается 50%-ное повышение частоты их возникновения в следующие 10 лет, приводя к 15 миллионам смертельных исходов. Единичные или множественные генные мутации, хромосомные аберрации могут вызывать раковые заболевания. Хотя для лечения рака используют многочисленные варианты лечения, они все же недостаточны против этих заболеваний. Поэтому изучается ряд новых стратегий ранней терапии злокачественных опухолей. Одной из наиболее современных и потенциально эффективных технологий, применяемых в последние годы для генных модификаций и онкотерапии является система Clustered Regularly Interspaced Short Palindromic Repeat (CRISPR)- ассоциированного протеина-9 (Cas9) – уникальная технология геномной инженерии, основанная на применении уникальной РНК-содержащей эндонуклеазы. Исходно, CRISPR/Cas9 возникла из противовирусного механизма защиты бактерий от вирусных инфекций. В настоящее время этот подход оказался полезным в лечении рака и генном редактировании. В целом, это сообщение является обзором этой ключевой технологии и ее компонентов. В частности, в этой работе мы касаемся возможных перспективных приложений и нынешних прорывов в технологии CRISPR/Cas9 для лечения рака, а также тех проблем, которые могут возникнуть при клинических исследованиях. В этом отношении мы намерены сделать вклад в оптимизацию работ по CRISPR/Cas9, а также сделать акцент на возможные будущие пути развития этой технологии. </p> <h2>Ключевые слова</h2> <p style="text-align: justify;">CRISP, Cas9, современная технология, рак, терапия.</p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(3303) "

Рак является заболеванием, обусловленным в основном, генетическими и эпигенетическими нарушениями. Эти заболевания – одна из ведущих причин смерти в мире и представляет собой крупную социальную и экономическую проблему. Согласно статистическим данным, более 10 миллионов человек погибают от злокачественных опухолей, и ожидается 50%-ное повышение частоты их возникновения в следующие 10 лет, приводя к 15 миллионам смертельных исходов. Единичные или множественные генные мутации, хромосомные аберрации могут вызывать раковые заболевания. Хотя для лечения рака используют многочисленные варианты лечения, они все же недостаточны против этих заболеваний. Поэтому изучается ряд новых стратегий ранней терапии злокачественных опухолей. Одной из наиболее современных и потенциально эффективных технологий, применяемых в последние годы для генных модификаций и онкотерапии является система Clustered Regularly Interspaced Short Palindromic Repeat (CRISPR)- ассоциированного протеина-9 (Cas9) – уникальная технология геномной инженерии, основанная на применении уникальной РНК-содержащей эндонуклеазы. Исходно, CRISPR/Cas9 возникла из противовирусного механизма защиты бактерий от вирусных инфекций. В настоящее время этот подход оказался полезным в лечении рака и генном редактировании. В целом, это сообщение является обзором этой ключевой технологии и ее компонентов. В частности, в этой работе мы касаемся возможных перспективных приложений и нынешних прорывов в технологии CRISPR/Cas9 для лечения рака, а также тех проблем, которые могут возникнуть при клинических исследованиях. В этом отношении мы намерены сделать вклад в оптимизацию работ по CRISPR/Cas9, а также сделать акцент на возможные будущие пути развития этой технологии.

Ключевые слова

CRISP, Cas9, современная технология, рак, терапия.

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Ali A. Saleem1, Khalida K. Al-Kelaby2

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1 Medical Laboratory Techniques, Pathological Analysis, Al-Hakim Hospital, Najaf, Iraq, 54001
2 Department of Clinical and Laboratory Sciences, Faculty of pharmacy, Kufa University, Najaf, Iraq, 54001


Correspondence:
Ali A. Saleem, Medical Laboratory Techniques, Pathological Analysis, Al-Hakim Hospital, Najaf, Iraq, 54001
Phone: (+964) 7711667130
E-mail: aliadil41994@gmail.com


Citation: Saleem AA, Al-Kelaby KK. A Review on CRISPR/Cas9 as a Novel Technique for Cancer Therapy. Cell Ther Transplant 2022; 11(3-4): 10-24.

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Cancer is a disorder that, basically, occurs as a result of genetic and epigenetic abnormalities. It's one of the leading causes of death in the globe, and it's still a major social and economic problem. According to statistics, over 10 million people die with malignancies, and cancer rates are expected to increase by 50% in the next ten years, culminating in approximately 15 million deaths. Single or multiple gene mutations, chromosomal abnormalities may cause cancer. Although numerous treatment options are used to treat cancer, they are still insufficient against malignant diseases. Therefore, a variety of novel strategies for early cancer therapy are examined. One of the most recent and potentially effective technologies that has been used in last years for genetic modification and cancer therapy is Clustered Regularly Interspaced Short Palindromic Repeat (CRISPR)-associated protein-9 (Cas9), a unique RNA domain-containing endonuclease-based genome engineering technology. In simple words, CRISPR/Cas9 has been derived from a bacterial defensive mechanism against viral infection. Recently, this approach has proved its usefulness in cancer therapy and gene editing. In general, this report presents a review of this key technology and its components. Specifically, in this work, we address the probable prospective uses and recent breakthroughs of CRISPR/Cas9 technology in cancer treatment, as well as the problems that can be encountered during clinical investigations. In this regard, we intend to contribute to optimizing work on CRISPR/Cas9 as well as to focus on the probable future paths of this technology.

Keywords

CRISP, Cas9, modern technology, сancer, therapy.

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Saleem<sup>1</sup>, Khalida K. Al-Kelaby<sup>2</sup></p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(66) "

Ali A. Saleem1, Khalida K. Al-Kelaby2

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Ali A. Saleem1, Khalida K. Al-Kelaby2

" } ["SUMMARY_EN"]=> array(37) { ["ID"]=> string(2) "39" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:02:59" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(21) "Description / Summary" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(10) "SUMMARY_EN" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "39" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "29496" ["VALUE"]=> array(2) { ["TEXT"]=> string(1830) "<p style="text-align: justify;">Cancer is a disorder that, basically, occurs as a result of genetic and epigenetic abnormalities. It's one of the leading causes of death in the globe, and it's still a major social and economic problem. According to statistics, over 10 million people die with malignancies, and cancer rates are expected to increase by 50% in the next ten years, culminating in approximately 15 million deaths. Single or multiple gene mutations, chromosomal abnormalities may cause cancer. Although numerous treatment options are used to treat cancer, they are still insufficient against malignant diseases. Therefore, a variety of novel strategies for early cancer therapy are examined. One of the most recent and potentially effective technologies that has been used in last years for genetic modification and cancer therapy is Clustered Regularly Interspaced Short Palindromic Repeat (CRISPR)-associated protein-9 (Cas9), a unique RNA domain-containing endonuclease-based genome engineering technology. In simple words, CRISPR/Cas9 has been derived from a bacterial defensive mechanism against viral infection. Recently, this approach has proved its usefulness in cancer therapy and gene editing. In general, this report presents a review of this key technology and its components. Specifically, in this work, we address the probable prospective uses and recent breakthroughs of CRISPR/Cas9 technology in cancer treatment, as well as the problems that can be encountered during clinical investigations. In this regard, we intend to contribute to optimizing work on CRISPR/Cas9 as well as to focus on the probable future paths of this technology.</p> <h2>Keywords</h2> <p style="text-align: justify;">CRISP, Cas9, modern technology, сancer, therapy.</p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(1774) "

Cancer is a disorder that, basically, occurs as a result of genetic and epigenetic abnormalities. It's one of the leading causes of death in the globe, and it's still a major social and economic problem. According to statistics, over 10 million people die with malignancies, and cancer rates are expected to increase by 50% in the next ten years, culminating in approximately 15 million deaths. Single or multiple gene mutations, chromosomal abnormalities may cause cancer. Although numerous treatment options are used to treat cancer, they are still insufficient against malignant diseases. Therefore, a variety of novel strategies for early cancer therapy are examined. One of the most recent and potentially effective technologies that has been used in last years for genetic modification and cancer therapy is Clustered Regularly Interspaced Short Palindromic Repeat (CRISPR)-associated protein-9 (Cas9), a unique RNA domain-containing endonuclease-based genome engineering technology. In simple words, CRISPR/Cas9 has been derived from a bacterial defensive mechanism against viral infection. Recently, this approach has proved its usefulness in cancer therapy and gene editing. In general, this report presents a review of this key technology and its components. Specifically, in this work, we address the probable prospective uses and recent breakthroughs of CRISPR/Cas9 technology in cancer treatment, as well as the problems that can be encountered during clinical investigations. In this regard, we intend to contribute to optimizing work on CRISPR/Cas9 as well as to focus on the probable future paths of this technology.

Keywords

CRISP, Cas9, modern technology, сancer, therapy.

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Cancer is a disorder that, basically, occurs as a result of genetic and epigenetic abnormalities. It's one of the leading causes of death in the globe, and it's still a major social and economic problem. According to statistics, over 10 million people die with malignancies, and cancer rates are expected to increase by 50% in the next ten years, culminating in approximately 15 million deaths. Single or multiple gene mutations, chromosomal abnormalities may cause cancer. Although numerous treatment options are used to treat cancer, they are still insufficient against malignant diseases. Therefore, a variety of novel strategies for early cancer therapy are examined. One of the most recent and potentially effective technologies that has been used in last years for genetic modification and cancer therapy is Clustered Regularly Interspaced Short Palindromic Repeat (CRISPR)-associated protein-9 (Cas9), a unique RNA domain-containing endonuclease-based genome engineering technology. In simple words, CRISPR/Cas9 has been derived from a bacterial defensive mechanism against viral infection. Recently, this approach has proved its usefulness in cancer therapy and gene editing. In general, this report presents a review of this key technology and its components. Specifically, in this work, we address the probable prospective uses and recent breakthroughs of CRISPR/Cas9 technology in cancer treatment, as well as the problems that can be encountered during clinical investigations. In this regard, we intend to contribute to optimizing work on CRISPR/Cas9 as well as to focus on the probable future paths of this technology.

Keywords

CRISP, Cas9, modern technology, сancer, therapy.

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1 Medical Laboratory Techniques, Pathological Analysis, Al-Hakim Hospital, Najaf, Iraq, 54001
2 Department of Clinical and Laboratory Sciences, Faculty of pharmacy, Kufa University, Najaf, Iraq, 54001


Correspondence:
Ali A. Saleem, Medical Laboratory Techniques, Pathological Analysis, Al-Hakim Hospital, Najaf, Iraq, 54001
Phone: (+964) 7711667130
E-mail: aliadil41994@gmail.com


Citation: Saleem AA, Al-Kelaby KK. A Review on CRISPR/Cas9 as a Novel Technique for Cancer Therapy. Cell Ther Transplant 2022; 11(3-4): 10-24.

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1 Medical Laboratory Techniques, Pathological Analysis, Al-Hakim Hospital, Najaf, Iraq, 54001
2 Department of Clinical and Laboratory Sciences, Faculty of pharmacy, Kufa University, Najaf, Iraq, 54001


Correspondence:
Ali A. Saleem, Medical Laboratory Techniques, Pathological Analysis, Al-Hakim Hospital, Najaf, Iraq, 54001
Phone: (+964) 7711667130
E-mail: aliadil41994@gmail.com


Citation: Saleem AA, Al-Kelaby KK. A Review on CRISPR/Cas9 as a Novel Technique for Cancer Therapy. Cell Ther Transplant 2022; 11(3-4): 10-24.

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Али А. Салем1, Халида К. Аль-Келаби2

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Эти заболевания – одна из ведущих причин смерти в мире и представляет собой крупную социальную и экономическую проблему. Согласно статистическим данным, более 10 миллионов человек погибают от злокачественных опухолей, и ожидается 50%-ное повышение частоты их возникновения в следующие 10 лет, приводя к 15 миллионам смертельных исходов. Единичные или множественные генные мутации, хромосомные аберрации могут вызывать раковые заболевания. Хотя для лечения рака используют многочисленные варианты лечения, они все же недостаточны против этих заболеваний. Поэтому изучается ряд новых стратегий ранней терапии злокачественных опухолей. Одной из наиболее современных и потенциально эффективных технологий, применяемых в последние годы для генных модификаций и онкотерапии является система Clustered Regularly Interspaced Short Palindromic Repeat (CRISPR)- ассоциированного протеина-9 (Cas9) – уникальная технология геномной инженерии, основанная на применении уникальной РНК-содержащей эндонуклеазы. Исходно, CRISPR/Cas9 возникла из противовирусного механизма защиты бактерий от вирусных инфекций. В настоящее время этот подход оказался полезным в лечении рака и генном редактировании. В целом, это сообщение является обзором этой ключевой технологии и ее компонентов. В частности, в этой работе мы касаемся возможных перспективных приложений и нынешних прорывов в технологии CRISPR/Cas9 для лечения рака, а также тех проблем, которые могут возникнуть при клинических исследованиях. В этом отношении мы намерены сделать вклад в оптимизацию работ по CRISPR/Cas9, а также сделать акцент на возможные будущие пути развития этой технологии. </p> <h2>Ключевые слова</h2> <p style="text-align: justify;">CRISP, Cas9, современная технология, рак, терапия.</p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(3303) "

Рак является заболеванием, обусловленным в основном, генетическими и эпигенетическими нарушениями. Эти заболевания – одна из ведущих причин смерти в мире и представляет собой крупную социальную и экономическую проблему. Согласно статистическим данным, более 10 миллионов человек погибают от злокачественных опухолей, и ожидается 50%-ное повышение частоты их возникновения в следующие 10 лет, приводя к 15 миллионам смертельных исходов. Единичные или множественные генные мутации, хромосомные аберрации могут вызывать раковые заболевания. Хотя для лечения рака используют многочисленные варианты лечения, они все же недостаточны против этих заболеваний. Поэтому изучается ряд новых стратегий ранней терапии злокачественных опухолей. Одной из наиболее современных и потенциально эффективных технологий, применяемых в последние годы для генных модификаций и онкотерапии является система Clustered Regularly Interspaced Short Palindromic Repeat (CRISPR)- ассоциированного протеина-9 (Cas9) – уникальная технология геномной инженерии, основанная на применении уникальной РНК-содержащей эндонуклеазы. Исходно, CRISPR/Cas9 возникла из противовирусного механизма защиты бактерий от вирусных инфекций. В настоящее время этот подход оказался полезным в лечении рака и генном редактировании. В целом, это сообщение является обзором этой ключевой технологии и ее компонентов. В частности, в этой работе мы касаемся возможных перспективных приложений и нынешних прорывов в технологии CRISPR/Cas9 для лечения рака, а также тех проблем, которые могут возникнуть при клинических исследованиях. В этом отношении мы намерены сделать вклад в оптимизацию работ по CRISPR/Cas9, а также сделать акцент на возможные будущие пути развития этой технологии.

Ключевые слова

CRISP, Cas9, современная технология, рак, терапия.

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Рак является заболеванием, обусловленным в основном, генетическими и эпигенетическими нарушениями. Эти заболевания – одна из ведущих причин смерти в мире и представляет собой крупную социальную и экономическую проблему. Согласно статистическим данным, более 10 миллионов человек погибают от злокачественных опухолей, и ожидается 50%-ное повышение частоты их возникновения в следующие 10 лет, приводя к 15 миллионам смертельных исходов. Единичные или множественные генные мутации, хромосомные аберрации могут вызывать раковые заболевания. Хотя для лечения рака используют многочисленные варианты лечения, они все же недостаточны против этих заболеваний. Поэтому изучается ряд новых стратегий ранней терапии злокачественных опухолей. Одной из наиболее современных и потенциально эффективных технологий, применяемых в последние годы для генных модификаций и онкотерапии является система Clustered Regularly Interspaced Short Palindromic Repeat (CRISPR)- ассоциированного протеина-9 (Cas9) – уникальная технология геномной инженерии, основанная на применении уникальной РНК-содержащей эндонуклеазы. Исходно, CRISPR/Cas9 возникла из противовирусного механизма защиты бактерий от вирусных инфекций. В настоящее время этот подход оказался полезным в лечении рака и генном редактировании. В целом, это сообщение является обзором этой ключевой технологии и ее компонентов. В частности, в этой работе мы касаемся возможных перспективных приложений и нынешних прорывов в технологии CRISPR/Cas9 для лечения рака, а также тех проблем, которые могут возникнуть при клинических исследованиях. В этом отношении мы намерены сделать вклад в оптимизацию работ по CRISPR/Cas9, а также сделать акцент на возможные будущие пути развития этой технологии.

Ключевые слова

CRISP, Cas9, современная технология, рак, терапия.

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1 Лаборатория медицинских технологий и патологического анализа, Госпиталь Аль-Хаким, Наджаф, Ирак
2 Департамент клинических и лабораторных исследований, Факультет фармации, Университет Куфа, Наджаф, Ирак

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1 Лаборатория медицинских технологий и патологического анализа, Госпиталь Аль-Хаким, Наджаф, Ирак
2 Департамент клинических и лабораторных исследований, Факультет фармации, Университет Куфа, Наджаф, Ирак

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Introduction

Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph-positive ALL) is the most common molecular type of B-lineage ALL in adults, characterized by the presence of the Philadelphia chromosome, caused by the reciprocal translocation t(9;22)(q34;q11), leading to BCR-ABL1 fusion gene encoding BCR-ABL oncoprotein, that has abnormal tyrosine kinase activity [1]. Its incidence increases with age and accounts for approximately 25-30% of adult ALL cases and close to 50% of cases in patients after 50 years old [2, 3]. Ph-positive ALL was historically associated with very poor outcomes before the advent of tyrosine kinase inhibitors (TKIs): even though complete response rates in some cases were from 46% to 96%, survival rates remained extremely low with the median overall survival (OS) times typically less than 11 months, mainly due to early relapses [4-6].

The TKIs incorporation into the treatment protocols of Ph-positive ALL has dramatically improved outcomes compared to chemotherapy alone [7-9]. For those patients who were treated by TKIs in combination with chemotherapy followed by allogeneic hematopoietic stem cell transplantation (allo-HSCT), the 5-year overall survival (OS) rates post-transplant have reached 52-61%, according to a donor type [10, 11]. In recent years, an increasing number of studies of 2nd and 3rd generation TKIs in the first-line treatment regardless of monitoring of BCR-ABL1 kinase domain (BCR-ABL1 KD) mutations were performed. The strategy to use more potent TKIs with chemotherapy or immunotherapy, such as bispecific T-cell engager antibody, in order to induce 1st remission leads to very high rates of sustained complete molecular responses (CMR), in about 83-90% of patients, and the 2-year OS rates of 80-88%. Interestingly, that the long-term survival among responding patients in these studies was not affected by allo-HSCT [12, 13]. Despite the impressive results of these recent studies, such therapy is still not uniformly available in real clinical practice in the most centers, due to its cost, lack of official indications, and coverage in the 1st-line therapy. Also, the long-term outcomes of TKIs combined with immunotherapy are still unknown. Thus, Ph-positive ALL patients remain within high-risk group. At the same time, allo-HSCT is still the standard consolidation therapy for young "fit" patients with available donor, according to current international recommendations, such as NCCN (Version 1.2022) and EBMT guidelines [14-16]. Despite all advances, the treatment of Ph-positive ALL is still challenging, especially in cases with relapsed and refractory (r/r) disease after allo-HSCT, thus remaining the main cause of transplant failure in ALL patients [17-19]. With improvement of posttransplant salvage, supportive care and disease monitoring, the 2-year OS after posttransplant relapse increased from 27.8% for patients relapsing between 2000 and 2004 to 54.8% over the period of 2015-2019 (p=0.001), which means that less than a half of the patients may be cured after allo-HSCT [20]. In these r/r cases, there are attempts to achieve further remissions with the use of salvage chemotherapy, second allo-HSCT, or TKIs with broader activity, and monoclonal antibodies, e.g., blinatumomab and inotuzumab [21-28].

Given that the prognosis of the patients who relapsed after allo-HCT remains poor, more promising strategy is the relapse prophylaxis or prevention after allo-HSCT using donor lymphocyte infusions (DLI), blinatumomab or posttransplant TKIs. Nonetheless, the need for systematic prolonged use of TKIs after allo-HSCT is still a matter of debate. Several retrospective and prospective comparative analyses were performed aiming to evaluate the impact of TKI usage after allo-HSCT upon clinical outcomes. Noteworthy, most of them found a positive impact of posttransplant TKIs administration despite controversial data obtained in other studies. At the same time, some of these studies had common limitations, due to small number of patients, heterogeneous groups, limited follow-up, variable doses of TKIs, starting date and duration of TKIs after allo-HSCT [29-37]. Another issue concerns the TKIs tolerance after allo-HSCT and need for dose adjustment [38, 39]. Acute Leukemia Working Party (ALWP) of the EBMT recommends to use prophylactic TKIs as soon as possible after engraftment, on the basis of pre- and posttransplant MRD status. However, a precise clinical strategy is still not described [40]. To address the issue if posttransplant TKIs offer a valid therapeutic approach to decrease the relapse rate, we conducted the study aimed for assessing its efficacy in multivariate analysis with respect to the disease- and allo-HSCT-specific factors.

Materials and methods

Patients, inclusion criteria and data collection

This single center study was conducted in the retrospective cohort of 106 Ph-positive ALL patients who received allo-HSCT in R. M. Gorbacheva Research Institute at the First St. Petersburg I. Pavlov State Medical University between 2002 and 2021. All patients had indications for allo-HSCT (complete remission (CR)≥1 or as a "salvage" treatment option if the CR had not been achieved previously) and were without severe cardiac, renal, pulmonary and other comorbidities. Inclusion criteria were: 1. Diagnosis of Ph-positive ALL and age ≥18 years at allo-HSCT; 2. Patients undergoing first allo-HSCT from any type of donor and in any response; 3. Treatment history with or without TKIs before allo-HSCT; 4. Donor bone marrow engraftment (absolute neutrophil counts (ANC) of >0.5×10*9/L without administration of colony-stimulating factor within 3 days with full donor chimerism in bone marrow). Prophylaxis with TKIs was not administrated in cases before introduction of second line TKIs into clinical practice and in cases of poor graft function (two or three cytopenias, >2 weeks after day +28 in the presence of >95% donor chimerism), severe infectious, cytopenias with mixed chimerism and graft rejection (<5% donor chimerism) [41]; 5. Available data about MRD status prior to allo-HSCT, as well as complete clinical data and outcome data. All data were retrieved retrospectively from clinical records according to the policy approved by the Medical Ethics Committee of the University and after obtaining written informed consent from the patients. The study was conducted according to the principles of Helsinki Declaration.

Response and clinical definitions

Complete remission (CR) before and after allo-HSCT was defined as blast cell ratio < 5% at the ANC counts of > 1×10*9/L, and platelet numbers of >100×10*9/L. CR with incomplete recovery (CRi) was defined as platelet count <100×10*9/L and/or absolute neutrophil count <1×10*9/L. Molecular response (MR) or minimal residual disease (MRD) negativity was defined as undetectable BCR-ABL1 transcript p210 or p190 level determined by real time quantitative polymerase chain reaction (qPCR) with an ABL1 level at least 10000 copies number in a sample after remission induction or relapse treatment. MRD was defined as detectable BCR-ABL1 p210 or p190 transcript level after remission induction or relapse treatment and was assessed for patients in CR only. We provided MRD data at the time of allo-HSCT (within 30 days before the procedure) and after allo-HSCT. Molecular relapse was defined as any detectable BCR-ABL1 transcript level by real time qPCR confirmed by, at least, two consecutive tests after previous molecular response. qPCR monitoring of BCR-ABL1 was carried out according to NCCN Guidelines every 3 months for patients with complete molecular remission (undetectable levels) at least for 2 years, the frequency could be increased if MRD levels were detectable [42]. Relapse was defined as a presence of >5% blasts in bone marrow or any extramedullary site in the patients with previously documented CR. The Consensus Conference criteria were used for acute GvHD grading and National Institutes of Health criteria were used for chronic GvHD grading [43, 44].

Laboratory tests

Conventional cytogenetic analysis was used for evaluation of chromosome aberrations at diagnosis, or assessment of therapeutic response during follow-up. Cytogenetic studies were carried out on G-banded chromosomes obtained from the non-stimulated 24-hr bone marrow cultures. Karyotypes were described according to an International System for Human Cytogenomic Nomenclature [45]. When the standard cytogenetics was not available, the interphase blast cells were evaluated using fluorescence in situ hybridization (FISH) probes designed for detection of (9;22) translocation (Dual Fusion Probe, Cytocell, UK). For molecular analysis at diagnosis, assessment of response and MRD status, relative expression levels of BCR-ABL1 were measured using standard qPCR approach. The ABL1 gene was used for normalization of the results. ABL1 kinase domain mutations were determined by direct Sanger sequencing [46]. To assess relative expression of e1a2 variant of the BCR-ABL1 chimeric transcript, total RNA was isolated from blood or bone marrow samples by means of phenol-chloroform extraction. The reverse transcription reaction and real-time qPCR were performed using the BCR-ABL1mbcr RQ Kit (Inogene, Russia) according to the manufacturer's instructions. The samples with, at least, >10,000 copies of the reference ABL1 gene per a reaction were considered valid when assessing MRD levels.

Statistical analysis

Primary endpoints in the present study were as follows: OS, relapse incidence (RI), non-relapse mortality (NRM), relapse-free survival (RFS) and GvHD incidence. OS was defined as the probability of survival, irrespective of the disease status at any point in time after allo-HSCT. OS time duration was estimated from the time of allo-HSCT to the date of last contact or the date of death. The RFS was estimated as a period from allo-HSCT to the last contact date, death, or relapse. Probabilities of OS and RFS were calculated using the Kaplan-Meier Method. The comparisons were made using the log-rank test. P-values are two-sided with type 1 error rate fixed at 0.05. The RI was defined as the probability to develop a disease relapse after allo-HSCT. NRM was defined as probability of death without a relapse after allo-HSCT. Analysis of time-dependent variables, such as RI, NRM, GvHD incidence were calculated using cumulative incidence estimates with a competing risk setting using Fine and Grey test: death in remission as a competing event to relapse, relapse as a competing risk to NRM, death before 100 days without acute GvHD after allo-HSCT to the cases of acute GvHD; death without chronic GvHD to lethal cases with chronic GvHD, respectively. Patients alive at the end of the follow-up were censored at this date. Patients who reached D+100 after allo-HSCT were included into the analysis to assess the impact of prophylaxis with TKIs on the risk of chronic GvHD. Patients who presented with chronic GvHD prior to TKIs prophylaxis were excluded from this analysis.

Secondary endpoint concerned assessment of efficacy of TKIs prophylaxis on RFS, in view of the disease- and HSCT-specific factors. To this purpose, multivariate analysis was performed with the use of Cox proportional hazard model. Landmark analysis for day+180, +270, +360 was used to assess the impact of chronic GvHD on RFS. Fisher's exact test and Pearson's Chi-square were used to find difference between two groups of categorial factors. Non-parametric Mann-Whitney U-test was used to compare the quantitative attributes between groups. Statistical analyses were performed with SPSS 26.0 (IBM Corp., Armonk, NY, USA), R programming language version 4.0.5. software packages (R Development Core Team, Vienna, Austria), EZR free statistical environment, version 2.15.2 (R Foundation for Statistical Computing, Vienna, Austria).

Results

Patients and allo-HSCT characteristics

A total of 106 Ph-positive ALL patients with median age of 30 (range 18-59) years were included into the study. The median follow-up time was 40.0 (range 5.0-150.4) months for the patients enrolled who were still alive at the end of the study. According to the current indications for allo-HSCT most of the patients (63 cases, 60%)) were transplanted in CR1; 15 (14%), in CR2; 11 (10%), in ≥CR3 and 17 (16%), in active disease ("salvage" allo-HSCT). There were no significant differences in gender, MRD status, extramedullary disease, BCR-ABL1 type of protein, cytogenetics, TKIs treatment prior to allo-HSCT, year of allo-HSCT, donor’s gender, ABO-combability, busulfan dosage, graft source, GvHD prophylaxis between patients in CR1, and advanced stage of the disease. At the same time, matched/mismatched unrelated donor type (MUD/MMUD) was the most frequent type of donors in all groups (60% vs 26% vs 14%). Busulfan-based conditioning was used in most cases for the both groups (85% vs 10% vs 5%). Median time from allo-HSCT to first relapse was 262 (range 14-1926) days, and 8 (30%) of cases had relapse during 100 days after allo-HSCT. Relapses developed in 42 (40%) of the patients: bone marrow relapse was registered in 34 cases (81%); neuroleukemia, in 3 (7%); extramedullary relapse, in 2 (5%); combined (CNS+bone marrow+other extramedullary) relapse, in 3 patients (7%). Nineteen patients experienced more than 1 relapse. By the end of analysis, 60 patients (57%) were alive, 46 (43%) of the patients died. Noteworthy, relapse was the main cause of death (n=27, 59%). Other causes of death were as follows: infection, 11 cases (24%), GvHD, 6 (13%), toxicity, 1 (2%), unknown reasons, 1 (2%). Other baseline characteristics for these patients and transplant procedure are presented in Table 1.

Table 1. Characteristics of the patients and allo-HSCT

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Notes: CR=complete remission, MRD=minimal residual disease, TKIs=tyrosine kinase inhibitors, allo-HSCT=allogeneic hematopoietic stem cell transplantation; MRD=matched related donor, MUD=matched unrelated donor, MMUD=mismatched unrelated donor, PBSC=peripheral blood stem cells, PtCy=posttransplant cyclophosphamide, ATG=Anti-thymocyte globulin, GvHD=graft-versus-host disease, TCR αβ-depletion=T cell receptor alpha/beta-depletion

Survival and relapse rates

At 5 years, the cumulative incidence of relapse (RI) and non-relapse mortality (NRM) were 49.1% (37.74-60.46) and 20.2% (95% CI 11.58-28.82), respectively. The Kaplan-Meier OS estimate at 5 years was 55.0% (95% CI 44.62–65.38), and the estimate of RFS at 5 years was 40.4% (95% CI 30.41-50.39). Median time from allo-HSCT to first relapse was 262.5 (range, 14-1926) days. Five-year RFS values was influenced by status of the disease, i.e., RFS was 52.9% (95% CI 39.58-66.22%) when transplanted in CR1; 18.2% (95% CI 3.31-33.09%), if transplanted in CR≥3, and 0% following allo-HSCT in active disease (p<0.001), as seen from Fig. 1A. Moreover, the disease status was a significant risk factor for NRM: patients in advanced-disease phase experienced higher 2-year NRM rates: 64.7% (95% CI 36.87-92.53) compared to 42.7% (95% CI 9.38-76.02%) in CR3 versus 12.5% (95% CI 4.47-20.53%) in CR1-2 (p=0.001). At the same time, there was no difference in 5-year OS, RFS, NRM and RI when performing allo-HSCT in CR1 or CR2 (p>0.05). Interestingly, 16 of 17 patients who underwent allo-HSCT in active disease died by 14 months after allo-HSCT. Of them, 11 patients died due to the disease progression; 2 patients due to infectious complications; 2 patients, due to severe acute and chronic GvHD; 1 patient, due to toxicity (multiorgan failure). Median time from MRD assessment to allo-HSCT was 16 (range 6-134) days. One should be noted that, despite the fact that MRD-positive status before allo-HSCT did not affect OS, RFS and NRM, the relapse rate was 22.8% higher in MRD-positive group (p=0.03), as shown in Fig. 1B. In univariate cumulative incidence analysis, we have shown that the 5-year RI for the patients who reached 100 days after allo-HSCT, was twice lower in the TKIs prophylaxis group compared with non-prophylaxis group, i.e., 30.08% (95% CI 17. 7-43.5) vs 62.85% (95% CI 44.8-76.5) (Fig. 1C). Univariate analysis for survival and RI of the patients, transplanted in CR are presented in Table 2. Allo-HSCT from haploidentical donors was the factor, which led to significantly worse RFS (p=0.05) and NRM (p=0.01), while there is no difference in other types of donors. Intensity of conditioning regimen (busulfan dose) did not influence the 1-, 2- and 5-year OS, RFS, NRM and RI rates (p>0.05). Simultaneously, exploratory analysis showed that patients after GvHD prophylaxis with posttransplant cyclophosphamide had a significantly higher 5-year OS, RFS and lower NRM and RI likelihood than those treated with other regimens of GvHD prophylaxis (classical, or TCR αβ-depletion). The cumulative incidence frequencies of grades 2-4 acute GvHD at day 100 was 27.57% (95% CI 19.4-36.3%), with the median onset time of 27 (range 7-99) days. The proportion of patients with moderate chronic GvHD was 13 (32.5%), severe chronic GvHD, in 16 cases (40%). Cumulative incidence of NIH-defined chronic GVHD was 41.92% (95% CI 31.7-51.8%), with the median onset time of 199.5 (range, 100 to 1172) days. Experience of chronic GvHD was significantly associated with reduced risk of relapse: 31.4% (95% СI 14.94-47.86%) vs 53.7% (95% CI 35.87-71.53%), p=0.04 in univariate analysis.

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Figure 1. A. Relapse-free survival (RFS) according to CR status prior to allo-HSCT; B. Relapse incidence (RI) according to MRD status prior to allo-HSCT; С. RI according to prophylactic TKIs after allo-HSCT

Table 2. Univariate analysis of predictors for OS, RFS, NRM and RI at 5 years after allo-HSCT for CR patients

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Treatment with TKIs after allo-HSCT

A total of 80 (75.8%) patients received posttransplant TKIs maintenance therapy used with the prophylactic aim (60 cases, 75%); at the first MRD positivity or molecular relapse post allo-HSCT as pre-emptive treatment (11 cases, 13.8%), or as relapse treatment (9 patients, 11.2%) (Table 3). Median time from allo-HSCT to initiation of prophylactic TKIs was 87 days (range, 19-378). TKI drug was changed in 15 patients, i.e., due to relapse (n=1); due to toxicity/intolerance (n=4) in prophylaxis group; in 5 patients due to relapse (n=3), due to toxicity/intolerance (n=2) in preemptive group, and in 1 patient with disease progression in the relapse treatment group. Frequency of chronic GvHD in the TKIs prophylaxis group was 48.2% vs 21.1% in non-prophylaxis group (p=0.05). Prophylaxis with TKIs was associated with increased risk of chronic GvHD: OR 3.47 (95% CI 1.03-11.84), at relative risk of 2.28 (95% CI 5.71-11.7). We did not find any difference in relapse risk according to the type of prophylactic TKIs (imatinib vs dasatinib, p=0.1).

Table 3. TKIs after allo-HSCT according to the aim of administration

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Note: combinations, switch from imatinib to dasatinib (n=2), dasatinib to bosutinib (n=1), imatinib to nilotinib (n=1).

To assess the impact of prophylactic TKIs after allo-HSCT upon RFS rates, we performed multivariate analysis including the factors associated with disease and allo-HSCT procedure. The following independent covariates were used: the year of allo-HSCT (2002-2012 vs. 2013-2021, separated by significant change in clinical practice), donor type, the fact of TKIs prophylaxis after transplant, and MRD status of the disease at transplant (Fig. 2). We performed the analysis using different classifications of donor type and status of the disease. The first one included haploidentical (n=15) vs other donor types (n=91), the second approach concerned matched (n=76) vs other donors (n=30).

In a multivariate analysis of RFS performed to assess the impact of MRD and relapsed/refractory (r/r) disease before allo-HSCT in the context of posttransplant TKIs, the following factors were associated with reduced risk of relapse or death: allo-HSCT after 2012 (HR=0.46, 95%CI 0.26-0.83, p=0.009), any MRD status of the disease before allo-HSCT except active disease with relatively the same HR in the context of the posttransplant TKIs prophylaxis. With another distribution of statuses and TKIs (CR and MRD statuses), we confirmed the data of favorable impact of later year of transplant (HR=0.49, 95%CI 0.27-0.89, p=0.019), and the ability of posttransplant TKIs to reduce negative effect of measurable disease. In addition, allo-HSCT from haploidentical donor increased the risks in both models (HR=2.71, 95% CI 1.20-6.13, p=0,016, and HR=2.49, 95% CI 1.08-5.75, p=0.032, respectively), as seen from Fig. 3. When analyzing RFS with another classification of donor (matched vs others) we confirmed the data about favorable impact of prophylaxis with TKIs, despite the status of the disease prior to allo-HSCT (p<0.001).

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To assess the effect of chronic GvHD on RFS in the context of TKI therapy after allo-HSCT, a landmark analysis was performed for day+180, +270, +360. By day+ 360, almost all patients with active disease and haploidentical donor have died, and this factor was excluded from the model. The following reasons were identified as the cause of death during first year after allo-HSCT in this group of patients: relapse, 9 patients (50%); acute GvHD grade IV, 3 patients (17%); infectious complications, 5 (28%); toxicity, 1 (5%). There was no impact of chronic GvHD on RFS when performing landmark analysis on day+180 and day+270 as based on available data (HR=0.43, 95% CI 0.13-1.45, p=0.17 and HR=0.5, 95% CI 0.19-1.32, p=0.161, respectively). Moreover, all remaining factors lose their significance on RFS for those patients who survived by day +360 (Fig. 4).

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Figure 4. Multivariate analysis of the factors influencing RFS (landmark analysis)

Toxicity of TKIs after allo-HSCT

While being very effective, the TKIs applied after allo-HSCT also have a toxicity profile that is relatively favorable. Among the entire group of patients who received any TKIs after allo-HSCT aimed for prophylaxis, preemptive, or relapse treatment, the TKIs’ dosage was reduced in 24 patients (30%), treatment was discontinued in 4 patients (5%), changed to another TKI type, in 5 patients (6%), temporarily stopped and then re-prescribed in 10 patients (13%), due to intolerance or severe toxicity. In prophylaxis group, the most common side effects were hematological (26%) and gastrointestinal (9%) toxicity. Rare adverse events included fluid retention (5%), fever (5%), skin rash (3%), muscle pain (2%), autoimmune thyroiditis (2%). Four patients had multiple manifestations of toxicity. Toxicity profile in prophylaxis TKIs group according to the TKI type is presented in Table 4.

Table 4. Adverse events in prophylaxis group according to the type of TKI

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The presented toxicity profile in the prophylaxis TKIs group is described for the non-standard TKI dosage. In most cases of TKIs dose modifications, the drug dosage was reduced, in order to manage the TKI-related side effects. After allo-HSCT, only about 32% of patients received prophylaxis with imatinib at a full dose of 400-600 mg, whereas 29% of patients were treated at a dose of 200 mg, and 39% of patients received a significantly reduced dose of 100 mg per day. The same situation was with dasatinib: full dose was prescribed to 33% of patients; 70 mg, to 50% of patients, and 35-50 mg, to 17% of patients (Fig. 5).

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Figure 5. Doses of prophylactic imatinib (A) and dasatinib (B)

Discussion

MRD-positive status prior to allo-HSCT is a well-known unfavorable risk factor for allo-HSCT outcomes in Ph-positive ALL patients, who did not receive prophylactic TKIs post-transplant [47,48]. Lussana et al. showed that MRD negativity at the time of conditioning was associated with a significant benefit in terms of risk of relapse at 5 years, with a RI of 8% compared with 39% for patients with MRD positivity (p=0.007). However, in this study post-transplantation administration of TKIs alleviated the difference in DFS (58% vs 41%, p=0.17) and OS (58% vs 49%, p=0.55) in MRD-negative and MRD-positive patients, respectively. Nonetheless, TKIs were used not with prophylactic, but with treatment aim in this study [49]. In our retrospective single-center analysis, we also demonstrated that TKIs prophylaxis improves long-term RFS and alleviates the negative impact of MRD on the outcomes in an unfavorable group of Ph-positive ALL adult patients. Previously, the same conclusions were made in several non-randomized studies, however, in extremely small groups of patients. Chen et al. reported superior outcomes for patients who received imatinib as prophylactic or preemptive maintenance regimens after allo- HSCT (n=62) compared with those who did not receive post-transplant TKIs (n=20) (5-year OS, 86.7% vs 34.3%, p <0.001; EFS, 81.5% vs 33.5%, p <0.001) [50]. At the same time, the data of a single randomized trial from the German multicenter study group for adult ALL obtained in 55 patients with Ph-positive ALL who underwent allo-HSCT, were randomly assigned to receive imatinib as prophylaxis or based on MRD positivity. Although prophylactic imatinib prevented molecular recurrence, EFS and OS did not differ significantly between the 2 treatment arms: 5-year OS was 80% in the prophylactic group vs 75% in the preemptive group [38]. Burke et al. compared outcomes for patients who received prophylactic imatinib (for 1 year) with patients who did not receive post-transplant TKIs: OS at 2 years for patients with imatinib (n=2) and without (n=17) were 100% and 41%, respectively, with a corresponding relapse-free survival of 100% and 35% [51]. The data about 2nd generation of TKIs after allo-HSCT are very scarce: dasatinib or nilotinib were studied as maintenance regimen after allo-HSCT in few studies (n=62) [35]: in the study by Czyz et al., 19 patients received dasatinib (treatment duration of 11 months), either prophylactically or preemptively. After a median follow-up of 3 years after allo-HSCT, the OS and LFS were 87% and 88%, respectively. Fourteen of 15 patients (93%) who were MRD positive after transplant converted to MRD negativity and continued to be MRD negative at last follow up. At the same time, there is an important limitation of nilotinib trials: they presented common results for CML and Ph-positive ALL patients, but not separate results for the Ph-positive ALL group, mainly due to small number of enrolled patients.

In our group, most of the patients (57%) received prophylactic TKIs after allo-HSCT. The majority of patients not assigned to prophylaxis and preemptive treatment with TKIs (n=35) was transplanted (n=21) before 2014. The patient group allografted since 2014 (n=11) who reached day+80 after allo-HSCT without TKIs, included patients with severe infectious complications, severe poor graft function, or uncontrolled GvHD. Six of them died from relapse, one patient was lost from infectious complications, two patients are alive without relapse. In two cases, the patients developed relapse and are alive at the last follow up. Thus, we presume that the results might be significantly affected by the time of transplant and status of patients. It is well known that the patients with severe poor graft function tend to have increased risk of NRM, but not relapse [52]. In early studies, TKIs demonstrated superior outcomes, but both prophylactic TKIs group, as well as patients without TKI prophylaxis included only limited number of patients. Authors did not explain the choice of strategy concerning prophylactic TKIs administration in non-randomized trials, but the reasons seem to be comparable across studies. A study by Ribera et al. concerned OS and DFS for 13 of 21 patients who received prophylaxis with imatinib that was only 30% (9-mo follow-up). Transplant- and treatment-related complications and patient selection may have contributed to poor outcomes in this small cohort. Ten of twelve patients had interruptions in treatment for various reasons, including relapse, severe chronic graft-versus-host disease (GVHD), grades 3 to 4 toxicity, non-relapse death, and patient preference [53]. Nishiwaki et al. showed superior outcomes for patients who received imatinib (pre-emptive, n=4; prophylactic, n=3) after allo-HSCT when compared with cases without TKI treatment (n=27). The OS at 1 year with TKIs versus without TKIs was 100% vs 33.3%, and the 2-year OS was 66.7% vs 29.6%, respectively (p=0.03). EFS was not significantly different between the 2 groups at 1 and 2 years (55.6% versus 55.6% and 33.3% versus 29.6%, p=0.29).

Newer TKIs’ generation, such as dasatinib and nilotinib, were shown to be more potent (respectively, 325-fold and 50-100-fold) when compared with imatinib [54]. Whether or not this higher potency plays any role in the context of post-transplant administration remains to be proven. Dasatinib demonstrated similar or better EFS and OS rates compared with imatinib in several trials [30, 33]. Nonetheless, the studies were retrospective and long-term outcomes were not available. Nilotinib also had similar clinical outcomes when compared with imatinib, but the studies on post-transplant nilotinib therapy included mixed group of CML and Ph-positive ALL patients [55, 56]. The numbers of patients in studies using 2nd TKIs generations are small and non-randomized. E.g., Saini et al. aimed to compare the efficacy of new-generation TKIs versus imatinib treatment: 28 patients received imatinib in the TKIs prophylactic group and 33 patients received newer generation TKIs. The relapse rate was similar, with three patients relapsing in each arm. However, in the MRD-triggered group, 6 (75%) out of 8 patients who received imatinib relapsed compared to 6 (45%) out of 11 patients who received new-generation TKI [36]. The newer generation TKIs appear to improve prognosis for these high-risk patients, but these results should be proven in further prospective trials. First and 2nd-generation TKIs were used with the prophylaxis aim in our group of patients. Imatinib was the most commonly used (48%) in the entire group, due to wider availability of the TKI in real clinical practice. At the same time, dasatinib was more frequently used (40%) over recent years, due to its broader activity and ability to penetrate the blood-brain barrier and prevent CNS relapses [54]. Isolated CNS relapse occurs in up to 20% of patients with Ph-positive ALL during imatinib monotherapy [57]. We did not find any difference in relapse risk dependent on the type of prophylactic TKIs (imatinib vs. dasatinib), p=0.1. First of all, we did not compare relapse rates for imatinib and dasatinib subgroups according to the disease status before allo-HSCT. In addition, the lack of difference between imatinib and dasatinib groups of patients may be due to pronounced graft-versus-leukemia (GvL) effect and shift of Ph-positive ALL subclones to less aggressive ones, thus lacking a need for a more active TKI in this case after allo-HSCT. Several studies have shown that BCR-ABL1 kinase mutation is the major cause of relapse in Ph-positive ALL, even after allo-HSCT [58], and newer TKIs generations can potentially overcome some of these mutations and lead to lower relapse rates in patients with resistant disease. However, lack of the data about the mutational status and insufficient patients’ numbers in study does not allow to make definitive conclusions.

There are also studies which did not show positive impact of post-transplant TKIs. E.g., Nishiwaki et al. confirmed that MRD status at allo-HSCT is one of the most important predictive factors for Ph-positive ALL patients transplanted in CR1. Post-transplant TKIs were administered to 103 patients. Surprisingly, post-transplant administration of TKIs was suggested to be a significant adverse prognostic factor for relapse, i.e., OS was significantly better in patients with post-transplant TKI therapy, but there was no significant difference in RFS. As for NRM, it might be underestimated in patients with post-transplant TKI administration because of technical issues for the competing risk analyses: of 103 patients with post-transplant administration, NRM occurred in only 3 patients (3%), whereas relapse was observed in 71 patients (69%). Since a decision to administer TKIs after allo-HSCT was made by each institution in this study, the TKIs might have been prescribed to the patients who were potentially at high risk for relapse [48]. The main difference between the studies is the patients’ enrollment, i.e., we described the patients in various disease status, while Nishiwaki and colleagues included only CR1 patients prior to allo-HSCT, and observed surprisingly high relapse rate without TKIs. In the retrospective study of Kebriaei et al., 102 adults and 11 children were included. TKIs’ use for maintenance (n=32) did not improve the outcomes. Only subgroups of younger patients who achieved CR1 at the time of allo-HSCT, and underwent transplants after 2000, demonstrated better outcomes and improved prognosis. In this study, on the contrary to Nishiwaki et al., the presence of MRD prior to allo-HSCT was not a significant predictor for progression-free survival [31]. Patients observed by Zheng et al. did not show favorable survival outcomes despite maintenance imatinib therapy after allo-HSCT. This result may be, in part, explained by the high proportion (36%) of patients who were not in CR at the time of allo-HSCT in this small cohort (n=11) [59].

Another valuable topic of interest is an influence of chronic GvHD upon RFS and RI. In CIBMTR-led study which recruited a large cohort of adult ALL patients (n=2593), the impact of acute GvHD and chronic GvHD of varying severity on transplant outcomes was explored. The patients with advanced ALL had better OS (reduction in mortality; HR, 0.69-0.73) when they developed chronic GvHD with or without grades I and II acute GvHD, which is explained by an increased GVL effect in ALL [59]. Simultaneously, the results refer to the common group of ALL patients, without any clarification regarding Ph-negative and Ph-positive ALL patients. There are also no conclusions about the GvHD incidence in case of TKIs maintenance after allo-HSCT. In another study (Akahoshi et al.), the association between TKIs prophylaxis and incidence of chronic GvHD was not described: WBC at diagnosis (HR, 1.36; 95% CI 1.10-1.68; p=0.004), unrelated cord blood transplantation (HR, 0.70; 95% CI 0.52-0.95; p=0.022), reduced conditioning intensity (HR, 0.77; 95% CI 0.60‐0.99; p=0.042), and grade II‐IV acute GvHD (HR, 1.36; 95% CI 1.10-1.68; p=0.004) were significantly associated with the incidence of chronic GVHD, while the incidence of chronic GvHD did not show significant association with TKIs prophylaxis (HR, 0.82; 95% CI 0.49-1.35; p=0.428) in the multivariate analysis [34]. In our study, chronic GvHD was significantly associated with reduced risk of relapse in our group: 31.4% (95% СI 14.94-47.86%) vs 53.7% (95% CI 35.87-71.53%), p=0.04 and increased RFS: 60% (95% CI 43.54-76.46) vs 38.4% (95% CI 22.92-53.88), p=0.003 in univariate analysis. At the same time, we were unable to prove a positive impact of chronic GvHD upon the landmark analysis. We realize the fact, that, due to the small groups of patients in our study, we can’t confidentially claim that, in the context of TKIs maintenance, chronic GvHD associated with GvL effect has no influence on clinical outcomes. We understand that a larger group of patients is needed to assess the effect of chronic GvHD upon RFS in the time-dependent manner. It is worth to mention, that TKIs, especially imatinib, being a multikinase inhibitor of several signaling pathways implicated in skin fibrosis, is known as potential option to treat sclerotic steroid refractory GvHD, in view of fibroblast growth inhibition, and decreased collagen production in dermal fibroblasts [60, 61]. However, the incidence of chronic GVHD in our group was even higher in the TKIs prophylaxis group. Among 31 patients who experienced chronic GvHD in the prophylaxis group, 23 (74.2%) of the patients exhibited skin involvement, and 12 of them (52.2%) received prophylaxis with post-transplant imatinib. Only 1 patient died from severe chronic GvHD in each group (imatinib vs other TKIs). In our opinion, not only imatinib, but also improvement of GvHD prophylaxis and treatment over recent years contributes to this low incidence of GvHD-associated mortality [62, 63]. In our study, several patients received other TKIs as a prophylactic component (nilotinib, n=2; bosutinib, n=3). Four of these patients developed chronic GvHD, 3 of them displayed skin involvement. However, clinical data concerning the potential use of 2nd-generation TKIs, which are active against a broader spectrum of kinases, are lacking in patients with chronic GVHD. Nonetheless, in vitro addition of nilotinib to chronic GVHD fibroblast cultures induced a decrease in the expression of both COL1α1 and COL1α2 mRNAs, indicating the antifibrotic potential of this drug [64]. On the other hand, ponatinib, 3rd-generation TKI, is described as a drug, which induces GvHD, suggesting that the efficacy of ponatinib could be related not only to the direct antileukemic effect but also to its ability to promote an indirect GvL effect. Petrungaro et al. have shown an increased number of circulating CD8+ and natural killer T cells, along with reduced numbers of CD4+ T cells observed during ponatinib treatment after allo-HSCT in patient without T315I mutation, which might be correlated with the onset of GVHD and GVL [65].

Conclusion

The study demonstrated positive impact of prophylactic TKIs in adult patients with Ph-positive ALL after allo-HSCT. Prophylactic TKIs can overcome the negative effects of MRD on clinical outcomes. However, in some cases, post-transplant TKIs administration is not possible, mainly because of transplantation-derived complications, rather than drug-specific toxicity. Final safe dose in the majority of patients was lower than recommended, thus dose de-escalation strategy is more justifiable after allo-HSCT. The issue of using first- or second-generation TKIs, as well as optimal duration of therapy should be clarified by the working group consensus.

Conflicts of interest

No conflicts of interest are reported by the authors.

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  65. Petrungaro A, Gentile M, Mazzone C, Greco R, Uccello G, Recchia AG, et al. Ponatinib-induced graft-versus-host disease/graft-versus-leukemia effect in a patient with Philadelphia-positive acute lymphoblastic leukemia without the T315I mutation relapsing after allogeneic transplant. Chemotherapy. 2017; 62:353-356. doi: 10.1159/000477714

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Introduction

Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph-positive ALL) is the most common molecular type of B-lineage ALL in adults, characterized by the presence of the Philadelphia chromosome, caused by the reciprocal translocation t(9;22)(q34;q11), leading to BCR-ABL1 fusion gene encoding BCR-ABL oncoprotein, that has abnormal tyrosine kinase activity [1]. Its incidence increases with age and accounts for approximately 25-30% of adult ALL cases and close to 50% of cases in patients after 50 years old [2, 3]. Ph-positive ALL was historically associated with very poor outcomes before the advent of tyrosine kinase inhibitors (TKIs): even though complete response rates in some cases were from 46% to 96%, survival rates remained extremely low with the median overall survival (OS) times typically less than 11 months, mainly due to early relapses [4-6].

The TKIs incorporation into the treatment protocols of Ph-positive ALL has dramatically improved outcomes compared to chemotherapy alone [7-9]. For those patients who were treated by TKIs in combination with chemotherapy followed by allogeneic hematopoietic stem cell transplantation (allo-HSCT), the 5-year overall survival (OS) rates post-transplant have reached 52-61%, according to a donor type [10, 11]. In recent years, an increasing number of studies of 2nd and 3rd generation TKIs in the first-line treatment regardless of monitoring of BCR-ABL1 kinase domain (BCR-ABL1 KD) mutations were performed. The strategy to use more potent TKIs with chemotherapy or immunotherapy, such as bispecific T-cell engager antibody, in order to induce 1st remission leads to very high rates of sustained complete molecular responses (CMR), in about 83-90% of patients, and the 2-year OS rates of 80-88%. Interestingly, that the long-term survival among responding patients in these studies was not affected by allo-HSCT [12, 13]. Despite the impressive results of these recent studies, such therapy is still not uniformly available in real clinical practice in the most centers, due to its cost, lack of official indications, and coverage in the 1st-line therapy. Also, the long-term outcomes of TKIs combined with immunotherapy are still unknown. Thus, Ph-positive ALL patients remain within high-risk group. At the same time, allo-HSCT is still the standard consolidation therapy for young "fit" patients with available donor, according to current international recommendations, such as NCCN (Version 1.2022) and EBMT guidelines [14-16]. Despite all advances, the treatment of Ph-positive ALL is still challenging, especially in cases with relapsed and refractory (r/r) disease after allo-HSCT, thus remaining the main cause of transplant failure in ALL patients [17-19]. With improvement of posttransplant salvage, supportive care and disease monitoring, the 2-year OS after posttransplant relapse increased from 27.8% for patients relapsing between 2000 and 2004 to 54.8% over the period of 2015-2019 (p=0.001), which means that less than a half of the patients may be cured after allo-HSCT [20]. In these r/r cases, there are attempts to achieve further remissions with the use of salvage chemotherapy, second allo-HSCT, or TKIs with broader activity, and monoclonal antibodies, e.g., blinatumomab and inotuzumab [21-28].

Given that the prognosis of the patients who relapsed after allo-HCT remains poor, more promising strategy is the relapse prophylaxis or prevention after allo-HSCT using donor lymphocyte infusions (DLI), blinatumomab or posttransplant TKIs. Nonetheless, the need for systematic prolonged use of TKIs after allo-HSCT is still a matter of debate. Several retrospective and prospective comparative analyses were performed aiming to evaluate the impact of TKI usage after allo-HSCT upon clinical outcomes. Noteworthy, most of them found a positive impact of posttransplant TKIs administration despite controversial data obtained in other studies. At the same time, some of these studies had common limitations, due to small number of patients, heterogeneous groups, limited follow-up, variable doses of TKIs, starting date and duration of TKIs after allo-HSCT [29-37]. Another issue concerns the TKIs tolerance after allo-HSCT and need for dose adjustment [38, 39]. Acute Leukemia Working Party (ALWP) of the EBMT recommends to use prophylactic TKIs as soon as possible after engraftment, on the basis of pre- and posttransplant MRD status. However, a precise clinical strategy is still not described [40]. To address the issue if posttransplant TKIs offer a valid therapeutic approach to decrease the relapse rate, we conducted the study aimed for assessing its efficacy in multivariate analysis with respect to the disease- and allo-HSCT-specific factors.

Materials and methods

Patients, inclusion criteria and data collection

This single center study was conducted in the retrospective cohort of 106 Ph-positive ALL patients who received allo-HSCT in R. M. Gorbacheva Research Institute at the First St. Petersburg I. Pavlov State Medical University between 2002 and 2021. All patients had indications for allo-HSCT (complete remission (CR)≥1 or as a "salvage" treatment option if the CR had not been achieved previously) and were without severe cardiac, renal, pulmonary and other comorbidities. Inclusion criteria were: 1. Diagnosis of Ph-positive ALL and age ≥18 years at allo-HSCT; 2. Patients undergoing first allo-HSCT from any type of donor and in any response; 3. Treatment history with or without TKIs before allo-HSCT; 4. Donor bone marrow engraftment (absolute neutrophil counts (ANC) of >0.5×10*9/L without administration of colony-stimulating factor within 3 days with full donor chimerism in bone marrow). Prophylaxis with TKIs was not administrated in cases before introduction of second line TKIs into clinical practice and in cases of poor graft function (two or three cytopenias, >2 weeks after day +28 in the presence of >95% donor chimerism), severe infectious, cytopenias with mixed chimerism and graft rejection (<5% donor chimerism) [41]; 5. Available data about MRD status prior to allo-HSCT, as well as complete clinical data and outcome data. All data were retrieved retrospectively from clinical records according to the policy approved by the Medical Ethics Committee of the University and after obtaining written informed consent from the patients. The study was conducted according to the principles of Helsinki Declaration.

Response and clinical definitions

Complete remission (CR) before and after allo-HSCT was defined as blast cell ratio < 5% at the ANC counts of > 1×10*9/L, and platelet numbers of >100×10*9/L. CR with incomplete recovery (CRi) was defined as platelet count <100×10*9/L and/or absolute neutrophil count <1×10*9/L. Molecular response (MR) or minimal residual disease (MRD) negativity was defined as undetectable BCR-ABL1 transcript p210 or p190 level determined by real time quantitative polymerase chain reaction (qPCR) with an ABL1 level at least 10000 copies number in a sample after remission induction or relapse treatment. MRD was defined as detectable BCR-ABL1 p210 or p190 transcript level after remission induction or relapse treatment and was assessed for patients in CR only. We provided MRD data at the time of allo-HSCT (within 30 days before the procedure) and after allo-HSCT. Molecular relapse was defined as any detectable BCR-ABL1 transcript level by real time qPCR confirmed by, at least, two consecutive tests after previous molecular response. qPCR monitoring of BCR-ABL1 was carried out according to NCCN Guidelines every 3 months for patients with complete molecular remission (undetectable levels) at least for 2 years, the frequency could be increased if MRD levels were detectable [42]. Relapse was defined as a presence of >5% blasts in bone marrow or any extramedullary site in the patients with previously documented CR. The Consensus Conference criteria were used for acute GvHD grading and National Institutes of Health criteria were used for chronic GvHD grading [43, 44].

Laboratory tests

Conventional cytogenetic analysis was used for evaluation of chromosome aberrations at diagnosis, or assessment of therapeutic response during follow-up. Cytogenetic studies were carried out on G-banded chromosomes obtained from the non-stimulated 24-hr bone marrow cultures. Karyotypes were described according to an International System for Human Cytogenomic Nomenclature [45]. When the standard cytogenetics was not available, the interphase blast cells were evaluated using fluorescence in situ hybridization (FISH) probes designed for detection of (9;22) translocation (Dual Fusion Probe, Cytocell, UK). For molecular analysis at diagnosis, assessment of response and MRD status, relative expression levels of BCR-ABL1 were measured using standard qPCR approach. The ABL1 gene was used for normalization of the results. ABL1 kinase domain mutations were determined by direct Sanger sequencing [46]. To assess relative expression of e1a2 variant of the BCR-ABL1 chimeric transcript, total RNA was isolated from blood or bone marrow samples by means of phenol-chloroform extraction. The reverse transcription reaction and real-time qPCR were performed using the BCR-ABL1mbcr RQ Kit (Inogene, Russia) according to the manufacturer's instructions. The samples with, at least, >10,000 copies of the reference ABL1 gene per a reaction were considered valid when assessing MRD levels.

Statistical analysis

Primary endpoints in the present study were as follows: OS, relapse incidence (RI), non-relapse mortality (NRM), relapse-free survival (RFS) and GvHD incidence. OS was defined as the probability of survival, irrespective of the disease status at any point in time after allo-HSCT. OS time duration was estimated from the time of allo-HSCT to the date of last contact or the date of death. The RFS was estimated as a period from allo-HSCT to the last contact date, death, or relapse. Probabilities of OS and RFS were calculated using the Kaplan-Meier Method. The comparisons were made using the log-rank test. P-values are two-sided with type 1 error rate fixed at 0.05. The RI was defined as the probability to develop a disease relapse after allo-HSCT. NRM was defined as probability of death without a relapse after allo-HSCT. Analysis of time-dependent variables, such as RI, NRM, GvHD incidence were calculated using cumulative incidence estimates with a competing risk setting using Fine and Grey test: death in remission as a competing event to relapse, relapse as a competing risk to NRM, death before 100 days without acute GvHD after allo-HSCT to the cases of acute GvHD; death without chronic GvHD to lethal cases with chronic GvHD, respectively. Patients alive at the end of the follow-up were censored at this date. Patients who reached D+100 after allo-HSCT were included into the analysis to assess the impact of prophylaxis with TKIs on the risk of chronic GvHD. Patients who presented with chronic GvHD prior to TKIs prophylaxis were excluded from this analysis.

Secondary endpoint concerned assessment of efficacy of TKIs prophylaxis on RFS, in view of the disease- and HSCT-specific factors. To this purpose, multivariate analysis was performed with the use of Cox proportional hazard model. Landmark analysis for day+180, +270, +360 was used to assess the impact of chronic GvHD on RFS. Fisher's exact test and Pearson's Chi-square were used to find difference between two groups of categorial factors. Non-parametric Mann-Whitney U-test was used to compare the quantitative attributes between groups. Statistical analyses were performed with SPSS 26.0 (IBM Corp., Armonk, NY, USA), R programming language version 4.0.5. software packages (R Development Core Team, Vienna, Austria), EZR free statistical environment, version 2.15.2 (R Foundation for Statistical Computing, Vienna, Austria).

Results

Patients and allo-HSCT characteristics

A total of 106 Ph-positive ALL patients with median age of 30 (range 18-59) years were included into the study. The median follow-up time was 40.0 (range 5.0-150.4) months for the patients enrolled who were still alive at the end of the study. According to the current indications for allo-HSCT most of the patients (63 cases, 60%)) were transplanted in CR1; 15 (14%), in CR2; 11 (10%), in ≥CR3 and 17 (16%), in active disease ("salvage" allo-HSCT). There were no significant differences in gender, MRD status, extramedullary disease, BCR-ABL1 type of protein, cytogenetics, TKIs treatment prior to allo-HSCT, year of allo-HSCT, donor’s gender, ABO-combability, busulfan dosage, graft source, GvHD prophylaxis between patients in CR1, and advanced stage of the disease. At the same time, matched/mismatched unrelated donor type (MUD/MMUD) was the most frequent type of donors in all groups (60% vs 26% vs 14%). Busulfan-based conditioning was used in most cases for the both groups (85% vs 10% vs 5%). Median time from allo-HSCT to first relapse was 262 (range 14-1926) days, and 8 (30%) of cases had relapse during 100 days after allo-HSCT. Relapses developed in 42 (40%) of the patients: bone marrow relapse was registered in 34 cases (81%); neuroleukemia, in 3 (7%); extramedullary relapse, in 2 (5%); combined (CNS+bone marrow+other extramedullary) relapse, in 3 patients (7%). Nineteen patients experienced more than 1 relapse. By the end of analysis, 60 patients (57%) were alive, 46 (43%) of the patients died. Noteworthy, relapse was the main cause of death (n=27, 59%). Other causes of death were as follows: infection, 11 cases (24%), GvHD, 6 (13%), toxicity, 1 (2%), unknown reasons, 1 (2%). Other baseline characteristics for these patients and transplant procedure are presented in Table 1.

Table 1. Characteristics of the patients and allo-HSCT

Afanaseva-tab01-01.jpgAfanaseva-tab01-02.jpg

Notes: CR=complete remission, MRD=minimal residual disease, TKIs=tyrosine kinase inhibitors, allo-HSCT=allogeneic hematopoietic stem cell transplantation; MRD=matched related donor, MUD=matched unrelated donor, MMUD=mismatched unrelated donor, PBSC=peripheral blood stem cells, PtCy=posttransplant cyclophosphamide, ATG=Anti-thymocyte globulin, GvHD=graft-versus-host disease, TCR αβ-depletion=T cell receptor alpha/beta-depletion

Survival and relapse rates

At 5 years, the cumulative incidence of relapse (RI) and non-relapse mortality (NRM) were 49.1% (37.74-60.46) and 20.2% (95% CI 11.58-28.82), respectively. The Kaplan-Meier OS estimate at 5 years was 55.0% (95% CI 44.62–65.38), and the estimate of RFS at 5 years was 40.4% (95% CI 30.41-50.39). Median time from allo-HSCT to first relapse was 262.5 (range, 14-1926) days. Five-year RFS values was influenced by status of the disease, i.e., RFS was 52.9% (95% CI 39.58-66.22%) when transplanted in CR1; 18.2% (95% CI 3.31-33.09%), if transplanted in CR≥3, and 0% following allo-HSCT in active disease (p<0.001), as seen from Fig. 1A. Moreover, the disease status was a significant risk factor for NRM: patients in advanced-disease phase experienced higher 2-year NRM rates: 64.7% (95% CI 36.87-92.53) compared to 42.7% (95% CI 9.38-76.02%) in CR3 versus 12.5% (95% CI 4.47-20.53%) in CR1-2 (p=0.001). At the same time, there was no difference in 5-year OS, RFS, NRM and RI when performing allo-HSCT in CR1 or CR2 (p>0.05). Interestingly, 16 of 17 patients who underwent allo-HSCT in active disease died by 14 months after allo-HSCT. Of them, 11 patients died due to the disease progression; 2 patients due to infectious complications; 2 patients, due to severe acute and chronic GvHD; 1 patient, due to toxicity (multiorgan failure). Median time from MRD assessment to allo-HSCT was 16 (range 6-134) days. One should be noted that, despite the fact that MRD-positive status before allo-HSCT did not affect OS, RFS and NRM, the relapse rate was 22.8% higher in MRD-positive group (p=0.03), as shown in Fig. 1B. In univariate cumulative incidence analysis, we have shown that the 5-year RI for the patients who reached 100 days after allo-HSCT, was twice lower in the TKIs prophylaxis group compared with non-prophylaxis group, i.e., 30.08% (95% CI 17. 7-43.5) vs 62.85% (95% CI 44.8-76.5) (Fig. 1C). Univariate analysis for survival and RI of the patients, transplanted in CR are presented in Table 2. Allo-HSCT from haploidentical donors was the factor, which led to significantly worse RFS (p=0.05) and NRM (p=0.01), while there is no difference in other types of donors. Intensity of conditioning regimen (busulfan dose) did not influence the 1-, 2- and 5-year OS, RFS, NRM and RI rates (p>0.05). Simultaneously, exploratory analysis showed that patients after GvHD prophylaxis with posttransplant cyclophosphamide had a significantly higher 5-year OS, RFS and lower NRM and RI likelihood than those treated with other regimens of GvHD prophylaxis (classical, or TCR αβ-depletion). The cumulative incidence frequencies of grades 2-4 acute GvHD at day 100 was 27.57% (95% CI 19.4-36.3%), with the median onset time of 27 (range 7-99) days. The proportion of patients with moderate chronic GvHD was 13 (32.5%), severe chronic GvHD, in 16 cases (40%). Cumulative incidence of NIH-defined chronic GVHD was 41.92% (95% CI 31.7-51.8%), with the median onset time of 199.5 (range, 100 to 1172) days. Experience of chronic GvHD was significantly associated with reduced risk of relapse: 31.4% (95% СI 14.94-47.86%) vs 53.7% (95% CI 35.87-71.53%), p=0.04 in univariate analysis.

Afanaseva-fig01.jpg

Figure 1. A. Relapse-free survival (RFS) according to CR status prior to allo-HSCT; B. Relapse incidence (RI) according to MRD status prior to allo-HSCT; С. RI according to prophylactic TKIs after allo-HSCT

Table 2. Univariate analysis of predictors for OS, RFS, NRM and RI at 5 years after allo-HSCT for CR patients

Afanaseva-tab02.jpg

Treatment with TKIs after allo-HSCT

A total of 80 (75.8%) patients received posttransplant TKIs maintenance therapy used with the prophylactic aim (60 cases, 75%); at the first MRD positivity or molecular relapse post allo-HSCT as pre-emptive treatment (11 cases, 13.8%), or as relapse treatment (9 patients, 11.2%) (Table 3). Median time from allo-HSCT to initiation of prophylactic TKIs was 87 days (range, 19-378). TKI drug was changed in 15 patients, i.e., due to relapse (n=1); due to toxicity/intolerance (n=4) in prophylaxis group; in 5 patients due to relapse (n=3), due to toxicity/intolerance (n=2) in preemptive group, and in 1 patient with disease progression in the relapse treatment group. Frequency of chronic GvHD in the TKIs prophylaxis group was 48.2% vs 21.1% in non-prophylaxis group (p=0.05). Prophylaxis with TKIs was associated with increased risk of chronic GvHD: OR 3.47 (95% CI 1.03-11.84), at relative risk of 2.28 (95% CI 5.71-11.7). We did not find any difference in relapse risk according to the type of prophylactic TKIs (imatinib vs dasatinib, p=0.1).

Table 3. TKIs after allo-HSCT according to the aim of administration

Afanaseva-tab03.jpg

Note: combinations, switch from imatinib to dasatinib (n=2), dasatinib to bosutinib (n=1), imatinib to nilotinib (n=1).

To assess the impact of prophylactic TKIs after allo-HSCT upon RFS rates, we performed multivariate analysis including the factors associated with disease and allo-HSCT procedure. The following independent covariates were used: the year of allo-HSCT (2002-2012 vs. 2013-2021, separated by significant change in clinical practice), donor type, the fact of TKIs prophylaxis after transplant, and MRD status of the disease at transplant (Fig. 2). We performed the analysis using different classifications of donor type and status of the disease. The first one included haploidentical (n=15) vs other donor types (n=91), the second approach concerned matched (n=76) vs other donors (n=30).

In a multivariate analysis of RFS performed to assess the impact of MRD and relapsed/refractory (r/r) disease before allo-HSCT in the context of posttransplant TKIs, the following factors were associated with reduced risk of relapse or death: allo-HSCT after 2012 (HR=0.46, 95%CI 0.26-0.83, p=0.009), any MRD status of the disease before allo-HSCT except active disease with relatively the same HR in the context of the posttransplant TKIs prophylaxis. With another distribution of statuses and TKIs (CR and MRD statuses), we confirmed the data of favorable impact of later year of transplant (HR=0.49, 95%CI 0.27-0.89, p=0.019), and the ability of posttransplant TKIs to reduce negative effect of measurable disease. In addition, allo-HSCT from haploidentical donor increased the risks in both models (HR=2.71, 95% CI 1.20-6.13, p=0,016, and HR=2.49, 95% CI 1.08-5.75, p=0.032, respectively), as seen from Fig. 3. When analyzing RFS with another classification of donor (matched vs others) we confirmed the data about favorable impact of prophylaxis with TKIs, despite the status of the disease prior to allo-HSCT (p<0.001).

Afanaseva-fig02-03.jpg

To assess the effect of chronic GvHD on RFS in the context of TKI therapy after allo-HSCT, a landmark analysis was performed for day+180, +270, +360. By day+ 360, almost all patients with active disease and haploidentical donor have died, and this factor was excluded from the model. The following reasons were identified as the cause of death during first year after allo-HSCT in this group of patients: relapse, 9 patients (50%); acute GvHD grade IV, 3 patients (17%); infectious complications, 5 (28%); toxicity, 1 (5%). There was no impact of chronic GvHD on RFS when performing landmark analysis on day+180 and day+270 as based on available data (HR=0.43, 95% CI 0.13-1.45, p=0.17 and HR=0.5, 95% CI 0.19-1.32, p=0.161, respectively). Moreover, all remaining factors lose their significance on RFS for those patients who survived by day +360 (Fig. 4).

Afanaseva-fig04.jpg

Figure 4. Multivariate analysis of the factors influencing RFS (landmark analysis)

Toxicity of TKIs after allo-HSCT

While being very effective, the TKIs applied after allo-HSCT also have a toxicity profile that is relatively favorable. Among the entire group of patients who received any TKIs after allo-HSCT aimed for prophylaxis, preemptive, or relapse treatment, the TKIs’ dosage was reduced in 24 patients (30%), treatment was discontinued in 4 patients (5%), changed to another TKI type, in 5 patients (6%), temporarily stopped and then re-prescribed in 10 patients (13%), due to intolerance or severe toxicity. In prophylaxis group, the most common side effects were hematological (26%) and gastrointestinal (9%) toxicity. Rare adverse events included fluid retention (5%), fever (5%), skin rash (3%), muscle pain (2%), autoimmune thyroiditis (2%). Four patients had multiple manifestations of toxicity. Toxicity profile in prophylaxis TKIs group according to the TKI type is presented in Table 4.

Table 4. Adverse events in prophylaxis group according to the type of TKI

Afanaseva-tab04.jpg

The presented toxicity profile in the prophylaxis TKIs group is described for the non-standard TKI dosage. In most cases of TKIs dose modifications, the drug dosage was reduced, in order to manage the TKI-related side effects. After allo-HSCT, only about 32% of patients received prophylaxis with imatinib at a full dose of 400-600 mg, whereas 29% of patients were treated at a dose of 200 mg, and 39% of patients received a significantly reduced dose of 100 mg per day. The same situation was with dasatinib: full dose was prescribed to 33% of patients; 70 mg, to 50% of patients, and 35-50 mg, to 17% of patients (Fig. 5).

Afanaseva-fig05.jpg

Figure 5. Doses of prophylactic imatinib (A) and dasatinib (B)

Discussion

MRD-positive status prior to allo-HSCT is a well-known unfavorable risk factor for allo-HSCT outcomes in Ph-positive ALL patients, who did not receive prophylactic TKIs post-transplant [47,48]. Lussana et al. showed that MRD negativity at the time of conditioning was associated with a significant benefit in terms of risk of relapse at 5 years, with a RI of 8% compared with 39% for patients with MRD positivity (p=0.007). However, in this study post-transplantation administration of TKIs alleviated the difference in DFS (58% vs 41%, p=0.17) and OS (58% vs 49%, p=0.55) in MRD-negative and MRD-positive patients, respectively. Nonetheless, TKIs were used not with prophylactic, but with treatment aim in this study [49]. In our retrospective single-center analysis, we also demonstrated that TKIs prophylaxis improves long-term RFS and alleviates the negative impact of MRD on the outcomes in an unfavorable group of Ph-positive ALL adult patients. Previously, the same conclusions were made in several non-randomized studies, however, in extremely small groups of patients. Chen et al. reported superior outcomes for patients who received imatinib as prophylactic or preemptive maintenance regimens after allo- HSCT (n=62) compared with those who did not receive post-transplant TKIs (n=20) (5-year OS, 86.7% vs 34.3%, p <0.001; EFS, 81.5% vs 33.5%, p <0.001) [50]. At the same time, the data of a single randomized trial from the German multicenter study group for adult ALL obtained in 55 patients with Ph-positive ALL who underwent allo-HSCT, were randomly assigned to receive imatinib as prophylaxis or based on MRD positivity. Although prophylactic imatinib prevented molecular recurrence, EFS and OS did not differ significantly between the 2 treatment arms: 5-year OS was 80% in the prophylactic group vs 75% in the preemptive group [38]. Burke et al. compared outcomes for patients who received prophylactic imatinib (for 1 year) with patients who did not receive post-transplant TKIs: OS at 2 years for patients with imatinib (n=2) and without (n=17) were 100% and 41%, respectively, with a corresponding relapse-free survival of 100% and 35% [51]. The data about 2nd generation of TKIs after allo-HSCT are very scarce: dasatinib or nilotinib were studied as maintenance regimen after allo-HSCT in few studies (n=62) [35]: in the study by Czyz et al., 19 patients received dasatinib (treatment duration of 11 months), either prophylactically or preemptively. After a median follow-up of 3 years after allo-HSCT, the OS and LFS were 87% and 88%, respectively. Fourteen of 15 patients (93%) who were MRD positive after transplant converted to MRD negativity and continued to be MRD negative at last follow up. At the same time, there is an important limitation of nilotinib trials: they presented common results for CML and Ph-positive ALL patients, but not separate results for the Ph-positive ALL group, mainly due to small number of enrolled patients.

In our group, most of the patients (57%) received prophylactic TKIs after allo-HSCT. The majority of patients not assigned to prophylaxis and preemptive treatment with TKIs (n=35) was transplanted (n=21) before 2014. The patient group allografted since 2014 (n=11) who reached day+80 after allo-HSCT without TKIs, included patients with severe infectious complications, severe poor graft function, or uncontrolled GvHD. Six of them died from relapse, one patient was lost from infectious complications, two patients are alive without relapse. In two cases, the patients developed relapse and are alive at the last follow up. Thus, we presume that the results might be significantly affected by the time of transplant and status of patients. It is well known that the patients with severe poor graft function tend to have increased risk of NRM, but not relapse [52]. In early studies, TKIs demonstrated superior outcomes, but both prophylactic TKIs group, as well as patients without TKI prophylaxis included only limited number of patients. Authors did not explain the choice of strategy concerning prophylactic TKIs administration in non-randomized trials, but the reasons seem to be comparable across studies. A study by Ribera et al. concerned OS and DFS for 13 of 21 patients who received prophylaxis with imatinib that was only 30% (9-mo follow-up). Transplant- and treatment-related complications and patient selection may have contributed to poor outcomes in this small cohort. Ten of twelve patients had interruptions in treatment for various reasons, including relapse, severe chronic graft-versus-host disease (GVHD), grades 3 to 4 toxicity, non-relapse death, and patient preference [53]. Nishiwaki et al. showed superior outcomes for patients who received imatinib (pre-emptive, n=4; prophylactic, n=3) after allo-HSCT when compared with cases without TKI treatment (n=27). The OS at 1 year with TKIs versus without TKIs was 100% vs 33.3%, and the 2-year OS was 66.7% vs 29.6%, respectively (p=0.03). EFS was not significantly different between the 2 groups at 1 and 2 years (55.6% versus 55.6% and 33.3% versus 29.6%, p=0.29).

Newer TKIs’ generation, such as dasatinib and nilotinib, were shown to be more potent (respectively, 325-fold and 50-100-fold) when compared with imatinib [54]. Whether or not this higher potency plays any role in the context of post-transplant administration remains to be proven. Dasatinib demonstrated similar or better EFS and OS rates compared with imatinib in several trials [30, 33]. Nonetheless, the studies were retrospective and long-term outcomes were not available. Nilotinib also had similar clinical outcomes when compared with imatinib, but the studies on post-transplant nilotinib therapy included mixed group of CML and Ph-positive ALL patients [55, 56]. The numbers of patients in studies using 2nd TKIs generations are small and non-randomized. E.g., Saini et al. aimed to compare the efficacy of new-generation TKIs versus imatinib treatment: 28 patients received imatinib in the TKIs prophylactic group and 33 patients received newer generation TKIs. The relapse rate was similar, with three patients relapsing in each arm. However, in the MRD-triggered group, 6 (75%) out of 8 patients who received imatinib relapsed compared to 6 (45%) out of 11 patients who received new-generation TKI [36]. The newer generation TKIs appear to improve prognosis for these high-risk patients, but these results should be proven in further prospective trials. First and 2nd-generation TKIs were used with the prophylaxis aim in our group of patients. Imatinib was the most commonly used (48%) in the entire group, due to wider availability of the TKI in real clinical practice. At the same time, dasatinib was more frequently used (40%) over recent years, due to its broader activity and ability to penetrate the blood-brain barrier and prevent CNS relapses [54]. Isolated CNS relapse occurs in up to 20% of patients with Ph-positive ALL during imatinib monotherapy [57]. We did not find any difference in relapse risk dependent on the type of prophylactic TKIs (imatinib vs. dasatinib), p=0.1. First of all, we did not compare relapse rates for imatinib and dasatinib subgroups according to the disease status before allo-HSCT. In addition, the lack of difference between imatinib and dasatinib groups of patients may be due to pronounced graft-versus-leukemia (GvL) effect and shift of Ph-positive ALL subclones to less aggressive ones, thus lacking a need for a more active TKI in this case after allo-HSCT. Several studies have shown that BCR-ABL1 kinase mutation is the major cause of relapse in Ph-positive ALL, even after allo-HSCT [58], and newer TKIs generations can potentially overcome some of these mutations and lead to lower relapse rates in patients with resistant disease. However, lack of the data about the mutational status and insufficient patients’ numbers in study does not allow to make definitive conclusions.

There are also studies which did not show positive impact of post-transplant TKIs. E.g., Nishiwaki et al. confirmed that MRD status at allo-HSCT is one of the most important predictive factors for Ph-positive ALL patients transplanted in CR1. Post-transplant TKIs were administered to 103 patients. Surprisingly, post-transplant administration of TKIs was suggested to be a significant adverse prognostic factor for relapse, i.e., OS was significantly better in patients with post-transplant TKI therapy, but there was no significant difference in RFS. As for NRM, it might be underestimated in patients with post-transplant TKI administration because of technical issues for the competing risk analyses: of 103 patients with post-transplant administration, NRM occurred in only 3 patients (3%), whereas relapse was observed in 71 patients (69%). Since a decision to administer TKIs after allo-HSCT was made by each institution in this study, the TKIs might have been prescribed to the patients who were potentially at high risk for relapse [48]. The main difference between the studies is the patients’ enrollment, i.e., we described the patients in various disease status, while Nishiwaki and colleagues included only CR1 patients prior to allo-HSCT, and observed surprisingly high relapse rate without TKIs. In the retrospective study of Kebriaei et al., 102 adults and 11 children were included. TKIs’ use for maintenance (n=32) did not improve the outcomes. Only subgroups of younger patients who achieved CR1 at the time of allo-HSCT, and underwent transplants after 2000, demonstrated better outcomes and improved prognosis. In this study, on the contrary to Nishiwaki et al., the presence of MRD prior to allo-HSCT was not a significant predictor for progression-free survival [31]. Patients observed by Zheng et al. did not show favorable survival outcomes despite maintenance imatinib therapy after allo-HSCT. This result may be, in part, explained by the high proportion (36%) of patients who were not in CR at the time of allo-HSCT in this small cohort (n=11) [59].

Another valuable topic of interest is an influence of chronic GvHD upon RFS and RI. In CIBMTR-led study which recruited a large cohort of adult ALL patients (n=2593), the impact of acute GvHD and chronic GvHD of varying severity on transplant outcomes was explored. The patients with advanced ALL had better OS (reduction in mortality; HR, 0.69-0.73) when they developed chronic GvHD with or without grades I and II acute GvHD, which is explained by an increased GVL effect in ALL [59]. Simultaneously, the results refer to the common group of ALL patients, without any clarification regarding Ph-negative and Ph-positive ALL patients. There are also no conclusions about the GvHD incidence in case of TKIs maintenance after allo-HSCT. In another study (Akahoshi et al.), the association between TKIs prophylaxis and incidence of chronic GvHD was not described: WBC at diagnosis (HR, 1.36; 95% CI 1.10-1.68; p=0.004), unrelated cord blood transplantation (HR, 0.70; 95% CI 0.52-0.95; p=0.022), reduced conditioning intensity (HR, 0.77; 95% CI 0.60‐0.99; p=0.042), and grade II‐IV acute GvHD (HR, 1.36; 95% CI 1.10-1.68; p=0.004) were significantly associated with the incidence of chronic GVHD, while the incidence of chronic GvHD did not show significant association with TKIs prophylaxis (HR, 0.82; 95% CI 0.49-1.35; p=0.428) in the multivariate analysis [34]. In our study, chronic GvHD was significantly associated with reduced risk of relapse in our group: 31.4% (95% СI 14.94-47.86%) vs 53.7% (95% CI 35.87-71.53%), p=0.04 and increased RFS: 60% (95% CI 43.54-76.46) vs 38.4% (95% CI 22.92-53.88), p=0.003 in univariate analysis. At the same time, we were unable to prove a positive impact of chronic GvHD upon the landmark analysis. We realize the fact, that, due to the small groups of patients in our study, we can’t confidentially claim that, in the context of TKIs maintenance, chronic GvHD associated with GvL effect has no influence on clinical outcomes. We understand that a larger group of patients is needed to assess the effect of chronic GvHD upon RFS in the time-dependent manner. It is worth to mention, that TKIs, especially imatinib, being a multikinase inhibitor of several signaling pathways implicated in skin fibrosis, is known as potential option to treat sclerotic steroid refractory GvHD, in view of fibroblast growth inhibition, and decreased collagen production in dermal fibroblasts [60, 61]. However, the incidence of chronic GVHD in our group was even higher in the TKIs prophylaxis group. Among 31 patients who experienced chronic GvHD in the prophylaxis group, 23 (74.2%) of the patients exhibited skin involvement, and 12 of them (52.2%) received prophylaxis with post-transplant imatinib. Only 1 patient died from severe chronic GvHD in each group (imatinib vs other TKIs). In our opinion, not only imatinib, but also improvement of GvHD prophylaxis and treatment over recent years contributes to this low incidence of GvHD-associated mortality [62, 63]. In our study, several patients received other TKIs as a prophylactic component (nilotinib, n=2; bosutinib, n=3). Four of these patients developed chronic GvHD, 3 of them displayed skin involvement. However, clinical data concerning the potential use of 2nd-generation TKIs, which are active against a broader spectrum of kinases, are lacking in patients with chronic GVHD. Nonetheless, in vitro addition of nilotinib to chronic GVHD fibroblast cultures induced a decrease in the expression of both COL1α1 and COL1α2 mRNAs, indicating the antifibrotic potential of this drug [64]. On the other hand, ponatinib, 3rd-generation TKI, is described as a drug, which induces GvHD, suggesting that the efficacy of ponatinib could be related not only to the direct antileukemic effect but also to its ability to promote an indirect GvL effect. Petrungaro et al. have shown an increased number of circulating CD8+ and natural killer T cells, along with reduced numbers of CD4+ T cells observed during ponatinib treatment after allo-HSCT in patient without T315I mutation, which might be correlated with the onset of GVHD and GVL [65].

Conclusion

The study demonstrated positive impact of prophylactic TKIs in adult patients with Ph-positive ALL after allo-HSCT. Prophylactic TKIs can overcome the negative effects of MRD on clinical outcomes. However, in some cases, post-transplant TKIs administration is not possible, mainly because of transplantation-derived complications, rather than drug-specific toxicity. Final safe dose in the majority of patients was lower than recommended, thus dose de-escalation strategy is more justifiable after allo-HSCT. The issue of using first- or second-generation TKIs, as well as optimal duration of therapy should be clarified by the working group consensus.

Conflicts of interest

No conflicts of interest are reported by the authors.

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Афанасьева, Ольга В. Пирогова, Евгений А. Бакин, Анна Г. Смирнова, Елена В. Морозова, Юлия Ю. Власова, Ильдар М. Бархатов, Татьяна Л. Гиндина, Иван С. Моисеев, Сергей Н. Бондаренко</p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(340) "

Ксения С. Афанасьева, Ольга В. Пирогова, Евгений А. Бакин, Анна Г. Смирнова, Елена В. Морозова, Юлия Ю. Власова, Ильдар М. Бархатов, Татьяна Л. Гиндина, Иван С. Моисеев, Сергей Н. Бондаренко

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НИИ детской онкологии, гематологии и трансплантологии им. Р. М. Горбачевой, Первый Санкт-Петербургский государственный медицинский университет им. акад. И. П. Павлова, Санкт-Петербург, Россия

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Роль профилактического назначения ИТК (ингибиторов тирозинкиназ) после аллогенной трансплантации гемопоэтических стволовых клеток (алло-ТГСК) остается не вполне определенной. Мы провели ретроспективный анализ 106 случаев алло-ТГСК у взрослых пациентов, которым трансплантация была выполнена от полностью совместимого родственного донора (26%), полностью или частично совместимого неродственного донора (60%) и гаплоидентичного донора (14%) в первой полной ремиссии (59%), второй полной ремиссии (14%) или в продвинутых стадиях заболевания (27%). Из них 60 пациентам (57%) проводилась профилактика посттрансплантационного рецидива ингибиторами тирозинкиназ 1 или 2 поколения. В многофакторном анализе безрецидивной выживаемости следующие факторы были связаны со снижением риска рецидива или смерти: алло-ТГСК, выполненная после 2012 года (ОР=0,46, 95% ДИ 0,26-0,83, р=0,009), любой статус МОБ перед алло-ТГСК на фоне посттрансплантационной профилактики ИТК. Алло-ТГСК от гаплоидентичного донора повышала риск рецидива или смерти (ОР=2,71, 95% ДИ 1,20-6,13, р=0,016). Нам не удалось продемонстрировать значимость хронической РТПХ при проведении лэндмарк анализа на день+180 и день+270 на имеющихся данных (ОР=0,43, 95% ДИ 0,13–1,45, р=0,17 и ОР=0,5, 95% ДИ 0,19-1,32, р=0,161, соответственно) на фоне профилактической терапии ИТК. Настоящее исследование, проведенное на относительно большой группе взрослых пациентов с Ph-позитивным ОЛЛ, демонстрирует, что ИТК являются важным компонентом профилактики посттрансплантационного рецидива. Для того, чтобы сформулировать строгие клинические рекомендации для данной когорты, необходима большая группа пациентов.

Ключевые слова

Острый лимфобластный лейкоз, Ph-позитивный, BCR-ABL1, ингибиторы тирозинкиназ, аллогенная трансплантация гемопоэтических стволовых клеток, рецидив, минимальная остаточная болезнь, хроническая реакция «трансплантат-против-хозяина».

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Kseniia S. Afanaseva, Olga V. Pirogova, Evgeny A. Bakin, Anna G. Smirnova, Elena V. Morozova, Yulia Yu.Vlasova, Ildar M. Barkhatov, Tatiana L. Gindina, Ivan S. Moiseev, Sergey N. Bondarenko

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RM Gorbacheva Research Institute of Pediatric Oncology, Hematology and Transplantology, Pavlov University, St. Petersburg, Russia


Correspondence:
Dr. Kseniia S. Afanaseva, RM Gorbacheva Research Institute of Pediatric Oncology, Hematology and Transpantology, Pavlov University, 6-8 L.Tolstoy St, 197022, St. Petersburg, Russia
Phone: +7 (921) 185-80-48
E-mail: afanasevaksenya11@gmail.com


Citation: Afanaseva KS, Pirogova OV, Bakin EA et al. Tyrosine kinase inhibitors: prophylaxis after allogeneic hematopoietic stem cell transplantation in adults with Philadelphia chromosome‐positive acute lymphoblastic leukemia. Cell Ther Transplant 2022; 11(3-4): 45-59.

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The role of prophylactic TKIs after allogeneic stem cell transplantation in Ph-positive acute lymphoblastic leukemia (ALL) remains controversial. We performed a retrospective study in 106 adult patients subjected to allogeneic hematopoietic stem cell transplantation (allo-HSCT) from matched related donors (MRD, 26%), matched unrelated donors (MUD/MMUD, 60%), and haploidentical donors (14%) in complete remission (CR1, 59%), CR2 (14%), and advanced disease (27%). Among them, 60 (57%), received 1st- or 2nd-generation TKIs as prophylaxis after allo-HSCT. In multivariate analysis of RFS, the following factors were associated with reduced risk of relapse or death: allo-HSCT after 2012 (HR=0.46, 95%CI 0.26-0.83, p=0.009), any MRD status of the disease before allo-HSCT except active disease with relatively similar HR in the context of post-transplant TKI prophylaxis. Allo-HSCT from haploidentical donor was associated with increased risk of relapse or death (HR=2.71, 95% CI 1.20-6.13 p=0.016). We were unable to demonstrate the significance of chronic GvHD when performing landmark analysis on day+180 and day+270, as based on available data (HR=0.43, 95% CI 0.13-1.45, p=0.17 and HR=0.5, 95% CI 0.19-1.32; p=0.161, respectively), under the conditions of maintaining TKI therapy after allo-HSCT. This relatively large study in unfavorable group of patients confirms an importance of TKIs prophylaxis for adult patients with Ph-positive ALL after allo-HSCT. A larger group of patients is required to formulate strong clinical recommendations in this cohort.

Keywords

Acute lymphoblastic leukemia, Ph-positive, BCR-ABL1, tyrosine kinase inhibitor, allogeneic hematopoietic stem cell transplantation, relapse, minimal residual disease, chronic GvHD.

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Afanaseva, Olga V. Pirogova, Evgeny A. Bakin, Anna G. Smirnova, Elena V. Morozova, Yulia Yu.Vlasova, Ildar M. Barkhatov, Tatiana L. Gindina, Ivan S. Moiseev, Sergey N. Bondarenko</p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(197) "

Kseniia S. Afanaseva, Olga V. Pirogova, Evgeny A. Bakin, Anna G. Smirnova, Elena V. Morozova, Yulia Yu.Vlasova, Ildar M. Barkhatov, Tatiana L. Gindina, Ivan S. Moiseev, Sergey N. Bondarenko

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Kseniia S. Afanaseva, Olga V. Pirogova, Evgeny A. Bakin, Anna G. Smirnova, Elena V. Morozova, Yulia Yu.Vlasova, Ildar M. Barkhatov, Tatiana L. Gindina, Ivan S. Moiseev, Sergey N. Bondarenko

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The role of prophylactic TKIs after allogeneic stem cell transplantation in Ph-positive acute lymphoblastic leukemia (ALL) remains controversial. We performed a retrospective study in 106 adult patients subjected to allogeneic hematopoietic stem cell transplantation (allo-HSCT) from matched related donors (MRD, 26%), matched unrelated donors (MUD/MMUD, 60%), and haploidentical donors (14%) in complete remission (CR1, 59%), CR2 (14%), and advanced disease (27%). Among them, 60 (57%), received 1st- or 2nd-generation TKIs as prophylaxis after allo-HSCT. In multivariate analysis of RFS, the following factors were associated with reduced risk of relapse or death: allo-HSCT after 2012 (HR=0.46, 95%CI 0.26-0.83, p=0.009), any MRD status of the disease before allo-HSCT except active disease with relatively similar HR in the context of post-transplant TKI prophylaxis. Allo-HSCT from haploidentical donor was associated with increased risk of relapse or death (HR=2.71, 95% CI 1.20-6.13 p=0.016). We were unable to demonstrate the significance of chronic GvHD when performing landmark analysis on day+180 and day+270, as based on available data (HR=0.43, 95% CI 0.13-1.45, p=0.17 and HR=0.5, 95% CI 0.19-1.32; p=0.161, respectively), under the conditions of maintaining TKI therapy after allo-HSCT. This relatively large study in unfavorable group of patients confirms an importance of TKIs prophylaxis for adult patients with Ph-positive ALL after allo-HSCT. A larger group of patients is required to formulate strong clinical recommendations in this cohort.

Keywords

Acute lymphoblastic leukemia, Ph-positive, BCR-ABL1, tyrosine kinase inhibitor, allogeneic hematopoietic stem cell transplantation, relapse, minimal residual disease, chronic GvHD.

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The role of prophylactic TKIs after allogeneic stem cell transplantation in Ph-positive acute lymphoblastic leukemia (ALL) remains controversial. We performed a retrospective study in 106 adult patients subjected to allogeneic hematopoietic stem cell transplantation (allo-HSCT) from matched related donors (MRD, 26%), matched unrelated donors (MUD/MMUD, 60%), and haploidentical donors (14%) in complete remission (CR1, 59%), CR2 (14%), and advanced disease (27%). Among them, 60 (57%), received 1st- or 2nd-generation TKIs as prophylaxis after allo-HSCT. In multivariate analysis of RFS, the following factors were associated with reduced risk of relapse or death: allo-HSCT after 2012 (HR=0.46, 95%CI 0.26-0.83, p=0.009), any MRD status of the disease before allo-HSCT except active disease with relatively similar HR in the context of post-transplant TKI prophylaxis. Allo-HSCT from haploidentical donor was associated with increased risk of relapse or death (HR=2.71, 95% CI 1.20-6.13 p=0.016). We were unable to demonstrate the significance of chronic GvHD when performing landmark analysis on day+180 and day+270, as based on available data (HR=0.43, 95% CI 0.13-1.45, p=0.17 and HR=0.5, 95% CI 0.19-1.32; p=0.161, respectively), under the conditions of maintaining TKI therapy after allo-HSCT. This relatively large study in unfavorable group of patients confirms an importance of TKIs prophylaxis for adult patients with Ph-positive ALL after allo-HSCT. A larger group of patients is required to formulate strong clinical recommendations in this cohort.

Keywords

Acute lymphoblastic leukemia, Ph-positive, BCR-ABL1, tyrosine kinase inhibitor, allogeneic hematopoietic stem cell transplantation, relapse, minimal residual disease, chronic GvHD.

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RM Gorbacheva Research Institute of Pediatric Oncology, Hematology and Transplantology, Pavlov University, St. Petersburg, Russia


Correspondence:
Dr. Kseniia S. Afanaseva, RM Gorbacheva Research Institute of Pediatric Oncology, Hematology and Transpantology, Pavlov University, 6-8 L.Tolstoy St, 197022, St. Petersburg, Russia
Phone: +7 (921) 185-80-48
E-mail: afanasevaksenya11@gmail.com


Citation: Afanaseva KS, Pirogova OV, Bakin EA et al. Tyrosine kinase inhibitors: prophylaxis after allogeneic hematopoietic stem cell transplantation in adults with Philadelphia chromosome‐positive acute lymphoblastic leukemia. Cell Ther Transplant 2022; 11(3-4): 45-59.

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RM Gorbacheva Research Institute of Pediatric Oncology, Hematology and Transplantology, Pavlov University, St. Petersburg, Russia


Correspondence:
Dr. Kseniia S. Afanaseva, RM Gorbacheva Research Institute of Pediatric Oncology, Hematology and Transpantology, Pavlov University, 6-8 L.Tolstoy St, 197022, St. Petersburg, Russia
Phone: +7 (921) 185-80-48
E-mail: afanasevaksenya11@gmail.com


Citation: Afanaseva KS, Pirogova OV, Bakin EA et al. Tyrosine kinase inhibitors: prophylaxis after allogeneic hematopoietic stem cell transplantation in adults with Philadelphia chromosome‐positive acute lymphoblastic leukemia. Cell Ther Transplant 2022; 11(3-4): 45-59.

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Ксения С. Афанасьева, Ольга В. Пирогова, Евгений А. Бакин, Анна Г. Смирнова, Елена В. Морозова, Юлия Ю. Власова, Ильдар М. Бархатов, Татьяна Л. Гиндина, Иван С. Моисеев, Сергей Н. Бондаренко

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Нам не удалось продемонстрировать значимость хронической РТПХ при проведении лэндмарк анализа на день+180 и день+270 на имеющихся данных (ОР=0,43, 95% ДИ 0,13–1,45, р=0,17 и ОР=0,5, 95% ДИ 0,19-1,32, р=0,161, соответственно) на фоне профилактической терапии ИТК. Настоящее исследование, проведенное на относительно большой группе взрослых пациентов с Ph-позитивным ОЛЛ, демонстрирует, что ИТК являются важным компонентом профилактики посттрансплантационного рецидива. Для того, чтобы сформулировать строгие клинические рекомендации для данной когорты, необходима большая группа пациентов. </p> <h2>Ключевые слова</h2> <p style="text-align: justify;">Острый лимфобластный лейкоз, Ph-позитивный, BCR-ABL1, ингибиторы тирозинкиназ, аллогенная трансплантация гемопоэтических стволовых клеток, рецидив, минимальная остаточная болезнь, хроническая реакция «трансплантат-против-хозяина».</p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(3458) "

Роль профилактического назначения ИТК (ингибиторов тирозинкиназ) после аллогенной трансплантации гемопоэтических стволовых клеток (алло-ТГСК) остается не вполне определенной. Мы провели ретроспективный анализ 106 случаев алло-ТГСК у взрослых пациентов, которым трансплантация была выполнена от полностью совместимого родственного донора (26%), полностью или частично совместимого неродственного донора (60%) и гаплоидентичного донора (14%) в первой полной ремиссии (59%), второй полной ремиссии (14%) или в продвинутых стадиях заболевания (27%). Из них 60 пациентам (57%) проводилась профилактика посттрансплантационного рецидива ингибиторами тирозинкиназ 1 или 2 поколения. В многофакторном анализе безрецидивной выживаемости следующие факторы были связаны со снижением риска рецидива или смерти: алло-ТГСК, выполненная после 2012 года (ОР=0,46, 95% ДИ 0,26-0,83, р=0,009), любой статус МОБ перед алло-ТГСК на фоне посттрансплантационной профилактики ИТК. Алло-ТГСК от гаплоидентичного донора повышала риск рецидива или смерти (ОР=2,71, 95% ДИ 1,20-6,13, р=0,016). Нам не удалось продемонстрировать значимость хронической РТПХ при проведении лэндмарк анализа на день+180 и день+270 на имеющихся данных (ОР=0,43, 95% ДИ 0,13–1,45, р=0,17 и ОР=0,5, 95% ДИ 0,19-1,32, р=0,161, соответственно) на фоне профилактической терапии ИТК. Настоящее исследование, проведенное на относительно большой группе взрослых пациентов с Ph-позитивным ОЛЛ, демонстрирует, что ИТК являются важным компонентом профилактики посттрансплантационного рецидива. Для того, чтобы сформулировать строгие клинические рекомендации для данной когорты, необходима большая группа пациентов.

Ключевые слова

Острый лимфобластный лейкоз, Ph-позитивный, BCR-ABL1, ингибиторы тирозинкиназ, аллогенная трансплантация гемопоэтических стволовых клеток, рецидив, минимальная остаточная болезнь, хроническая реакция «трансплантат-против-хозяина».

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Роль профилактического назначения ИТК (ингибиторов тирозинкиназ) после аллогенной трансплантации гемопоэтических стволовых клеток (алло-ТГСК) остается не вполне определенной. Мы провели ретроспективный анализ 106 случаев алло-ТГСК у взрослых пациентов, которым трансплантация была выполнена от полностью совместимого родственного донора (26%), полностью или частично совместимого неродственного донора (60%) и гаплоидентичного донора (14%) в первой полной ремиссии (59%), второй полной ремиссии (14%) или в продвинутых стадиях заболевания (27%). Из них 60 пациентам (57%) проводилась профилактика посттрансплантационного рецидива ингибиторами тирозинкиназ 1 или 2 поколения. В многофакторном анализе безрецидивной выживаемости следующие факторы были связаны со снижением риска рецидива или смерти: алло-ТГСК, выполненная после 2012 года (ОР=0,46, 95% ДИ 0,26-0,83, р=0,009), любой статус МОБ перед алло-ТГСК на фоне посттрансплантационной профилактики ИТК. Алло-ТГСК от гаплоидентичного донора повышала риск рецидива или смерти (ОР=2,71, 95% ДИ 1,20-6,13, р=0,016). Нам не удалось продемонстрировать значимость хронической РТПХ при проведении лэндмарк анализа на день+180 и день+270 на имеющихся данных (ОР=0,43, 95% ДИ 0,13–1,45, р=0,17 и ОР=0,5, 95% ДИ 0,19-1,32, р=0,161, соответственно) на фоне профилактической терапии ИТК. Настоящее исследование, проведенное на относительно большой группе взрослых пациентов с Ph-позитивным ОЛЛ, демонстрирует, что ИТК являются важным компонентом профилактики посттрансплантационного рецидива. Для того, чтобы сформулировать строгие клинические рекомендации для данной когорты, необходима большая группа пациентов.

Ключевые слова

Острый лимфобластный лейкоз, Ph-позитивный, BCR-ABL1, ингибиторы тирозинкиназ, аллогенная трансплантация гемопоэтических стволовых клеток, рецидив, минимальная остаточная болезнь, хроническая реакция «трансплантат-против-хозяина».

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НИИ детской онкологии, гематологии и трансплантологии им. Р. М. Горбачевой, Первый Санкт-Петербургский государственный медицинский университет им. акад. И. П. Павлова, Санкт-Петербург, Россия

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НИИ детской онкологии, гематологии и трансплантологии им. Р. М. Горбачевой, Первый Санкт-Петербургский государственный медицинский университет им. акад. И. П. Павлова, Санкт-Петербург, Россия

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Introduction

Allogeneic hemopoietic stem cell transplantation (allo-HSCT) is still the only potentially curative treatment option for most children with high-risk acute leukemia [1, 2, 3] as standard chemotherapy is drastically ineffective in these cases. However, in spite of allo-HSCT being actively used up to this moment, its indications and place in treatment strategy are constantly subject to changes as new targeted drugs and immunotherapy methods enter into clinical practice. The undisputable indications are presence of unfavorable risk factors, relapse development (especially an early one), therapy resistance, and, what’s important, an ability to obtain second or subsequent remission. Patient’s age at diagnosis is still an important factor when actual treatment decision is made. We, therefore, find it important to evaluate its contribution into long-term survival of children and young adults with acute leukemia undergoing allo-HSCT.

Materials and methods

A total of 712 patients with acute leukemia (AL) of different age (median age of 14 years, range 6 months to 29 years) undergoing allo-HSCT in R. M. Gorbacheva research institute clinic in 2000-2019 were included in our retrospective study cohort. The median follow-up is 5-5.4 years. Based on the age at diagnosis all patients were divided into the following four age groups:
• Group 1 (infants): children below the age of 1 year (n=57);
• Group 2 (children): 1 to 10 years (n=248);
• Group 3 (adolescents): 11 to 20 years (n=227);
• Group 4 (young adults): 21 to 29 years (n=180).

Most patients (n=390, 55%) received an allo-HSCT from matched unrelated donor, in 139 (20%) cases a matched related, and in 183 (25%) – a mismatched related (haploidentical) donor was used. The hemopoietic stem cells (HSC) sources were bone marrow (BM) in 399 (56%), and peripheral blood stem cells (PBSC) in 313 (44%) cases. A total of 375 patients were initially diagnosed acute lymphoblastic leukemia (ALL), and 337 – acute myeloblastic leukemia (AML). The age distribution and disease status at allo-HSCT are summarized in Table 1.

Table 1. Diagnoses, cytogenetic aberrations and disease status distribution at the moment of allo-HSCT

Semenova-tab01.jpg

The indications for allo-HSCT in infants with ALL in 1st remission were induction failure (n=5), unfavorable biological factors (KMT2A (11q23)-r), early disease manifestation (in children younger than 6 months) or high initial white blood cells counts (n=6). For children of 1 to 20 years the following: induction failure, minimal residual disease-positive (MRD+) status (n=28), and presence of the following unfavorable cytogenetic or molecular aberrations: KMT2A (11q23)-r (n=15), and Ph+ ALL (valid till 2010; n=4). In young adults the criteria were induction failure or MRD+ status (n=13), KMT2A (11q23)-r (n=7), Ph+ ALL (n=4), or hypodiploidy (n=3).

In patients with AML the indications were induction failure or MRD+ status (n=26), as well as presence of monosomy 7 (n=12), KMT2A (11q23)-r (n=23), t(6;9) (p23;q34,1) (n=4), FLT3 ITD (n=12), inv3/t(3;3) (q21;q26) MECOM(EVI1) (n=7), and М5 (n=30), М6 (n=7), or М7 (n=11) variants according to FAB classification. AML, myelodysplasia-related (AML-MR) (n=18) and secondary AML (n=6) were also viewed as unfavorable factors and indications for allo-HSCT.

Remission was defined as lack of blasts in peripheral blood and <5% blasts in bone marrow as well as absence of extramedullary disease and with recovery of peripheral counts.

Conditioning regimens used were based on different combinations of cytostatics (see Tab. 2). Myeloablative conditioning (MAC) regimens were used in 412 (58%), and reduced intensity conditioning (RIC) in 300 (42%) cases.

Table 2. Conditioning regimens in allo-HSCT

Semenova-tab02.jpg

In 2003-2013 the following indications for RIC regimens were employed:
• "Pretreatment" status seriously affecting patient’s performance score (Karnofsky/Lansky score value of <80%),
• History of severe complications after preceding chemotherapy courses (serious adverse events, grade 3-4 toxicity, infectious complications),
• Verified ongoing infection at the time of allo-HSCT,
• History of autologous HSCT.

Since 2014 the indications for RIC regimens were reviewed and limited to:
• History of severe complications after preceding chemotherapy courses (serious adverse events, grade 3-4 toxicity, infectious complications),
• Verified ongoing infection at the time of allo-HSCT.

Patient cohorts receiving MAC and RIC regimens were comparable by the following characteristics: age (р=0.087), diagnosis (р=0.567), status at allo-HSCT (р=0.721), HSC donor type (р=0.878). The only factor different was performance status evaluated via Karnofsky/Lansky score value. There were 198 (66%) patients with <80% values in RIC cohort, while in MAC recipients these values were only registered in 39 (9%) cases (р=0.021).

Since 2013 post-transplant cyclophosphamide given at 50 mg/kg on days +3 and +4 was used as a backbone for acute graft-versus-host disease (aGVHD) prophylaxis. As a whole, these regimens were used in 447 (63%) patients. Also in 282 case the GVHD prophylaxis was based on pre-transplant antithymocyte/antilymphocyte globulins, and in 3 cases transplant modification by TCR α/β immunomagnetic depletion was used. The basic immunosupression by calceneurin inhibitors was used in most cases with cyclosporine-A based regimen in 242 and tacrolimus-based one in 398 patients.

Statistical analysis was performed with SPSS statistics 20.0 software. Patients alive at the time of analysis were censored at October 1st 2020. Survival data was evaluated by Kaplan-Meier method. Survival comparison was performed using log-rаnk test. The difference was deemed statistically significant in cases when р value was <0.05. (CES B. I. Smirnov).

Results

Cytogenetic markers: age dependence

The cytogenetic aberrations found in ALL and AML patients differed for various age groups (Fig. 1).

Based in prognostic significance of genetic aberrations all patients were divided into 3 groups (see Tab. 3 and Tab. 4).

Semenova-fig01-01.jpg Semenova-fig01-02.jpg

Figure 1. Cytogenetic aberrations rate found in patients with ALL (A) and AML (B) of different age groups. The data was provided by R. M. Gorbacheva research institute cytegenetics lab (headed by T. L. Gindina)

Table 3. Frequency of different cytogenetic and molecular aberrations in different age groups based on their prognostic significance for children with ALL

Semenova-tab03.jpg

Notes: ’– t(9;22) (q34; q11), KMT2A-r, hypodiploidy, iAMP21, t(17;19)(q22;p13) TCF3-HLF, CRLF2-r; ’’ – t(12;21) (p13; q21) ETV6RUNX1, hyperdiploidy; ’’’ – all other aberrations and normal karyotype.

Table 4. Frequency of different cytogenetic and molecular aberrations in different age groups based on their prognostic significance for children with AML

Semenova-tab04.jpg

Notes: ’ – KMT2A-r (except t(9;11) ad t(1;11)), FLT3ITD, t (6;9)(p23;q34), inv3/t(3;3) (q21;q26) MECOM(EVI1), chromosome 7 involvement; ’’ – t(8;21) (q22; q22) RUNX1-RUNX1T1, inv 16(p13;q22) and t(16;16) (p13;q22) CBFB-MYH11; ’’’ – all other aberrations and normal karyotype.

Acute lymphoblastic leukemia

As the disease status at allo-HSCT (presence or absence of remission) is indisputably a major influence at allo-HSCT outcome, all patients were divided into 2 groups: ones receiving allo-HSCT in 1st or 2nd remission (n=203), and patients, in whom allo-HSCT was performed in 3rd to 4th remission or in presence of active disease (n=172).

While analyzing the influence of conditioning regimen (RIC vs. MAC) on outcome of allo-HSCT performed in infants, children or young adults with ALL achieving 1st or 2nd remission prior to allo-HSCT, there was no significant difference in overall survival (OS). The values for RIC and MAC recipients were 100% vs. 75% (р=0.511) in infants, 55% vs. 69% (р=0.263) in children, 47% vs. 46% (р=0.865) in adolescents, and 52% vs. 44% (р=0.547) in young adults, accordingly.

The OS of patients in 1st or 2nd remission was significantly higher in children younger than 1 year (79%) and 1 to 10 years (65%) compared to values of 46% achieved in adolescents (11-20 years) and 47% achieved in adults (21-29 years) (р=0.043 and р=0.050, accordingly).

In patients receiving allo-HSCT outside of 1st or 2nd remission the age also influenced the outcome with OS being 22% in infants (<1 year) and 30% in children (1-10 years), which was significantly better compared to results achieved in adolescents (11-20 years) and young adults (21-29 years), in whom the OS did not exceed 10% and 6%, accordingly (р=0.001) (Fig. 2).

Semenova-fig02.jpg

Figure 2. The overall survival of patients (0.5-29 years) with high-risk ALL based on their age and disease status at allo-HSCT (20 years of follow-up). А: patients in 1st or 2nd remission. B: patients outside of 1st or 2nd remission.

The cytogenetic and molecular factors assessment in different age groups has shown that older age is associated in ALL patients with prevalence of unfavorable and lack of favorable aberrations (р=0.034) (Table 3).

The overall survival of patients with "favorable" genetic aberrations was significantly higher and reached 82% in patients achieving remission at the time of allo-HSCT. On the contrary, the corresponding OS values for patients with "unfavorable" and "neutral" aberrations were only 44% and 45%, accordingly (р=0.002).

The positive influence of "favorable" aberrations presence on OS is evident for each age group with OS being 85% in children aged 1 to 10 years and 73% in adolescents. The rate of these genetic changes is also higher in children aged 1 to 10 years compared to other age cohorts. Unfavorable aberrations show universally bad influence for all age groups with OS being 54% in children 1 to 10 years, 42% in adolescents, and 23% in young adults, accordingly. While neutral aberrations influence on outcomes seemed to be age-dependent (OS of 60% in infants, 49% in children, 35% in adolescents, and 48% in young adults, accordingly), this difference was not statistically significant (р>0.05).

The influence of the disease status on outcome was performed separately for each age group. The overall survival in children younger than 1 year achieving 1st hematological remission prior to allo-HSCT was 82%. For children in 2nd remission, 3rd to 4th remission and relapse it was 75%, 0%, and 33%, accordingly. For children aged 1 to 10 years, adolescents and young adults these values amounted to 93%, 57%, 45% and 16%; 56%, 43%, 11%, and 9%; and 51%, 40%, 0%, and 7%, accordingly.

In patients with ALL aged 1 to 10 years at diagnosis there was a statistically significant difference in OS between groups with different disease status (р<0.001). Also, if allo-HSCT was performed in 1st remission the overall survival was significantly better compared to all other groups including the one consisting of children transplanted in 2nd remission (р=0.030).

In infants (<1 year), adolescents (11-20 years) and young adults (21-29 years) groups the OS also consistently decreased in more advanced disease stages, although there was no significant difference in OS between patients receiving allo-HSCT in 1st and 2nd remission (р=0.353, р=0.219, р=0.357) or between ones transplanted in 3rd to 4th remission or relapse (р=0.779, р=0.650, р=0.390). Therefore, for these age groups allo-HSCT was equally effective when performed during 1st as well 2nd remission being also much better compared to results seen in patients with 3rd to 4th remission or relapse (р<0.001).

This correlation between long-term OS and disease status at HSCT is highly expected for patients with ALL. This factor could, however, be omitted due to significant body of data confirming the negative influence of ALL MRD-positive status on allo-HSCT results [13]. The OS of children in 1st to 2nd remission with present of absent MRD at allo-HSCT was 80% vs. 86% for infants (р=0.539), 74% vs. 61% for children aged 1 to 10 years (р=0.141), and 57% vs. 41% for adolescents (р=0.561), accordingly.

The influence of studied parameters on overall survival is summarized in Table 5.

Table 5. Overall survival based on patient’s age, disease status, cytogenetic prognostic group and MRD presence for children with ALL

Semenova-tab05.jpg

The post allo-HSCT ALL relapse rate in infants, children aged 1 to 10 years and adolescents was very similar in case the 1st or 2nd CR achievement (27%, 35% and 34%, accordingly). In patients transplanted outside of 1st or 2nd remission it was as high as78%, 58%, and 57%, accordingly. The relapse rate as also significantly higher for young adults with any disease status being 55% for patients with and 97% for patients without remission at allo-HSCT (р=0.001). All patients developing a post-transplant relapse received some kind of therapy of varying intensity. Its effectiveness differed based on age group. With a median follow-up of 46 (1-125) months a total of 36% of infants, 24% of children aged 1 to 10 years, 12% of adolescents, and 4% of young adults are alive (р=0.005).

Acute myeloid leukemia

All patients with AML were divided into two groups based on their disease status at allo-HSCT. Group 1 (n=219) consisted of ones receiving allo-HSCT in 1st or 2nd remission, while Group 2 (n=118) included patients with primary resistant disease or resistant relapse.

We evaluated the conditioning regimen intensity (MAC vs. RIC) influence on OS in each AML patient age group, but the analysis performed yielded no significant difference between MAC and RIC recipients. The overall survival of patients with high-risk AML in remission (MAC vs. RIC) was 80% vs. 70% for infants (р=0.737), 60% vs. 52% for children aged 1 to 10 years (p=0.731), 50% vs. 67% for adolescents (р=0.413), and 73% vs. 67% for young adults (р=0.523), accordingly.

The overall survival after allo-HSCT performed in 1st or 2nd remission was 78% for infants, 59% for children aged 1 to 10 years, 59% for adolescents, and 70% for young adults, while in patients transplanted outside of remission these values were as low as 30%, 7%, 11%, and 17%, accordingly.

In spite of OS advantage observed in younger patients with AML, this different was not statistically significant for either Group 1 (р=0.564) or Group 2 (р=0.604) (Fig. 3).

Semenova-fig03.jpg

Figure 3. The overall survival of patients (6 months to 29 years) with high-risk AML based on their age at diagnosis and disease status at allo-HSCT (20 years of follow-up). А: patients in 1st or 2nd remission. B: patients outside of 1st or 2nd remission.

We analyzed the influence of genetic changes on overall survival of patients with AML belonging to different age groups. Unlike ALL cohort, the age distribution of different prognostically significant aberrations in AML patients was relatively even (р=0.546), while young adult group being also characterized by lower "unfavorable" aberrations rate compared to other age cohorts (р=0.002) (Table 4).

The overall survival of patients with "favorable" aberrations was slightly better (86%) compared to ones harboring "unfavorable" (71%) or "neutral" genetic defects (59%), with difference tending to be statistically significant in responders (р=0.060) as well as in ones with resistant disease at the moment of allo-HSCT (р=0.062).

The further statistical analysis has shown disease status to have more important influence on prognosis than genetic changes for all AML patients’ age groups.

The OS of patients in 1st remission, 2nd remission or resistant disease was 80%, 50% and 30% for infants vs. 59%, 52%, and 7% for children aged 1 to 10 years. The OS was not significantly different for children receiving allo-HSCT in 1st or 2nd remission for both these age groups (р=0.231 and р=0.577, accordingly), although the OS of patients transplanted outside of remission was significantly worse (р=0.003 and р<0.001, accordingly). This correlation was also seen in young adults, in whom the OS was 69% if transplanted in 1st and 71% in transplanted in 2nd remission (р=0.888) with corresponding value in patients with resistant disease being as low as 16% (р<0.001). There was a significant difference in OS between all disease stages in adolescents: 74% when transplanted in 1st, 30% in 2nd remission, and 10% in patients with resistant disease (р=0.009 and р<0.001).

The post-transplant relapse rate in patients with AML depended on disease status prior to allo-HSCT and did not differ between age groups. For infants in 1st or 2nd remission relapses were seen in 22% and 50% (р=0.067), in children ages 1 to 10 years in 36% and 62% (р=0.013), in adolescents in 15% and 67% (р=0.001), and in young adults in 11% and 92% of cases (р=0.001), accordingly.

Infant leukemia

We performed a separate outcomes analysis for patients with infant leukemia (n=57) combining both patients with AML (n=33) and ALL (n=24) younger than 1 year at the time of diagnosis. The overall survival of infants with AML or ALL was 64% and 59%, accordingly (р=0.762). It did not differ between children with AML and ALL achieving 1st or 2nd remission prior to allo-HSCT (79% and 80%, accordingly; р=0.924). There was also no difference between survival of MAC and RIC regimens recipients with OS being 79% in prior and 80% in the latter group (р=0.897).

Discussion

For several last decades the survival registered in children with acute leukemia was better compared to one observed in adolescents and young adults. There is a number of researchers advocating for age-related biological factors being the reason [4, 5] as there is an evident tendency to higher risk factors and somatic mutations rate (manifesting as molecular and cytogenetic aberrations) in young adults accompanied by age-related changes in immune response, which may as a whole change disease course to the worse [6, 7, 8]. Some also point at very young (infant) age as a potent adverse prognostic factor [6, 9].

We analyzed in our cohort the influence of age on results of allo-HSCT, which is an important stage for high-risk leukemia patients’ treatment. All patients were diagnosed high-risk leukemia and were divided into infants (<1 year), children (1-10 years), adolescents (11-20 years), and young adults (21-29 years) subcohorts. The data obtained suggests an increase in "unfavorable" genetic changes rate and decrease in one for "favorable" aberrations for overall ALL group, which may explain worse long-term results in older patients.

There is an evidence for more important role of older age in allo-HSCT recipients with ALL compared to ones diagnosed AML, although this relation is not universal and is more pronounced in certain subgroups. Thus, in Group 1 consisting of patients achieving remission prior to allo-HSCT the OS was 79% in infants and 65% in children aged 1 to 10 years, which was significantly better compared to results obtained in adolescents (46%; p=0.043) or young adults (47%; р=0.050).

The overall survival of infants with ALL in 1st remission was 82%, in group of children of 1 to 10 years it reached 93%. There was no difference in OS in children with 1st and 2nd ALL remission prior to allo-HSCT for all age groups except the group of 1 to 10 years, where OS was 93% and 57% (р=0.030), accordingly. The long-term OS in children with infant leukemia was higher compared to historic cohorts receiving no allo-HSCT [10, 11]. Thus, international high-risk infant ALL trial Interfant-06 noted unsatisfactory results in children not receiving allo-HSCT with 6-year OS being only 20.9% [9]. The allo-HSCT may be the factor helping overcome the negative effect of KMT2A rearrangements in this age group.

The analysis of our data was not able to pinpoint a negative influence of MRD positivity for any pediatric subcohort with difference being insignificant in infants (р=0.539), children aged 1 to 10 years (р=0.141), and adolescents (р=0.561). Although this data contradicts the results of some well-organized studies [12], it may be explained by retrospective nature of studied cohort, in which most patients were treated before modern targeted and immunotherapeutic interventions were introduced. Also, constant MRD status monitoring after allo-HSCT allows counterbalancing this factor by timely interventions via prophylactic or preventive immunotherapy (donor lymphocyte infusions, monoclonal antibodies) or targeted therapy in cases with persistent MRD.

Well-timed allo-HSCT scheduling is extremely important for children (younger than 10 years) with adverse prognostic factors. It should, therefore, be provided for as soon as high-risk leukemia is diagnosed. On the other hand, our data suggests equal allo-HSCT effectiveness in adolescents and young adults with ALL when performed in 1st and 2nd remission (р=0.231 and р=0.339, accordingly), while the results in 3rd or 4th remission are as poor as ones obtained in patients with resistant disease (р=0.697 and р=0.390, accordingly).

The overall survival analysis in high-risk AML patients of different age groups uncovered a very different trend as long-term results depended much more on disease status at allo-HSCT, than patient’s age (р=0.564 and р=0.604). This correlation was, however, a bit different for various age groups. The OS achieved in children aged 1 to 10 years and young adults transplanted in 1st remission was not significantly different from patients of the same age cohorts receiving transplant in 2nd remission (р=0.218 and р=0.888, accordingly). On the contrary, in adolescent cohort the transplantation in 1st remission provided much better results, even compared to transplants performed in 2nd remission (р<0.001). Thereof, the patient’s age should be taken into account when allo-HSCT is planned.

Our clinic is actively implementing RIC regimens in patients with high-risk leukemia from all age groups in order to alleviate the cytostatic burden and mitigate long-term negative effects of anticancer treatment. We have been monitoring and comparing the effectiveness of different intensity conditioning regimens for more than 20 years. The first results of allo-HSCT with RIC regimens in children with ALL were published in 2010 [13], but up to this moment there is very few data on RIC regimens effectiveness in adolescent and young adult acute leukemia cohorts [14]. IN this retrospective study we have compared the OS obtained in children of different age groups receiving allo-HSCT with RIC. It is important that there was no statistically significant difference in OS for any of age groups in RIC vs. MAC comparison with 100% vs. 75% (р=0.511) in infants, 55% vs. 69% (р=0.263) in children aged 1 to 10 years, 47% vs. 46% (р=0.865) in adolescents, and 52% vs. 44% (р=0.547) in young adults, accordingly.

The long-term OS in patients receiving allo-HSCT outside of 1st or 2nd remission was 22% for infants and 30% for children aged 1 to 10 years, which was significantly higher than 10% and 6% OS obtained in adolescents and young adults, accordingly (р=0.001). The relapse treatment effectiveness was also different depending on patient’s age with 36% of infants, 24% of children aged 1 to 10 years, 12% of adolescent and only 4% of young adults being able to achieve subsequent remission (р=0.005). In order to further consolidate the remission (based on relapse risk factors present) some of the patients needed preventive/prophylactic interventions. The factors taken into account here may include patient’s age, genetic aberrations, disease and MRD status at the moment of allo-HSCT.

Conclusions

The allo-HSCT improved the survival in patients with high-risk acute leukemia of different age allowing to reach long-term survival values comparable to those seen in standard and intermediate-risk cohorts, in which treatment intensification is not necessary. Allo-HSCT improves the OS in infants with ALL, when additional adverse risk factors are present. It also provides sizable advantage in children with high-risk ALL aged 1 to 10 years when performed in 1st remission. The overall survival of children younger than 10 years with high-risk ALL is better compared to older cohorts, which is probably explained by presence of additional unfavorable genetic aberrations in latter cases. Although MRD status at time of allo-HSCT is an important factor for patients with ALL, it may be mitigated by timely use of post-transplant targeted and immunotherapy. The long-term results in cohorts receiving allo-HSCT with RIC regimens suggest this tactic to be non-inferior compared to more traditional MAC-based approach.

Authors contribution: all authors contributed equally to this manuscript, revised its final version and agreed for the publication.

Funding: all authors received no financial support for this manuscript.

Competing interests

The authors declare that they have no competing interests.

References

  1. Afanasyev B, Afanasyeva KS, Barabanshchikova MV, Bondarenko SN, Bykova TA, Vlasova JY, et al. Indications for hematopoietic stem cell transplantation. Cell Ther Transplant. 2019; 8(4):101-145. doi: 10.18620/ctt-1866-8836-2019-8-4-101-145
  2. Afanasyev BV, Zubarovskaya LS, Moiseev IS. Allogeneic hematopoietic stem cell transplantation in children: present, future, prospective. Russian J Pediatric Hematology/Oncology. 2015; 2(2): 28-42. (In Russian). doi: 10.17650/2311-1267-2015-2-2-28-42
  3. Bondarenko SN, Moiseev IS, Slesarchuk OA, Darskaya EI, Ekushev KA, Smirnova AG, et al. Allogeneic hematopoietic stem cell transplantation in children and adults with acute lymphoblastic leukemia. Cell Ther Transplant. 2016; 5(2): 12-20.
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  4. Gu Z, Churchman ML, Roberts KG, Moore I, Zhou X, Nakitandwe J, et al. PAX5-driven subtypes of B-progenitor acute lymphoblastic leukemia. Nat Genet. 2019;51(2):296-307. doi: 10.1038/s41588-018-0315-5
  5. Paina OV, Semenova EV, Markova IV, Zubarovskaya LS, Afanasyev BV. Modern views on the treatment of acute leukemia in children under 1 year. Russ J Pediatric Hematology/ Oncology. 2019; 6(2):11-19. (In Russian). doi: 10.21682/2311-1267-2019-6-2-11-19
  6. Inaba H, Mullighan CG. Pediatric acute lymphoblastic leukemia. Haematologica. 2020; 1; 105(11):2524-2539. doi: 10.3324/haematol.2020.247031
  7. Roberts KG. Genetics and prognosis of ALL in children vs adults. Hematology Am Soc Hematol Educ Program. 2018; 30;2018(1):137-145. doi: 10.1182/asheducation-2018.1.137
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  9. Pieters R, De Lorenzo P, Ancliffe P, Aversa LA, Brethon B, Biondi A, et al. Outcome of infants younger than 1 year with acute lymphoblastic leukemia treated with the Interfant-06 protocol: Results from an international Phase III randomized study. J Clin Oncol. 2019;37(25):2246-2256. doi: 10.1200/JCO.19.00261
  10. Clesham K, Rao V, Bartram J, Ancliff P, Ghorashian S, O'Connor D , et al. Blinatumomab for infant acute lymphoblastic leukemia. Blood. 2020 23;135(17):1501-1504. doi: 10.1182/blood.2019004008
  11. Brown P, Pieters R, Biondi A. How I treat infant leukemia. Blood. 2019 17;133(3):205-214. doi: 10.1182/blood-2018-04-785980
  12. Health Quality Ontario. Minimal Residual Disease Evaluation in Childhood Acute Lymphoblastic Leukemia: A Clinical Evidence Review. Ont Health Technol Assess Ser. 2016; 16(7):1-52. PMID: 27099643; eCollection 2016.
  13. Verneris MR, Eapen M, Duerst R, Carpenter PA, Burke MJ, Afanasyev BV, et al. Reduced-intensity conditioning regimens for allogeneic transplantation in children with acute lymphoblastic leukemia. Biol Blood Marrow Transplant. 2010;16(9):1237-1244.
    doi: 10.1016/j.bbmt.2010.03.009
  14. Tracey J, Zhang MJ, Thiel E, Sobocinski KA, Eapen M. Transplantation conditioning regimens and outcomes after allogeneic hematopoietic cell transplantation in children and adolescents with acute lymphoblastic leukemia. Biol Blood Marrow Transplant. 2013; 19(2):255-259. doi: 10.1016/j.bbmt.2012.09.019

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Introduction

Allogeneic hemopoietic stem cell transplantation (allo-HSCT) is still the only potentially curative treatment option for most children with high-risk acute leukemia [1, 2, 3] as standard chemotherapy is drastically ineffective in these cases. However, in spite of allo-HSCT being actively used up to this moment, its indications and place in treatment strategy are constantly subject to changes as new targeted drugs and immunotherapy methods enter into clinical practice. The undisputable indications are presence of unfavorable risk factors, relapse development (especially an early one), therapy resistance, and, what’s important, an ability to obtain second or subsequent remission. Patient’s age at diagnosis is still an important factor when actual treatment decision is made. We, therefore, find it important to evaluate its contribution into long-term survival of children and young adults with acute leukemia undergoing allo-HSCT.

Materials and methods

A total of 712 patients with acute leukemia (AL) of different age (median age of 14 years, range 6 months to 29 years) undergoing allo-HSCT in R. M. Gorbacheva research institute clinic in 2000-2019 were included in our retrospective study cohort. The median follow-up is 5-5.4 years. Based on the age at diagnosis all patients were divided into the following four age groups:
• Group 1 (infants): children below the age of 1 year (n=57);
• Group 2 (children): 1 to 10 years (n=248);
• Group 3 (adolescents): 11 to 20 years (n=227);
• Group 4 (young adults): 21 to 29 years (n=180).

Most patients (n=390, 55%) received an allo-HSCT from matched unrelated donor, in 139 (20%) cases a matched related, and in 183 (25%) – a mismatched related (haploidentical) donor was used. The hemopoietic stem cells (HSC) sources were bone marrow (BM) in 399 (56%), and peripheral blood stem cells (PBSC) in 313 (44%) cases. A total of 375 patients were initially diagnosed acute lymphoblastic leukemia (ALL), and 337 – acute myeloblastic leukemia (AML). The age distribution and disease status at allo-HSCT are summarized in Table 1.

Table 1. Diagnoses, cytogenetic aberrations and disease status distribution at the moment of allo-HSCT

Semenova-tab01.jpg

The indications for allo-HSCT in infants with ALL in 1st remission were induction failure (n=5), unfavorable biological factors (KMT2A (11q23)-r), early disease manifestation (in children younger than 6 months) or high initial white blood cells counts (n=6). For children of 1 to 20 years the following: induction failure, minimal residual disease-positive (MRD+) status (n=28), and presence of the following unfavorable cytogenetic or molecular aberrations: KMT2A (11q23)-r (n=15), and Ph+ ALL (valid till 2010; n=4). In young adults the criteria were induction failure or MRD+ status (n=13), KMT2A (11q23)-r (n=7), Ph+ ALL (n=4), or hypodiploidy (n=3).

In patients with AML the indications were induction failure or MRD+ status (n=26), as well as presence of monosomy 7 (n=12), KMT2A (11q23)-r (n=23), t(6;9) (p23;q34,1) (n=4), FLT3 ITD (n=12), inv3/t(3;3) (q21;q26) MECOM(EVI1) (n=7), and М5 (n=30), М6 (n=7), or М7 (n=11) variants according to FAB classification. AML, myelodysplasia-related (AML-MR) (n=18) and secondary AML (n=6) were also viewed as unfavorable factors and indications for allo-HSCT.

Remission was defined as lack of blasts in peripheral blood and <5% blasts in bone marrow as well as absence of extramedullary disease and with recovery of peripheral counts.

Conditioning regimens used were based on different combinations of cytostatics (see Tab. 2). Myeloablative conditioning (MAC) regimens were used in 412 (58%), and reduced intensity conditioning (RIC) in 300 (42%) cases.

Table 2. Conditioning regimens in allo-HSCT

Semenova-tab02.jpg

In 2003-2013 the following indications for RIC regimens were employed:
• "Pretreatment" status seriously affecting patient’s performance score (Karnofsky/Lansky score value of <80%),
• History of severe complications after preceding chemotherapy courses (serious adverse events, grade 3-4 toxicity, infectious complications),
• Verified ongoing infection at the time of allo-HSCT,
• History of autologous HSCT.

Since 2014 the indications for RIC regimens were reviewed and limited to:
• History of severe complications after preceding chemotherapy courses (serious adverse events, grade 3-4 toxicity, infectious complications),
• Verified ongoing infection at the time of allo-HSCT.

Patient cohorts receiving MAC and RIC regimens were comparable by the following characteristics: age (р=0.087), diagnosis (р=0.567), status at allo-HSCT (р=0.721), HSC donor type (р=0.878). The only factor different was performance status evaluated via Karnofsky/Lansky score value. There were 198 (66%) patients with <80% values in RIC cohort, while in MAC recipients these values were only registered in 39 (9%) cases (р=0.021).

Since 2013 post-transplant cyclophosphamide given at 50 mg/kg on days +3 and +4 was used as a backbone for acute graft-versus-host disease (aGVHD) prophylaxis. As a whole, these regimens were used in 447 (63%) patients. Also in 282 case the GVHD prophylaxis was based on pre-transplant antithymocyte/antilymphocyte globulins, and in 3 cases transplant modification by TCR α/β immunomagnetic depletion was used. The basic immunosupression by calceneurin inhibitors was used in most cases with cyclosporine-A based regimen in 242 and tacrolimus-based one in 398 patients.

Statistical analysis was performed with SPSS statistics 20.0 software. Patients alive at the time of analysis were censored at October 1st 2020. Survival data was evaluated by Kaplan-Meier method. Survival comparison was performed using log-rаnk test. The difference was deemed statistically significant in cases when р value was <0.05. (CES B. I. Smirnov).

Results

Cytogenetic markers: age dependence

The cytogenetic aberrations found in ALL and AML patients differed for various age groups (Fig. 1).

Based in prognostic significance of genetic aberrations all patients were divided into 3 groups (see Tab. 3 and Tab. 4).

Semenova-fig01-01.jpg Semenova-fig01-02.jpg

Figure 1. Cytogenetic aberrations rate found in patients with ALL (A) and AML (B) of different age groups. The data was provided by R. M. Gorbacheva research institute cytegenetics lab (headed by T. L. Gindina)

Table 3. Frequency of different cytogenetic and molecular aberrations in different age groups based on their prognostic significance for children with ALL

Semenova-tab03.jpg

Notes: ’– t(9;22) (q34; q11), KMT2A-r, hypodiploidy, iAMP21, t(17;19)(q22;p13) TCF3-HLF, CRLF2-r; ’’ – t(12;21) (p13; q21) ETV6RUNX1, hyperdiploidy; ’’’ – all other aberrations and normal karyotype.

Table 4. Frequency of different cytogenetic and molecular aberrations in different age groups based on their prognostic significance for children with AML

Semenova-tab04.jpg

Notes: ’ – KMT2A-r (except t(9;11) ad t(1;11)), FLT3ITD, t (6;9)(p23;q34), inv3/t(3;3) (q21;q26) MECOM(EVI1), chromosome 7 involvement; ’’ – t(8;21) (q22; q22) RUNX1-RUNX1T1, inv 16(p13;q22) and t(16;16) (p13;q22) CBFB-MYH11; ’’’ – all other aberrations and normal karyotype.

Acute lymphoblastic leukemia

As the disease status at allo-HSCT (presence or absence of remission) is indisputably a major influence at allo-HSCT outcome, all patients were divided into 2 groups: ones receiving allo-HSCT in 1st or 2nd remission (n=203), and patients, in whom allo-HSCT was performed in 3rd to 4th remission or in presence of active disease (n=172).

While analyzing the influence of conditioning regimen (RIC vs. MAC) on outcome of allo-HSCT performed in infants, children or young adults with ALL achieving 1st or 2nd remission prior to allo-HSCT, there was no significant difference in overall survival (OS). The values for RIC and MAC recipients were 100% vs. 75% (р=0.511) in infants, 55% vs. 69% (р=0.263) in children, 47% vs. 46% (р=0.865) in adolescents, and 52% vs. 44% (р=0.547) in young adults, accordingly.

The OS of patients in 1st or 2nd remission was significantly higher in children younger than 1 year (79%) and 1 to 10 years (65%) compared to values of 46% achieved in adolescents (11-20 years) and 47% achieved in adults (21-29 years) (р=0.043 and р=0.050, accordingly).

In patients receiving allo-HSCT outside of 1st or 2nd remission the age also influenced the outcome with OS being 22% in infants (<1 year) and 30% in children (1-10 years), which was significantly better compared to results achieved in adolescents (11-20 years) and young adults (21-29 years), in whom the OS did not exceed 10% and 6%, accordingly (р=0.001) (Fig. 2).

Semenova-fig02.jpg

Figure 2. The overall survival of patients (0.5-29 years) with high-risk ALL based on their age and disease status at allo-HSCT (20 years of follow-up). А: patients in 1st or 2nd remission. B: patients outside of 1st or 2nd remission.

The cytogenetic and molecular factors assessment in different age groups has shown that older age is associated in ALL patients with prevalence of unfavorable and lack of favorable aberrations (р=0.034) (Table 3).

The overall survival of patients with "favorable" genetic aberrations was significantly higher and reached 82% in patients achieving remission at the time of allo-HSCT. On the contrary, the corresponding OS values for patients with "unfavorable" and "neutral" aberrations were only 44% and 45%, accordingly (р=0.002).

The positive influence of "favorable" aberrations presence on OS is evident for each age group with OS being 85% in children aged 1 to 10 years and 73% in adolescents. The rate of these genetic changes is also higher in children aged 1 to 10 years compared to other age cohorts. Unfavorable aberrations show universally bad influence for all age groups with OS being 54% in children 1 to 10 years, 42% in adolescents, and 23% in young adults, accordingly. While neutral aberrations influence on outcomes seemed to be age-dependent (OS of 60% in infants, 49% in children, 35% in adolescents, and 48% in young adults, accordingly), this difference was not statistically significant (р>0.05).

The influence of the disease status on outcome was performed separately for each age group. The overall survival in children younger than 1 year achieving 1st hematological remission prior to allo-HSCT was 82%. For children in 2nd remission, 3rd to 4th remission and relapse it was 75%, 0%, and 33%, accordingly. For children aged 1 to 10 years, adolescents and young adults these values amounted to 93%, 57%, 45% and 16%; 56%, 43%, 11%, and 9%; and 51%, 40%, 0%, and 7%, accordingly.

In patients with ALL aged 1 to 10 years at diagnosis there was a statistically significant difference in OS between groups with different disease status (р<0.001). Also, if allo-HSCT was performed in 1st remission the overall survival was significantly better compared to all other groups including the one consisting of children transplanted in 2nd remission (р=0.030).

In infants (<1 year), adolescents (11-20 years) and young adults (21-29 years) groups the OS also consistently decreased in more advanced disease stages, although there was no significant difference in OS between patients receiving allo-HSCT in 1st and 2nd remission (р=0.353, р=0.219, р=0.357) or between ones transplanted in 3rd to 4th remission or relapse (р=0.779, р=0.650, р=0.390). Therefore, for these age groups allo-HSCT was equally effective when performed during 1st as well 2nd remission being also much better compared to results seen in patients with 3rd to 4th remission or relapse (р<0.001).

This correlation between long-term OS and disease status at HSCT is highly expected for patients with ALL. This factor could, however, be omitted due to significant body of data confirming the negative influence of ALL MRD-positive status on allo-HSCT results [13]. The OS of children in 1st to 2nd remission with present of absent MRD at allo-HSCT was 80% vs. 86% for infants (р=0.539), 74% vs. 61% for children aged 1 to 10 years (р=0.141), and 57% vs. 41% for adolescents (р=0.561), accordingly.

The influence of studied parameters on overall survival is summarized in Table 5.

Table 5. Overall survival based on patient’s age, disease status, cytogenetic prognostic group and MRD presence for children with ALL

Semenova-tab05.jpg

The post allo-HSCT ALL relapse rate in infants, children aged 1 to 10 years and adolescents was very similar in case the 1st or 2nd CR achievement (27%, 35% and 34%, accordingly). In patients transplanted outside of 1st or 2nd remission it was as high as78%, 58%, and 57%, accordingly. The relapse rate as also significantly higher for young adults with any disease status being 55% for patients with and 97% for patients without remission at allo-HSCT (р=0.001). All patients developing a post-transplant relapse received some kind of therapy of varying intensity. Its effectiveness differed based on age group. With a median follow-up of 46 (1-125) months a total of 36% of infants, 24% of children aged 1 to 10 years, 12% of adolescents, and 4% of young adults are alive (р=0.005).

Acute myeloid leukemia

All patients with AML were divided into two groups based on their disease status at allo-HSCT. Group 1 (n=219) consisted of ones receiving allo-HSCT in 1st or 2nd remission, while Group 2 (n=118) included patients with primary resistant disease or resistant relapse.

We evaluated the conditioning regimen intensity (MAC vs. RIC) influence on OS in each AML patient age group, but the analysis performed yielded no significant difference between MAC and RIC recipients. The overall survival of patients with high-risk AML in remission (MAC vs. RIC) was 80% vs. 70% for infants (р=0.737), 60% vs. 52% for children aged 1 to 10 years (p=0.731), 50% vs. 67% for adolescents (р=0.413), and 73% vs. 67% for young adults (р=0.523), accordingly.

The overall survival after allo-HSCT performed in 1st or 2nd remission was 78% for infants, 59% for children aged 1 to 10 years, 59% for adolescents, and 70% for young adults, while in patients transplanted outside of remission these values were as low as 30%, 7%, 11%, and 17%, accordingly.

In spite of OS advantage observed in younger patients with AML, this different was not statistically significant for either Group 1 (р=0.564) or Group 2 (р=0.604) (Fig. 3).

Semenova-fig03.jpg

Figure 3. The overall survival of patients (6 months to 29 years) with high-risk AML based on their age at diagnosis and disease status at allo-HSCT (20 years of follow-up). А: patients in 1st or 2nd remission. B: patients outside of 1st or 2nd remission.

We analyzed the influence of genetic changes on overall survival of patients with AML belonging to different age groups. Unlike ALL cohort, the age distribution of different prognostically significant aberrations in AML patients was relatively even (р=0.546), while young adult group being also characterized by lower "unfavorable" aberrations rate compared to other age cohorts (р=0.002) (Table 4).

The overall survival of patients with "favorable" aberrations was slightly better (86%) compared to ones harboring "unfavorable" (71%) or "neutral" genetic defects (59%), with difference tending to be statistically significant in responders (р=0.060) as well as in ones with resistant disease at the moment of allo-HSCT (р=0.062).

The further statistical analysis has shown disease status to have more important influence on prognosis than genetic changes for all AML patients’ age groups.

The OS of patients in 1st remission, 2nd remission or resistant disease was 80%, 50% and 30% for infants vs. 59%, 52%, and 7% for children aged 1 to 10 years. The OS was not significantly different for children receiving allo-HSCT in 1st or 2nd remission for both these age groups (р=0.231 and р=0.577, accordingly), although the OS of patients transplanted outside of remission was significantly worse (р=0.003 and р<0.001, accordingly). This correlation was also seen in young adults, in whom the OS was 69% if transplanted in 1st and 71% in transplanted in 2nd remission (р=0.888) with corresponding value in patients with resistant disease being as low as 16% (р<0.001). There was a significant difference in OS between all disease stages in adolescents: 74% when transplanted in 1st, 30% in 2nd remission, and 10% in patients with resistant disease (р=0.009 and р<0.001).

The post-transplant relapse rate in patients with AML depended on disease status prior to allo-HSCT and did not differ between age groups. For infants in 1st or 2nd remission relapses were seen in 22% and 50% (р=0.067), in children ages 1 to 10 years in 36% and 62% (р=0.013), in adolescents in 15% and 67% (р=0.001), and in young adults in 11% and 92% of cases (р=0.001), accordingly.

Infant leukemia

We performed a separate outcomes analysis for patients with infant leukemia (n=57) combining both patients with AML (n=33) and ALL (n=24) younger than 1 year at the time of diagnosis. The overall survival of infants with AML or ALL was 64% and 59%, accordingly (р=0.762). It did not differ between children with AML and ALL achieving 1st or 2nd remission prior to allo-HSCT (79% and 80%, accordingly; р=0.924). There was also no difference between survival of MAC and RIC regimens recipients with OS being 79% in prior and 80% in the latter group (р=0.897).

Discussion

For several last decades the survival registered in children with acute leukemia was better compared to one observed in adolescents and young adults. There is a number of researchers advocating for age-related biological factors being the reason [4, 5] as there is an evident tendency to higher risk factors and somatic mutations rate (manifesting as molecular and cytogenetic aberrations) in young adults accompanied by age-related changes in immune response, which may as a whole change disease course to the worse [6, 7, 8]. Some also point at very young (infant) age as a potent adverse prognostic factor [6, 9].

We analyzed in our cohort the influence of age on results of allo-HSCT, which is an important stage for high-risk leukemia patients’ treatment. All patients were diagnosed high-risk leukemia and were divided into infants (<1 year), children (1-10 years), adolescents (11-20 years), and young adults (21-29 years) subcohorts. The data obtained suggests an increase in "unfavorable" genetic changes rate and decrease in one for "favorable" aberrations for overall ALL group, which may explain worse long-term results in older patients.

There is an evidence for more important role of older age in allo-HSCT recipients with ALL compared to ones diagnosed AML, although this relation is not universal and is more pronounced in certain subgroups. Thus, in Group 1 consisting of patients achieving remission prior to allo-HSCT the OS was 79% in infants and 65% in children aged 1 to 10 years, which was significantly better compared to results obtained in adolescents (46%; p=0.043) or young adults (47%; р=0.050).

The overall survival of infants with ALL in 1st remission was 82%, in group of children of 1 to 10 years it reached 93%. There was no difference in OS in children with 1st and 2nd ALL remission prior to allo-HSCT for all age groups except the group of 1 to 10 years, where OS was 93% and 57% (р=0.030), accordingly. The long-term OS in children with infant leukemia was higher compared to historic cohorts receiving no allo-HSCT [10, 11]. Thus, international high-risk infant ALL trial Interfant-06 noted unsatisfactory results in children not receiving allo-HSCT with 6-year OS being only 20.9% [9]. The allo-HSCT may be the factor helping overcome the negative effect of KMT2A rearrangements in this age group.

The analysis of our data was not able to pinpoint a negative influence of MRD positivity for any pediatric subcohort with difference being insignificant in infants (р=0.539), children aged 1 to 10 years (р=0.141), and adolescents (р=0.561). Although this data contradicts the results of some well-organized studies [12], it may be explained by retrospective nature of studied cohort, in which most patients were treated before modern targeted and immunotherapeutic interventions were introduced. Also, constant MRD status monitoring after allo-HSCT allows counterbalancing this factor by timely interventions via prophylactic or preventive immunotherapy (donor lymphocyte infusions, monoclonal antibodies) or targeted therapy in cases with persistent MRD.

Well-timed allo-HSCT scheduling is extremely important for children (younger than 10 years) with adverse prognostic factors. It should, therefore, be provided for as soon as high-risk leukemia is diagnosed. On the other hand, our data suggests equal allo-HSCT effectiveness in adolescents and young adults with ALL when performed in 1st and 2nd remission (р=0.231 and р=0.339, accordingly), while the results in 3rd or 4th remission are as poor as ones obtained in patients with resistant disease (р=0.697 and р=0.390, accordingly).

The overall survival analysis in high-risk AML patients of different age groups uncovered a very different trend as long-term results depended much more on disease status at allo-HSCT, than patient’s age (р=0.564 and р=0.604). This correlation was, however, a bit different for various age groups. The OS achieved in children aged 1 to 10 years and young adults transplanted in 1st remission was not significantly different from patients of the same age cohorts receiving transplant in 2nd remission (р=0.218 and р=0.888, accordingly). On the contrary, in adolescent cohort the transplantation in 1st remission provided much better results, even compared to transplants performed in 2nd remission (р<0.001). Thereof, the patient’s age should be taken into account when allo-HSCT is planned.

Our clinic is actively implementing RIC regimens in patients with high-risk leukemia from all age groups in order to alleviate the cytostatic burden and mitigate long-term negative effects of anticancer treatment. We have been monitoring and comparing the effectiveness of different intensity conditioning regimens for more than 20 years. The first results of allo-HSCT with RIC regimens in children with ALL were published in 2010 [13], but up to this moment there is very few data on RIC regimens effectiveness in adolescent and young adult acute leukemia cohorts [14]. IN this retrospective study we have compared the OS obtained in children of different age groups receiving allo-HSCT with RIC. It is important that there was no statistically significant difference in OS for any of age groups in RIC vs. MAC comparison with 100% vs. 75% (р=0.511) in infants, 55% vs. 69% (р=0.263) in children aged 1 to 10 years, 47% vs. 46% (р=0.865) in adolescents, and 52% vs. 44% (р=0.547) in young adults, accordingly.

The long-term OS in patients receiving allo-HSCT outside of 1st or 2nd remission was 22% for infants and 30% for children aged 1 to 10 years, which was significantly higher than 10% and 6% OS obtained in adolescents and young adults, accordingly (р=0.001). The relapse treatment effectiveness was also different depending on patient’s age with 36% of infants, 24% of children aged 1 to 10 years, 12% of adolescent and only 4% of young adults being able to achieve subsequent remission (р=0.005). In order to further consolidate the remission (based on relapse risk factors present) some of the patients needed preventive/prophylactic interventions. The factors taken into account here may include patient’s age, genetic aberrations, disease and MRD status at the moment of allo-HSCT.

Conclusions

The allo-HSCT improved the survival in patients with high-risk acute leukemia of different age allowing to reach long-term survival values comparable to those seen in standard and intermediate-risk cohorts, in which treatment intensification is not necessary. Allo-HSCT improves the OS in infants with ALL, when additional adverse risk factors are present. It also provides sizable advantage in children with high-risk ALL aged 1 to 10 years when performed in 1st remission. The overall survival of children younger than 10 years with high-risk ALL is better compared to older cohorts, which is probably explained by presence of additional unfavorable genetic aberrations in latter cases. Although MRD status at time of allo-HSCT is an important factor for patients with ALL, it may be mitigated by timely use of post-transplant targeted and immunotherapy. The long-term results in cohorts receiving allo-HSCT with RIC regimens suggest this tactic to be non-inferior compared to more traditional MAC-based approach.

Authors contribution: all authors contributed equally to this manuscript, revised its final version and agreed for the publication.

Funding: all authors received no financial support for this manuscript.

Competing interests

The authors declare that they have no competing interests.

References

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string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "29514" ["VALUE"]=> array(2) { ["TEXT"]=> string(1143) "<p>Елена В. Семенова<sup>1</sup>, Олеся И. Паина<sup>1</sup>, Полина В. Кожокарь<sup>1</sup>, Ольга А. Слесарчук<sup>1</sup>, Анастасия С. Боровкова<sup>1</sup>, Анастасия С. Фролова<sup>1</sup>, Жемал З. Рахманова<sup>1</sup>, Aнна A. Осипова<sup>1</sup>, Любовь А. Цветкова<sup>1</sup>, Светлана В. Разумова<sup>1</sup>, Татьяна А. Быкова<sup>1</sup>, Сергей Н. Бондаренко<sup>1</sup>, Mария В. Латыпова<sup>1</sup>, Tатьяна Л. Гиндина<sup>1</sup>, Елена В. Бабенко<sup>1</sup>, Александр Л. Алянский<sup>1</sup>, Ильдар М. Бархатов<sup>1</sup>, Борис И. Смирнов<sup>2</sup>, Людмила С. Зубаровская<sup>1</sup></p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(903) "

Елена В. Семенова1, Олеся И. Паина1, Полина В. Кожокарь1, Ольга А. Слесарчук1, Анастасия С. Боровкова1, Анастасия С. Фролова1, Жемал З. Рахманова1, Aнна A. Осипова1, Любовь А. Цветкова1, Светлана В. Разумова1, Татьяна А. Быкова1, Сергей Н. Бондаренко1, Mария В. Латыпова1, Tатьяна Л. Гиндина1, Елена В. Бабенко1, Александр Л. Алянский1, Ильдар М. Бархатов1, Борис И. Смирнов2, Людмила С. Зубаровская1

" ["TYPE"]=> string(4) "HTML" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(12) "Авторы" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } } ["ORGANIZATION_RU"]=> array(36) { ["ID"]=> string(2) "26" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:01:20" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(22) "Организации" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(15) "ORGANIZATION_RU" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "26" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "29515" ["VALUE"]=> array(2) { ["TEXT"]=> string(669) "<p><sup>1</sup> НИИ детской онкологии, гематологии и трансплантологии им. Р. М. Горбачевой, Первый Санкт-Петербургский государственный медицинский университет им. акад. И. П. Павлова, Санкт-Петербург, Россия<br> <sup>2</sup> Санкт-Петербургский государственный электротехнический университет «ЛЭТИ» им. В. И. Ульянова (Ленина), Санкт-Петербург, Россия</p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(627) "

1 НИИ детской онкологии, гематологии и трансплантологии им. Р. М. Горбачевой, Первый Санкт-Петербургский государственный медицинский университет им. акад. И. П. Павлова, Санкт-Петербург, Россия
2 Санкт-Петербургский государственный электротехнический университет «ЛЭТИ» им. В. И. Ульянова (Ленина), Санкт-Петербург, Россия

" ["TYPE"]=> string(4) "HTML" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(22) "Организации" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } } ["SUMMARY_RU"]=> array(36) { ["ID"]=> string(2) "27" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:01:20" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(29) "Описание/Резюме" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(10) "SUMMARY_RU" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "27" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "29516" ["VALUE"]=> array(2) { ["TEXT"]=> string(1949) "<p style="text-align: justify;">Целью нашей работы был анализ влияния возраста на общую выживаемость (ОВ) пациентов с острыми лейкозами (ОЛ) после аллогенной трансплантации гемопоэтических клеток (алло-ТГСК).</p> <h3>Материалы и методы</h3> <p style="text-align: justify;">В исследование включены данные 712 пациентов с ОЛ (от 0,5 до 29 лет), которым была выполнена алло-ТГСК в клинике НИИ ДОГиТ им. Р. М. Горбачевой с 2000 г. по 2019 г.</p> <h3>Результаты</h3> <p style="text-align: justify;">ОВ детей с ОЛЛ (1 или 2 рем) до года и от 1 до 10 лет составила 79% и 65%, эти показатели были выше в сравнении с ОВ подростков (11-20 лет) – 46% и молодых взрослых (21-29 лет) – 47% (р=0,039). ОВ младенцев с ОМЛ (1 или 2 рем) – 78%, детей – 59%, подростков – 59%, молодых взрослых – 70% (р=0,564).</p> <h3>Заключение</h3> <p style="text-align: justify;">Возраст оказывает значимое влияние на ОВ после алло-ТГСК у пациентов с ОЛЛ и в меньшей степени у больных с ОМЛ. </p> <h2>Ключевые слова</h2> <p style="text-align: justify;">Острые лейкозы, аллогенная трансплантация гемопоэтических стволовых клеток крови, возрастные группы.</p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(1791) "

Целью нашей работы был анализ влияния возраста на общую выживаемость (ОВ) пациентов с острыми лейкозами (ОЛ) после аллогенной трансплантации гемопоэтических клеток (алло-ТГСК).

Материалы и методы

В исследование включены данные 712 пациентов с ОЛ (от 0,5 до 29 лет), которым была выполнена алло-ТГСК в клинике НИИ ДОГиТ им. Р. М. Горбачевой с 2000 г. по 2019 г.

Результаты

ОВ детей с ОЛЛ (1 или 2 рем) до года и от 1 до 10 лет составила 79% и 65%, эти показатели были выше в сравнении с ОВ подростков (11-20 лет) – 46% и молодых взрослых (21-29 лет) – 47% (р=0,039). ОВ младенцев с ОМЛ (1 или 2 рем) – 78%, детей – 59%, подростков – 59%, молодых взрослых – 70% (р=0,564).

Заключение

Возраст оказывает значимое влияние на ОВ после алло-ТГСК у пациентов с ОЛЛ и в меньшей степени у больных с ОМЛ.

Ключевые слова

Острые лейкозы, аллогенная трансплантация гемопоэтических стволовых клеток крови, возрастные группы.

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Elena V. Semenova1, Olesya V. Paina1, Polina V. Kozhokar1, Olga A. Slesarchuk1, Anastasia S. Borovkova1, Anastasia S. Frolova1, Zhemal Z. Rakhmanova1, Anna A. Osipova1, Liubov A. Tsvetkova1, Svetlana V. Razumova1, Tatyana A. Bykova1, Sergey N. Bondarenko1, Maria V. Latypova1, Tatyana L. Gindina1, Elena V. Babenko1, Alexander L. Alyanskiy1, Ildar M. Barkhatov1, Boris I. Smirnov2, Ludmila S. Zubarovskaya1

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1 RM Gorbacheva Research Institute of Pediatric Oncology, Hematology and Transplantology, Pavlov University, St. Petersburg, Russia
2 St. Petersburg State Electrotechnical University "LETI", St. Petersburg, Russia


Correspondence:
Prof. Elena V. Semenova, RM Gorbacheva Research Institute of Pediatric Oncology, Hematology and Transplantology, Pavlov University, 6-8 L Tolstoy St, 197022, St. Petersburg, Russia
Phone: +7 (921) 420-46-22
E-mail: alena-semenova@yandex.ru


Citation: Semenova EV, Paina OV, Kozokhar PV, et al. Results of allogeneic hemopoietic stem cell transplantation in patients with acute leukemia for different age groups. Cell Ther Transplant 2022; 11(3-4): 36-44.

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To analyze the effect of age on the overall survival (OS) of patients with acute leukemia (AL) after allogeneic hematopoietic cell transplantation (allo-HSCT).

Materials

The data of 712 patients with AL (from 0.5 to 29 years old) who underwent allo-HSCT at the R. M. Gorbacheva Research Institute from 2000 to 2019 y.

Results

The OS of children with ALL under one year and from 1 to 10 years was 79% and 65%, these indicators were higher in comparison with the OS of adolescents (11-20 years) – 46% and young adults (21-29 years) – 47% (p=0.039). OS of infants with AML – 78%, children – 59%, adolescents – 59%, young adults – 70% (p=0.564).

Conclusion

Age has a significant effect on OS after allo-HSCT in patients with ALL and to a lesser extent in patients with AML.

Keywords

Acute leukemia, allogeneic hematopoietic stem cell transplantation, age groups.

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Elena V. Semenova1, Olesya V. Paina1, Polina V. Kozhokar1, Olga A. Slesarchuk1, Anastasia S. Borovkova1, Anastasia S. Frolova1, Zhemal Z. Rakhmanova1, Anna A. Osipova1, Liubov A. Tsvetkova1, Svetlana V. Razumova1, Tatyana A. Bykova1, Sergey N. Bondarenko1, Maria V. Latypova1, Tatyana L. Gindina1, Elena V. Babenko1, Alexander L. Alyanskiy1, Ildar M. Barkhatov1, Boris I. Smirnov2, Ludmila S. Zubarovskaya1

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To analyze the effect of age on the overall survival (OS) of patients with acute leukemia (AL) after allogeneic hematopoietic cell transplantation (allo-HSCT).

Materials

The data of 712 patients with AL (from 0.5 to 29 years old) who underwent allo-HSCT at the R. M. Gorbacheva Research Institute from 2000 to 2019 y.

Results

The OS of children with ALL under one year and from 1 to 10 years was 79% and 65%, these indicators were higher in comparison with the OS of adolescents (11-20 years) – 46% and young adults (21-29 years) – 47% (p=0.039). OS of infants with AML – 78%, children – 59%, adolescents – 59%, young adults – 70% (p=0.564).

Conclusion

Age has a significant effect on OS after allo-HSCT in patients with ALL and to a lesser extent in patients with AML.

Keywords

Acute leukemia, allogeneic hematopoietic stem cell transplantation, age groups.

" ["TYPE"]=> string(4) "HTML" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(21) "Description / Summary" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["DISPLAY_VALUE"]=> string(1094) "

To analyze the effect of age on the overall survival (OS) of patients with acute leukemia (AL) after allogeneic hematopoietic cell transplantation (allo-HSCT).

Materials

The data of 712 patients with AL (from 0.5 to 29 years old) who underwent allo-HSCT at the R. M. Gorbacheva Research Institute from 2000 to 2019 y.

Results

The OS of children with ALL under one year and from 1 to 10 years was 79% and 65%, these indicators were higher in comparison with the OS of adolescents (11-20 years) – 46% and young adults (21-29 years) – 47% (p=0.039). OS of infants with AML – 78%, children – 59%, adolescents – 59%, young adults – 70% (p=0.564).

Conclusion

Age has a significant effect on OS after allo-HSCT in patients with ALL and to a lesser extent in patients with AML.

Keywords

Acute leukemia, allogeneic hematopoietic stem cell transplantation, age groups.

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1 RM Gorbacheva Research Institute of Pediatric Oncology, Hematology and Transplantology, Pavlov University, St. Petersburg, Russia
2 St. Petersburg State Electrotechnical University "LETI", St. Petersburg, Russia


Correspondence:
Prof. Elena V. Semenova, RM Gorbacheva Research Institute of Pediatric Oncology, Hematology and Transplantology, Pavlov University, 6-8 L Tolstoy St, 197022, St. Petersburg, Russia
Phone: +7 (921) 420-46-22
E-mail: alena-semenova@yandex.ru


Citation: Semenova EV, Paina OV, Kozokhar PV, et al. Results of allogeneic hemopoietic stem cell transplantation in patients with acute leukemia for different age groups. Cell Ther Transplant 2022; 11(3-4): 36-44.

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1 RM Gorbacheva Research Institute of Pediatric Oncology, Hematology and Transplantology, Pavlov University, St. Petersburg, Russia
2 St. Petersburg State Electrotechnical University "LETI", St. Petersburg, Russia


Correspondence:
Prof. Elena V. Semenova, RM Gorbacheva Research Institute of Pediatric Oncology, Hematology and Transplantology, Pavlov University, 6-8 L Tolstoy St, 197022, St. Petersburg, Russia
Phone: +7 (921) 420-46-22
E-mail: alena-semenova@yandex.ru


Citation: Semenova EV, Paina OV, Kozokhar PV, et al. Results of allogeneic hemopoietic stem cell transplantation in patients with acute leukemia for different age groups. Cell Ther Transplant 2022; 11(3-4): 36-44.

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Елена В. Семенова1, Олеся И. Паина1, Полина В. Кожокарь1, Ольга А. Слесарчук1, Анастасия С. Боровкова1, Анастасия С. Фролова1, Жемал З. Рахманова1, Aнна A. Осипова1, Любовь А. Цветкова1, Светлана В. Разумова1, Татьяна А. Быкова1, Сергей Н. Бондаренко1, Mария В. Латыпова1, Tатьяна Л. Гиндина1, Елена В. Бабенко1, Александр Л. Алянский1, Ильдар М. Бархатов1, Борис И. Смирнов2, Людмила С. Зубаровская1

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Елена В. Семенова1, Олеся И. Паина1, Полина В. Кожокарь1, Ольга А. Слесарчук1, Анастасия С. Боровкова1, Анастасия С. Фролова1, Жемал З. Рахманова1, Aнна A. Осипова1, Любовь А. Цветкова1, Светлана В. Разумова1, Татьяна А. Быкова1, Сергей Н. Бондаренко1, Mария В. Латыпова1, Tатьяна Л. Гиндина1, Елена В. Бабенко1, Александр Л. Алянский1, Ильдар М. Бархатов1, Борис И. Смирнов2, Людмила С. Зубаровская1

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Целью нашей работы был анализ влияния возраста на общую выживаемость (ОВ) пациентов с острыми лейкозами (ОЛ) после аллогенной трансплантации гемопоэтических клеток (алло-ТГСК).

Материалы и методы

В исследование включены данные 712 пациентов с ОЛ (от 0,5 до 29 лет), которым была выполнена алло-ТГСК в клинике НИИ ДОГиТ им. Р. М. Горбачевой с 2000 г. по 2019 г.

Результаты

ОВ детей с ОЛЛ (1 или 2 рем) до года и от 1 до 10 лет составила 79% и 65%, эти показатели были выше в сравнении с ОВ подростков (11-20 лет) – 46% и молодых взрослых (21-29 лет) – 47% (р=0,039). ОВ младенцев с ОМЛ (1 или 2 рем) – 78%, детей – 59%, подростков – 59%, молодых взрослых – 70% (р=0,564).

Заключение

Возраст оказывает значимое влияние на ОВ после алло-ТГСК у пациентов с ОЛЛ и в меньшей степени у больных с ОМЛ.

Ключевые слова

Острые лейкозы, аллогенная трансплантация гемопоэтических стволовых клеток крови, возрастные группы.

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Целью нашей работы был анализ влияния возраста на общую выживаемость (ОВ) пациентов с острыми лейкозами (ОЛ) после аллогенной трансплантации гемопоэтических клеток (алло-ТГСК).

Материалы и методы

В исследование включены данные 712 пациентов с ОЛ (от 0,5 до 29 лет), которым была выполнена алло-ТГСК в клинике НИИ ДОГиТ им. Р. М. Горбачевой с 2000 г. по 2019 г.

Результаты

ОВ детей с ОЛЛ (1 или 2 рем) до года и от 1 до 10 лет составила 79% и 65%, эти показатели были выше в сравнении с ОВ подростков (11-20 лет) – 46% и молодых взрослых (21-29 лет) – 47% (р=0,039). ОВ младенцев с ОМЛ (1 или 2 рем) – 78%, детей – 59%, подростков – 59%, молодых взрослых – 70% (р=0,564).

Заключение

Возраст оказывает значимое влияние на ОВ после алло-ТГСК у пациентов с ОЛЛ и в меньшей степени у больных с ОМЛ.

Ключевые слова

Острые лейкозы, аллогенная трансплантация гемопоэтических стволовых клеток крови, возрастные группы.

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2 Санкт-Петербургский государственный электротехнический университет «ЛЭТИ» им. В. И. Ульянова (Ленина), Санкт-Петербург, Россия

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2 Санкт-Петербургский государственный электротехнический университет «ЛЭТИ» им. В. И. Ульянова (Ленина), Санкт-Петербург, Россия

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Introduction

Acute lymphoblastic leukemia (ALL) is one of the most common malignant diseases in children. Despite the fact that overall survival rate in pediatric ALL reaches 90%, unfortunately, 10-15% of patients develop relapses after achieving first clinical and hematological remission [1]. Prior to the advent of immunotherapy, the only treatment for relapsing and refractory ALL was a more intensive second-line chemotherapy which usually included alternating blocks of high-dose chemotherapy, followed by allogeneic bone marrow or hematopoietic stem cell transplantation (allo-HSCT). However, this therapy increased the degree of toxicity and contributed to development of complications, with mortality of up to lethal in 10-15% of cases [2]. Moreover, it is necessary to achieve MRD-negative status prior to HSCT procedure. This task may represent a difficult challenge [3]. The success of allo-HSCT in pediatric ALL depends on the level of minimal residual disease (MRD) before transplantation. At the present time, all therapeutic options are aimed at achieving clinical and hematological remission and reducing the MRD level [4].

MRD-negative status in relapses and refractory forms of ALL may be achieved by usage of targeted drugs, e.g., bispecific antibodies BiTE (AT), which may activate effector T-cells providing antitumor effect [5]. Blinatumomab is a bispecific anti-СD19/CD3 antibody, consisting of 2 single-chain variable fragments (scFv), specific for to CD19 (B-lymphocyte marker) and epsilon chains of CD3+ T-lymphocytes [6]. The mechanism of the drug action is to "redirect" effector functions of the patient’s own T-lymphocytes to the target cells that carry CD19 including blast cells in B-ALL patients. Given the opportunity of such "redirection" at the time of blinatumomab administration, a mediated cytolytic effect is induced (with subsequent activation and proliferation of T cells) towards the CD19-expressing cells. Of note, the anti-CD19-scFv has a higher affinity than the anti-CD3 fragment, which may cast doubt on the drug efficiency at low levels of CD3 cells in the patient's peripheral blood [7], as seen in Fig. 1.

Stepanyan-fig01.jpg

Figure 1. The mechanism of action of blinatumomab (bispecific BiTE molecule consisting of 2-single-chain variable fragments (scFv) specific for the CD19 and CD3 epsilon chain. The main mechanism involves recruitment of the own T-cells and redirecting their effector functions into target cells carrying the CD19 marker, which include B-lineage blast cells [8]

The advantage of blinatumomab is independence of this effect on the specificity of T-cell receptors (TCR), or presence of class 1 MHC molecules on the surface of antigen-presenting cells. T-cell activation increases the secretion of cytokines, especially IL-2, IFN-y, TNF-a, IL-4, IL-6, and IL-10. Moreover, at the moment of T-lymphocyte activation, granzyme B and perforin are released, which penetrate into CD19-positive tumor cells and activate apoptosis [9].

Taking into account the mechanism of action of the drug, one may assume that, during the period of immunotherapy, additional transfusions of autolymphocytes may increase the number of lymphocytes, thus promoting favorable effect of the drug and enhance its effectiveness. The transfusions should be performed at 7-day intervals, to maintain a stable concentration of CD3+cells in peripheral blood [10].

Despite the lack of convincing data on the correlation between the absolute levels of peripheral lymphocytes, especially, CD3+ cells, before starting the immunotherapy and transfusions of auto-lymphocytes may be reasonable, especially in severe aplasia of hematopoiesis [11].

Materials and methods

Transfusions of autologous CD3+ lymphocytes were performed in three patients with recurrent ALL who underwent immunotherapy with blinatumomab from July 2021 to February 2022 at the Research Institute of Pediatric Oncology and Hematology, N. N. Blokhin National Research Cancer Center. All patients were MRD-positive, and blinatumomab was administered as a bridge therapy to HSCT (Table 1).

Table 1. Characteristics of patients included in the study

Stepanyan-tab01.jpg

Previously, the 3 patients at the N. N. Blokhin National Medical Research Center of Oncology underwent consolidation and anti-relapse therapy according to the ALL IC-BFM 2009 and ALL-REZ BFM 2002 protocols, which included distinct chemotherapy blocks with the following chemotherapy drugs:
F1- dexamethasone, vincristine, PEG-asparaginase, methotrexate,
F2- dexamethasone, cytarabine, PEG-asparaginase,
R1- vincristine, methotrexate, cytarabine, dexamethasone, 6-mercaptopurine,
R2- dexamethasone, 6-mercaptopurine, vincristine, methotrexate, ifosfamide, daunorubicin,
FLAI- fludarabine, cytarabine, idarubicin.

Cell apheresis procedure

The lymphocyte collection was carried out at the confirmed levels of >107CD3+( cells per µL of peripheral blood, blood hemoglobin levels of >90 g/l; platelets, >50×109/L, without prior cell mobilization. To adjust correct anticoagulant ratio during cell collection, the blood clotting coagulation parameters were monitored a day before the procedure, due to possible hypocoagulation in excess of the ACD-A solution is possible with the introduction of anticoagulant [12].

Apheresis of autologous lymphocyte was performed at the Department of Bone Marrow Transplantation, using "Spectra Optia" cell separator (Terumo BCT Inc, USA). Detailed information on the technical features of collecting lymphocytes from patients of different groups and types of device software is described in the manufacturer’s instructions, as well as recommendations on the optimal procedure modes [13]. Central venous catheter (CVC) was pre-installed on the day of scheduled apheresis. Four units of the lymphocyte concentrates with predominant CD3+cells were prepared for each patient, at the median of 44.8% (32.8-55.7) of the nucleated cells in the mononuclear concentrat. Each patient received from 2 to 4 transfusions of autologous lymphocytes with the concentration of cells in the dose, respectively 25-36×106 cells in 35 mL. The number of transfusions depended on the total level of leukocytes, efficiency of lymphocyte harvesting, somatic and infectious status of the patient on the day of reinfusion.

An informed consent was obtained of the legal representative of the child before each session of lymphocyte apheresis.

Efficiency of the procedure was determined by achieving the target levels of CD3+ cells in apheresis product (>20 cells/µl). The average level of separated CD3+lymphocytes in the study group was 30.0 cells/µl, indicating a sufficient cell harvest. Lymphocyte concentration in the final product was assigned to the distinct patient. The lymphocyte-containing products underwent volume reduction up to 140 ml, and concentration 23-36×107 cells in 35 mL. The separated cells have been sent to the cryostorage being immersed in liquid nitrogen (-196°C).

The method for determining minimal residual disease(MRD) is represented by flow cytometry. The studies were carried out on a FACSCantoII cytometer (Becton Dickinson, USA). Flow cytometry data were analyzed with FACSDiva 6.1 software (Becton Dickinson)[14]. The result was given taking into account changes in the antigenic profile under the influence of therapy according to the ALL-REZ BFM 2002 protocol.

Therapy with blinatumomab

In all 3 patients, blinatumomab was administered by continuous intravenous infusion through a pre-installed central venous catheter (CVC). The initial dose was 5 µg/m2/day for 7 days followed by 15 µg/m2/day for 21 days. In one case, the patient's body weight exceeded 45 kg. Therefore, according to the official prescriptions, this patient received a dose of 9 μg/m2/day for 7 days then 15 μg/m2/day for 21 days. CD3+ lymphocytes have been infused to all three patients, at courses of every 7 days. Two patients from our group received the lymphocyte transfusions at +14, +21 and +28 days of therapy, one patient received only +7 and +14 days therapy, due to poor somatic condition. On the first day of therapy, all patients underwent spinal puncture with endolumbar chemoprophylaxis with methotrexate (at the age-matched doses) followed by bone marrow puncture, myelogram counts and MRD determination. When using blinatumomab in combination with lymphocyte transfusions, 2 out of 3 patients experienced skin allergic reactions [15].

Laboratory studies

Technical recommendations ISHAGE (International Society of Hematotherapy and Graft Engineering) were used to determine the numbers of CD3+ cells in peripheral blood before apheresis procedure. The results were presented both as a percentage and absolute values. The number of lymphocytes was determined by the expression of membrane CD3 and CD45 markers in the direct immunofluorescence reaction [14]. The result was evaluated by flow cytometry in the CD3+ PE-A population.

Case reports

Patient 1

The patient, a 10-year-old boy, was diagnosed with acute lymphoblastic leukemia LI-II according to the FAB classification, B-linear variant, BII immunosubvariant (pre-pre-B, common) with a chimeric gene TEL/AML 1, CNS 3, relapse I.

He received treatment according to the ALL-REZ BFM 2002, 1 course of induction anti-relapse blocks F1 and F2 were performed, given the lack of sanitation of cerebrospinal fluid after F1. After the end of therapy, control bone marrow punctures were performed. According to the myelograms, the presence of a blast population in the bone marrow remains 27% blast cells, as well as the persistence of minimal residual disease (MRD)-positive status. In the post-block period, complications were noted in the form of oropharyngeal mucositis and vincristine polyneuropathy (with following complete resolving). Next, the patient underwent an anti-relapse block R1 according to the ALL-REZ BFM 2002 protocol. The child tolerated the block of therapy satisfactorily, there were no complications. After the block of chemotherapy, repeated bone marrow punctures were performed which showed normal levels of blast cells. However, the MRD-positive status of the disease still persisted. Taking into account these results, the child has received the anti-relapse R2 block, according to the ALL-REZ BFM 2022 protocol. The block of therapy was tolerated satisfactorily, on control studies according to bone marrow punctures, the minimal residual disease positive status of the disease remains, which requires the start of an additional block of FLAI chemotherapy. After the chemotherapy, some complications were observed, i.e., febrile neutropenia, accompanied by multiple episodes of fever, requiring correction of antibacterial and supportive therapy. Upon restoration of hematopoiesis, control bone marrow punctures were performed which have shown MRD-positive status retained in the patient. Taking into account persistence of the MRD-positive status, the patient was administered immunotherapy with a bispecific T-cell activator drug – blinatumomab as part of the "bridge"-therapy with the reinfusion of CD3 autolymphocytes weekly. Control of MRD status on days 14 and 28 of immunotherapy. The patient received 4 transfusions of autologous CD3+lymphocytes, and achieved MRD-negative status, which further required HSCT, but during the pre-transplant examination he was infected with COVID-19. The persistence of the virus had been recorded for 2 months, on the 60th day of the disease, control punctures were carried out, which revealed a relapse of the underlying disease. The relapse occurred 55-60 days after the start of immunotherapy.

Patient 2

The patient, a 15-year-old girl, was diagnosed with acute lymphoblastic leukemia L-1 morphological variant, B-II immune subvariant. After therapy according to the ALL-MB-2015 protocol, her clinical condition corresponded to Relapse I. No specific gene aberration was found.

The patient maintained long-term clinical and hematological remission I, but 4 years later the disease relapsed, and she was administered the ALL-REZ BFM 2002 protocol, with second-line anti-relapse blocks been performed according to the F1, F2, R2, R1 blocks. After the end of anti-relapse therapy, control bone marrow punctures were performed. The myelograms revealed a remaining blast population in the bone marrow 38%, as well as the preservation of the MRD-positive status 0.8%. In the post-block period, the following complications were noted, i.e., grade 2 oropharyngeal mucositis. Further, according to the results of the myelogram, in view of the progression of the disease, a decision was made to intensify chemotherapy by the FLAI block regimen. The child tolerated the therapy block satisfactorily, there were no complications. After the end of this chemotherapy, the repeated bone marrow punctures were performed which have shown reduced level of blast cells (from 38 to 18%), but the bone marrow was not completely purged and the MRD-positive disease proved to persist (0.5%). Taking into account these results, the second course of the FLAI block was started for the child. The therapy block was satisfactorily tolerated, there were no pronounced infections. Examination of the bone marrow punctures still showed MRD-positive status, but the level of marrow blast cells was less than 5%. The following complications were associated with chemotherapy: febrile neutropenia, episodes of fever, requiring correction of antibacterial and supportive therapy. Due to persistence of MRD-positive status, the patient has received immunotherapy with blinatumomab, a bispecific T-cell activator drug as an anti-relapse treatment, with reinfusion of CD3+ autologous lymphocytes once every 7 days. Control of MRD status was performed on days 14 and 28 of immunotherapy. The patient received 2 transfusions of auto-lymphocytes, at +7 and +14 days from the start of Blinatumomab therapy. Then, according to the results of the bone marrow study on day +14 (during immunotherapy), an increased level of blast cells and MRD-positive status of the disease were noted, thus indicating the progression of the disease. The patient continued therapy with blinatumomab until the 21st day. Later on, the therapy was completed, due to worsening of the patient's somatic condition (development of pulmonary and renal failure).

Patient 3

The patient, a 5-year-old girl, was diagnosed with acute lymphoblastic leukemia B II immune subvariant, CNS 1. Relapse I. No specific gene aberration was found.

As part of intensive care, she received treatment according to the ALL-REZ BFM 2002 protocol, one course of induction anti-relapse blocks F1 and F2 were performed, due to the lack of CSF sanitation after F1. After the end of therapy, control bone marrow punctures were performed showing a detectable blast population in the bone marrow, as well as persistence of MRD-positive status. In the post-block period, some complications were noted, including oropharyngeal mucositis and vincristine polyneuropathy. Later on, the patient underwent an anti-relapse block R1 according to the ALL-REZ BFM 2002 protocol. The block of therapy was tolerated satisfactorily, without complications. At the end of chemotherapy block, a repeated bone marrow puncture has shown normal level of blast cells, however, with persistent MRD-positive status. In view of these findings, the child was subjected to the anti-relapse R2 block, according to the ALL-REZ BFM 2022 protocol. This block of therapy was tolerated satisfactorily, however, bone marrow examination revealed MRD-positive status of the disease, which required an additional block of FLAI chemotherapy. This therapy was followed by several complications including febrile neutropenia accompanied by multiple episodes of fever, requiring correction of antibacterial and accompanying therapy. Upon recovery of hematopoiesis, the control bone marrow punctures still confirmed the MRD-positive status. Taking into account the persistence of MRD-positive status, the patient was administered immunotherapy with blinatumomab in the frames of "bridge"-therapy along with weekly reinfusions of CD3+ autologous lymphocytes. MRD status was controlled on days +14 and +28 of immunotherapy. The patient received 4 auto-transfusions of CD3 lymphocytes, and achieved MRD-negative status, which allowed him to enter the next stage of treatment, i.e., HSCT. Two weeks later, after the pre-transplant examination, the patient underwent haploidentical transplantation from her father.

Discussion

The presented experience of using transfusions of CD3+ autolymphocytes in combination with blinatumomab showed that this technique is safe, reproducible, and can be effective in patients with relapses of ALL. In 2 out of 3 patients with the introduction of auto-lymphocytes, we have achieved a complete clinical, hematological and immunological remission of the disease.

Modern cellular and targeted technologies have improved the survival rate of patients with recurrent ALL. When conducting therapy with blinatumomab, it is necessary to take into account the level of CD3+ lymphocytes, which are an integral component of effect of blinatumomab against lymphoid malignancies. The drug is able to attract T-regulatory CD3+lymphocytes (Treg), which induce an immunosuppressive response, due to local increase in the IL-10 and TGF-b concentrations [16]. Thus, the transfusions of autologous lymphocytes with high contents of CD3+ cells is well justified, due to elevation of their contents in the patients’ blood and probable anti-leukemic effect of blinatumomab [11]. Infusions of donor lymphocytes to the patients after allogeneic HSCT may be also potentially effective, pursuing the goal of both replacing the pool of CD3 + cells (in case of lymphopenia), and contributing to the general phenomenon of "graft against leukemia" effect [17]. Both immunotherapeutic approaches require more detailed study.

Conclusion

Transfusion of CD3+ autologous lymphocytes in combination with blinatumomab therapy in pediatric patients with relapses and refractory forms of ALL is a quite safe therapeutic option being effective in achieving the disease remission, and as a tool of bridge therapy before allo-HSCT.

Conflict of interest

None declared.

References

  1. Jeha S, Pei D, Choi J, Cheng C, Sandlund JT, Coustan-Smith E, Campana D, et al. Improved CNS control of childhood acute lymphoblastic leukemia without cranial irradiation: St Jude Total Therapy Study 16. J Clin Oncol. 2019; 37(35):3377-3391.
    doi: 10.1200/JCO.19.01692
  2. Locatelli F, Moretta F, Rutella S. Management of relapsed acute lymphoblastic leukemia in childhood with conventional and innovative approaches. Curr Opin Oncol. 2013; 25:707-715. doi: 10.1097/CCO.0000000000000011
  3. Benjamin JE, Stein AS. The role of blinatumomab in patients with relapsed/refractory acute lymphoblastic leukemia. Ther Adv Hematol. 2016;7(3);142-156. doi: 10.1177/2040620716640422
  4. Locatelly F, Whitlock J, Peters C, Chen-Santel C, Chia V, Dennis R, et al. Blinatumomab versus historical standard therapy in pediatric patients with relapsed/ refractory Ph-negative B-cell precursor acute lymphoblastic leukemia. Leukemia. 2020;34(9):2473-8.
    doi: 10.1038/s41375-020-0770-8
  5. Le Jeune C, Thomas X. Potential for bispecific T-cell engagers: role of blinatumomab in acute lymphoblastic leukemia. Drug Des Devel Ther. 2016;10:757-765. doi: 10.2147/DDDT.S83848
  6. Achtari M, Kum-Ja L, Weissman A, Tulpule S, Aldoss I, Akhtari M. Clinical use of blinatumomab for B-cell acute lymphoblastic leukemia in adults. Ther Clin Risk Manag. 2016;12:1301-1310. doi: 10.2147/TCRM.S84261
  7. Zugmaier G, Klinger M, Schmidt M, Subklewe M. Clinical overview of anti- CD19 BiTE® and ex vivo data from anti- CD33 BiTE® as examples for retargeting T-cells in hematologic malignancies. Mol Immunol. 2015;67(2 Pt A):58-66. doi: 10.1016/j.molimm.2015.02.033
  8. Nagorsen D, Baeuerle P. Immunomodulatory therapy of cancer with T-cell-engaging BiTE antibody blinatumomab. Exp Cell Res. 2011;317(9):1255-1260. doi: 10.1016/j.yexcr.2011.03.010
  9. Wu J, Fu J, Zhang M, Liu D. Blinatumomab: a bispecific T cell engager (BiTE) antibody against CD19/CD3 for refractory acute lymphoid leukemia. J Hematol Oncol. 2015 Sep 4;8:104. doi: 10.1186/s13045-015-0195-4
  10. Ueda M, de Lima M, Caimi P, Tomlinson B, Little J, Creger R, Lazarus H, Cooper B. Concurrent blinatumomab and donor lymphocyte infusions for treatment of relapsed pre-B-cell ALL after allogeneic hematopoietic cell transplant. Bone Marrow Transplant. 2016; 51(9):1253-1255. doi: 10.1038/bmt.2016.104
  11. Duell J, Dittrich M, Bedke T, Mueller T, Eisele F, Rosenwald A, et al. Frequency of regulatory T cells determines the outcome of the T-cell-engaging antibody blinatumomab in patients with B-precursor ALL. Leukemia 2017; 31(10):2181-2190. doi: 10.1038/leu.2017.41
  12. Barrett D, Fish JD, Grupp SA. Autologous and allogeneic cellular therapies for high-risk pediatric solid tumors. Pediatr Clin North Am. 2010; 57(1): 47-66. doi: 10.1016/j.pcl.2010.01.001
  13. Spectra Optia Apheresis System& Operator’s Manual. Part No. 777379-124. Reorder No. 703261-001 2018-04 Terumo BCT.
  14. Movchan LV. Leukemia-associated immunophenotype in children with B-precursor acute lymphoblastic leukemia. Onkogematologiya. 2012; 1:22-28. (In Russian).
  15. Nagorsen D, Kufer P, Baeuerle PA, Bargou R. Blinatumomab: a historical perspective. Pharmacol Ther. 2012; 136(3):334-342.
    doi: 10.1016/j.pharmthera.2012.07.013
  16. Illarionova O, Gluhanyuk E, Kashpor S. Changes in leukemic blasts CD19 expression in children with relapsed/ refractory B-cell precursor ALL treated with blinatumomab. Blood. 2017;130(Suppl. 1):3991 (In Russian). doi: 10.3324/haematol.2019.2415966
  17. Chan WYK, Cheuk DKL, Lee PPW, Chan GCF, Leung W, Yeung EWM, et al. Blinatumomab with donor lymphocyte infusions post haploidentical hematopoietic stem cell transplantation as salvage therapy for relapsed refractory acute lymphoblastic leukemia post chimeric antigen receptor T-cell therapy. Pediat Blood Cancer 2022; Jun 21;e29852. doi: 10.1002/pbc.29852

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Introduction

Acute lymphoblastic leukemia (ALL) is one of the most common malignant diseases in children. Despite the fact that overall survival rate in pediatric ALL reaches 90%, unfortunately, 10-15% of patients develop relapses after achieving first clinical and hematological remission [1]. Prior to the advent of immunotherapy, the only treatment for relapsing and refractory ALL was a more intensive second-line chemotherapy which usually included alternating blocks of high-dose chemotherapy, followed by allogeneic bone marrow or hematopoietic stem cell transplantation (allo-HSCT). However, this therapy increased the degree of toxicity and contributed to development of complications, with mortality of up to lethal in 10-15% of cases [2]. Moreover, it is necessary to achieve MRD-negative status prior to HSCT procedure. This task may represent a difficult challenge [3]. The success of allo-HSCT in pediatric ALL depends on the level of minimal residual disease (MRD) before transplantation. At the present time, all therapeutic options are aimed at achieving clinical and hematological remission and reducing the MRD level [4].

MRD-negative status in relapses and refractory forms of ALL may be achieved by usage of targeted drugs, e.g., bispecific antibodies BiTE (AT), which may activate effector T-cells providing antitumor effect [5]. Blinatumomab is a bispecific anti-СD19/CD3 antibody, consisting of 2 single-chain variable fragments (scFv), specific for to CD19 (B-lymphocyte marker) and epsilon chains of CD3+ T-lymphocytes [6]. The mechanism of the drug action is to "redirect" effector functions of the patient’s own T-lymphocytes to the target cells that carry CD19 including blast cells in B-ALL patients. Given the opportunity of such "redirection" at the time of blinatumomab administration, a mediated cytolytic effect is induced (with subsequent activation and proliferation of T cells) towards the CD19-expressing cells. Of note, the anti-CD19-scFv has a higher affinity than the anti-CD3 fragment, which may cast doubt on the drug efficiency at low levels of CD3 cells in the patient's peripheral blood [7], as seen in Fig. 1.

Stepanyan-fig01.jpg

Figure 1. The mechanism of action of blinatumomab (bispecific BiTE molecule consisting of 2-single-chain variable fragments (scFv) specific for the CD19 and CD3 epsilon chain. The main mechanism involves recruitment of the own T-cells and redirecting their effector functions into target cells carrying the CD19 marker, which include B-lineage blast cells [8]

The advantage of blinatumomab is independence of this effect on the specificity of T-cell receptors (TCR), or presence of class 1 MHC molecules on the surface of antigen-presenting cells. T-cell activation increases the secretion of cytokines, especially IL-2, IFN-y, TNF-a, IL-4, IL-6, and IL-10. Moreover, at the moment of T-lymphocyte activation, granzyme B and perforin are released, which penetrate into CD19-positive tumor cells and activate apoptosis [9].

Taking into account the mechanism of action of the drug, one may assume that, during the period of immunotherapy, additional transfusions of autolymphocytes may increase the number of lymphocytes, thus promoting favorable effect of the drug and enhance its effectiveness. The transfusions should be performed at 7-day intervals, to maintain a stable concentration of CD3+cells in peripheral blood [10].

Despite the lack of convincing data on the correlation between the absolute levels of peripheral lymphocytes, especially, CD3+ cells, before starting the immunotherapy and transfusions of auto-lymphocytes may be reasonable, especially in severe aplasia of hematopoiesis [11].

Materials and methods

Transfusions of autologous CD3+ lymphocytes were performed in three patients with recurrent ALL who underwent immunotherapy with blinatumomab from July 2021 to February 2022 at the Research Institute of Pediatric Oncology and Hematology, N. N. Blokhin National Research Cancer Center. All patients were MRD-positive, and blinatumomab was administered as a bridge therapy to HSCT (Table 1).

Table 1. Characteristics of patients included in the study

Stepanyan-tab01.jpg

Previously, the 3 patients at the N. N. Blokhin National Medical Research Center of Oncology underwent consolidation and anti-relapse therapy according to the ALL IC-BFM 2009 and ALL-REZ BFM 2002 protocols, which included distinct chemotherapy blocks with the following chemotherapy drugs:
F1- dexamethasone, vincristine, PEG-asparaginase, methotrexate,
F2- dexamethasone, cytarabine, PEG-asparaginase,
R1- vincristine, methotrexate, cytarabine, dexamethasone, 6-mercaptopurine,
R2- dexamethasone, 6-mercaptopurine, vincristine, methotrexate, ifosfamide, daunorubicin,
FLAI- fludarabine, cytarabine, idarubicin.

Cell apheresis procedure

The lymphocyte collection was carried out at the confirmed levels of >107CD3+( cells per µL of peripheral blood, blood hemoglobin levels of >90 g/l; platelets, >50×109/L, without prior cell mobilization. To adjust correct anticoagulant ratio during cell collection, the blood clotting coagulation parameters were monitored a day before the procedure, due to possible hypocoagulation in excess of the ACD-A solution is possible with the introduction of anticoagulant [12].

Apheresis of autologous lymphocyte was performed at the Department of Bone Marrow Transplantation, using "Spectra Optia" cell separator (Terumo BCT Inc, USA). Detailed information on the technical features of collecting lymphocytes from patients of different groups and types of device software is described in the manufacturer’s instructions, as well as recommendations on the optimal procedure modes [13]. Central venous catheter (CVC) was pre-installed on the day of scheduled apheresis. Four units of the lymphocyte concentrates with predominant CD3+cells were prepared for each patient, at the median of 44.8% (32.8-55.7) of the nucleated cells in the mononuclear concentrat. Each patient received from 2 to 4 transfusions of autologous lymphocytes with the concentration of cells in the dose, respectively 25-36×106 cells in 35 mL. The number of transfusions depended on the total level of leukocytes, efficiency of lymphocyte harvesting, somatic and infectious status of the patient on the day of reinfusion.

An informed consent was obtained of the legal representative of the child before each session of lymphocyte apheresis.

Efficiency of the procedure was determined by achieving the target levels of CD3+ cells in apheresis product (>20 cells/µl). The average level of separated CD3+lymphocytes in the study group was 30.0 cells/µl, indicating a sufficient cell harvest. Lymphocyte concentration in the final product was assigned to the distinct patient. The lymphocyte-containing products underwent volume reduction up to 140 ml, and concentration 23-36×107 cells in 35 mL. The separated cells have been sent to the cryostorage being immersed in liquid nitrogen (-196°C).

The method for determining minimal residual disease(MRD) is represented by flow cytometry. The studies were carried out on a FACSCantoII cytometer (Becton Dickinson, USA). Flow cytometry data were analyzed with FACSDiva 6.1 software (Becton Dickinson)[14]. The result was given taking into account changes in the antigenic profile under the influence of therapy according to the ALL-REZ BFM 2002 protocol.

Therapy with blinatumomab

In all 3 patients, blinatumomab was administered by continuous intravenous infusion through a pre-installed central venous catheter (CVC). The initial dose was 5 µg/m2/day for 7 days followed by 15 µg/m2/day for 21 days. In one case, the patient's body weight exceeded 45 kg. Therefore, according to the official prescriptions, this patient received a dose of 9 μg/m2/day for 7 days then 15 μg/m2/day for 21 days. CD3+ lymphocytes have been infused to all three patients, at courses of every 7 days. Two patients from our group received the lymphocyte transfusions at +14, +21 and +28 days of therapy, one patient received only +7 and +14 days therapy, due to poor somatic condition. On the first day of therapy, all patients underwent spinal puncture with endolumbar chemoprophylaxis with methotrexate (at the age-matched doses) followed by bone marrow puncture, myelogram counts and MRD determination. When using blinatumomab in combination with lymphocyte transfusions, 2 out of 3 patients experienced skin allergic reactions [15].

Laboratory studies

Technical recommendations ISHAGE (International Society of Hematotherapy and Graft Engineering) were used to determine the numbers of CD3+ cells in peripheral blood before apheresis procedure. The results were presented both as a percentage and absolute values. The number of lymphocytes was determined by the expression of membrane CD3 and CD45 markers in the direct immunofluorescence reaction [14]. The result was evaluated by flow cytometry in the CD3+ PE-A population.

Case reports

Patient 1

The patient, a 10-year-old boy, was diagnosed with acute lymphoblastic leukemia LI-II according to the FAB classification, B-linear variant, BII immunosubvariant (pre-pre-B, common) with a chimeric gene TEL/AML 1, CNS 3, relapse I.

He received treatment according to the ALL-REZ BFM 2002, 1 course of induction anti-relapse blocks F1 and F2 were performed, given the lack of sanitation of cerebrospinal fluid after F1. After the end of therapy, control bone marrow punctures were performed. According to the myelograms, the presence of a blast population in the bone marrow remains 27% blast cells, as well as the persistence of minimal residual disease (MRD)-positive status. In the post-block period, complications were noted in the form of oropharyngeal mucositis and vincristine polyneuropathy (with following complete resolving). Next, the patient underwent an anti-relapse block R1 according to the ALL-REZ BFM 2002 protocol. The child tolerated the block of therapy satisfactorily, there were no complications. After the block of chemotherapy, repeated bone marrow punctures were performed which showed normal levels of blast cells. However, the MRD-positive status of the disease still persisted. Taking into account these results, the child has received the anti-relapse R2 block, according to the ALL-REZ BFM 2022 protocol. The block of therapy was tolerated satisfactorily, on control studies according to bone marrow punctures, the minimal residual disease positive status of the disease remains, which requires the start of an additional block of FLAI chemotherapy. After the chemotherapy, some complications were observed, i.e., febrile neutropenia, accompanied by multiple episodes of fever, requiring correction of antibacterial and supportive therapy. Upon restoration of hematopoiesis, control bone marrow punctures were performed which have shown MRD-positive status retained in the patient. Taking into account persistence of the MRD-positive status, the patient was administered immunotherapy with a bispecific T-cell activator drug – blinatumomab as part of the "bridge"-therapy with the reinfusion of CD3 autolymphocytes weekly. Control of MRD status on days 14 and 28 of immunotherapy. The patient received 4 transfusions of autologous CD3+lymphocytes, and achieved MRD-negative status, which further required HSCT, but during the pre-transplant examination he was infected with COVID-19. The persistence of the virus had been recorded for 2 months, on the 60th day of the disease, control punctures were carried out, which revealed a relapse of the underlying disease. The relapse occurred 55-60 days after the start of immunotherapy.

Patient 2

The patient, a 15-year-old girl, was diagnosed with acute lymphoblastic leukemia L-1 morphological variant, B-II immune subvariant. After therapy according to the ALL-MB-2015 protocol, her clinical condition corresponded to Relapse I. No specific gene aberration was found.

The patient maintained long-term clinical and hematological remission I, but 4 years later the disease relapsed, and she was administered the ALL-REZ BFM 2002 protocol, with second-line anti-relapse blocks been performed according to the F1, F2, R2, R1 blocks. After the end of anti-relapse therapy, control bone marrow punctures were performed. The myelograms revealed a remaining blast population in the bone marrow 38%, as well as the preservation of the MRD-positive status 0.8%. In the post-block period, the following complications were noted, i.e., grade 2 oropharyngeal mucositis. Further, according to the results of the myelogram, in view of the progression of the disease, a decision was made to intensify chemotherapy by the FLAI block regimen. The child tolerated the therapy block satisfactorily, there were no complications. After the end of this chemotherapy, the repeated bone marrow punctures were performed which have shown reduced level of blast cells (from 38 to 18%), but the bone marrow was not completely purged and the MRD-positive disease proved to persist (0.5%). Taking into account these results, the second course of the FLAI block was started for the child. The therapy block was satisfactorily tolerated, there were no pronounced infections. Examination of the bone marrow punctures still showed MRD-positive status, but the level of marrow blast cells was less than 5%. The following complications were associated with chemotherapy: febrile neutropenia, episodes of fever, requiring correction of antibacterial and supportive therapy. Due to persistence of MRD-positive status, the patient has received immunotherapy with blinatumomab, a bispecific T-cell activator drug as an anti-relapse treatment, with reinfusion of CD3+ autologous lymphocytes once every 7 days. Control of MRD status was performed on days 14 and 28 of immunotherapy. The patient received 2 transfusions of auto-lymphocytes, at +7 and +14 days from the start of Blinatumomab therapy. Then, according to the results of the bone marrow study on day +14 (during immunotherapy), an increased level of blast cells and MRD-positive status of the disease were noted, thus indicating the progression of the disease. The patient continued therapy with blinatumomab until the 21st day. Later on, the therapy was completed, due to worsening of the patient's somatic condition (development of pulmonary and renal failure).

Patient 3

The patient, a 5-year-old girl, was diagnosed with acute lymphoblastic leukemia B II immune subvariant, CNS 1. Relapse I. No specific gene aberration was found.

As part of intensive care, she received treatment according to the ALL-REZ BFM 2002 protocol, one course of induction anti-relapse blocks F1 and F2 were performed, due to the lack of CSF sanitation after F1. After the end of therapy, control bone marrow punctures were performed showing a detectable blast population in the bone marrow, as well as persistence of MRD-positive status. In the post-block period, some complications were noted, including oropharyngeal mucositis and vincristine polyneuropathy. Later on, the patient underwent an anti-relapse block R1 according to the ALL-REZ BFM 2002 protocol. The block of therapy was tolerated satisfactorily, without complications. At the end of chemotherapy block, a repeated bone marrow puncture has shown normal level of blast cells, however, with persistent MRD-positive status. In view of these findings, the child was subjected to the anti-relapse R2 block, according to the ALL-REZ BFM 2022 protocol. This block of therapy was tolerated satisfactorily, however, bone marrow examination revealed MRD-positive status of the disease, which required an additional block of FLAI chemotherapy. This therapy was followed by several complications including febrile neutropenia accompanied by multiple episodes of fever, requiring correction of antibacterial and accompanying therapy. Upon recovery of hematopoiesis, the control bone marrow punctures still confirmed the MRD-positive status. Taking into account the persistence of MRD-positive status, the patient was administered immunotherapy with blinatumomab in the frames of "bridge"-therapy along with weekly reinfusions of CD3+ autologous lymphocytes. MRD status was controlled on days +14 and +28 of immunotherapy. The patient received 4 auto-transfusions of CD3 lymphocytes, and achieved MRD-negative status, which allowed him to enter the next stage of treatment, i.e., HSCT. Two weeks later, after the pre-transplant examination, the patient underwent haploidentical transplantation from her father.

Discussion

The presented experience of using transfusions of CD3+ autolymphocytes in combination with blinatumomab showed that this technique is safe, reproducible, and can be effective in patients with relapses of ALL. In 2 out of 3 patients with the introduction of auto-lymphocytes, we have achieved a complete clinical, hematological and immunological remission of the disease.

Modern cellular and targeted technologies have improved the survival rate of patients with recurrent ALL. When conducting therapy with blinatumomab, it is necessary to take into account the level of CD3+ lymphocytes, which are an integral component of effect of blinatumomab against lymphoid malignancies. The drug is able to attract T-regulatory CD3+lymphocytes (Treg), which induce an immunosuppressive response, due to local increase in the IL-10 and TGF-b concentrations [16]. Thus, the transfusions of autologous lymphocytes with high contents of CD3+ cells is well justified, due to elevation of their contents in the patients’ blood and probable anti-leukemic effect of blinatumomab [11]. Infusions of donor lymphocytes to the patients after allogeneic HSCT may be also potentially effective, pursuing the goal of both replacing the pool of CD3 + cells (in case of lymphopenia), and contributing to the general phenomenon of "graft against leukemia" effect [17]. Both immunotherapeutic approaches require more detailed study.

Conclusion

Transfusion of CD3+ autologous lymphocytes in combination with blinatumomab therapy in pediatric patients with relapses and refractory forms of ALL is a quite safe therapeutic option being effective in achieving the disease remission, and as a tool of bridge therapy before allo-HSCT.

Conflict of interest

None declared.

References

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string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "25" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "29550" ["VALUE"]=> array(2) { ["TEXT"]=> string(267) "<p>Нара Г. Степанян, Тимур Т. Валиев, Рамиль Р. Фатхуллин, Татьяна Ю. Павлова, Наталья С. Цаплина, Кирилл И. Киргизов, Светлана Р. Варфоломеева</p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(255) "

Нара Г. Степанян, Тимур Т. Валиев, Рамиль Р. Фатхуллин, Татьяна Ю. Павлова, Наталья С. Цаплина, Кирилл И. Киргизов, Светлана Р. Варфоломеева

" ["TYPE"]=> string(4) "HTML" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(12) "Авторы" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } } ["ORGANIZATION_RU"]=> array(36) { ["ID"]=> string(2) "26" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:01:20" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(22) "Организации" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(15) "ORGANIZATION_RU" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "26" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "29551" ["VALUE"]=> array(2) { ["TEXT"]=> string(188) "<p>Национальный медицинский исследовательский центр онкологии им. Н. Н. Блохина, Москва, Россия</p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(176) "

Национальный медицинский исследовательский центр онкологии им. Н. Н. Блохина, Москва, Россия

" ["TYPE"]=> string(4) "HTML" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(22) "Организации" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } } ["SUMMARY_RU"]=> array(36) { ["ID"]=> string(2) "27" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:01:20" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(29) "Описание/Резюме" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(10) "SUMMARY_RU" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "27" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "29552" ["VALUE"]=> array(2) { ["TEXT"]=> string(4298) "<p style="text-align: justify;">Около 85-90% пациентов с острым лимфобластным лейкозом (ОЛЛ) после проведения современной программной терапии выздоравливают, но у 10-15% детей заболевание рецидивирует или приобретает рефрактерное течение. Для данной категории пациентов стандартно предусмотрена химиотерапия второй линии с последующей аллогенной трансплантацией гемопоэтических стволовых клеток (алло-ТГСК). Тем не менее, не всегда удается достичь молекулярной/иммунологической ремиссии. В эру таргетной терапии большие надежды возлагаются на молекулярно-направленные препараты для достижения полной молекулярной/иммунологической ремиссии и получения более высоких показателей выживаемости при проведении алло-ТГСК. Одним из таргетных препаратов, применяемых для достижения ремиссии при ОЛЛ, является блинатумомаб, эффективность терапии которым зависит от достаточного уровня СD3-лимфоцитов, экспрессии СD19 и количества бластных клеток в крови и костном мозге. Целью работы было представить опыт терапии блинатумомабом с трансфузиями СD3-аутолимфоцитов у детей с рецидивом ОЛЛ и оценить эффективность данной методики для достижения ремиссии.</p> <h3>Материалы и методы</h3> <p style="text-align: justify;">В настоящей статье представлены 3 клинических случая пациентов с рецидивом ОЛЛ, получавших лечение с июля 2021 года по февраль 2022 года в НИИ детской онкологии и гематологии НМИЦ онкологии им. Н. Н. Блохина.</p> <h3>Результаты</h3> <p style="text-align: justify;">Два пациента из данного наблюдения, проходившие терапию блинатумомабом, получили 4 трансфузии CD3-лимфоцитов, достигли клинико-гематологической ремиссии c МОБ-негативным статусом болезни. Один пациент, ввиду сопутствующей соматической патологии, получил только 2 ауто-трансфузии, но ремиссия ОЛЛ не была достигнута.</p> <h3>Заключение</h3> <p style="text-align: justify;">Опыт применения трансфузий СD3+ауто-лимфоцитов в сочетании с блинатумомабом показал, что данная методика безопасна, воспроизводима и может быть эффективна у пациентов с рецидивами ОЛЛ. У двух пациентов из трех при введении ауто-лимфоцитов каждые 7 дней была зафиксирована полная клинико-гематологическая и иммунологическая ремиссии заболевания. </p> <h2>Ключевые слова</h2> <p style="text-align: justify;">Острый лимфобластный лейкоз, блинатумомаб, лимфоциты, аутологичные, аферез, дети, МОБ-статус.</p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(4140) "

Около 85-90% пациентов с острым лимфобластным лейкозом (ОЛЛ) после проведения современной программной терапии выздоравливают, но у 10-15% детей заболевание рецидивирует или приобретает рефрактерное течение. Для данной категории пациентов стандартно предусмотрена химиотерапия второй линии с последующей аллогенной трансплантацией гемопоэтических стволовых клеток (алло-ТГСК). Тем не менее, не всегда удается достичь молекулярной/иммунологической ремиссии. В эру таргетной терапии большие надежды возлагаются на молекулярно-направленные препараты для достижения полной молекулярной/иммунологической ремиссии и получения более высоких показателей выживаемости при проведении алло-ТГСК. Одним из таргетных препаратов, применяемых для достижения ремиссии при ОЛЛ, является блинатумомаб, эффективность терапии которым зависит от достаточного уровня СD3-лимфоцитов, экспрессии СD19 и количества бластных клеток в крови и костном мозге. Целью работы было представить опыт терапии блинатумомабом с трансфузиями СD3-аутолимфоцитов у детей с рецидивом ОЛЛ и оценить эффективность данной методики для достижения ремиссии.

Материалы и методы

В настоящей статье представлены 3 клинических случая пациентов с рецидивом ОЛЛ, получавших лечение с июля 2021 года по февраль 2022 года в НИИ детской онкологии и гематологии НМИЦ онкологии им. Н. Н. Блохина.

Результаты

Два пациента из данного наблюдения, проходившие терапию блинатумомабом, получили 4 трансфузии CD3-лимфоцитов, достигли клинико-гематологической ремиссии c МОБ-негативным статусом болезни. Один пациент, ввиду сопутствующей соматической патологии, получил только 2 ауто-трансфузии, но ремиссия ОЛЛ не была достигнута.

Заключение

Опыт применения трансфузий СD3+ауто-лимфоцитов в сочетании с блинатумомабом показал, что данная методика безопасна, воспроизводима и может быть эффективна у пациентов с рецидивами ОЛЛ. У двух пациентов из трех при введении ауто-лимфоцитов каждые 7 дней была зафиксирована полная клинико-гематологическая и иммунологическая ремиссии заболевания.

Ключевые слова

Острый лимфобластный лейкоз, блинатумомаб, лимфоциты, аутологичные, аферез, дети, МОБ-статус.

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Nara G. Stepanyan, Timur T. Valiev, Ramil R. Fatkhullin, Tatiana Y. Pavlova, Natalia S. Tsaplina, Kirill I. Kirgizov, Svetlana R. Varfolomeeva

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N. N. Blokhin Russian Cancer Research Center, Moscow, Russia


Correspondence:
Dr. Nara G. Stepanyan, Bone Marrow Transplantation Department, N. N. Blokhin Russian Cancer Research Center, 23B Kashirskaya St, 115522, Moscow, Russia
Phone: +7 (903) 247-30-82
E-mail: nara19922@yandex.ru


Citation: Stepanyan NG, Valiev TT, Fatkhullin RR, et al. Efficacy of therapy with blinatumomab and autologous CD3 cell transfusions in relapsing acute lymphoblastic leukemia: A single center experience. Cell Ther Transplant 2022; 11(3-4): 70-76.

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About 85-90% of patients with acute lymphoblastic leukemia (ALL) recover after modern program therapy. However, the disease may relapse, or acquires a refractory course in 10-15% of the children. For this category of patients, second-line chemotherapy is standardly provided, followed by allogeneic hematopoietic stem cell transplantation (allo-HSCT). However, achievement of molecular/immunological remission is not always possible. In the era of targeted therapy, great hopes are placed on molecularly targeted drugs in order to reach complete molecular/immunological remission and obtain higher survival rates with allo-HSCT. Blinatumomab is among the targeted drugs used to achieve remission in ALL. Its effectiveness depends on a sufficient level of CD3-lymphocytes, CD19 expression, and the number of blast cells in peripheral blood and bone marrow. Our purpose was to present the experience of blinatumomab therapy with transfusions of autologous CD3 lymphocytes in children with recurrent ALL and to evaluate the efficiency of this technique in achieving remission.

Materials and methods

This article presents three clinical cases of patients with recurrent ALL treated at the Research Institute of Pediatric Oncology and Hematology at N. N. Blokhin National Cancer Research Center from July 2021 to February 2022.

Results

Two patients from our series were treated with blinatumomab and received 3 transfusions of CD3-lymphocytes followed by clinical and hematological remission with MRD-negative disease status. One patient, due to concomitant somatic pathology, received only 2 auto-transfusions, but ALL remission was not achieved.

Conclusion

Our experience of using autologous CD3+ lymphocyte transfusions in combination with blinatumomab showed that this technique is safe, reproducible, and may be effective in patients with ALL relapses. In 2 out of 3 patients with weekly infusion of autologous lymphocytes, a complete clinical, hematological and immunological remission of the disease was registered.

Keywords

Acute lymphoblastic leukemia, blinatumomab, lymphocytes, autologous, apheresis, children, MRD status.

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Nara G. Stepanyan, Timur T. Valiev, Ramil R. Fatkhullin, Tatiana Y. Pavlova, Natalia S. Tsaplina, Kirill I. Kirgizov, Svetlana R. Varfolomeeva

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Nara G. Stepanyan, Timur T. Valiev, Ramil R. Fatkhullin, Tatiana Y. Pavlova, Natalia S. Tsaplina, Kirill I. Kirgizov, Svetlana R. Varfolomeeva

" } ["SUMMARY_EN"]=> array(37) { ["ID"]=> string(2) "39" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:02:59" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(21) "Description / Summary" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(10) "SUMMARY_EN" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "39" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "29556" ["VALUE"]=> array(2) { ["TEXT"]=> string(2513) "<p style="text-align: justify;">About 85-90% of patients with acute lymphoblastic leukemia (ALL) recover after modern program therapy. However, the disease may relapse, or acquires a refractory course in 10-15% of the children. For this category of patients, second-line chemotherapy is standardly provided, followed by allogeneic hematopoietic stem cell transplantation (allo-HSCT). However, achievement of molecular/immunological remission is not always possible. In the era of targeted therapy, great hopes are placed on molecularly targeted drugs in order to reach complete molecular/immunological remission and obtain higher survival rates with allo-HSCT. Blinatumomab is among the targeted drugs used to achieve remission in ALL. Its effectiveness depends on a sufficient level of CD3-lymphocytes, CD19 expression, and the number of blast cells in peripheral blood and bone marrow. Our purpose was to present the experience of blinatumomab therapy with transfusions of autologous CD3 lymphocytes in children with recurrent ALL and to evaluate the efficiency of this technique in achieving remission.</p> <h3>Materials and methods</h3> <p style="text-align: justify;">This article presents three clinical cases of patients with recurrent ALL treated at the Research Institute of Pediatric Oncology and Hematology at N. N. Blokhin National Cancer Research Center from July 2021 to February 2022. </p> <h3>Results</h3> <p style="text-align: justify;">Two patients from our series were treated with blinatumomab and received 3 transfusions of CD3-lymphocytes followed by clinical and hematological remission with MRD-negative disease status. One patient, due to concomitant somatic pathology, received only 2 auto-transfusions, but ALL remission was not achieved.</p> <h3>Conclusion</h3> <p style="text-align: justify;">Our experience of using autologous CD3+ lymphocyte transfusions in combination with blinatumomab showed that this technique is safe, reproducible, and may be effective in patients with ALL relapses. In 2 out of 3 patients with weekly infusion of autologous lymphocytes, a complete clinical, hematological and immunological remission of the disease was registered.</p> <h2>Keywords</h2> <p style="text-align: justify;">Acute lymphoblastic leukemia, blinatumomab, lymphocytes, autologous, apheresis, children, MRD status.</p> " ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(2355) "

About 85-90% of patients with acute lymphoblastic leukemia (ALL) recover after modern program therapy. However, the disease may relapse, or acquires a refractory course in 10-15% of the children. For this category of patients, second-line chemotherapy is standardly provided, followed by allogeneic hematopoietic stem cell transplantation (allo-HSCT). However, achievement of molecular/immunological remission is not always possible. In the era of targeted therapy, great hopes are placed on molecularly targeted drugs in order to reach complete molecular/immunological remission and obtain higher survival rates with allo-HSCT. Blinatumomab is among the targeted drugs used to achieve remission in ALL. Its effectiveness depends on a sufficient level of CD3-lymphocytes, CD19 expression, and the number of blast cells in peripheral blood and bone marrow. Our purpose was to present the experience of blinatumomab therapy with transfusions of autologous CD3 lymphocytes in children with recurrent ALL and to evaluate the efficiency of this technique in achieving remission.

Materials and methods

This article presents three clinical cases of patients with recurrent ALL treated at the Research Institute of Pediatric Oncology and Hematology at N. N. Blokhin National Cancer Research Center from July 2021 to February 2022.

Results

Two patients from our series were treated with blinatumomab and received 3 transfusions of CD3-lymphocytes followed by clinical and hematological remission with MRD-negative disease status. One patient, due to concomitant somatic pathology, received only 2 auto-transfusions, but ALL remission was not achieved.

Conclusion

Our experience of using autologous CD3+ lymphocyte transfusions in combination with blinatumomab showed that this technique is safe, reproducible, and may be effective in patients with ALL relapses. In 2 out of 3 patients with weekly infusion of autologous lymphocytes, a complete clinical, hematological and immunological remission of the disease was registered.

Keywords

Acute lymphoblastic leukemia, blinatumomab, lymphocytes, autologous, apheresis, children, MRD status.

" ["TYPE"]=> string(4) "HTML" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(21) "Description / Summary" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["DISPLAY_VALUE"]=> string(2355) "

About 85-90% of patients with acute lymphoblastic leukemia (ALL) recover after modern program therapy. However, the disease may relapse, or acquires a refractory course in 10-15% of the children. For this category of patients, second-line chemotherapy is standardly provided, followed by allogeneic hematopoietic stem cell transplantation (allo-HSCT). However, achievement of molecular/immunological remission is not always possible. In the era of targeted therapy, great hopes are placed on molecularly targeted drugs in order to reach complete molecular/immunological remission and obtain higher survival rates with allo-HSCT. Blinatumomab is among the targeted drugs used to achieve remission in ALL. Its effectiveness depends on a sufficient level of CD3-lymphocytes, CD19 expression, and the number of blast cells in peripheral blood and bone marrow. Our purpose was to present the experience of blinatumomab therapy with transfusions of autologous CD3 lymphocytes in children with recurrent ALL and to evaluate the efficiency of this technique in achieving remission.

Materials and methods

This article presents three clinical cases of patients with recurrent ALL treated at the Research Institute of Pediatric Oncology and Hematology at N. N. Blokhin National Cancer Research Center from July 2021 to February 2022.

Results

Two patients from our series were treated with blinatumomab and received 3 transfusions of CD3-lymphocytes followed by clinical and hematological remission with MRD-negative disease status. One patient, due to concomitant somatic pathology, received only 2 auto-transfusions, but ALL remission was not achieved.

Conclusion

Our experience of using autologous CD3+ lymphocyte transfusions in combination with blinatumomab showed that this technique is safe, reproducible, and may be effective in patients with ALL relapses. In 2 out of 3 patients with weekly infusion of autologous lymphocytes, a complete clinical, hematological and immunological remission of the disease was registered.

Keywords

Acute lymphoblastic leukemia, blinatumomab, lymphocytes, autologous, apheresis, children, MRD status.

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N. N. Blokhin Russian Cancer Research Center, Moscow, Russia


Correspondence:
Dr. Nara G. Stepanyan, Bone Marrow Transplantation Department, N. N. Blokhin Russian Cancer Research Center, 23B Kashirskaya St, 115522, Moscow, Russia
Phone: +7 (903) 247-30-82
E-mail: nara19922@yandex.ru


Citation: Stepanyan NG, Valiev TT, Fatkhullin RR, et al. Efficacy of therapy with blinatumomab and autologous CD3 cell transfusions in relapsing acute lymphoblastic leukemia: A single center experience. Cell Ther Transplant 2022; 11(3-4): 70-76.

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N. N. Blokhin Russian Cancer Research Center, Moscow, Russia


Correspondence:
Dr. Nara G. Stepanyan, Bone Marrow Transplantation Department, N. N. Blokhin Russian Cancer Research Center, 23B Kashirskaya St, 115522, Moscow, Russia
Phone: +7 (903) 247-30-82
E-mail: nara19922@yandex.ru


Citation: Stepanyan NG, Valiev TT, Fatkhullin RR, et al. Efficacy of therapy with blinatumomab and autologous CD3 cell transfusions in relapsing acute lymphoblastic leukemia: A single center experience. Cell Ther Transplant 2022; 11(3-4): 70-76.

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Нара Г. Степанян, Тимур Т. Валиев, Рамиль Р. Фатхуллин, Татьяна Ю. Павлова, Наталья С. Цаплина, Кирилл И. Киргизов, Светлана Р. Варфоломеева

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Нара Г. Степанян, Тимур Т. Валиев, Рамиль Р. Фатхуллин, Татьяна Ю. Павлова, Наталья С. Цаплина, Кирилл И. Киргизов, Светлана Р. Варфоломеева

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Для данной категории пациентов стандартно предусмотрена химиотерапия второй линии с последующей аллогенной трансплантацией гемопоэтических стволовых клеток (алло-ТГСК). Тем не менее, не всегда удается достичь молекулярной/иммунологической ремиссии. В эру таргетной терапии большие надежды возлагаются на молекулярно-направленные препараты для достижения полной молекулярной/иммунологической ремиссии и получения более высоких показателей выживаемости при проведении алло-ТГСК. Одним из таргетных препаратов, применяемых для достижения ремиссии при ОЛЛ, является блинатумомаб, эффективность терапии которым зависит от достаточного уровня СD3-лимфоцитов, экспрессии СD19 и количества бластных клеток в крови и костном мозге. Целью работы было представить опыт терапии блинатумомабом с трансфузиями СD3-аутолимфоцитов у детей с рецидивом ОЛЛ и оценить эффективность данной методики для достижения ремиссии.</p> <h3>Материалы и методы</h3> <p style="text-align: justify;">В настоящей статье представлены 3 клинических случая пациентов с рецидивом ОЛЛ, получавших лечение с июля 2021 года по февраль 2022 года в НИИ детской онкологии и гематологии НМИЦ онкологии им. Н. Н. Блохина.</p> <h3>Результаты</h3> <p style="text-align: justify;">Два пациента из данного наблюдения, проходившие терапию блинатумомабом, получили 4 трансфузии CD3-лимфоцитов, достигли клинико-гематологической ремиссии c МОБ-негативным статусом болезни. Один пациент, ввиду сопутствующей соматической патологии, получил только 2 ауто-трансфузии, но ремиссия ОЛЛ не была достигнута.</p> <h3>Заключение</h3> <p style="text-align: justify;">Опыт применения трансфузий СD3+ауто-лимфоцитов в сочетании с блинатумомабом показал, что данная методика безопасна, воспроизводима и может быть эффективна у пациентов с рецидивами ОЛЛ. У двух пациентов из трех при введении ауто-лимфоцитов каждые 7 дней была зафиксирована полная клинико-гематологическая и иммунологическая ремиссии заболевания. </p> <h2>Ключевые слова</h2> <p style="text-align: justify;">Острый лимфобластный лейкоз, блинатумомаб, лимфоциты, аутологичные, аферез, дети, МОБ-статус.</p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(4140) "

Около 85-90% пациентов с острым лимфобластным лейкозом (ОЛЛ) после проведения современной программной терапии выздоравливают, но у 10-15% детей заболевание рецидивирует или приобретает рефрактерное течение. Для данной категории пациентов стандартно предусмотрена химиотерапия второй линии с последующей аллогенной трансплантацией гемопоэтических стволовых клеток (алло-ТГСК). Тем не менее, не всегда удается достичь молекулярной/иммунологической ремиссии. В эру таргетной терапии большие надежды возлагаются на молекулярно-направленные препараты для достижения полной молекулярной/иммунологической ремиссии и получения более высоких показателей выживаемости при проведении алло-ТГСК. Одним из таргетных препаратов, применяемых для достижения ремиссии при ОЛЛ, является блинатумомаб, эффективность терапии которым зависит от достаточного уровня СD3-лимфоцитов, экспрессии СD19 и количества бластных клеток в крови и костном мозге. Целью работы было представить опыт терапии блинатумомабом с трансфузиями СD3-аутолимфоцитов у детей с рецидивом ОЛЛ и оценить эффективность данной методики для достижения ремиссии.

Материалы и методы

В настоящей статье представлены 3 клинических случая пациентов с рецидивом ОЛЛ, получавших лечение с июля 2021 года по февраль 2022 года в НИИ детской онкологии и гематологии НМИЦ онкологии им. Н. Н. Блохина.

Результаты

Два пациента из данного наблюдения, проходившие терапию блинатумомабом, получили 4 трансфузии CD3-лимфоцитов, достигли клинико-гематологической ремиссии c МОБ-негативным статусом болезни. Один пациент, ввиду сопутствующей соматической патологии, получил только 2 ауто-трансфузии, но ремиссия ОЛЛ не была достигнута.

Заключение

Опыт применения трансфузий СD3+ауто-лимфоцитов в сочетании с блинатумомабом показал, что данная методика безопасна, воспроизводима и может быть эффективна у пациентов с рецидивами ОЛЛ. У двух пациентов из трех при введении ауто-лимфоцитов каждые 7 дней была зафиксирована полная клинико-гематологическая и иммунологическая ремиссии заболевания.

Ключевые слова

Острый лимфобластный лейкоз, блинатумомаб, лимфоциты, аутологичные, аферез, дети, МОБ-статус.

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Около 85-90% пациентов с острым лимфобластным лейкозом (ОЛЛ) после проведения современной программной терапии выздоравливают, но у 10-15% детей заболевание рецидивирует или приобретает рефрактерное течение. Для данной категории пациентов стандартно предусмотрена химиотерапия второй линии с последующей аллогенной трансплантацией гемопоэтических стволовых клеток (алло-ТГСК). Тем не менее, не всегда удается достичь молекулярной/иммунологической ремиссии. В эру таргетной терапии большие надежды возлагаются на молекулярно-направленные препараты для достижения полной молекулярной/иммунологической ремиссии и получения более высоких показателей выживаемости при проведении алло-ТГСК. Одним из таргетных препаратов, применяемых для достижения ремиссии при ОЛЛ, является блинатумомаб, эффективность терапии которым зависит от достаточного уровня СD3-лимфоцитов, экспрессии СD19 и количества бластных клеток в крови и костном мозге. Целью работы было представить опыт терапии блинатумомабом с трансфузиями СD3-аутолимфоцитов у детей с рецидивом ОЛЛ и оценить эффективность данной методики для достижения ремиссии.

Материалы и методы

В настоящей статье представлены 3 клинических случая пациентов с рецидивом ОЛЛ, получавших лечение с июля 2021 года по февраль 2022 года в НИИ детской онкологии и гематологии НМИЦ онкологии им. Н. Н. Блохина.

Результаты

Два пациента из данного наблюдения, проходившие терапию блинатумомабом, получили 4 трансфузии CD3-лимфоцитов, достигли клинико-гематологической ремиссии c МОБ-негативным статусом болезни. Один пациент, ввиду сопутствующей соматической патологии, получил только 2 ауто-трансфузии, но ремиссия ОЛЛ не была достигнута.

Заключение

Опыт применения трансфузий СD3+ауто-лимфоцитов в сочетании с блинатумомабом показал, что данная методика безопасна, воспроизводима и может быть эффективна у пациентов с рецидивами ОЛЛ. У двух пациентов из трех при введении ауто-лимфоцитов каждые 7 дней была зафиксирована полная клинико-гематологическая и иммунологическая ремиссии заболевания.

Ключевые слова

Острый лимфобластный лейкоз, блинатумомаб, лимфоциты, аутологичные, аферез, дети, МОБ-статус.

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Национальный медицинский исследовательский центр онкологии им. Н. Н. Блохина, Москва, Россия

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Национальный медицинский исследовательский центр онкологии им. Н. Н. Блохина, Москва, Россия

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Introduction

Acute myeloid leukemia (AML) with a mutation in tyrosine kinase 3 (FLT3) gene represents one-third of the de novo AML cases [1, 2, 3, 4]. Mutations in the FLT3 gene (in particular, internal tandem duplication (ITD)) tend to cause poor outcomes, with an increased risk of relapse and shorter overall survival (OS) compared to patients without the mutation [4, 5, 6]. Thus, according to the NCCN Clinical Practice Guidelines in Oncology, AML cases with FLT3-ITD mutation in presence of normal karyotype should be interpreted as patients with poor prognosis [5, 7]. Based on European LeukemiaNet risk stratification by genetics (ELN risk), the prognostic risk in AML with FLT3-mutation also depends on FLT3-ITD allelic ratio, presence of an additional NPM1-mutation and accessory karyotype abnormalities [3, 5, 8].

The rate of remission after standard chemotherapy (ChT) varies from 60 to 70% for patients with de novo AML younger than 50 years [10]. The addition of midostaurin to frontline ChT improved OS (by 7.1% after 4 years to 51.4%). Also event-free survival (EFS) and disease-free survival (DFS) showed better result in the midostaurin group (8.2 months vs. 3.0 months and 26.7 months vs. 15.5 months, respectively) [9]. Nevertheless, challenges of the treatment of patients with refractory/relapsed (R/R) AML remain, where the chances for achieving remission do not exceed 30% [12]. As a result, patients with R/R AML have poor outcomes with 3-year overall survival (OS) around 10% [11].

A retrospective analysis of the 2-year overall survival (OS2) after allogeneic hematopoietic stem cell transplantation (allo-HSCT) in a second complete remission demonstrated promising 50% OS, compared to allo-HSCT performed in active disease (first relapsed or refractory AML) with OS2 of ca. 20% [13, 14]. Thus, the main goal of therapy in patients with R/R AML is to achieve remission then followed by allogeneic HSCT.

A combination of high-dose cytarabine and purine analogues (fludarabine, cladribine) demonstrated a higher response rate in patients with R/R AML being, however, associated with considerable toxicity [16, 17, 18]. For patients with FLT3-mutated AML, therapy with FLT3 inhibitors showed promising results even in the case of R/R AML [19].

The current study aims to evaluate the response rate, overall survival (OS), relapse-free survival (RFS) and toxicity of gilteritinib in adult patients with R/R AML with FLT3-mutation.

Patients and methods

Between 2019 and 2021, 48 patients with R/R AML FLT3-mutated with a median age of 53 (18-79) years were included in the study. Most of the patients were with de novo AML (79.2%). Patients with secondary AML (20.8%) included transition form myelodysplastic syndrome (MDS), chronic myelomonocytic leukemia (CMML) and chronic myeloproliferative neoplasm (CMN). Primary-refractory patients (p/r AML) comprised 31.2%; among relapsed AML, 54.2% had a first relapse and 14.6% had 2 or more relapses (relAML). The ITD mutation was detected in 89.6% and TKD –mutation in 10.4% of cases.

Despite the median age of patients included in the study, allo-HSCT after gilteritinib was performed in 29% of cases. The type of donors was as follows: unrelated, in 9 cases; haploidentical, in 5 patients. The median time between treatment by gilteritinib and allo-HSCT was 12 days (range 7-54 days). In 3 patients, the relapses after first allo-HSCT were treated with ginteritinib. Characteristics of the patients are presented in Table 1.

Table 1. Characteristics of the patients

Aubova-tab01-01.jpgAubova-tab01-02.jpg Aubova-tab01-03.jpg

Notes: AML, acute myeloid leukemia; MDS, Myelodysplastic syndrome; CMML, Chronic myelomonocytic leukemia; CMN, Chronic myeloproliferative neoplasm; ECOG, Eastern Cooperative Oncology Group (ECOG) Performance Status; FLT3, FMS-like tyrosin kinase 3; ITD, internal tandem mutation; TKD, mutation surrounding D835 in TK domain; BM, bone marrow; CNS, central nervous system; allo-HSCT, allogeneic hematopoietic stem cell transplantation.

Morphological evaluation of bone marrow (BM) aspirate, immunophenotyping of bone marrow cells, standard cytogenetic and molecular assays were performed in all patients before therapy. The median level of blasts in the BM was 47.6% (6-97). Cytogenetic analysis was performed on R-banded metaphases after 24-h culture using standard procedures. The following targets were evaluated by real-time polymerase chain reaction (PCR): CBFB-MYH11, BCR/ABL p210 and BCR/ABL p190, PML/RARa, RUNX1-RUNX1T1, EVI1, FLT3-ITD, FLT3-TKD (D835), DMT3A, MLL partial tandem duplication, WT1, BAALC gene expression. Assessment of minimal residual disease (MRD) status included both flow cytometric assays (FCI) and PCR.

This study included patients with Eastern Cooperative Oncology Group (ECOG) performance status ≤3 as well as without moderate/severe hepatic dysfunction or heart disease. P/r AML was defined as more than 5% of clonal blast cells in bone marrow after one (or more) induction chemotherapy with anthracyclines (with or without FLT3-inhibitors). Response criteria after treatment were based on The European Leukemia Net (ELN) 2017 Recommendations [8]. Response was assessed on day 28 of 1st course (or 2nd in cases without response after first course). Toxicity was determined by the National Cancer Institute Grading Scale (NCI Grading Scale) version 5.0.

All patients recieved gilteritinib 120 mg once daily for at least 28 days (single-course therapy) [19]. Patients, who achieved response after 1st course, continued the therapy up to allo-HSCT. Those who achieved reduced blasts count in the bone marrow were able to receive 2nd course. Antiviral prophylaxis (acyclovir) and Pneumocystis prophylaxis (trimethoprim-sulfamethoxazole) were given to all patients. Primary antifungal prophylaxis for patients was performed with voriconazole. All patients received prophylactic treatment for infections during the period when the absolute neutrophil count was less than 0.5×109/l.

Statistical analysis

Overall survival (OS) and disease-free survival (DFS), event-free survival (EFS) were evaluated using Kaplan-Meier method, the influence of factors on OS and RFS were evaluated by the Mantel-Cox log-rank criterion. Multivariate analysis was performed with Cox model after the proportional hazards assumption was checked. The OS was calculated from the starting date of the treatment to the date of the last contact. RFS was defined from the date of overall response (complete remission, remission with incomplete recovery) to the date of relapse, death or last contact. EFS was defined as the time from the start date of treatment to the time when refractory disease was confirmed (the date of failure to achieve a response), relapse, or death from any cause (censored at last contact). Overall response (OR) assessment included patients with complete remission (CR), remission with incomplete recovery (CRi/r), morphological leukaemia-free state (MLFS). Therapy-related mortality was defined as death within 30 days of Giteritinib initiation. Pearson's chi-square test was used for binary variables with the number of expected observations in any of the fields in a four-field table less than 5, Fisher's exact test was used to assess the level of significance of the differences. Multivariate analysis was done using proportional hazard regression. Differences at a p-value less than 0.05 were considered statistically significant. Statistical analyses were performed with the standard statistical software package StatTech 2.8.4.

Results

Clinical response to gilteritinib

More than a half of the patients received the 28-day gilteritinib therapy administered in 1 or >2 cycles (56.2% and 27.1%, respectively), as seen from Table 1. Overall response (OR) rate was 77.1% (CI 95% 65.7-88.3): complete remission (CR) was documented in 15 (31.2%) patients, remission with incomplete recovery (CRi/r) and morphological leukemia-free state (MLFS) were registered in 11 patients (22.9%) each. Among the responders, CR/CRi/r/MLFS were achieved in 83.8% (31 patients) after 1st cycle and in 16.2% after 2nd treatment cycle. Among 15 patients with CR, MRD was evaluated in 6 patients on day 28 after starting the therapy), being positive in 5 cases.

In 14 of 48 patients, allo-HSCT was subsequently performed, thus making up 29.2% (CI 95% 18.2-43.2) of all treated patients. The median age of this group was 43.1 (18-68) years. The median time from OR after gilteritinib to allo-HSCT was 45 (24-156) days. The main reasons for failure to undergo allo-HSCT was elderly age (18 patients over 65), and sufficient co-morbidities; relapse of AML during donor search revealed in 6 cases (at <60 days); early death (<60 days of therapy), in 8 patients. Poor performance status was the reason for postponing allograft in 2 patients.

In the univariate and multivariate analysis, there was no correlations between the response rates and clinical factors, e.g., patient’s age, ELN risk, WT1 levels before therapy, presence ITD or TKD mutation in the FLT3 gene, previous therapy, relAML or p/r AML, early versus late relapse, blast cell counts.

Analysis of survival outcomes after gilteritinib therapy

The median follow-up period was 16.5 (CI 95% 11.4-21.6) months. One-year OS (OS1) after gilteritinib was 39.9%, with a median survival of 6.3 months (95% CI: 4.7-12.0 months). DFS (DFS1) in the group of patients who achieved remission (37 patients) was 40.5%. The median DFS1 was 7.7 months (4.4-11.0 months) in this group of patients.

In the multivariate analysis, statistically significant factors influencing OS were as follows: achievement of response (HR=0.16; CI 95%: 0.05-0.47; p<0.01) (Table 2; Fig. 1) and allo-HSCT (HR=0.06; CI 95%: 0.01-0.44; p<0.01) (Table 2; Fig. 2). DFS was also significantly better in group of patients with subsequent allo-HSCT (HR=0.18; CI 95%: 0.04-0.8; p=0.02) (Fig. 2).

Table 2. Analysis of potential OS predictors in the patients treated with gilteritinib

Aubova-tab02.jpg

* – association of the outcome value with the predictor value is statistically significant (p < 0.05)
Notes: allo-HSCT, allogeneic hematopoietic stem cell transplantation; ELN risk, genetic risk stratification scale by ELN criteria (2017)

Aubova-fig01-02.jpg

Median survival in patient without OR was 2.2 months (95% CI: 0.6-3.5 months), median survival in patients with OR was 10.7 months (95% CI: 5.9-30.2 months).

Median survival in patients without allo-HSCT was 5.3 months (95% CI: 2.5-6.9 months), whereas median survival in patients with subsequent allo-HSCT cannot be estimated.

Median survival in cases without allo-HSCT was 5.7 months (95% CI: 4.3-10.7 months), median survival in patients with subsequent allo-HSCT was 20.3 months as seen from Fig. 3 (95% CI: 5.9 > months).

In the multivariate analysis, EFS was significantly associated with successful bridging to allo-HSCT (HR=0.31; CI 95%: 0.12-0.82; p<0.018). Age, status of AML before gilteritinib therapy, previously therapy showed no correlation with EFS, as seen from Fig. 4 and Table 3.

Table 3. Relative risk analysis for the different EFS predictors in the gilteritinib-treated patients

Aubova-tab03.jpg

* – association of the outcome value with the predictor value is statistically significant (p < 0.05)
Notes: Allo-HSCT, allogeneic hematopoietic stem cell transplantation; Previous therapies: A, Induction therapy (1 or 2 cycles of chemotherapy with anthracyclines); B, High-dose chemotherapy (consolidation) or second-line chemotherapy (no intensive therapy); C, Previous allo-HSCT.

Aubova-fig03-04.jpg

Toxicity of gilteritinib therapy

Hematological toxicity was the most common complication of the therapy. Among 39 patients, neutropenia (grade 3-4) was observed in 97.4% of cases (38/39); grade 3-4 thrombocytopenia, in 69.3% (27/39), and grade 3-4 anemia was registered in 37.2% (18/35). The median duration of grade 4 neutropenia and thrombocytopenia was 36 (4-425) days and 55 (4-325) days, respectively. Severe hemorrhagic complications occurred in 1 of 48 patients (cerebral hemorrhage, 2.1%). In 29.4% (10/34), we have diagnosed infectious complications. Sepsis/bacteremia developed in 7 of 34 patients, 20.6% (CI 95% 10.4-36.8). Bacterial pneumonia was observed in 3 cases (8.8%, CI 95% 3.1-23).

Non-haematological toxicity of any grade included myalgia or arthralgia (15.2%), dry skin (12.1%), dyspnoea (6.1%), nausea (6.1%), headache (3%), arrhythmia (3%), increased transaminases (3%), and high blood pressure (3%). A prolonged QT syndrome has been reported in one patient. The observed complications after gilteritinib therapy are summarized in Fig. 5.

Aubova-fig05.jpg

Figure 5. Frequencies of complications observed after gilteritinib treatment

Mortality during treatment (up to 30 days) was 6.3% (CI95% 3.3-19.6), i.e. 3 of 48 patients. The causes of death in 2 patients were infectious complications (including 1 case of COVID-19), and 1 patient died after cerebral hemorrhage.

Discussion

AML with FLT3 mutations is of particular interest thus being quite often considered a separate group for several reasons, e.g.: epidemiological, prognostic, and special therapeutic features options. Mutations in FMS-like tyrosin kinase 3 proteins occur in approximately 30% of patients with AML. ITD is the most common mutation which is found in up to 25% (and in >30% of patients older than 55 years). Approximately 10% of mutations in the FLT3 gene involve point mutations, deletions, and insertions in codons surrounding D835 position within the FLT3 TK domain (FLT3-TKD) [1-8].

AML with FLT3 mutations (primary FLT3-ITD) is associated as subtype of AML with higher relapse rate, shorter remission period, decreased survival, especially when NPM1 is not co-mutated and the allelic FLT3-ITD/wild-type ratio is high [6, 7, 20]. According to some recent studies by Kiyoi et al., Sakaguchi M. et al, which concerned Japanese AML patients, the long-term prognosis in FLT3-ITDlow AML was similar to FLT3-ITDhigh patient group [21, 22].

In a view of the above, mutations in FLT3 can be considered as a promising molecular target for the treatment of patients with FLT3-mutated AML. The first-generation FLT3 inhibitors (sunitinib, tandutinib, and lestaurtinib) applied as monotherapy for AML patients with FLT3 mutation did not demonstrate efficacy and have shown clinically relevant adverse events [6, 21]. However, according to the CALGB 10603 (RATIFY) trial, the addition of midostaurin to induction ChT improved OS by 7.1% after 4 years to 51.4%, with satisfactory toxicity profile of the therapy [9]. Based on the results of this study, midostaurin was approved as a combination agent with standard ("7+3" ChT) induction therapy for newly diagnosed AML by the US Food and Drug Administration (FDA) in 2017. In the RATIFY study, allo-HSCT in first remission was performed in 28.1% (n=101) of patients, and the transplants did not show therapeutic benefit (p=0.85). Observations are still ongoing, but the currently available data show up to 8-11% of relapses even after allo- HSCT in the first remission on the background of FLT3 inhibitor therapy [6]. Of note, the patients in the midostaurin group underwent allo-HSCT earlier than those in the control group. Hence, the timing of allo-HSCT in the first remission may influence the positive outcomes [23].

The outcome in the patients with primary refractory or relapsed AML remains dismal. Retrospective analysis found OS rates from 4% to 38%, being dependent on time of relapse and previous allo-HSCT [3, 24]. Allo-HSCT remains the only option to achieve a long-term favorable outcomes in R/R AML [3, 15, 25]. A retrospective analysis of the 2-year overall survival (OS2) after allo-HSCT in the 2nd complete remission demonstrated promising 50% OS, compared to allo-HSCT in active disease (first relapsed or RefAML) where OS2 was around 20% [13, 14]. Multivariate analysis in these studies identified allo-HSCT in a first CR as the single favorable prognostic factor (RFS, p=0.001; OS, p=0.001). Sakaguchi M. et al. also found that prognosis was unfavorable in NPM1mut AML with FLT3-ITDlow in patients, who have not received allo-HSCT in first CR [22].

Intensive ChT may improve outcomes for R/R AML by increasing remission rates to 40-60%, but it is associated with considerable toxicity [16, 17, 18]. FLT3 inhibitors demonstrate encouraging results in AML patients with FLT3 mutations [3, 19, 24]. Based on the results of the ADMIRAL study, the FDA approved gilteritinib for R/R FLT3-mutated AML therapy in adult patients in 2018 [7]. This study demonstrated a favorable response rate (ORR was achieved in 67.2%) and improved OS compared with ChT (median OS 9.3 vs 5.6 months) [4].

Treatment-related adverse events of grade ≥ 3 were reported in 60.2% of patients. The most common were, e.g., anemia (40.7%), febrile neutropenia (45.9%) and thrombocytopenia (22.8%). Increased alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels were observed in 13.8% and 14.6% of patients, respectively. Dose reduction or interruption of the therapy due to a toxicity were required in 6% and 29%, respectively [4].

Despite favorable response rate and lower toxicity of therapy compared to salvage ChT, only 25.5% (63 of 247 patients) of gilteritinib-treated patients underwent allo-HSCT in the ADMIRAL study [7]. In our study, this rate was slightly higher and reached 29.2%. The main reason for refusal of allo-HSCT was older age of patients (in the study ADMIRAL the median age of patients ware 62 years, in our study, 53 years with 18 patients over 65 years). Considering the importance of early allo-HSCT option, finding a relative donor for patients over the age of 65 is a challenging task. In our study, allo-HSCT was performed from haploidentical donors in 5 cases and from unrelated donors, in 9 cases, with median time of 45 days from OR after gilteritinib to HSCT.

According to the data of ADMIRAL trial, the median event-free survival was 2.8 months in the gilteritinib group. In our study, subsequent transplantation was an independent factor improving the outcome of leukemia. An extremely short window for transplantation after remission might be the key issue for favorable outcome.

Conclusion

Gilteritinib in patients with R/R FLT3-mutated AML demonstrated favorable outcomes with a satisfactory tolerance to the therapy. Patients who subsequently underwent allo-HSCT had statistically significantly better OS, DFS and EFS. Thus, gilteritinib can be used as a bridge to allo-HSCT in adult patients with R/R FLT3-mutated AML.

Conflict of interest

The authors declare that they have no conflict of interest.

Compliance with ethical standards

All human studies have been approved by the appropriate University Ethics Committee and have been performed in accordance with the ethical standards laid down in the 1964 Declaration of Helsinki and its later amendments. All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1975, as revised in 2008.

References

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Introduction

Acute myeloid leukemia (AML) with a mutation in tyrosine kinase 3 (FLT3) gene represents one-third of the de novo AML cases [1, 2, 3, 4]. Mutations in the FLT3 gene (in particular, internal tandem duplication (ITD)) tend to cause poor outcomes, with an increased risk of relapse and shorter overall survival (OS) compared to patients without the mutation [4, 5, 6]. Thus, according to the NCCN Clinical Practice Guidelines in Oncology, AML cases with FLT3-ITD mutation in presence of normal karyotype should be interpreted as patients with poor prognosis [5, 7]. Based on European LeukemiaNet risk stratification by genetics (ELN risk), the prognostic risk in AML with FLT3-mutation also depends on FLT3-ITD allelic ratio, presence of an additional NPM1-mutation and accessory karyotype abnormalities [3, 5, 8].

The rate of remission after standard chemotherapy (ChT) varies from 60 to 70% for patients with de novo AML younger than 50 years [10]. The addition of midostaurin to frontline ChT improved OS (by 7.1% after 4 years to 51.4%). Also event-free survival (EFS) and disease-free survival (DFS) showed better result in the midostaurin group (8.2 months vs. 3.0 months and 26.7 months vs. 15.5 months, respectively) [9]. Nevertheless, challenges of the treatment of patients with refractory/relapsed (R/R) AML remain, where the chances for achieving remission do not exceed 30% [12]. As a result, patients with R/R AML have poor outcomes with 3-year overall survival (OS) around 10% [11].

A retrospective analysis of the 2-year overall survival (OS2) after allogeneic hematopoietic stem cell transplantation (allo-HSCT) in a second complete remission demonstrated promising 50% OS, compared to allo-HSCT performed in active disease (first relapsed or refractory AML) with OS2 of ca. 20% [13, 14]. Thus, the main goal of therapy in patients with R/R AML is to achieve remission then followed by allogeneic HSCT.

A combination of high-dose cytarabine and purine analogues (fludarabine, cladribine) demonstrated a higher response rate in patients with R/R AML being, however, associated with considerable toxicity [16, 17, 18]. For patients with FLT3-mutated AML, therapy with FLT3 inhibitors showed promising results even in the case of R/R AML [19].

The current study aims to evaluate the response rate, overall survival (OS), relapse-free survival (RFS) and toxicity of gilteritinib in adult patients with R/R AML with FLT3-mutation.

Patients and methods

Between 2019 and 2021, 48 patients with R/R AML FLT3-mutated with a median age of 53 (18-79) years were included in the study. Most of the patients were with de novo AML (79.2%). Patients with secondary AML (20.8%) included transition form myelodysplastic syndrome (MDS), chronic myelomonocytic leukemia (CMML) and chronic myeloproliferative neoplasm (CMN). Primary-refractory patients (p/r AML) comprised 31.2%; among relapsed AML, 54.2% had a first relapse and 14.6% had 2 or more relapses (relAML). The ITD mutation was detected in 89.6% and TKD –mutation in 10.4% of cases.

Despite the median age of patients included in the study, allo-HSCT after gilteritinib was performed in 29% of cases. The type of donors was as follows: unrelated, in 9 cases; haploidentical, in 5 patients. The median time between treatment by gilteritinib and allo-HSCT was 12 days (range 7-54 days). In 3 patients, the relapses after first allo-HSCT were treated with ginteritinib. Characteristics of the patients are presented in Table 1.

Table 1. Characteristics of the patients

Aubova-tab01-01.jpgAubova-tab01-02.jpg Aubova-tab01-03.jpg

Notes: AML, acute myeloid leukemia; MDS, Myelodysplastic syndrome; CMML, Chronic myelomonocytic leukemia; CMN, Chronic myeloproliferative neoplasm; ECOG, Eastern Cooperative Oncology Group (ECOG) Performance Status; FLT3, FMS-like tyrosin kinase 3; ITD, internal tandem mutation; TKD, mutation surrounding D835 in TK domain; BM, bone marrow; CNS, central nervous system; allo-HSCT, allogeneic hematopoietic stem cell transplantation.

Morphological evaluation of bone marrow (BM) aspirate, immunophenotyping of bone marrow cells, standard cytogenetic and molecular assays were performed in all patients before therapy. The median level of blasts in the BM was 47.6% (6-97). Cytogenetic analysis was performed on R-banded metaphases after 24-h culture using standard procedures. The following targets were evaluated by real-time polymerase chain reaction (PCR): CBFB-MYH11, BCR/ABL p210 and BCR/ABL p190, PML/RARa, RUNX1-RUNX1T1, EVI1, FLT3-ITD, FLT3-TKD (D835), DMT3A, MLL partial tandem duplication, WT1, BAALC gene expression. Assessment of minimal residual disease (MRD) status included both flow cytometric assays (FCI) and PCR.

This study included patients with Eastern Cooperative Oncology Group (ECOG) performance status ≤3 as well as without moderate/severe hepatic dysfunction or heart disease. P/r AML was defined as more than 5% of clonal blast cells in bone marrow after one (or more) induction chemotherapy with anthracyclines (with or without FLT3-inhibitors). Response criteria after treatment were based on The European Leukemia Net (ELN) 2017 Recommendations [8]. Response was assessed on day 28 of 1st course (or 2nd in cases without response after first course). Toxicity was determined by the National Cancer Institute Grading Scale (NCI Grading Scale) version 5.0.

All patients recieved gilteritinib 120 mg once daily for at least 28 days (single-course therapy) [19]. Patients, who achieved response after 1st course, continued the therapy up to allo-HSCT. Those who achieved reduced blasts count in the bone marrow were able to receive 2nd course. Antiviral prophylaxis (acyclovir) and Pneumocystis prophylaxis (trimethoprim-sulfamethoxazole) were given to all patients. Primary antifungal prophylaxis for patients was performed with voriconazole. All patients received prophylactic treatment for infections during the period when the absolute neutrophil count was less than 0.5×109/l.

Statistical analysis

Overall survival (OS) and disease-free survival (DFS), event-free survival (EFS) were evaluated using Kaplan-Meier method, the influence of factors on OS and RFS were evaluated by the Mantel-Cox log-rank criterion. Multivariate analysis was performed with Cox model after the proportional hazards assumption was checked. The OS was calculated from the starting date of the treatment to the date of the last contact. RFS was defined from the date of overall response (complete remission, remission with incomplete recovery) to the date of relapse, death or last contact. EFS was defined as the time from the start date of treatment to the time when refractory disease was confirmed (the date of failure to achieve a response), relapse, or death from any cause (censored at last contact). Overall response (OR) assessment included patients with complete remission (CR), remission with incomplete recovery (CRi/r), morphological leukaemia-free state (MLFS). Therapy-related mortality was defined as death within 30 days of Giteritinib initiation. Pearson's chi-square test was used for binary variables with the number of expected observations in any of the fields in a four-field table less than 5, Fisher's exact test was used to assess the level of significance of the differences. Multivariate analysis was done using proportional hazard regression. Differences at a p-value less than 0.05 were considered statistically significant. Statistical analyses were performed with the standard statistical software package StatTech 2.8.4.

Results

Clinical response to gilteritinib

More than a half of the patients received the 28-day gilteritinib therapy administered in 1 or >2 cycles (56.2% and 27.1%, respectively), as seen from Table 1. Overall response (OR) rate was 77.1% (CI 95% 65.7-88.3): complete remission (CR) was documented in 15 (31.2%) patients, remission with incomplete recovery (CRi/r) and morphological leukemia-free state (MLFS) were registered in 11 patients (22.9%) each. Among the responders, CR/CRi/r/MLFS were achieved in 83.8% (31 patients) after 1st cycle and in 16.2% after 2nd treatment cycle. Among 15 patients with CR, MRD was evaluated in 6 patients on day 28 after starting the therapy), being positive in 5 cases.

In 14 of 48 patients, allo-HSCT was subsequently performed, thus making up 29.2% (CI 95% 18.2-43.2) of all treated patients. The median age of this group was 43.1 (18-68) years. The median time from OR after gilteritinib to allo-HSCT was 45 (24-156) days. The main reasons for failure to undergo allo-HSCT was elderly age (18 patients over 65), and sufficient co-morbidities; relapse of AML during donor search revealed in 6 cases (at <60 days); early death (<60 days of therapy), in 8 patients. Poor performance status was the reason for postponing allograft in 2 patients.

In the univariate and multivariate analysis, there was no correlations between the response rates and clinical factors, e.g., patient’s age, ELN risk, WT1 levels before therapy, presence ITD or TKD mutation in the FLT3 gene, previous therapy, relAML or p/r AML, early versus late relapse, blast cell counts.

Analysis of survival outcomes after gilteritinib therapy

The median follow-up period was 16.5 (CI 95% 11.4-21.6) months. One-year OS (OS1) after gilteritinib was 39.9%, with a median survival of 6.3 months (95% CI: 4.7-12.0 months). DFS (DFS1) in the group of patients who achieved remission (37 patients) was 40.5%. The median DFS1 was 7.7 months (4.4-11.0 months) in this group of patients.

In the multivariate analysis, statistically significant factors influencing OS were as follows: achievement of response (HR=0.16; CI 95%: 0.05-0.47; p<0.01) (Table 2; Fig. 1) and allo-HSCT (HR=0.06; CI 95%: 0.01-0.44; p<0.01) (Table 2; Fig. 2). DFS was also significantly better in group of patients with subsequent allo-HSCT (HR=0.18; CI 95%: 0.04-0.8; p=0.02) (Fig. 2).

Table 2. Analysis of potential OS predictors in the patients treated with gilteritinib

Aubova-tab02.jpg

* – association of the outcome value with the predictor value is statistically significant (p < 0.05)
Notes: allo-HSCT, allogeneic hematopoietic stem cell transplantation; ELN risk, genetic risk stratification scale by ELN criteria (2017)

Aubova-fig01-02.jpg

Median survival in patient without OR was 2.2 months (95% CI: 0.6-3.5 months), median survival in patients with OR was 10.7 months (95% CI: 5.9-30.2 months).

Median survival in patients without allo-HSCT was 5.3 months (95% CI: 2.5-6.9 months), whereas median survival in patients with subsequent allo-HSCT cannot be estimated.

Median survival in cases without allo-HSCT was 5.7 months (95% CI: 4.3-10.7 months), median survival in patients with subsequent allo-HSCT was 20.3 months as seen from Fig. 3 (95% CI: 5.9 > months).

In the multivariate analysis, EFS was significantly associated with successful bridging to allo-HSCT (HR=0.31; CI 95%: 0.12-0.82; p<0.018). Age, status of AML before gilteritinib therapy, previously therapy showed no correlation with EFS, as seen from Fig. 4 and Table 3.

Table 3. Relative risk analysis for the different EFS predictors in the gilteritinib-treated patients

Aubova-tab03.jpg

* – association of the outcome value with the predictor value is statistically significant (p < 0.05)
Notes: Allo-HSCT, allogeneic hematopoietic stem cell transplantation; Previous therapies: A, Induction therapy (1 or 2 cycles of chemotherapy with anthracyclines); B, High-dose chemotherapy (consolidation) or second-line chemotherapy (no intensive therapy); C, Previous allo-HSCT.

Aubova-fig03-04.jpg

Toxicity of gilteritinib therapy

Hematological toxicity was the most common complication of the therapy. Among 39 patients, neutropenia (grade 3-4) was observed in 97.4% of cases (38/39); grade 3-4 thrombocytopenia, in 69.3% (27/39), and grade 3-4 anemia was registered in 37.2% (18/35). The median duration of grade 4 neutropenia and thrombocytopenia was 36 (4-425) days and 55 (4-325) days, respectively. Severe hemorrhagic complications occurred in 1 of 48 patients (cerebral hemorrhage, 2.1%). In 29.4% (10/34), we have diagnosed infectious complications. Sepsis/bacteremia developed in 7 of 34 patients, 20.6% (CI 95% 10.4-36.8). Bacterial pneumonia was observed in 3 cases (8.8%, CI 95% 3.1-23).

Non-haematological toxicity of any grade included myalgia or arthralgia (15.2%), dry skin (12.1%), dyspnoea (6.1%), nausea (6.1%), headache (3%), arrhythmia (3%), increased transaminases (3%), and high blood pressure (3%). A prolonged QT syndrome has been reported in one patient. The observed complications after gilteritinib therapy are summarized in Fig. 5.

Aubova-fig05.jpg

Figure 5. Frequencies of complications observed after gilteritinib treatment

Mortality during treatment (up to 30 days) was 6.3% (CI95% 3.3-19.6), i.e. 3 of 48 patients. The causes of death in 2 patients were infectious complications (including 1 case of COVID-19), and 1 patient died after cerebral hemorrhage.

Discussion

AML with FLT3 mutations is of particular interest thus being quite often considered a separate group for several reasons, e.g.: epidemiological, prognostic, and special therapeutic features options. Mutations in FMS-like tyrosin kinase 3 proteins occur in approximately 30% of patients with AML. ITD is the most common mutation which is found in up to 25% (and in >30% of patients older than 55 years). Approximately 10% of mutations in the FLT3 gene involve point mutations, deletions, and insertions in codons surrounding D835 position within the FLT3 TK domain (FLT3-TKD) [1-8].

AML with FLT3 mutations (primary FLT3-ITD) is associated as subtype of AML with higher relapse rate, shorter remission period, decreased survival, especially when NPM1 is not co-mutated and the allelic FLT3-ITD/wild-type ratio is high [6, 7, 20]. According to some recent studies by Kiyoi et al., Sakaguchi M. et al, which concerned Japanese AML patients, the long-term prognosis in FLT3-ITDlow AML was similar to FLT3-ITDhigh patient group [21, 22].

In a view of the above, mutations in FLT3 can be considered as a promising molecular target for the treatment of patients with FLT3-mutated AML. The first-generation FLT3 inhibitors (sunitinib, tandutinib, and lestaurtinib) applied as monotherapy for AML patients with FLT3 mutation did not demonstrate efficacy and have shown clinically relevant adverse events [6, 21]. However, according to the CALGB 10603 (RATIFY) trial, the addition of midostaurin to induction ChT improved OS by 7.1% after 4 years to 51.4%, with satisfactory toxicity profile of the therapy [9]. Based on the results of this study, midostaurin was approved as a combination agent with standard ("7+3" ChT) induction therapy for newly diagnosed AML by the US Food and Drug Administration (FDA) in 2017. In the RATIFY study, allo-HSCT in first remission was performed in 28.1% (n=101) of patients, and the transplants did not show therapeutic benefit (p=0.85). Observations are still ongoing, but the currently available data show up to 8-11% of relapses even after allo- HSCT in the first remission on the background of FLT3 inhibitor therapy [6]. Of note, the patients in the midostaurin group underwent allo-HSCT earlier than those in the control group. Hence, the timing of allo-HSCT in the first remission may influence the positive outcomes [23].

The outcome in the patients with primary refractory or relapsed AML remains dismal. Retrospective analysis found OS rates from 4% to 38%, being dependent on time of relapse and previous allo-HSCT [3, 24]. Allo-HSCT remains the only option to achieve a long-term favorable outcomes in R/R AML [3, 15, 25]. A retrospective analysis of the 2-year overall survival (OS2) after allo-HSCT in the 2nd complete remission demonstrated promising 50% OS, compared to allo-HSCT in active disease (first relapsed or RefAML) where OS2 was around 20% [13, 14]. Multivariate analysis in these studies identified allo-HSCT in a first CR as the single favorable prognostic factor (RFS, p=0.001; OS, p=0.001). Sakaguchi M. et al. also found that prognosis was unfavorable in NPM1mut AML with FLT3-ITDlow in patients, who have not received allo-HSCT in first CR [22].

Intensive ChT may improve outcomes for R/R AML by increasing remission rates to 40-60%, but it is associated with considerable toxicity [16, 17, 18]. FLT3 inhibitors demonstrate encouraging results in AML patients with FLT3 mutations [3, 19, 24]. Based on the results of the ADMIRAL study, the FDA approved gilteritinib for R/R FLT3-mutated AML therapy in adult patients in 2018 [7]. This study demonstrated a favorable response rate (ORR was achieved in 67.2%) and improved OS compared with ChT (median OS 9.3 vs 5.6 months) [4].

Treatment-related adverse events of grade ≥ 3 were reported in 60.2% of patients. The most common were, e.g., anemia (40.7%), febrile neutropenia (45.9%) and thrombocytopenia (22.8%). Increased alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels were observed in 13.8% and 14.6% of patients, respectively. Dose reduction or interruption of the therapy due to a toxicity were required in 6% and 29%, respectively [4].

Despite favorable response rate and lower toxicity of therapy compared to salvage ChT, only 25.5% (63 of 247 patients) of gilteritinib-treated patients underwent allo-HSCT in the ADMIRAL study [7]. In our study, this rate was slightly higher and reached 29.2%. The main reason for refusal of allo-HSCT was older age of patients (in the study ADMIRAL the median age of patients ware 62 years, in our study, 53 years with 18 patients over 65 years). Considering the importance of early allo-HSCT option, finding a relative donor for patients over the age of 65 is a challenging task. In our study, allo-HSCT was performed from haploidentical donors in 5 cases and from unrelated donors, in 9 cases, with median time of 45 days from OR after gilteritinib to HSCT.

According to the data of ADMIRAL trial, the median event-free survival was 2.8 months in the gilteritinib group. In our study, subsequent transplantation was an independent factor improving the outcome of leukemia. An extremely short window for transplantation after remission might be the key issue for favorable outcome.

Conclusion

Gilteritinib in patients with R/R FLT3-mutated AML demonstrated favorable outcomes with a satisfactory tolerance to the therapy. Patients who subsequently underwent allo-HSCT had statistically significantly better OS, DFS and EFS. Thus, gilteritinib can be used as a bridge to allo-HSCT in adult patients with R/R FLT3-mutated AML.

Conflict of interest

The authors declare that they have no conflict of interest.

Compliance with ethical standards

All human studies have been approved by the appropriate University Ethics Committee and have been performed in accordance with the ethical standards laid down in the 1964 Declaration of Helsinki and its later amendments. All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1975, as revised in 2008.

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Аюбова<sup>1</sup>, Сергей Н. Бондаренко<sup>1</sup>, Анна Г. Смирнова<sup>1</sup>, Юлия Ю. Власова<sup>1</sup>, Николай Ю. Цветков<sup>1</sup>, Михаил М. Канунников<sup>1</sup>, Дмитрий К. Жоголев<sup>1</sup>, Юлия Д. Олейникова<sup>1</sup>, Елена В. Карягина<sup>2</sup>, Ридван К. Ильясов<sup>3</sup>, Наталья А. Зорина<sup>4</sup>, Светлана С. Беляева<sup>5</sup>, Юлия С. Нередько<sup>6</sup>, Ирина А. Самородова<sup>7</sup>, Юлия Б. Черных<sup>8</sup>, Михаил Ю. Лазарев<sup>9</sup>, Анна П. Кочергина<sup>10</sup>, Анна А. Насрединова<sup>1</sup>, Ильдар М. Бархатов<sup>1</sup>, Татьяна Л. Гиндина<sup>1</sup>, Иван С. Моисеев<sup>1</sup>, Александр Д. Кулагин<sup>1</sup></p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(1017) "

Белла И. Аюбова1, Сергей Н. Бондаренко1, Анна Г. Смирнова1, Юлия Ю. Власова1, Николай Ю. Цветков1, Михаил М. Канунников1, Дмитрий К. Жоголев1, Юлия Д. Олейникова1, Елена В. Карягина2, Ридван К. Ильясов3, Наталья А. Зорина4, Светлана С. Беляева5, Юлия С. Нередько6, Ирина А. Самородова7, Юлия Б. Черных8, Михаил Ю. Лазарев9, Анна П. Кочергина10, Анна А. Насрединова1, Ильдар М. Бархатов1, Татьяна Л. Гиндина1, Иван С. Моисеев1, Александр Д. Кулагин1

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1 НИИ детской онкологии, гематологии и трансплантологии им. Р. М. Горбачевой, Первый Санкт-Петербургский государственный медицинский университет им. акад. И. П. Павлова, Санкт-Петербург, Россия
2 Городская больница №15, Санкт-Петербург, Россия
3 Крымский республиканский онкологический клинический диспансер им. В. М. Ефетова, Симферополь, Россия
4 Кировский научно-исследовательский институт гематологии и переливания крови ФМБА, Киров, Россия
5 Белгородская областная клиническая больница святителя Иоасафа, Белгород, Россия
6 Ставропольский краевой клинический онкологический диспансер, Ставрополь, Россия
7 Городская клиническая больница №31, Санкт-Петербург, Россия
8 Московский областной научно-исследовательский клинический институт им. М. Ф. Владимирского, Москва, Россия
9 Городская клиническая больница №40, Москва, Россия
10 Краевая клиническая больница, Барнаул, Россия

" ["TYPE"]=> string(4) "HTML" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(22) "Организации" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } } ["SUMMARY_RU"]=> array(36) { ["ID"]=> string(2) "27" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:01:20" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(29) "Описание/Резюме" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(10) "SUMMARY_RU" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "27" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "29540" ["VALUE"]=> array(2) { ["TEXT"]=> string(3914) "<p style="text-align: justify;">Острый миелоидный лейкоз с мутациями в гене FLT3 (ОМЛ FLT3+) как клинический подтип ОМЛ характеризуется коротким периодом ремиссии заболевания, высокой частотой рецидивов, низкими показателями выживаемости, особенно в случаях с высоким соотношением FLT3-ITD к дикому типу и отсутствием мутации в гене NPM1. При этом FLT3-мутации можно рассматривать как перспективную молекулярную мишень для лечения пациентов c ОМЛ, в том числе с рефрактерным или рецидивирующим (Р/Р) ОМЛ. В исследование были включены 48 пациентов с Р/Р ОМЛ FLT3+ с медианой возраста 53 (18-79) лет. Первично-рефрактерное течение отмечено в 31,2% случаев; с первым рецидивом были включены 54,2%; с последующими рецидивами – 14,6%. Мутация ITD наблюдалась у 89,6%, TKD – у 10,4%. Больные получали гилтеритиниб в дозе 120 мг/сут в течение 28-дневного курса, преимущественно – по 1 или 2 курса (56,2% и 27,1%, соответственно). Общий ответ (ОО) достигнут в 77,1% (ДИ 95% 65,7-88,3): полная ремиссия – в 15 случаях (31,2%), ремиссия без восстановления – у 11 пациентов (22,9%) и морфологически свободный от лейкоза статус достигнут также у 11 больных (22,9%). ТГСК в последующем выполнена в 29,2% случаев (ДИ 95% 18,2-43,2). Средний возраст этой группы составил 43,1 (18-68) года. Медиана времени от достижения ОО до ТГСК составил 45 (24-156) дней.</p> <p style="text-align: justify;">Однолетняя общая выживаемость составила 39,9% с медианой 6,3 (95% ДИ: 4,7-12,0) мес. Безрецидивная выживаемость в группе пациентов, достигших ОО (n=37), составила 40,5%, медиана по срокам – 7,7 (4,4-11,0) мес. Выявлены следующие факторы, благоприятно влияющие на бессобытийную выживаемость: выполнение ТГСК после терапии (HR=0,16; CI 95%: 0,04-0,62; p<0,01) и достижение ОО (HR=0,11; CI 95%: 0,04-0,33; p<0,01). У пациентов с поздним рецидивом, напротив, наблюдалось увеличение риска событий (HR=3,42; CI 95%: 1,2-9,64; p=0,02). Непредвиденной токсичности после терапии не наблюдалось. Применение гилтеритиниба у пациентов с Р/Р FLT3+ ОМЛ показало благоприятные исходы при удовлетворительной переносимости терапии и может быть использовано в качестве «мост-терапии» к ТГСК у взрослых пациентов с Р/Р FLT3+ ОМЛ. </p> <h2>Ключевые слова</h2> <p style="text-align: justify;">Острый миелоидный лейкоз, таргетная терапия, гилтеритиниб.</p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(3830) "

Острый миелоидный лейкоз с мутациями в гене FLT3 (ОМЛ FLT3+) как клинический подтип ОМЛ характеризуется коротким периодом ремиссии заболевания, высокой частотой рецидивов, низкими показателями выживаемости, особенно в случаях с высоким соотношением FLT3-ITD к дикому типу и отсутствием мутации в гене NPM1. При этом FLT3-мутации можно рассматривать как перспективную молекулярную мишень для лечения пациентов c ОМЛ, в том числе с рефрактерным или рецидивирующим (Р/Р) ОМЛ. В исследование были включены 48 пациентов с Р/Р ОМЛ FLT3+ с медианой возраста 53 (18-79) лет. Первично-рефрактерное течение отмечено в 31,2% случаев; с первым рецидивом были включены 54,2%; с последующими рецидивами – 14,6%. Мутация ITD наблюдалась у 89,6%, TKD – у 10,4%. Больные получали гилтеритиниб в дозе 120 мг/сут в течение 28-дневного курса, преимущественно – по 1 или 2 курса (56,2% и 27,1%, соответственно). Общий ответ (ОО) достигнут в 77,1% (ДИ 95% 65,7-88,3): полная ремиссия – в 15 случаях (31,2%), ремиссия без восстановления – у 11 пациентов (22,9%) и морфологически свободный от лейкоза статус достигнут также у 11 больных (22,9%). ТГСК в последующем выполнена в 29,2% случаев (ДИ 95% 18,2-43,2). Средний возраст этой группы составил 43,1 (18-68) года. Медиана времени от достижения ОО до ТГСК составил 45 (24-156) дней.

Однолетняя общая выживаемость составила 39,9% с медианой 6,3 (95% ДИ: 4,7-12,0) мес. Безрецидивная выживаемость в группе пациентов, достигших ОО (n=37), составила 40,5%, медиана по срокам – 7,7 (4,4-11,0) мес. Выявлены следующие факторы, благоприятно влияющие на бессобытийную выживаемость: выполнение ТГСК после терапии (HR=0,16; CI 95%: 0,04-0,62; p<0,01) и достижение ОО (HR=0,11; CI 95%: 0,04-0,33; p<0,01). У пациентов с поздним рецидивом, напротив, наблюдалось увеличение риска событий (HR=3,42; CI 95%: 1,2-9,64; p=0,02). Непредвиденной токсичности после терапии не наблюдалось. Применение гилтеритиниба у пациентов с Р/Р FLT3+ ОМЛ показало благоприятные исходы при удовлетворительной переносимости терапии и может быть использовано в качестве «мост-терапии» к ТГСК у взрослых пациентов с Р/Р FLT3+ ОМЛ.

Ключевые слова

Острый миелоидный лейкоз, таргетная терапия, гилтеритиниб.

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Bella I. Ayubova1, Sergey N. Bondarenko1, Anna G. Smirnova1, Yulia Yu. Vlasova1, Nikolay Yu. Tsvetkov1, Michail M. Kanunnikov1, Dmitry K. Zhogolev1, Yuliya D. Oleynikova1, Elena V. Karyagina2, Ridvan K. Ilyasov3, Natalya A. Zorina4, Svetlana S. Belyaeva5, Yulia S. Neredko6, Irina A. Samorodova7, Yulia B. Chernih8, Mikhail Yu. Lazarev9, Anna P. Kochergina10, Anna A. Nasredinova1, Ildar M. Barkhatov1, Tatyana L. Gindina1, Ivan S. Moiseev1, Alexander D. Kulagin1

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1 RM Gorbacheva Research Institute of Pediatric Oncology, Hematology and Transplantology, Pavlov University, St. Petersburg, Russia
2 City Hospital No. 15 of St. Petersburg, Russia
3 Crimean V. М. Efetov Republican Oncological Clinical Dispensary, Simferopol, Russia
4 Kirov Research Institute of Hematology and Blood Transfusion, Kirov, Russia
5 Belgorod Regional Clinical Hospital of St. Joasaph, Belgorod, Russia
6 Stavropol Regional Clinical Oncological Dispensary, Stavropol, Russia
7 City Hospital No. 31 of St. Petersburg, Russia
8 Moscow M. F. Vladimirsky Regional Research Clinical Institute, Moscow, Russia
9 City Clinical Hospital No. 40, Moscow, Russia
10 Regional Clinical Hospital, Barnaul, Russia


Correspondence:
Dr. Bella I. Ayubova, RM Gorbacheva Research Institute of Pediatric Oncology, Hematology and Transpantology, Pavlov University, 6-8 L.Tolstoy St, 197022, St. Petersburg, Russia
E-mail: bella_ayubova@mail.ru


Citation: Ayubova BI, Bondarenko SN, Smirnova AG et al. Gilteritinib as a bridge to allogeneic hematopoietic stem cell transplantation in adult patients with refractory/relapsed acute myeloid leukemia with FLT3 mutations. Cell Ther Transplant 2022; 11(3-4): 60-69.

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Acute myeloid leukemia (AML) with FLT3 mutations, being a clinical subtype of AML, is associated with higher relapse rate, shorter remission period, decreased survival, especially without NPM1 co-mutation, and at high FLT3-ITD/wild-type allelic ratios. FLT3 mutations can be considered as a promising molecular target for the treatment of patients with FLT3-mutated AML, particularly in refractory or relapsed (R/R) AML cases. Allogeneic hematopoietic stem cell transplantation (allo- HSCT) gives chance for a potential cure in patients with R/R AML. The present study included 48 patients with R/R AML with FLT3-mutation, at a median age of 53 (18-79) years. Primarily refractory patients (p/r AML) made 31.2% of them; among recurrent AML, 54.2% had a first relapse, and 14.6% had 2 or more relapses (relAML). The ITD mutation was detected in 89.6% and TKD-mutation in 10.4% of cases. The patients received gilteritinib 120 mg once daily, administered as one (in most cases), or >2 28-day cycles of therapy (56.2% and 27.1%, respectively). Overall response (OR) rate was 77.1% (CI 95% 65.7-88.3): complete remission (CR) was documented in 15 (31.2%) patients, remission with incomplete recovery (CRi/r) and morphological leukemia-free state (MLFS) were observed in 11 patients (22.9%) each. Allo-HSCT was subsequently performed in 29.2% (CI 95% 18.2-43.2) of all treated patients. The median age of this group of patients was 43.1 (18-68) years. The median time from overall response achieved after gilteritinib to allo-HSCT was 45 (24-156) days. One-year overall survival was 39.9%, with median survival terms of 6.3 months (95% CI: 4.7-12.0). Disease-free survival in the group of patients who achieved remission (37 patients) was 40.5%, and the median was 7.7 months (4.4-11.0 months). In the multivariate analysis, event-free survival was significantly associated with successful bridging to allo-HSCT (HR=0.16; CI 95%: 0.04-0.62; p<0.01) and in patients who achieved OR (HR=0.11; CI 95%: 0.04-0.33; p<0.01). In contrast, the patients with late relapse showed an increase in the risk of the events (HR=3.42; CI 95%: 1.2-9.64; p=0.02). No unexpected toxicity was observed after the therapy. Gilteritinib in patients with R/R FLT3-mutated AML demonstrated favorable outcomes with a satisfactory tolerance to therapy. Thus, gilteritinib may be used for a bridge therapy to allo-HSCT in adult patients with R/R FLT3-mutated AML.

Keywords

Acute myeloid leukemia, target therapy, gilteritinib.

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Ayubova<sup>1</sup>, Sergey N. Bondarenko<sup>1</sup>, Anna G. Smirnova<sup>1</sup>, Yulia Yu. Vlasova<sup>1</sup>, Nikolay Yu. Tsvetkov<sup>1</sup>, Michail M. Kanunnikov<sup>1</sup>, Dmitry K. Zhogolev<sup>1</sup>, Yuliya D. Oleynikova<sup>1</sup>, Elena V. Karyagina<sup>2</sup>, Ridvan K. Ilyasov<sup>3</sup>, Natalya A. Zorina<sup>4</sup>, Svetlana S. Belyaeva<sup>5</sup>, Yulia S. Neredko<sup>6</sup>, Irina A. Samorodova<sup>7</sup>, Yulia B. Chernih<sup>8</sup>, Mikhail Yu. Lazarev<sup>9</sup>, Anna P. Kochergina<sup>10</sup>, Anna A. Nasredinova<sup>1</sup>, Ildar M. Barkhatov<sup>1</sup>, Tatyana L. Gindina<sup>1</sup>, Ivan S. Moiseev<sup>1</sup>, Alexander D. Kulagin<sup>1</sup></p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(716) "

Bella I. Ayubova1, Sergey N. Bondarenko1, Anna G. Smirnova1, Yulia Yu. Vlasova1, Nikolay Yu. Tsvetkov1, Michail M. Kanunnikov1, Dmitry K. Zhogolev1, Yuliya D. Oleynikova1, Elena V. Karyagina2, Ridvan K. Ilyasov3, Natalya A. Zorina4, Svetlana S. Belyaeva5, Yulia S. Neredko6, Irina A. Samorodova7, Yulia B. Chernih8, Mikhail Yu. Lazarev9, Anna P. Kochergina10, Anna A. Nasredinova1, Ildar M. Barkhatov1, Tatyana L. Gindina1, Ivan S. Moiseev1, Alexander D. Kulagin1

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Bella I. Ayubova1, Sergey N. Bondarenko1, Anna G. Smirnova1, Yulia Yu. Vlasova1, Nikolay Yu. Tsvetkov1, Michail M. Kanunnikov1, Dmitry K. Zhogolev1, Yuliya D. Oleynikova1, Elena V. Karyagina2, Ridvan K. Ilyasov3, Natalya A. Zorina4, Svetlana S. Belyaeva5, Yulia S. Neredko6, Irina A. Samorodova7, Yulia B. Chernih8, Mikhail Yu. Lazarev9, Anna P. Kochergina10, Anna A. Nasredinova1, Ildar M. Barkhatov1, Tatyana L. Gindina1, Ivan S. Moiseev1, Alexander D. Kulagin1

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Acute myeloid leukemia (AML) with FLT3 mutations, being a clinical subtype of AML, is associated with higher relapse rate, shorter remission period, decreased survival, especially without NPM1 co-mutation, and at high FLT3-ITD/wild-type allelic ratios. FLT3 mutations can be considered as a promising molecular target for the treatment of patients with FLT3-mutated AML, particularly in refractory or relapsed (R/R) AML cases. Allogeneic hematopoietic stem cell transplantation (allo- HSCT) gives chance for a potential cure in patients with R/R AML. The present study included 48 patients with R/R AML with FLT3-mutation, at a median age of 53 (18-79) years. Primarily refractory patients (p/r AML) made 31.2% of them; among recurrent AML, 54.2% had a first relapse, and 14.6% had 2 or more relapses (relAML). The ITD mutation was detected in 89.6% and TKD-mutation in 10.4% of cases. The patients received gilteritinib 120 mg once daily, administered as one (in most cases), or >2 28-day cycles of therapy (56.2% and 27.1%, respectively). Overall response (OR) rate was 77.1% (CI 95% 65.7-88.3): complete remission (CR) was documented in 15 (31.2%) patients, remission with incomplete recovery (CRi/r) and morphological leukemia-free state (MLFS) were observed in 11 patients (22.9%) each. Allo-HSCT was subsequently performed in 29.2% (CI 95% 18.2-43.2) of all treated patients. The median age of this group of patients was 43.1 (18-68) years. The median time from overall response achieved after gilteritinib to allo-HSCT was 45 (24-156) days. One-year overall survival was 39.9%, with median survival terms of 6.3 months (95% CI: 4.7-12.0). Disease-free survival in the group of patients who achieved remission (37 patients) was 40.5%, and the median was 7.7 months (4.4-11.0 months). In the multivariate analysis, event-free survival was significantly associated with successful bridging to allo-HSCT (HR=0.16; CI 95%: 0.04-0.62; p<0.01) and in patients who achieved OR (HR=0.11; CI 95%: 0.04-0.33; p<0.01). In contrast, the patients with late relapse showed an increase in the risk of the events (HR=3.42; CI 95%: 1.2-9.64; p=0.02). No unexpected toxicity was observed after the therapy. Gilteritinib in patients with R/R FLT3-mutated AML demonstrated favorable outcomes with a satisfactory tolerance to therapy. Thus, gilteritinib may be used for a bridge therapy to allo-HSCT in adult patients with R/R FLT3-mutated AML.

Keywords

Acute myeloid leukemia, target therapy, gilteritinib.

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Acute myeloid leukemia (AML) with FLT3 mutations, being a clinical subtype of AML, is associated with higher relapse rate, shorter remission period, decreased survival, especially without NPM1 co-mutation, and at high FLT3-ITD/wild-type allelic ratios. FLT3 mutations can be considered as a promising molecular target for the treatment of patients with FLT3-mutated AML, particularly in refractory or relapsed (R/R) AML cases. Allogeneic hematopoietic stem cell transplantation (allo- HSCT) gives chance for a potential cure in patients with R/R AML. The present study included 48 patients with R/R AML with FLT3-mutation, at a median age of 53 (18-79) years. Primarily refractory patients (p/r AML) made 31.2% of them; among recurrent AML, 54.2% had a first relapse, and 14.6% had 2 or more relapses (relAML). The ITD mutation was detected in 89.6% and TKD-mutation in 10.4% of cases. The patients received gilteritinib 120 mg once daily, administered as one (in most cases), or >2 28-day cycles of therapy (56.2% and 27.1%, respectively). Overall response (OR) rate was 77.1% (CI 95% 65.7-88.3): complete remission (CR) was documented in 15 (31.2%) patients, remission with incomplete recovery (CRi/r) and morphological leukemia-free state (MLFS) were observed in 11 patients (22.9%) each. Allo-HSCT was subsequently performed in 29.2% (CI 95% 18.2-43.2) of all treated patients. The median age of this group of patients was 43.1 (18-68) years. The median time from overall response achieved after gilteritinib to allo-HSCT was 45 (24-156) days. One-year overall survival was 39.9%, with median survival terms of 6.3 months (95% CI: 4.7-12.0). Disease-free survival in the group of patients who achieved remission (37 patients) was 40.5%, and the median was 7.7 months (4.4-11.0 months). In the multivariate analysis, event-free survival was significantly associated with successful bridging to allo-HSCT (HR=0.16; CI 95%: 0.04-0.62; p<0.01) and in patients who achieved OR (HR=0.11; CI 95%: 0.04-0.33; p<0.01). In contrast, the patients with late relapse showed an increase in the risk of the events (HR=3.42; CI 95%: 1.2-9.64; p=0.02). No unexpected toxicity was observed after the therapy. Gilteritinib in patients with R/R FLT3-mutated AML demonstrated favorable outcomes with a satisfactory tolerance to therapy. Thus, gilteritinib may be used for a bridge therapy to allo-HSCT in adult patients with R/R FLT3-mutated AML.

Keywords

Acute myeloid leukemia, target therapy, gilteritinib.

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Efetov Republican Oncological Clinical Dispensary, Simferopol, Russia<br> <sup>4</sup> Kirov Research Institute of Hematology and Blood Transfusion, Kirov, Russia<br> <sup>5</sup> Belgorod Regional Clinical Hospital of St. Joasaph, Belgorod, Russia<br> <sup>6</sup> Stavropol Regional Clinical Oncological Dispensary, Stavropol, Russia<br> <sup>7</sup> City Hospital No. 31 of St. Petersburg, Russia<br> <sup>8</sup> Moscow M. F. Vladimirsky Regional Research Clinical Institute, Moscow, Russia<br> <sup>9</sup> City Clinical Hospital No. 40, Moscow, Russia<br> <sup>10</sup> Regional Clinical Hospital, Barnaul, Russia</p><br> <p><b>Correspondence:</b><br> Dr. Bella I. Ayubova, RM Gorbacheva Research Institute of Pediatric Oncology, Hematology and Transpantology, Pavlov University, 6-8 L.Tolstoy St, 197022, St. Petersburg, Russia<br> E-mail: bella_ayubova@mail.ru</p><br> <p><b> Citation:</b> Ayubova BI, Bondarenko SN, Smirnova AG et al. Gilteritinib as a bridge to allogeneic hematopoietic stem cell transplantation in adult patients with refractory/relapsed acute myeloid leukemia with FLT3 mutations. Cell Ther Transplant 2022; 11(3-4): 60-69.</p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(1414) "

1 RM Gorbacheva Research Institute of Pediatric Oncology, Hematology and Transplantology, Pavlov University, St. Petersburg, Russia
2 City Hospital No. 15 of St. Petersburg, Russia
3 Crimean V. М. Efetov Republican Oncological Clinical Dispensary, Simferopol, Russia
4 Kirov Research Institute of Hematology and Blood Transfusion, Kirov, Russia
5 Belgorod Regional Clinical Hospital of St. Joasaph, Belgorod, Russia
6 Stavropol Regional Clinical Oncological Dispensary, Stavropol, Russia
7 City Hospital No. 31 of St. Petersburg, Russia
8 Moscow M. F. Vladimirsky Regional Research Clinical Institute, Moscow, Russia
9 City Clinical Hospital No. 40, Moscow, Russia
10 Regional Clinical Hospital, Barnaul, Russia


Correspondence:
Dr. Bella I. Ayubova, RM Gorbacheva Research Institute of Pediatric Oncology, Hematology and Transpantology, Pavlov University, 6-8 L.Tolstoy St, 197022, St. Petersburg, Russia
E-mail: bella_ayubova@mail.ru


Citation: Ayubova BI, Bondarenko SN, Smirnova AG et al. Gilteritinib as a bridge to allogeneic hematopoietic stem cell transplantation in adult patients with refractory/relapsed acute myeloid leukemia with FLT3 mutations. Cell Ther Transplant 2022; 11(3-4): 60-69.

" ["TYPE"]=> string(4) "HTML" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(12) "Organization" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["DISPLAY_VALUE"]=> string(1414) "

1 RM Gorbacheva Research Institute of Pediatric Oncology, Hematology and Transplantology, Pavlov University, St. Petersburg, Russia
2 City Hospital No. 15 of St. Petersburg, Russia
3 Crimean V. М. Efetov Republican Oncological Clinical Dispensary, Simferopol, Russia
4 Kirov Research Institute of Hematology and Blood Transfusion, Kirov, Russia
5 Belgorod Regional Clinical Hospital of St. Joasaph, Belgorod, Russia
6 Stavropol Regional Clinical Oncological Dispensary, Stavropol, Russia
7 City Hospital No. 31 of St. Petersburg, Russia
8 Moscow M. F. Vladimirsky Regional Research Clinical Institute, Moscow, Russia
9 City Clinical Hospital No. 40, Moscow, Russia
10 Regional Clinical Hospital, Barnaul, Russia


Correspondence:
Dr. Bella I. Ayubova, RM Gorbacheva Research Institute of Pediatric Oncology, Hematology and Transpantology, Pavlov University, 6-8 L.Tolstoy St, 197022, St. Petersburg, Russia
E-mail: bella_ayubova@mail.ru


Citation: Ayubova BI, Bondarenko SN, Smirnova AG et al. Gilteritinib as a bridge to allogeneic hematopoietic stem cell transplantation in adult patients with refractory/relapsed acute myeloid leukemia with FLT3 mutations. Cell Ther Transplant 2022; 11(3-4): 60-69.

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Белла И. Аюбова1, Сергей Н. Бондаренко1, Анна Г. Смирнова1, Юлия Ю. Власова1, Николай Ю. Цветков1, Михаил М. Канунников1, Дмитрий К. Жоголев1, Юлия Д. Олейникова1, Елена В. Карягина2, Ридван К. Ильясов3, Наталья А. Зорина4, Светлана С. Беляева5, Юлия С. Нередько6, Ирина А. Самородова7, Юлия Б. Черных8, Михаил Ю. Лазарев9, Анна П. Кочергина10, Анна А. Насрединова1, Ильдар М. Бархатов1, Татьяна Л. Гиндина1, Иван С. Моисеев1, Александр Д. Кулагин1

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Белла И. Аюбова1, Сергей Н. Бондаренко1, Анна Г. Смирнова1, Юлия Ю. Власова1, Николай Ю. Цветков1, Михаил М. Канунников1, Дмитрий К. Жоголев1, Юлия Д. Олейникова1, Елена В. Карягина2, Ридван К. Ильясов3, Наталья А. Зорина4, Светлана С. Беляева5, Юлия С. Нередько6, Ирина А. Самородова7, Юлия Б. Черных8, Михаил Ю. Лазарев9, Анна П. Кочергина10, Анна А. Насрединова1, Ильдар М. Бархатов1, Татьяна Л. Гиндина1, Иван С. Моисеев1, Александр Д. Кулагин1

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При этом FLT3-мутации можно рассматривать как перспективную молекулярную мишень для лечения пациентов c ОМЛ, в том числе с рефрактерным или рецидивирующим (Р/Р) ОМЛ. В исследование были включены 48 пациентов с Р/Р ОМЛ FLT3+ с медианой возраста 53 (18-79) лет. Первично-рефрактерное течение отмечено в 31,2% случаев; с первым рецидивом были включены 54,2%; с последующими рецидивами – 14,6%. Мутация ITD наблюдалась у 89,6%, TKD – у 10,4%. Больные получали гилтеритиниб в дозе 120 мг/сут в течение 28-дневного курса, преимущественно – по 1 или 2 курса (56,2% и 27,1%, соответственно). Общий ответ (ОО) достигнут в 77,1% (ДИ 95% 65,7-88,3): полная ремиссия – в 15 случаях (31,2%), ремиссия без восстановления – у 11 пациентов (22,9%) и морфологически свободный от лейкоза статус достигнут также у 11 больных (22,9%). ТГСК в последующем выполнена в 29,2% случаев (ДИ 95% 18,2-43,2). Средний возраст этой группы составил 43,1 (18-68) года. Медиана времени от достижения ОО до ТГСК составил 45 (24-156) дней.</p> <p style="text-align: justify;">Однолетняя общая выживаемость составила 39,9% с медианой 6,3 (95% ДИ: 4,7-12,0) мес. Безрецидивная выживаемость в группе пациентов, достигших ОО (n=37), составила 40,5%, медиана по срокам – 7,7 (4,4-11,0) мес. Выявлены следующие факторы, благоприятно влияющие на бессобытийную выживаемость: выполнение ТГСК после терапии (HR=0,16; CI 95%: 0,04-0,62; p<0,01) и достижение ОО (HR=0,11; CI 95%: 0,04-0,33; p<0,01). У пациентов с поздним рецидивом, напротив, наблюдалось увеличение риска событий (HR=3,42; CI 95%: 1,2-9,64; p=0,02). Непредвиденной токсичности после терапии не наблюдалось. Применение гилтеритиниба у пациентов с Р/Р FLT3+ ОМЛ показало благоприятные исходы при удовлетворительной переносимости терапии и может быть использовано в качестве «мост-терапии» к ТГСК у взрослых пациентов с Р/Р FLT3+ ОМЛ. </p> <h2>Ключевые слова</h2> <p style="text-align: justify;">Острый миелоидный лейкоз, таргетная терапия, гилтеритиниб.</p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(3830) "

Острый миелоидный лейкоз с мутациями в гене FLT3 (ОМЛ FLT3+) как клинический подтип ОМЛ характеризуется коротким периодом ремиссии заболевания, высокой частотой рецидивов, низкими показателями выживаемости, особенно в случаях с высоким соотношением FLT3-ITD к дикому типу и отсутствием мутации в гене NPM1. При этом FLT3-мутации можно рассматривать как перспективную молекулярную мишень для лечения пациентов c ОМЛ, в том числе с рефрактерным или рецидивирующим (Р/Р) ОМЛ. В исследование были включены 48 пациентов с Р/Р ОМЛ FLT3+ с медианой возраста 53 (18-79) лет. Первично-рефрактерное течение отмечено в 31,2% случаев; с первым рецидивом были включены 54,2%; с последующими рецидивами – 14,6%. Мутация ITD наблюдалась у 89,6%, TKD – у 10,4%. Больные получали гилтеритиниб в дозе 120 мг/сут в течение 28-дневного курса, преимущественно – по 1 или 2 курса (56,2% и 27,1%, соответственно). Общий ответ (ОО) достигнут в 77,1% (ДИ 95% 65,7-88,3): полная ремиссия – в 15 случаях (31,2%), ремиссия без восстановления – у 11 пациентов (22,9%) и морфологически свободный от лейкоза статус достигнут также у 11 больных (22,9%). ТГСК в последующем выполнена в 29,2% случаев (ДИ 95% 18,2-43,2). Средний возраст этой группы составил 43,1 (18-68) года. Медиана времени от достижения ОО до ТГСК составил 45 (24-156) дней.

Однолетняя общая выживаемость составила 39,9% с медианой 6,3 (95% ДИ: 4,7-12,0) мес. Безрецидивная выживаемость в группе пациентов, достигших ОО (n=37), составила 40,5%, медиана по срокам – 7,7 (4,4-11,0) мес. Выявлены следующие факторы, благоприятно влияющие на бессобытийную выживаемость: выполнение ТГСК после терапии (HR=0,16; CI 95%: 0,04-0,62; p<0,01) и достижение ОО (HR=0,11; CI 95%: 0,04-0,33; p<0,01). У пациентов с поздним рецидивом, напротив, наблюдалось увеличение риска событий (HR=3,42; CI 95%: 1,2-9,64; p=0,02). Непредвиденной токсичности после терапии не наблюдалось. Применение гилтеритиниба у пациентов с Р/Р FLT3+ ОМЛ показало благоприятные исходы при удовлетворительной переносимости терапии и может быть использовано в качестве «мост-терапии» к ТГСК у взрослых пациентов с Р/Р FLT3+ ОМЛ.

Ключевые слова

Острый миелоидный лейкоз, таргетная терапия, гилтеритиниб.

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Острый миелоидный лейкоз с мутациями в гене FLT3 (ОМЛ FLT3+) как клинический подтип ОМЛ характеризуется коротким периодом ремиссии заболевания, высокой частотой рецидивов, низкими показателями выживаемости, особенно в случаях с высоким соотношением FLT3-ITD к дикому типу и отсутствием мутации в гене NPM1. При этом FLT3-мутации можно рассматривать как перспективную молекулярную мишень для лечения пациентов c ОМЛ, в том числе с рефрактерным или рецидивирующим (Р/Р) ОМЛ. В исследование были включены 48 пациентов с Р/Р ОМЛ FLT3+ с медианой возраста 53 (18-79) лет. Первично-рефрактерное течение отмечено в 31,2% случаев; с первым рецидивом были включены 54,2%; с последующими рецидивами – 14,6%. Мутация ITD наблюдалась у 89,6%, TKD – у 10,4%. Больные получали гилтеритиниб в дозе 120 мг/сут в течение 28-дневного курса, преимущественно – по 1 или 2 курса (56,2% и 27,1%, соответственно). Общий ответ (ОО) достигнут в 77,1% (ДИ 95% 65,7-88,3): полная ремиссия – в 15 случаях (31,2%), ремиссия без восстановления – у 11 пациентов (22,9%) и морфологически свободный от лейкоза статус достигнут также у 11 больных (22,9%). ТГСК в последующем выполнена в 29,2% случаев (ДИ 95% 18,2-43,2). Средний возраст этой группы составил 43,1 (18-68) года. Медиана времени от достижения ОО до ТГСК составил 45 (24-156) дней.

Однолетняя общая выживаемость составила 39,9% с медианой 6,3 (95% ДИ: 4,7-12,0) мес. Безрецидивная выживаемость в группе пациентов, достигших ОО (n=37), составила 40,5%, медиана по срокам – 7,7 (4,4-11,0) мес. Выявлены следующие факторы, благоприятно влияющие на бессобытийную выживаемость: выполнение ТГСК после терапии (HR=0,16; CI 95%: 0,04-0,62; p<0,01) и достижение ОО (HR=0,11; CI 95%: 0,04-0,33; p<0,01). У пациентов с поздним рецидивом, напротив, наблюдалось увеличение риска событий (HR=3,42; CI 95%: 1,2-9,64; p=0,02). Непредвиденной токсичности после терапии не наблюдалось. Применение гилтеритиниба у пациентов с Р/Р FLT3+ ОМЛ показало благоприятные исходы при удовлетворительной переносимости терапии и может быть использовано в качестве «мост-терапии» к ТГСК у взрослых пациентов с Р/Р FLT3+ ОМЛ.

Ключевые слова

Острый миелоидный лейкоз, таргетная терапия, гилтеритиниб.

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1 НИИ детской онкологии, гематологии и трансплантологии им. Р. М. Горбачевой, Первый Санкт-Петербургский государственный медицинский университет им. акад. И. П. Павлова, Санкт-Петербург, Россия
2 Городская больница №15, Санкт-Петербург, Россия
3 Крымский республиканский онкологический клинический диспансер им. В. М. Ефетова, Симферополь, Россия
4 Кировский научно-исследовательский институт гематологии и переливания крови ФМБА, Киров, Россия
5 Белгородская областная клиническая больница святителя Иоасафа, Белгород, Россия
6 Ставропольский краевой клинический онкологический диспансер, Ставрополь, Россия
7 Городская клиническая больница №31, Санкт-Петербург, Россия
8 Московский областной научно-исследовательский клинический институт им. М. Ф. Владимирского, Москва, Россия
9 Городская клиническая больница №40, Москва, Россия
10 Краевая клиническая больница, Барнаул, Россия

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1 НИИ детской онкологии, гематологии и трансплантологии им. Р. М. Горбачевой, Первый Санкт-Петербургский государственный медицинский университет им. акад. И. П. Павлова, Санкт-Петербург, Россия
2 Городская больница №15, Санкт-Петербург, Россия
3 Крымский республиканский онкологический клинический диспансер им. В. М. Ефетова, Симферополь, Россия
4 Кировский научно-исследовательский институт гематологии и переливания крови ФМБА, Киров, Россия
5 Белгородская областная клиническая больница святителя Иоасафа, Белгород, Россия
6 Ставропольский краевой клинический онкологический диспансер, Ставрополь, Россия
7 Городская клиническая больница №31, Санкт-Петербург, Россия
8 Московский областной научно-исследовательский клинический институт им. М. Ф. Владимирского, Москва, Россия
9 Городская клиническая больница №40, Москва, Россия
10 Краевая клиническая больница, Барнаул, Россия

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Introduction

Lymphoma is the third most common cancer in children. Opposite to adult tumors, pediatric non-Hodgkin lymphomas (NHL) tend to proceed in aggressive manner [1]. Pediatricians usually face only distinct types of NHL, i.e., anaplastic large cell lymphoma, ALK+ (ALCL) which occurs in 10-12% of the cases, lymphoblastic lymphoma (LL), in 20-25%; diffuse large B-cell lymphoma (DLBCL), primary mediastinal large B-cell lymphoma (10-15%), and Burkitt lymphoma affecting 50-60% of the patients [2]. Other types of NHL are uncommon in children. In developed countries, the relapsed or refractory (R-R) NHL occur in 10-25%, being more common in low-income and middle-income countries [3]. The choice of intensive first-line therapy is one of the reasons for high level of chemoresistance in case of relapse [4]. Mistiming, unreasonable dose reduction and excessive surgical activity may also affect prognosis [5]. Targeted therapy and immunotherapy increase chance of cure in cases of R-R NHL. However, hematopoietic stem cell transplantation (HSCT) still remains a cornerstone in its treatment [6]. There is no doubt that autologous hematopoietic stem cell transplantation (auto-HSCT) is a gold standard for the remission consolidation in R-R NHL, except of LL and, probably, ALCL where allogeneic HSCT (allo-HSCT) is more effective. This fact reflects weak or absent graft-versus-tumor effect (GVT) in B-NHL, and presence of GVT in LL and ALCL. These data were supported in randomized clinical trials in adult cohorts [7, 8]. The randomized trials in children were not yet performed due to ethical reasons and limited number of patients. Anyway, effectiveness of HSCT was demonstrated in many non-randomized studies in children [9, 10]. In general, HSCT doesn't solve the problem of R-R NHL but it may increase chances for cure approximately to 40-50% in the entire group. At the same time, allo-HSCT is associated with increased overall survival (OS) rates to 83% and should be regarded as very effective approach in the first ALCL relapse. Moreover, ALCL patients can be rescued with allo-HSCT even in progression observed pre-transplant, and in cases of relapse after auto-HSCT [11]. ALCL is a unique clinical entity that has a more favorable outcome in the cases with R-R course compared to other NHL subtypes. Presence of several effective targeted therapies (brentuximab vedotin, ALK-inhibitors) and high efficiency of allo-HSCT results in high rates of survival in children with R-R ALCL, ALK+.

Present case report demonstrates an adolescent patient with R-R ALCL successfully treated with several lines of chemoimmunotherapy and two HSCTs.

Case description

The patient is a 12-year-old girl from Donetsk. First symptoms of the disease consisted of abdominal pains and nausea since July 2018, later followed by fatigue, cough, dyspnea, and weight loss. Abdominal ultrasound demonstrated tumor in mesogastric region (140×60×47 mm). By computed tomography (CT), pleural effusion was revealed (right, 1140 mL; left, 360 mL). The tumor biopsy (August 17, 2018) showed initial morphology of leiomyosarcoma. First-line chemotherapy (2.10.18-1.11.18) consisted of I2VAd (ifosfamide 3000 mg/m2 №2, doxorubicin 40 mg/m2 №2 and vincristine 1.5 mg/m2 №3), followed by I2VA (ifosfamide 3000 mg/m2 №2, vincristine 1.5 mg/m2 №2, actinomycin D). Reduction of tumor volume was registered according to ultrasonography.

Later revision of histology and immunohistochemistry revealed ALCL, ALK+, and appropriate therapy was initiated according to NHL-BFM-like protocol (3 courses of A, and 3 courses of B, with 3 g/m2 of methotrexate in each block) continued from November 2018 to April 2019. Complete remission was achieved at the end of treatment.

Kozlov-fig01.jpg

Figure 1. Anaplastic large cell lymphoma. Hematoxylin & eosin stain (x400)

The ALCL, ALK+ was confirmed histologically, upon H&E staining (Fig. 1). Large polymorphic cells showed ovoid, polygonal and round pattern, with eosinophylic or translucent cytoplasm. Cell nuclei are irregular and ovoid, with lumpy chromatin. Apoptotic and mitotic activity were high. Immunohistochemistry demonstrated positive reaction with ALK (Fig. 2A), CD30 (Fig. 2B), GrB antibodies in intraplasmatic cytotoxic granules. Reactive microenvironment was presented by CD3+ lymphocytes. Ki-67 proliferation marker was seen in 50% of tumor cells.

On June 12, 2019 (two months after ending the therapy), the patient manifested with fatigue, pain in the right thigh, and fever. CT scans demonstrated a conglomerate of lymph nodes (8.5×5.2 cm) in the right iliac region with the involvement of m.iliacus. No tumor cells were found in bone marrow and cerebrospinal fluid. Serum lactatdehydrogenase level was 883.2 U/l. Clinical relapse was diagnosed after biopsy, and the patient was admitted to the N. N. Blokhin National Medical Research Center of Oncology (Moscow) for further treatment.

Kozlov-fig02.jpg

Figure 2. Anaplastic large cell lymphoma. Immunohistochemical staining of tumor cells for ALK+ (A) and by CD30+ cells (B). The reaction product is brown

Second-line treatment consisted of vinblastine 6 mg/m2 №2 and methotrexate 5000 g/m2 №1 every 21-28 days (3 cycles, from 12.07.19 to 11.10.19). Partial response was diagnosed after second cycle, but progression occurred after third course, according to CT results (17.10.19), with enlarged lesion of iliac muscle up to 11×4.8×8.6 cm.

Kozlov-fig03.jpg

Figure 3. PET-CT scan after 3rd-line therapy in ALCL patient. Black arrow demonstrates diffuse thickening of right iliac muscle with local metabolic activity

Third-line therapy consisted of brentuximab vedotin 1.8 mg/kg+ ICE №3 (05.11.19-28.01.2020): ifosfamide 1800 mg/m2 №5, etoposide 100 mg/m2 №5, carboplatin 400 mg/m2 №1. Partial response was achieved according to PET-CT data (20.01.2020) (Fig. 3).

On 26.03.2020, the patient underwent auto-HSCT in RM Gorbacheva Research Institute (St. Petersburg) with BeEAM conditioning regimen (bendamustine 160 mg/m2 №2, cytarabine 400 mg/m2 №4, etoposide 200 mg/m2 №4, melphalan 140 mg/m2 №1). A total of 3.2×106 CD34+ cells were reinfused. Prior to beginning the conditioning regimen, the patient progressed with right forearm involvement, confirmed by ALCL-positive cytology. Due to limited options for the remission reinduction and their presumably low efficiency, it was decided to proceed with auto-HSCT in the progression state. Posttransplant period was, generally, well tolerated, with febrile neutropenia and mucositis. Crizotinib 250 mg was initiated post-HSCT twice daily, in order to prevent progression. Three months after transplantation, the malignancy progression was registered with involvement of iliac muscle and right forearm. Glucocorticoid therapy was started to control the disease.

The 4th-line therapy at the N. N. Blokhin Research Center of Oncology consisted of VIGEPD №2 (gemcitabine 1000 mg/m2 №3, vinorelbine 30 mg/m2 №2, dacarbazine 375 mg/m2, prednisolone 20 mg/m2)+ brentuximab vedotin №2 and crizotinib (08.2020-09.2020). Infection complications and cytopenia were registered after the therapy. Partial remission was achieved, and patient was readmitted to RM Gorbacheva Research Institute for haploidentical HSCT (haplo-HSCT). On the 1st day of conditioning regimen, the patient experienced puffiness of the right forearm in the area of previous tumor location, and the disease progression could not be ruled out. Haplo-HSCT (26.10.2020) was performed from father, with conditioning by fludarabine (90 mg/m2) and bendamustine (390 mg/m2). Graft-versus-host disease (GVHD) prophylaxis consisted of posttransplant cyclophosphamide (100 mg/m2), tacrolimus and sirolimus. Posttransplant period was complicated by steroid-refractory acute skin GVHD Stage 2 (Day+42) that responded to ruxolitinib (10 mg/day). Bacterial pneumonia was diagnosed on Day +73 followed by complete recovery after combined antibacterial therapy (meropenem+vancomycin). As seen from Fig. 4, no lymphoma signs are observed by PET-CT from February 2022. At the present moment (1.5 years after haplo-HSCT), the patient is clinically disease-free, without symptoms of GVDH and with excellent transplant function, due to full donor chimerism.

Kozlov-fig04.jpg

Figure 4. PET-CT scan after haplo-HSCT in ALCL patient

Discussion

The present case report demonstrates wide therapeutic options for the treatment of R-R ALCL, ALK+. Taken together, they result in high chance of curation, even in refractory patients following several relapses. The treatment resistance may be registered to any known therapeutic modes (chemotherapy, targeted therapy, immunotherapy, HSCT). The mechanisms of resistance are diverse, including tumor clonal evolution, presence of residual tumor stem cells, various intercellular and intracellular mechanisms (for example, PDL-1 expression levels, etc.) [12]. Nowadays, the majority of patients with ALK+ ALCL enter continuous remission after first-line therapy. There is higher incidence of relapsed or refractory course of disease in cases of primary misdiagnosis and inadequate first-line therapy. Our patient received initial therapy according to the leiomyosarcoma protocol, thus being a probable factor of refractory course. After assessing correct diagnosis, the patient received therapy according to NHL-BFM-like protocol with complete response achieved. However, a relapse developed several months after finishing the protocol. Hence, the case could be regarded as early relapse or primary refractory state. Second-line therapy was based on high-dose methotrexate and vinblastine, the two highly effective drugs in this clinical setting. After initial response, the disease progressed and third-line therapy was started which consisted of ICE combined with brentuximab vedotin (BV). ICE is a classical regimen for R-R NHL, whereas BV is an established targeted drug for CD 30+ lymphomas [13]. In our case, this drug combination resulted in partial remission. Unfortunately, auto-HSCT was performed in progression, since the tumor appeared on right forearm several days prior to conditioning. Therefore, starting auto-HSCT in progression was a controversial decision. In general, the results of auto-HSCT in progression of ALCL are disappointing, and the transplant is not recommended in such cases [14]. We performed transplantation due to limited options for remission induction in heavily pretreated patient, relatively good somatic status and the intention-to-treat strategy. We used BeEAM, a conditioning regimen standard for lymphomas [15]. Toxicity of auto-HSCT is similar to high-dose chemotherapy, and usually manifests as mucositis, cytopenia and febrile neutropenia [16].

Posttransplant period in our patient proceeded typically, without unusual complications. In general, total body irradiation (TBI) is not indicated for lymphoma patients, due to its efficiency similar to the cytostatic drug-based conditioning regimens, and higher incidence of late side effects [17, 18]. According to CIBMTR data BEAM, ТBI and BuCy (busulfan+cyclophosphamide) are equally effective in auto-HSCT as conditioning regimens for NHL therapy [19]. BEAM is a non-myeloablative conditioning as most patients recover hematopoiesis even without reinfusion of hematopoietic stem cells. Auto-HSCT shortens cytopenia and reduces complications [20].

Our patient progressed 3 months after auto-HSCT. Relapses and progression after auto-HSCT are common in the patients with R-R NHL, despite modern treatment options and are still a challenge in all but ALK+ ALCL [10,11,21]. Hopefully, one more remission could be achieved after ViGePD scheme combined with targeted therapy (BV+crizotinib). This protocol earlier demonstrated efficiency in pretreated R-R NHL [22]. The idea was to add gemcitabine which was not previously used in the therapy. The remission state was considered till the first day of conditioning for allo-HSCT, when clinical progression with the involvement of right forearm was suspected. Allogeneic HSCT was not cancelled. There are data supporting its effectiveness despite absence of remission in ALK+ ALCL. The patients who receive allo-HSCT after relapse post auto-HSCT, or in ALCL progression, may be cured. Thus, the progression state is not desirable but it is not a contraindication for HSCT [11, 23].

Non-myeloablative conditioning (fludarabine and bendamustine) was used prior to haplo-HSCT. This conditioning regimen demonstrated effectiveness, and low level of toxicity in lymphoma patients [24]. It is also the proven fact that GVT effect plays major role in this clinical setting [25]. We did not apply intensive regimen, due to chemoresistance and four chemotherapy lines in previous history of this patient. This strategy appeared effective and safe, despite evidence of clinical progression and heavy pretreatment. Moderate complications of early posttransplant period (acute GVHD and pneumonia) were manageable and time-limited. The patient still maintains the remission state being also free of significant GVHD for 1.5 years.

In conclusion, a wide range of therapeutic options could be offered to the patients with ALK+ ALCL, e.g., chemotherapy, targeted therapy, HSCT that make this clinical subgroup unique among other R-R NHLs, due to favorable prognosis even in case of failure at the first line of therapy.

Conflict of interests

No conflicts of interest reported.

References

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  10. Fujita N, Kobayashi R, Atsuta Y, Iwasaki F, Suzumiya J, Sasahara Y, et al. Hematopoietic stem cell transplantation in children and adolescents with relapsed or refractory B-cell non-Hodgkin lymphoma. Int J Hematol. 2019; 109(4):483-490. doi: 10.1007/s12185-019-02608-y
  11. Knörr F, Brugières L, Pillon M, Zimmermann M, Ruf S, Attarbaschi A, et al; European Inter-Group for Childhood Non-Hodgkin Lymphoma. Stem cell transplantation and vinblastine monotherapy for relapsed pediatric anaplastic large cell lymphoma: Results of the international, prospective ALCL-relapse trial. J Clin Oncol. 2020;38(34):3999-4009. doi: 10.1200/JCO.20.00157
  12. Klener P, Klanova M. Drug resistance in non-Hodgkin lymphomas. Int J Mol Sci. 2020; 21, 2081. doi: 10.3390/ijms21062081
  13. Gentille C, Sarfraz H, Joshi J, Randhawa J, Shah S, Pingali SR. Use of ifosfamide, carboplatin and etoposide in combination with brentuximab vedotin or romidepsin based on CD30 positivity in relapsed/refractory peripheral T-cell lymphoma. Cancer Rep (Hoboken). 2022; Mar 8:e1581. doi: 10.1002/cnr2.1581
  14. Domingo-Domènech E, Boumendil A, Climent F, Sengeloev H, Wahlin B, Wattad W, et al. Autologous hematopoietic stem cell transplantation for relapsed/refractory systemic anaplastic large cell lymphoma. A retrospective analysis of the lymphoma working party (LWP) of the EBMT. Bone Marrow Transplant. 2020; 55, 796-803. doi: 10.1038/s41409-019-0734-7
  15. Gilli S, Novak U, Taleghani BM, Baerlocher GM, Leibundgut K, Banz Y, et al. BeEAM conditioning with bendamustine-replacing BCNU before autologous transplantation is safe and effective in lymphoma patients. Ann Hematol. 2017; 96(3):421-429. doi: 10.1007/s00277-016-2900-y
  16. Frankiewicz A, Saduś-Wojciechowska M, Najda J, Czerw T, Mendrek W, Sobczyk-Kruszelnicka M, et al. Comparable safety profile of BeEAM (bendamustine, etoposide, cytarabine, melphalan) and BEAM (carmustine, etoposide, cytarabine, melphalan) as conditioning before autologous haematopoietic cell transplantation. Contemp Oncol (Poznan). 2018; 22(2):113-117. doi: 10.5114/wo.2018.77046
  17. Gustavsson A, Osterman B, Cavallin-Stahl E. A systematic overview of radiation therapy effects in non-Hodgkin’s lymphoma. Acta Oncol 2003; 42:605-619. doi: 10.1080/02841860310014435
  18. Linsenmeier C, Thoennessen D, Negretti L, Bourquin JP, Streller T, Lütolf UM, et al. Total body irradiation (TBI) in pediatric patients.
    A single-center experience after 30 years of low-dose rate irradiation. Strahlenther Onkol. 2010; 186(11):614-620. doi: 10.1007/s00066-010-2089-2
  19. Chen Y-B, Lane AA, Logan BR, Zhu X, Akpek G, Aljurf MD, et al. Impact of conditioning regimen on outcomes for patients with lymphoma undergoing high-dose therapy with autologous hematopoietic cell transplantation. Biol Blood Marrow Transplant. 2015; 21 (6):1046-1053. doi: 10.1016/j.bbmt.2015.02.005
  20. Laporte JP, Fouillard L, Douay L, Eugene-Jolchine I, Isnard F, Stachowiak J, et al. GM-CSF instead of autologous bone-marrow transplantation after the BEAM regimen. Lancet. 1991; 338(8767):601-602. doi: 10.1016/0140-6736(91)90609-s
  21. Giulino-Roth L, Ricafort R, Kernan NA, Small TN, Trippett TM, Steinherz PG, et al. Ten-year follow-up of pediatric patients with non-Hodgkin lymphoma treated with allogeneic or autologous stem cell transplantation. Pediatr Blood Cancer. 2013; 60(12): 2018-2024. doi: 10.1002/pbc.24722
  22. Di Renzo N, Brugiatelli M, Montanini A, Vigliotti ML, Cervetti G, Liberati AM, et al. Vinorelbine, gemcitabine, procarbazine and prednisone (ViGePP) as salvage therapy in relapsed or refractory aggressive non-Hodgkin's lymphoma (NHL): results of a phase II study conducted by the Gruppo Italiano per lo Studio dei Linfomi. Leuk Lymphoma. 2006; 47(3):473-479.
    doi: 10.1080/10428190500312295
  23. Woessmann W, Peters C, Lenhard M, Burkhardt B, Sykora KW, Dilloo D, et al. Allogeneic haematopoietic stem cell transplantation in relapsed or refractory anaplastic large cell lymphoma of children and adolescents – a Berlin-Frankfurt-Münster group report. Br J Haematol. 2006; 133(2):176-182. doi: 10.1111/j.1365-2141.2006.06004.x
  24. Beynarovich A, Lepik K, Mikhailova N, Borzenkova E, Volkov N, Moiseev I, et al. Favorable outcomes of allogeneic hematopoietic stem cell transplantation with fludarabine–bendamustine conditioning and posttransplantation cyclophosphamide in classical Hodgkin lymphoma. Int J Hematol. 2022; 116(3):401-410. doi: 10.1007/s12185-022-03355-3
  25. Sarina B, Castagna L, Farina L, Patriarca F, Benedetti F, Carella, et al. Allogeneic transplantation improves the overall and progression-free survival of Hodgkin lymphoma patients relapsing after autologous transplantation: a retrospective study based on the time of HLA typing and donor availability. Blood. 2010; 115(18):3671-3677. doi: 10.1182/blood-2009-12-253856

" ["~DETAIL_TEXT"]=> string(24324) "

Introduction

Lymphoma is the third most common cancer in children. Opposite to adult tumors, pediatric non-Hodgkin lymphomas (NHL) tend to proceed in aggressive manner [1]. Pediatricians usually face only distinct types of NHL, i.e., anaplastic large cell lymphoma, ALK+ (ALCL) which occurs in 10-12% of the cases, lymphoblastic lymphoma (LL), in 20-25%; diffuse large B-cell lymphoma (DLBCL), primary mediastinal large B-cell lymphoma (10-15%), and Burkitt lymphoma affecting 50-60% of the patients [2]. Other types of NHL are uncommon in children. In developed countries, the relapsed or refractory (R-R) NHL occur in 10-25%, being more common in low-income and middle-income countries [3]. The choice of intensive first-line therapy is one of the reasons for high level of chemoresistance in case of relapse [4]. Mistiming, unreasonable dose reduction and excessive surgical activity may also affect prognosis [5]. Targeted therapy and immunotherapy increase chance of cure in cases of R-R NHL. However, hematopoietic stem cell transplantation (HSCT) still remains a cornerstone in its treatment [6]. There is no doubt that autologous hematopoietic stem cell transplantation (auto-HSCT) is a gold standard for the remission consolidation in R-R NHL, except of LL and, probably, ALCL where allogeneic HSCT (allo-HSCT) is more effective. This fact reflects weak or absent graft-versus-tumor effect (GVT) in B-NHL, and presence of GVT in LL and ALCL. These data were supported in randomized clinical trials in adult cohorts [7, 8]. The randomized trials in children were not yet performed due to ethical reasons and limited number of patients. Anyway, effectiveness of HSCT was demonstrated in many non-randomized studies in children [9, 10]. In general, HSCT doesn't solve the problem of R-R NHL but it may increase chances for cure approximately to 40-50% in the entire group. At the same time, allo-HSCT is associated with increased overall survival (OS) rates to 83% and should be regarded as very effective approach in the first ALCL relapse. Moreover, ALCL patients can be rescued with allo-HSCT even in progression observed pre-transplant, and in cases of relapse after auto-HSCT [11]. ALCL is a unique clinical entity that has a more favorable outcome in the cases with R-R course compared to other NHL subtypes. Presence of several effective targeted therapies (brentuximab vedotin, ALK-inhibitors) and high efficiency of allo-HSCT results in high rates of survival in children with R-R ALCL, ALK+.

Present case report demonstrates an adolescent patient with R-R ALCL successfully treated with several lines of chemoimmunotherapy and two HSCTs.

Case description

The patient is a 12-year-old girl from Donetsk. First symptoms of the disease consisted of abdominal pains and nausea since July 2018, later followed by fatigue, cough, dyspnea, and weight loss. Abdominal ultrasound demonstrated tumor in mesogastric region (140×60×47 mm). By computed tomography (CT), pleural effusion was revealed (right, 1140 mL; left, 360 mL). The tumor biopsy (August 17, 2018) showed initial morphology of leiomyosarcoma. First-line chemotherapy (2.10.18-1.11.18) consisted of I2VAd (ifosfamide 3000 mg/m2 №2, doxorubicin 40 mg/m2 №2 and vincristine 1.5 mg/m2 №3), followed by I2VA (ifosfamide 3000 mg/m2 №2, vincristine 1.5 mg/m2 №2, actinomycin D). Reduction of tumor volume was registered according to ultrasonography.

Later revision of histology and immunohistochemistry revealed ALCL, ALK+, and appropriate therapy was initiated according to NHL-BFM-like protocol (3 courses of A, and 3 courses of B, with 3 g/m2 of methotrexate in each block) continued from November 2018 to April 2019. Complete remission was achieved at the end of treatment.

Kozlov-fig01.jpg

Figure 1. Anaplastic large cell lymphoma. Hematoxylin & eosin stain (x400)

The ALCL, ALK+ was confirmed histologically, upon H&E staining (Fig. 1). Large polymorphic cells showed ovoid, polygonal and round pattern, with eosinophylic or translucent cytoplasm. Cell nuclei are irregular and ovoid, with lumpy chromatin. Apoptotic and mitotic activity were high. Immunohistochemistry demonstrated positive reaction with ALK (Fig. 2A), CD30 (Fig. 2B), GrB antibodies in intraplasmatic cytotoxic granules. Reactive microenvironment was presented by CD3+ lymphocytes. Ki-67 proliferation marker was seen in 50% of tumor cells.

On June 12, 2019 (two months after ending the therapy), the patient manifested with fatigue, pain in the right thigh, and fever. CT scans demonstrated a conglomerate of lymph nodes (8.5×5.2 cm) in the right iliac region with the involvement of m.iliacus. No tumor cells were found in bone marrow and cerebrospinal fluid. Serum lactatdehydrogenase level was 883.2 U/l. Clinical relapse was diagnosed after biopsy, and the patient was admitted to the N. N. Blokhin National Medical Research Center of Oncology (Moscow) for further treatment.

Kozlov-fig02.jpg

Figure 2. Anaplastic large cell lymphoma. Immunohistochemical staining of tumor cells for ALK+ (A) and by CD30+ cells (B). The reaction product is brown

Second-line treatment consisted of vinblastine 6 mg/m2 №2 and methotrexate 5000 g/m2 №1 every 21-28 days (3 cycles, from 12.07.19 to 11.10.19). Partial response was diagnosed after second cycle, but progression occurred after third course, according to CT results (17.10.19), with enlarged lesion of iliac muscle up to 11×4.8×8.6 cm.

Kozlov-fig03.jpg

Figure 3. PET-CT scan after 3rd-line therapy in ALCL patient. Black arrow demonstrates diffuse thickening of right iliac muscle with local metabolic activity

Third-line therapy consisted of brentuximab vedotin 1.8 mg/kg+ ICE №3 (05.11.19-28.01.2020): ifosfamide 1800 mg/m2 №5, etoposide 100 mg/m2 №5, carboplatin 400 mg/m2 №1. Partial response was achieved according to PET-CT data (20.01.2020) (Fig. 3).

On 26.03.2020, the patient underwent auto-HSCT in RM Gorbacheva Research Institute (St. Petersburg) with BeEAM conditioning regimen (bendamustine 160 mg/m2 №2, cytarabine 400 mg/m2 №4, etoposide 200 mg/m2 №4, melphalan 140 mg/m2 №1). A total of 3.2×106 CD34+ cells were reinfused. Prior to beginning the conditioning regimen, the patient progressed with right forearm involvement, confirmed by ALCL-positive cytology. Due to limited options for the remission reinduction and their presumably low efficiency, it was decided to proceed with auto-HSCT in the progression state. Posttransplant period was, generally, well tolerated, with febrile neutropenia and mucositis. Crizotinib 250 mg was initiated post-HSCT twice daily, in order to prevent progression. Three months after transplantation, the malignancy progression was registered with involvement of iliac muscle and right forearm. Glucocorticoid therapy was started to control the disease.

The 4th-line therapy at the N. N. Blokhin Research Center of Oncology consisted of VIGEPD №2 (gemcitabine 1000 mg/m2 №3, vinorelbine 30 mg/m2 №2, dacarbazine 375 mg/m2, prednisolone 20 mg/m2)+ brentuximab vedotin №2 and crizotinib (08.2020-09.2020). Infection complications and cytopenia were registered after the therapy. Partial remission was achieved, and patient was readmitted to RM Gorbacheva Research Institute for haploidentical HSCT (haplo-HSCT). On the 1st day of conditioning regimen, the patient experienced puffiness of the right forearm in the area of previous tumor location, and the disease progression could not be ruled out. Haplo-HSCT (26.10.2020) was performed from father, with conditioning by fludarabine (90 mg/m2) and bendamustine (390 mg/m2). Graft-versus-host disease (GVHD) prophylaxis consisted of posttransplant cyclophosphamide (100 mg/m2), tacrolimus and sirolimus. Posttransplant period was complicated by steroid-refractory acute skin GVHD Stage 2 (Day+42) that responded to ruxolitinib (10 mg/day). Bacterial pneumonia was diagnosed on Day +73 followed by complete recovery after combined antibacterial therapy (meropenem+vancomycin). As seen from Fig. 4, no lymphoma signs are observed by PET-CT from February 2022. At the present moment (1.5 years after haplo-HSCT), the patient is clinically disease-free, without symptoms of GVDH and with excellent transplant function, due to full donor chimerism.

Kozlov-fig04.jpg

Figure 4. PET-CT scan after haplo-HSCT in ALCL patient

Discussion

The present case report demonstrates wide therapeutic options for the treatment of R-R ALCL, ALK+. Taken together, they result in high chance of curation, even in refractory patients following several relapses. The treatment resistance may be registered to any known therapeutic modes (chemotherapy, targeted therapy, immunotherapy, HSCT). The mechanisms of resistance are diverse, including tumor clonal evolution, presence of residual tumor stem cells, various intercellular and intracellular mechanisms (for example, PDL-1 expression levels, etc.) [12]. Nowadays, the majority of patients with ALK+ ALCL enter continuous remission after first-line therapy. There is higher incidence of relapsed or refractory course of disease in cases of primary misdiagnosis and inadequate first-line therapy. Our patient received initial therapy according to the leiomyosarcoma protocol, thus being a probable factor of refractory course. After assessing correct diagnosis, the patient received therapy according to NHL-BFM-like protocol with complete response achieved. However, a relapse developed several months after finishing the protocol. Hence, the case could be regarded as early relapse or primary refractory state. Second-line therapy was based on high-dose methotrexate and vinblastine, the two highly effective drugs in this clinical setting. After initial response, the disease progressed and third-line therapy was started which consisted of ICE combined with brentuximab vedotin (BV). ICE is a classical regimen for R-R NHL, whereas BV is an established targeted drug for CD 30+ lymphomas [13]. In our case, this drug combination resulted in partial remission. Unfortunately, auto-HSCT was performed in progression, since the tumor appeared on right forearm several days prior to conditioning. Therefore, starting auto-HSCT in progression was a controversial decision. In general, the results of auto-HSCT in progression of ALCL are disappointing, and the transplant is not recommended in such cases [14]. We performed transplantation due to limited options for remission induction in heavily pretreated patient, relatively good somatic status and the intention-to-treat strategy. We used BeEAM, a conditioning regimen standard for lymphomas [15]. Toxicity of auto-HSCT is similar to high-dose chemotherapy, and usually manifests as mucositis, cytopenia and febrile neutropenia [16].

Posttransplant period in our patient proceeded typically, without unusual complications. In general, total body irradiation (TBI) is not indicated for lymphoma patients, due to its efficiency similar to the cytostatic drug-based conditioning regimens, and higher incidence of late side effects [17, 18]. According to CIBMTR data BEAM, ТBI and BuCy (busulfan+cyclophosphamide) are equally effective in auto-HSCT as conditioning regimens for NHL therapy [19]. BEAM is a non-myeloablative conditioning as most patients recover hematopoiesis even without reinfusion of hematopoietic stem cells. Auto-HSCT shortens cytopenia and reduces complications [20].

Our patient progressed 3 months after auto-HSCT. Relapses and progression after auto-HSCT are common in the patients with R-R NHL, despite modern treatment options and are still a challenge in all but ALK+ ALCL [10,11,21]. Hopefully, one more remission could be achieved after ViGePD scheme combined with targeted therapy (BV+crizotinib). This protocol earlier demonstrated efficiency in pretreated R-R NHL [22]. The idea was to add gemcitabine which was not previously used in the therapy. The remission state was considered till the first day of conditioning for allo-HSCT, when clinical progression with the involvement of right forearm was suspected. Allogeneic HSCT was not cancelled. There are data supporting its effectiveness despite absence of remission in ALK+ ALCL. The patients who receive allo-HSCT after relapse post auto-HSCT, or in ALCL progression, may be cured. Thus, the progression state is not desirable but it is not a contraindication for HSCT [11, 23].

Non-myeloablative conditioning (fludarabine and bendamustine) was used prior to haplo-HSCT. This conditioning regimen demonstrated effectiveness, and low level of toxicity in lymphoma patients [24]. It is also the proven fact that GVT effect plays major role in this clinical setting [25]. We did not apply intensive regimen, due to chemoresistance and four chemotherapy lines in previous history of this patient. This strategy appeared effective and safe, despite evidence of clinical progression and heavy pretreatment. Moderate complications of early posttransplant period (acute GVHD and pneumonia) were manageable and time-limited. The patient still maintains the remission state being also free of significant GVHD for 1.5 years.

In conclusion, a wide range of therapeutic options could be offered to the patients with ALK+ ALCL, e.g., chemotherapy, targeted therapy, HSCT that make this clinical subgroup unique among other R-R NHLs, due to favorable prognosis even in case of failure at the first line of therapy.

Conflict of interests

No conflicts of interest reported.

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string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "29562" ["VALUE"]=> array(2) { ["TEXT"]=> string(602) "<p>Андрей В. Козлов<sup>1</sup>, Тимур Т. Валиев<sup>2</sup>, Светлана А. Юлдашева<sup>3</sup>, Асмик Г. Геворгян<sup>1</sup>, Илья В. Казанцев<sup>1</sup>, Татьяна В. Юхта<sup>1</sup>, Акгуль А. Оджарова<sup>2</sup>, Кирилл И. Киргизов<sup>2</sup>, Наталья Б. Михайлова<sup>1</sup>, Людмила С. Зубаровская<sup>1</sup></p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(470) "

Андрей В. Козлов1, Тимур Т. Валиев2, Светлана А. Юлдашева3, Асмик Г. Геворгян1, Илья В. Казанцев1, Татьяна В. Юхта1, Акгуль А. Оджарова2, Кирилл И. Киргизов2, Наталья Б. Михайлова1, Людмила С. Зубаровская1

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1 НИИ детской онкологии, гематологии и трансплантологии им. Р. М. Горбачевой, Первый Санкт-Петербургский государственный медицинский университет им. акад. И. П. Павлова, Санкт-Петербург, Россия
2 Национальный медицинский исследовательский центр онкологии им. Н. Н. Блохина, Москва, Россия
3 Институт неотложной и восстановительной хирургии им. В. К. Гусака, Донецк, Донецкая Народная Республика

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Представленный клинический случай отражает современные возможности лечения ALK-позитивной рецидивирующей/рефрактерной (Р-Р) анапластической крупноклеточной лимфомы у детей и подростков. Для этого варианта лимфомы даже в случае Р-Р течения шанс на излечение остается относительно неплохим благодаря наличию эффективной таргетной терапии и высокой эффективности аллогенной трансплантации гемопоэтических стволовых клеток, которая может успешно применяться при данной патологии в том числе у пациентов вне ремиссии.

Ключевые слова

Анапластическая крупноклеточная лимфома, ALK+, рецидивирующее/рефрактерное течение, таргетная терапия, трансплантация гемопоэтических стволовых клеток.

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Andrey V. Kozlov1, Timur T. Valiev2, Svetlana A. Uldasheva3, Asmik G. Gevorgian1, Ilya V. Kazantsev1, Tatyana V. Yukhta1, Akgul A. Odzharova2, Kirill I. Kirgizov2, Natalya B. Mikhailova1, Ludmila S. Zubarovskaya1

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1 RM Gorbacheva Research Institute of Pediatric Oncology, Hematology and Transplantology, Pavlov University, St. Petersburg, Russia
2 N. N. Blokhin Russian Cancer Research Center, Moscow, Russia
3 V. K. Gusak Institute of Urgent and Reconstructive Surgery, Donetsk People’s Republic, Donetsk, Donetsk People’s Republic


Correspondence:
Dr. Andrey V. Kozlov, RM Gorbacheva Research Institute of Pediatric Oncology, Hematology and Transplantology, Pavlov University, 6-8 L.Tolstoy St, St. Petersburg, Russia
Phone: +7 (921) 327-28-79
E-mail: kozlovandrew1983@ya.ru


Citation: Kozlov AV, Valiev TT, Uldasheva SA et al. Successful treatment of relapsed/refractory anaplastic large cell lymphoma in adolescent patient: a case report. Cell Ther Transplant 2022; 11(3-4): 77-82.

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The present case report demonstrates current opportunities for the treatment of relapsed/refractory anaplastic large cell lymphoma, ALK-positive (R-R ALCL) in children and adolescents. This type of lymphoma lends sufficient chance of cure even in R-R cases, due to effective targeted therapy and high efficiency of allogeneic hematopoetic stem cell transplantation, thus demonstrating curative potential in the patients with active disease prior to transplantation.

Keywords

Anaplastic large cell lymphoma, ALK+, relapsed/refractory, targeted therapy, hematopoetic stem cell transplantation.

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Kozlov<sup>1</sup>, Timur T. Valiev<sup>2</sup>, Svetlana A. Uldasheva<sup>3</sup>, Asmik G. Gevorgian<sup>1</sup>, Ilya V. Kazantsev<sup>1</sup>, Tatyana V. Yukhta<sup>1</sup>, Akgul A. Odzharova<sup>2</sup>, Kirill I. Kirgizov<sup>2</sup>, Natalya B. Mikhailova<sup>1</sup>, Ludmila S. Zubarovskaya<sup>1</sup></p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(329) "

Andrey V. Kozlov1, Timur T. Valiev2, Svetlana A. Uldasheva3, Asmik G. Gevorgian1, Ilya V. Kazantsev1, Tatyana V. Yukhta1, Akgul A. Odzharova2, Kirill I. Kirgizov2, Natalya B. Mikhailova1, Ludmila S. Zubarovskaya1

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Andrey V. Kozlov1, Timur T. Valiev2, Svetlana A. Uldasheva3, Asmik G. Gevorgian1, Ilya V. Kazantsev1, Tatyana V. Yukhta1, Akgul A. Odzharova2, Kirill I. Kirgizov2, Natalya B. Mikhailova1, Ludmila S. Zubarovskaya1

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The present case report demonstrates current opportunities for the treatment of relapsed/refractory anaplastic large cell lymphoma, ALK-positive (R-R ALCL) in children and adolescents. This type of lymphoma lends sufficient chance of cure even in R-R cases, due to effective targeted therapy and high efficiency of allogeneic hematopoetic stem cell transplantation, thus demonstrating curative potential in the patients with active disease prior to transplantation.

Keywords

Anaplastic large cell lymphoma, ALK+, relapsed/refractory, targeted therapy, hematopoetic stem cell transplantation.

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The present case report demonstrates current opportunities for the treatment of relapsed/refractory anaplastic large cell lymphoma, ALK-positive (R-R ALCL) in children and adolescents. This type of lymphoma lends sufficient chance of cure even in R-R cases, due to effective targeted therapy and high efficiency of allogeneic hematopoetic stem cell transplantation, thus demonstrating curative potential in the patients with active disease prior to transplantation.

Keywords

Anaplastic large cell lymphoma, ALK+, relapsed/refractory, targeted therapy, hematopoetic stem cell transplantation.

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1 RM Gorbacheva Research Institute of Pediatric Oncology, Hematology and Transplantology, Pavlov University, St. Petersburg, Russia
2 N. N. Blokhin Russian Cancer Research Center, Moscow, Russia
3 V. K. Gusak Institute of Urgent and Reconstructive Surgery, Donetsk People’s Republic, Donetsk, Donetsk People’s Republic


Correspondence:
Dr. Andrey V. Kozlov, RM Gorbacheva Research Institute of Pediatric Oncology, Hematology and Transplantology, Pavlov University, 6-8 L.Tolstoy St, St. Petersburg, Russia
Phone: +7 (921) 327-28-79
E-mail: kozlovandrew1983@ya.ru


Citation: Kozlov AV, Valiev TT, Uldasheva SA et al. Successful treatment of relapsed/refractory anaplastic large cell lymphoma in adolescent patient: a case report. Cell Ther Transplant 2022; 11(3-4): 77-82.

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1 RM Gorbacheva Research Institute of Pediatric Oncology, Hematology and Transplantology, Pavlov University, St. Petersburg, Russia
2 N. N. Blokhin Russian Cancer Research Center, Moscow, Russia
3 V. K. Gusak Institute of Urgent and Reconstructive Surgery, Donetsk People’s Republic, Donetsk, Donetsk People’s Republic


Correspondence:
Dr. Andrey V. Kozlov, RM Gorbacheva Research Institute of Pediatric Oncology, Hematology and Transplantology, Pavlov University, 6-8 L.Tolstoy St, St. Petersburg, Russia
Phone: +7 (921) 327-28-79
E-mail: kozlovandrew1983@ya.ru


Citation: Kozlov AV, Valiev TT, Uldasheva SA et al. Successful treatment of relapsed/refractory anaplastic large cell lymphoma in adolescent patient: a case report. Cell Ther Transplant 2022; 11(3-4): 77-82.

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Андрей В. Козлов1, Тимур Т. Валиев2, Светлана А. Юлдашева3, Асмик Г. Геворгян1, Илья В. Казанцев1, Татьяна В. Юхта1, Акгуль А. Оджарова2, Кирилл И. Киргизов2, Наталья Б. Михайлова1, Людмила С. Зубаровская1

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Андрей В. Козлов1, Тимур Т. Валиев2, Светлана А. Юлдашева3, Асмик Г. Геворгян1, Илья В. Казанцев1, Татьяна В. Юхта1, Акгуль А. Оджарова2, Кирилл И. Киргизов2, Наталья Б. Михайлова1, Людмила С. Зубаровская1

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Представленный клинический случай отражает современные возможности лечения ALK-позитивной рецидивирующей/рефрактерной (Р-Р) анапластической крупноклеточной лимфомы у детей и подростков. Для этого варианта лимфомы даже в случае Р-Р течения шанс на излечение остается относительно неплохим благодаря наличию эффективной таргетной терапии и высокой эффективности аллогенной трансплантации гемопоэтических стволовых клеток, которая может успешно применяться при данной патологии в том числе у пациентов вне ремиссии.

Ключевые слова

Анапластическая крупноклеточная лимфома, ALK+, рецидивирующее/рефрактерное течение, таргетная терапия, трансплантация гемопоэтических стволовых клеток.

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Представленный клинический случай отражает современные возможности лечения ALK-позитивной рецидивирующей/рефрактерной (Р-Р) анапластической крупноклеточной лимфомы у детей и подростков. Для этого варианта лимфомы даже в случае Р-Р течения шанс на излечение остается относительно неплохим благодаря наличию эффективной таргетной терапии и высокой эффективности аллогенной трансплантации гемопоэтических стволовых клеток, которая может успешно применяться при данной патологии в том числе у пациентов вне ремиссии.

Ключевые слова

Анапластическая крупноклеточная лимфома, ALK+, рецидивирующее/рефрактерное течение, таргетная терапия, трансплантация гемопоэтических стволовых клеток.

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1 НИИ детской онкологии, гематологии и трансплантологии им. Р. М. Горбачевой, Первый Санкт-Петербургский государственный медицинский университет им. акад. И. П. Павлова, Санкт-Петербург, Россия
2 Национальный медицинский исследовательский центр онкологии им. Н. Н. Блохина, Москва, Россия
3 Институт неотложной и восстановительной хирургии им. В. К. Гусака, Донецк, Донецкая Народная Республика

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1 НИИ детской онкологии, гематологии и трансплантологии им. Р. М. Горбачевой, Первый Санкт-Петербургский государственный медицинский университет им. акад. И. П. Павлова, Санкт-Петербург, Россия
2 Национальный медицинский исследовательский центр онкологии им. Н. Н. Блохина, Москва, Россия
3 Институт неотложной и восстановительной хирургии им. В. К. Гусака, Донецк, Донецкая Народная Республика

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Introduction

Systemic mastocytosis (SM) is a group of heterogeneous diseases associated with abnormal proliferation and infiltration of mast cells (MC) in extra-cutaneous organs. According to the WHO 2016 classification, it is a separate nosological category in the group of myeloproliferative neoplasias [1]. Systemic mastocytosis is sub-classified into five sub-categories as indolent systemic mastocytosis (ISM), smoldering systemic mastocytosis (SSM), systemic mastocytosis associated with hematologic neoplasm (SM-AHN) and mast cell leukemia (MCL). According to the results of event-free and total life expectancy, indolent and smoldering systemic mastocytoses are among the most favorable sub-categories in terms of life expectancy, statistically not significantly different than the control group [2]. In the present communication, we report a clinical case of smoldering systemic mastocytosis in young adult patient with later progression to mast cell leukemia, on targeted therapy with the partial response.

Case description

We describe a male patient, 1968 year of birth. The disease manifested at the age of 22 years with single monomorphic rash elements throughout the body, without involvement of the face, palmar and plantar parts of the arms and feet, respectively with Darier sign (skin becomes swollen, itchy and red after physical exposure at the point of contact), on symptomatic therapy with H1-histamine blockers (ketotifen and cetirizine) with partial response. Upon visit to RM Gorbacheva Research Institute of Pediatric Oncology, Hematology and Transplantology (July 2021), there were no deviations from the clinical blood test, with hepatomegaly shown at ultrasound examination (not palpable under the right costal arch), increased tryptase levels (>200 μg/mL Upon the bone marrow sample examination, high mast cell contents (10%), the features of dysgranulopoiesis and dyserythropoiesis, 46XY karyotype, KIT D816V mutation (allele burden,16.6%) were revealed. When examining bone marrow biopsy with immunohistochemistry (IHC), the following markers were found: >30% of the cells in the infiltrate were MS, CD117 +, MCTrypt +, CD25 +, CD2 +/- (Fig. 1 A, B). In view of all B-signs (high mast cell burden on BM biopsy: >30% infiltration by mast cells (focal, dense aggregates) and serum total tryptase level >200 ng/ml; signs of dysplasia or myeloproliferation, in non-mast cell lineage(s). There were, however, no sufficient criteria for definitive diagnosis of an associated hematological neoplasm (AHN), with normal or only slightly abnormal blood counts. Moreover, hepatomegaly is not accompanied by altered liver function, palpable splenomegaly proceeds without hypersplenism, and/or lymphadenopathy upon palpation or visualization, however, in absence of C-signs (bone marrow dysfunction caused by neoplastic mast cell infiltration, manifesting by ≥1-lineage cytopenia(s); palpable hepatomegaly with impairment of liver function, ascites and/or portal hypertension; skeletal involvement with large osteolytic lesions with/without pathological fractures; palpable splenomegaly with hypersplenism; malabsorption with weight loss due to gastrointestinal mast cell infiltrates) [3]. On this basis, smoldering systemic mastocytosis was diagnosed, with KITD816V (+) mutation, 46XY karyotype, and typical skin damage registered from 07/2021. Continuous therapy with H1-histamine blockers was prescribed. 3 months later, an increased frequency of upper respiratory tract infections was noted. According to the results of repeated bone marrow puncture, 20% of mast cells were revealed in the bone marrow, which, in the absence of C-signs (without cytopenia, organ dysfunctions, malabsorption, skeletal involvement), and absence of mast cells in leukocyte formula fits the criteria of chronic mast cell leukemia (CMCL). This disorder is a rare form of SM that requires immediate targeted therapy and making a decision on allogeneic hematopoietic stem cell transplantation (HSCT) [4]. Due to lack of compatible donors, the feasibility of haploidentical HSCT still remains in question. Nonhematological toxicity (diarrhea) of 3rd degree, which is controlled by loperamide, was observed upon initiating therapy with midostaurin (200 mg/day). By the 3rd month of therapy, a clinical improvement was seen, in presenting as reduced bone marrow infiltration with MS from 20% to 5.8%, the KITD816V allelic mutation load decreased from 12.46 to 5.2% in BM, like as blood reduced serum tryptase (from 186 to 50 μg/mL) accompanied by partial resolution of skin lesions (Fig. 2B).

Abdulkhalikova-fig01.jpg

Figure 1. The bone marrow (BM) biopsy (H&E staining) (A); IHC staining CD117 in mast cells in BM (B). The microphotographs are presented by Prof. V. Baikov

Abdulkhalikova-fig02.jpg

Figure 2. Patient with the skin lesion before target therapy (A). B, Same case, after 3 months of treatment

Discussion

Like as any other chronic myeloproliferative disease, SM may undergo progression to more unfavorable forms, e.g., ASM and MCL [5, 6] thus requiring immediate treatment (chemotherapy, therapy with inhibitors of FLT3- tyrosine kinases, HSCT). Currently, patients with smoldering systemic mastocytosis do not receive specific anti-tumor treatment in absence of symptoms/tumor proliferation syndromes. Potential treatment options in these cases include therapy with tyrosine kinase inhibitors imatinib, dasatinib [7], interferon alpha [8], hydroxycarbamide [7], which, however, show limited efficacy, and cannot affect the risk of potential transformation to ASM and MCL. Therapy with midostaurin FLT3-inhibitor is indicated in aggressive forms of SM and mast cell leukemia. Midostaurin is a small molecule affecting the KIT-kinase signaling activity. It inhibits aberrant signal transmission by KIT kinase, thus causing decreased cell proliferation and histamine release, as well as induction of mast cell apoptosis [9]. It should be noted that the drug is effective both in presence of a KITD816V mutation as well as without this mutation. In addition, midostaurin inhibits IgE-mediated release of histamine from basophils and mast cells, thus potentially reducing the severity of symptoms mediated by mast cell mediators and alleviating organ damage [10]. Thus, midostaurin is currently the first targeted drug that has shown efficacy in the treatment of systemic mastocytosis. For comparison, therapy with other drugs, such as cladribine and interferon alpha, imatinib was accompanied by lower frequency and duration of clinical response [11]. Prognosis in the case of mast cell leukemia in historical group was poor with median survival of only 2 months [7]. The result of study D2201 showed that the overall response rate in advanced systemic mastocytosis was 60% (95% confidence interval [CI], 49 to 70) with 45% of the patients showing a major response. Among 16 patients with mast-cell leukemia, the median overall survival was 9.4 months (95% CI, 7.5 to non-estimated) [12]. The overall response rate in the study А2213 was 69% (major/partial response: 50/19%), with clinical benefit in all advanced SM variants. Median overall survival was 18.5 months for MCL patients [13]. Therefore, the use of midostaurin as a monotherapy of mastocytic neoplasias is of great clinical interest.

Conclusion

Systemic mastocytosis is a heterogeneous and rare disease among other hematological neoplasms, with a complex polymorphic clinical picture that makes it difficult to diagnose and start therapy. There is a risk of ISM and SSM progression to advanced step (ASM, MCL and SM-AHN) requiring immediate therapy, thus and which determining the need for lifelong monitoring and invasive studies (BM puncture, trepanobiopsy). A dynamic follow-up of the patient is planned, followed by a decision on allogeneic bone marrow transplantation.

Conflict of interest

None declared.

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    doi: 10.1002/ajh.21561
  12. Gotlib J, Kluin-Nelemans HC, George TI, Akin C, Sotlar K, Hermine O, et al. Efficacy and safety of midostaurin in advanced systemic mastocytosis. N Engl J Med. 2016; 374(26): 2530-2541. doi: 10.1056/NEJMoa1513098
  13. DeAngelo D J, George TI, Linder A, Langford C, Perkins C, Ma J, et al. Efficacy and safety of midostaurin in patients with advanced systemic mastocytosis: 10-year median follow-up of a phase II trial. Leukemia. 2018; 32(2): 470-478. doi: 10.1038/leu.2017.234

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Introduction

Systemic mastocytosis (SM) is a group of heterogeneous diseases associated with abnormal proliferation and infiltration of mast cells (MC) in extra-cutaneous organs. According to the WHO 2016 classification, it is a separate nosological category in the group of myeloproliferative neoplasias [1]. Systemic mastocytosis is sub-classified into five sub-categories as indolent systemic mastocytosis (ISM), smoldering systemic mastocytosis (SSM), systemic mastocytosis associated with hematologic neoplasm (SM-AHN) and mast cell leukemia (MCL). According to the results of event-free and total life expectancy, indolent and smoldering systemic mastocytoses are among the most favorable sub-categories in terms of life expectancy, statistically not significantly different than the control group [2]. In the present communication, we report a clinical case of smoldering systemic mastocytosis in young adult patient with later progression to mast cell leukemia, on targeted therapy with the partial response.

Case description

We describe a male patient, 1968 year of birth. The disease manifested at the age of 22 years with single monomorphic rash elements throughout the body, without involvement of the face, palmar and plantar parts of the arms and feet, respectively with Darier sign (skin becomes swollen, itchy and red after physical exposure at the point of contact), on symptomatic therapy with H1-histamine blockers (ketotifen and cetirizine) with partial response. Upon visit to RM Gorbacheva Research Institute of Pediatric Oncology, Hematology and Transplantology (July 2021), there were no deviations from the clinical blood test, with hepatomegaly shown at ultrasound examination (not palpable under the right costal arch), increased tryptase levels (>200 μg/mL Upon the bone marrow sample examination, high mast cell contents (10%), the features of dysgranulopoiesis and dyserythropoiesis, 46XY karyotype, KIT D816V mutation (allele burden,16.6%) were revealed. When examining bone marrow biopsy with immunohistochemistry (IHC), the following markers were found: >30% of the cells in the infiltrate were MS, CD117 +, MCTrypt +, CD25 +, CD2 +/- (Fig. 1 A, B). In view of all B-signs (high mast cell burden on BM biopsy: >30% infiltration by mast cells (focal, dense aggregates) and serum total tryptase level >200 ng/ml; signs of dysplasia or myeloproliferation, in non-mast cell lineage(s). There were, however, no sufficient criteria for definitive diagnosis of an associated hematological neoplasm (AHN), with normal or only slightly abnormal blood counts. Moreover, hepatomegaly is not accompanied by altered liver function, palpable splenomegaly proceeds without hypersplenism, and/or lymphadenopathy upon palpation or visualization, however, in absence of C-signs (bone marrow dysfunction caused by neoplastic mast cell infiltration, manifesting by ≥1-lineage cytopenia(s); palpable hepatomegaly with impairment of liver function, ascites and/or portal hypertension; skeletal involvement with large osteolytic lesions with/without pathological fractures; palpable splenomegaly with hypersplenism; malabsorption with weight loss due to gastrointestinal mast cell infiltrates) [3]. On this basis, smoldering systemic mastocytosis was diagnosed, with KITD816V (+) mutation, 46XY karyotype, and typical skin damage registered from 07/2021. Continuous therapy with H1-histamine blockers was prescribed. 3 months later, an increased frequency of upper respiratory tract infections was noted. According to the results of repeated bone marrow puncture, 20% of mast cells were revealed in the bone marrow, which, in the absence of C-signs (without cytopenia, organ dysfunctions, malabsorption, skeletal involvement), and absence of mast cells in leukocyte formula fits the criteria of chronic mast cell leukemia (CMCL). This disorder is a rare form of SM that requires immediate targeted therapy and making a decision on allogeneic hematopoietic stem cell transplantation (HSCT) [4]. Due to lack of compatible donors, the feasibility of haploidentical HSCT still remains in question. Nonhematological toxicity (diarrhea) of 3rd degree, which is controlled by loperamide, was observed upon initiating therapy with midostaurin (200 mg/day). By the 3rd month of therapy, a clinical improvement was seen, in presenting as reduced bone marrow infiltration with MS from 20% to 5.8%, the KITD816V allelic mutation load decreased from 12.46 to 5.2% in BM, like as blood reduced serum tryptase (from 186 to 50 μg/mL) accompanied by partial resolution of skin lesions (Fig. 2B).

Abdulkhalikova-fig01.jpg

Figure 1. The bone marrow (BM) biopsy (H&E staining) (A); IHC staining CD117 in mast cells in BM (B). The microphotographs are presented by Prof. V. Baikov

Abdulkhalikova-fig02.jpg

Figure 2. Patient with the skin lesion before target therapy (A). B, Same case, after 3 months of treatment

Discussion

Like as any other chronic myeloproliferative disease, SM may undergo progression to more unfavorable forms, e.g., ASM and MCL [5, 6] thus requiring immediate treatment (chemotherapy, therapy with inhibitors of FLT3- tyrosine kinases, HSCT). Currently, patients with smoldering systemic mastocytosis do not receive specific anti-tumor treatment in absence of symptoms/tumor proliferation syndromes. Potential treatment options in these cases include therapy with tyrosine kinase inhibitors imatinib, dasatinib [7], interferon alpha [8], hydroxycarbamide [7], which, however, show limited efficacy, and cannot affect the risk of potential transformation to ASM and MCL. Therapy with midostaurin FLT3-inhibitor is indicated in aggressive forms of SM and mast cell leukemia. Midostaurin is a small molecule affecting the KIT-kinase signaling activity. It inhibits aberrant signal transmission by KIT kinase, thus causing decreased cell proliferation and histamine release, as well as induction of mast cell apoptosis [9]. It should be noted that the drug is effective both in presence of a KITD816V mutation as well as without this mutation. In addition, midostaurin inhibits IgE-mediated release of histamine from basophils and mast cells, thus potentially reducing the severity of symptoms mediated by mast cell mediators and alleviating organ damage [10]. Thus, midostaurin is currently the first targeted drug that has shown efficacy in the treatment of systemic mastocytosis. For comparison, therapy with other drugs, such as cladribine and interferon alpha, imatinib was accompanied by lower frequency and duration of clinical response [11]. Prognosis in the case of mast cell leukemia in historical group was poor with median survival of only 2 months [7]. The result of study D2201 showed that the overall response rate in advanced systemic mastocytosis was 60% (95% confidence interval [CI], 49 to 70) with 45% of the patients showing a major response. Among 16 patients with mast-cell leukemia, the median overall survival was 9.4 months (95% CI, 7.5 to non-estimated) [12]. The overall response rate in the study А2213 was 69% (major/partial response: 50/19%), with clinical benefit in all advanced SM variants. Median overall survival was 18.5 months for MCL patients [13]. Therefore, the use of midostaurin as a monotherapy of mastocytic neoplasias is of great clinical interest.

Conclusion

Systemic mastocytosis is a heterogeneous and rare disease among other hematological neoplasms, with a complex polymorphic clinical picture that makes it difficult to diagnose and start therapy. There is a risk of ISM and SSM progression to advanced step (ASM, MCL and SM-AHN) requiring immediate therapy, thus and which determining the need for lifelong monitoring and invasive studies (BM puncture, trepanobiopsy). A dynamic follow-up of the patient is planned, followed by a decision on allogeneic bone marrow transplantation.

Conflict of interest

None declared.

References

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  2. Lim KH, Tefferi A, Lasho TL, Finke C, Patnaik M, Butterfield JH, et al. Systemic mastocytosis in 342 consecutive adults: survival studies and prognostic factors. Blood. 2009; 113:5727-5736. doi: 10.1182/blood-2009-02-205237
  3. NCCN Guidelines version 3.2021. Systemic Mastocytosis.
  4. Ustun C, Reiter A, Scott BL. Hematopoietic stem-cell transplantation for advanced systemic mastocytosis. J Clin Oncol. 2014; 32(29): 3264-3274. doi: 10.1200/JCO.2014.55.2018
  5. Lim KH, Tefferi A, Lasho TL. Systemic mastocytosis in 342 consecutive adults: survival studies and prognostic factors. Blood. 2009; 113(23): 5727-5736. doi: 10.1182/blood-2009-02-205237
  6. Escribano L, Alvarez-Twose I, Sánchez-Muñoz L, Garcia-Montero A, Núñez R, Almeida J, et al. Prognosis in adult indolent systemic mastocytosis: A long-term study of the Spanish Network on Mastocytosis in a series of 145 patients. Clin Immunol. 2009; 124(3): 514-521. doi: 10.1016/j.jaci.2009.05.003
  7. Pardanani A. Systemic mastocytosis in adults: 2021 Update on diagnosis, risk stratification and management. Am J Hematol 2021; 96(4): 508-525. doi: 10.1002/ajh.26118
  8. Buonomo A, Nucera E, Criscuolo M. Treatment of indolent and advanced systemic mastocytosis. Meditter J Hematol Infect Dis. 2022; 14(1): e2022040. doi: 10.4084/MJHID.2022.040
  9. Rydapt (midostaurin) [summary of product characteristics]. Basel, Switzerland: Novartis Pharma AG; 2018.
  10. Krauth MT, Mirkina I, Herrmann H, Baumgartner C, Kneidinger M, Valent P, et al. Midostaurin (PKC412) inhibits immunoglobulin E-dependent activation and mediator release in human blood basophils and mast cells. Clin Exp Allergy. 2009;39:1711-1720.
    doi: 10.1111/j.1365-2222.2009.03353.x
  11. Lim KH, Pardanani A, Butterfield JH, Li CY, Tefferi A. Cytoreductive therapy in 108 adults with systemic mastocytosis: Outcome analysis and response prediction during treatment with interferon-alpha, hydroxyurea. Hematol. 2009; 84 (2):790-794.
    doi: 10.1002/ajh.21561
  12. Gotlib J, Kluin-Nelemans HC, George TI, Akin C, Sotlar K, Hermine O, et al. Efficacy and safety of midostaurin in advanced systemic mastocytosis. N Engl J Med. 2016; 374(26): 2530-2541. doi: 10.1056/NEJMoa1513098
  13. DeAngelo D J, George TI, Linder A, Langford C, Perkins C, Ma J, et al. Efficacy and safety of midostaurin in patients with advanced systemic mastocytosis: 10-year median follow-up of a phase II trial. Leukemia. 2018; 32(2): 470-478. doi: 10.1038/leu.2017.234

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string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "29575" ["VALUE"]=> array(2) { ["TEXT"]=> string(204) "<p>Зарема К. Абдулхаликова, Ильдар М. Бархатов, Вадим В. Байков, Мария В. Барабанщикова, Елена В. Морозова </p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(192) "

Зарема К. Абдулхаликова, Ильдар М. Бархатов, Вадим В. Байков, Мария В. Барабанщикова, Елена В. Морозова

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НИИ детской онкологии, гематологии и трансплантологии им. Р. М. Горбачевой, Первый Санкт-Петербургский государственный медицинский университет им. акад. И. П. Павлова, Санкт-Петербург, Россия

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Нами приводится описание редкого случая прогрессии «тлеющего» системного мастоцитоза в тучноклеточный лейкоз. Проведено лечение злокачественного заболевания с применением таргетной терапии и достижением клинического ответа в течение 3 месяцев лечения.

Ключевые слова

Системный мастоцитоз, тучные клетки, аллогенная трансплантация костного мозга.

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Zarema K. Abdulkhalikova, Ildar M. Barkhatov, Vadim V. Baykov, Maria V. Barabanshikova, Elena V. Morozova

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RM Gorbacheva Research Institute of Pediatric Oncology, Hematology and Transplantology, Pavlov University, St. Petersburg, Russia


Correspondence:
Dr. Zarema K. Abdulkhalikova, RM Gorbacheva Research Institute of Pediatric Oncology, Hematology and Transplantology, Pavlov University, 6-8 L.Tolstoy St, 197022, St. Petersburg, Russia
Phone: +7 (965) 799-38-73
E-mail: dr.abdulhalikova@gmail.com


Citation: Abdulkhalikova ZK, Barkhatov IM, Baykov VV, et al. Transition from the smoldering systemic mastocytosis to chronic mast cell leukemia: a clinical case. Cell Ther Transplant 2022; 11(3-4): 83-86.

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We describe a rare clinical case of smoldering systemic mastocytosis which progressed to mast cell leukemia. The malignant disorder was treated with targeted therapy resulting into clinical improvement after 3 months during therapy.

Keywords

Systemic mastocytosis, mast cells, allogeneic bone marrow transplantation.

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Abdulkhalikova, Ildar M. Barkhatov, Vadim V. Baykov, Maria V. Barabanshikova, Elena V. Morozova </p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(114) "

Zarema K. Abdulkhalikova, Ildar M. Barkhatov, Vadim V. Baykov, Maria V. Barabanshikova, Elena V. Morozova

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Zarema K. Abdulkhalikova, Ildar M. Barkhatov, Vadim V. Baykov, Maria V. Barabanshikova, Elena V. Morozova

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We describe a rare clinical case of smoldering systemic mastocytosis which progressed to mast cell leukemia. The malignant disorder was treated with targeted therapy resulting into clinical improvement after 3 months during therapy.

Keywords

Systemic mastocytosis, mast cells, allogeneic bone marrow transplantation.

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We describe a rare clinical case of smoldering systemic mastocytosis which progressed to mast cell leukemia. The malignant disorder was treated with targeted therapy resulting into clinical improvement after 3 months during therapy.

Keywords

Systemic mastocytosis, mast cells, allogeneic bone marrow transplantation.

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RM Gorbacheva Research Institute of Pediatric Oncology, Hematology and Transplantology, Pavlov University, St. Petersburg, Russia


Correspondence:
Dr. Zarema K. Abdulkhalikova, RM Gorbacheva Research Institute of Pediatric Oncology, Hematology and Transplantology, Pavlov University, 6-8 L.Tolstoy St, 197022, St. Petersburg, Russia
Phone: +7 (965) 799-38-73
E-mail: dr.abdulhalikova@gmail.com


Citation: Abdulkhalikova ZK, Barkhatov IM, Baykov VV, et al. Transition from the smoldering systemic mastocytosis to chronic mast cell leukemia: a clinical case. Cell Ther Transplant 2022; 11(3-4): 83-86.

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RM Gorbacheva Research Institute of Pediatric Oncology, Hematology and Transplantology, Pavlov University, St. Petersburg, Russia


Correspondence:
Dr. Zarema K. Abdulkhalikova, RM Gorbacheva Research Institute of Pediatric Oncology, Hematology and Transplantology, Pavlov University, 6-8 L.Tolstoy St, 197022, St. Petersburg, Russia
Phone: +7 (965) 799-38-73
E-mail: dr.abdulhalikova@gmail.com


Citation: Abdulkhalikova ZK, Barkhatov IM, Baykov VV, et al. Transition from the smoldering systemic mastocytosis to chronic mast cell leukemia: a clinical case. Cell Ther Transplant 2022; 11(3-4): 83-86.

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Зарема К. Абдулхаликова, Ильдар М. Бархатов, Вадим В. Байков, Мария В. Барабанщикова, Елена В. Морозова

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Зарема К. Абдулхаликова, Ильдар М. Бархатов, Вадим В. Байков, Мария В. Барабанщикова, Елена В. Морозова

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Нами приводится описание редкого случая прогрессии «тлеющего» системного мастоцитоза в тучноклеточный лейкоз. Проведено лечение злокачественного заболевания с применением таргетной терапии и достижением клинического ответа в течение 3 месяцев лечения.

Ключевые слова

Системный мастоцитоз, тучные клетки, аллогенная трансплантация костного мозга.

" ["TYPE"]=> string(4) "HTML" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(29) "Описание/Резюме" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["DISPLAY_VALUE"]=> string(729) "

Нами приводится описание редкого случая прогрессии «тлеющего» системного мастоцитоза в тучноклеточный лейкоз. Проведено лечение злокачественного заболевания с применением таргетной терапии и достижением клинического ответа в течение 3 месяцев лечения.

Ключевые слова

Системный мастоцитоз, тучные клетки, аллогенная трансплантация костного мозга.

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НИИ детской онкологии, гематологии и трансплантологии им. Р. М. Горбачевой, Первый Санкт-Петербургский государственный медицинский университет им. акад. И. П. Павлова, Санкт-Петербург, Россия

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НИИ детской онкологии, гематологии и трансплантологии им. Р. М. Горбачевой, Первый Санкт-Петербургский государственный медицинский университет им. акад. И. П. Павлова, Санкт-Петербург, Россия

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Introduction

Ameloblastoma (AB) and dentigerous cyst (DC) are both clinically common benign odontogenic lesions. Due to the significant differences in biological behaviors these two diseases have different treatment strategies. Surgical management is the only effective method in the treatment for odontogenic tumors, but the choice of effective surgical method is controversial. The treatment plan for AB mainly includes the radical operation of partial resection of the jawbone, for DC – the preservation surgery of decompression combined with curettage. Because of the different treatment principles of the two lesions, it is very important to find a more accurate preoperative differential diagnosis method. Differential diagnosis of these two lesions is difficult because they share many clinical and radiographic features. Therefore, it is difficult to differentiate these lesions radiographically, and definitive diagnosis is based only on histopathologic examination. Thus, differences in radiographic findings of these two lesions may play an important role in making the diagnosis.

The conversion of digital medical images into mineable high-dimensional data is motivated by the concept that biomedical images contain information that reflects underlying pathophysiology and that these relationships can be revealed via quantitative image analyses. Radiomics is a process that allows the extraction and analysis of quantitative data from medical images. Radiomics is designed to develop decision support tools; therefore, it involves combining radiomic data with other patient characteristics, as available, to increase the power of the decision support models.

In the past few years, radiomics has been used for diagnosis Nasopharyngeal carcinoma [3]; prediction of treatment response in non-small-cell lung cancer [4]; for preoperative prediction of microvascular invasion in hepatocellular carcinoma [5]; for the Non-Invasive Assessment of Coronary Inflammation [6]; in precision diagnosis, prognostication and treatment planning of head and neck squamous cell carcinomas [7]. Textural analysis of images in the studies was aimed at identifying prognostic biomarkers of disease imaging. Such objective biomarkers are readily available and have the potential to improve personalized treatment and precision medicine.

We hypothesized that CT texture analysis can detect subtle differences of the jaw neoplasm. This information is required to determine the correct treatment tactics.

The purpose of this study was to evaluate the utility of CT texture features in distinguishing common jaw neoplasms, i.e., ameloblastoma (AB) from dentigerous cysts (DC).

Materials and methods

1. Patient selection

A total of 35 records of patients with jaw neoplasm attended at the department of maxilla-facial surgery of the First Pavlov state medical university of Saint-Petersburg were analyzed. The inclusion criteria for the selection of the medical records were:
• The cases should present a report of the histipathological examination of AB or DC. Samples were fixated in 10% buffered formalin, later they were bathed in paraffin and histological cuts of X microns were performed, after hematoxylin and eosine stain, cuts examined under a light microscope Leica.
• There should be CBCT of the jaw before surgical treatment.

The exclusion criteria were:
• no histological conclusion,
• presence of recurrent lesion and with odontogenic keratocyst,
• imaging slices with severe artifact.

We excluded 17 cases according to the exclusion criteria. The remaining 18 patients: 10 patients with DC (9 men, 1 woman; median age 45 years) and 8 patients with AB (2 men, 6 women; median age, 58 years) were enrolled in this study.

2. CT imaging protocol

CT examinations were performed on 64-slice CT scanners (Toshiba Aquilion 64) with 120 kV, 225 mA and 1 s/rotation, and 0.5 mm thick images were reconstructed using per our institutional clinical protocol. Axial 0.5-mm images in reconstruction were used for this analysis.

3. Image Interpretation

Characteristics of the lesions were qualitatively assessed by radiologist with 7-year experience in oral and maxillofacial radiology.

3.1. Image segmentation and texture analysis

Segmentation is an essential step of the radiomics workflow, as highly distinctive features will be obtained from the segmented region of interest that can be traced in a volume, the accuracy of the segmentation will determine the radiomics features that will be extracted. The lesion was manually contoured by an oral and maxillofacial radiologist with 7-year professional experience. Segmentation of the lesion was performed using 3D Slicer on each axial image which includes the lesion, septum and peripheral bone up to 2 mm from visible edge of the formation.

Feature extraction is the next step after the region of interest is segmented. It is the selection of useful information to assist in the characterization of normal and abnormal radiological images. This step is the heart of radiomics. To extract radiomics features from the manually-segmented volumes, the Radiomics extension of 3D Slicer was used.

The extracted characteristics were shape-based features (e.g., maximum diameter, surface area, volume), first-order features (based on histogram statistics), second-order and higher-order statistics (based on spatial dependence matrices).

4. Statistical analysis

Due to relatively small number of cases, we chose nonparametric methods for statistical analysis: description of quantitative variables was performed with median and interquartile range, Mann-Whitney U test was used to compare them. Fisher's exact test with Freeman-Halton extension was used in the analysis of contingency tables.

Results

5. Characteristics of lesions

The characteristics of lesions and segmented volumes included in the study are shown in Table 1.

The anterior maxillary region was the most frequently encountered location in dentigerous cyst and posterior mandibular region has been most often observed in ameloblastomas.

Table 1. Characteristics of lesions and segmented volume

Lysenko-tab01.jpg

6. Texture features and statistical analysis

The examples of segmented volumes are shown on Fig. 1.

Lysenko-fig01.jpg

Figure 1. Segmented CT images: A, ameloblastoma; B, dentigerous cyst

The shape-based features are descriptors of the region of interest 3D size and shape. They are independent from the region of interest gray level intensity distribution and give a quantitative description of the region of interest geometrical characteristics.

First-order statistics features consider the distribution of values of individual voxels disregarding the spatial relationships. Second-order features, are based on the joint probability distribution of pairs of voxels, describing the spatial arrangement of patterns, sometimes imperceptible to the human eye. We used Gray Level Cooccurrence Matrix (GLCM), Gray Level Run Length Matrix (GLRLM), Gray Level Size Zone Matrix (GLSZM), Neighboring Gray Tone Difference Matrix (NGTDM), Gray Level Dependence Matrix (GLDM).

In our study, we evaluated the CT image texture features of DC and AB. After texture analysis we didn’t found difference in the shape-based features and the first-order statistics values in two groups. In our opinion, this was expected, since both formations have similar radiographic features that can be superficially assessed during routine image analysis.

We found statistically significant differences in 13 second-order features of DC and AB (Fig. 2).

Lysenko-fig02-01.jpgLysenko-fig02-02.jpg

Figure 2. Differences in 13 second-order features of DC and AB

Cluster shade is a measure of the skewness and uniformity of the GLCM. Cluster prominence is a measure of the skewness and asymmetry of the GLCM. Contrast is a measure of the local intensity variation, favoring values away from the diagonal. Difference variance is a measure of heterogeneity that places higher weights on differing intensity level pairs that show more deviation from the mean. Informational Measure of Correlation is a quantification of the complexity of the texture. Dependence variance is the variance in dependence size in the image. Large dependence emphasis is the joint distribution of large dependence with lower gray level values. Long run emphasis – a measure of the distribution of long run lengths, with a greater value indicative of longer run lengths and more coarse structural textures. Run percentage is a measure of the coarseness of the texture by taking the ratio of number of runs and number of voxels in the region of interest. Run variance is the variance in runs for the run lengths. Gray level variance (GLSZM) is the variance in gray level intensities for the zones. Zone percentage is a measure of the coarseness of the texture by taking the ratio of number of zones and number of voxels in the region of interest. Complexity is a measure of non-uniformity and rapid changes in gray levels.

Multiple logistic regression analysis with direct stepwise inclusion of factors (forward LR) was performed to rank features and to determine most significant predictors. The final model included Cluster shade and IMC 1. Combined use of these indicators significantly increased the predictive value of the model (the area under a ROC=0.93).

Discussion

Jaws are the only site in the body where epithelium may normally be found within bone. The epithelium of the dental lamina is involved in the formation of enamel and maps out the shape of the tooth. On completion of tooth formation, epithelial remnants remain in the jaws. These give rise to a range of lesions, including neoplasms, which should pose no problem with diagnosis when seen to be associated with teeth, but can cause difficulty in other situations.

Two different types of lesions were the sample of this study: ameloblastoma, and dentigerous cyst. This selection was based on 2 factors: the frequency and the similarity of the radiographic image among these lesions.

As the components of the various lesions are inherently different pathologically, the texture features should also be different.

Ameloblastomas are composed of epithelium and do not show induction of dental hard tissues. In the conventional type, the epithelium may show a follicular or a plexiform pattern, but a mixture of patterns is often seen within a single tumor. The most common pattern is follicular, characterized by islands of epithelium with peripheral palisading of elongated columnar cells with reversed polarity, in that the nuclei are orientated away from the basement membrane. These cells resemble the preameloblasts of normal tooth development. Centrally the follicles contain loosely arranged stellate cells, showing a resemblance to the stellate reticulum of the tooth germ.

Dentigerous cyst consist of epithelial lining and wall. Epithelial lining – typically, 2-4 cells thick. Flattened non-keratinsing cells with a regular flat interface with the underlying wall. Inflammation results in features identical to radicular cyst. Metaplastic changes with mucous cells and cilia occur more commonly in dentigerous cysts than other types. Inflamed specimens may also show hyperplasia, occasionally with keratinization. Hyaline bodies and even sebaceous cells can be included. Wall – typically, uninflamed fibromyxoid connective tissue (similar to dental follicle) with plentiful glycosaminoglycan-rich ground substance. Odontogenic epithelial rests present in variable numbers and may undergo calcification. Increased fibrosis along with cholesterol clefts and haemosiderin deposition seen in longstanding and inflamed cysts.

We suppose the differences between radiomic features reflected the differences in X-ray density of lesions components.

Conclusion

Our pilot study demonstrates a new technique for non-invasive differential diagnosis of jaw neoplasms based on texture features. This research may contribute to actual implementation of these radiomics-based techniques into clinical practice, contributing the effective support of clinical decision-making and the fostering of precision medicine.

Funding sources

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

Conflict of interest

None declared.

References

  1. Fedorov A, Beichel R, Kalpathy-Cramer J, Finet J, Fillion-Robin JC, Pujol S, et al. 3D Slicer as an image computing platform for the quantitative imaging network. Magn Reson Imaging. 2012 ;30(9):1323-1341. doi: 10.1016/j.mri.2012.05.001
  2. van Griethuysen JJM, Fedorov A, Parmar C, Hosny A, Aucoin N, Narayan V, et al. Computational radiomics system to decode the radiographic phenotype. Cancer Res. 2017; 77(21):e104-e107. doi: 10.1158/0008-5472.CAN-17-0339
  3. Duan W, Xiong B, Tian T, Zou X, He Z, Zhang L. Radiomics in nasopharyngeal carcinoma. Clin Med Insights Oncol. 2022; 16:11795549221079186. doi: 10.1177/11795549221079186
  4. Chetan MR, Gleeson FV. Radiomics in predicting treatment response in non-small-cell lung cancer: current status, challenges and future perspectives. Eur Radiol. 2021;31(2):1049-1058. doi: 10.1007/s00330-020-07141-9
  5. Yang L, Gu D, Wei J, Yang C, Rao S, Wang W, et al. A radiomics nomogram for preoperative prediction of microvascular invasion in hepatocellular carcinoma. Liver Cancer. 2019;8(5):373-386. doi: 10.1159/000494099
  6. Cheng K, Lin A, Yuvaraj J, Nicholls SJ, Wong DTL. Cardiac computed tomography radiomics for the non-invasive assessment of coronary inflammation. Cells. 2021; 10(4):879. doi: 10.3390/cells10040879
  7. Haider SP, Burtness B, Yarbrough WG, Payabvash S. Applications of radiomics in precision diagnosis, prognostication and treatment planning of head and neck squamous cell carcinomas. Cancers Head Neck. 2020; 5:6. doi: 10.1186/s41199-020-00053-7

" ["~DETAIL_TEXT"]=> string(16500) "

Introduction

Ameloblastoma (AB) and dentigerous cyst (DC) are both clinically common benign odontogenic lesions. Due to the significant differences in biological behaviors these two diseases have different treatment strategies. Surgical management is the only effective method in the treatment for odontogenic tumors, but the choice of effective surgical method is controversial. The treatment plan for AB mainly includes the radical operation of partial resection of the jawbone, for DC – the preservation surgery of decompression combined with curettage. Because of the different treatment principles of the two lesions, it is very important to find a more accurate preoperative differential diagnosis method. Differential diagnosis of these two lesions is difficult because they share many clinical and radiographic features. Therefore, it is difficult to differentiate these lesions radiographically, and definitive diagnosis is based only on histopathologic examination. Thus, differences in radiographic findings of these two lesions may play an important role in making the diagnosis.

The conversion of digital medical images into mineable high-dimensional data is motivated by the concept that biomedical images contain information that reflects underlying pathophysiology and that these relationships can be revealed via quantitative image analyses. Radiomics is a process that allows the extraction and analysis of quantitative data from medical images. Radiomics is designed to develop decision support tools; therefore, it involves combining radiomic data with other patient characteristics, as available, to increase the power of the decision support models.

In the past few years, radiomics has been used for diagnosis Nasopharyngeal carcinoma [3]; prediction of treatment response in non-small-cell lung cancer [4]; for preoperative prediction of microvascular invasion in hepatocellular carcinoma [5]; for the Non-Invasive Assessment of Coronary Inflammation [6]; in precision diagnosis, prognostication and treatment planning of head and neck squamous cell carcinomas [7]. Textural analysis of images in the studies was aimed at identifying prognostic biomarkers of disease imaging. Such objective biomarkers are readily available and have the potential to improve personalized treatment and precision medicine.

We hypothesized that CT texture analysis can detect subtle differences of the jaw neoplasm. This information is required to determine the correct treatment tactics.

The purpose of this study was to evaluate the utility of CT texture features in distinguishing common jaw neoplasms, i.e., ameloblastoma (AB) from dentigerous cysts (DC).

Materials and methods

1. Patient selection

A total of 35 records of patients with jaw neoplasm attended at the department of maxilla-facial surgery of the First Pavlov state medical university of Saint-Petersburg were analyzed. The inclusion criteria for the selection of the medical records were:
• The cases should present a report of the histipathological examination of AB or DC. Samples were fixated in 10% buffered formalin, later they were bathed in paraffin and histological cuts of X microns were performed, after hematoxylin and eosine stain, cuts examined under a light microscope Leica.
• There should be CBCT of the jaw before surgical treatment.

The exclusion criteria were:
• no histological conclusion,
• presence of recurrent lesion and with odontogenic keratocyst,
• imaging slices with severe artifact.

We excluded 17 cases according to the exclusion criteria. The remaining 18 patients: 10 patients with DC (9 men, 1 woman; median age 45 years) and 8 patients with AB (2 men, 6 women; median age, 58 years) were enrolled in this study.

2. CT imaging protocol

CT examinations were performed on 64-slice CT scanners (Toshiba Aquilion 64) with 120 kV, 225 mA and 1 s/rotation, and 0.5 mm thick images were reconstructed using per our institutional clinical protocol. Axial 0.5-mm images in reconstruction were used for this analysis.

3. Image Interpretation

Characteristics of the lesions were qualitatively assessed by radiologist with 7-year experience in oral and maxillofacial radiology.

3.1. Image segmentation and texture analysis

Segmentation is an essential step of the radiomics workflow, as highly distinctive features will be obtained from the segmented region of interest that can be traced in a volume, the accuracy of the segmentation will determine the radiomics features that will be extracted. The lesion was manually contoured by an oral and maxillofacial radiologist with 7-year professional experience. Segmentation of the lesion was performed using 3D Slicer on each axial image which includes the lesion, septum and peripheral bone up to 2 mm from visible edge of the formation.

Feature extraction is the next step after the region of interest is segmented. It is the selection of useful information to assist in the characterization of normal and abnormal radiological images. This step is the heart of radiomics. To extract radiomics features from the manually-segmented volumes, the Radiomics extension of 3D Slicer was used.

The extracted characteristics were shape-based features (e.g., maximum diameter, surface area, volume), first-order features (based on histogram statistics), second-order and higher-order statistics (based on spatial dependence matrices).

4. Statistical analysis

Due to relatively small number of cases, we chose nonparametric methods for statistical analysis: description of quantitative variables was performed with median and interquartile range, Mann-Whitney U test was used to compare them. Fisher's exact test with Freeman-Halton extension was used in the analysis of contingency tables.

Results

5. Characteristics of lesions

The characteristics of lesions and segmented volumes included in the study are shown in Table 1.

The anterior maxillary region was the most frequently encountered location in dentigerous cyst and posterior mandibular region has been most often observed in ameloblastomas.

Table 1. Characteristics of lesions and segmented volume

Lysenko-tab01.jpg

6. Texture features and statistical analysis

The examples of segmented volumes are shown on Fig. 1.

Lysenko-fig01.jpg

Figure 1. Segmented CT images: A, ameloblastoma; B, dentigerous cyst

The shape-based features are descriptors of the region of interest 3D size and shape. They are independent from the region of interest gray level intensity distribution and give a quantitative description of the region of interest geometrical characteristics.

First-order statistics features consider the distribution of values of individual voxels disregarding the spatial relationships. Second-order features, are based on the joint probability distribution of pairs of voxels, describing the spatial arrangement of patterns, sometimes imperceptible to the human eye. We used Gray Level Cooccurrence Matrix (GLCM), Gray Level Run Length Matrix (GLRLM), Gray Level Size Zone Matrix (GLSZM), Neighboring Gray Tone Difference Matrix (NGTDM), Gray Level Dependence Matrix (GLDM).

In our study, we evaluated the CT image texture features of DC and AB. After texture analysis we didn’t found difference in the shape-based features and the first-order statistics values in two groups. In our opinion, this was expected, since both formations have similar radiographic features that can be superficially assessed during routine image analysis.

We found statistically significant differences in 13 second-order features of DC and AB (Fig. 2).

Lysenko-fig02-01.jpgLysenko-fig02-02.jpg

Figure 2. Differences in 13 second-order features of DC and AB

Cluster shade is a measure of the skewness and uniformity of the GLCM. Cluster prominence is a measure of the skewness and asymmetry of the GLCM. Contrast is a measure of the local intensity variation, favoring values away from the diagonal. Difference variance is a measure of heterogeneity that places higher weights on differing intensity level pairs that show more deviation from the mean. Informational Measure of Correlation is a quantification of the complexity of the texture. Dependence variance is the variance in dependence size in the image. Large dependence emphasis is the joint distribution of large dependence with lower gray level values. Long run emphasis – a measure of the distribution of long run lengths, with a greater value indicative of longer run lengths and more coarse structural textures. Run percentage is a measure of the coarseness of the texture by taking the ratio of number of runs and number of voxels in the region of interest. Run variance is the variance in runs for the run lengths. Gray level variance (GLSZM) is the variance in gray level intensities for the zones. Zone percentage is a measure of the coarseness of the texture by taking the ratio of number of zones and number of voxels in the region of interest. Complexity is a measure of non-uniformity and rapid changes in gray levels.

Multiple logistic regression analysis with direct stepwise inclusion of factors (forward LR) was performed to rank features and to determine most significant predictors. The final model included Cluster shade and IMC 1. Combined use of these indicators significantly increased the predictive value of the model (the area under a ROC=0.93).

Discussion

Jaws are the only site in the body where epithelium may normally be found within bone. The epithelium of the dental lamina is involved in the formation of enamel and maps out the shape of the tooth. On completion of tooth formation, epithelial remnants remain in the jaws. These give rise to a range of lesions, including neoplasms, which should pose no problem with diagnosis when seen to be associated with teeth, but can cause difficulty in other situations.

Two different types of lesions were the sample of this study: ameloblastoma, and dentigerous cyst. This selection was based on 2 factors: the frequency and the similarity of the radiographic image among these lesions.

As the components of the various lesions are inherently different pathologically, the texture features should also be different.

Ameloblastomas are composed of epithelium and do not show induction of dental hard tissues. In the conventional type, the epithelium may show a follicular or a plexiform pattern, but a mixture of patterns is often seen within a single tumor. The most common pattern is follicular, characterized by islands of epithelium with peripheral palisading of elongated columnar cells with reversed polarity, in that the nuclei are orientated away from the basement membrane. These cells resemble the preameloblasts of normal tooth development. Centrally the follicles contain loosely arranged stellate cells, showing a resemblance to the stellate reticulum of the tooth germ.

Dentigerous cyst consist of epithelial lining and wall. Epithelial lining – typically, 2-4 cells thick. Flattened non-keratinsing cells with a regular flat interface with the underlying wall. Inflammation results in features identical to radicular cyst. Metaplastic changes with mucous cells and cilia occur more commonly in dentigerous cysts than other types. Inflamed specimens may also show hyperplasia, occasionally with keratinization. Hyaline bodies and even sebaceous cells can be included. Wall – typically, uninflamed fibromyxoid connective tissue (similar to dental follicle) with plentiful glycosaminoglycan-rich ground substance. Odontogenic epithelial rests present in variable numbers and may undergo calcification. Increased fibrosis along with cholesterol clefts and haemosiderin deposition seen in longstanding and inflamed cysts.

We suppose the differences between radiomic features reflected the differences in X-ray density of lesions components.

Conclusion

Our pilot study demonstrates a new technique for non-invasive differential diagnosis of jaw neoplasms based on texture features. This research may contribute to actual implementation of these radiomics-based techniques into clinical practice, contributing the effective support of clinical decision-making and the fostering of precision medicine.

Funding sources

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

Conflict of interest

None declared.

References

  1. Fedorov A, Beichel R, Kalpathy-Cramer J, Finet J, Fillion-Robin JC, Pujol S, et al. 3D Slicer as an image computing platform for the quantitative imaging network. Magn Reson Imaging. 2012 ;30(9):1323-1341. doi: 10.1016/j.mri.2012.05.001
  2. van Griethuysen JJM, Fedorov A, Parmar C, Hosny A, Aucoin N, Narayan V, et al. Computational radiomics system to decode the radiographic phenotype. Cancer Res. 2017; 77(21):e104-e107. doi: 10.1158/0008-5472.CAN-17-0339
  3. Duan W, Xiong B, Tian T, Zou X, He Z, Zhang L. Radiomics in nasopharyngeal carcinoma. Clin Med Insights Oncol. 2022; 16:11795549221079186. doi: 10.1177/11795549221079186
  4. Chetan MR, Gleeson FV. Radiomics in predicting treatment response in non-small-cell lung cancer: current status, challenges and future perspectives. Eur Radiol. 2021;31(2):1049-1058. doi: 10.1007/s00330-020-07141-9
  5. Yang L, Gu D, Wei J, Yang C, Rao S, Wang W, et al. A radiomics nomogram for preoperative prediction of microvascular invasion in hepatocellular carcinoma. Liver Cancer. 2019;8(5):373-386. doi: 10.1159/000494099
  6. Cheng K, Lin A, Yuvaraj J, Nicholls SJ, Wong DTL. Cardiac computed tomography radiomics for the non-invasive assessment of coronary inflammation. Cells. 2021; 10(4):879. doi: 10.3390/cells10040879
  7. Haider SP, Burtness B, Yarbrough WG, Payabvash S. Applications of radiomics in precision diagnosis, prognostication and treatment planning of head and neck squamous cell carcinomas. Cancers Head Neck. 2020; 5:6. doi: 10.1186/s41199-020-00053-7

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Part 2" ["ELEMENT_PREVIEW_PICTURE_FILE_ALT"]=> string(3416) "<p style="text-align: justify;">Амелобластомы и одонтогенные кисты имеют идентичный клинический и рентгенологический вид. В нашем исследовании мы демонстрируем важность тщательного рассмотрения радиологических особенностей, которые могут помочь в неинвазивной дифференциальной диагностике и обеспечении надлежащего лечения этих поражений.</p> <h3>Методы</h3> <p style="text-align: justify;">Было проведено ретроспективное исследование, включавшее 18 КТ-изображений пациентов с новообразованиями челюсти (8 амелобластом и 10 зубочелюстных кист с гистопатологической верификацией). Каждое поражение было вручную сегментировано с помощью программного обеспечения 3D Slicer на КТ-изображениях, а текстурные особенности были извлечены с использованием расширения 3D Slicer Radiomics. Был проведен статистический анализ.</p> <h3>Результаты</h3> <p style="text-align: justify;">После анализа текстуры мы не обнаружили (статистически значимых) различий в характеристиках формы и статистических значениях первого порядка этих поражений. Мы обнаружили статистически значимые различия по 13 признакам второго порядка зубочелюстных кист и амелобластом, большинство из которых тесно коррелировали. Был проведен множественный логистический регрессионный анализ для ранжирования признаков и определения наиболее значимых предикторов. 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Лысенко<sup>1</sup>, Андрей И. Яременко<sup>2</sup>, Анна А. Зубарева<sup>3</sup>, Александр В. Ширшин<sup>4</sup>, Александр И. Любимов<sup>5</sup>, Елизавета А. Иванова<sup>1</sup></p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(287) "

Анна В. Лысенко1, Андрей И. Яременко2, Анна А. Зубарева3, Александр В. Ширшин4, Александр И. Любимов5, Елизавета А. Иванова1

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1 Отдел челюстно-лицевой хирургии НИИ стоматологии и челюстно-лицевой хирургии, Санкт-Петербург, Россия
2 Кафедра челюстно-лицевой хирургии, Первый Санкт-Петербургский государственный медицинский университет им. И. П. Павлова, Санкт-Петербург, Россия
3 Кафедра оториноларингологии, Первый Санкт-Петербургский государственный медицинский университет им. И. П. Павлова, Санкт-Петербург, Россия
4 Клиника рентгенорадиологии и ультразвуковой диагностики Военно-медицинской академии имени Кирова, факультет систем управления и робототехники, Университет ИТМО, Санкт-Петербург, Россия
5 1-е отделение усовершенствования хирургов, Военно-медицинская академия им. С.М. Кирова, Санкт-Петербург, Россия

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Амелобластомы и одонтогенные кисты имеют идентичный клинический и рентгенологический вид. В нашем исследовании мы демонстрируем важность тщательного рассмотрения радиологических особенностей, которые могут помочь в неинвазивной дифференциальной диагностике и обеспечении надлежащего лечения этих поражений.

Методы

Было проведено ретроспективное исследование, включавшее 18 КТ-изображений пациентов с новообразованиями челюсти (8 амелобластом и 10 зубочелюстных кист с гистопатологической верификацией). Каждое поражение было вручную сегментировано с помощью программного обеспечения 3D Slicer на КТ-изображениях, а текстурные особенности были извлечены с использованием расширения 3D Slicer Radiomics. Был проведен статистический анализ.

Результаты

После анализа текстуры мы не обнаружили (статистически значимых) различий в характеристиках формы и статистических значениях первого порядка этих поражений. Мы обнаружили статистически значимые различия по 13 признакам второго порядка зубочелюстных кист и амелобластом, большинство из которых тесно коррелировали. Был проведен множественный логистический регрессионный анализ для ранжирования признаков и определения наиболее значимых предикторов. Окончательная модель включала 2 признака (кластерный оттенок и IMC 1) и обеспечивала высокую прогностическую ценность (площадь под ROC=0,93).

Выводы

В нашем пилотном исследовании мы продемонстрирован новый метод неинвазивной дифференциальной диагностики новообразований челюстей на основе особенностей текстуры, извлеченных из данных КТ.

Ключевые слова

Радиомика, новообразования челюстей, амелобластома, одонтогенные кисты, компьютерная томография.

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Anna V. Lysenko1, Andrey I. Yaremenko2, Anna A. Zubareva3, Alexander V. Shirshin4, Aleksandr I. Lуubimov5, Elizaveta A. Ivanova1

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1 Department of Maxillofacial Surgery, Research Institute of Dentistry and Maxillofacial Surgery, St. Petersburg, Russia
2 Department of Maxillofacial Surgery, Pavlov University, St. Petersburg, Russia
3 Department of Otorhinolaryngology, Pavlov University, St. Petersburg, Russia
4 Clinic of X-ray Radiology and Ultrasound Diagnostics, Kirov’s Military Medical Academy, Faculty of control Systems and Robotics, ITMO University, St. Petersburg, Russia
5 1st Department for Surgeons’ Advanced Training, Kirov’s Military Medical Academy, St. Petersburg, Russia


Correspondence:
Dr. Anna V. Lysenko, Department of Maxillofacial Surgery, Research Institute of Dentistry and Maxillofacial Surgery, Pavlov University, 44 Petrogradskaya Emb., 197101, St. Petersburg, Russia
Phone: +7 (812) 429-03-33
E-mail: lysenko.anna@mail.ru


Citation: Lysenko AV, Yaremenko AI, Zubareva AA, et al. Application of radiomics in the differential diagnosis in ameloblastomas and dentigerous cysts. Part 2. Cell Ther Transplant 2022; 11(3-4): 93-98.

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Ameloblastomas and dentigerous cysts have an identical clinical and radiographic appearance. In our study we demonstrate the importance of radiological features careful consideration that can help in non-invasive differential diagnosis and ensuring appropriate management of these lesions.

Methods

This was a retrospective study including 18 CT images of patients with jaw neoplasm (8 ameloblastomas and 10 dentigerous cysts with histopathological verification). Each lesion was manually segmented using 3D Slicer software [1] on CT images, and textural features were extracted using 3D Slicer Radiomics extension [2]. Statistical analysis was performed.

Results

After texture analysis we found no (statistically significant) differences in the shape-based features and the first-order statistics values of these lesions. We found statistically significant differences in 13 second-order features of dentigerous cysts and ameloblastomas, most of them were closely correlated. Multiple logistic regression analysis was performed to rank features and to determine most significant predictors. The final model included 2 features (Cluster shade and IMC 1) and provided high predictive value (the area under a ROC=0.93).

Conclusions

Our pilot study demonstrates a new technique for non-invasive differential diagnosis of jaw neoplasms based on texture features extracted from CT-data.

Keywords

Radiomics, jaw neoplasms, ameloblastoma, dentigerous cysts, CT scan.

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"37" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:02:59" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(6) "Author" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(9) "AUTHOR_EN" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "37" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "29603" ["VALUE"]=> array(2) { ["TEXT"]=> string(288) "<p>Anna V. Lysenko<sup>1</sup>, Andrey I. Yaremenko<sup>2</sup>, Anna A. Zubareva<sup>3</sup>, Alexander V. Shirshin<sup>4</sup>, Aleksandr I. Lуubimov<sup>5</sup>, Elizaveta A. Ivanova<sup>1</sup> </p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(204) "

Anna V. Lysenko1, Andrey I. Yaremenko2, Anna A. Zubareva3, Alexander V. Shirshin4, Aleksandr I. Lуubimov5, Elizaveta A. Ivanova1

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Anna V. Lysenko1, Andrey I. Yaremenko2, Anna A. Zubareva3, Alexander V. Shirshin4, Aleksandr I. Lуubimov5, Elizaveta A. Ivanova1

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Ameloblastomas and dentigerous cysts have an identical clinical and radiographic appearance. In our study we demonstrate the importance of radiological features careful consideration that can help in non-invasive differential diagnosis and ensuring appropriate management of these lesions.

Methods

This was a retrospective study including 18 CT images of patients with jaw neoplasm (8 ameloblastomas and 10 dentigerous cysts with histopathological verification). Each lesion was manually segmented using 3D Slicer software [1] on CT images, and textural features were extracted using 3D Slicer Radiomics extension [2]. Statistical analysis was performed.

Results

After texture analysis we found no (statistically significant) differences in the shape-based features and the first-order statistics values of these lesions. We found statistically significant differences in 13 second-order features of dentigerous cysts and ameloblastomas, most of them were closely correlated. Multiple logistic regression analysis was performed to rank features and to determine most significant predictors. The final model included 2 features (Cluster shade and IMC 1) and provided high predictive value (the area under a ROC=0.93).

Conclusions

Our pilot study demonstrates a new technique for non-invasive differential diagnosis of jaw neoplasms based on texture features extracted from CT-data.

Keywords

Radiomics, jaw neoplasms, ameloblastoma, dentigerous cysts, CT scan.

" ["TYPE"]=> string(4) "HTML" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(21) "Description / Summary" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["DISPLAY_VALUE"]=> string(1684) "

Ameloblastomas and dentigerous cysts have an identical clinical and radiographic appearance. In our study we demonstrate the importance of radiological features careful consideration that can help in non-invasive differential diagnosis and ensuring appropriate management of these lesions.

Methods

This was a retrospective study including 18 CT images of patients with jaw neoplasm (8 ameloblastomas and 10 dentigerous cysts with histopathological verification). Each lesion was manually segmented using 3D Slicer software [1] on CT images, and textural features were extracted using 3D Slicer Radiomics extension [2]. Statistical analysis was performed.

Results

After texture analysis we found no (statistically significant) differences in the shape-based features and the first-order statistics values of these lesions. We found statistically significant differences in 13 second-order features of dentigerous cysts and ameloblastomas, most of them were closely correlated. Multiple logistic regression analysis was performed to rank features and to determine most significant predictors. The final model included 2 features (Cluster shade and IMC 1) and provided high predictive value (the area under a ROC=0.93).

Conclusions

Our pilot study demonstrates a new technique for non-invasive differential diagnosis of jaw neoplasms based on texture features extracted from CT-data.

Keywords

Radiomics, jaw neoplasms, ameloblastoma, dentigerous cysts, CT scan.

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Part 2" ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> string(102) "Application of radiomics in the differential diagnosis in ameloblastomas and dentigerous cysts. Part 2" ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(4) "Name" ["~DEFAULT_VALUE"]=> string(0) "" ["DISPLAY_VALUE"]=> string(102) "Application of radiomics in the differential diagnosis in ameloblastomas and dentigerous cysts. Part 2" } ["ORGANIZATION_EN"]=> array(37) { ["ID"]=> string(2) "38" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:02:59" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(12) "Organization" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(15) "ORGANIZATION_EN" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "38" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "29604" ["VALUE"]=> array(2) { ["TEXT"]=> string(1362) "<p><sup>1</sup> Department of Maxillofacial Surgery, Research Institute of Dentistry and Maxillofacial Surgery, St. Petersburg, Russia<br> <sup>2</sup> Department of Maxillofacial Surgery, Pavlov University, St. Petersburg, Russia<br> <sup>3</sup> Department of Otorhinolaryngology, Pavlov University, St. Petersburg, Russia<br> <sup>4</sup> Clinic of X-ray Radiology and Ultrasound Diagnostics, Kirov’s Military Medical Academy, Faculty of control Systems and Robotics, ITMO University, St. Petersburg, Russia<br> <sup>5</sup> 1<sup>st</sup> Department for Surgeons’ Advanced Training, Kirov’s Military Medical Academy, St. Petersburg, Russia</p><br> <p><b>Correspondence:</b><br> Dr. Anna V. Lysenko, Department of Maxillofacial Surgery, Research Institute of Dentistry and Maxillofacial Surgery, Pavlov University, 44 Petrogradskaya Emb., 197101, St. Petersburg, Russia<br> Phone: +7 (812) 429-03-33<br> E-mail: lysenko.anna@mail.ru</p><br> <p><b>Citation:</b> Lysenko AV, Yaremenko AI, Zubareva AA, et al. Application of radiomics in the differential diagnosis in ameloblastomas and dentigerous cysts. Part 2. Cell Ther Transplant 2022; 11(3-4): 93-98.</p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(1176) "

1 Department of Maxillofacial Surgery, Research Institute of Dentistry and Maxillofacial Surgery, St. Petersburg, Russia
2 Department of Maxillofacial Surgery, Pavlov University, St. Petersburg, Russia
3 Department of Otorhinolaryngology, Pavlov University, St. Petersburg, Russia
4 Clinic of X-ray Radiology and Ultrasound Diagnostics, Kirov’s Military Medical Academy, Faculty of control Systems and Robotics, ITMO University, St. Petersburg, Russia
5 1st Department for Surgeons’ Advanced Training, Kirov’s Military Medical Academy, St. Petersburg, Russia


Correspondence:
Dr. Anna V. Lysenko, Department of Maxillofacial Surgery, Research Institute of Dentistry and Maxillofacial Surgery, Pavlov University, 44 Petrogradskaya Emb., 197101, St. Petersburg, Russia
Phone: +7 (812) 429-03-33
E-mail: lysenko.anna@mail.ru


Citation: Lysenko AV, Yaremenko AI, Zubareva AA, et al. Application of radiomics in the differential diagnosis in ameloblastomas and dentigerous cysts. Part 2. Cell Ther Transplant 2022; 11(3-4): 93-98.

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1 Department of Maxillofacial Surgery, Research Institute of Dentistry and Maxillofacial Surgery, St. Petersburg, Russia
2 Department of Maxillofacial Surgery, Pavlov University, St. Petersburg, Russia
3 Department of Otorhinolaryngology, Pavlov University, St. Petersburg, Russia
4 Clinic of X-ray Radiology and Ultrasound Diagnostics, Kirov’s Military Medical Academy, Faculty of control Systems and Robotics, ITMO University, St. Petersburg, Russia
5 1st Department for Surgeons’ Advanced Training, Kirov’s Military Medical Academy, St. Petersburg, Russia


Correspondence:
Dr. Anna V. Lysenko, Department of Maxillofacial Surgery, Research Institute of Dentistry and Maxillofacial Surgery, Pavlov University, 44 Petrogradskaya Emb., 197101, St. Petersburg, Russia
Phone: +7 (812) 429-03-33
E-mail: lysenko.anna@mail.ru


Citation: Lysenko AV, Yaremenko AI, Zubareva AA, et al. Application of radiomics in the differential diagnosis in ameloblastomas and dentigerous cysts. Part 2. Cell Ther Transplant 2022; 11(3-4): 93-98.

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Анна В. Лысенко1, Андрей И. Яременко2, Анна А. Зубарева3, Александр В. Ширшин4, Александр И. Любимов5, Елизавета А. Иванова1

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Анна В. Лысенко1, Андрей И. Яременко2, Анна А. Зубарева3, Александр В. Ширшин4, Александр И. Любимов5, Елизавета А. Иванова1

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В нашем исследовании мы демонстрируем важность тщательного рассмотрения радиологических особенностей, которые могут помочь в неинвазивной дифференциальной диагностике и обеспечении надлежащего лечения этих поражений.</p> <h3>Методы</h3> <p style="text-align: justify;">Было проведено ретроспективное исследование, включавшее 18 КТ-изображений пациентов с новообразованиями челюсти (8 амелобластом и 10 зубочелюстных кист с гистопатологической верификацией). Каждое поражение было вручную сегментировано с помощью программного обеспечения 3D Slicer на КТ-изображениях, а текстурные особенности были извлечены с использованием расширения 3D Slicer Radiomics. Был проведен статистический анализ.</p> <h3>Результаты</h3> <p style="text-align: justify;">После анализа текстуры мы не обнаружили (статистически значимых) различий в характеристиках формы и статистических значениях первого порядка этих поражений. Мы обнаружили статистически значимые различия по 13 признакам второго порядка зубочелюстных кист и амелобластом, большинство из которых тесно коррелировали. Был проведен множественный логистический регрессионный анализ для ранжирования признаков и определения наиболее значимых предикторов. Окончательная модель включала 2 признака (кластерный оттенок и IMC 1) и обеспечивала высокую прогностическую ценность (площадь под ROC=0,93).</p> <h3>Выводы</h3> <p style="text-align: justify;">В нашем пилотном исследовании мы продемонстрирован новый метод неинвазивной дифференциальной диагностики новообразований челюстей на основе особенностей текстуры, извлеченных из данных КТ.</p> <h2>Ключевые слова</h2> <p style="text-align: justify;">Радиомика, новообразования челюстей, амелобластома, одонтогенные кисты, компьютерная томография.</p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(3258) "

Амелобластомы и одонтогенные кисты имеют идентичный клинический и рентгенологический вид. В нашем исследовании мы демонстрируем важность тщательного рассмотрения радиологических особенностей, которые могут помочь в неинвазивной дифференциальной диагностике и обеспечении надлежащего лечения этих поражений.

Методы

Было проведено ретроспективное исследование, включавшее 18 КТ-изображений пациентов с новообразованиями челюсти (8 амелобластом и 10 зубочелюстных кист с гистопатологической верификацией). Каждое поражение было вручную сегментировано с помощью программного обеспечения 3D Slicer на КТ-изображениях, а текстурные особенности были извлечены с использованием расширения 3D Slicer Radiomics. Был проведен статистический анализ.

Результаты

После анализа текстуры мы не обнаружили (статистически значимых) различий в характеристиках формы и статистических значениях первого порядка этих поражений. Мы обнаружили статистически значимые различия по 13 признакам второго порядка зубочелюстных кист и амелобластом, большинство из которых тесно коррелировали. Был проведен множественный логистический регрессионный анализ для ранжирования признаков и определения наиболее значимых предикторов. Окончательная модель включала 2 признака (кластерный оттенок и IMC 1) и обеспечивала высокую прогностическую ценность (площадь под ROC=0,93).

Выводы

В нашем пилотном исследовании мы продемонстрирован новый метод неинвазивной дифференциальной диагностики новообразований челюстей на основе особенностей текстуры, извлеченных из данных КТ.

Ключевые слова

Радиомика, новообразования челюстей, амелобластома, одонтогенные кисты, компьютерная томография.

" ["TYPE"]=> string(4) "HTML" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(29) "Описание/Резюме" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["DISPLAY_VALUE"]=> string(3258) "

Амелобластомы и одонтогенные кисты имеют идентичный клинический и рентгенологический вид. В нашем исследовании мы демонстрируем важность тщательного рассмотрения радиологических особенностей, которые могут помочь в неинвазивной дифференциальной диагностике и обеспечении надлежащего лечения этих поражений.

Методы

Было проведено ретроспективное исследование, включавшее 18 КТ-изображений пациентов с новообразованиями челюсти (8 амелобластом и 10 зубочелюстных кист с гистопатологической верификацией). Каждое поражение было вручную сегментировано с помощью программного обеспечения 3D Slicer на КТ-изображениях, а текстурные особенности были извлечены с использованием расширения 3D Slicer Radiomics. Был проведен статистический анализ.

Результаты

После анализа текстуры мы не обнаружили (статистически значимых) различий в характеристиках формы и статистических значениях первого порядка этих поражений. Мы обнаружили статистически значимые различия по 13 признакам второго порядка зубочелюстных кист и амелобластом, большинство из которых тесно коррелировали. Был проведен множественный логистический регрессионный анализ для ранжирования признаков и определения наиболее значимых предикторов. Окончательная модель включала 2 признака (кластерный оттенок и IMC 1) и обеспечивала высокую прогностическую ценность (площадь под ROC=0,93).

Выводы

В нашем пилотном исследовании мы продемонстрирован новый метод неинвазивной дифференциальной диагностики новообразований челюстей на основе особенностей текстуры, извлеченных из данных КТ.

Ключевые слова

Радиомика, новообразования челюстей, амелобластома, одонтогенные кисты, компьютерная томография.

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1 Отдел челюстно-лицевой хирургии НИИ стоматологии и челюстно-лицевой хирургии, Санкт-Петербург, Россия
2 Кафедра челюстно-лицевой хирургии, Первый Санкт-Петербургский государственный медицинский университет им. И. П. Павлова, Санкт-Петербург, Россия
3 Кафедра оториноларингологии, Первый Санкт-Петербургский государственный медицинский университет им. И. П. Павлова, Санкт-Петербург, Россия
4 Клиника рентгенорадиологии и ультразвуковой диагностики Военно-медицинской академии имени Кирова, факультет систем управления и робототехники, Университет ИТМО, Санкт-Петербург, Россия
5 1-е отделение усовершенствования хирургов, Военно-медицинская академия им. С.М. Кирова, Санкт-Петербург, Россия

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1 Отдел челюстно-лицевой хирургии НИИ стоматологии и челюстно-лицевой хирургии, Санкт-Петербург, Россия
2 Кафедра челюстно-лицевой хирургии, Первый Санкт-Петербургский государственный медицинский университет им. И. П. Павлова, Санкт-Петербург, Россия
3 Кафедра оториноларингологии, Первый Санкт-Петербургский государственный медицинский университет им. И. П. Павлова, Санкт-Петербург, Россия
4 Клиника рентгенорадиологии и ультразвуковой диагностики Военно-медицинской академии имени Кирова, факультет систем управления и робототехники, Университет ИТМО, Санкт-Петербург, Россия
5 1-е отделение усовершенствования хирургов, Военно-медицинская академия им. С.М. Кирова, Санкт-Петербург, Россия

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Introduction

Doxorubicin (DOX) is a common potent antibiotic and anticancer agent. Virtually all highly efficient antibiotics exhibit some degree of toxicity; particularly, DOX demonstrates the dose-dependent toxicity [1]. To reduce toxicity and provide prolonged release of the preparation into blood, delivery systems of various structures are used [2]. Porous СаСО3 vaterites were proposed as delivery systems for biologically active compounds as early as 2004 [3]. The vaterite carriers have been modified with polymers (alginate and sodium dextran sulfate, DexS [4, 5]) with the objective of stabilizing vaterites in active media of an organism and reducing their size [6, 7]. This modification made it possible to increase bioavailability of carbonate cores and to use these carriers for delivery of various biologically active compounds [8-10].

Distribution of a drug preparation within organs and systems depends not only on its structure, but also on the used administration method [11, 12]. Recently, the trends are developed towards use of less invasive routes of drug administration, which reduce the possibility of entry of non-sterile components into blood. In our study, along with in vivo intraperitoneal administration [13], attention is given to subcutaneous introduction of the DOX delivery systems. Creation of a depot that will provide prolonged release of certain doses of the medicinal compound and maintain relatively low concentration of the drug in blood (thus preventing toxic effects) can increase DOX therapeutic efficiency. The micron-sized drug carriers are more suitable for this purpose; unlike nano-sized carriers, they do not enter bloodstream and only provide prolonged drug release. The duration of drug release also depends on the carrier. For instance, release of DOX from the carriers 3 µm in size (СаСО3 doped with carboxymethyl chitosan) proceeds longer than from the nano-sized carriers (650 nm) of the same composition. In the first case (micron-sized particles), 60% of the administered DOX was released from the carriers in 10 days, whereas, in the second case (nano-sized particles), 90% of the drug was released in 6 days [14]. In the present work, the micron-sized СаСО3 vaterites were used to create a depot.

The aim of this work was to investigate behavior of DOX administered subcutaneously (4 mg) to a healthy animal; the drug was loaded into the delivery systems based on СаСО3 vaterites modified with DexS. The experimental tasks included establishing time profiles of DOX concentration in rat blood; revealing toxic action of the preparation on particular organs by morphological analysis; confirmation of the absence of cytotoxicity of the studied delivery systems (without DOX) as tested with MCF7 tumor cells.

Materials and methods

Reagents

Doxorubicin hydrochloride in the form of pharmaceutical preparation "Sindroxocin", which contains 17% of doxorubicin (DOX) and 83% of lactose, was purchased from Actavis (Hafnarfjordur, Iceland). In the experiments, doxorubicin salt with protonated amino group (–NH3+) was used. Salts (CaCl2 × 2H2O, Na2CO3), acetone, and dextran sulfate (Mw = 9-20 kDa) were purchased from Sigma-Aldrich (St. Louis, MO).

Synthesis of carbonate cores

The synthesis of porous СаСО3 vaterites was performed according to the modified technique [3] described in [13]. Co-precipitation of 1 M solutions of CaCl2 × 2H2O and Na2CO3 was carried out at vigorous stirring for 30 s; then the suspension was centrifuged, the precipitate was rinsed and dried.

Doping of carbonate cores with DexS and loading DOX into delivery systems

Coating of carbonate cores with dextran sulfate polyanions was performed as follows: the suspension of СаСО3 vaterites (С=10 mg/mL) in aqueous solution of the polymer (С=5 mg/mL) was stirred for 1 h, then centrifuged; the precipitate was washed and dried [15].

Loading of DOX into the doped CaCO3 cores proceeded in the mixture of CaCO3 suspension and DOX solution (C=2 mg/mL) at continuous stirring for 24 hours. The DOX/(CaCO3+DexS) ratio was 0.4. After mixing, the suspension was centrifuged at 8000 rpm for 3 min, and the DOX amount in supernatant was determined. The DOX load (L) was calculated using the following equation:
L = (mi − ms)/mP
where mi is the initial weight of DOX (mg), ms is the weight of non-encapsulated DOX in supernatant solution (mg), mP is the weight of particles (mg). DOX concentrations were determined using the calibration curves obtained from optical density measurements in the corresponding solvents at λ = 480 nm. The DOX load (L) varied from 230 to 250 µg/mg.

Animal experiments

Three healthy female outbred rats with body weight ranging from 256 to 300 g ("Rappolovo" nursery for laboratory animals) were used in the experiments with subcutaneous (s.c.) administration of DOX delivery systems. All manipulations with animals were performed under general anesthesia: Sol. Zoletil 50 (0.05 mL per 0.1 kg of body mass), Sol. Rometаrum 20 mg/mL (0.0125 mL per 0.1 kg of body mass) intramuscularly. The animals were caged and given free access to water and food. They were fed the standard diet for laboratory rats used in the vivarium of Granov Russian Research Center for Radiology and Surgical Technologies, St. Petersburg, Russia (4R F18 prolonged keeping formula for rodents, Macedonia, Italy).

The animals were examined daily; consumption of water and food was registered, body temperature and weight were measured. Behavior of animals and life span were estimated. All manipulations with animals were performed in accordance with State Standard 33216-2014 "Regulations for work with laboratory rodents and rabbits".

Administration of encapsulated DOX into rats

DOX encapsulated into calcium carbonate cores doped with the dextran sulfate polyanion was administered subcutaneously (s.c.) to the rat's nape. The procedure was carried out under anesthesia. The drug (DOX in CаСО3+DexS cores, 4 mg of DOX per 1 animal) was injected in 1.5 mL of 5% glucose solution. The preparations were injected with the use of 21-gauge needles.

Along with visual inspection, peripheral blood samples (1.0 mL) were taken from the rat tail vein on the 1st, 4th, 7th, 14th, 17th and 21st days after s.c. drug injection.

Before blood sampling, the animal was examined and weighed; its body temperature was measured, then it was anesthetized and fixed in a holder for immobilizing rodents. Plasma was obtained from the blood specimens 10 min after blood sampling by centrifugation for 15 min at 1500 rpm. The supernatants were frozen and stored in closed vessels at -40°C for further analysis.

Determination of DOX content in rat blood plasma

Content of doxorubicin (DOX) in rat blood plasma was determined by high performance liquid chromatography (HPLC) with the aid of a Prominence-I LC 2030C 3D Plus instrument (Shimadzu) equipped with an RF-20A fluorimetric detector and a 5 µm Luna C18 column (Phenomenex). The excitation wavelength was 475 nm, the emission wavelength was 555 nm. The analysis was performed in the gradient elution regime (with acetonitrile) in 0.01 N sodium formiate buffer (рН 3.68). The experiment duration was 20 min; the detection limit was 1 ng/mL. All the measurements were carried out thrice.

Morphological studies

Prior to histological studies, the material was fixated in 10% neutral formalin in phosphate buffer (рН = 7.4) for not less than 24 hrs, dehydrated using a series of ethanol solutions with increasing concentrations, and enclosed in paraffin blocks according to the standard histological technique. To obtain comparable results, the samples were treated simultaneously under similar conditions. The paraffin cuts (5 μm thick) were prepared with the use of an Accu-Cut SRT 200 microtome (Sakura, Japan) and stained with Mayer hematoxylin and eosin (BioVitrum, Russia). Microscopic analysis was performed using a Nikon Eclipse E200 light microscope (Nikon, Japan) with a 10× ocular and 4, 10, 20, and 40× objectives. Digital images were recorded with a Nikon DS-Fi3 camera (Nikon, Japan).

Cytological experiments

Before contact with cells, the delivery systems were sterilized for 40 min at 120°С. Proliferation dynamics of MCF7 cells (breast adenocarcinoma) was studied with the use of an RTCA iCELLIgence System cell analyzer (ACEA Biosciences, USA) that enables to determine the real-time state of the cell cultures without additional coloring. Cell growth was monitored by changing the impedance created by cells in the wells equipped with gold electrodes upon contact of the cells with different types of DS. The adhesion and proliferation of cells on the surface of the electrodes increase the medium impedance and are recorded as a cellular index (CI): the ratio of the impedance at a particular time to the initial value of the impedance. When there are no cells, the value of CI is equal to the background value (about zero). The CI values increase as the cells attach to the electrodes.

The cells were incubated in DMEM nutrient medium (Pane-co, Russia). Cultivation was carried out in an incubator (Thermo Fisher Scientific, USA) at 37°С and at increased humidity; the CO2 concentration was 5%. 35 000 MCF7 cells were placed in each well containing the nutrient medium (0.2 mL). In 24 h, DexS, empty DS (CaCO3+DexS) and the DS loaded with DOX were added to the wells. As a result, the time dependencies of the CI of the control and cells with the addition of DS averaged over three wells. The graphs were used to evaluate the dynamics of adhesion, cell proliferation, and the beginning of the stationary phase of cell growth.

Statistical evaluations of CI were carried out by the iCELLIgence System cell analyzer program.

Results and discussion

To form the depot providing prolonged DOX release, the micron-sized СаСО3+DexS vaterites were used. The core size varied from 1 to 3 µm. Subcutaneous administration of the calcium carbonate DOX delivery systems to healthy female rats was performed as follows. DOX (4 mg) in СаСО3+DexS carriers was introduced into three rats. One rat (№1) died in 17 days, rats №2 and №3 were sacrificed on the 23rd day.

Macroscopic description

After administering vaterites to laboratory rats, no changes in behavior, consumption of food and water, state of hair coat were observed. No signs of inflammation at the injection site were revealed.

Autopsy of the rat that died on the 17th day showed sanguine organs. The large intestine (colon, sigmoid colon, upper rectum) was enlarged; the content was semi-liquid. The intestine wall was moderately edematous. Histological analysis of rat liver, one lung, a fragment of large intestine, and a fragment of adipose tissue taken near the injection site of DOX delivery systems was performed.

The large intestine (colon, sigmoid colon, upper rectum) of sacrificed rats (№2 and №3) was not enlarged and contained small amounts of feces. The intestinal wall was edematous. The liver was uniformly colored, lungs were pink. The changes were less pronounced than those in rat №1. Histological analysis of the liver, a lung, and a fragment of large intestine was performed.

Tissue morphology studies

Microscopic study of adipose tissue of rat № 1 (that died on the 17th day) taken from the injection site of delivery systems (СаСО3+DexS) containing DOX revealed bright red calcium carbonate cores surrounded with loose fibrous connective tissue with high amount of adipose cells. The vessels were thick, varicose and plethoric; small extravasates were observed. Endothelium of vessels was swollen; sludges of erythrocytes were visible. Epithelium was absent in an extended segment of intestinal mucosa. The villous stroma (a connective tissue layer) on this part of mucous membrane was strongly infiltrated with macrophages and lymphocytes. Epithelium remained in small parts of intestinal mucosa, mainly in intestinal crypts.

Histological analysis of the material taken from rats №2 and №3 revealed morphological changes in liver and lungs, while the morphology picture of the large intestine remained unchanged. The change in cytoarchitectonics of hepatic lobules (manifested as a disorder in the hepatocyte plates) was observed. Granular dystrophy was observed in the cytoplasm of most hepatocytes; some hepatocytes showed signs of hydropic degeneration. All vessels in the lung were broad, varicose and plethoric which could be, in part, ascribed to potential toxic action of the antitumor preparation. These changes seemed, however, mostly physiologically tolerated, thus, probably, being reversible.

In our previous works, it has been shown [17] that morphological changes in liver occurring upon intramuscular administration of DOX-containing delivery systems were reversible. The experiment that involved observation of morphological changes in the tissues at the implantation site lasted from 3 days to 3 months. At the early stages of experiment, we revealed doxorubicin toxicity toward the surrounding muscle tissue and liver. In the course of time, manifestations of DOX toxicity became less pronounced, and complete bioresorption of the introduced sample occurred within 3 months after beginning of the experiment.

It should be noted that the procedure of implantation of delivery systems causes a muscle tissue trauma, no matter how carefully it is performed. This is why its recovery takes sufficient time. In the case of subcutaneous administration, there is no extensive trauma, which is an additional reason for using this administration route.

DOX concentrations in rat blood plasma after subcutaneous administration of delivery systems

Sudareva-fig01.jpg

Figure 1. Release profile of DOX into rat blood plasma after intraperitoneal (1, 3) and subcutaneous administration (2) of 4 mg DOX using delivery systems based on CaCO3 vaterites doped by DexS (1, 2) and free DOX (3)

Sudareva-fig02.jpg

Figure 2. Increase in the cell index value in the course of three days during interaction between MCF7 cells and DS (СаСО3+DexS), their components, and the DS containing DOX (0.05 mg/mL). 1 – control sample; 2 – DS; 3 – DS+DOX; 4 – DexS. The arrow shows the moment when DS and their components were added to cultivated cells (in 24 h after beginning of growth)

Time profiles of DOX concentration in rat blood plasma after subcutaneous administration of the preparation in СаСО3 + DexS delivery systems (Fig. 1, curve 2) were compared with the previously observed concentration profiles [13] during the same period of time after intraperitoneal administration of DOX with the same delivery system DS (curve 1). The amounts of injected DOX were similar in both cases (4 mg per animal). As is seen in Fig. 1, DOX is present in circulating blood after subcutaneous and intraperitoneal administration for at least two weeks, while after i.p. administration of free DOX, the preparation is cleared already on the 3rd day of the experiment (curve 3). The concentration of drug in blood after subcutaneous administration of free DOX was not determined, since such route of DOX injection may cause a severe local inflammation and necrosis of muscle tissue within one week after injection [18]. This fact further confirms efficiency of using these delivery systems for subcutaneous administration.

Dextran sulfate effects on the rat organism and tumor cells

The question now arises of whether DexS included in the delivery systems could cause acute colitis observed in one of the rats (№1). Indeed, DexS is used for inducing colitis in rats and mice, for which purpose DexS is administered orally (510 mg and 150 mg, respectively) daily for a week [16]. In our experiments, the DS containing 4 mg DOX were introduced into rats. When the DOX load was 230-250 µg per 1 mg of DS, which, in turn, contained 20% of DexS (determined by the combustion method from the sulfur content in DS), one dose of DexS introduced into rat organism was equal to 3.3 mg. This is much lower than the amount of the polymer inducing appearance of ulcerative colitis.

The influence of DexS and the DS based on CaCO3+DexS on proliferation of tumor cells was also studied.

Our further studies will involve administration of DOX in the studied DS into rats with breast adenocarcinoma MCF7. These cells were selected for estimation of toxicity of the delivery systems and their components. Fig. 2 presents cell indices of growing MCF7 cells obtained in real time in the presence of delivery systems (drug-free calcium carbonate cores and the carriers containing encapsulated DOX). In addition, profiles of cell proliferation in the presence of DexS (a component of delivery systems) are given (see Fig. 2).

The presented results indicate insignificant toxicity of the DexS polyanion. One may suggest the influence of negatively charged polymer molecules on cell proliferative activity and viability. However, similar amount of DexS included in the СаСО3-based delivery system did not cause toxic effects. Apparently, the excess negative charge (δ-) present on the surface of DexS molecules may be compensated after interaction with calcium carbonate (which carries the excess positive charge (δ+) at рН< 8.5 [3]).

Conclusion

Aiming for design of a depot tool containing anti-cancer drug doxorubicin, we studied the consequences of subcutaneous administration of DOX delivery systems based on porous calcium carbonate vaterites doped with dextran sulfate polyanion. It was demonstrated that this method of DOX administration facilitated prolonged (up to two weeks) presence of the preparation in blood of laboratory rats. The time-concentration profile of DOX in blood after less invasive subcutaneous administration was comparable to that obtained after intraperitoneal injection of the delivery systems containing similar amount of DOX. Subcutaneous administration of DOX delivery systems did not cause local inflammation (unlike introduction of free DOX which resulted in acute inflammation reaction). Histological analysis of rat organs revealed morphological changes in liver and lungs; no changes in the state of intestines were observed. Since the revealed internal changes were tolerated by the rats without noticeable clinical manifestations, there is a good chance for their reversibility.

Hence, subcutaneous administration of the DOX delivery systems based on СаСО3+ DexS can be considered efficient method for formation of minimally invasive depot with prolonged release of this antitumor drug.

Financial support

The study was performed within the framework of budget-supported research project №АААА-А20-120022090044-2, Institute of Macromolecular Compounds, RAS.

Conflict of interests

None declared.

References

  1. Minotti G, Menna P, Salvatorelli E, Cairo G, Gianni L. Anthracyclines: molecular advances and pharmacologic developments in antitumor activity and cardiotoxicity. Pharmacol Rev. 2004;56:185-229. doi: 10.1124/pr.56.2.6
  2. Matyszewska D. Drug delivery systems in the transport of doxorubicin. Inst Civil Eng Surface Innovat. 2014;2(4):201-210.
    doi: 10.1680/si.13.00040
  3. Volodkin D, Petrov A, Prevot M, Sukhorukov G. Matrix polyelectrolyte microcapsules: new system for macromolecule encapsulation. Langmuir. 2004;20: 3398-3406. doi: 10.1021/la036177z
  4. Zhao D, Zhuo R, Cheng S. Alginate modified nanostructured calcium carbonate with enhanced delivery efficiency for gene and drug delivery. Mol. BioSystems. 2012; 8: 753-759. doi: 10.1039/C1MB05337J
  5. Sudareva N, Suvorova O, Tarasenko I, Saprykina N, Smirnova N, Petunov S, et al. Hybrid systems for oral delivery of a therapeutic neuropeptide. Mendeleev Commun. 2020;30: 25-27. doi: 10.1016/j.mencom.2020.01.008
  6. Svenskaya Y, Parakhonskiy B, Haase A, Atkin V, Lukyanets E, Gorin D et al. Anticancer drug delivery system based on calcium carbonate particles loaded with a photosensitizer. Biophys Chem. 2013;182:11-15. doi: 10.1016/j.bpc.2013.07.006
  7. Feoktistova N. Vaterite microspheres as a basis for the preparation of multifunctional carriers of biologically active substances. PhD in Chemistry, Moscow State University M. V. Lomonosov, Moscow, 2019 (In Russian).
  8. Sudareva N, Suvorova O, Saprykina N, Vilesov A, Bel'tiukov P, Petunov S. Alginate-containing systems for oral delivery of superoxide dismutase. Comparison of various configurations and their properties. J Microencapsul. 2016; 33(5): 487-496. doi: 10.1080/02652048.2016.1206146
  9. Mydin R, Zahidi I, Ishak N, Ghazali N, Moshawih S, Siddiquee S. Potential of calcium carbonate nanoparticles for therapeutic applications. Mal J Med Health Sci. 2018;201-206.
  10. Sudareva N, Suvorova O, Saprykina N, Smirnova N, Bel'tiukov P, Petunov S et al. Two-level delivery systems based on CaCO3 cores for oral administration of therapeutic peptides. J Microencapsul. 2018;35: 619-634. doi: 10.1080/02652048.2018.1559247
  11. Adiseshaiah P, Hall J, McNeil S. Nanomaterial standards for efficacy and toxicity assessment. WIREs Nanomed Nanobiotechnol. 2009;2: 99-112. doi: 10.1002/wnan.66
  12. Ansar F, Latifah S, Kamal W, Khong K, Ng Y, Foong J, et al. Pharmacokinetics and biodistribution of thymoquinone-loaded nanostructured lipid carrier after oral and intravenous administration into rats. Int J Nanomed. 2020;15:7703-7717.
    doi: 10.2147/IJN.S262395
  13. Sudareva N, Suvorova O, Suslov D, Galibin O, Vilesov A. Dextran sulfate coated CaCO3 vaterites as the systems for regional administration of doxorubicin to rats. Cell Ther Transplant. 2021;10(3/4):71-77. doi: 10.18620/ctt-1866-8836-2021-10-3-4-71-77
  14. Wang J, Chen J, Zong J, Zhao D, Li F, Zhuo R, et al. Calcium carbonate/carboxymethyl chitosan hybrid microspheres and nanospheres for drug delivery. J Phys Chem C. 2010; 114:18940-18945. doi: 10.1021/jp105906p
  15. Sudareva N, Suvorova O, Saprykina N, Tomson V, Suslov D, Galibin O, et al. Morphology of hybrid doxorubicin delivery systems (dextran sulfate-coated CaCO3 vaterites) in human blood plasma. Cell Ther Transplant. 2021;10(1):79-85.
    doi: 10.18620/ctt-1866-8836-2021-10-1-79-85
  16. Wang J, Zhang C, Guo C, Li X. Chitosan ameliorates DSS-induced ulcerative colitis mice by enhancing intestinal barrier function and improving microflora. Int J Mol Sci. 2019;20:5751. doi: 10.3390/ijms20225751
  17. Sudareva N, Popryadukhin P, Suvorova O, Yukina G, Sukhorukova E. Morphology of rat muscle tissue after implantation of delivery systems consisting of porous CaCO3 vaterites doped with dextran sulfate and containing doxorubicin. Cell Tissue Biol 2022; 16(4): 392-399. doi: 10.1134/S1990519X22040083
  18. Oussoren C, Eling W, Crommelin D, Storm G, Zuidema J. The influence of the route of administration and liposome composition on the potential of liposomes to protect tissue against local toxicity of two antitumor drugs. Biochim Biophys Acta. 1998:1369;159-172.

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Introduction

Doxorubicin (DOX) is a common potent antibiotic and anticancer agent. Virtually all highly efficient antibiotics exhibit some degree of toxicity; particularly, DOX demonstrates the dose-dependent toxicity [1]. To reduce toxicity and provide prolonged release of the preparation into blood, delivery systems of various structures are used [2]. Porous СаСО3 vaterites were proposed as delivery systems for biologically active compounds as early as 2004 [3]. The vaterite carriers have been modified with polymers (alginate and sodium dextran sulfate, DexS [4, 5]) with the objective of stabilizing vaterites in active media of an organism and reducing their size [6, 7]. This modification made it possible to increase bioavailability of carbonate cores and to use these carriers for delivery of various biologically active compounds [8-10].

Distribution of a drug preparation within organs and systems depends not only on its structure, but also on the used administration method [11, 12]. Recently, the trends are developed towards use of less invasive routes of drug administration, which reduce the possibility of entry of non-sterile components into blood. In our study, along with in vivo intraperitoneal administration [13], attention is given to subcutaneous introduction of the DOX delivery systems. Creation of a depot that will provide prolonged release of certain doses of the medicinal compound and maintain relatively low concentration of the drug in blood (thus preventing toxic effects) can increase DOX therapeutic efficiency. The micron-sized drug carriers are more suitable for this purpose; unlike nano-sized carriers, they do not enter bloodstream and only provide prolonged drug release. The duration of drug release also depends on the carrier. For instance, release of DOX from the carriers 3 µm in size (СаСО3 doped with carboxymethyl chitosan) proceeds longer than from the nano-sized carriers (650 nm) of the same composition. In the first case (micron-sized particles), 60% of the administered DOX was released from the carriers in 10 days, whereas, in the second case (nano-sized particles), 90% of the drug was released in 6 days [14]. In the present work, the micron-sized СаСО3 vaterites were used to create a depot.

The aim of this work was to investigate behavior of DOX administered subcutaneously (4 mg) to a healthy animal; the drug was loaded into the delivery systems based on СаСО3 vaterites modified with DexS. The experimental tasks included establishing time profiles of DOX concentration in rat blood; revealing toxic action of the preparation on particular organs by morphological analysis; confirmation of the absence of cytotoxicity of the studied delivery systems (without DOX) as tested with MCF7 tumor cells.

Materials and methods

Reagents

Doxorubicin hydrochloride in the form of pharmaceutical preparation "Sindroxocin", which contains 17% of doxorubicin (DOX) and 83% of lactose, was purchased from Actavis (Hafnarfjordur, Iceland). In the experiments, doxorubicin salt with protonated amino group (–NH3+) was used. Salts (CaCl2 × 2H2O, Na2CO3), acetone, and dextran sulfate (Mw = 9-20 kDa) were purchased from Sigma-Aldrich (St. Louis, MO).

Synthesis of carbonate cores

The synthesis of porous СаСО3 vaterites was performed according to the modified technique [3] described in [13]. Co-precipitation of 1 M solutions of CaCl2 × 2H2O and Na2CO3 was carried out at vigorous stirring for 30 s; then the suspension was centrifuged, the precipitate was rinsed and dried.

Doping of carbonate cores with DexS and loading DOX into delivery systems

Coating of carbonate cores with dextran sulfate polyanions was performed as follows: the suspension of СаСО3 vaterites (С=10 mg/mL) in aqueous solution of the polymer (С=5 mg/mL) was stirred for 1 h, then centrifuged; the precipitate was washed and dried [15].

Loading of DOX into the doped CaCO3 cores proceeded in the mixture of CaCO3 suspension and DOX solution (C=2 mg/mL) at continuous stirring for 24 hours. The DOX/(CaCO3+DexS) ratio was 0.4. After mixing, the suspension was centrifuged at 8000 rpm for 3 min, and the DOX amount in supernatant was determined. The DOX load (L) was calculated using the following equation:
L = (mi − ms)/mP
where mi is the initial weight of DOX (mg), ms is the weight of non-encapsulated DOX in supernatant solution (mg), mP is the weight of particles (mg). DOX concentrations were determined using the calibration curves obtained from optical density measurements in the corresponding solvents at λ = 480 nm. The DOX load (L) varied from 230 to 250 µg/mg.

Animal experiments

Three healthy female outbred rats with body weight ranging from 256 to 300 g ("Rappolovo" nursery for laboratory animals) were used in the experiments with subcutaneous (s.c.) administration of DOX delivery systems. All manipulations with animals were performed under general anesthesia: Sol. Zoletil 50 (0.05 mL per 0.1 kg of body mass), Sol. Rometаrum 20 mg/mL (0.0125 mL per 0.1 kg of body mass) intramuscularly. The animals were caged and given free access to water and food. They were fed the standard diet for laboratory rats used in the vivarium of Granov Russian Research Center for Radiology and Surgical Technologies, St. Petersburg, Russia (4R F18 prolonged keeping formula for rodents, Macedonia, Italy).

The animals were examined daily; consumption of water and food was registered, body temperature and weight were measured. Behavior of animals and life span were estimated. All manipulations with animals were performed in accordance with State Standard 33216-2014 "Regulations for work with laboratory rodents and rabbits".

Administration of encapsulated DOX into rats

DOX encapsulated into calcium carbonate cores doped with the dextran sulfate polyanion was administered subcutaneously (s.c.) to the rat's nape. The procedure was carried out under anesthesia. The drug (DOX in CаСО3+DexS cores, 4 mg of DOX per 1 animal) was injected in 1.5 mL of 5% glucose solution. The preparations were injected with the use of 21-gauge needles.

Along with visual inspection, peripheral blood samples (1.0 mL) were taken from the rat tail vein on the 1st, 4th, 7th, 14th, 17th and 21st days after s.c. drug injection.

Before blood sampling, the animal was examined and weighed; its body temperature was measured, then it was anesthetized and fixed in a holder for immobilizing rodents. Plasma was obtained from the blood specimens 10 min after blood sampling by centrifugation for 15 min at 1500 rpm. The supernatants were frozen and stored in closed vessels at -40°C for further analysis.

Determination of DOX content in rat blood plasma

Content of doxorubicin (DOX) in rat blood plasma was determined by high performance liquid chromatography (HPLC) with the aid of a Prominence-I LC 2030C 3D Plus instrument (Shimadzu) equipped with an RF-20A fluorimetric detector and a 5 µm Luna C18 column (Phenomenex). The excitation wavelength was 475 nm, the emission wavelength was 555 nm. The analysis was performed in the gradient elution regime (with acetonitrile) in 0.01 N sodium formiate buffer (рН 3.68). The experiment duration was 20 min; the detection limit was 1 ng/mL. All the measurements were carried out thrice.

Morphological studies

Prior to histological studies, the material was fixated in 10% neutral formalin in phosphate buffer (рН = 7.4) for not less than 24 hrs, dehydrated using a series of ethanol solutions with increasing concentrations, and enclosed in paraffin blocks according to the standard histological technique. To obtain comparable results, the samples were treated simultaneously under similar conditions. The paraffin cuts (5 μm thick) were prepared with the use of an Accu-Cut SRT 200 microtome (Sakura, Japan) and stained with Mayer hematoxylin and eosin (BioVitrum, Russia). Microscopic analysis was performed using a Nikon Eclipse E200 light microscope (Nikon, Japan) with a 10× ocular and 4, 10, 20, and 40× objectives. Digital images were recorded with a Nikon DS-Fi3 camera (Nikon, Japan).

Cytological experiments

Before contact with cells, the delivery systems were sterilized for 40 min at 120°С. Proliferation dynamics of MCF7 cells (breast adenocarcinoma) was studied with the use of an RTCA iCELLIgence System cell analyzer (ACEA Biosciences, USA) that enables to determine the real-time state of the cell cultures without additional coloring. Cell growth was monitored by changing the impedance created by cells in the wells equipped with gold electrodes upon contact of the cells with different types of DS. The adhesion and proliferation of cells on the surface of the electrodes increase the medium impedance and are recorded as a cellular index (CI): the ratio of the impedance at a particular time to the initial value of the impedance. When there are no cells, the value of CI is equal to the background value (about zero). The CI values increase as the cells attach to the electrodes.

The cells were incubated in DMEM nutrient medium (Pane-co, Russia). Cultivation was carried out in an incubator (Thermo Fisher Scientific, USA) at 37°С and at increased humidity; the CO2 concentration was 5%. 35 000 MCF7 cells were placed in each well containing the nutrient medium (0.2 mL). In 24 h, DexS, empty DS (CaCO3+DexS) and the DS loaded with DOX were added to the wells. As a result, the time dependencies of the CI of the control and cells with the addition of DS averaged over three wells. The graphs were used to evaluate the dynamics of adhesion, cell proliferation, and the beginning of the stationary phase of cell growth.

Statistical evaluations of CI were carried out by the iCELLIgence System cell analyzer program.

Results and discussion

To form the depot providing prolonged DOX release, the micron-sized СаСО3+DexS vaterites were used. The core size varied from 1 to 3 µm. Subcutaneous administration of the calcium carbonate DOX delivery systems to healthy female rats was performed as follows. DOX (4 mg) in СаСО3+DexS carriers was introduced into three rats. One rat (№1) died in 17 days, rats №2 and №3 were sacrificed on the 23rd day.

Macroscopic description

After administering vaterites to laboratory rats, no changes in behavior, consumption of food and water, state of hair coat were observed. No signs of inflammation at the injection site were revealed.

Autopsy of the rat that died on the 17th day showed sanguine organs. The large intestine (colon, sigmoid colon, upper rectum) was enlarged; the content was semi-liquid. The intestine wall was moderately edematous. Histological analysis of rat liver, one lung, a fragment of large intestine, and a fragment of adipose tissue taken near the injection site of DOX delivery systems was performed.

The large intestine (colon, sigmoid colon, upper rectum) of sacrificed rats (№2 and №3) was not enlarged and contained small amounts of feces. The intestinal wall was edematous. The liver was uniformly colored, lungs were pink. The changes were less pronounced than those in rat №1. Histological analysis of the liver, a lung, and a fragment of large intestine was performed.

Tissue morphology studies

Microscopic study of adipose tissue of rat № 1 (that died on the 17th day) taken from the injection site of delivery systems (СаСО3+DexS) containing DOX revealed bright red calcium carbonate cores surrounded with loose fibrous connective tissue with high amount of adipose cells. The vessels were thick, varicose and plethoric; small extravasates were observed. Endothelium of vessels was swollen; sludges of erythrocytes were visible. Epithelium was absent in an extended segment of intestinal mucosa. The villous stroma (a connective tissue layer) on this part of mucous membrane was strongly infiltrated with macrophages and lymphocytes. Epithelium remained in small parts of intestinal mucosa, mainly in intestinal crypts.

Histological analysis of the material taken from rats №2 and №3 revealed morphological changes in liver and lungs, while the morphology picture of the large intestine remained unchanged. The change in cytoarchitectonics of hepatic lobules (manifested as a disorder in the hepatocyte plates) was observed. Granular dystrophy was observed in the cytoplasm of most hepatocytes; some hepatocytes showed signs of hydropic degeneration. All vessels in the lung were broad, varicose and plethoric which could be, in part, ascribed to potential toxic action of the antitumor preparation. These changes seemed, however, mostly physiologically tolerated, thus, probably, being reversible.

In our previous works, it has been shown [17] that morphological changes in liver occurring upon intramuscular administration of DOX-containing delivery systems were reversible. The experiment that involved observation of morphological changes in the tissues at the implantation site lasted from 3 days to 3 months. At the early stages of experiment, we revealed doxorubicin toxicity toward the surrounding muscle tissue and liver. In the course of time, manifestations of DOX toxicity became less pronounced, and complete bioresorption of the introduced sample occurred within 3 months after beginning of the experiment.

It should be noted that the procedure of implantation of delivery systems causes a muscle tissue trauma, no matter how carefully it is performed. This is why its recovery takes sufficient time. In the case of subcutaneous administration, there is no extensive trauma, which is an additional reason for using this administration route.

DOX concentrations in rat blood plasma after subcutaneous administration of delivery systems

Sudareva-fig01.jpg

Figure 1. Release profile of DOX into rat blood plasma after intraperitoneal (1, 3) and subcutaneous administration (2) of 4 mg DOX using delivery systems based on CaCO3 vaterites doped by DexS (1, 2) and free DOX (3)

Sudareva-fig02.jpg

Figure 2. Increase in the cell index value in the course of three days during interaction between MCF7 cells and DS (СаСО3+DexS), their components, and the DS containing DOX (0.05 mg/mL). 1 – control sample; 2 – DS; 3 – DS+DOX; 4 – DexS. The arrow shows the moment when DS and their components were added to cultivated cells (in 24 h after beginning of growth)

Time profiles of DOX concentration in rat blood plasma after subcutaneous administration of the preparation in СаСО3 + DexS delivery systems (Fig. 1, curve 2) were compared with the previously observed concentration profiles [13] during the same period of time after intraperitoneal administration of DOX with the same delivery system DS (curve 1). The amounts of injected DOX were similar in both cases (4 mg per animal). As is seen in Fig. 1, DOX is present in circulating blood after subcutaneous and intraperitoneal administration for at least two weeks, while after i.p. administration of free DOX, the preparation is cleared already on the 3rd day of the experiment (curve 3). The concentration of drug in blood after subcutaneous administration of free DOX was not determined, since such route of DOX injection may cause a severe local inflammation and necrosis of muscle tissue within one week after injection [18]. This fact further confirms efficiency of using these delivery systems for subcutaneous administration.

Dextran sulfate effects on the rat organism and tumor cells

The question now arises of whether DexS included in the delivery systems could cause acute colitis observed in one of the rats (№1). Indeed, DexS is used for inducing colitis in rats and mice, for which purpose DexS is administered orally (510 mg and 150 mg, respectively) daily for a week [16]. In our experiments, the DS containing 4 mg DOX were introduced into rats. When the DOX load was 230-250 µg per 1 mg of DS, which, in turn, contained 20% of DexS (determined by the combustion method from the sulfur content in DS), one dose of DexS introduced into rat organism was equal to 3.3 mg. This is much lower than the amount of the polymer inducing appearance of ulcerative colitis.

The influence of DexS and the DS based on CaCO3+DexS on proliferation of tumor cells was also studied.

Our further studies will involve administration of DOX in the studied DS into rats with breast adenocarcinoma MCF7. These cells were selected for estimation of toxicity of the delivery systems and their components. Fig. 2 presents cell indices of growing MCF7 cells obtained in real time in the presence of delivery systems (drug-free calcium carbonate cores and the carriers containing encapsulated DOX). In addition, profiles of cell proliferation in the presence of DexS (a component of delivery systems) are given (see Fig. 2).

The presented results indicate insignificant toxicity of the DexS polyanion. One may suggest the influence of negatively charged polymer molecules on cell proliferative activity and viability. However, similar amount of DexS included in the СаСО3-based delivery system did not cause toxic effects. Apparently, the excess negative charge (δ-) present on the surface of DexS molecules may be compensated after interaction with calcium carbonate (which carries the excess positive charge (δ+) at рН< 8.5 [3]).

Conclusion

Aiming for design of a depot tool containing anti-cancer drug doxorubicin, we studied the consequences of subcutaneous administration of DOX delivery systems based on porous calcium carbonate vaterites doped with dextran sulfate polyanion. It was demonstrated that this method of DOX administration facilitated prolonged (up to two weeks) presence of the preparation in blood of laboratory rats. The time-concentration profile of DOX in blood after less invasive subcutaneous administration was comparable to that obtained after intraperitoneal injection of the delivery systems containing similar amount of DOX. Subcutaneous administration of DOX delivery systems did not cause local inflammation (unlike introduction of free DOX which resulted in acute inflammation reaction). Histological analysis of rat organs revealed morphological changes in liver and lungs; no changes in the state of intestines were observed. Since the revealed internal changes were tolerated by the rats without noticeable clinical manifestations, there is a good chance for their reversibility.

Hence, subcutaneous administration of the DOX delivery systems based on СаСО3+ DexS can be considered efficient method for formation of minimally invasive depot with prolonged release of this antitumor drug.

Financial support

The study was performed within the framework of budget-supported research project №АААА-А20-120022090044-2, Institute of Macromolecular Compounds, RAS.

Conflict of interests

None declared.

References

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Сударева<sup>1,2</sup>, Ольга М. Суворова<sup>1</sup>, Константин А. Колбе<sup>1</sup>, Дмитрий Н. Суслов<sup>3</sup>, Олег В. Галибин<sup>2</sup>, Александр Д. Вилесов<sup>1</sup>, Галина Ю. Юкина<sup>2</sup>, Елена Г. Сухорукова<sup>2</sup></p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(378) "

Наталия Н. Сударева1,2, Ольга М. Суворова1, Константин А. Колбе1, Дмитрий Н. Суслов3, Олег В. Галибин2, Александр Д. Вилесов1, Галина Ю. Юкина2, Елена Г. Сухорукова2

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1 Институт высокомолекулярных соединений РАН, Санкт-Петербург, Россия
2 Первый Санкт-Петербургский государственный медицинский университет им. акад. И. П. Павлова, Санкт-Петербург, Россия
3 Российский научный центр радиологии и хирургических технологий им. акад. А. М. Гранова, Санкт-Петербург, Россия

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Исследован метод подкожного введения лабораторным крысам систем доставки противоонкологического препарата доксорубицин (ДОХ). В качестве систем доставки использованы СаСО3 ватериты, покрытые полианионом декстрансульфатом Na, применяемые ранее для интраперитонеального введения ДОХ. Концентрационные профили высвобождения ДОХ в плазму крови крыс после подкожного введения систем доставки, содержащих по 4 мг ДОХ, получали при помощи ВЭЖХ. Рабочая концентрация ДОХ в крови после подкожного введения поддерживается в течение 10 дней, что сопоставимо с результатами интраперитонеального введения тех же носителей ДОХ. Для оценки токсичности использованных систем доставки ДОХ проведены гистологические исследования органов крыс (печени, кишки, легкого) после выведения животных из эксперимента на 17 и 23 сутки. Гистологический анализ исследуемого материала показал морфологические изменения в печени и легком, в то время как в кишке морфологическая картина без изменений. Изменений в поведении, в том числе пищевом, у животных не наблюдали.

Ключевые слова

Доксорубицин, система доставки лекарств, карбонат кальция СаСО3, декстран сульфат, плазма крови, подкожное введение.

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Natalia N. Sudareva1,2, Olga М. Suvorova1, Konstantin A. Kolbe1, Dmitry N. Suslov3, Oleg V. Galibin2, Alexander D. Vilesov1, Galina Y. Yukina2, Elena G. Sukhorukova2

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1 Institute of Macromolecular Compounds RAS, St. Petersburg, Russia
2 Pavlov University, St. Petersburg, Russia
3 Granov Russian Research Center for Radiology and Surgical Technologies, St. Petersburg, Russia


Correspondence:
Dr. Natalia N. Sudareva, Institute of Macromolecular Compounds RAS, St. Petersburg, Russia
E-mail: nnsas@mail.ru


Citation: Sudareva NN, Suvorova OM, Kolbe KA et al. Subcutaneous administration of doxorubicin delivery systems based on CaCO3 vaterites coated with dextran sulfate. Cell Ther Transplant 2022; 11(3-4): 87-92.

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Subcutaneous administration of drug delivery systems containing antitumor drug doxorubicin (DOX) was studied in laboratory rats. The drug delivery systems consisted of СаСО3 vaterites coated with the dextran sulfate polyanion; these particles have been used earlier for intraperitoneal administration of DOX. Time profile of DOX release into blood plasma of rats after subcutaneous administration of the delivery systems loaded with 4 mg of DOX was studied by high-performance liquid chromatography (HPLC). The working concentration of DOX in blood was maintained for 10 days after subcutaneous administration, which is comparable with the results obtained after intraperitoneal introduction of similar DOX carriers. To estimate toxicity of the used DOX delivery systems, histological studies of different rat organs (liver, intestines, lungs) were performed at 17 and 23 days after beginning of the experiment. Histological analysis of the material revealed morphological changes in rat liver and lungs, while the morphological pattern of intestines remained unchanged. No changes in animal behavior (including their feeding behavior) were observed.

Keywords

Doxorubicin, drug delivery system, calcium carbonate, dextran sulfate, blood plasma, subcutaneous administration.

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Sudareva<sup>1,2</sup>, Olga М. Suvorova<sup>1</sup>, Konstantin A. Kolbe<sup>1</sup>, Dmitry N. Suslov<sup>3</sup>, Oleg V. Galibin<sup>2</sup>, Alexander D. Vilesov<sup>1</sup>, Galina Y. Yukina<sup>2</sup>, Elena G. Sukhorukova<sup>2</sup></p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(262) "

Natalia N. Sudareva1,2, Olga М. Suvorova1, Konstantin A. Kolbe1, Dmitry N. Suslov3, Oleg V. Galibin2, Alexander D. Vilesov1, Galina Y. Yukina2, Elena G. Sukhorukova2

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Natalia N. Sudareva1,2, Olga М. Suvorova1, Konstantin A. Kolbe1, Dmitry N. Suslov3, Oleg V. Galibin2, Alexander D. Vilesov1, Galina Y. Yukina2, Elena G. Sukhorukova2

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Subcutaneous administration of drug delivery systems containing antitumor drug doxorubicin (DOX) was studied in laboratory rats. The drug delivery systems consisted of СаСО3 vaterites coated with the dextran sulfate polyanion; these particles have been used earlier for intraperitoneal administration of DOX. Time profile of DOX release into blood plasma of rats after subcutaneous administration of the delivery systems loaded with 4 mg of DOX was studied by high-performance liquid chromatography (HPLC). The working concentration of DOX in blood was maintained for 10 days after subcutaneous administration, which is comparable with the results obtained after intraperitoneal introduction of similar DOX carriers. To estimate toxicity of the used DOX delivery systems, histological studies of different rat organs (liver, intestines, lungs) were performed at 17 and 23 days after beginning of the experiment. Histological analysis of the material revealed morphological changes in rat liver and lungs, while the morphological pattern of intestines remained unchanged. No changes in animal behavior (including their feeding behavior) were observed.

Keywords

Doxorubicin, drug delivery system, calcium carbonate, dextran sulfate, blood plasma, subcutaneous administration.

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Subcutaneous administration of drug delivery systems containing antitumor drug doxorubicin (DOX) was studied in laboratory rats. The drug delivery systems consisted of СаСО3 vaterites coated with the dextran sulfate polyanion; these particles have been used earlier for intraperitoneal administration of DOX. Time profile of DOX release into blood plasma of rats after subcutaneous administration of the delivery systems loaded with 4 mg of DOX was studied by high-performance liquid chromatography (HPLC). The working concentration of DOX in blood was maintained for 10 days after subcutaneous administration, which is comparable with the results obtained after intraperitoneal introduction of similar DOX carriers. To estimate toxicity of the used DOX delivery systems, histological studies of different rat organs (liver, intestines, lungs) were performed at 17 and 23 days after beginning of the experiment. Histological analysis of the material revealed morphological changes in rat liver and lungs, while the morphological pattern of intestines remained unchanged. No changes in animal behavior (including their feeding behavior) were observed.

Keywords

Doxorubicin, drug delivery system, calcium carbonate, dextran sulfate, blood plasma, subcutaneous administration.

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1 Institute of Macromolecular Compounds RAS, St. Petersburg, Russia
2 Pavlov University, St. Petersburg, Russia
3 Granov Russian Research Center for Radiology and Surgical Technologies, St. Petersburg, Russia


Correspondence:
Dr. Natalia N. Sudareva, Institute of Macromolecular Compounds RAS, St. Petersburg, Russia
E-mail: nnsas@mail.ru


Citation: Sudareva NN, Suvorova OM, Kolbe KA et al. Subcutaneous administration of doxorubicin delivery systems based on CaCO3 vaterites coated with dextran sulfate. Cell Ther Transplant 2022; 11(3-4): 87-92.

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1 Institute of Macromolecular Compounds RAS, St. Petersburg, Russia
2 Pavlov University, St. Petersburg, Russia
3 Granov Russian Research Center for Radiology and Surgical Technologies, St. Petersburg, Russia


Correspondence:
Dr. Natalia N. Sudareva, Institute of Macromolecular Compounds RAS, St. Petersburg, Russia
E-mail: nnsas@mail.ru


Citation: Sudareva NN, Suvorova OM, Kolbe KA et al. Subcutaneous administration of doxorubicin delivery systems based on CaCO3 vaterites coated with dextran sulfate. Cell Ther Transplant 2022; 11(3-4): 87-92.

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Наталия Н. Сударева1,2, Ольга М. Суворова1, Константин А. Колбе1, Дмитрий Н. Суслов3, Олег В. Галибин2, Александр Д. Вилесов1, Галина Ю. Юкина2, Елена Г. Сухорукова2

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Наталия Н. Сударева1,2, Ольга М. Суворова1, Константин А. Колбе1, Дмитрий Н. Суслов3, Олег В. Галибин2, Александр Д. Вилесов1, Галина Ю. Юкина2, Елена Г. Сухорукова2

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Исследован метод подкожного введения лабораторным крысам систем доставки противоонкологического препарата доксорубицин (ДОХ). В качестве систем доставки использованы СаСО3 ватериты, покрытые полианионом декстрансульфатом Na, применяемые ранее для интраперитонеального введения ДОХ. Концентрационные профили высвобождения ДОХ в плазму крови крыс после подкожного введения систем доставки, содержащих по 4 мг ДОХ, получали при помощи ВЭЖХ. Рабочая концентрация ДОХ в крови после подкожного введения поддерживается в течение 10 дней, что сопоставимо с результатами интраперитонеального введения тех же носителей ДОХ. Для оценки токсичности использованных систем доставки ДОХ проведены гистологические исследования органов крыс (печени, кишки, легкого) после выведения животных из эксперимента на 17 и 23 сутки. Гистологический анализ исследуемого материала показал морфологические изменения в печени и легком, в то время как в кишке морфологическая картина без изменений. Изменений в поведении, в том числе пищевом, у животных не наблюдали.

Ключевые слова

Доксорубицин, система доставки лекарств, карбонат кальция СаСО3, декстран сульфат, плазма крови, подкожное введение.

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Исследован метод подкожного введения лабораторным крысам систем доставки противоонкологического препарата доксорубицин (ДОХ). В качестве систем доставки использованы СаСО3 ватериты, покрытые полианионом декстрансульфатом Na, применяемые ранее для интраперитонеального введения ДОХ. Концентрационные профили высвобождения ДОХ в плазму крови крыс после подкожного введения систем доставки, содержащих по 4 мг ДОХ, получали при помощи ВЭЖХ. Рабочая концентрация ДОХ в крови после подкожного введения поддерживается в течение 10 дней, что сопоставимо с результатами интраперитонеального введения тех же носителей ДОХ. Для оценки токсичности использованных систем доставки ДОХ проведены гистологические исследования органов крыс (печени, кишки, легкого) после выведения животных из эксперимента на 17 и 23 сутки. Гистологический анализ исследуемого материала показал морфологические изменения в печени и легком, в то время как в кишке морфологическая картина без изменений. Изменений в поведении, в том числе пищевом, у животных не наблюдали.

Ключевые слова

Доксорубицин, система доставки лекарств, карбонат кальция СаСО3, декстран сульфат, плазма крови, подкожное введение.

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1 Институт высокомолекулярных соединений РАН, Санкт-Петербург, Россия
2 Первый Санкт-Петербургский государственный медицинский университет им. акад. И. П. Павлова, Санкт-Петербург, Россия
3 Российский научный центр радиологии и хирургических технологий им. акад. А. М. Гранова, Санкт-Петербург, Россия

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1 Институт высокомолекулярных соединений РАН, Санкт-Петербург, Россия
2 Первый Санкт-Петербургский государственный медицинский университет им. акад. И. П. Павлова, Санкт-Петербург, Россия
3 Российский научный центр радиологии и хирургических технологий им. акад. А. М. Гранова, Санкт-Петербург, Россия

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Zaritskiy.jpg

Prof. Andrey Zaritskey (10.03.1950 – 16.10.2021)

I met Andrey Zaritskey in 2004 or 2005 when he insisted that both the Almazov Center and Pavlov University joined the European LeukemiaNet (ELN). He was the only ELN investigator who promoted contracts with two institutions. His persistence facilitated cooperation of the Gorbacheva Research Institute with ELN later. I was impressed by his comprehensive research interests, his cooperative spirit, and his vision. At his invitation, I visited St. Petersburg in September 2006, starting 15 years of fruitful cooperation in the field of leukemia. I remember this visit very well. It was one of his early meetings, maybe the first one with international speakers. The meeting was also attended by Prof. Valery Savchenko from Moscow with his mentor Prof. Andrey Vorobiev and his wife Prof. Elena Parovichnikova. Valery was an old friend of mine whom I had met in Wilsede around 1990, who unexpectedly died in July 2021, 3 months before Andrey.

At that time, in 2006, the Almazov Center was under development. Its activities were limited to diseases of the Heart, Blood and Endocrinology, with Andrey Zaritskey appointed Head of the Blood Section. Andrey used the occasion to show me with pride the evolving Almazov Center and to introduce me to his chief, Prof. Evgeny Shlyakhto. Even if things had just started, he saw the chances and had a plan – like his chief. He also used the occasion to show me the beauty of St. Petersburg. With the help of Dr. Elza Lomaia, we succeeded visiting the beautifully rebuilt Katherine’s palace with the perfectly restored amber room.

During the following years, the Almazov Center evolved to the National Medical Research Center of today, one of the largest in Russia. Of critical importance for Andrey Zaritskey’s success was the trust and continuous support by Evgeny Shlyakhto, General Director of the Center, who is a cardiologist. In 2008, Andrey Zaritskey was appointed Director of the new Institute of Hematology at the Almazov Center. In the years to follow, he established with great energy the new Institute with research facilities and, most notably, a transplantation unit, although access to the International Donor Registry was still a challenge at the time. He was its director for 14 years. In the same year, again in Wilsede, I met Professor Boris Afanasyev and Dr. Alexei Chukhlovin. Afanasiev’s invitation to the 2nd Raisa Gorbacheva Memorial Meeting started the cooperation of the Raisa Gorbacheva Research Institute with ELN which was facilitated by the already existing contract with Pavlov University at the insistence of Andrey Zaritskey.

From the very beginning of our collaboration, I realized the importance which Andrey attributed to national and international connections. Particularly visible cooperations concerned ELN, resulting in his election to the panel for the development of the prestigious ELN recommendations for treating CML in 2014. At the photo (Fig. 1) made at the ELN symposium in Mannheim in 2015, you can see, in addition to Andrey, his close associate Elza Lomaya, the Moscow colleagues Elena Parovichnikova, Anna Turkina, Sergej Kulikov, Ekaterina Chelisheva and many others. The Recommendations were published in 2020 (Fig. 2).

Other important cooperative studies included stem cell research with Anthony Ho from Heidelberg University, supported by the German Government and the European Union, as well as common work with the European Investigators on CML (EI-CML) resulting in hosting the 22nd EI-CML meeting in St. Petersburg in 2014 (Fig. 3).

Hehlmann-fig01.jpg

Figure 1. ELN Symposium Mannheim 2015

Hehlmann-fig02-03.jpg
Hehlmann-fig04.jpg

Figure 4. The ELN-Merit-Award to Professor Zaritskey in 2011

Moreover, he performed long-term cooperative leukemia and stem cell research with Michael Andreeff and Hagop Kanterjian from the MD Anderson Cancer Center (USA) visibly documented by a common symposium in St. Petersburg in 2017. In 2011, in recognition of his integrative and cooperative activities, Andrey Zaritzkey received the ELN-Merit-Award for European Integration of Leukemia Research (Fig. 4).

Almost every year, Andrey Zaritskey organized national and international meetings at the Almazov Center on new developments in leukemia, stem cells and transplantation. Members of his group spent time at European or American Centers for educational or cooperative purposes. In addition, Andrey promoted the Almazov Center and his institute by lectures all over Russia. I had the pleasure and honor to accompany him at some of these occasions. The visits to Samara and Irkutsk were impressive, showing Russian advanced research and development at its best. In Samara, the visit to the rocket center and, with the help of Prof. Igor Davydkin, an old friend of Andrey, to the Institute for Experimental Medicine provided examples of the excellence of Russian research. With these activities Andrey may have been a typical offspring of St. Petersburg: Reaching far out beyond Russia, but in the interest and for further development of St. Petersburg and Russia in the field of hematology. He was proud of Russia, but was worried hoping that the premises stayed stable for continued international cooperative research.

Over 16 years I had the pleasure to know and cooperate with Andrey Zaritskey. I learned that the key to his success was not only academic brilliance. Most important was his sympathetic, open, reliable, modest, but nevertheless determined personality. He knew that a successful and lasting cooperation needs trust and friendship, that one must consider the cultural background of the cooperators, but also that one must bring his own heritage into a partnership, which the partner has to understand. Maybe he learned this way of dealing with international partners from the wisdom of the founders of the European Investigators on CML, notably the legendary Italian hematologist Sante Tura, who died at age 92, just 5 days before Andrey. On Sante Tura’s incentive, the European Investigators traditionally spend at their 2-day meetings across Europe, from the very beginning in 1993, half a day for exposure to the host country’s cultural heritage. Thus, international colleagues learned about Russia and to appreciate the country. And Andrey himself was open for other countries and cultures. In those successful years he did not forget those who worked with him and helped him to make all this possible. Andrey gave credit to his coworkers and cooperators and to his supporters.

Hehlmann-fig05.jpg

Figure 5. Symposium with the MD Anderson Cancer Center, St. Petersburg, July 2017

Highlights of Andrey Zaritskey’s professional career were the successful cooperative projects with ELN, particularly on CML, and with the MD Anderson Cancer Center culminating in the common meeting in July 2017 (Fig. 5).

This meeting turned out to be the culmination of his professional life. Andrey was 67, successful, internationally visible and respected by his colleagues, an admirable career. When he did not attend the ASH conference later in 2017, nor the ELN symposium in Venice in March 2018, it was clear that something was wrong. I knew that he was a heavy smoker, but now he had developed cancer of the lung. Despite his cancer, he resumed work in 2018 and continued all his activities unabated. When I came to St. Petersburg in 2018, he met me at the airport as usual and took me to Valday monastery, a cultural heritage close to the Wolga origin. He tried to play his cancer down, but looking at him showed the truth. As disciplined as he was, he continued leading his group even after he was confined to intensive care in early 2021, planning for the 4th St. Petersburg Medical Innovation Forum in May in his usual careful way including chairing a session himself from the bedside. We still hoped for a turn to the better. He planned to leave the hospital soon and reminded me to see Valaam monastery in Lake Ladoga which he had urged me to do repeatedly.

When I saw him again on September 20, 2021, his course unfortunately had turned to the worse. He still hoped, but knew what was coming. He was satisfied with my trip to Valaam which I had visited the day before, and we spoke about the ELN symposium in Mannheim planned for March 2022. When I left him saying that I was looking forward to seeing him again in Mannheim next March, or elsewhere, he immediately understood: with elsewhere you mean heaven, don’t you?

With Andrey Zaritzkey, the Almazov National Medical Research Center has lost a great researcher and international communicator, Russia has lost ambassador. His legacy is international cooperative research in the interest of patients, of his Institute, of St. Petersburg, and of Russia. It will be associated with the memory of Professor Andrey Zaritskey.


" ["~DETAIL_TEXT"]=> string(10207) "
Zaritskiy.jpg

Prof. Andrey Zaritskey (10.03.1950 – 16.10.2021)

I met Andrey Zaritskey in 2004 or 2005 when he insisted that both the Almazov Center and Pavlov University joined the European LeukemiaNet (ELN). He was the only ELN investigator who promoted contracts with two institutions. His persistence facilitated cooperation of the Gorbacheva Research Institute with ELN later. I was impressed by his comprehensive research interests, his cooperative spirit, and his vision. At his invitation, I visited St. Petersburg in September 2006, starting 15 years of fruitful cooperation in the field of leukemia. I remember this visit very well. It was one of his early meetings, maybe the first one with international speakers. The meeting was also attended by Prof. Valery Savchenko from Moscow with his mentor Prof. Andrey Vorobiev and his wife Prof. Elena Parovichnikova. Valery was an old friend of mine whom I had met in Wilsede around 1990, who unexpectedly died in July 2021, 3 months before Andrey.

At that time, in 2006, the Almazov Center was under development. Its activities were limited to diseases of the Heart, Blood and Endocrinology, with Andrey Zaritskey appointed Head of the Blood Section. Andrey used the occasion to show me with pride the evolving Almazov Center and to introduce me to his chief, Prof. Evgeny Shlyakhto. Even if things had just started, he saw the chances and had a plan – like his chief. He also used the occasion to show me the beauty of St. Petersburg. With the help of Dr. Elza Lomaia, we succeeded visiting the beautifully rebuilt Katherine’s palace with the perfectly restored amber room.

During the following years, the Almazov Center evolved to the National Medical Research Center of today, one of the largest in Russia. Of critical importance for Andrey Zaritskey’s success was the trust and continuous support by Evgeny Shlyakhto, General Director of the Center, who is a cardiologist. In 2008, Andrey Zaritskey was appointed Director of the new Institute of Hematology at the Almazov Center. In the years to follow, he established with great energy the new Institute with research facilities and, most notably, a transplantation unit, although access to the International Donor Registry was still a challenge at the time. He was its director for 14 years. In the same year, again in Wilsede, I met Professor Boris Afanasyev and Dr. Alexei Chukhlovin. Afanasiev’s invitation to the 2nd Raisa Gorbacheva Memorial Meeting started the cooperation of the Raisa Gorbacheva Research Institute with ELN which was facilitated by the already existing contract with Pavlov University at the insistence of Andrey Zaritskey.

From the very beginning of our collaboration, I realized the importance which Andrey attributed to national and international connections. Particularly visible cooperations concerned ELN, resulting in his election to the panel for the development of the prestigious ELN recommendations for treating CML in 2014. At the photo (Fig. 1) made at the ELN symposium in Mannheim in 2015, you can see, in addition to Andrey, his close associate Elza Lomaya, the Moscow colleagues Elena Parovichnikova, Anna Turkina, Sergej Kulikov, Ekaterina Chelisheva and many others. The Recommendations were published in 2020 (Fig. 2).

Other important cooperative studies included stem cell research with Anthony Ho from Heidelberg University, supported by the German Government and the European Union, as well as common work with the European Investigators on CML (EI-CML) resulting in hosting the 22nd EI-CML meeting in St. Petersburg in 2014 (Fig. 3).

Hehlmann-fig01.jpg

Figure 1. ELN Symposium Mannheim 2015

Hehlmann-fig02-03.jpg
Hehlmann-fig04.jpg

Figure 4. The ELN-Merit-Award to Professor Zaritskey in 2011

Moreover, he performed long-term cooperative leukemia and stem cell research with Michael Andreeff and Hagop Kanterjian from the MD Anderson Cancer Center (USA) visibly documented by a common symposium in St. Petersburg in 2017. In 2011, in recognition of his integrative and cooperative activities, Andrey Zaritzkey received the ELN-Merit-Award for European Integration of Leukemia Research (Fig. 4).

Almost every year, Andrey Zaritskey organized national and international meetings at the Almazov Center on new developments in leukemia, stem cells and transplantation. Members of his group spent time at European or American Centers for educational or cooperative purposes. In addition, Andrey promoted the Almazov Center and his institute by lectures all over Russia. I had the pleasure and honor to accompany him at some of these occasions. The visits to Samara and Irkutsk were impressive, showing Russian advanced research and development at its best. In Samara, the visit to the rocket center and, with the help of Prof. Igor Davydkin, an old friend of Andrey, to the Institute for Experimental Medicine provided examples of the excellence of Russian research. With these activities Andrey may have been a typical offspring of St. Petersburg: Reaching far out beyond Russia, but in the interest and for further development of St. Petersburg and Russia in the field of hematology. He was proud of Russia, but was worried hoping that the premises stayed stable for continued international cooperative research.

Over 16 years I had the pleasure to know and cooperate with Andrey Zaritskey. I learned that the key to his success was not only academic brilliance. Most important was his sympathetic, open, reliable, modest, but nevertheless determined personality. He knew that a successful and lasting cooperation needs trust and friendship, that one must consider the cultural background of the cooperators, but also that one must bring his own heritage into a partnership, which the partner has to understand. Maybe he learned this way of dealing with international partners from the wisdom of the founders of the European Investigators on CML, notably the legendary Italian hematologist Sante Tura, who died at age 92, just 5 days before Andrey. On Sante Tura’s incentive, the European Investigators traditionally spend at their 2-day meetings across Europe, from the very beginning in 1993, half a day for exposure to the host country’s cultural heritage. Thus, international colleagues learned about Russia and to appreciate the country. And Andrey himself was open for other countries and cultures. In those successful years he did not forget those who worked with him and helped him to make all this possible. Andrey gave credit to his coworkers and cooperators and to his supporters.

Hehlmann-fig05.jpg

Figure 5. Symposium with the MD Anderson Cancer Center, St. Petersburg, July 2017

Highlights of Andrey Zaritskey’s professional career were the successful cooperative projects with ELN, particularly on CML, and with the MD Anderson Cancer Center culminating in the common meeting in July 2017 (Fig. 5).

This meeting turned out to be the culmination of his professional life. Andrey was 67, successful, internationally visible and respected by his colleagues, an admirable career. When he did not attend the ASH conference later in 2017, nor the ELN symposium in Venice in March 2018, it was clear that something was wrong. I knew that he was a heavy smoker, but now he had developed cancer of the lung. Despite his cancer, he resumed work in 2018 and continued all his activities unabated. When I came to St. Petersburg in 2018, he met me at the airport as usual and took me to Valday monastery, a cultural heritage close to the Wolga origin. He tried to play his cancer down, but looking at him showed the truth. As disciplined as he was, he continued leading his group even after he was confined to intensive care in early 2021, planning for the 4th St. Petersburg Medical Innovation Forum in May in his usual careful way including chairing a session himself from the bedside. We still hoped for a turn to the better. He planned to leave the hospital soon and reminded me to see Valaam monastery in Lake Ladoga which he had urged me to do repeatedly.

When I saw him again on September 20, 2021, his course unfortunately had turned to the worse. He still hoped, but knew what was coming. He was satisfied with my trip to Valaam which I had visited the day before, and we spoke about the ELN symposium in Mannheim planned for March 2022. When I left him saying that I was looking forward to seeing him again in Mannheim next March, or elsewhere, he immediately understood: with elsewhere you mean heaven, don’t you?

With Andrey Zaritzkey, the Almazov National Medical Research Center has lost a great researcher and international communicator, Russia has lost ambassador. His legacy is international cooperative research in the interest of patients, of his Institute, of St. Petersburg, and of Russia. It will be associated with the memory of Professor Andrey Zaritskey.


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Гейдельбергский университет и European LeukemiaNet, Вайнхайм, Германия

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Центр им. В. А. Алмазова и российское гематологическое сообщество потеряли лидера и организатора международных программ, я потерял друга. В октябре прошлого года скончался профессор Андрей Юрьевич Зарицкий, который стал пионером создания нового Института гематологии в Национальном медицинском исследовательском центре имени В. А. Алмазова. Центральное место в его работе занимала идея включения института в программы сотрудничества, что позволило создать известный и конкурентоспособный медицинский центр. Сегодняшний уровень наших дискуссий отражает видение А. Ю. Зарицким задач сотрудничества в области гематологии.

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Prof. Rüdiger Hehlmann

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Heidelberg University, Mannheim, and European LeukemiaNet, Weinheim, Germany


Correspondence:
Prof. Dr. Rüdiger Hehlmann, Heidelberg University, Mannheim, and European LeukemiaNet, Weinheim, Germany
E-mail: hehlmann.eln@gmail.com


Citation: Hehlmann R. Tribute to Prof. Andrey Zaritskey from an international perspective. Cell Ther Transplant 2022; 11(3-4): 99-103.

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The Almazov Centre and the Russian hematologic community lost a leader and communicator and I lost a friend. Prof. Andrey Zaritskey who pioneered the new Institute of Hematology at the V. Almazov National Medical Research Center passed away in October 2021. Central to his work was his vision of embedding his institute in a network of cooperative studies, thereby creating an institute that was internationally visible and competitive. The Professor Zaritskey Discussion Club which took place in St. Petersburg on September 2, 2022 reflects his vision of cooperation in the field of hematology.

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Зарицким в 2004 или 2005 году, когда он настоял на том, чтобы и Центр им. В. А. Алмазова, и Первый Санкт-Петербургский государственный медицинский университет им. И. Павлова (ПСПбГМУ) присоединились к Европейской сети по изучению лейкозов (ELN). Он был единственным исследователем ELN, настаивавшим на заключении договора с обоими учреждениями – Национальным медицинским исследовательским Центром им. В. А. Алмазова и Первым Санкт-Петербургским государственным медицинским университетом им. И. П. Павлова, но его настойчивость способствовала сотрудничеству в дальнейшем между НИИ им. Р. М. Горбачевой и ELN. На меня произвели впечатление его обширные исследовательские интересы, его дух сотрудничества и его видение. По его приглашению я посетил Санкт-Петербург в сентябре 2006 года, положив начало 15-летнему плодотворному сотрудничеству в области лейкемии. Это была одна из его первых встреч с докладами иностранных участников. На встрече также присутствовали московские коллеги – профессор В. Г. Савченко и Е. Н. Паровичникова. В. Г. Савченко был моим старым другом, с которым я познакомился в Вильзеде около 1990 года, он безвременно ушел из жизни за 3 месяца до А. Ю. Зарицкого, в июле 2021 года. </p> <p style="text-align: justify;">В то время, в 2006 году, Центр имени В. А. Алмазова находился в стадии развития, и там велись работы, главным образом, в области кардиологии, болезней крови и эндокринологии, а А. Ю. Зарицкий был назначен руководителем секции гематологии. Андрей воспользовался случаем, чтобы с гордостью показать мне развивающийся Центр Алмазова и познакомить меня со своим руководителем профессором Евгением Владимировичем Шляхто. Несмотря на то, что все только начиналось, он видел открывающиеся возможности и имел план действий, согласованный с профессором Е. В. Шляхто. Он также воспользовался случаем, чтобы показать мне красоты Санкт-Петербурга. С помощью Эльзы Галактионовны Ломайя нам удалось посетить прекрасный Екатерининский дворец с реставрированной янтарной комнатой. </p> <p style="text-align: justify;">В последующие годы Центр им. В. А. Алмазова превратился в Национальный медицинский исследовательский центр, один из крупнейших в России. Огромное значение для успеха А. Ю. Зарицкого имело доверие и постоянная поддержка со стороны председателя Центра, профессора Евгения Владимировича Шляхто – известного кардиолога. В 2008 году Андрей Зарицкий был назначен директором нового Института гематологии Национального медицинского исследовательского центра имени В. А. Алмазова. В последующие годы он с большой энергией создавал новый институт с исследовательской базой и, что особенно важно, с отделением трансплантации. А. Ю. Зарицкий был его директором почти 14 лет. Доступ к международному регистру доноров в то время все еще оставался проблемой. </p> <p style="text-align: justify;">В том же году, снова в Вильзеде, я познакомился с профессором Борисом Афанасьевым и Алексеем Чухловиным. Приглашение от профессора Б. В. Афанасьева на II Симпозиум памяти Р. М. Горбачевой в Санкт-Петербурге положило начало сотрудничеству НИИ им. Горбачевой с European LeukemiaNet, чему способствовал уже существующий договор с ПСПбГМУ им. И. П. Павлова, заключенный по настоянию А. Ю. Зарицкого. С самого начала нашего сотрудничества я понял, какое значение профессор А. Ю. Зарицкий придавал национальным и международным связям. Четыре программы сотрудничества были особенно заметными и успешными. Усилия Андрея по ознакомлению своих международных партнеров с его и российским наследием иллюстрируют некоторые фотографии, за которые я благодарю Эльзу Галактионовну Ломайя и ее команду. </p> <p style="text-align: justify;">В частности, мы многие годы сотрудничали в рамках European LeukemiaNet, одним из первых участников которого был Медицинский Центр им. В. А. Алмазова, в результате чего в 2014 году А. Ю. Зарицкий был избран членом комиссии по разработке престижных рекомендаций ELN по лечению хронического миелоидного лейкоза. Помимо Андрея, вы можете видеть на фото Эльзу Галактионовну Ломайя, наших московских коллег Елену Николаевну Паровичникову, Анну Григорьевну Туркину, Сергея Михайловича Куликова, Екатерину Юрьевну Челышеву и многих других (Рис. 1). Эти рекомендации были опубликованы в 2020 году (Рис. 2). Кроме того, А. Ю. Зарицкий участвовал в проектах по стволовым клеткам с профессором Энтони Хо из Гейдельбергского университета при поддержке правительства Германии и Европейского Союза, принимал участие в деятельности Европейских исследований в области ХМЛ (EI-CML), и проведении 22-го заседания EI-CML в Санкт-Петербурге в 2014 году (Рис. 3). Наряду с этим, он руководил совместными проектами с профессорами Майклом Андреефф и Агопом Кантарджяном из Онкологического центра MD Anderson (Хьюстон, США). Эти результаты были представлены на совместном симпозиуме в Санкт-Петербурге в июле 2017 года. В 2011 году в знак признания его организационной деятельности и сотрудничества, Андрей Зарицкий получил награду ELN Merit Award за общеевропейскую интеграцию работ по исследованию лейкозов (Рис. 4). </p> <p style="text-align: justify;">Почти каждый год Андрей Зарицкий организовывал в Центре им. В. А. Алмазова национальные и международные встречи, посвященные новым разработкам в области лейкемии, стволовых клеток и трансплантации (Рис. 5). Члены его группы проводили время в европейских или американских центрах с целью обучения или сотрудничества. Кроме того, А. Ю. Зарицкий пропагандировал Центр Алмазова и свой институт, выступая с лекциями по всей России. Я имел удовольствие и честь сопровождать его на некоторых из этих мероприятий. Наши визиты в Самару и Иркутск были впечатляющими, демонстрируя с лучшей стороны российские передовые исследования и разработки. Так, в Самаре была неоценима помощь и участие профессора Игоря Леонидовича Давыдкина, старого друга профессора А. Ю. Зарицкого. При осуществлении этой деятельности Андрей показал себя типичным представителем Петербурга, стремясь выйти далеко за пределы России, но в интересах и для дальнейшего развития города и России в области гематологии. Он гордился Россией, но беспокоился, чтобы предпосылки для продолжения международных совместных исследований оставались стабильными. </p> <p style="text-align: justify;">За 16 лет, которые я имел удовольствие знать и сотрудничать с Андреем Зарицким, я понял, что ключ к его успеху – не только академический блеск. Важнее всего была его отзывчивость, открытость, надежность, скромность, но, тем не менее – решительность. Он знал, что для успешного и продолжительного сотрудничества необходимы доверие и дружба, что необходимо учитывать культурный фон участников сотрудничества, а также собственное наследие, которое должно быть понято другой стороной. Возможно, он научился этому способу общения с международными партнерами благодаря мудрости основателей группы европейских исследований в области хронического миелоидного лейкоза, в частности, легендарного итальянского гематолога Санте Тура, который умер всего за 5 дней до Андрея, однако – в возрасте 92 лет. По традиции Санте Тура, начиная с 1993 года, эта группа традиционно проводит свои двухдневные встречи по всей Европе, посвящая полдня знакомству с культурным наследием принимающей страны. Таким образом, зарубежные коллеги узнавали о России и по достоинству оценивали страну, так же как сам А. Ю. Зарицкий был открыт для других стран и культур. В эти успешные годы он не забывал о тех, кто работал с ним и помогал ему сделать все это возможным. В Медицинском исследовательском центре им. В. А. Алмазова, сколько я себя помню, Эльза Галактионовна Ломайя была рядом с ним, всегда поддерживала и всегда эффективно работала. Андрей отдавал должное своим коллегам и сотрудникам, а также своим сторонникам. Он неоднократно упоминал, как важно для него было то, что профессоры Евгений Владимирович Шляхто и Александра Олеговна Конради открыты его предложениям и дружественно отвечают на его запросы. </p> <p style="text-align: justify;">Ключевыми моментами в профессиональной карьере Андрея Зарицкого стало успешное сотрудничество с ELN, в частности по хроническому миелоидному лейкозу, и с Онкологическим центром MD Anderson. Их общий симпозиум состоялся в июле 2017 года в Санкт-Петербурге. Для меня эта встреча была высшей точкой его карьеры. Андрею было 67 лет, он был успешен, известен на международном уровне и уважаем своими коллегами – карьера, достойная восхищения. Однако, когда он не посетил ни конференцию ASH в конце 2017 года, ни симпозиум ELN в Венеции в марте 2018 года, стало ясно, что что-то не так. Я знал, что он был заядлым курильщиком, но теперь у него развился рак легкого. </p> <p style="text-align: justify;">Несмотря на свою болезнь, он возобновил работу в 2018 году и продолжал всю свою деятельность без перерыва. Когда я приехал в Санкт-Петербург в 2018 году, он, как обычно, встретил меня в аэропорту, чтобы отвезти в Валдайский монастырь, памятник культуры на пути в Москву, рядом с истоком Волги. Он пытался преуменьшить значение своего рака, но его внешний вид выдавал истинное состояние. Будучи дисциплинированным, он продолжал руководить своей группой даже после того, как его положили в реанимацию в начале 2021 года, планируя, как обычно, 4-й Санкт-Петербургский медицинский инновационный форум в мае, включая руководство с больничной койки одним из заседаний. Он и Эльза Галактионовна договорились, что один из его молодых врачей встретит меня далеко за полночь в Пулково с приветственным плакатом на немецком языке. Я был глубоко тронут. Мы все еще надеялись, что ситуация изменится к лучшему. Он планировал вскоре покинуть больницу и напомнил мне о необходимости посетить Валаамский монастырь на Ладожском озере, о чем он неоднократно меня просил. </p> <p style="text-align: justify;">Когда я снова увидел его 20 сентября 2021 года, его состояние, к сожалению, ухудшилось. Он все еще надеялся, но знал, что его ждет. Он был доволен моей поездкой на Валаам, который я посетил накануне, и мы поговорили о симпозиуме ELN в Мангейме, запланированном на март 2022 года. Когда я сказал ему на прощание, что с нетерпением жду новой встречи с ним в Мангейме в марте следующего года или в другом месте, он сразу понял: под другим местом вы подразумеваете рай, не так ли? </p> <p style="text-align: justify;">С Андреем Зарицким российская гематология и Национальный медицинский исследовательский центр имени В. А. Алмазова потерял крупного ученого и организатора международных программ, Россия потеряла посла. Его наследие – международные совместные исследования в интересах пациентов, его института, Санкт-Петербурга и России. Они будут связаны с памятью о профессоре Андрее Юрьевиче Зарицком. </p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(19102) "

Я познакомился с А. Ю. Зарицким в 2004 или 2005 году, когда он настоял на том, чтобы и Центр им. В. А. Алмазова, и Первый Санкт-Петербургский государственный медицинский университет им. И. Павлова (ПСПбГМУ) присоединились к Европейской сети по изучению лейкозов (ELN). Он был единственным исследователем ELN, настаивавшим на заключении договора с обоими учреждениями – Национальным медицинским исследовательским Центром им. В. А. Алмазова и Первым Санкт-Петербургским государственным медицинским университетом им. И. П. Павлова, но его настойчивость способствовала сотрудничеству в дальнейшем между НИИ им. Р. М. Горбачевой и ELN. На меня произвели впечатление его обширные исследовательские интересы, его дух сотрудничества и его видение. По его приглашению я посетил Санкт-Петербург в сентябре 2006 года, положив начало 15-летнему плодотворному сотрудничеству в области лейкемии. Это была одна из его первых встреч с докладами иностранных участников. На встрече также присутствовали московские коллеги – профессор В. Г. Савченко и Е. Н. Паровичникова. В. Г. Савченко был моим старым другом, с которым я познакомился в Вильзеде около 1990 года, он безвременно ушел из жизни за 3 месяца до А. Ю. Зарицкого, в июле 2021 года.

В то время, в 2006 году, Центр имени В. А. Алмазова находился в стадии развития, и там велись работы, главным образом, в области кардиологии, болезней крови и эндокринологии, а А. Ю. Зарицкий был назначен руководителем секции гематологии. Андрей воспользовался случаем, чтобы с гордостью показать мне развивающийся Центр Алмазова и познакомить меня со своим руководителем профессором Евгением Владимировичем Шляхто. Несмотря на то, что все только начиналось, он видел открывающиеся возможности и имел план действий, согласованный с профессором Е. В. Шляхто. Он также воспользовался случаем, чтобы показать мне красоты Санкт-Петербурга. С помощью Эльзы Галактионовны Ломайя нам удалось посетить прекрасный Екатерининский дворец с реставрированной янтарной комнатой.

В последующие годы Центр им. В. А. Алмазова превратился в Национальный медицинский исследовательский центр, один из крупнейших в России. Огромное значение для успеха А. Ю. Зарицкого имело доверие и постоянная поддержка со стороны председателя Центра, профессора Евгения Владимировича Шляхто – известного кардиолога. В 2008 году Андрей Зарицкий был назначен директором нового Института гематологии Национального медицинского исследовательского центра имени В. А. Алмазова. В последующие годы он с большой энергией создавал новый институт с исследовательской базой и, что особенно важно, с отделением трансплантации. А. Ю. Зарицкий был его директором почти 14 лет. Доступ к международному регистру доноров в то время все еще оставался проблемой.

В том же году, снова в Вильзеде, я познакомился с профессором Борисом Афанасьевым и Алексеем Чухловиным. Приглашение от профессора Б. В. Афанасьева на II Симпозиум памяти Р. М. Горбачевой в Санкт-Петербурге положило начало сотрудничеству НИИ им. Горбачевой с European LeukemiaNet, чему способствовал уже существующий договор с ПСПбГМУ им. И. П. Павлова, заключенный по настоянию А. Ю. Зарицкого. С самого начала нашего сотрудничества я понял, какое значение профессор А. Ю. Зарицкий придавал национальным и международным связям. Четыре программы сотрудничества были особенно заметными и успешными. Усилия Андрея по ознакомлению своих международных партнеров с его и российским наследием иллюстрируют некоторые фотографии, за которые я благодарю Эльзу Галактионовну Ломайя и ее команду.

В частности, мы многие годы сотрудничали в рамках European LeukemiaNet, одним из первых участников которого был Медицинский Центр им. В. А. Алмазова, в результате чего в 2014 году А. Ю. Зарицкий был избран членом комиссии по разработке престижных рекомендаций ELN по лечению хронического миелоидного лейкоза. Помимо Андрея, вы можете видеть на фото Эльзу Галактионовну Ломайя, наших московских коллег Елену Николаевну Паровичникову, Анну Григорьевну Туркину, Сергея Михайловича Куликова, Екатерину Юрьевну Челышеву и многих других (Рис. 1). Эти рекомендации были опубликованы в 2020 году (Рис. 2). Кроме того, А. Ю. Зарицкий участвовал в проектах по стволовым клеткам с профессором Энтони Хо из Гейдельбергского университета при поддержке правительства Германии и Европейского Союза, принимал участие в деятельности Европейских исследований в области ХМЛ (EI-CML), и проведении 22-го заседания EI-CML в Санкт-Петербурге в 2014 году (Рис. 3). Наряду с этим, он руководил совместными проектами с профессорами Майклом Андреефф и Агопом Кантарджяном из Онкологического центра MD Anderson (Хьюстон, США). Эти результаты были представлены на совместном симпозиуме в Санкт-Петербурге в июле 2017 года. В 2011 году в знак признания его организационной деятельности и сотрудничества, Андрей Зарицкий получил награду ELN Merit Award за общеевропейскую интеграцию работ по исследованию лейкозов (Рис. 4).

Почти каждый год Андрей Зарицкий организовывал в Центре им. В. А. Алмазова национальные и международные встречи, посвященные новым разработкам в области лейкемии, стволовых клеток и трансплантации (Рис. 5). Члены его группы проводили время в европейских или американских центрах с целью обучения или сотрудничества. Кроме того, А. Ю. Зарицкий пропагандировал Центр Алмазова и свой институт, выступая с лекциями по всей России. Я имел удовольствие и честь сопровождать его на некоторых из этих мероприятий. Наши визиты в Самару и Иркутск были впечатляющими, демонстрируя с лучшей стороны российские передовые исследования и разработки. Так, в Самаре была неоценима помощь и участие профессора Игоря Леонидовича Давыдкина, старого друга профессора А. Ю. Зарицкого. При осуществлении этой деятельности Андрей показал себя типичным представителем Петербурга, стремясь выйти далеко за пределы России, но в интересах и для дальнейшего развития города и России в области гематологии. Он гордился Россией, но беспокоился, чтобы предпосылки для продолжения международных совместных исследований оставались стабильными.

За 16 лет, которые я имел удовольствие знать и сотрудничать с Андреем Зарицким, я понял, что ключ к его успеху – не только академический блеск. Важнее всего была его отзывчивость, открытость, надежность, скромность, но, тем не менее – решительность. Он знал, что для успешного и продолжительного сотрудничества необходимы доверие и дружба, что необходимо учитывать культурный фон участников сотрудничества, а также собственное наследие, которое должно быть понято другой стороной. Возможно, он научился этому способу общения с международными партнерами благодаря мудрости основателей группы европейских исследований в области хронического миелоидного лейкоза, в частности, легендарного итальянского гематолога Санте Тура, который умер всего за 5 дней до Андрея, однако – в возрасте 92 лет. По традиции Санте Тура, начиная с 1993 года, эта группа традиционно проводит свои двухдневные встречи по всей Европе, посвящая полдня знакомству с культурным наследием принимающей страны. Таким образом, зарубежные коллеги узнавали о России и по достоинству оценивали страну, так же как сам А. Ю. Зарицкий был открыт для других стран и культур. В эти успешные годы он не забывал о тех, кто работал с ним и помогал ему сделать все это возможным. В Медицинском исследовательском центре им. В. А. Алмазова, сколько я себя помню, Эльза Галактионовна Ломайя была рядом с ним, всегда поддерживала и всегда эффективно работала. Андрей отдавал должное своим коллегам и сотрудникам, а также своим сторонникам. Он неоднократно упоминал, как важно для него было то, что профессоры Евгений Владимирович Шляхто и Александра Олеговна Конради открыты его предложениям и дружественно отвечают на его запросы.

Ключевыми моментами в профессиональной карьере Андрея Зарицкого стало успешное сотрудничество с ELN, в частности по хроническому миелоидному лейкозу, и с Онкологическим центром MD Anderson. Их общий симпозиум состоялся в июле 2017 года в Санкт-Петербурге. Для меня эта встреча была высшей точкой его карьеры. Андрею было 67 лет, он был успешен, известен на международном уровне и уважаем своими коллегами – карьера, достойная восхищения. Однако, когда он не посетил ни конференцию ASH в конце 2017 года, ни симпозиум ELN в Венеции в марте 2018 года, стало ясно, что что-то не так. Я знал, что он был заядлым курильщиком, но теперь у него развился рак легкого.

Несмотря на свою болезнь, он возобновил работу в 2018 году и продолжал всю свою деятельность без перерыва. Когда я приехал в Санкт-Петербург в 2018 году, он, как обычно, встретил меня в аэропорту, чтобы отвезти в Валдайский монастырь, памятник культуры на пути в Москву, рядом с истоком Волги. Он пытался преуменьшить значение своего рака, но его внешний вид выдавал истинное состояние. Будучи дисциплинированным, он продолжал руководить своей группой даже после того, как его положили в реанимацию в начале 2021 года, планируя, как обычно, 4-й Санкт-Петербургский медицинский инновационный форум в мае, включая руководство с больничной койки одним из заседаний. Он и Эльза Галактионовна договорились, что один из его молодых врачей встретит меня далеко за полночь в Пулково с приветственным плакатом на немецком языке. Я был глубоко тронут. Мы все еще надеялись, что ситуация изменится к лучшему. Он планировал вскоре покинуть больницу и напомнил мне о необходимости посетить Валаамский монастырь на Ладожском озере, о чем он неоднократно меня просил.

Когда я снова увидел его 20 сентября 2021 года, его состояние, к сожалению, ухудшилось. Он все еще надеялся, но знал, что его ждет. Он был доволен моей поездкой на Валаам, который я посетил накануне, и мы поговорили о симпозиуме ELN в Мангейме, запланированном на март 2022 года. Когда я сказал ему на прощание, что с нетерпением жду новой встречи с ним в Мангейме в марте следующего года или в другом месте, он сразу понял: под другим местом вы подразумеваете рай, не так ли?

С Андреем Зарицким российская гематология и Национальный медицинский исследовательский центр имени В. А. Алмазова потерял крупного ученого и организатора международных программ, Россия потеряла посла. Его наследие – международные совместные исследования в интересах пациентов, его института, Санкт-Петербурга и России. Они будут связаны с памятью о профессоре Андрее Юрьевиче Зарицком.

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Prof. Rüdiger Hehlmann

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Prof. Rüdiger Hehlmann

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The Almazov Centre and the Russian hematologic community lost a leader and communicator and I lost a friend. Prof. Andrey Zaritskey who pioneered the new Institute of Hematology at the V. Almazov National Medical Research Center passed away in October 2021. Central to his work was his vision of embedding his institute in a network of cooperative studies, thereby creating an institute that was internationally visible and competitive. The Professor Zaritskey Discussion Club which took place in St. Petersburg on September 2, 2022 reflects his vision of cooperation in the field of hematology.

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The Almazov Centre and the Russian hematologic community lost a leader and communicator and I lost a friend. Prof. Andrey Zaritskey who pioneered the new Institute of Hematology at the V. Almazov National Medical Research Center passed away in October 2021. Central to his work was his vision of embedding his institute in a network of cooperative studies, thereby creating an institute that was internationally visible and competitive. The Professor Zaritskey Discussion Club which took place in St. Petersburg on September 2, 2022 reflects his vision of cooperation in the field of hematology.

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Heidelberg University, Mannheim, and European LeukemiaNet, Weinheim, Germany


Correspondence:
Prof. Dr. Rüdiger Hehlmann, Heidelberg University, Mannheim, and European LeukemiaNet, Weinheim, Germany
E-mail: hehlmann.eln@gmail.com


Citation: Hehlmann R. Tribute to Prof. Andrey Zaritskey from an international perspective. Cell Ther Transplant 2022; 11(3-4): 99-103.

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Heidelberg University, Mannheim, and European LeukemiaNet, Weinheim, Germany


Correspondence:
Prof. Dr. Rüdiger Hehlmann, Heidelberg University, Mannheim, and European LeukemiaNet, Weinheim, Germany
E-mail: hehlmann.eln@gmail.com


Citation: Hehlmann R. Tribute to Prof. Andrey Zaritskey from an international perspective. Cell Ther Transplant 2022; 11(3-4): 99-103.

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Рюдигер Хелльман

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Рюдигер Хелльман

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Центр им. В. А. Алмазова и российское гематологическое сообщество потеряли лидера и организатора международных программ, я потерял друга. В октябре прошлого года скончался профессор Андрей Юрьевич Зарицкий, который стал пионером создания нового Института гематологии в Национальном медицинском исследовательском центре имени В. А. Алмазова. Центральное место в его работе занимала идея включения института в программы сотрудничества, что позволило создать известный и конкурентоспособный медицинский центр. Сегодняшний уровень наших дискуссий отражает видение А. Ю. Зарицким задач сотрудничества в области гематологии.

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Центр им. В. А. Алмазова и российское гематологическое сообщество потеряли лидера и организатора международных программ, я потерял друга. В октябре прошлого года скончался профессор Андрей Юрьевич Зарицкий, который стал пионером создания нового Института гематологии в Национальном медицинском исследовательском центре имени В. А. Алмазова. Центральное место в его работе занимала идея включения института в программы сотрудничества, что позволило создать известный и конкурентоспособный медицинский центр. Сегодняшний уровень наших дискуссий отражает видение А. Ю. Зарицким задач сотрудничества в области гематологии.

" } ["ORGANIZATION_RU"]=> array(37) { ["ID"]=> string(2) "26" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:01:20" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(22) "Организации" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(15) "ORGANIZATION_RU" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "26" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "29612" ["VALUE"]=> array(2) { ["TEXT"]=> string(132) "<p>Гейдельбергский университет и European LeukemiaNet, Вайнхайм, Германия</p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(120) "

Гейдельбергский университет и European LeukemiaNet, Вайнхайм, Германия

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Гейдельбергский университет и European LeukemiaNet, Вайнхайм, Германия

" } ["FULL_TEXT_RU"]=> array(37) { ["ID"]=> string(2) "42" ["TIMESTAMP_X"]=> string(19) "2015-09-07 20:29:18" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(23) "Полный текст" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(12) "FULL_TEXT_RU" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "42" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "29619" ["VALUE"]=> array(2) { ["TEXT"]=> string(19344) "<p style="text-align: justify;">Я познакомился с А. Ю. Зарицким в 2004 или 2005 году, когда он настоял на том, чтобы и Центр им. В. А. Алмазова, и Первый Санкт-Петербургский государственный медицинский университет им. И. Павлова (ПСПбГМУ) присоединились к Европейской сети по изучению лейкозов (ELN). Он был единственным исследователем ELN, настаивавшим на заключении договора с обоими учреждениями – Национальным медицинским исследовательским Центром им. В. А. Алмазова и Первым Санкт-Петербургским государственным медицинским университетом им. И. П. Павлова, но его настойчивость способствовала сотрудничеству в дальнейшем между НИИ им. Р. М. Горбачевой и ELN. На меня произвели впечатление его обширные исследовательские интересы, его дух сотрудничества и его видение. По его приглашению я посетил Санкт-Петербург в сентябре 2006 года, положив начало 15-летнему плодотворному сотрудничеству в области лейкемии. Это была одна из его первых встреч с докладами иностранных участников. На встрече также присутствовали московские коллеги – профессор В. Г. Савченко и Е. Н. Паровичникова. В. Г. Савченко был моим старым другом, с которым я познакомился в Вильзеде около 1990 года, он безвременно ушел из жизни за 3 месяца до А. Ю. Зарицкого, в июле 2021 года. </p> <p style="text-align: justify;">В то время, в 2006 году, Центр имени В. А. Алмазова находился в стадии развития, и там велись работы, главным образом, в области кардиологии, болезней крови и эндокринологии, а А. Ю. Зарицкий был назначен руководителем секции гематологии. Андрей воспользовался случаем, чтобы с гордостью показать мне развивающийся Центр Алмазова и познакомить меня со своим руководителем профессором Евгением Владимировичем Шляхто. Несмотря на то, что все только начиналось, он видел открывающиеся возможности и имел план действий, согласованный с профессором Е. В. Шляхто. Он также воспользовался случаем, чтобы показать мне красоты Санкт-Петербурга. С помощью Эльзы Галактионовны Ломайя нам удалось посетить прекрасный Екатерининский дворец с реставрированной янтарной комнатой. </p> <p style="text-align: justify;">В последующие годы Центр им. В. А. Алмазова превратился в Национальный медицинский исследовательский центр, один из крупнейших в России. Огромное значение для успеха А. Ю. Зарицкого имело доверие и постоянная поддержка со стороны председателя Центра, профессора Евгения Владимировича Шляхто – известного кардиолога. В 2008 году Андрей Зарицкий был назначен директором нового Института гематологии Национального медицинского исследовательского центра имени В. А. Алмазова. В последующие годы он с большой энергией создавал новый институт с исследовательской базой и, что особенно важно, с отделением трансплантации. А. Ю. Зарицкий был его директором почти 14 лет. Доступ к международному регистру доноров в то время все еще оставался проблемой. </p> <p style="text-align: justify;">В том же году, снова в Вильзеде, я познакомился с профессором Борисом Афанасьевым и Алексеем Чухловиным. Приглашение от профессора Б. В. Афанасьева на II Симпозиум памяти Р. М. Горбачевой в Санкт-Петербурге положило начало сотрудничеству НИИ им. Горбачевой с European LeukemiaNet, чему способствовал уже существующий договор с ПСПбГМУ им. И. П. Павлова, заключенный по настоянию А. Ю. Зарицкого. С самого начала нашего сотрудничества я понял, какое значение профессор А. Ю. Зарицкий придавал национальным и международным связям. Четыре программы сотрудничества были особенно заметными и успешными. Усилия Андрея по ознакомлению своих международных партнеров с его и российским наследием иллюстрируют некоторые фотографии, за которые я благодарю Эльзу Галактионовну Ломайя и ее команду. </p> <p style="text-align: justify;">В частности, мы многие годы сотрудничали в рамках European LeukemiaNet, одним из первых участников которого был Медицинский Центр им. В. А. Алмазова, в результате чего в 2014 году А. Ю. Зарицкий был избран членом комиссии по разработке престижных рекомендаций ELN по лечению хронического миелоидного лейкоза. Помимо Андрея, вы можете видеть на фото Эльзу Галактионовну Ломайя, наших московских коллег Елену Николаевну Паровичникову, Анну Григорьевну Туркину, Сергея Михайловича Куликова, Екатерину Юрьевну Челышеву и многих других (Рис. 1). Эти рекомендации были опубликованы в 2020 году (Рис. 2). Кроме того, А. Ю. Зарицкий участвовал в проектах по стволовым клеткам с профессором Энтони Хо из Гейдельбергского университета при поддержке правительства Германии и Европейского Союза, принимал участие в деятельности Европейских исследований в области ХМЛ (EI-CML), и проведении 22-го заседания EI-CML в Санкт-Петербурге в 2014 году (Рис. 3). Наряду с этим, он руководил совместными проектами с профессорами Майклом Андреефф и Агопом Кантарджяном из Онкологического центра MD Anderson (Хьюстон, США). Эти результаты были представлены на совместном симпозиуме в Санкт-Петербурге в июле 2017 года. В 2011 году в знак признания его организационной деятельности и сотрудничества, Андрей Зарицкий получил награду ELN Merit Award за общеевропейскую интеграцию работ по исследованию лейкозов (Рис. 4). </p> <p style="text-align: justify;">Почти каждый год Андрей Зарицкий организовывал в Центре им. В. А. Алмазова национальные и международные встречи, посвященные новым разработкам в области лейкемии, стволовых клеток и трансплантации (Рис. 5). Члены его группы проводили время в европейских или американских центрах с целью обучения или сотрудничества. Кроме того, А. Ю. Зарицкий пропагандировал Центр Алмазова и свой институт, выступая с лекциями по всей России. Я имел удовольствие и честь сопровождать его на некоторых из этих мероприятий. Наши визиты в Самару и Иркутск были впечатляющими, демонстрируя с лучшей стороны российские передовые исследования и разработки. Так, в Самаре была неоценима помощь и участие профессора Игоря Леонидовича Давыдкина, старого друга профессора А. Ю. Зарицкого. При осуществлении этой деятельности Андрей показал себя типичным представителем Петербурга, стремясь выйти далеко за пределы России, но в интересах и для дальнейшего развития города и России в области гематологии. Он гордился Россией, но беспокоился, чтобы предпосылки для продолжения международных совместных исследований оставались стабильными. </p> <p style="text-align: justify;">За 16 лет, которые я имел удовольствие знать и сотрудничать с Андреем Зарицким, я понял, что ключ к его успеху – не только академический блеск. Важнее всего была его отзывчивость, открытость, надежность, скромность, но, тем не менее – решительность. Он знал, что для успешного и продолжительного сотрудничества необходимы доверие и дружба, что необходимо учитывать культурный фон участников сотрудничества, а также собственное наследие, которое должно быть понято другой стороной. Возможно, он научился этому способу общения с международными партнерами благодаря мудрости основателей группы европейских исследований в области хронического миелоидного лейкоза, в частности, легендарного итальянского гематолога Санте Тура, который умер всего за 5 дней до Андрея, однако – в возрасте 92 лет. По традиции Санте Тура, начиная с 1993 года, эта группа традиционно проводит свои двухдневные встречи по всей Европе, посвящая полдня знакомству с культурным наследием принимающей страны. Таким образом, зарубежные коллеги узнавали о России и по достоинству оценивали страну, так же как сам А. Ю. Зарицкий был открыт для других стран и культур. В эти успешные годы он не забывал о тех, кто работал с ним и помогал ему сделать все это возможным. В Медицинском исследовательском центре им. В. А. Алмазова, сколько я себя помню, Эльза Галактионовна Ломайя была рядом с ним, всегда поддерживала и всегда эффективно работала. Андрей отдавал должное своим коллегам и сотрудникам, а также своим сторонникам. Он неоднократно упоминал, как важно для него было то, что профессоры Евгений Владимирович Шляхто и Александра Олеговна Конради открыты его предложениям и дружественно отвечают на его запросы. </p> <p style="text-align: justify;">Ключевыми моментами в профессиональной карьере Андрея Зарицкого стало успешное сотрудничество с ELN, в частности по хроническому миелоидному лейкозу, и с Онкологическим центром MD Anderson. Их общий симпозиум состоялся в июле 2017 года в Санкт-Петербурге. Для меня эта встреча была высшей точкой его карьеры. Андрею было 67 лет, он был успешен, известен на международном уровне и уважаем своими коллегами – карьера, достойная восхищения. Однако, когда он не посетил ни конференцию ASH в конце 2017 года, ни симпозиум ELN в Венеции в марте 2018 года, стало ясно, что что-то не так. Я знал, что он был заядлым курильщиком, но теперь у него развился рак легкого. </p> <p style="text-align: justify;">Несмотря на свою болезнь, он возобновил работу в 2018 году и продолжал всю свою деятельность без перерыва. Когда я приехал в Санкт-Петербург в 2018 году, он, как обычно, встретил меня в аэропорту, чтобы отвезти в Валдайский монастырь, памятник культуры на пути в Москву, рядом с истоком Волги. Он пытался преуменьшить значение своего рака, но его внешний вид выдавал истинное состояние. Будучи дисциплинированным, он продолжал руководить своей группой даже после того, как его положили в реанимацию в начале 2021 года, планируя, как обычно, 4-й Санкт-Петербургский медицинский инновационный форум в мае, включая руководство с больничной койки одним из заседаний. Он и Эльза Галактионовна договорились, что один из его молодых врачей встретит меня далеко за полночь в Пулково с приветственным плакатом на немецком языке. Я был глубоко тронут. Мы все еще надеялись, что ситуация изменится к лучшему. Он планировал вскоре покинуть больницу и напомнил мне о необходимости посетить Валаамский монастырь на Ладожском озере, о чем он неоднократно меня просил. </p> <p style="text-align: justify;">Когда я снова увидел его 20 сентября 2021 года, его состояние, к сожалению, ухудшилось. Он все еще надеялся, но знал, что его ждет. Он был доволен моей поездкой на Валаам, который я посетил накануне, и мы поговорили о симпозиуме ELN в Мангейме, запланированном на март 2022 года. Когда я сказал ему на прощание, что с нетерпением жду новой встречи с ним в Мангейме в марте следующего года или в другом месте, он сразу понял: под другим местом вы подразумеваете рай, не так ли? </p> <p style="text-align: justify;">С Андреем Зарицким российская гематология и Национальный медицинский исследовательский центр имени В. А. Алмазова потерял крупного ученого и организатора международных программ, Россия потеряла посла. Его наследие – международные совместные исследования в интересах пациентов, его института, Санкт-Петербурга и России. Они будут связаны с памятью о профессоре Андрее Юрьевиче Зарицком. </p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(19102) "

Я познакомился с А. Ю. Зарицким в 2004 или 2005 году, когда он настоял на том, чтобы и Центр им. В. А. Алмазова, и Первый Санкт-Петербургский государственный медицинский университет им. И. Павлова (ПСПбГМУ) присоединились к Европейской сети по изучению лейкозов (ELN). Он был единственным исследователем ELN, настаивавшим на заключении договора с обоими учреждениями – Национальным медицинским исследовательским Центром им. В. А. Алмазова и Первым Санкт-Петербургским государственным медицинским университетом им. И. П. Павлова, но его настойчивость способствовала сотрудничеству в дальнейшем между НИИ им. Р. М. Горбачевой и ELN. На меня произвели впечатление его обширные исследовательские интересы, его дух сотрудничества и его видение. По его приглашению я посетил Санкт-Петербург в сентябре 2006 года, положив начало 15-летнему плодотворному сотрудничеству в области лейкемии. Это была одна из его первых встреч с докладами иностранных участников. На встрече также присутствовали московские коллеги – профессор В. Г. Савченко и Е. Н. Паровичникова. В. Г. Савченко был моим старым другом, с которым я познакомился в Вильзеде около 1990 года, он безвременно ушел из жизни за 3 месяца до А. Ю. Зарицкого, в июле 2021 года.

В то время, в 2006 году, Центр имени В. А. Алмазова находился в стадии развития, и там велись работы, главным образом, в области кардиологии, болезней крови и эндокринологии, а А. Ю. Зарицкий был назначен руководителем секции гематологии. Андрей воспользовался случаем, чтобы с гордостью показать мне развивающийся Центр Алмазова и познакомить меня со своим руководителем профессором Евгением Владимировичем Шляхто. Несмотря на то, что все только начиналось, он видел открывающиеся возможности и имел план действий, согласованный с профессором Е. В. Шляхто. Он также воспользовался случаем, чтобы показать мне красоты Санкт-Петербурга. С помощью Эльзы Галактионовны Ломайя нам удалось посетить прекрасный Екатерининский дворец с реставрированной янтарной комнатой.

В последующие годы Центр им. В. А. Алмазова превратился в Национальный медицинский исследовательский центр, один из крупнейших в России. Огромное значение для успеха А. Ю. Зарицкого имело доверие и постоянная поддержка со стороны председателя Центра, профессора Евгения Владимировича Шляхто – известного кардиолога. В 2008 году Андрей Зарицкий был назначен директором нового Института гематологии Национального медицинского исследовательского центра имени В. А. Алмазова. В последующие годы он с большой энергией создавал новый институт с исследовательской базой и, что особенно важно, с отделением трансплантации. А. Ю. Зарицкий был его директором почти 14 лет. Доступ к международному регистру доноров в то время все еще оставался проблемой.

В том же году, снова в Вильзеде, я познакомился с профессором Борисом Афанасьевым и Алексеем Чухловиным. Приглашение от профессора Б. В. Афанасьева на II Симпозиум памяти Р. М. Горбачевой в Санкт-Петербурге положило начало сотрудничеству НИИ им. Горбачевой с European LeukemiaNet, чему способствовал уже существующий договор с ПСПбГМУ им. И. П. Павлова, заключенный по настоянию А. Ю. Зарицкого. С самого начала нашего сотрудничества я понял, какое значение профессор А. Ю. Зарицкий придавал национальным и международным связям. Четыре программы сотрудничества были особенно заметными и успешными. Усилия Андрея по ознакомлению своих международных партнеров с его и российским наследием иллюстрируют некоторые фотографии, за которые я благодарю Эльзу Галактионовну Ломайя и ее команду.

В частности, мы многие годы сотрудничали в рамках European LeukemiaNet, одним из первых участников которого был Медицинский Центр им. В. А. Алмазова, в результате чего в 2014 году А. Ю. Зарицкий был избран членом комиссии по разработке престижных рекомендаций ELN по лечению хронического миелоидного лейкоза. Помимо Андрея, вы можете видеть на фото Эльзу Галактионовну Ломайя, наших московских коллег Елену Николаевну Паровичникову, Анну Григорьевну Туркину, Сергея Михайловича Куликова, Екатерину Юрьевну Челышеву и многих других (Рис. 1). Эти рекомендации были опубликованы в 2020 году (Рис. 2). Кроме того, А. Ю. Зарицкий участвовал в проектах по стволовым клеткам с профессором Энтони Хо из Гейдельбергского университета при поддержке правительства Германии и Европейского Союза, принимал участие в деятельности Европейских исследований в области ХМЛ (EI-CML), и проведении 22-го заседания EI-CML в Санкт-Петербурге в 2014 году (Рис. 3). Наряду с этим, он руководил совместными проектами с профессорами Майклом Андреефф и Агопом Кантарджяном из Онкологического центра MD Anderson (Хьюстон, США). Эти результаты были представлены на совместном симпозиуме в Санкт-Петербурге в июле 2017 года. В 2011 году в знак признания его организационной деятельности и сотрудничества, Андрей Зарицкий получил награду ELN Merit Award за общеевропейскую интеграцию работ по исследованию лейкозов (Рис. 4).

Почти каждый год Андрей Зарицкий организовывал в Центре им. В. А. Алмазова национальные и международные встречи, посвященные новым разработкам в области лейкемии, стволовых клеток и трансплантации (Рис. 5). Члены его группы проводили время в европейских или американских центрах с целью обучения или сотрудничества. Кроме того, А. Ю. Зарицкий пропагандировал Центр Алмазова и свой институт, выступая с лекциями по всей России. Я имел удовольствие и честь сопровождать его на некоторых из этих мероприятий. Наши визиты в Самару и Иркутск были впечатляющими, демонстрируя с лучшей стороны российские передовые исследования и разработки. Так, в Самаре была неоценима помощь и участие профессора Игоря Леонидовича Давыдкина, старого друга профессора А. Ю. Зарицкого. При осуществлении этой деятельности Андрей показал себя типичным представителем Петербурга, стремясь выйти далеко за пределы России, но в интересах и для дальнейшего развития города и России в области гематологии. Он гордился Россией, но беспокоился, чтобы предпосылки для продолжения международных совместных исследований оставались стабильными.

За 16 лет, которые я имел удовольствие знать и сотрудничать с Андреем Зарицким, я понял, что ключ к его успеху – не только академический блеск. Важнее всего была его отзывчивость, открытость, надежность, скромность, но, тем не менее – решительность. Он знал, что для успешного и продолжительного сотрудничества необходимы доверие и дружба, что необходимо учитывать культурный фон участников сотрудничества, а также собственное наследие, которое должно быть понято другой стороной. Возможно, он научился этому способу общения с международными партнерами благодаря мудрости основателей группы европейских исследований в области хронического миелоидного лейкоза, в частности, легендарного итальянского гематолога Санте Тура, который умер всего за 5 дней до Андрея, однако – в возрасте 92 лет. По традиции Санте Тура, начиная с 1993 года, эта группа традиционно проводит свои двухдневные встречи по всей Европе, посвящая полдня знакомству с культурным наследием принимающей страны. Таким образом, зарубежные коллеги узнавали о России и по достоинству оценивали страну, так же как сам А. Ю. Зарицкий был открыт для других стран и культур. В эти успешные годы он не забывал о тех, кто работал с ним и помогал ему сделать все это возможным. В Медицинском исследовательском центре им. В. А. Алмазова, сколько я себя помню, Эльза Галактионовна Ломайя была рядом с ним, всегда поддерживала и всегда эффективно работала. Андрей отдавал должное своим коллегам и сотрудникам, а также своим сторонникам. Он неоднократно упоминал, как важно для него было то, что профессоры Евгений Владимирович Шляхто и Александра Олеговна Конради открыты его предложениям и дружественно отвечают на его запросы.

Ключевыми моментами в профессиональной карьере Андрея Зарицкого стало успешное сотрудничество с ELN, в частности по хроническому миелоидному лейкозу, и с Онкологическим центром MD Anderson. Их общий симпозиум состоялся в июле 2017 года в Санкт-Петербурге. Для меня эта встреча была высшей точкой его карьеры. Андрею было 67 лет, он был успешен, известен на международном уровне и уважаем своими коллегами – карьера, достойная восхищения. Однако, когда он не посетил ни конференцию ASH в конце 2017 года, ни симпозиум ELN в Венеции в марте 2018 года, стало ясно, что что-то не так. Я знал, что он был заядлым курильщиком, но теперь у него развился рак легкого.

Несмотря на свою болезнь, он возобновил работу в 2018 году и продолжал всю свою деятельность без перерыва. Когда я приехал в Санкт-Петербург в 2018 году, он, как обычно, встретил меня в аэропорту, чтобы отвезти в Валдайский монастырь, памятник культуры на пути в Москву, рядом с истоком Волги. Он пытался преуменьшить значение своего рака, но его внешний вид выдавал истинное состояние. Будучи дисциплинированным, он продолжал руководить своей группой даже после того, как его положили в реанимацию в начале 2021 года, планируя, как обычно, 4-й Санкт-Петербургский медицинский инновационный форум в мае, включая руководство с больничной койки одним из заседаний. Он и Эльза Галактионовна договорились, что один из его молодых врачей встретит меня далеко за полночь в Пулково с приветственным плакатом на немецком языке. Я был глубоко тронут. Мы все еще надеялись, что ситуация изменится к лучшему. Он планировал вскоре покинуть больницу и напомнил мне о необходимости посетить Валаамский монастырь на Ладожском озере, о чем он неоднократно меня просил.

Когда я снова увидел его 20 сентября 2021 года, его состояние, к сожалению, ухудшилось. Он все еще надеялся, но знал, что его ждет. Он был доволен моей поездкой на Валаам, который я посетил накануне, и мы поговорили о симпозиуме ELN в Мангейме, запланированном на март 2022 года. Когда я сказал ему на прощание, что с нетерпением жду новой встречи с ним в Мангейме в марте следующего года или в другом месте, он сразу понял: под другим местом вы подразумеваете рай, не так ли?

С Андреем Зарицким российская гематология и Национальный медицинский исследовательский центр имени В. А. Алмазова потерял крупного ученого и организатора международных программ, Россия потеряла посла. Его наследие – международные совместные исследования в интересах пациентов, его института, Санкт-Петербурга и России. Они будут связаны с памятью о профессоре Андрее Юрьевиче Зарицком.

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Я познакомился с А. Ю. Зарицким в 2004 или 2005 году, когда он настоял на том, чтобы и Центр им. В. А. Алмазова, и Первый Санкт-Петербургский государственный медицинский университет им. И. Павлова (ПСПбГМУ) присоединились к Европейской сети по изучению лейкозов (ELN). Он был единственным исследователем ELN, настаивавшим на заключении договора с обоими учреждениями – Национальным медицинским исследовательским Центром им. В. А. Алмазова и Первым Санкт-Петербургским государственным медицинским университетом им. И. П. Павлова, но его настойчивость способствовала сотрудничеству в дальнейшем между НИИ им. Р. М. Горбачевой и ELN. На меня произвели впечатление его обширные исследовательские интересы, его дух сотрудничества и его видение. По его приглашению я посетил Санкт-Петербург в сентябре 2006 года, положив начало 15-летнему плодотворному сотрудничеству в области лейкемии. Это была одна из его первых встреч с докладами иностранных участников. На встрече также присутствовали московские коллеги – профессор В. Г. Савченко и Е. Н. Паровичникова. В. Г. Савченко был моим старым другом, с которым я познакомился в Вильзеде около 1990 года, он безвременно ушел из жизни за 3 месяца до А. Ю. Зарицкого, в июле 2021 года.

В то время, в 2006 году, Центр имени В. А. Алмазова находился в стадии развития, и там велись работы, главным образом, в области кардиологии, болезней крови и эндокринологии, а А. Ю. Зарицкий был назначен руководителем секции гематологии. Андрей воспользовался случаем, чтобы с гордостью показать мне развивающийся Центр Алмазова и познакомить меня со своим руководителем профессором Евгением Владимировичем Шляхто. Несмотря на то, что все только начиналось, он видел открывающиеся возможности и имел план действий, согласованный с профессором Е. В. Шляхто. Он также воспользовался случаем, чтобы показать мне красоты Санкт-Петербурга. С помощью Эльзы Галактионовны Ломайя нам удалось посетить прекрасный Екатерининский дворец с реставрированной янтарной комнатой.

В последующие годы Центр им. В. А. Алмазова превратился в Национальный медицинский исследовательский центр, один из крупнейших в России. Огромное значение для успеха А. Ю. Зарицкого имело доверие и постоянная поддержка со стороны председателя Центра, профессора Евгения Владимировича Шляхто – известного кардиолога. В 2008 году Андрей Зарицкий был назначен директором нового Института гематологии Национального медицинского исследовательского центра имени В. А. Алмазова. В последующие годы он с большой энергией создавал новый институт с исследовательской базой и, что особенно важно, с отделением трансплантации. А. Ю. Зарицкий был его директором почти 14 лет. Доступ к международному регистру доноров в то время все еще оставался проблемой.

В том же году, снова в Вильзеде, я познакомился с профессором Борисом Афанасьевым и Алексеем Чухловиным. Приглашение от профессора Б. В. Афанасьева на II Симпозиум памяти Р. М. Горбачевой в Санкт-Петербурге положило начало сотрудничеству НИИ им. Горбачевой с European LeukemiaNet, чему способствовал уже существующий договор с ПСПбГМУ им. И. П. Павлова, заключенный по настоянию А. Ю. Зарицкого. С самого начала нашего сотрудничества я понял, какое значение профессор А. Ю. Зарицкий придавал национальным и международным связям. Четыре программы сотрудничества были особенно заметными и успешными. Усилия Андрея по ознакомлению своих международных партнеров с его и российским наследием иллюстрируют некоторые фотографии, за которые я благодарю Эльзу Галактионовну Ломайя и ее команду.

В частности, мы многие годы сотрудничали в рамках European LeukemiaNet, одним из первых участников которого был Медицинский Центр им. В. А. Алмазова, в результате чего в 2014 году А. Ю. Зарицкий был избран членом комиссии по разработке престижных рекомендаций ELN по лечению хронического миелоидного лейкоза. Помимо Андрея, вы можете видеть на фото Эльзу Галактионовну Ломайя, наших московских коллег Елену Николаевну Паровичникову, Анну Григорьевну Туркину, Сергея Михайловича Куликова, Екатерину Юрьевну Челышеву и многих других (Рис. 1). Эти рекомендации были опубликованы в 2020 году (Рис. 2). Кроме того, А. Ю. Зарицкий участвовал в проектах по стволовым клеткам с профессором Энтони Хо из Гейдельбергского университета при поддержке правительства Германии и Европейского Союза, принимал участие в деятельности Европейских исследований в области ХМЛ (EI-CML), и проведении 22-го заседания EI-CML в Санкт-Петербурге в 2014 году (Рис. 3). Наряду с этим, он руководил совместными проектами с профессорами Майклом Андреефф и Агопом Кантарджяном из Онкологического центра MD Anderson (Хьюстон, США). Эти результаты были представлены на совместном симпозиуме в Санкт-Петербурге в июле 2017 года. В 2011 году в знак признания его организационной деятельности и сотрудничества, Андрей Зарицкий получил награду ELN Merit Award за общеевропейскую интеграцию работ по исследованию лейкозов (Рис. 4).

Почти каждый год Андрей Зарицкий организовывал в Центре им. В. А. Алмазова национальные и международные встречи, посвященные новым разработкам в области лейкемии, стволовых клеток и трансплантации (Рис. 5). Члены его группы проводили время в европейских или американских центрах с целью обучения или сотрудничества. Кроме того, А. Ю. Зарицкий пропагандировал Центр Алмазова и свой институт, выступая с лекциями по всей России. Я имел удовольствие и честь сопровождать его на некоторых из этих мероприятий. Наши визиты в Самару и Иркутск были впечатляющими, демонстрируя с лучшей стороны российские передовые исследования и разработки. Так, в Самаре была неоценима помощь и участие профессора Игоря Леонидовича Давыдкина, старого друга профессора А. Ю. Зарицкого. При осуществлении этой деятельности Андрей показал себя типичным представителем Петербурга, стремясь выйти далеко за пределы России, но в интересах и для дальнейшего развития города и России в области гематологии. Он гордился Россией, но беспокоился, чтобы предпосылки для продолжения международных совместных исследований оставались стабильными.

За 16 лет, которые я имел удовольствие знать и сотрудничать с Андреем Зарицким, я понял, что ключ к его успеху – не только академический блеск. Важнее всего была его отзывчивость, открытость, надежность, скромность, но, тем не менее – решительность. Он знал, что для успешного и продолжительного сотрудничества необходимы доверие и дружба, что необходимо учитывать культурный фон участников сотрудничества, а также собственное наследие, которое должно быть понято другой стороной. Возможно, он научился этому способу общения с международными партнерами благодаря мудрости основателей группы европейских исследований в области хронического миелоидного лейкоза, в частности, легендарного итальянского гематолога Санте Тура, который умер всего за 5 дней до Андрея, однако – в возрасте 92 лет. По традиции Санте Тура, начиная с 1993 года, эта группа традиционно проводит свои двухдневные встречи по всей Европе, посвящая полдня знакомству с культурным наследием принимающей страны. Таким образом, зарубежные коллеги узнавали о России и по достоинству оценивали страну, так же как сам А. Ю. Зарицкий был открыт для других стран и культур. В эти успешные годы он не забывал о тех, кто работал с ним и помогал ему сделать все это возможным. В Медицинском исследовательском центре им. В. А. Алмазова, сколько я себя помню, Эльза Галактионовна Ломайя была рядом с ним, всегда поддерживала и всегда эффективно работала. Андрей отдавал должное своим коллегам и сотрудникам, а также своим сторонникам. Он неоднократно упоминал, как важно для него было то, что профессоры Евгений Владимирович Шляхто и Александра Олеговна Конради открыты его предложениям и дружественно отвечают на его запросы.

Ключевыми моментами в профессиональной карьере Андрея Зарицкого стало успешное сотрудничество с ELN, в частности по хроническому миелоидному лейкозу, и с Онкологическим центром MD Anderson. Их общий симпозиум состоялся в июле 2017 года в Санкт-Петербурге. Для меня эта встреча была высшей точкой его карьеры. Андрею было 67 лет, он был успешен, известен на международном уровне и уважаем своими коллегами – карьера, достойная восхищения. Однако, когда он не посетил ни конференцию ASH в конце 2017 года, ни симпозиум ELN в Венеции в марте 2018 года, стало ясно, что что-то не так. Я знал, что он был заядлым курильщиком, но теперь у него развился рак легкого.

Несмотря на свою болезнь, он возобновил работу в 2018 году и продолжал всю свою деятельность без перерыва. Когда я приехал в Санкт-Петербург в 2018 году, он, как обычно, встретил меня в аэропорту, чтобы отвезти в Валдайский монастырь, памятник культуры на пути в Москву, рядом с истоком Волги. Он пытался преуменьшить значение своего рака, но его внешний вид выдавал истинное состояние. Будучи дисциплинированным, он продолжал руководить своей группой даже после того, как его положили в реанимацию в начале 2021 года, планируя, как обычно, 4-й Санкт-Петербургский медицинский инновационный форум в мае, включая руководство с больничной койки одним из заседаний. Он и Эльза Галактионовна договорились, что один из его молодых врачей встретит меня далеко за полночь в Пулково с приветственным плакатом на немецком языке. Я был глубоко тронут. Мы все еще надеялись, что ситуация изменится к лучшему. Он планировал вскоре покинуть больницу и напомнил мне о необходимости посетить Валаамский монастырь на Ладожском озере, о чем он неоднократно меня просил.

Когда я снова увидел его 20 сентября 2021 года, его состояние, к сожалению, ухудшилось. Он все еще надеялся, но знал, что его ждет. Он был доволен моей поездкой на Валаам, который я посетил накануне, и мы поговорили о симпозиуме ELN в Мангейме, запланированном на март 2022 года. Когда я сказал ему на прощание, что с нетерпением жду новой встречи с ним в Мангейме в марте следующего года или в другом месте, он сразу понял: под другим местом вы подразумеваете рай, не так ли?

С Андреем Зарицким российская гематология и Национальный медицинский исследовательский центр имени В. А. Алмазова потерял крупного ученого и организатора международных программ, Россия потеряла посла. Его наследие – международные совместные исследования в интересах пациентов, его института, Санкт-Петербурга и России. Они будут связаны с памятью о профессоре Андрее Юрьевиче Зарицком.

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Том 11, Номер 3-4
20.12.2022
Том 11, Номер 3-4
Главный редактор
Кулагин А. Д. (Санкт-Петербург, Россия)
Со-редакторы
Вагемакер Г. (Роттердам, Нидерланды)
Цандер А. Р. (Гамбург, Германия)
Заместитель главного редактора
Фезе Б. (Гамбург, Германия)
Ответственный редактор
Чухловин А. Б. (Санкт-Петербург, Россия)
Редакционная коллегия
Алейникова О. В. (Минск, Беларусь)
Борсет М. (Трондхейм, Норвегия)
Галибин О. В. (Санкт-Петербург, Россия)
Гэйл Р. П. (Лос-Анжелес, США)
Зубаровская Л. С. (Санкт-Петербург, Россия)
Климко Н. Н. (Санкт-Петербург, Россия)
Кольб Х. (Мюнхен, Германия)
Крёгер Н. (Гамбург, Германия)
Ланге К. (Гамбург, Германия)
Мамаев Н. Н. (Санкт-Петербург, Россия)
Михайлова Н. Б. (Санкт-Петербург, Россия)
Моисеев И. С. (Санкт-Петербург, Россия)
Наглер А. (Тель-Авив, Израиль)
Немков А. С. (Санкт-Петербург, Россия)
Парамонов И. В. (Киров, Россия)
Румянцев А. Г. (Москва, Россия)
Смирнов А. В. (Санкт-Петербург, Россия)
Усс А. Л. (Минск, Беларусь)
Фиббе В. (Лейден, Нидерланды)
Хельманн Р. (Маннгейм, Германия)
Хельтцер Д. (Франкфурт-на-Майне, Германия)
Чечеткин А. В. (Санкт-Петербург, Россия)
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Применение радиомики в дифференциальной диагностике амелобластом и одонтогенных кист челюстей: часть 2

Анна В. Лысенко1, Андрей И. Яременко2, Анна А. Зубарева3, Александр В. Ширшин4, Александр И. Любимов5, Елизавета А. Иванова1

Подкожное введение доксорубицина в системах доставки, состоящих из СаСО3 ватеритов, покрытых декстран сульфатом

Наталия Н. Сударева1,2, Ольга М. Суворова1, Константин А. Колбе1, Дмитрий Н. Суслов3, Олег В. Галибин2, Александр Д. Вилесов1, Галина Ю. Юкина2, Елена Г. Сухорукова2

Некролог

Мнение эксперта

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Роберт Питер Гэйл

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Имперский Колледж науки, технологии и медицины, Лондон, Великобритания; Университетский онкологический центр им. Сун-Ятсена, Гуанчжоу, Китай

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В статье затрагивается вопрос: нужно ли нам пересматривать применение трансплантации гемопоэтических клеток в качестве адекватной терапии у некоторых пациентов с хроническим миелоидным лейкозом в хронической фазе? Ответ может быть положительным для некоторых больных, которые не отвечают на лечение ингибиторами тирозинкиназы или вряд ли достигнут ремиссии без дальнейшей терапии.

Ключевые слова

Хронический миелоидный лейкоз, иматиниб, трансплантация гемопоэтических стволовых клеток, стратегия лечения.

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Robert Peter Gale

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Imperial College of Science, Technology and Medicine, London, UK; Sun Yat-sen Univ. Cancer Centre, Guangzhou, China


Correspondence:
Robert Peter Gale, MD, PhD DSc(hc), FACP, FRCP, FRSPI(hon), FRSM, Centre for Haematology Research, Department of Immunology and Inflammation, Imperial College of Science, Technology and Medicine, London, UK SW7 2BX


Citation: Robert Peter Gale. Time to reconsider haematopoietic cell transplants in chronic myeloid leukaemia? Cell Ther Transplant 2022; 11(3-4): 6-9.

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The article concerns whether we need to reconsider whether haematopoietic cell transplants are an appropriate therapy in some persons with chronic phase chronic myeloid leukaemia. The answer may be yes in some persons failing tyrosine kinase-inhibitor therapy or unlikely to achieve therapy-free remission. 

Keywords

Сhronic myeloid leukemia, imatinib, hematopoietic stem cell transplantation, treatment strategy.

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К вопросу о роли трансплантации гемопоэтических клеток при хроническом миелоидном лейкозе

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Роберт Питер Гэйл

Имперский Колледж науки, технологии и медицины, Лондон, Великобритания; Университетский онкологический центр им. Сун-Ятсена, Гуанчжоу, Китай

В статье затрагивается вопрос: нужно ли нам пересматривать применение трансплантации гемопоэтических клеток в качестве адекватной терапии у некоторых пациентов с хроническим миелоидным лейкозом в хронической фазе? Ответ может быть положительным для некоторых больных, которые не отвечают на лечение ингибиторами тирозинкиназы или вряд ли достигнут ремиссии без дальнейшей терапии.

Ключевые слова

Хронический миелоидный лейкоз, иматиниб, трансплантация гемопоэтических стволовых клеток, стратегия лечения.

Обзорные статьи

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	Алексей Ю. Полушин, Александр А. Цынченко, Юрий Р. Залялов, Евгения И. Лопатина, Наталья А. Тотолян, Александр Д. Кулагин
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Алексей Ю. Полушин, Александр А. Цынченко, Юрий Р. Залялов, Евгения И. Лопатина, Наталья А. Тотолян, Александр Д. Кулагин

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Первый Санкт-Петербургский государственный медицинский университет им. акад. И. П. Павлова, Санкт-Петербург, Россия

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Высокодозная иммуносупрессивная терапия с аутологичной трансплантацией гемопоэтических стволовых клеток (ВИСТ-АТГСК) является перспективным и эффективным методом лечения аутоиммунных заболеваний, в том числе, рассеянного склероза. За последние 20 лет значимо уменьшена частота и выраженность нежелательных явлений терапии за счет накопления опыта трансплантационных центров, изменения принципов отбора пациентов и снижения интенсивности режимов кондиционирования. Однако терапевтические протоколы средней интенсивности также могут приводить к нежелательным последствиям. В работе проанализированы данные литературы и собственный опыт по ранним и отсроченным осложнениям ВИСТ-АТГСК. Также представлен профиль вероятного кандидата на ВИСТ-АТГСК исходя из характеристик пациента и течения заболевания. Сформулированы виды ВИСТ-АТГСК исходя из целей и ожиданий от проводимого метода лечения.

Ключевые слова

Рассеянный склероз, высокодозная иммуносупрессивная терапия, гемопоэтические стволовые клетки, аутологичная трансплантация, побочные эффекты, ранние осложнения, отсроченные осложнения, показания к трансплантации.

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Alexey Yu. Polushin, Alexander A. Tsynchenko, Yuri R. Zalyalov, Evgenia I. Lopatina, Natalia A. Totolyan, Alexander D. Kulagin

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Pavlov University, St. Petersburg, Russia


Correspondence:
Dr. Alexey Yu. Polushin, First St. Petersburg State I. Pavlov Medical University, 6-8 L.Tolstoy St, 197022, St. Petersburg, Russia
Phone: +7 (911) 816-75-59
E-mail: alexpolushin@yandex.ru


Citation: Polushin AY, Tsynchenko AA, Zalyalov YR et al. High-dose immunosuppressive therapy with autologous hematopoietic stem cell transplantation in multiple sclerosis: side effects and the tools of their reduction. Cell Ther Transplant 2022; 11(3-4): 25-35.

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High-dose immunosuppressive therapy with autologous hematopoietic stem cell transplantation (HDIT-AHSCT) is a promising and effective method of treatment of autoimmune diseases, including multiple sclerosis. Over the past 20 years, the frequency and severity of side effects of therapy have been significantly reduced due to the accumulation of experience of transplant centers, changing principles of patient selection and decreased intensity of conditioning regimens. However, the medium-intensity therapeutic protocols may also be accompanied by complications. We have analyzed the literature data and our own experience on early and late side effects of HDIT-AHSCT. The profile of an appropriate schedule of HDIT-AHSCT is also presented, as determined by characteristics of the patients and the clinical course of multiple sclerosis. The types of HDIT-AHSCT are formulated, as based on the goals and expectations of the treatment approach.

Keywords

Multiple sclerosis, high-dose immunosuppressive therapy, hematopoietic stem cells, autologous transplantation, side effects, early complications, late complications, indications for transplantation.

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Высокодозная иммуносупрессивная терапия с аутологичной трансплантацией гемопоэтических стволовых клеток при рассеянном склерозе: побочные эффекты и способы их ослабления

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Алексей Ю. Полушин, Александр А. Цынченко, Юрий Р. Залялов, Евгения И. Лопатина, Наталья А. Тотолян, Александр Д. Кулагин

Первый Санкт-Петербургский государственный медицинский университет им. акад. И. П. Павлова, Санкт-Петербург, Россия

Высокодозная иммуносупрессивная терапия с аутологичной трансплантацией гемопоэтических стволовых клеток (ВИСТ-АТГСК) является перспективным и эффективным методом лечения аутоиммунных заболеваний, в том числе, рассеянного склероза. За последние 20 лет значимо уменьшена частота и выраженность нежелательных явлений терапии за счет накопления опыта трансплантационных центров, изменения принципов отбора пациентов и снижения интенсивности режимов кондиционирования. Однако терапевтические протоколы средней интенсивности также могут приводить к нежелательным последствиям. В работе проанализированы данные литературы и собственный опыт по ранним и отсроченным осложнениям ВИСТ-АТГСК. Также представлен профиль вероятного кандидата на ВИСТ-АТГСК исходя из характеристик пациента и течения заболевания. Сформулированы виды ВИСТ-АТГСК исходя из целей и ожиданий от проводимого метода лечения.

Ключевые слова

Рассеянный склероз, высокодозная иммуносупрессивная терапия, гемопоэтические стволовые клетки, аутологичная трансплантация, побочные эффекты, ранние осложнения, отсроченные осложнения, показания к трансплантации.

Обзорные статьи

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Али А. Салем1, Халида К. Аль-Келаби2

[TYPE] => HTML ) [~DESCRIPTION] => [~NAME] => Авторы [~DEFAULT_VALUE] => Array ( [TEXT] => [TYPE] => HTML ) ) [ORGANIZATION_RU] => Array ( [ID] => 26 [TIMESTAMP_X] => 2015-09-02 18:01:20 [IBLOCK_ID] => 2 [NAME] => Организации [ACTIVE] => Y [SORT] => 500 [CODE] => ORGANIZATION_RU [DEFAULT_VALUE] => Array ( [TEXT] => [TYPE] => HTML ) [PROPERTY_TYPE] => S [ROW_COUNT] => 1 [COL_COUNT] => 30 [LIST_TYPE] => L [MULTIPLE] => N [XML_ID] => 26 [FILE_TYPE] => [MULTIPLE_CNT] => 5 [TMP_ID] => [LINK_IBLOCK_ID] => 0 [WITH_DESCRIPTION] => N [SEARCHABLE] => N [FILTRABLE] => N [IS_REQUIRED] => N [VERSION] => 1 [USER_TYPE] => HTML [USER_TYPE_SETTINGS] => Array ( [height] => 200 ) [HINT] => [PROPERTY_VALUE_ID] => 29491 [VALUE] => Array ( [TEXT] => <p><sup>1</sup> Лаборатория медицинских технологий и патологического анализа, Госпиталь Аль-Хаким, Наджаф, Ирак<br> <sup>2</sup> Департамент клинических и лабораторных исследований, Факультет фармации, Университет Куфа, Наджаф, Ирак</p> [TYPE] => HTML ) [DESCRIPTION] => [VALUE_ENUM] => [VALUE_XML_ID] => [VALUE_SORT] => [~VALUE] => Array ( [TEXT] =>

1 Лаборатория медицинских технологий и патологического анализа, Госпиталь Аль-Хаким, Наджаф, Ирак
2 Департамент клинических и лабораторных исследований, Факультет фармации, Университет Куфа, Наджаф, Ирак

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Рак является заболеванием, обусловленным в основном, генетическими и эпигенетическими нарушениями. Эти заболевания – одна из ведущих причин смерти в мире и представляет собой крупную социальную и экономическую проблему. Согласно статистическим данным, более 10 миллионов человек погибают от злокачественных опухолей, и ожидается 50%-ное повышение частоты их возникновения в следующие 10 лет, приводя к 15 миллионам смертельных исходов. Единичные или множественные генные мутации, хромосомные аберрации могут вызывать раковые заболевания. Хотя для лечения рака используют многочисленные варианты лечения, они все же недостаточны против этих заболеваний. Поэтому изучается ряд новых стратегий ранней терапии злокачественных опухолей. Одной из наиболее современных и потенциально эффективных технологий, применяемых в последние годы для генных модификаций и онкотерапии является система Clustered Regularly Interspaced Short Palindromic Repeat (CRISPR)- ассоциированного протеина-9 (Cas9) – уникальная технология геномной инженерии, основанная на применении уникальной РНК-содержащей эндонуклеазы. Исходно, CRISPR/Cas9 возникла из противовирусного механизма защиты бактерий от вирусных инфекций. В настоящее время этот подход оказался полезным в лечении рака и генном редактировании. В целом, это сообщение является обзором этой ключевой технологии и ее компонентов. В частности, в этой работе мы касаемся возможных перспективных приложений и нынешних прорывов в технологии CRISPR/Cas9 для лечения рака, а также тех проблем, которые могут возникнуть при клинических исследованиях. В этом отношении мы намерены сделать вклад в оптимизацию работ по CRISPR/Cas9, а также сделать акцент на возможные будущие пути развития этой технологии.

Ключевые слова

CRISP, Cas9, современная технология, рак, терапия.

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Ali A. Saleem1, Khalida K. Al-Kelaby2

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1 Medical Laboratory Techniques, Pathological Analysis, Al-Hakim Hospital, Najaf, Iraq, 54001
2 Department of Clinical and Laboratory Sciences, Faculty of pharmacy, Kufa University, Najaf, Iraq, 54001


Correspondence:
Ali A. Saleem, Medical Laboratory Techniques, Pathological Analysis, Al-Hakim Hospital, Najaf, Iraq, 54001
Phone: (+964) 7711667130
E-mail: aliadil41994@gmail.com


Citation: Saleem AA, Al-Kelaby KK. A Review on CRISPR/Cas9 as a Novel Technique for Cancer Therapy. Cell Ther Transplant 2022; 11(3-4): 10-24.

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Cancer is a disorder that, basically, occurs as a result of genetic and epigenetic abnormalities. It's one of the leading causes of death in the globe, and it's still a major social and economic problem. According to statistics, over 10 million people die with malignancies, and cancer rates are expected to increase by 50% in the next ten years, culminating in approximately 15 million deaths. Single or multiple gene mutations, chromosomal abnormalities may cause cancer. Although numerous treatment options are used to treat cancer, they are still insufficient against malignant diseases. Therefore, a variety of novel strategies for early cancer therapy are examined. One of the most recent and potentially effective technologies that has been used in last years for genetic modification and cancer therapy is Clustered Regularly Interspaced Short Palindromic Repeat (CRISPR)-associated protein-9 (Cas9), a unique RNA domain-containing endonuclease-based genome engineering technology. In simple words, CRISPR/Cas9 has been derived from a bacterial defensive mechanism against viral infection. Recently, this approach has proved its usefulness in cancer therapy and gene editing. In general, this report presents a review of this key technology and its components. Specifically, in this work, we address the probable prospective uses and recent breakthroughs of CRISPR/Cas9 technology in cancer treatment, as well as the problems that can be encountered during clinical investigations. In this regard, we intend to contribute to optimizing work on CRISPR/Cas9 as well as to focus on the probable future paths of this technology.

Keywords

CRISP, Cas9, modern technology, сancer, therapy.

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CRISPR/Cas9 как новая технология терапии рака

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Али А. Салем1, Халида К. Аль-Келаби2

1 Лаборатория медицинских технологий и патологического анализа, Госпиталь Аль-Хаким, Наджаф, Ирак
2 Департамент клинических и лабораторных исследований, Факультет фармации, Университет Куфа, Наджаф, Ирак

Рак является заболеванием, обусловленным в основном, генетическими и эпигенетическими нарушениями. Эти заболевания – одна из ведущих причин смерти в мире и представляет собой крупную социальную и экономическую проблему. Согласно статистическим данным, более 10 миллионов человек погибают от злокачественных опухолей, и ожидается 50%-ное повышение частоты их возникновения в следующие 10 лет, приводя к 15 миллионам смертельных исходов. Единичные или множественные генные мутации, хромосомные аберрации могут вызывать раковые заболевания. Хотя для лечения рака используют многочисленные варианты лечения, они все же недостаточны против этих заболеваний. Поэтому изучается ряд новых стратегий ранней терапии злокачественных опухолей. Одной из наиболее современных и потенциально эффективных технологий, применяемых в последние годы для генных модификаций и онкотерапии является система Clustered Regularly Interspaced Short Palindromic Repeat (CRISPR)- ассоциированного протеина-9 (Cas9) – уникальная технология геномной инженерии, основанная на применении уникальной РНК-содержащей эндонуклеазы. Исходно, CRISPR/Cas9 возникла из противовирусного механизма защиты бактерий от вирусных инфекций. В настоящее время этот подход оказался полезным в лечении рака и генном редактировании. В целом, это сообщение является обзором этой ключевой технологии и ее компонентов. В частности, в этой работе мы касаемся возможных перспективных приложений и нынешних прорывов в технологии CRISPR/Cas9 для лечения рака, а также тех проблем, которые могут возникнуть при клинических исследованиях. В этом отношении мы намерены сделать вклад в оптимизацию работ по CRISPR/Cas9, а также сделать акцент на возможные будущие пути развития этой технологии.

Ключевые слова

CRISP, Cas9, современная технология, рак, терапия.

Клинические работы

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Ксения С. Афанасьева, Ольга В. Пирогова, Евгений А. Бакин, Анна Г. Смирнова, Елена В. Морозова, Юлия Ю. Власова, Ильдар М. Бархатов, Татьяна Л. Гиндина, Иван С. Моисеев, Сергей Н. Бондаренко

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НИИ детской онкологии, гематологии и трансплантологии им. Р. М. Горбачевой, Первый Санкт-Петербургский государственный медицинский университет им. акад. И. П. Павлова, Санкт-Петербург, Россия

[TYPE] => HTML ) [~DESCRIPTION] => [~NAME] => Организации [~DEFAULT_VALUE] => Array ( [TEXT] => [TYPE] => HTML ) ) [SUMMARY_RU] => Array ( [ID] => 27 [TIMESTAMP_X] => 2015-09-02 18:01:20 [IBLOCK_ID] => 2 [NAME] => Описание/Резюме [ACTIVE] => Y [SORT] => 500 [CODE] => SUMMARY_RU [DEFAULT_VALUE] => Array ( [TEXT] => [TYPE] => HTML ) [PROPERTY_TYPE] => S [ROW_COUNT] => 1 [COL_COUNT] => 30 [LIST_TYPE] => L [MULTIPLE] => N [XML_ID] => 27 [FILE_TYPE] => [MULTIPLE_CNT] => 5 [TMP_ID] => [LINK_IBLOCK_ID] => 0 [WITH_DESCRIPTION] => N [SEARCHABLE] => N [FILTRABLE] => N [IS_REQUIRED] => N [VERSION] => 1 [USER_TYPE] => HTML [USER_TYPE_SETTINGS] => Array ( [height] => 200 ) [HINT] => [PROPERTY_VALUE_ID] => 29528 [VALUE] => Array ( [TEXT] => <p style="text-align: justify;">Роль профилактического назначения ИТК (ингибиторов тирозинкиназ) после аллогенной трансплантации гемопоэтических стволовых клеток (алло-ТГСК) остается не вполне определенной. Мы провели ретроспективный анализ 106 случаев алло-ТГСК у взрослых пациентов, которым трансплантация была выполнена от полностью совместимого родственного донора (26%), полностью или частично совместимого неродственного донора (60%) и гаплоидентичного донора (14%) в первой полной ремиссии (59%), второй полной ремиссии (14%) или в продвинутых стадиях заболевания (27%). Из них 60 пациентам (57%) проводилась профилактика посттрансплантационного рецидива ингибиторами тирозинкиназ 1 или 2 поколения. В многофакторном анализе безрецидивной выживаемости следующие факторы были связаны со снижением риска рецидива или смерти: алло-ТГСК, выполненная после 2012 года (ОР=0,46, 95% ДИ 0,26-0,83, р=0,009), любой статус МОБ перед алло-ТГСК на фоне посттрансплантационной профилактики ИТК. Алло-ТГСК от гаплоидентичного донора повышала риск рецидива или смерти (ОР=2,71, 95% ДИ 1,20-6,13, р=0,016). Нам не удалось продемонстрировать значимость хронической РТПХ при проведении лэндмарк анализа на день+180 и день+270 на имеющихся данных (ОР=0,43, 95% ДИ 0,13–1,45, р=0,17 и ОР=0,5, 95% ДИ 0,19-1,32, р=0,161, соответственно) на фоне профилактической терапии ИТК. Настоящее исследование, проведенное на относительно большой группе взрослых пациентов с Ph-позитивным ОЛЛ, демонстрирует, что ИТК являются важным компонентом профилактики посттрансплантационного рецидива. Для того, чтобы сформулировать строгие клинические рекомендации для данной когорты, необходима большая группа пациентов. </p> <h2>Ключевые слова</h2> <p style="text-align: justify;">Острый лимфобластный лейкоз, Ph-позитивный, BCR-ABL1, ингибиторы тирозинкиназ, аллогенная трансплантация гемопоэтических стволовых клеток, рецидив, минимальная остаточная болезнь, хроническая реакция «трансплантат-против-хозяина».</p> [TYPE] => HTML ) [DESCRIPTION] => [VALUE_ENUM] => [VALUE_XML_ID] => [VALUE_SORT] => [~VALUE] => Array ( [TEXT] =>

Роль профилактического назначения ИТК (ингибиторов тирозинкиназ) после аллогенной трансплантации гемопоэтических стволовых клеток (алло-ТГСК) остается не вполне определенной. Мы провели ретроспективный анализ 106 случаев алло-ТГСК у взрослых пациентов, которым трансплантация была выполнена от полностью совместимого родственного донора (26%), полностью или частично совместимого неродственного донора (60%) и гаплоидентичного донора (14%) в первой полной ремиссии (59%), второй полной ремиссии (14%) или в продвинутых стадиях заболевания (27%). Из них 60 пациентам (57%) проводилась профилактика посттрансплантационного рецидива ингибиторами тирозинкиназ 1 или 2 поколения. В многофакторном анализе безрецидивной выживаемости следующие факторы были связаны со снижением риска рецидива или смерти: алло-ТГСК, выполненная после 2012 года (ОР=0,46, 95% ДИ 0,26-0,83, р=0,009), любой статус МОБ перед алло-ТГСК на фоне посттрансплантационной профилактики ИТК. Алло-ТГСК от гаплоидентичного донора повышала риск рецидива или смерти (ОР=2,71, 95% ДИ 1,20-6,13, р=0,016). Нам не удалось продемонстрировать значимость хронической РТПХ при проведении лэндмарк анализа на день+180 и день+270 на имеющихся данных (ОР=0,43, 95% ДИ 0,13–1,45, р=0,17 и ОР=0,5, 95% ДИ 0,19-1,32, р=0,161, соответственно) на фоне профилактической терапии ИТК. Настоящее исследование, проведенное на относительно большой группе взрослых пациентов с Ph-позитивным ОЛЛ, демонстрирует, что ИТК являются важным компонентом профилактики посттрансплантационного рецидива. Для того, чтобы сформулировать строгие клинические рекомендации для данной когорты, необходима большая группа пациентов.

Ключевые слова

Острый лимфобластный лейкоз, Ph-позитивный, BCR-ABL1, ингибиторы тирозинкиназ, аллогенная трансплантация гемопоэтических стволовых клеток, рецидив, минимальная остаточная болезнь, хроническая реакция «трансплантат-против-хозяина».

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Kseniia S. Afanaseva, Olga V. Pirogova, Evgeny A. Bakin, Anna G. Smirnova, Elena V. Morozova, Yulia Yu.Vlasova, Ildar M. Barkhatov, Tatiana L. Gindina, Ivan S. Moiseev, Sergey N. Bondarenko

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RM Gorbacheva Research Institute of Pediatric Oncology, Hematology and Transplantology, Pavlov University, St. Petersburg, Russia


Correspondence:
Dr. Kseniia S. Afanaseva, RM Gorbacheva Research Institute of Pediatric Oncology, Hematology and Transpantology, Pavlov University, 6-8 L.Tolstoy St, 197022, St. Petersburg, Russia
Phone: +7 (921) 185-80-48
E-mail: afanasevaksenya11@gmail.com


Citation: Afanaseva KS, Pirogova OV, Bakin EA et al. Tyrosine kinase inhibitors: prophylaxis after allogeneic hematopoietic stem cell transplantation in adults with Philadelphia chromosome‐positive acute lymphoblastic leukemia. Cell Ther Transplant 2022; 11(3-4): 45-59.

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The role of prophylactic TKIs after allogeneic stem cell transplantation in Ph-positive acute lymphoblastic leukemia (ALL) remains controversial. We performed a retrospective study in 106 adult patients subjected to allogeneic hematopoietic stem cell transplantation (allo-HSCT) from matched related donors (MRD, 26%), matched unrelated donors (MUD/MMUD, 60%), and haploidentical donors (14%) in complete remission (CR1, 59%), CR2 (14%), and advanced disease (27%). Among them, 60 (57%), received 1st- or 2nd-generation TKIs as prophylaxis after allo-HSCT. In multivariate analysis of RFS, the following factors were associated with reduced risk of relapse or death: allo-HSCT after 2012 (HR=0.46, 95%CI 0.26-0.83, p=0.009), any MRD status of the disease before allo-HSCT except active disease with relatively similar HR in the context of post-transplant TKI prophylaxis. Allo-HSCT from haploidentical donor was associated with increased risk of relapse or death (HR=2.71, 95% CI 1.20-6.13 p=0.016). We were unable to demonstrate the significance of chronic GvHD when performing landmark analysis on day+180 and day+270, as based on available data (HR=0.43, 95% CI 0.13-1.45, p=0.17 and HR=0.5, 95% CI 0.19-1.32; p=0.161, respectively), under the conditions of maintaining TKI therapy after allo-HSCT. This relatively large study in unfavorable group of patients confirms an importance of TKIs prophylaxis for adult patients with Ph-positive ALL after allo-HSCT. A larger group of patients is required to formulate strong clinical recommendations in this cohort.

Keywords

Acute lymphoblastic leukemia, Ph-positive, BCR-ABL1, tyrosine kinase inhibitor, allogeneic hematopoietic stem cell transplantation, relapse, minimal residual disease, chronic GvHD.

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Ингибиторы тирозинкиназ: профилактика рецидива после аллогенной трансплантации гемопоэтических стволовых клеток у взрослых пациентов с Ph-позитивным острым лимфобластным лейкозом

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Ксения С. Афанасьева, Ольга В. Пирогова, Евгений А. Бакин, Анна Г. Смирнова, Елена В. Морозова, Юлия Ю. Власова, Ильдар М. Бархатов, Татьяна Л. Гиндина, Иван С. Моисеев, Сергей Н. Бондаренко

НИИ детской онкологии, гематологии и трансплантологии им. Р. М. Горбачевой, Первый Санкт-Петербургский государственный медицинский университет им. акад. И. П. Павлова, Санкт-Петербург, Россия

Роль профилактического назначения ИТК (ингибиторов тирозинкиназ) после аллогенной трансплантации гемопоэтических стволовых клеток (алло-ТГСК) остается не вполне определенной. Мы провели ретроспективный анализ 106 случаев алло-ТГСК у взрослых пациентов, которым трансплантация была выполнена от полностью совместимого родственного донора (26%), полностью или частично совместимого неродственного донора (60%) и гаплоидентичного донора (14%) в первой полной ремиссии (59%), второй полной ремиссии (14%) или в продвинутых стадиях заболевания (27%). Из них 60 пациентам (57%) проводилась профилактика посттрансплантационного рецидива ингибиторами тирозинкиназ 1 или 2 поколения. В многофакторном анализе безрецидивной выживаемости следующие факторы были связаны со снижением риска рецидива или смерти: алло-ТГСК, выполненная после 2012 года (ОР=0,46, 95% ДИ 0,26-0,83, р=0,009), любой статус МОБ перед алло-ТГСК на фоне посттрансплантационной профилактики ИТК. Алло-ТГСК от гаплоидентичного донора повышала риск рецидива или смерти (ОР=2,71, 95% ДИ 1,20-6,13, р=0,016). Нам не удалось продемонстрировать значимость хронической РТПХ при проведении лэндмарк анализа на день+180 и день+270 на имеющихся данных (ОР=0,43, 95% ДИ 0,13–1,45, р=0,17 и ОР=0,5, 95% ДИ 0,19-1,32, р=0,161, соответственно) на фоне профилактической терапии ИТК. Настоящее исследование, проведенное на относительно большой группе взрослых пациентов с Ph-позитивным ОЛЛ, демонстрирует, что ИТК являются важным компонентом профилактики посттрансплантационного рецидива. Для того, чтобы сформулировать строгие клинические рекомендации для данной когорты, необходима большая группа пациентов.

Ключевые слова

Острый лимфобластный лейкоз, Ph-позитивный, BCR-ABL1, ингибиторы тирозинкиназ, аллогенная трансплантация гемопоэтических стволовых клеток, рецидив, минимальная остаточная болезнь, хроническая реакция «трансплантат-против-хозяина».

Клинические работы

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Елена В. Семенова1, Олеся И. Паина1, Полина В. Кожокарь1, Ольга А. Слесарчук1, Анастасия С. Боровкова1, Анастасия С. Фролова1, Жемал З. Рахманова1, Aнна A. Осипова1, Любовь А. Цветкова1, Светлана В. Разумова1, Татьяна А. Быкова1, Сергей Н. Бондаренко1, Mария В. Латыпова1, Tатьяна Л. Гиндина1, Елена В. Бабенко1, Александр Л. Алянский1, Ильдар М. Бархатов1, Борис И. Смирнов2, Людмила С. Зубаровская1

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1 НИИ детской онкологии, гематологии и трансплантологии им. Р. М. Горбачевой, Первый Санкт-Петербургский государственный медицинский университет им. акад. И. П. Павлова, Санкт-Петербург, Россия
2 Санкт-Петербургский государственный электротехнический университет «ЛЭТИ» им. В. И. Ульянова (Ленина), Санкт-Петербург, Россия

[TYPE] => HTML ) [~DESCRIPTION] => [~NAME] => Организации [~DEFAULT_VALUE] => Array ( [TEXT] => [TYPE] => HTML ) ) [SUMMARY_RU] => Array ( [ID] => 27 [TIMESTAMP_X] => 2015-09-02 18:01:20 [IBLOCK_ID] => 2 [NAME] => Описание/Резюме [ACTIVE] => Y [SORT] => 500 [CODE] => SUMMARY_RU [DEFAULT_VALUE] => Array ( [TEXT] => [TYPE] => HTML ) [PROPERTY_TYPE] => S [ROW_COUNT] => 1 [COL_COUNT] => 30 [LIST_TYPE] => L [MULTIPLE] => N [XML_ID] => 27 [FILE_TYPE] => [MULTIPLE_CNT] => 5 [TMP_ID] => [LINK_IBLOCK_ID] => 0 [WITH_DESCRIPTION] => N [SEARCHABLE] => N [FILTRABLE] => N [IS_REQUIRED] => N [VERSION] => 1 [USER_TYPE] => HTML [USER_TYPE_SETTINGS] => Array ( [height] => 200 ) [HINT] => [PROPERTY_VALUE_ID] => 29516 [VALUE] => Array ( [TEXT] => <p style="text-align: justify;">Целью нашей работы был анализ влияния возраста на общую выживаемость (ОВ) пациентов с острыми лейкозами (ОЛ) после аллогенной трансплантации гемопоэтических клеток (алло-ТГСК).</p> <h3>Материалы и методы</h3> <p style="text-align: justify;">В исследование включены данные 712 пациентов с ОЛ (от 0,5 до 29 лет), которым была выполнена алло-ТГСК в клинике НИИ ДОГиТ им. Р. М. Горбачевой с 2000 г. по 2019 г.</p> <h3>Результаты</h3> <p style="text-align: justify;">ОВ детей с ОЛЛ (1 или 2 рем) до года и от 1 до 10 лет составила 79% и 65%, эти показатели были выше в сравнении с ОВ подростков (11-20 лет) – 46% и молодых взрослых (21-29 лет) – 47% (р=0,039). ОВ младенцев с ОМЛ (1 или 2 рем) – 78%, детей – 59%, подростков – 59%, молодых взрослых – 70% (р=0,564).</p> <h3>Заключение</h3> <p style="text-align: justify;">Возраст оказывает значимое влияние на ОВ после алло-ТГСК у пациентов с ОЛЛ и в меньшей степени у больных с ОМЛ. </p> <h2>Ключевые слова</h2> <p style="text-align: justify;">Острые лейкозы, аллогенная трансплантация гемопоэтических стволовых клеток крови, возрастные группы.</p> [TYPE] => HTML ) [DESCRIPTION] => [VALUE_ENUM] => [VALUE_XML_ID] => [VALUE_SORT] => [~VALUE] => Array ( [TEXT] =>

Целью нашей работы был анализ влияния возраста на общую выживаемость (ОВ) пациентов с острыми лейкозами (ОЛ) после аллогенной трансплантации гемопоэтических клеток (алло-ТГСК).

Материалы и методы

В исследование включены данные 712 пациентов с ОЛ (от 0,5 до 29 лет), которым была выполнена алло-ТГСК в клинике НИИ ДОГиТ им. Р. М. Горбачевой с 2000 г. по 2019 г.

Результаты

ОВ детей с ОЛЛ (1 или 2 рем) до года и от 1 до 10 лет составила 79% и 65%, эти показатели были выше в сравнении с ОВ подростков (11-20 лет) – 46% и молодых взрослых (21-29 лет) – 47% (р=0,039). ОВ младенцев с ОМЛ (1 или 2 рем) – 78%, детей – 59%, подростков – 59%, молодых взрослых – 70% (р=0,564).

Заключение

Возраст оказывает значимое влияние на ОВ после алло-ТГСК у пациентов с ОЛЛ и в меньшей степени у больных с ОМЛ.

Ключевые слова

Острые лейкозы, аллогенная трансплантация гемопоэтических стволовых клеток крови, возрастные группы.

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Elena V. Semenova1, Olesya V. Paina1, Polina V. Kozhokar1, Olga A. Slesarchuk1, Anastasia S. Borovkova1, Anastasia S. Frolova1, Zhemal Z. Rakhmanova1, Anna A. Osipova1, Liubov A. Tsvetkova1, Svetlana V. Razumova1, Tatyana A. Bykova1, Sergey N. Bondarenko1, Maria V. Latypova1, Tatyana L. Gindina1, Elena V. Babenko1, Alexander L. Alyanskiy1, Ildar M. Barkhatov1, Boris I. Smirnov2, Ludmila S. Zubarovskaya1

[TYPE] => HTML ) [~DESCRIPTION] => [~NAME] => Author [~DEFAULT_VALUE] => Array ( [TEXT] => [TYPE] => HTML ) ) [ORGANIZATION_EN] => Array ( [ID] => 38 [TIMESTAMP_X] => 2015-09-02 18:02:59 [IBLOCK_ID] => 2 [NAME] => Organization [ACTIVE] => Y [SORT] => 500 [CODE] => ORGANIZATION_EN [DEFAULT_VALUE] => Array ( [TEXT] => [TYPE] => HTML ) [PROPERTY_TYPE] => S [ROW_COUNT] => 1 [COL_COUNT] => 30 [LIST_TYPE] => L [MULTIPLE] => N [XML_ID] => 38 [FILE_TYPE] => [MULTIPLE_CNT] => 5 [TMP_ID] => [LINK_IBLOCK_ID] => 0 [WITH_DESCRIPTION] => N [SEARCHABLE] => N [FILTRABLE] => N [IS_REQUIRED] => N [VERSION] => 1 [USER_TYPE] => HTML [USER_TYPE_SETTINGS] => Array ( [height] => 200 ) [HINT] => [PROPERTY_VALUE_ID] => 29519 [VALUE] => Array ( [TEXT] => <p><sup>1</sup> RM Gorbacheva Research Institute of Pediatric Oncology, Hematology and Transplantology, Pavlov University, St. Petersburg, Russia<br> <sup>2</sup> St. Petersburg State Electrotechnical University "LETI", St. Petersburg, Russia</p><br> <p><b>Correspondence:</b><br> Prof. Elena V. Semenova, RM Gorbacheva Research Institute of Pediatric Oncology, Hematology and Transplantology, Pavlov University, 6-8 L Tolstoy St, 197022, St. Petersburg, Russia<br> Phone: +7 (921) 420-46-22<br> E-mail: alena-semenova@yandex.ru</p><br> <p><b>Citation:</b> Semenova EV, Paina OV, Kozokhar PV, et al. Results of allogeneic hemopoietic stem cell transplantation in patients with acute leukemia for different age groups. Cell Ther Transplant 2022; 11(3-4): 36-44.</p> [TYPE] => HTML ) [DESCRIPTION] => [VALUE_ENUM] => [VALUE_XML_ID] => [VALUE_SORT] => [~VALUE] => Array ( [TEXT] =>

1 RM Gorbacheva Research Institute of Pediatric Oncology, Hematology and Transplantology, Pavlov University, St. Petersburg, Russia
2 St. Petersburg State Electrotechnical University "LETI", St. Petersburg, Russia


Correspondence:
Prof. Elena V. Semenova, RM Gorbacheva Research Institute of Pediatric Oncology, Hematology and Transplantology, Pavlov University, 6-8 L Tolstoy St, 197022, St. Petersburg, Russia
Phone: +7 (921) 420-46-22
E-mail: alena-semenova@yandex.ru


Citation: Semenova EV, Paina OV, Kozokhar PV, et al. Results of allogeneic hemopoietic stem cell transplantation in patients with acute leukemia for different age groups. Cell Ther Transplant 2022; 11(3-4): 36-44.

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To analyze the effect of age on the overall survival (OS) of patients with acute leukemia (AL) after allogeneic hematopoietic cell transplantation (allo-HSCT).

Materials

The data of 712 patients with AL (from 0.5 to 29 years old) who underwent allo-HSCT at the R. M. Gorbacheva Research Institute from 2000 to 2019 y.

Results

The OS of children with ALL under one year and from 1 to 10 years was 79% and 65%, these indicators were higher in comparison with the OS of adolescents (11-20 years) – 46% and young adults (21-29 years) – 47% (p=0.039). OS of infants with AML – 78%, children – 59%, adolescents – 59%, young adults – 70% (p=0.564).

Conclusion

Age has a significant effect on OS after allo-HSCT in patients with ALL and to a lesser extent in patients with AML.

Keywords

Acute leukemia, allogeneic hematopoietic stem cell transplantation, age groups.

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Результаты трансплантации аллогенных гемопоэтических стволовых клеток при острых лейкозах у пациентов различного возраста

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Елена В. Семенова1, Олеся И. Паина1, Полина В. Кожокарь1, Ольга А. Слесарчук1, Анастасия С. Боровкова1, Анастасия С. Фролова1, Жемал З. Рахманова1, Aнна A. Осипова1, Любовь А. Цветкова1, Светлана В. Разумова1, Татьяна А. Быкова1, Сергей Н. Бондаренко1, Mария В. Латыпова1, Tатьяна Л. Гиндина1, Елена В. Бабенко1, Александр Л. Алянский1, Ильдар М. Бархатов1, Борис И. Смирнов2, Людмила С. Зубаровская1

1 НИИ детской онкологии, гематологии и трансплантологии им. Р. М. Горбачевой, Первый Санкт-Петербургский государственный медицинский университет им. акад. И. П. Павлова, Санкт-Петербург, Россия
2 Санкт-Петербургский государственный электротехнический университет «ЛЭТИ» им. В. И. Ульянова (Ленина), Санкт-Петербург, Россия

Целью нашей работы был анализ влияния возраста на общую выживаемость (ОВ) пациентов с острыми лейкозами (ОЛ) после аллогенной трансплантации гемопоэтических клеток (алло-ТГСК).

Материалы и методы

В исследование включены данные 712 пациентов с ОЛ (от 0,5 до 29 лет), которым была выполнена алло-ТГСК в клинике НИИ ДОГиТ им. Р. М. Горбачевой с 2000 г. по 2019 г.

Результаты

ОВ детей с ОЛЛ (1 или 2 рем) до года и от 1 до 10 лет составила 79% и 65%, эти показатели были выше в сравнении с ОВ подростков (11-20 лет) – 46% и молодых взрослых (21-29 лет) – 47% (р=0,039). ОВ младенцев с ОМЛ (1 или 2 рем) – 78%, детей – 59%, подростков – 59%, молодых взрослых – 70% (р=0,564).

Заключение

Возраст оказывает значимое влияние на ОВ после алло-ТГСК у пациентов с ОЛЛ и в меньшей степени у больных с ОМЛ.

Ключевые слова

Острые лейкозы, аллогенная трансплантация гемопоэтических стволовых клеток крови, возрастные группы.

Клинические работы

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Нара Г. Степанян, Тимур Т. Валиев, Рамиль Р. Фатхуллин, Татьяна Ю. Павлова, Наталья С. Цаплина, Кирилл И. Киргизов, Светлана Р. Варфоломеева

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Национальный медицинский исследовательский центр онкологии им. Н. Н. Блохина, Москва, Россия

[TYPE] => HTML ) [~DESCRIPTION] => [~NAME] => Организации [~DEFAULT_VALUE] => Array ( [TEXT] => [TYPE] => HTML ) ) [SUMMARY_RU] => Array ( [ID] => 27 [TIMESTAMP_X] => 2015-09-02 18:01:20 [IBLOCK_ID] => 2 [NAME] => Описание/Резюме [ACTIVE] => Y [SORT] => 500 [CODE] => SUMMARY_RU [DEFAULT_VALUE] => Array ( [TEXT] => [TYPE] => HTML ) [PROPERTY_TYPE] => S [ROW_COUNT] => 1 [COL_COUNT] => 30 [LIST_TYPE] => L [MULTIPLE] => N [XML_ID] => 27 [FILE_TYPE] => [MULTIPLE_CNT] => 5 [TMP_ID] => [LINK_IBLOCK_ID] => 0 [WITH_DESCRIPTION] => N [SEARCHABLE] => N [FILTRABLE] => N [IS_REQUIRED] => N [VERSION] => 1 [USER_TYPE] => HTML [USER_TYPE_SETTINGS] => Array ( [height] => 200 ) [HINT] => [PROPERTY_VALUE_ID] => 29552 [VALUE] => Array ( [TEXT] => <p style="text-align: justify;">Около 85-90% пациентов с острым лимфобластным лейкозом (ОЛЛ) после проведения современной программной терапии выздоравливают, но у 10-15% детей заболевание рецидивирует или приобретает рефрактерное течение. Для данной категории пациентов стандартно предусмотрена химиотерапия второй линии с последующей аллогенной трансплантацией гемопоэтических стволовых клеток (алло-ТГСК). Тем не менее, не всегда удается достичь молекулярной/иммунологической ремиссии. В эру таргетной терапии большие надежды возлагаются на молекулярно-направленные препараты для достижения полной молекулярной/иммунологической ремиссии и получения более высоких показателей выживаемости при проведении алло-ТГСК. Одним из таргетных препаратов, применяемых для достижения ремиссии при ОЛЛ, является блинатумомаб, эффективность терапии которым зависит от достаточного уровня СD3-лимфоцитов, экспрессии СD19 и количества бластных клеток в крови и костном мозге. Целью работы было представить опыт терапии блинатумомабом с трансфузиями СD3-аутолимфоцитов у детей с рецидивом ОЛЛ и оценить эффективность данной методики для достижения ремиссии.</p> <h3>Материалы и методы</h3> <p style="text-align: justify;">В настоящей статье представлены 3 клинических случая пациентов с рецидивом ОЛЛ, получавших лечение с июля 2021 года по февраль 2022 года в НИИ детской онкологии и гематологии НМИЦ онкологии им. Н. Н. Блохина.</p> <h3>Результаты</h3> <p style="text-align: justify;">Два пациента из данного наблюдения, проходившие терапию блинатумомабом, получили 4 трансфузии CD3-лимфоцитов, достигли клинико-гематологической ремиссии c МОБ-негативным статусом болезни. Один пациент, ввиду сопутствующей соматической патологии, получил только 2 ауто-трансфузии, но ремиссия ОЛЛ не была достигнута.</p> <h3>Заключение</h3> <p style="text-align: justify;">Опыт применения трансфузий СD3+ауто-лимфоцитов в сочетании с блинатумомабом показал, что данная методика безопасна, воспроизводима и может быть эффективна у пациентов с рецидивами ОЛЛ. У двух пациентов из трех при введении ауто-лимфоцитов каждые 7 дней была зафиксирована полная клинико-гематологическая и иммунологическая ремиссии заболевания. </p> <h2>Ключевые слова</h2> <p style="text-align: justify;">Острый лимфобластный лейкоз, блинатумомаб, лимфоциты, аутологичные, аферез, дети, МОБ-статус.</p> [TYPE] => HTML ) [DESCRIPTION] => [VALUE_ENUM] => [VALUE_XML_ID] => [VALUE_SORT] => [~VALUE] => Array ( [TEXT] =>

Около 85-90% пациентов с острым лимфобластным лейкозом (ОЛЛ) после проведения современной программной терапии выздоравливают, но у 10-15% детей заболевание рецидивирует или приобретает рефрактерное течение. Для данной категории пациентов стандартно предусмотрена химиотерапия второй линии с последующей аллогенной трансплантацией гемопоэтических стволовых клеток (алло-ТГСК). Тем не менее, не всегда удается достичь молекулярной/иммунологической ремиссии. В эру таргетной терапии большие надежды возлагаются на молекулярно-направленные препараты для достижения полной молекулярной/иммунологической ремиссии и получения более высоких показателей выживаемости при проведении алло-ТГСК. Одним из таргетных препаратов, применяемых для достижения ремиссии при ОЛЛ, является блинатумомаб, эффективность терапии которым зависит от достаточного уровня СD3-лимфоцитов, экспрессии СD19 и количества бластных клеток в крови и костном мозге. Целью работы было представить опыт терапии блинатумомабом с трансфузиями СD3-аутолимфоцитов у детей с рецидивом ОЛЛ и оценить эффективность данной методики для достижения ремиссии.

Материалы и методы

В настоящей статье представлены 3 клинических случая пациентов с рецидивом ОЛЛ, получавших лечение с июля 2021 года по февраль 2022 года в НИИ детской онкологии и гематологии НМИЦ онкологии им. Н. Н. Блохина.

Результаты

Два пациента из данного наблюдения, проходившие терапию блинатумомабом, получили 4 трансфузии CD3-лимфоцитов, достигли клинико-гематологической ремиссии c МОБ-негативным статусом болезни. Один пациент, ввиду сопутствующей соматической патологии, получил только 2 ауто-трансфузии, но ремиссия ОЛЛ не была достигнута.

Заключение

Опыт применения трансфузий СD3+ауто-лимфоцитов в сочетании с блинатумомабом показал, что данная методика безопасна, воспроизводима и может быть эффективна у пациентов с рецидивами ОЛЛ. У двух пациентов из трех при введении ауто-лимфоцитов каждые 7 дней была зафиксирована полная клинико-гематологическая и иммунологическая ремиссии заболевания.

Ключевые слова

Острый лимфобластный лейкоз, блинатумомаб, лимфоциты, аутологичные, аферез, дети, МОБ-статус.

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Nara G. Stepanyan, Timur T. Valiev, Ramil R. Fatkhullin, Tatiana Y. Pavlova, Natalia S. Tsaplina, Kirill I. Kirgizov, Svetlana R. Varfolomeeva

[TYPE] => HTML ) [~DESCRIPTION] => [~NAME] => Author [~DEFAULT_VALUE] => Array ( [TEXT] => [TYPE] => HTML ) ) [ORGANIZATION_EN] => Array ( [ID] => 38 [TIMESTAMP_X] => 2015-09-02 18:02:59 [IBLOCK_ID] => 2 [NAME] => Organization [ACTIVE] => Y [SORT] => 500 [CODE] => ORGANIZATION_EN [DEFAULT_VALUE] => Array ( [TEXT] => [TYPE] => HTML ) [PROPERTY_TYPE] => S [ROW_COUNT] => 1 [COL_COUNT] => 30 [LIST_TYPE] => L [MULTIPLE] => N [XML_ID] => 38 [FILE_TYPE] => [MULTIPLE_CNT] => 5 [TMP_ID] => [LINK_IBLOCK_ID] => 0 [WITH_DESCRIPTION] => N [SEARCHABLE] => N [FILTRABLE] => N [IS_REQUIRED] => N [VERSION] => 1 [USER_TYPE] => HTML [USER_TYPE_SETTINGS] => Array ( [height] => 200 ) [HINT] => [PROPERTY_VALUE_ID] => 29555 [VALUE] => Array ( [TEXT] => <p>N. N. Blokhin Russian Cancer Research Center, Moscow, Russia </p><br> <p><b>Correspondence:</b><br> Dr. Nara G. Stepanyan, Bone Marrow Transplantation Department, N. N. Blokhin Russian Cancer Research Center, 23B Kashirskaya St, 115522, Moscow, Russia<br> Phone: +7 (903) 247-30-82<br> E-mail: nara19922@yandex.ru</p><br> <p><b>Citation:</b> Stepanyan NG, Valiev TT, Fatkhullin RR, et al. Efficacy of therapy with blinatumomab and autologous CD3 cell transfusions in relapsing acute lymphoblastic leukemia: A single center experience. Cell Ther Transplant 2022; 11(3-4): 70-76.</p> [TYPE] => HTML ) [DESCRIPTION] => [VALUE_ENUM] => [VALUE_XML_ID] => [VALUE_SORT] => [~VALUE] => Array ( [TEXT] =>

N. N. Blokhin Russian Cancer Research Center, Moscow, Russia


Correspondence:
Dr. Nara G. Stepanyan, Bone Marrow Transplantation Department, N. N. Blokhin Russian Cancer Research Center, 23B Kashirskaya St, 115522, Moscow, Russia
Phone: +7 (903) 247-30-82
E-mail: nara19922@yandex.ru


Citation: Stepanyan NG, Valiev TT, Fatkhullin RR, et al. Efficacy of therapy with blinatumomab and autologous CD3 cell transfusions in relapsing acute lymphoblastic leukemia: A single center experience. Cell Ther Transplant 2022; 11(3-4): 70-76.

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About 85-90% of patients with acute lymphoblastic leukemia (ALL) recover after modern program therapy. However, the disease may relapse, or acquires a refractory course in 10-15% of the children. For this category of patients, second-line chemotherapy is standardly provided, followed by allogeneic hematopoietic stem cell transplantation (allo-HSCT). However, achievement of molecular/immunological remission is not always possible. In the era of targeted therapy, great hopes are placed on molecularly targeted drugs in order to reach complete molecular/immunological remission and obtain higher survival rates with allo-HSCT. Blinatumomab is among the targeted drugs used to achieve remission in ALL. Its effectiveness depends on a sufficient level of CD3-lymphocytes, CD19 expression, and the number of blast cells in peripheral blood and bone marrow. Our purpose was to present the experience of blinatumomab therapy with transfusions of autologous CD3 lymphocytes in children with recurrent ALL and to evaluate the efficiency of this technique in achieving remission.

Materials and methods

This article presents three clinical cases of patients with recurrent ALL treated at the Research Institute of Pediatric Oncology and Hematology at N. N. Blokhin National Cancer Research Center from July 2021 to February 2022.

Results

Two patients from our series were treated with blinatumomab and received 3 transfusions of CD3-lymphocytes followed by clinical and hematological remission with MRD-negative disease status. One patient, due to concomitant somatic pathology, received only 2 auto-transfusions, but ALL remission was not achieved.

Conclusion

Our experience of using autologous CD3+ lymphocyte transfusions in combination with blinatumomab showed that this technique is safe, reproducible, and may be effective in patients with ALL relapses. In 2 out of 3 patients with weekly infusion of autologous lymphocytes, a complete clinical, hematological and immunological remission of the disease was registered.

Keywords

Acute lymphoblastic leukemia, blinatumomab, lymphocytes, autologous, apheresis, children, MRD status.

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Оценка эффективности блинатумомаба с аутологичными трансфузиями СD3-лимфоцитов в лечении рецидивов острого лимфобластного лейкоза: опыт одного центра

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Нара Г. Степанян, Тимур Т. Валиев, Рамиль Р. Фатхуллин, Татьяна Ю. Павлова, Наталья С. Цаплина, Кирилл И. Киргизов, Светлана Р. Варфоломеева

Национальный медицинский исследовательский центр онкологии им. Н. Н. Блохина, Москва, Россия

Около 85-90% пациентов с острым лимфобластным лейкозом (ОЛЛ) после проведения современной программной терапии выздоравливают, но у 10-15% детей заболевание рецидивирует или приобретает рефрактерное течение. Для данной категории пациентов стандартно предусмотрена химиотерапия второй линии с последующей аллогенной трансплантацией гемопоэтических стволовых клеток (алло-ТГСК). Тем не менее, не всегда удается достичь молекулярной/иммунологической ремиссии. В эру таргетной терапии большие надежды возлагаются на молекулярно-направленные препараты для достижения полной молекулярной/иммунологической ремиссии и получения более высоких показателей выживаемости при проведении алло-ТГСК. Одним из таргетных препаратов, применяемых для достижения ремиссии при ОЛЛ, является блинатумомаб, эффективность терапии которым зависит от достаточного уровня СD3-лимфоцитов, экспрессии СD19 и количества бластных клеток в крови и костном мозге. Целью работы было представить опыт терапии блинатумомабом с трансфузиями СD3-аутолимфоцитов у детей с рецидивом ОЛЛ и оценить эффективность данной методики для достижения ремиссии.

Материалы и методы

В настоящей статье представлены 3 клинических случая пациентов с рецидивом ОЛЛ, получавших лечение с июля 2021 года по февраль 2022 года в НИИ детской онкологии и гематологии НМИЦ онкологии им. Н. Н. Блохина.

Результаты

Два пациента из данного наблюдения, проходившие терапию блинатумомабом, получили 4 трансфузии CD3-лимфоцитов, достигли клинико-гематологической ремиссии c МОБ-негативным статусом болезни. Один пациент, ввиду сопутствующей соматической патологии, получил только 2 ауто-трансфузии, но ремиссия ОЛЛ не была достигнута.

Заключение

Опыт применения трансфузий СD3+ауто-лимфоцитов в сочетании с блинатумомабом показал, что данная методика безопасна, воспроизводима и может быть эффективна у пациентов с рецидивами ОЛЛ. У двух пациентов из трех при введении ауто-лимфоцитов каждые 7 дней была зафиксирована полная клинико-гематологическая и иммунологическая ремиссии заболевания.

Ключевые слова

Острый лимфобластный лейкоз, блинатумомаб, лимфоциты, аутологичные, аферез, дети, МОБ-статус.

Клинические работы

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Белла И. Аюбова1, Сергей Н. Бондаренко1, Анна Г. Смирнова1, Юлия Ю. Власова1, Николай Ю. Цветков1, Михаил М. Канунников1, Дмитрий К. Жоголев1, Юлия Д. Олейникова1, Елена В. Карягина2, Ридван К. Ильясов3, Наталья А. Зорина4, Светлана С. Беляева5, Юлия С. Нередько6, Ирина А. Самородова7, Юлия Б. Черных8, Михаил Ю. Лазарев9, Анна П. Кочергина10, Анна А. Насрединова1, Ильдар М. Бархатов1, Татьяна Л. Гиндина1, Иван С. Моисеев1, Александр Д. Кулагин1

[TYPE] => HTML ) [~DESCRIPTION] => [~NAME] => Авторы [~DEFAULT_VALUE] => Array ( [TEXT] => [TYPE] => HTML ) ) [ORGANIZATION_RU] => Array ( [ID] => 26 [TIMESTAMP_X] => 2015-09-02 18:01:20 [IBLOCK_ID] => 2 [NAME] => Организации [ACTIVE] => Y [SORT] => 500 [CODE] => ORGANIZATION_RU [DEFAULT_VALUE] => Array ( [TEXT] => [TYPE] => HTML ) [PROPERTY_TYPE] => S [ROW_COUNT] => 1 [COL_COUNT] => 30 [LIST_TYPE] => L [MULTIPLE] => N [XML_ID] => 26 [FILE_TYPE] => [MULTIPLE_CNT] => 5 [TMP_ID] => [LINK_IBLOCK_ID] => 0 [WITH_DESCRIPTION] => N [SEARCHABLE] => N [FILTRABLE] => N [IS_REQUIRED] => N [VERSION] => 1 [USER_TYPE] => HTML [USER_TYPE_SETTINGS] => Array ( [height] => 200 ) [HINT] => [PROPERTY_VALUE_ID] => 29539 [VALUE] => Array ( [TEXT] => <p><sup>1</sup> НИИ детской онкологии, гематологии и трансплантологии им. Р. М. Горбачевой, Первый Санкт-Петербургский государственный медицинский университет им. акад. И. П. Павлова, Санкт-Петербург, Россия<br> <sup>2</sup> Городская больница №15, Санкт-Петербург, Россия<br> <sup>3</sup> Крымский республиканский онкологический клинический диспансер им. В. М. Ефетова, Симферополь, Россия<br> <sup>4</sup> Кировский научно-исследовательский институт гематологии и переливания крови ФМБА, Киров, Россия<br> <sup>5</sup> Белгородская областная клиническая больница святителя Иоасафа, Белгород, Россия<br> <sup>6</sup> Ставропольский краевой клинический онкологический диспансер, Ставрополь, Россия<br> <sup>7</sup> Городская клиническая больница №31, Санкт-Петербург, Россия<br> <sup>8</sup> Московский областной научно-исследовательский клинический институт им. М. Ф. Владимирского, Москва, Россия<br> <sup>9</sup> Городская клиническая больница №40, Москва, Россия<br> <sup>10</sup> Краевая клиническая больница, Барнаул, Россия</p> [TYPE] => HTML ) [DESCRIPTION] => [VALUE_ENUM] => [VALUE_XML_ID] => [VALUE_SORT] => [~VALUE] => Array ( [TEXT] =>

1 НИИ детской онкологии, гематологии и трансплантологии им. Р. М. Горбачевой, Первый Санкт-Петербургский государственный медицинский университет им. акад. И. П. Павлова, Санкт-Петербург, Россия
2 Городская больница №15, Санкт-Петербург, Россия
3 Крымский республиканский онкологический клинический диспансер им. В. М. Ефетова, Симферополь, Россия
4 Кировский научно-исследовательский институт гематологии и переливания крови ФМБА, Киров, Россия
5 Белгородская областная клиническая больница святителя Иоасафа, Белгород, Россия
6 Ставропольский краевой клинический онкологический диспансер, Ставрополь, Россия
7 Городская клиническая больница №31, Санкт-Петербург, Россия
8 Московский областной научно-исследовательский клинический институт им. М. Ф. Владимирского, Москва, Россия
9 Городская клиническая больница №40, Москва, Россия
10 Краевая клиническая больница, Барнаул, Россия

[TYPE] => HTML ) [~DESCRIPTION] => [~NAME] => Организации [~DEFAULT_VALUE] => Array ( [TEXT] => [TYPE] => HTML ) ) [SUMMARY_RU] => Array ( [ID] => 27 [TIMESTAMP_X] => 2015-09-02 18:01:20 [IBLOCK_ID] => 2 [NAME] => Описание/Резюме [ACTIVE] => Y [SORT] => 500 [CODE] => SUMMARY_RU [DEFAULT_VALUE] => Array ( [TEXT] => [TYPE] => HTML ) [PROPERTY_TYPE] => S [ROW_COUNT] => 1 [COL_COUNT] => 30 [LIST_TYPE] => L [MULTIPLE] => N [XML_ID] => 27 [FILE_TYPE] => [MULTIPLE_CNT] => 5 [TMP_ID] => [LINK_IBLOCK_ID] => 0 [WITH_DESCRIPTION] => N [SEARCHABLE] => N [FILTRABLE] => N [IS_REQUIRED] => N [VERSION] => 1 [USER_TYPE] => HTML [USER_TYPE_SETTINGS] => Array ( [height] => 200 ) [HINT] => [PROPERTY_VALUE_ID] => 29540 [VALUE] => Array ( [TEXT] => <p style="text-align: justify;">Острый миелоидный лейкоз с мутациями в гене FLT3 (ОМЛ FLT3+) как клинический подтип ОМЛ характеризуется коротким периодом ремиссии заболевания, высокой частотой рецидивов, низкими показателями выживаемости, особенно в случаях с высоким соотношением FLT3-ITD к дикому типу и отсутствием мутации в гене NPM1. При этом FLT3-мутации можно рассматривать как перспективную молекулярную мишень для лечения пациентов c ОМЛ, в том числе с рефрактерным или рецидивирующим (Р/Р) ОМЛ. В исследование были включены 48 пациентов с Р/Р ОМЛ FLT3+ с медианой возраста 53 (18-79) лет. Первично-рефрактерное течение отмечено в 31,2% случаев; с первым рецидивом были включены 54,2%; с последующими рецидивами – 14,6%. Мутация ITD наблюдалась у 89,6%, TKD – у 10,4%. Больные получали гилтеритиниб в дозе 120 мг/сут в течение 28-дневного курса, преимущественно – по 1 или 2 курса (56,2% и 27,1%, соответственно). Общий ответ (ОО) достигнут в 77,1% (ДИ 95% 65,7-88,3): полная ремиссия – в 15 случаях (31,2%), ремиссия без восстановления – у 11 пациентов (22,9%) и морфологически свободный от лейкоза статус достигнут также у 11 больных (22,9%). ТГСК в последующем выполнена в 29,2% случаев (ДИ 95% 18,2-43,2). Средний возраст этой группы составил 43,1 (18-68) года. Медиана времени от достижения ОО до ТГСК составил 45 (24-156) дней.</p> <p style="text-align: justify;">Однолетняя общая выживаемость составила 39,9% с медианой 6,3 (95% ДИ: 4,7-12,0) мес. Безрецидивная выживаемость в группе пациентов, достигших ОО (n=37), составила 40,5%, медиана по срокам – 7,7 (4,4-11,0) мес. Выявлены следующие факторы, благоприятно влияющие на бессобытийную выживаемость: выполнение ТГСК после терапии (HR=0,16; CI 95%: 0,04-0,62; p<0,01) и достижение ОО (HR=0,11; CI 95%: 0,04-0,33; p<0,01). У пациентов с поздним рецидивом, напротив, наблюдалось увеличение риска событий (HR=3,42; CI 95%: 1,2-9,64; p=0,02). Непредвиденной токсичности после терапии не наблюдалось. Применение гилтеритиниба у пациентов с Р/Р FLT3+ ОМЛ показало благоприятные исходы при удовлетворительной переносимости терапии и может быть использовано в качестве «мост-терапии» к ТГСК у взрослых пациентов с Р/Р FLT3+ ОМЛ. </p> <h2>Ключевые слова</h2> <p style="text-align: justify;">Острый миелоидный лейкоз, таргетная терапия, гилтеритиниб.</p> [TYPE] => HTML ) [DESCRIPTION] => [VALUE_ENUM] => [VALUE_XML_ID] => [VALUE_SORT] => [~VALUE] => Array ( [TEXT] =>

Острый миелоидный лейкоз с мутациями в гене FLT3 (ОМЛ FLT3+) как клинический подтип ОМЛ характеризуется коротким периодом ремиссии заболевания, высокой частотой рецидивов, низкими показателями выживаемости, особенно в случаях с высоким соотношением FLT3-ITD к дикому типу и отсутствием мутации в гене NPM1. При этом FLT3-мутации можно рассматривать как перспективную молекулярную мишень для лечения пациентов c ОМЛ, в том числе с рефрактерным или рецидивирующим (Р/Р) ОМЛ. В исследование были включены 48 пациентов с Р/Р ОМЛ FLT3+ с медианой возраста 53 (18-79) лет. Первично-рефрактерное течение отмечено в 31,2% случаев; с первым рецидивом были включены 54,2%; с последующими рецидивами – 14,6%. Мутация ITD наблюдалась у 89,6%, TKD – у 10,4%. Больные получали гилтеритиниб в дозе 120 мг/сут в течение 28-дневного курса, преимущественно – по 1 или 2 курса (56,2% и 27,1%, соответственно). Общий ответ (ОО) достигнут в 77,1% (ДИ 95% 65,7-88,3): полная ремиссия – в 15 случаях (31,2%), ремиссия без восстановления – у 11 пациентов (22,9%) и морфологически свободный от лейкоза статус достигнут также у 11 больных (22,9%). ТГСК в последующем выполнена в 29,2% случаев (ДИ 95% 18,2-43,2). Средний возраст этой группы составил 43,1 (18-68) года. Медиана времени от достижения ОО до ТГСК составил 45 (24-156) дней.

Однолетняя общая выживаемость составила 39,9% с медианой 6,3 (95% ДИ: 4,7-12,0) мес. Безрецидивная выживаемость в группе пациентов, достигших ОО (n=37), составила 40,5%, медиана по срокам – 7,7 (4,4-11,0) мес. Выявлены следующие факторы, благоприятно влияющие на бессобытийную выживаемость: выполнение ТГСК после терапии (HR=0,16; CI 95%: 0,04-0,62; p<0,01) и достижение ОО (HR=0,11; CI 95%: 0,04-0,33; p<0,01). У пациентов с поздним рецидивом, напротив, наблюдалось увеличение риска событий (HR=3,42; CI 95%: 1,2-9,64; p=0,02). Непредвиденной токсичности после терапии не наблюдалось. Применение гилтеритиниба у пациентов с Р/Р FLT3+ ОМЛ показало благоприятные исходы при удовлетворительной переносимости терапии и может быть использовано в качестве «мост-терапии» к ТГСК у взрослых пациентов с Р/Р FLT3+ ОМЛ.

Ключевые слова

Острый миелоидный лейкоз, таргетная терапия, гилтеритиниб.

[TYPE] => HTML ) [~DESCRIPTION] => [~NAME] => Описание/Резюме [~DEFAULT_VALUE] => Array ( [TEXT] => [TYPE] => HTML ) ) [DOI] => Array ( [ID] => 28 [TIMESTAMP_X] => 2016-04-06 14:11:12 [IBLOCK_ID] => 2 [NAME] => DOI [ACTIVE] => Y [SORT] => 500 [CODE] => DOI [DEFAULT_VALUE] => [PROPERTY_TYPE] => S [ROW_COUNT] => 1 [COL_COUNT] => 80 [LIST_TYPE] => L [MULTIPLE] => N [XML_ID] => 28 [FILE_TYPE] => [MULTIPLE_CNT] => 5 [TMP_ID] => [LINK_IBLOCK_ID] => 0 [WITH_DESCRIPTION] => N [SEARCHABLE] => N [FILTRABLE] => N [IS_REQUIRED] => N [VERSION] => 1 [USER_TYPE] => [USER_TYPE_SETTINGS] => [HINT] => [PROPERTY_VALUE_ID] => 29541 [VALUE] => 10.18620/ctt-1866-8836-2022-11-3-4-60-69 [DESCRIPTION] => [VALUE_ENUM] => [VALUE_XML_ID] => [VALUE_SORT] => [~VALUE] => 10.18620/ctt-1866-8836-2022-11-3-4-60-69 [~DESCRIPTION] => [~NAME] => DOI [~DEFAULT_VALUE] => ) [AUTHOR_EN] => Array ( [ID] => 37 [TIMESTAMP_X] => 2015-09-02 18:02:59 [IBLOCK_ID] => 2 [NAME] => Author [ACTIVE] => Y [SORT] => 500 [CODE] => AUTHOR_EN [DEFAULT_VALUE] => Array ( [TEXT] => [TYPE] => HTML ) [PROPERTY_TYPE] => S [ROW_COUNT] => 1 [COL_COUNT] => 30 [LIST_TYPE] => L [MULTIPLE] => N [XML_ID] => 37 [FILE_TYPE] => [MULTIPLE_CNT] => 5 [TMP_ID] => [LINK_IBLOCK_ID] => 0 [WITH_DESCRIPTION] => N [SEARCHABLE] => N [FILTRABLE] => N [IS_REQUIRED] => N [VERSION] => 1 [USER_TYPE] => HTML [USER_TYPE_SETTINGS] => Array ( [height] => 200 ) [HINT] => [PROPERTY_VALUE_ID] => 29542 [VALUE] => Array ( [TEXT] => <p>Bella I. Ayubova<sup>1</sup>, Sergey N. Bondarenko<sup>1</sup>, Anna G. Smirnova<sup>1</sup>, Yulia Yu. Vlasova<sup>1</sup>, Nikolay Yu. Tsvetkov<sup>1</sup>, Michail M. Kanunnikov<sup>1</sup>, Dmitry K. Zhogolev<sup>1</sup>, Yuliya D. Oleynikova<sup>1</sup>, Elena V. Karyagina<sup>2</sup>, Ridvan K. Ilyasov<sup>3</sup>, Natalya A. Zorina<sup>4</sup>, Svetlana S. Belyaeva<sup>5</sup>, Yulia S. Neredko<sup>6</sup>, Irina A. Samorodova<sup>7</sup>, Yulia B. Chernih<sup>8</sup>, Mikhail Yu. Lazarev<sup>9</sup>, Anna P. Kochergina<sup>10</sup>, Anna A. Nasredinova<sup>1</sup>, Ildar M. Barkhatov<sup>1</sup>, Tatyana L. Gindina<sup>1</sup>, Ivan S. Moiseev<sup>1</sup>, Alexander D. Kulagin<sup>1</sup></p> [TYPE] => HTML ) [DESCRIPTION] => [VALUE_ENUM] => [VALUE_XML_ID] => [VALUE_SORT] => [~VALUE] => Array ( [TEXT] =>

Bella I. Ayubova1, Sergey N. Bondarenko1, Anna G. Smirnova1, Yulia Yu. Vlasova1, Nikolay Yu. Tsvetkov1, Michail M. Kanunnikov1, Dmitry K. Zhogolev1, Yuliya D. Oleynikova1, Elena V. Karyagina2, Ridvan K. Ilyasov3, Natalya A. Zorina4, Svetlana S. Belyaeva5, Yulia S. Neredko6, Irina A. Samorodova7, Yulia B. Chernih8, Mikhail Yu. Lazarev9, Anna P. Kochergina10, Anna A. Nasredinova1, Ildar M. Barkhatov1, Tatyana L. Gindina1, Ivan S. Moiseev1, Alexander D. Kulagin1

[TYPE] => HTML ) [~DESCRIPTION] => [~NAME] => Author [~DEFAULT_VALUE] => Array ( [TEXT] => [TYPE] => HTML ) ) [ORGANIZATION_EN] => Array ( [ID] => 38 [TIMESTAMP_X] => 2015-09-02 18:02:59 [IBLOCK_ID] => 2 [NAME] => Organization [ACTIVE] => Y [SORT] => 500 [CODE] => ORGANIZATION_EN [DEFAULT_VALUE] => Array ( [TEXT] => [TYPE] => HTML ) [PROPERTY_TYPE] => S [ROW_COUNT] => 1 [COL_COUNT] => 30 [LIST_TYPE] => L [MULTIPLE] => N [XML_ID] => 38 [FILE_TYPE] => [MULTIPLE_CNT] => 5 [TMP_ID] => [LINK_IBLOCK_ID] => 0 [WITH_DESCRIPTION] => N [SEARCHABLE] => N [FILTRABLE] => N [IS_REQUIRED] => N [VERSION] => 1 [USER_TYPE] => HTML [USER_TYPE_SETTINGS] => Array ( [height] => 200 ) [HINT] => [PROPERTY_VALUE_ID] => 29543 [VALUE] => Array ( [TEXT] => <p><sup>1</sup> RM Gorbacheva Research Institute of Pediatric Oncology, Hematology and Transplantology, Pavlov University, St. Petersburg, Russia<br> <sup>2</sup> City Hospital No. 15 of St. Petersburg, Russia<br> <sup>3</sup> Crimean V. М. Efetov Republican Oncological Clinical Dispensary, Simferopol, Russia<br> <sup>4</sup> Kirov Research Institute of Hematology and Blood Transfusion, Kirov, Russia<br> <sup>5</sup> Belgorod Regional Clinical Hospital of St. Joasaph, Belgorod, Russia<br> <sup>6</sup> Stavropol Regional Clinical Oncological Dispensary, Stavropol, Russia<br> <sup>7</sup> City Hospital No. 31 of St. Petersburg, Russia<br> <sup>8</sup> Moscow M. F. Vladimirsky Regional Research Clinical Institute, Moscow, Russia<br> <sup>9</sup> City Clinical Hospital No. 40, Moscow, Russia<br> <sup>10</sup> Regional Clinical Hospital, Barnaul, Russia</p><br> <p><b>Correspondence:</b><br> Dr. Bella I. Ayubova, RM Gorbacheva Research Institute of Pediatric Oncology, Hematology and Transpantology, Pavlov University, 6-8 L.Tolstoy St, 197022, St. Petersburg, Russia<br> E-mail: bella_ayubova@mail.ru</p><br> <p><b> Citation:</b> Ayubova BI, Bondarenko SN, Smirnova AG et al. Gilteritinib as a bridge to allogeneic hematopoietic stem cell transplantation in adult patients with refractory/relapsed acute myeloid leukemia with FLT3 mutations. Cell Ther Transplant 2022; 11(3-4): 60-69.</p> [TYPE] => HTML ) [DESCRIPTION] => [VALUE_ENUM] => [VALUE_XML_ID] => [VALUE_SORT] => [~VALUE] => Array ( [TEXT] =>

1 RM Gorbacheva Research Institute of Pediatric Oncology, Hematology and Transplantology, Pavlov University, St. Petersburg, Russia
2 City Hospital No. 15 of St. Petersburg, Russia
3 Crimean V. М. Efetov Republican Oncological Clinical Dispensary, Simferopol, Russia
4 Kirov Research Institute of Hematology and Blood Transfusion, Kirov, Russia
5 Belgorod Regional Clinical Hospital of St. Joasaph, Belgorod, Russia
6 Stavropol Regional Clinical Oncological Dispensary, Stavropol, Russia
7 City Hospital No. 31 of St. Petersburg, Russia
8 Moscow M. F. Vladimirsky Regional Research Clinical Institute, Moscow, Russia
9 City Clinical Hospital No. 40, Moscow, Russia
10 Regional Clinical Hospital, Barnaul, Russia


Correspondence:
Dr. Bella I. Ayubova, RM Gorbacheva Research Institute of Pediatric Oncology, Hematology and Transpantology, Pavlov University, 6-8 L.Tolstoy St, 197022, St. Petersburg, Russia
E-mail: bella_ayubova@mail.ru


Citation: Ayubova BI, Bondarenko SN, Smirnova AG et al. Gilteritinib as a bridge to allogeneic hematopoietic stem cell transplantation in adult patients with refractory/relapsed acute myeloid leukemia with FLT3 mutations. Cell Ther Transplant 2022; 11(3-4): 60-69.

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Acute myeloid leukemia (AML) with FLT3 mutations, being a clinical subtype of AML, is associated with higher relapse rate, shorter remission period, decreased survival, especially without NPM1 co-mutation, and at high FLT3-ITD/wild-type allelic ratios. FLT3 mutations can be considered as a promising molecular target for the treatment of patients with FLT3-mutated AML, particularly in refractory or relapsed (R/R) AML cases. Allogeneic hematopoietic stem cell transplantation (allo- HSCT) gives chance for a potential cure in patients with R/R AML. The present study included 48 patients with R/R AML with FLT3-mutation, at a median age of 53 (18-79) years. Primarily refractory patients (p/r AML) made 31.2% of them; among recurrent AML, 54.2% had a first relapse, and 14.6% had 2 or more relapses (relAML). The ITD mutation was detected in 89.6% and TKD-mutation in 10.4% of cases. The patients received gilteritinib 120 mg once daily, administered as one (in most cases), or >2 28-day cycles of therapy (56.2% and 27.1%, respectively). Overall response (OR) rate was 77.1% (CI 95% 65.7-88.3): complete remission (CR) was documented in 15 (31.2%) patients, remission with incomplete recovery (CRi/r) and morphological leukemia-free state (MLFS) were observed in 11 patients (22.9%) each. Allo-HSCT was subsequently performed in 29.2% (CI 95% 18.2-43.2) of all treated patients. The median age of this group of patients was 43.1 (18-68) years. The median time from overall response achieved after gilteritinib to allo-HSCT was 45 (24-156) days. One-year overall survival was 39.9%, with median survival terms of 6.3 months (95% CI: 4.7-12.0). Disease-free survival in the group of patients who achieved remission (37 patients) was 40.5%, and the median was 7.7 months (4.4-11.0 months). In the multivariate analysis, event-free survival was significantly associated with successful bridging to allo-HSCT (HR=0.16; CI 95%: 0.04-0.62; p<0.01) and in patients who achieved OR (HR=0.11; CI 95%: 0.04-0.33; p<0.01). In contrast, the patients with late relapse showed an increase in the risk of the events (HR=3.42; CI 95%: 1.2-9.64; p=0.02). No unexpected toxicity was observed after the therapy. Gilteritinib in patients with R/R FLT3-mutated AML demonstrated favorable outcomes with a satisfactory tolerance to therapy. Thus, gilteritinib may be used for a bridge therapy to allo-HSCT in adult patients with R/R FLT3-mutated AML.

Keywords

Acute myeloid leukemia, target therapy, gilteritinib.

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Гилтеритиниб как «мост»-терапия перед аллогенной трансплантацией костного мозга у пациентов с рефрактерным/рецидивирующим острым миелоидным лейкозом с мутацией в гене FLT3

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Белла И. Аюбова1, Сергей Н. Бондаренко1, Анна Г. Смирнова1, Юлия Ю. Власова1, Николай Ю. Цветков1, Михаил М. Канунников1, Дмитрий К. Жоголев1, Юлия Д. Олейникова1, Елена В. Карягина2, Ридван К. Ильясов3, Наталья А. Зорина4, Светлана С. Беляева5, Юлия С. Нередько6, Ирина А. Самородова7, Юлия Б. Черных8, Михаил Ю. Лазарев9, Анна П. Кочергина10, Анна А. Насрединова1, Ильдар М. Бархатов1, Татьяна Л. Гиндина1, Иван С. Моисеев1, Александр Д. Кулагин1

1 НИИ детской онкологии, гематологии и трансплантологии им. Р. М. Горбачевой, Первый Санкт-Петербургский государственный медицинский университет им. акад. И. П. Павлова, Санкт-Петербург, Россия
2 Городская больница №15, Санкт-Петербург, Россия
3 Крымский республиканский онкологический клинический диспансер им. В. М. Ефетова, Симферополь, Россия
4 Кировский научно-исследовательский институт гематологии и переливания крови ФМБА, Киров, Россия
5 Белгородская областная клиническая больница святителя Иоасафа, Белгород, Россия
6 Ставропольский краевой клинический онкологический диспансер, Ставрополь, Россия
7 Городская клиническая больница №31, Санкт-Петербург, Россия
8 Московский областной научно-исследовательский клинический институт им. М. Ф. Владимирского, Москва, Россия
9 Городская клиническая больница №40, Москва, Россия
10 Краевая клиническая больница, Барнаул, Россия

Острый миелоидный лейкоз с мутациями в гене FLT3 (ОМЛ FLT3+) как клинический подтип ОМЛ характеризуется коротким периодом ремиссии заболевания, высокой частотой рецидивов, низкими показателями выживаемости, особенно в случаях с высоким соотношением FLT3-ITD к дикому типу и отсутствием мутации в гене NPM1. При этом FLT3-мутации можно рассматривать как перспективную молекулярную мишень для лечения пациентов c ОМЛ, в том числе с рефрактерным или рецидивирующим (Р/Р) ОМЛ. В исследование были включены 48 пациентов с Р/Р ОМЛ FLT3+ с медианой возраста 53 (18-79) лет. Первично-рефрактерное течение отмечено в 31,2% случаев; с первым рецидивом были включены 54,2%; с последующими рецидивами – 14,6%. Мутация ITD наблюдалась у 89,6%, TKD – у 10,4%. Больные получали гилтеритиниб в дозе 120 мг/сут в течение 28-дневного курса, преимущественно – по 1 или 2 курса (56,2% и 27,1%, соответственно). Общий ответ (ОО) достигнут в 77,1% (ДИ 95% 65,7-88,3): полная ремиссия – в 15 случаях (31,2%), ремиссия без восстановления – у 11 пациентов (22,9%) и морфологически свободный от лейкоза статус достигнут также у 11 больных (22,9%). ТГСК в последующем выполнена в 29,2% случаев (ДИ 95% 18,2-43,2). Средний возраст этой группы составил 43,1 (18-68) года. Медиана времени от достижения ОО до ТГСК составил 45 (24-156) дней.

Однолетняя общая выживаемость составила 39,9% с медианой 6,3 (95% ДИ: 4,7-12,0) мес. Безрецидивная выживаемость в группе пациентов, достигших ОО (n=37), составила 40,5%, медиана по срокам – 7,7 (4,4-11,0) мес. Выявлены следующие факторы, благоприятно влияющие на бессобытийную выживаемость: выполнение ТГСК после терапии (HR=0,16; CI 95%: 0,04-0,62; p<0,01) и достижение ОО (HR=0,11; CI 95%: 0,04-0,33; p<0,01). У пациентов с поздним рецидивом, напротив, наблюдалось увеличение риска событий (HR=3,42; CI 95%: 1,2-9,64; p=0,02). Непредвиденной токсичности после терапии не наблюдалось. Применение гилтеритиниба у пациентов с Р/Р FLT3+ ОМЛ показало благоприятные исходы при удовлетворительной переносимости терапии и может быть использовано в качестве «мост-терапии» к ТГСК у взрослых пациентов с Р/Р FLT3+ ОМЛ.

Ключевые слова

Острый миелоидный лейкоз, таргетная терапия, гилтеритиниб.

Клинические случаи

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Андрей В. Козлов1, Тимур Т. Валиев2, Светлана А. Юлдашева3, Асмик Г. Геворгян1, Илья В. Казанцев1, Татьяна В. Юхта1, Акгуль А. Оджарова2, Кирилл И. Киргизов2, Наталья Б. Михайлова1, Людмила С. Зубаровская1

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2 Национальный медицинский исследовательский центр онкологии им. Н. Н. Блохина, Москва, Россия
3 Институт неотложной и восстановительной хирургии им. В. К. Гусака, Донецк, Донецкая Народная Республика

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Представленный клинический случай отражает современные возможности лечения ALK-позитивной рецидивирующей/рефрактерной (Р-Р) анапластической крупноклеточной лимфомы у детей и подростков. Для этого варианта лимфомы даже в случае Р-Р течения шанс на излечение остается относительно неплохим благодаря наличию эффективной таргетной терапии и высокой эффективности аллогенной трансплантации гемопоэтических стволовых клеток, которая может успешно применяться при данной патологии в том числе у пациентов вне ремиссии.

Ключевые слова

Анапластическая крупноклеточная лимфома, ALK+, рецидивирующее/рефрактерное течение, таргетная терапия, трансплантация гемопоэтических стволовых клеток.

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Andrey V. Kozlov1, Timur T. Valiev2, Svetlana A. Uldasheva3, Asmik G. Gevorgian1, Ilya V. Kazantsev1, Tatyana V. Yukhta1, Akgul A. Odzharova2, Kirill I. Kirgizov2, Natalya B. Mikhailova1, Ludmila S. Zubarovskaya1

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1 RM Gorbacheva Research Institute of Pediatric Oncology, Hematology and Transplantology, Pavlov University, St. Petersburg, Russia
2 N. N. Blokhin Russian Cancer Research Center, Moscow, Russia
3 V. K. Gusak Institute of Urgent and Reconstructive Surgery, Donetsk People’s Republic, Donetsk, Donetsk People’s Republic


Correspondence:
Dr. Andrey V. Kozlov, RM Gorbacheva Research Institute of Pediatric Oncology, Hematology and Transplantology, Pavlov University, 6-8 L.Tolstoy St, St. Petersburg, Russia
Phone: +7 (921) 327-28-79
E-mail: kozlovandrew1983@ya.ru


Citation: Kozlov AV, Valiev TT, Uldasheva SA et al. Successful treatment of relapsed/refractory anaplastic large cell lymphoma in adolescent patient: a case report. Cell Ther Transplant 2022; 11(3-4): 77-82.

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The present case report demonstrates current opportunities for the treatment of relapsed/refractory anaplastic large cell lymphoma, ALK-positive (R-R ALCL) in children and adolescents. This type of lymphoma lends sufficient chance of cure even in R-R cases, due to effective targeted therapy and high efficiency of allogeneic hematopoetic stem cell transplantation, thus demonstrating curative potential in the patients with active disease prior to transplantation.

Keywords

Anaplastic large cell lymphoma, ALK+, relapsed/refractory, targeted therapy, hematopoetic stem cell transplantation.

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Клинический случай успешной терапии рецидивирующей/рефрактерной анапластической крупноклеточной лимфомы у подростка

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Андрей В. Козлов1, Тимур Т. Валиев2, Светлана А. Юлдашева3, Асмик Г. Геворгян1, Илья В. Казанцев1, Татьяна В. Юхта1, Акгуль А. Оджарова2, Кирилл И. Киргизов2, Наталья Б. Михайлова1, Людмила С. Зубаровская1

1 НИИ детской онкологии, гематологии и трансплантологии им. Р. М. Горбачевой, Первый Санкт-Петербургский государственный медицинский университет им. акад. И. П. Павлова, Санкт-Петербург, Россия
2 Национальный медицинский исследовательский центр онкологии им. Н. Н. Блохина, Москва, Россия
3 Институт неотложной и восстановительной хирургии им. В. К. Гусака, Донецк, Донецкая Народная Республика

Представленный клинический случай отражает современные возможности лечения ALK-позитивной рецидивирующей/рефрактерной (Р-Р) анапластической крупноклеточной лимфомы у детей и подростков. Для этого варианта лимфомы даже в случае Р-Р течения шанс на излечение остается относительно неплохим благодаря наличию эффективной таргетной терапии и высокой эффективности аллогенной трансплантации гемопоэтических стволовых клеток, которая может успешно применяться при данной патологии в том числе у пациентов вне ремиссии.

Ключевые слова

Анапластическая крупноклеточная лимфома, ALK+, рецидивирующее/рефрактерное течение, таргетная терапия, трансплантация гемопоэтических стволовых клеток.

Клинические случаи

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Зарема К. Абдулхаликова, Ильдар М. Бархатов, Вадим В. Байков, Мария В. Барабанщикова, Елена В. Морозова

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Нами приводится описание редкого случая прогрессии «тлеющего» системного мастоцитоза в тучноклеточный лейкоз. Проведено лечение злокачественного заболевания с применением таргетной терапии и достижением клинического ответа в течение 3 месяцев лечения.

Ключевые слова

Системный мастоцитоз, тучные клетки, аллогенная трансплантация костного мозга.

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Zarema K. Abdulkhalikova, Ildar M. Barkhatov, Vadim V. Baykov, Maria V. Barabanshikova, Elena V. Morozova

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RM Gorbacheva Research Institute of Pediatric Oncology, Hematology and Transplantology, Pavlov University, St. Petersburg, Russia


Correspondence:
Dr. Zarema K. Abdulkhalikova, RM Gorbacheva Research Institute of Pediatric Oncology, Hematology and Transplantology, Pavlov University, 6-8 L.Tolstoy St, 197022, St. Petersburg, Russia
Phone: +7 (965) 799-38-73
E-mail: dr.abdulhalikova@gmail.com


Citation: Abdulkhalikova ZK, Barkhatov IM, Baykov VV, et al. Transition from the smoldering systemic mastocytosis to chronic mast cell leukemia: a clinical case. Cell Ther Transplant 2022; 11(3-4): 83-86.

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We describe a rare clinical case of smoldering systemic mastocytosis which progressed to mast cell leukemia. The malignant disorder was treated with targeted therapy resulting into clinical improvement after 3 months during therapy.

Keywords

Systemic mastocytosis, mast cells, allogeneic bone marrow transplantation.

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Прогрессия «тлеющего» системного мастоцитоза в хронический тучноклеточный лейкоз (клинический случай)

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Зарема К. Абдулхаликова, Ильдар М. Бархатов, Вадим В. Байков, Мария В. Барабанщикова, Елена В. Морозова

НИИ детской онкологии, гематологии и трансплантологии им. Р. М. Горбачевой, Первый Санкт-Петербургский государственный медицинский университет им. акад. И. П. Павлова, Санкт-Петербург, Россия

Нами приводится описание редкого случая прогрессии «тлеющего» системного мастоцитоза в тучноклеточный лейкоз. Проведено лечение злокачественного заболевания с применением таргетной терапии и достижением клинического ответа в течение 3 месяцев лечения.

Ключевые слова

Системный мастоцитоз, тучные клетки, аллогенная трансплантация костного мозга.

Экспериментальные исследования

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Анна В. Лысенко1, Андрей И. Яременко2, Анна А. Зубарева3, Александр В. Ширшин4, Александр И. Любимов5, Елизавета А. Иванова1

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1 Отдел челюстно-лицевой хирургии НИИ стоматологии и челюстно-лицевой хирургии, Санкт-Петербург, Россия
2 Кафедра челюстно-лицевой хирургии, Первый Санкт-Петербургский государственный медицинский университет им. И. П. Павлова, Санкт-Петербург, Россия
3 Кафедра оториноларингологии, Первый Санкт-Петербургский государственный медицинский университет им. И. П. Павлова, Санкт-Петербург, Россия
4 Клиника рентгенорадиологии и ультразвуковой диагностики Военно-медицинской академии имени Кирова, факультет систем управления и робототехники, Университет ИТМО, Санкт-Петербург, Россия
5 1-е отделение усовершенствования хирургов, Военно-медицинская академия им. С.М. Кирова, Санкт-Петербург, Россия

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Амелобластомы и одонтогенные кисты имеют идентичный клинический и рентгенологический вид. В нашем исследовании мы демонстрируем важность тщательного рассмотрения радиологических особенностей, которые могут помочь в неинвазивной дифференциальной диагностике и обеспечении надлежащего лечения этих поражений.

Методы

Было проведено ретроспективное исследование, включавшее 18 КТ-изображений пациентов с новообразованиями челюсти (8 амелобластом и 10 зубочелюстных кист с гистопатологической верификацией). Каждое поражение было вручную сегментировано с помощью программного обеспечения 3D Slicer на КТ-изображениях, а текстурные особенности были извлечены с использованием расширения 3D Slicer Radiomics. Был проведен статистический анализ.

Результаты

После анализа текстуры мы не обнаружили (статистически значимых) различий в характеристиках формы и статистических значениях первого порядка этих поражений. Мы обнаружили статистически значимые различия по 13 признакам второго порядка зубочелюстных кист и амелобластом, большинство из которых тесно коррелировали. Был проведен множественный логистический регрессионный анализ для ранжирования признаков и определения наиболее значимых предикторов. Окончательная модель включала 2 признака (кластерный оттенок и IMC 1) и обеспечивала высокую прогностическую ценность (площадь под ROC=0,93).

Выводы

В нашем пилотном исследовании мы продемонстрирован новый метод неинвазивной дифференциальной диагностики новообразований челюстей на основе особенностей текстуры, извлеченных из данных КТ.

Ключевые слова

Радиомика, новообразования челюстей, амелобластома, одонтогенные кисты, компьютерная томография.

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Anna V. Lysenko1, Andrey I. Yaremenko2, Anna A. Zubareva3, Alexander V. Shirshin4, Aleksandr I. Lуubimov5, Elizaveta A. Ivanova1

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1 Department of Maxillofacial Surgery, Research Institute of Dentistry and Maxillofacial Surgery, St. Petersburg, Russia
2 Department of Maxillofacial Surgery, Pavlov University, St. Petersburg, Russia
3 Department of Otorhinolaryngology, Pavlov University, St. Petersburg, Russia
4 Clinic of X-ray Radiology and Ultrasound Diagnostics, Kirov’s Military Medical Academy, Faculty of control Systems and Robotics, ITMO University, St. Petersburg, Russia
5 1st Department for Surgeons’ Advanced Training, Kirov’s Military Medical Academy, St. Petersburg, Russia


Correspondence:
Dr. Anna V. Lysenko, Department of Maxillofacial Surgery, Research Institute of Dentistry and Maxillofacial Surgery, Pavlov University, 44 Petrogradskaya Emb., 197101, St. Petersburg, Russia
Phone: +7 (812) 429-03-33
E-mail: lysenko.anna@mail.ru


Citation: Lysenko AV, Yaremenko AI, Zubareva AA, et al. Application of radiomics in the differential diagnosis in ameloblastomas and dentigerous cysts. Part 2. Cell Ther Transplant 2022; 11(3-4): 93-98.

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Ameloblastomas and dentigerous cysts have an identical clinical and radiographic appearance. In our study we demonstrate the importance of radiological features careful consideration that can help in non-invasive differential diagnosis and ensuring appropriate management of these lesions.

Methods

This was a retrospective study including 18 CT images of patients with jaw neoplasm (8 ameloblastomas and 10 dentigerous cysts with histopathological verification). Each lesion was manually segmented using 3D Slicer software [1] on CT images, and textural features were extracted using 3D Slicer Radiomics extension [2]. Statistical analysis was performed.

Results

After texture analysis we found no (statistically significant) differences in the shape-based features and the first-order statistics values of these lesions. We found statistically significant differences in 13 second-order features of dentigerous cysts and ameloblastomas, most of them were closely correlated. Multiple logistic regression analysis was performed to rank features and to determine most significant predictors. The final model included 2 features (Cluster shade and IMC 1) and provided high predictive value (the area under a ROC=0.93).

Conclusions

Our pilot study demonstrates a new technique for non-invasive differential diagnosis of jaw neoplasms based on texture features extracted from CT-data.

Keywords

Radiomics, jaw neoplasms, ameloblastoma, dentigerous cysts, CT scan.

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Применение радиомики в дифференциальной диагностике амелобластом и одонтогенных кист челюстей: часть 2

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Анна В. Лысенко1, Андрей И. Яременко2, Анна А. Зубарева3, Александр В. Ширшин4, Александр И. Любимов5, Елизавета А. Иванова1

1 Отдел челюстно-лицевой хирургии НИИ стоматологии и челюстно-лицевой хирургии, Санкт-Петербург, Россия
2 Кафедра челюстно-лицевой хирургии, Первый Санкт-Петербургский государственный медицинский университет им. И. П. Павлова, Санкт-Петербург, Россия
3 Кафедра оториноларингологии, Первый Санкт-Петербургский государственный медицинский университет им. И. П. Павлова, Санкт-Петербург, Россия
4 Клиника рентгенорадиологии и ультразвуковой диагностики Военно-медицинской академии имени Кирова, факультет систем управления и робототехники, Университет ИТМО, Санкт-Петербург, Россия
5 1-е отделение усовершенствования хирургов, Военно-медицинская академия им. С.М. Кирова, Санкт-Петербург, Россия

Амелобластомы и одонтогенные кисты имеют идентичный клинический и рентгенологический вид. В нашем исследовании мы демонстрируем важность тщательного рассмотрения радиологических особенностей, которые могут помочь в неинвазивной дифференциальной диагностике и обеспечении надлежащего лечения этих поражений.

Методы

Было проведено ретроспективное исследование, включавшее 18 КТ-изображений пациентов с новообразованиями челюсти (8 амелобластом и 10 зубочелюстных кист с гистопатологической верификацией). Каждое поражение было вручную сегментировано с помощью программного обеспечения 3D Slicer на КТ-изображениях, а текстурные особенности были извлечены с использованием расширения 3D Slicer Radiomics. Был проведен статистический анализ.

Результаты

После анализа текстуры мы не обнаружили (статистически значимых) различий в характеристиках формы и статистических значениях первого порядка этих поражений. Мы обнаружили статистически значимые различия по 13 признакам второго порядка зубочелюстных кист и амелобластом, большинство из которых тесно коррелировали. Был проведен множественный логистический регрессионный анализ для ранжирования признаков и определения наиболее значимых предикторов. Окончательная модель включала 2 признака (кластерный оттенок и IMC 1) и обеспечивала высокую прогностическую ценность (площадь под ROC=0,93).

Выводы

В нашем пилотном исследовании мы продемонстрирован новый метод неинвазивной дифференциальной диагностики новообразований челюстей на основе особенностей текстуры, извлеченных из данных КТ.

Ключевые слова

Радиомика, новообразования челюстей, амелобластома, одонтогенные кисты, компьютерная томография.

Экспериментальные исследования

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1 Институт высокомолекулярных соединений РАН, Санкт-Петербург, Россия
2 Первый Санкт-Петербургский государственный медицинский университет им. акад. И. П. Павлова, Санкт-Петербург, Россия
3 Российский научный центр радиологии и хирургических технологий им. акад. А. М. Гранова, Санкт-Петербург, Россия

[TYPE] => HTML ) [~DESCRIPTION] => [~NAME] => Организации [~DEFAULT_VALUE] => Array ( [TEXT] => [TYPE] => HTML ) ) [SUMMARY_RU] => Array ( [ID] => 27 [TIMESTAMP_X] => 2015-09-02 18:01:20 [IBLOCK_ID] => 2 [NAME] => Описание/Резюме [ACTIVE] => Y [SORT] => 500 [CODE] => SUMMARY_RU [DEFAULT_VALUE] => Array ( [TEXT] => [TYPE] => HTML ) [PROPERTY_TYPE] => S [ROW_COUNT] => 1 [COL_COUNT] => 30 [LIST_TYPE] => L [MULTIPLE] => N [XML_ID] => 27 [FILE_TYPE] => [MULTIPLE_CNT] => 5 [TMP_ID] => [LINK_IBLOCK_ID] => 0 [WITH_DESCRIPTION] => N [SEARCHABLE] => N [FILTRABLE] => N [IS_REQUIRED] => N [VERSION] => 1 [USER_TYPE] => HTML [USER_TYPE_SETTINGS] => Array ( [height] => 200 ) [HINT] => [PROPERTY_VALUE_ID] => 29589 [VALUE] => Array ( [TEXT] => <p style="text-align: justify;">Исследован метод подкожного введения лабораторным крысам систем доставки противоонкологического препарата доксорубицин (ДОХ). В качестве систем доставки использованы СаСО<sub>3</sub> ватериты, покрытые полианионом декстрансульфатом Na, применяемые ранее для интраперитонеального введения ДОХ. Концентрационные профили высвобождения ДОХ в плазму крови крыс после подкожного введения систем доставки, содержащих по 4 мг ДОХ, получали при помощи ВЭЖХ. Рабочая концентрация ДОХ в крови после подкожного введения поддерживается в течение 10 дней, что сопоставимо с результатами интраперитонеального введения тех же носителей ДОХ. Для оценки токсичности использованных систем доставки ДОХ проведены гистологические исследования органов крыс (печени, кишки, легкого) после выведения животных из эксперимента на 17 и 23 сутки. Гистологический анализ исследуемого материала показал морфологические изменения в печени и легком, в то время как в кишке морфологическая картина без изменений. Изменений в поведении, в том числе пищевом, у животных не наблюдали. </p> <h2>Ключевые слова</h2> <p style="text-align: justify;">Доксорубицин, система доставки лекарств, карбонат кальция СаСО<sub>3</sub>, декстран сульфат, плазма крови, подкожное введение.</p> [TYPE] => HTML ) [DESCRIPTION] => [VALUE_ENUM] => [VALUE_XML_ID] => [VALUE_SORT] => [~VALUE] => Array ( [TEXT] =>

Исследован метод подкожного введения лабораторным крысам систем доставки противоонкологического препарата доксорубицин (ДОХ). В качестве систем доставки использованы СаСО3 ватериты, покрытые полианионом декстрансульфатом Na, применяемые ранее для интраперитонеального введения ДОХ. Концентрационные профили высвобождения ДОХ в плазму крови крыс после подкожного введения систем доставки, содержащих по 4 мг ДОХ, получали при помощи ВЭЖХ. Рабочая концентрация ДОХ в крови после подкожного введения поддерживается в течение 10 дней, что сопоставимо с результатами интраперитонеального введения тех же носителей ДОХ. Для оценки токсичности использованных систем доставки ДОХ проведены гистологические исследования органов крыс (печени, кишки, легкого) после выведения животных из эксперимента на 17 и 23 сутки. Гистологический анализ исследуемого материала показал морфологические изменения в печени и легком, в то время как в кишке морфологическая картина без изменений. Изменений в поведении, в том числе пищевом, у животных не наблюдали.

Ключевые слова

Доксорубицин, система доставки лекарств, карбонат кальция СаСО3, декстран сульфат, плазма крови, подкожное введение.

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Natalia N. Sudareva1,2, Olga М. Suvorova1, Konstantin A. Kolbe1, Dmitry N. Suslov3, Oleg V. Galibin2, Alexander D. Vilesov1, Galina Y. Yukina2, Elena G. Sukhorukova2

[TYPE] => HTML ) [~DESCRIPTION] => [~NAME] => Author [~DEFAULT_VALUE] => Array ( [TEXT] => [TYPE] => HTML ) ) [ORGANIZATION_EN] => Array ( [ID] => 38 [TIMESTAMP_X] => 2015-09-02 18:02:59 [IBLOCK_ID] => 2 [NAME] => Organization [ACTIVE] => Y [SORT] => 500 [CODE] => ORGANIZATION_EN [DEFAULT_VALUE] => Array ( [TEXT] => [TYPE] => HTML ) [PROPERTY_TYPE] => S [ROW_COUNT] => 1 [COL_COUNT] => 30 [LIST_TYPE] => L [MULTIPLE] => N [XML_ID] => 38 [FILE_TYPE] => [MULTIPLE_CNT] => 5 [TMP_ID] => [LINK_IBLOCK_ID] => 0 [WITH_DESCRIPTION] => N [SEARCHABLE] => N [FILTRABLE] => N [IS_REQUIRED] => N [VERSION] => 1 [USER_TYPE] => HTML [USER_TYPE_SETTINGS] => Array ( [height] => 200 ) [HINT] => [PROPERTY_VALUE_ID] => 29592 [VALUE] => Array ( [TEXT] => <p><sup>1</sup> Institute of Macromolecular Compounds RAS, St. Petersburg, Russia<br> <sup>2</sup> Pavlov University, St. Petersburg, Russia<br> <sup>3</sup> Granov Russian Research Center for Radiology and Surgical Technologies, St. Petersburg, Russia</p><br> <p><b>Correspondence:</b><br> Dr. Natalia N. Sudareva, Institute of Macromolecular Compounds RAS, St. Petersburg, Russia<br> E-mail: nnsas@mail.ru</p><br> <p><b>Citation:</b> Sudareva NN, Suvorova OM, Kolbe KA et al. Subcutaneous administration of doxorubicin delivery systems based on CaCO<sub>3</sub> vaterites coated with dextran sulfate. Cell Ther Transplant 2022; 11(3-4): 87-92.</p> [TYPE] => HTML ) [DESCRIPTION] => [VALUE_ENUM] => [VALUE_XML_ID] => [VALUE_SORT] => [~VALUE] => Array ( [TEXT] =>

1 Institute of Macromolecular Compounds RAS, St. Petersburg, Russia
2 Pavlov University, St. Petersburg, Russia
3 Granov Russian Research Center for Radiology and Surgical Technologies, St. Petersburg, Russia


Correspondence:
Dr. Natalia N. Sudareva, Institute of Macromolecular Compounds RAS, St. Petersburg, Russia
E-mail: nnsas@mail.ru


Citation: Sudareva NN, Suvorova OM, Kolbe KA et al. Subcutaneous administration of doxorubicin delivery systems based on CaCO3 vaterites coated with dextran sulfate. Cell Ther Transplant 2022; 11(3-4): 87-92.

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Subcutaneous administration of drug delivery systems containing antitumor drug doxorubicin (DOX) was studied in laboratory rats. The drug delivery systems consisted of СаСО3 vaterites coated with the dextran sulfate polyanion; these particles have been used earlier for intraperitoneal administration of DOX. Time profile of DOX release into blood plasma of rats after subcutaneous administration of the delivery systems loaded with 4 mg of DOX was studied by high-performance liquid chromatography (HPLC). The working concentration of DOX in blood was maintained for 10 days after subcutaneous administration, which is comparable with the results obtained after intraperitoneal introduction of similar DOX carriers. To estimate toxicity of the used DOX delivery systems, histological studies of different rat organs (liver, intestines, lungs) were performed at 17 and 23 days after beginning of the experiment. Histological analysis of the material revealed morphological changes in rat liver and lungs, while the morphological pattern of intestines remained unchanged. No changes in animal behavior (including their feeding behavior) were observed.

Keywords

Doxorubicin, drug delivery system, calcium carbonate, dextran sulfate, blood plasma, subcutaneous administration.

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Подкожное введение доксорубицина в системах доставки, состоящих из СаСО3 ватеритов, покрытых декстран сульфатом

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Наталия Н. Сударева1,2, Ольга М. Суворова1, Константин А. Колбе1, Дмитрий Н. Суслов3, Олег В. Галибин2, Александр Д. Вилесов1, Галина Ю. Юкина2, Елена Г. Сухорукова2

1 Институт высокомолекулярных соединений РАН, Санкт-Петербург, Россия
2 Первый Санкт-Петербургский государственный медицинский университет им. акад. И. П. Павлова, Санкт-Петербург, Россия
3 Российский научный центр радиологии и хирургических технологий им. акад. А. М. Гранова, Санкт-Петербург, Россия

Исследован метод подкожного введения лабораторным крысам систем доставки противоонкологического препарата доксорубицин (ДОХ). В качестве систем доставки использованы СаСО3 ватериты, покрытые полианионом декстрансульфатом Na, применяемые ранее для интраперитонеального введения ДОХ. Концентрационные профили высвобождения ДОХ в плазму крови крыс после подкожного введения систем доставки, содержащих по 4 мг ДОХ, получали при помощи ВЭЖХ. Рабочая концентрация ДОХ в крови после подкожного введения поддерживается в течение 10 дней, что сопоставимо с результатами интраперитонеального введения тех же носителей ДОХ. Для оценки токсичности использованных систем доставки ДОХ проведены гистологические исследования органов крыс (печени, кишки, легкого) после выведения животных из эксперимента на 17 и 23 сутки. Гистологический анализ исследуемого материала показал морфологические изменения в печени и легком, в то время как в кишке морфологическая картина без изменений. Изменений в поведении, в том числе пищевом, у животных не наблюдали.

Ключевые слова

Доксорубицин, система доставки лекарств, карбонат кальция СаСО3, декстран сульфат, плазма крови, подкожное введение.

Некролог

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Рюдигер Хелльман

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Гейдельбергский университет и European LeukemiaNet, Вайнхайм, Германия

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Центр им. В. А. Алмазова и российское гематологическое сообщество потеряли лидера и организатора международных программ, я потерял друга. В октябре прошлого года скончался профессор Андрей Юрьевич Зарицкий, который стал пионером создания нового Института гематологии в Национальном медицинском исследовательском центре имени В. А. Алмазова. Центральное место в его работе занимала идея включения института в программы сотрудничества, что позволило создать известный и конкурентоспособный медицинский центр. Сегодняшний уровень наших дискуссий отражает видение А. Ю. Зарицким задач сотрудничества в области гематологии.

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Prof. Rüdiger Hehlmann

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Heidelberg University, Mannheim, and European LeukemiaNet, Weinheim, Germany


Correspondence:
Prof. Dr. Rüdiger Hehlmann, Heidelberg University, Mannheim, and European LeukemiaNet, Weinheim, Germany
E-mail: hehlmann.eln@gmail.com


Citation: Hehlmann R. Tribute to Prof. Andrey Zaritskey from an international perspective. Cell Ther Transplant 2022; 11(3-4): 99-103.

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The Almazov Centre and the Russian hematologic community lost a leader and communicator and I lost a friend. Prof. Andrey Zaritskey who pioneered the new Institute of Hematology at the V. Almazov National Medical Research Center passed away in October 2021. Central to his work was his vision of embedding his institute in a network of cooperative studies, thereby creating an institute that was internationally visible and competitive. The Professor Zaritskey Discussion Club which took place in St. Petersburg on September 2, 2022 reflects his vision of cooperation in the field of hematology.

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Зарицким в 2004 или 2005 году, когда он настоял на том, чтобы и Центр им. В. А. Алмазова, и Первый Санкт-Петербургский государственный медицинский университет им. И. Павлова (ПСПбГМУ) присоединились к Европейской сети по изучению лейкозов (ELN). Он был единственным исследователем ELN, настаивавшим на заключении договора с обоими учреждениями – Национальным медицинским исследовательским Центром им. В. А. Алмазова и Первым Санкт-Петербургским государственным медицинским университетом им. И. П. Павлова, но его настойчивость способствовала сотрудничеству в дальнейшем между НИИ им. Р. М. Горбачевой и ELN. На меня произвели впечатление его обширные исследовательские интересы, его дух сотрудничества и его видение. По его приглашению я посетил Санкт-Петербург в сентябре 2006 года, положив начало 15-летнему плодотворному сотрудничеству в области лейкемии. Это была одна из его первых встреч с докладами иностранных участников. На встрече также присутствовали московские коллеги – профессор В. Г. Савченко и Е. Н. Паровичникова. В. Г. Савченко был моим старым другом, с которым я познакомился в Вильзеде около 1990 года, он безвременно ушел из жизни за 3 месяца до А. Ю. Зарицкого, в июле 2021 года. </p> <p style="text-align: justify;">В то время, в 2006 году, Центр имени В. А. Алмазова находился в стадии развития, и там велись работы, главным образом, в области кардиологии, болезней крови и эндокринологии, а А. Ю. Зарицкий был назначен руководителем секции гематологии. Андрей воспользовался случаем, чтобы с гордостью показать мне развивающийся Центр Алмазова и познакомить меня со своим руководителем профессором Евгением Владимировичем Шляхто. Несмотря на то, что все только начиналось, он видел открывающиеся возможности и имел план действий, согласованный с профессором Е. В. Шляхто. Он также воспользовался случаем, чтобы показать мне красоты Санкт-Петербурга. С помощью Эльзы Галактионовны Ломайя нам удалось посетить прекрасный Екатерининский дворец с реставрированной янтарной комнатой. </p> <p style="text-align: justify;">В последующие годы Центр им. В. А. Алмазова превратился в Национальный медицинский исследовательский центр, один из крупнейших в России. Огромное значение для успеха А. Ю. Зарицкого имело доверие и постоянная поддержка со стороны председателя Центра, профессора Евгения Владимировича Шляхто – известного кардиолога. В 2008 году Андрей Зарицкий был назначен директором нового Института гематологии Национального медицинского исследовательского центра имени В. А. Алмазова. В последующие годы он с большой энергией создавал новый институт с исследовательской базой и, что особенно важно, с отделением трансплантации. А. Ю. Зарицкий был его директором почти 14 лет. Доступ к международному регистру доноров в то время все еще оставался проблемой. </p> <p style="text-align: justify;">В том же году, снова в Вильзеде, я познакомился с профессором Борисом Афанасьевым и Алексеем Чухловиным. Приглашение от профессора Б. В. Афанасьева на II Симпозиум памяти Р. М. Горбачевой в Санкт-Петербурге положило начало сотрудничеству НИИ им. Горбачевой с European LeukemiaNet, чему способствовал уже существующий договор с ПСПбГМУ им. И. П. Павлова, заключенный по настоянию А. Ю. Зарицкого. С самого начала нашего сотрудничества я понял, какое значение профессор А. Ю. Зарицкий придавал национальным и международным связям. Четыре программы сотрудничества были особенно заметными и успешными. Усилия Андрея по ознакомлению своих международных партнеров с его и российским наследием иллюстрируют некоторые фотографии, за которые я благодарю Эльзу Галактионовну Ломайя и ее команду. </p> <p style="text-align: justify;">В частности, мы многие годы сотрудничали в рамках European LeukemiaNet, одним из первых участников которого был Медицинский Центр им. В. А. Алмазова, в результате чего в 2014 году А. Ю. Зарицкий был избран членом комиссии по разработке престижных рекомендаций ELN по лечению хронического миелоидного лейкоза. Помимо Андрея, вы можете видеть на фото Эльзу Галактионовну Ломайя, наших московских коллег Елену Николаевну Паровичникову, Анну Григорьевну Туркину, Сергея Михайловича Куликова, Екатерину Юрьевну Челышеву и многих других (Рис. 1). Эти рекомендации были опубликованы в 2020 году (Рис. 2). Кроме того, А. Ю. Зарицкий участвовал в проектах по стволовым клеткам с профессором Энтони Хо из Гейдельбергского университета при поддержке правительства Германии и Европейского Союза, принимал участие в деятельности Европейских исследований в области ХМЛ (EI-CML), и проведении 22-го заседания EI-CML в Санкт-Петербурге в 2014 году (Рис. 3). Наряду с этим, он руководил совместными проектами с профессорами Майклом Андреефф и Агопом Кантарджяном из Онкологического центра MD Anderson (Хьюстон, США). Эти результаты были представлены на совместном симпозиуме в Санкт-Петербурге в июле 2017 года. В 2011 году в знак признания его организационной деятельности и сотрудничества, Андрей Зарицкий получил награду ELN Merit Award за общеевропейскую интеграцию работ по исследованию лейкозов (Рис. 4). </p> <p style="text-align: justify;">Почти каждый год Андрей Зарицкий организовывал в Центре им. В. А. Алмазова национальные и международные встречи, посвященные новым разработкам в области лейкемии, стволовых клеток и трансплантации (Рис. 5). Члены его группы проводили время в европейских или американских центрах с целью обучения или сотрудничества. Кроме того, А. Ю. Зарицкий пропагандировал Центр Алмазова и свой институт, выступая с лекциями по всей России. Я имел удовольствие и честь сопровождать его на некоторых из этих мероприятий. Наши визиты в Самару и Иркутск были впечатляющими, демонстрируя с лучшей стороны российские передовые исследования и разработки. Так, в Самаре была неоценима помощь и участие профессора Игоря Леонидовича Давыдкина, старого друга профессора А. Ю. Зарицкого. При осуществлении этой деятельности Андрей показал себя типичным представителем Петербурга, стремясь выйти далеко за пределы России, но в интересах и для дальнейшего развития города и России в области гематологии. Он гордился Россией, но беспокоился, чтобы предпосылки для продолжения международных совместных исследований оставались стабильными. </p> <p style="text-align: justify;">За 16 лет, которые я имел удовольствие знать и сотрудничать с Андреем Зарицким, я понял, что ключ к его успеху – не только академический блеск. Важнее всего была его отзывчивость, открытость, надежность, скромность, но, тем не менее – решительность. Он знал, что для успешного и продолжительного сотрудничества необходимы доверие и дружба, что необходимо учитывать культурный фон участников сотрудничества, а также собственное наследие, которое должно быть понято другой стороной. Возможно, он научился этому способу общения с международными партнерами благодаря мудрости основателей группы европейских исследований в области хронического миелоидного лейкоза, в частности, легендарного итальянского гематолога Санте Тура, который умер всего за 5 дней до Андрея, однако – в возрасте 92 лет. По традиции Санте Тура, начиная с 1993 года, эта группа традиционно проводит свои двухдневные встречи по всей Европе, посвящая полдня знакомству с культурным наследием принимающей страны. Таким образом, зарубежные коллеги узнавали о России и по достоинству оценивали страну, так же как сам А. Ю. Зарицкий был открыт для других стран и культур. В эти успешные годы он не забывал о тех, кто работал с ним и помогал ему сделать все это возможным. В Медицинском исследовательском центре им. В. А. Алмазова, сколько я себя помню, Эльза Галактионовна Ломайя была рядом с ним, всегда поддерживала и всегда эффективно работала. Андрей отдавал должное своим коллегам и сотрудникам, а также своим сторонникам. Он неоднократно упоминал, как важно для него было то, что профессоры Евгений Владимирович Шляхто и Александра Олеговна Конради открыты его предложениям и дружественно отвечают на его запросы. </p> <p style="text-align: justify;">Ключевыми моментами в профессиональной карьере Андрея Зарицкого стало успешное сотрудничество с ELN, в частности по хроническому миелоидному лейкозу, и с Онкологическим центром MD Anderson. Их общий симпозиум состоялся в июле 2017 года в Санкт-Петербурге. Для меня эта встреча была высшей точкой его карьеры. Андрею было 67 лет, он был успешен, известен на международном уровне и уважаем своими коллегами – карьера, достойная восхищения. Однако, когда он не посетил ни конференцию ASH в конце 2017 года, ни симпозиум ELN в Венеции в марте 2018 года, стало ясно, что что-то не так. Я знал, что он был заядлым курильщиком, но теперь у него развился рак легкого. </p> <p style="text-align: justify;">Несмотря на свою болезнь, он возобновил работу в 2018 году и продолжал всю свою деятельность без перерыва. Когда я приехал в Санкт-Петербург в 2018 году, он, как обычно, встретил меня в аэропорту, чтобы отвезти в Валдайский монастырь, памятник культуры на пути в Москву, рядом с истоком Волги. Он пытался преуменьшить значение своего рака, но его внешний вид выдавал истинное состояние. Будучи дисциплинированным, он продолжал руководить своей группой даже после того, как его положили в реанимацию в начале 2021 года, планируя, как обычно, 4-й Санкт-Петербургский медицинский инновационный форум в мае, включая руководство с больничной койки одним из заседаний. Он и Эльза Галактионовна договорились, что один из его молодых врачей встретит меня далеко за полночь в Пулково с приветственным плакатом на немецком языке. Я был глубоко тронут. Мы все еще надеялись, что ситуация изменится к лучшему. Он планировал вскоре покинуть больницу и напомнил мне о необходимости посетить Валаамский монастырь на Ладожском озере, о чем он неоднократно меня просил. </p> <p style="text-align: justify;">Когда я снова увидел его 20 сентября 2021 года, его состояние, к сожалению, ухудшилось. Он все еще надеялся, но знал, что его ждет. Он был доволен моей поездкой на Валаам, который я посетил накануне, и мы поговорили о симпозиуме ELN в Мангейме, запланированном на март 2022 года. Когда я сказал ему на прощание, что с нетерпением жду новой встречи с ним в Мангейме в марте следующего года или в другом месте, он сразу понял: под другим местом вы подразумеваете рай, не так ли? </p> <p style="text-align: justify;">С Андреем Зарицким российская гематология и Национальный медицинский исследовательский центр имени В. А. Алмазова потерял крупного ученого и организатора международных программ, Россия потеряла посла. Его наследие – международные совместные исследования в интересах пациентов, его института, Санкт-Петербурга и России. Они будут связаны с памятью о профессоре Андрее Юрьевиче Зарицком. </p> [TYPE] => HTML ) [DESCRIPTION] => [VALUE_ENUM] => [VALUE_XML_ID] => [VALUE_SORT] => [~VALUE] => Array ( [TEXT] =>

Я познакомился с А. Ю. Зарицким в 2004 или 2005 году, когда он настоял на том, чтобы и Центр им. В. А. Алмазова, и Первый Санкт-Петербургский государственный медицинский университет им. И. Павлова (ПСПбГМУ) присоединились к Европейской сети по изучению лейкозов (ELN). Он был единственным исследователем ELN, настаивавшим на заключении договора с обоими учреждениями – Национальным медицинским исследовательским Центром им. В. А. Алмазова и Первым Санкт-Петербургским государственным медицинским университетом им. И. П. Павлова, но его настойчивость способствовала сотрудничеству в дальнейшем между НИИ им. Р. М. Горбачевой и ELN. На меня произвели впечатление его обширные исследовательские интересы, его дух сотрудничества и его видение. По его приглашению я посетил Санкт-Петербург в сентябре 2006 года, положив начало 15-летнему плодотворному сотрудничеству в области лейкемии. Это была одна из его первых встреч с докладами иностранных участников. На встрече также присутствовали московские коллеги – профессор В. Г. Савченко и Е. Н. Паровичникова. В. Г. Савченко был моим старым другом, с которым я познакомился в Вильзеде около 1990 года, он безвременно ушел из жизни за 3 месяца до А. Ю. Зарицкого, в июле 2021 года.

В то время, в 2006 году, Центр имени В. А. Алмазова находился в стадии развития, и там велись работы, главным образом, в области кардиологии, болезней крови и эндокринологии, а А. Ю. Зарицкий был назначен руководителем секции гематологии. Андрей воспользовался случаем, чтобы с гордостью показать мне развивающийся Центр Алмазова и познакомить меня со своим руководителем профессором Евгением Владимировичем Шляхто. Несмотря на то, что все только начиналось, он видел открывающиеся возможности и имел план действий, согласованный с профессором Е. В. Шляхто. Он также воспользовался случаем, чтобы показать мне красоты Санкт-Петербурга. С помощью Эльзы Галактионовны Ломайя нам удалось посетить прекрасный Екатерининский дворец с реставрированной янтарной комнатой.

В последующие годы Центр им. В. А. Алмазова превратился в Национальный медицинский исследовательский центр, один из крупнейших в России. Огромное значение для успеха А. Ю. Зарицкого имело доверие и постоянная поддержка со стороны председателя Центра, профессора Евгения Владимировича Шляхто – известного кардиолога. В 2008 году Андрей Зарицкий был назначен директором нового Института гематологии Национального медицинского исследовательского центра имени В. А. Алмазова. В последующие годы он с большой энергией создавал новый институт с исследовательской базой и, что особенно важно, с отделением трансплантации. А. Ю. Зарицкий был его директором почти 14 лет. Доступ к международному регистру доноров в то время все еще оставался проблемой.

В том же году, снова в Вильзеде, я познакомился с профессором Борисом Афанасьевым и Алексеем Чухловиным. Приглашение от профессора Б. В. Афанасьева на II Симпозиум памяти Р. М. Горбачевой в Санкт-Петербурге положило начало сотрудничеству НИИ им. Горбачевой с European LeukemiaNet, чему способствовал уже существующий договор с ПСПбГМУ им. И. П. Павлова, заключенный по настоянию А. Ю. Зарицкого. С самого начала нашего сотрудничества я понял, какое значение профессор А. Ю. Зарицкий придавал национальным и международным связям. Четыре программы сотрудничества были особенно заметными и успешными. Усилия Андрея по ознакомлению своих международных партнеров с его и российским наследием иллюстрируют некоторые фотографии, за которые я благодарю Эльзу Галактионовну Ломайя и ее команду.

В частности, мы многие годы сотрудничали в рамках European LeukemiaNet, одним из первых участников которого был Медицинский Центр им. В. А. Алмазова, в результате чего в 2014 году А. Ю. Зарицкий был избран членом комиссии по разработке престижных рекомендаций ELN по лечению хронического миелоидного лейкоза. Помимо Андрея, вы можете видеть на фото Эльзу Галактионовну Ломайя, наших московских коллег Елену Николаевну Паровичникову, Анну Григорьевну Туркину, Сергея Михайловича Куликова, Екатерину Юрьевну Челышеву и многих других (Рис. 1). Эти рекомендации были опубликованы в 2020 году (Рис. 2). Кроме того, А. Ю. Зарицкий участвовал в проектах по стволовым клеткам с профессором Энтони Хо из Гейдельбергского университета при поддержке правительства Германии и Европейского Союза, принимал участие в деятельности Европейских исследований в области ХМЛ (EI-CML), и проведении 22-го заседания EI-CML в Санкт-Петербурге в 2014 году (Рис. 3). Наряду с этим, он руководил совместными проектами с профессорами Майклом Андреефф и Агопом Кантарджяном из Онкологического центра MD Anderson (Хьюстон, США). Эти результаты были представлены на совместном симпозиуме в Санкт-Петербурге в июле 2017 года. В 2011 году в знак признания его организационной деятельности и сотрудничества, Андрей Зарицкий получил награду ELN Merit Award за общеевропейскую интеграцию работ по исследованию лейкозов (Рис. 4).

Почти каждый год Андрей Зарицкий организовывал в Центре им. В. А. Алмазова национальные и международные встречи, посвященные новым разработкам в области лейкемии, стволовых клеток и трансплантации (Рис. 5). Члены его группы проводили время в европейских или американских центрах с целью обучения или сотрудничества. Кроме того, А. Ю. Зарицкий пропагандировал Центр Алмазова и свой институт, выступая с лекциями по всей России. Я имел удовольствие и честь сопровождать его на некоторых из этих мероприятий. Наши визиты в Самару и Иркутск были впечатляющими, демонстрируя с лучшей стороны российские передовые исследования и разработки. Так, в Самаре была неоценима помощь и участие профессора Игоря Леонидовича Давыдкина, старого друга профессора А. Ю. Зарицкого. При осуществлении этой деятельности Андрей показал себя типичным представителем Петербурга, стремясь выйти далеко за пределы России, но в интересах и для дальнейшего развития города и России в области гематологии. Он гордился Россией, но беспокоился, чтобы предпосылки для продолжения международных совместных исследований оставались стабильными.

За 16 лет, которые я имел удовольствие знать и сотрудничать с Андреем Зарицким, я понял, что ключ к его успеху – не только академический блеск. Важнее всего была его отзывчивость, открытость, надежность, скромность, но, тем не менее – решительность. Он знал, что для успешного и продолжительного сотрудничества необходимы доверие и дружба, что необходимо учитывать культурный фон участников сотрудничества, а также собственное наследие, которое должно быть понято другой стороной. Возможно, он научился этому способу общения с международными партнерами благодаря мудрости основателей группы европейских исследований в области хронического миелоидного лейкоза, в частности, легендарного итальянского гематолога Санте Тура, который умер всего за 5 дней до Андрея, однако – в возрасте 92 лет. По традиции Санте Тура, начиная с 1993 года, эта группа традиционно проводит свои двухдневные встречи по всей Европе, посвящая полдня знакомству с культурным наследием принимающей страны. Таким образом, зарубежные коллеги узнавали о России и по достоинству оценивали страну, так же как сам А. Ю. Зарицкий был открыт для других стран и культур. В эти успешные годы он не забывал о тех, кто работал с ним и помогал ему сделать все это возможным. В Медицинском исследовательском центре им. В. А. Алмазова, сколько я себя помню, Эльза Галактионовна Ломайя была рядом с ним, всегда поддерживала и всегда эффективно работала. Андрей отдавал должное своим коллегам и сотрудникам, а также своим сторонникам. Он неоднократно упоминал, как важно для него было то, что профессоры Евгений Владимирович Шляхто и Александра Олеговна Конради открыты его предложениям и дружественно отвечают на его запросы.

Ключевыми моментами в профессиональной карьере Андрея Зарицкого стало успешное сотрудничество с ELN, в частности по хроническому миелоидному лейкозу, и с Онкологическим центром MD Anderson. Их общий симпозиум состоялся в июле 2017 года в Санкт-Петербурге. Для меня эта встреча была высшей точкой его карьеры. Андрею было 67 лет, он был успешен, известен на международном уровне и уважаем своими коллегами – карьера, достойная восхищения. Однако, когда он не посетил ни конференцию ASH в конце 2017 года, ни симпозиум ELN в Венеции в марте 2018 года, стало ясно, что что-то не так. Я знал, что он был заядлым курильщиком, но теперь у него развился рак легкого.

Несмотря на свою болезнь, он возобновил работу в 2018 году и продолжал всю свою деятельность без перерыва. Когда я приехал в Санкт-Петербург в 2018 году, он, как обычно, встретил меня в аэропорту, чтобы отвезти в Валдайский монастырь, памятник культуры на пути в Москву, рядом с истоком Волги. Он пытался преуменьшить значение своего рака, но его внешний вид выдавал истинное состояние. Будучи дисциплинированным, он продолжал руководить своей группой даже после того, как его положили в реанимацию в начале 2021 года, планируя, как обычно, 4-й Санкт-Петербургский медицинский инновационный форум в мае, включая руководство с больничной койки одним из заседаний. Он и Эльза Галактионовна договорились, что один из его молодых врачей встретит меня далеко за полночь в Пулково с приветственным плакатом на немецком языке. Я был глубоко тронут. Мы все еще надеялись, что ситуация изменится к лучшему. Он планировал вскоре покинуть больницу и напомнил мне о необходимости посетить Валаамский монастырь на Ладожском озере, о чем он неоднократно меня просил.

Когда я снова увидел его 20 сентября 2021 года, его состояние, к сожалению, ухудшилось. Он все еще надеялся, но знал, что его ждет. Он был доволен моей поездкой на Валаам, который я посетил накануне, и мы поговорили о симпозиуме ELN в Мангейме, запланированном на март 2022 года. Когда я сказал ему на прощание, что с нетерпением жду новой встречи с ним в Мангейме в марте следующего года или в другом месте, он сразу понял: под другим местом вы подразумеваете рай, не так ли?

С Андреем Зарицким российская гематология и Национальный медицинский исследовательский центр имени В. А. Алмазова потерял крупного ученого и организатора международных программ, Россия потеряла посла. Его наследие – международные совместные исследования в интересах пациентов, его института, Санкт-Петербурга и России. Они будут связаны с памятью о профессоре Андрее Юрьевиче Зарицком.

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В память о профессоре Андрее Зарицком и его международной деятельности

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Рюдигер Хелльман

Гейдельбергский университет и European LeukemiaNet, Вайнхайм, Германия

Центр им. В. А. Алмазова и российское гематологическое сообщество потеряли лидера и организатора международных программ, я потерял друга. В октябре прошлого года скончался профессор Андрей Юрьевич Зарицкий, который стал пионером создания нового Института гематологии в Национальном медицинском исследовательском центре имени В. А. Алмазова. Центральное место в его работе занимала идея включения института в программы сотрудничества, что позволило создать известный и конкурентоспособный медицинский центр. Сегодняшний уровень наших дискуссий отражает видение А. Ю. Зарицким задач сотрудничества в области гематологии.