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Introduction

The T-cell/natural killer (NK) cell lymphomas are a heterogeneous group of generally aggressive neoplasms that constitute less than 10-15 percent of all non-Hodgkin lymphomas (NHLs) in adults [1, 2]. Modern classification of T/NK-cell lymphomas was developed on the basis of histological, immunohistochemical studies of tumor tissue and clinical presentation of lymphomas. In 2016, the World Health Organization classification revised the classification of both nodal and extranodal T/NK-cell lymphomas, which led to the introduction of new temporary structures [3]. Many of these changes were caused by the results of genomic studies using approaches to study gene expression profiling (GEP) and the genetic landscape of T/NK cell lymphomas. However, despite advances in molecular diagnostic methods, histological examination of tumor tissue and clinical manifestations remain the main diagnostic approach.

Another area of research concerns dismal outcomes in the patients with T/NK-cell lymphomas, except for anaplastic large-cell lymphoma (ALCL) positive for anaplastic lymphoma kinase (ALK) [4]. There are currently no successful treatment standards for the T/NK-cell lymphomas, both in the first-line therapy, and in refractory/relapsed (r/r) settings. Today, almost 70% of patients undergoing first-line therapy develop a relapse or refractory disease. A review of the scientific literature allowed us to identify a range of therapeutic options for patients with T/NK-cell lymphomas [5]. It includes the following approaches:
- Hematopoietic stem cells transplantation (HSCT);
- Therapy with monoclonal antibodies (Mabs), e.g., anti-CD30 antibody-drug conjugate (Brentuximab vedotin), anti-CC chemokine receptor 4 antibodies (Mogamulizumab), a monoclonal antibody that binds to CD52 (Alemtuzumab), the monoclonal anti-vascular endothelial growth factor (Bevacizumab) [6-19];
- ALK inhibitors (Crizotinib, Ceritinib) [20];
- Therapy with immune checkpoint inhibitors, e.g., Nivolumab, Pembrolizumab, Ipilimumab, Durvalumab [21-27];
- Histone deacetylase inhibitors (Belinostat, Panobinostat, Chidamide, Romidepsin, Vorinostat) [28-34];
- CAR-T/NK-cell therapy [35, 36];
- In situ vaccination [37].

There are a lot of studies and a large number of drugs being introduced into clinical studies, but at the present time, greatest evidence base should be recognized for brentuximab and bone marrow transplantation. E.g., patients with r/r T/NK-cell lymphomas who received hematopoietic stem cell transplantation (allogeneic and/or autologous) had a better outcome compared to the subset of non-transplanted patients (3-year survival rates of 48% and 18%, respectively) [5]. These conclusions also supported by data of Abekasis et al., demonstrating that autologous and/or allogeneic HSCT is an effective and safe option for the consolidation of patients with TCL [38].

Recently published results of a clinical study ECHELON-2 showed that front-line treatment with Adcetris (brentuximab vedotin) + CHP protocol is superior to CHOP for patients with CD30-positive peripheral T-cell lymphomas, thus suggesting that A+CHP is likely to be the standard first-line therapy [39].

Also, brentuximab vedotin showed good results in the treatment of r/r CD30 positive TCL [40]. Mostly, there were anaplastic large cell lymphoma (ALСL), angioimmunoblastic T-cell lymphoma (AITL), Sézary syndrome and Mycosis Fungoides (MF) [7]. The objective response was from 92% to 40%, with best results obtained in ALСL treatment [41, 42]. These methods are actively used at our center.

Hence, the aim of this study was to present our single-center experience in the treatment of patients with T/NK-cell lymphomas.

Patients and methods

We analyzed data of 47 patients with TCL eligible for stem cells transplantation treated in the R. Gorbacheva Memorial Research Institute of Pediatric Oncology, Hematology and Transplantation at the Pavlov University from 2005 to 2019 including 44 cases with r/r TCL and 3 patients being in complete response after first-line therapy. Among them, 10 patients were diagnosed with anaplastic large cell lymphoma (ALK+); 5 cases with anaplastic large cell lymphoma (ALK); 4 cases with angioimmunoblastic TCL (AITL); 4 patients with hepatosplenic T-cell lymphoma (HSTCL); 1 case of γδ T cell lymphoma (γδ TCL); 20 patients with peripheral T-cell lymphoma not otherwise specified (PTCL-NOS); 1 patient with mucosis fungoides (MF); 1, with primary cutaneous CD4+ T-cell lymphoma (CD4+ PCSM-TCL), and one patient with subcutaneous panniculitis-like T-cell lymphoma (SPTCL), as seen from Fig. 1.

General characteristics of the patients are outlined in Table 1.

Table 1. Clinical characteristics of T-cell lymphoma patients

The treatment was tailored according to biological tumor markers revealed in the patients. In 10 patients with CD30+ PTCL (n=4 with PTCL-NOS; n=4 with ALK+; n=1 with ALK; n=1 with AITL), Brentuximab vedotin was used. One patient with ALK+ anaplastic lymphoma received ALK inhibitor crizotinib. Five patients with PD-L1 hyperexpression (n=4 with PTCL-NOS; n=1 with γδ TCL) were treated with nivolumab. Overall 24 patients underwent HSCT: high-dose chemotherapy with auto-HSCT was performed in 16 patients, 13 patients underwent allo-HSCT (among them 5 patients with relapses after auto-HSCT). Place of auto-HSCT in the treatment of TCL in our center could be seen from Table 2.

Main characteristics of patients who underwent allogeneic hematopoietic stem cells transplantation are shown in Table 3.

Table 3. Main clinical characteristics of 13 patients with r/r TCL subjected to allo-HSCT

Statistical analysis

Data analysis was performed using SPSS software. The descriptive statistics methods were applied when appropriate. Both OS and PFS were censored at the date of the last contact and were estimated using the Kaplan-Meier method. The difference in OS was tested with log-rank test.

Results

At the time of analysis, 35 patients remained alive. These were mainly patients with peripheral T-cell lymphoma not otherwise specified (TCL-NOS), and anaplastic large cell lymphoma (LCL), ALK+ as the most common histological subtype and the histological subtype with the best prognosis, respectively (Fig. 2).

Results of treatment of patients of our center are presented in the Table 4.

The median follow-up of alive patients was 35 months (6-122 mo). The median overall survival was not reached, 5-year survival rate was 81% and 8-year survival rate was 78% (Fig. 3 and 4).

Figure 3, 4. 5-year (A) and 8-year (B) overall survival patients with T-cell lymphoma treated at R. Gorbacheva Memorial Institute

Table 4. Clinical state and survival rates of the TCL patients after HSCT

Complete remission (CR) state was maintained at the last follow up in 22 patients, partial remission (PR) was documented in 4 patients and PD, in 21 case. Among factors significantly associated with adverse prognosis were: lower ECOG performance status and B-symptoms at the time of diagnosis (p=0.06) (Fig. 5 and 6).

Figure 5, 6. 5-year survival rates depend on ECOG performance status (A), and presence of B-symptoms (B). The difference is significant by p=0.06

Patients that had undergo HSCT showed significantly better disease status at the moment of last follow up: 17/19 (89%) were in CR, versus 5/16 (31%) in patients who did not undergo HSCT (Fig. 7). This can probably be attributed to the fact that patients had a good disease status before transplantation. I would also like to note that such a large number of patients who have not undergone HSCT is associated with age and severe comorbid status, the absence of a donor, unsuccessful apheresis of hematopoietic stem cell, or patient refusal from HSCT.

3-year progression-free survival in patients with TCL after auto-HSCT and allo-HSCT was 50%. And 61%, respectively (Fig. 8, 9).

Figure 8, 9. 5-year progression-free survival for patients with T-cell lymphoma after autoHSCT (A) and allogeneic HSCT (B)

5-year overall survival after auto-HSCT and allo-HSCT rate was 87% and 77% respectively (Fig. 10 and 11).

Figure 10, 11. 5-year overall survival for patients with T-cell lymphoma after auto-HSCT (A) and allo-HSCT (B)

Discussion

Today there is no generally adopted strategy for achievement of responses for r/r patients with PTCL and CTCL (cutaneous TCL), and significant improvements are needed in treatment methods for all subtypes of T/NK-cell lymphomas.

One such solution may be in the future, that we can expect combination therapies of new agents with cytotoxic chemotherapies, therapeutic combinations consisting of new agents and the use of these combinations in earlier in the course of treatment – addition to the first line of therapy. This statement is generally confirmed by the successful experience of our center, which consists in the use of some new drugs, taking into account biological tumor markers.

Our study also shows that HSCT improves the results, which is comparable with the data in world literature.

The consolidation auto-HSCT of achieved remission after first-line therapy can change overall survival for the better [5].

Allo-HSCT has the most solid evidence of the potential to significantly prolong survival or for the cure of disease [43]. But this method is not perfect due to a number of reasons: transplant-related mortality, absence of a donor for allo-HSCT, few appropriate candidates because of age, lack of adequate response to primary therapy, and/or absence of effective agents in the relapsed/refractory setting [44].

Nevertheless, over the past year, there has been a positive trend in allogeneic bone marrow transplantation, which is associated with the introduction of new conditioning regimens, prevention of graft-versus-host disease, new accompanying therapy.

These methods are used at our institute, but it should be noted that not only the improvement of approaches to the treatment of patients with TCL led to good results, but also the artificial selection of patients. Historically, we have accommodated patients who could theoretically become candidates for HSCT, which means patients with good comorbid status.

For the patients who are not candidates for hematopoietic stem cell transplantation the novel therapies (CAR-T/NK-cell therapy; monoclonal antibodies therapy, molecularly targeted therapy) may become the new successful standard of treatment [45].

Conclusion

Our results show that introduction of novel agents and consolidation with high dose chemotherapy and auto-HSCT or allo-HSCT in selected cases improve outcomes in patients with r/r TCL. Brentuximab vedotin and nivolumab based treatment may be successfully used as a bridge therapy before HSCT. The treatment was tailored according to hyperexpression CD30 and PD-L1.

Conflict of interest

The authors report no conflicts of interest.

References

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" ["~DETAIL_TEXT"]=> string(28885) "

Introduction

The T-cell/natural killer (NK) cell lymphomas are a heterogeneous group of generally aggressive neoplasms that constitute less than 10-15 percent of all non-Hodgkin lymphomas (NHLs) in adults [1, 2]. Modern classification of T/NK-cell lymphomas was developed on the basis of histological, immunohistochemical studies of tumor tissue and clinical presentation of lymphomas. In 2016, the World Health Organization classification revised the classification of both nodal and extranodal T/NK-cell lymphomas, which led to the introduction of new temporary structures [3]. Many of these changes were caused by the results of genomic studies using approaches to study gene expression profiling (GEP) and the genetic landscape of T/NK cell lymphomas. However, despite advances in molecular diagnostic methods, histological examination of tumor tissue and clinical manifestations remain the main diagnostic approach.

Another area of research concerns dismal outcomes in the patients with T/NK-cell lymphomas, except for anaplastic large-cell lymphoma (ALCL) positive for anaplastic lymphoma kinase (ALK) [4]. There are currently no successful treatment standards for the T/NK-cell lymphomas, both in the first-line therapy, and in refractory/relapsed (r/r) settings. Today, almost 70% of patients undergoing first-line therapy develop a relapse or refractory disease. A review of the scientific literature allowed us to identify a range of therapeutic options for patients with T/NK-cell lymphomas [5]. It includes the following approaches:
- Hematopoietic stem cells transplantation (HSCT);
- Therapy with monoclonal antibodies (Mabs), e.g., anti-CD30 antibody-drug conjugate (Brentuximab vedotin), anti-CC chemokine receptor 4 antibodies (Mogamulizumab), a monoclonal antibody that binds to CD52 (Alemtuzumab), the monoclonal anti-vascular endothelial growth factor (Bevacizumab) [6-19];
- ALK inhibitors (Crizotinib, Ceritinib) [20];
- Therapy with immune checkpoint inhibitors, e.g., Nivolumab, Pembrolizumab, Ipilimumab, Durvalumab [21-27];
- Histone deacetylase inhibitors (Belinostat, Panobinostat, Chidamide, Romidepsin, Vorinostat) [28-34];
- CAR-T/NK-cell therapy [35, 36];
- In situ vaccination [37].

There are a lot of studies and a large number of drugs being introduced into clinical studies, but at the present time, greatest evidence base should be recognized for brentuximab and bone marrow transplantation. E.g., patients with r/r T/NK-cell lymphomas who received hematopoietic stem cell transplantation (allogeneic and/or autologous) had a better outcome compared to the subset of non-transplanted patients (3-year survival rates of 48% and 18%, respectively) [5]. These conclusions also supported by data of Abekasis et al., demonstrating that autologous and/or allogeneic HSCT is an effective and safe option for the consolidation of patients with TCL [38].

Recently published results of a clinical study ECHELON-2 showed that front-line treatment with Adcetris (brentuximab vedotin) + CHP protocol is superior to CHOP for patients with CD30-positive peripheral T-cell lymphomas, thus suggesting that A+CHP is likely to be the standard first-line therapy [39].

Also, brentuximab vedotin showed good results in the treatment of r/r CD30 positive TCL [40]. Mostly, there were anaplastic large cell lymphoma (ALСL), angioimmunoblastic T-cell lymphoma (AITL), Sézary syndrome and Mycosis Fungoides (MF) [7]. The objective response was from 92% to 40%, with best results obtained in ALСL treatment [41, 42]. These methods are actively used at our center.

Hence, the aim of this study was to present our single-center experience in the treatment of patients with T/NK-cell lymphomas.

Patients and methods

We analyzed data of 47 patients with TCL eligible for stem cells transplantation treated in the R. Gorbacheva Memorial Research Institute of Pediatric Oncology, Hematology and Transplantation at the Pavlov University from 2005 to 2019 including 44 cases with r/r TCL and 3 patients being in complete response after first-line therapy. Among them, 10 patients were diagnosed with anaplastic large cell lymphoma (ALK+); 5 cases with anaplastic large cell lymphoma (ALK); 4 cases with angioimmunoblastic TCL (AITL); 4 patients with hepatosplenic T-cell lymphoma (HSTCL); 1 case of γδ T cell lymphoma (γδ TCL); 20 patients with peripheral T-cell lymphoma not otherwise specified (PTCL-NOS); 1 patient with mucosis fungoides (MF); 1, with primary cutaneous CD4+ T-cell lymphoma (CD4+ PCSM-TCL), and one patient with subcutaneous panniculitis-like T-cell lymphoma (SPTCL), as seen from Fig. 1.

General characteristics of the patients are outlined in Table 1.

Table 1. Clinical characteristics of T-cell lymphoma patients

The treatment was tailored according to biological tumor markers revealed in the patients. In 10 patients with CD30+ PTCL (n=4 with PTCL-NOS; n=4 with ALK+; n=1 with ALK; n=1 with AITL), Brentuximab vedotin was used. One patient with ALK+ anaplastic lymphoma received ALK inhibitor crizotinib. Five patients with PD-L1 hyperexpression (n=4 with PTCL-NOS; n=1 with γδ TCL) were treated with nivolumab. Overall 24 patients underwent HSCT: high-dose chemotherapy with auto-HSCT was performed in 16 patients, 13 patients underwent allo-HSCT (among them 5 patients with relapses after auto-HSCT). Place of auto-HSCT in the treatment of TCL in our center could be seen from Table 2.

Main characteristics of patients who underwent allogeneic hematopoietic stem cells transplantation are shown in Table 3.

Table 3. Main clinical characteristics of 13 patients with r/r TCL subjected to allo-HSCT

Statistical analysis

Data analysis was performed using SPSS software. The descriptive statistics methods were applied when appropriate. Both OS and PFS were censored at the date of the last contact and were estimated using the Kaplan-Meier method. The difference in OS was tested with log-rank test.

Results

At the time of analysis, 35 patients remained alive. These were mainly patients with peripheral T-cell lymphoma not otherwise specified (TCL-NOS), and anaplastic large cell lymphoma (LCL), ALK+ as the most common histological subtype and the histological subtype with the best prognosis, respectively (Fig. 2).

Results of treatment of patients of our center are presented in the Table 4.

The median follow-up of alive patients was 35 months (6-122 mo). The median overall survival was not reached, 5-year survival rate was 81% and 8-year survival rate was 78% (Fig. 3 and 4).

Figure 3, 4. 5-year (A) and 8-year (B) overall survival patients with T-cell lymphoma treated at R. Gorbacheva Memorial Institute

Table 4. Clinical state and survival rates of the TCL patients after HSCT

Complete remission (CR) state was maintained at the last follow up in 22 patients, partial remission (PR) was documented in 4 patients and PD, in 21 case. Among factors significantly associated with adverse prognosis were: lower ECOG performance status and B-symptoms at the time of diagnosis (p=0.06) (Fig. 5 and 6).

Figure 5, 6. 5-year survival rates depend on ECOG performance status (A), and presence of B-symptoms (B). The difference is significant by p=0.06

Patients that had undergo HSCT showed significantly better disease status at the moment of last follow up: 17/19 (89%) were in CR, versus 5/16 (31%) in patients who did not undergo HSCT (Fig. 7). This can probably be attributed to the fact that patients had a good disease status before transplantation. I would also like to note that such a large number of patients who have not undergone HSCT is associated with age and severe comorbid status, the absence of a donor, unsuccessful apheresis of hematopoietic stem cell, or patient refusal from HSCT.

3-year progression-free survival in patients with TCL after auto-HSCT and allo-HSCT was 50%. And 61%, respectively (Fig. 8, 9).

Figure 8, 9. 5-year progression-free survival for patients with T-cell lymphoma after autoHSCT (A) and allogeneic HSCT (B)

5-year overall survival after auto-HSCT and allo-HSCT rate was 87% and 77% respectively (Fig. 10 and 11).

Figure 10, 11. 5-year overall survival for patients with T-cell lymphoma after auto-HSCT (A) and allo-HSCT (B)

Discussion

Today there is no generally adopted strategy for achievement of responses for r/r patients with PTCL and CTCL (cutaneous TCL), and significant improvements are needed in treatment methods for all subtypes of T/NK-cell lymphomas.

One such solution may be in the future, that we can expect combination therapies of new agents with cytotoxic chemotherapies, therapeutic combinations consisting of new agents and the use of these combinations in earlier in the course of treatment – addition to the first line of therapy. This statement is generally confirmed by the successful experience of our center, which consists in the use of some new drugs, taking into account biological tumor markers.

Our study also shows that HSCT improves the results, which is comparable with the data in world literature.

The consolidation auto-HSCT of achieved remission after first-line therapy can change overall survival for the better [5].

Allo-HSCT has the most solid evidence of the potential to significantly prolong survival or for the cure of disease [43]. But this method is not perfect due to a number of reasons: transplant-related mortality, absence of a donor for allo-HSCT, few appropriate candidates because of age, lack of adequate response to primary therapy, and/or absence of effective agents in the relapsed/refractory setting [44].

Nevertheless, over the past year, there has been a positive trend in allogeneic bone marrow transplantation, which is associated with the introduction of new conditioning regimens, prevention of graft-versus-host disease, new accompanying therapy.

These methods are used at our institute, but it should be noted that not only the improvement of approaches to the treatment of patients with TCL led to good results, but also the artificial selection of patients. Historically, we have accommodated patients who could theoretically become candidates for HSCT, which means patients with good comorbid status.

For the patients who are not candidates for hematopoietic stem cell transplantation the novel therapies (CAR-T/NK-cell therapy; monoclonal antibodies therapy, molecularly targeted therapy) may become the new successful standard of treatment [45].

Conclusion

Our results show that introduction of novel agents and consolidation with high dose chemotherapy and auto-HSCT or allo-HSCT in selected cases improve outcomes in patients with r/r TCL. Brentuximab vedotin and nivolumab based treatment may be successfully used as a bridge therapy before HSCT. The treatment was tailored according to hyperexpression CD30 and PD-L1.

Conflict of interest

The authors report no conflicts of interest.

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Почти у 70% пациентов после первой линии терапии развивается рецидив или рефрактерное течение (р/р). Ряд новых терапевтических подходов нацелены на улучшение результатов лечения у пациентов с р/р ТКЛ. В данной статье обобщен опыт Первого Санкт-Петербургского государственного медицинского университета им. Павлова в лечении пациентов с Т-клеточными лимфомами. Мы проанализировали данные 47 пациентов, которые проходила лечение с 2005 по 2019 год – на момент анализа 44 пациента имеют р/р течение заболевания и 3 пациента находятся в полном ответе после проведенной первой линии терапии. Средний возраст составил 45 лет (от 1 года до 72 лет). Это были преимущественно пациенты с периферическими Т-клеточными лимфомами, неуточненными (41%). Среди всех пациентов n26 (55%) имели первичное химиорезистентное течение, в то время как у остальных n18 (38%) был рецидив после первой линии терапии.</p> <p style="text-align: justify;"> Опыт нашего центра включает в себя использование новых вариантов лечения р/р ТКЛ: антиCD30 моноклональное антитело – брентуксимаб, ингибитор ALK – кризотиниб, ингибитор контрольных точек – ниволумаб и иммунотерапию, включающую проведение трансплантации гемопоэтических стволовых клеток (ТГСК). В общей сложности 24 пациентам выполнена ТГСК: высокодозная химиотерапия с последующей аутологичной ТГСК (ауто-ТГСК) проведена 16 пациентам, 13 пациентам – аллогенная ТГСК (алло-ТГСК) (из них 5 пациентов с рецидивами после ауто-ТГСК). На момент анализа 35 пациентов были живы. Медиана наблюдения за живыми пациентами составила 35 месяцев (6-122 мес.). Медиана общей выживаемости не была достигнута, 5-летняя выживаемость составила 81%, 8-летняя общая выживаемость – 78%. Статус заболевания при последнем наблюдении был следующий: полный ответ у 22 пациентов, частичный ответ у 4 пациентов и прогрессия заболевания у 21. Среди факторов, значительно связанных с неблагоприятным прогнозом, были низкий статус ECOG и B-симптомы на момент постановки диагноза (p=0,06). Пациенты, которые перенесли ТГСК, имели лучший статус заболевания на момент последнего наблюдения: 17/19 (89%) были в полном ответе, по сравнению с 5/16 (31%) у пациентов, которым не проводилась ТГСК. 5-летняя общая выживаемость у пациентов с ТКЛ после ауто-ТГСК и алло-ТГСК составила 87% и 77% соответственно. Результаты анализа показывают, что введение новых агентов и консолидация с помощью высокодозной химиотерапии с последующей ауто-ТГСК или алло-ТГСК в отдельных случаях могут улучшить результаты у пациентов с рецидивирующей или рефрактерной Т-клеточной лимфомой. 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Лепик¹, Андрей В. Козлов¹, Евгения С. Борзенкова¹, Юрий Р. Залялов¹, Кирилл В. Лепик¹, <br> Елена В. Кондакова¹, Вадим В. Байков¹, Иван С. Моисеев¹, Татьяна В. Шнайдер², Наталья Б. Михайлова¹, <br> <span style="border: 1px solid black; margin: 0; padding: 1px 2px;">Борис В. Афанасьев¹</span> </p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(592) "

Елена Е. Лепик¹, Андрей В. Козлов¹, Евгения С. Борзенкова¹, Юрий Р. Залялов¹, Кирилл В. Лепик¹,
Елена В. Кондакова¹, Вадим В. Байков¹, Иван С. Моисеев¹, Татьяна В. Шнайдер², Наталья Б. Михайлова¹,
Борис В. Афанасьев¹

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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 Ленинградская областная клиническая больница, Санкт-Петербург, Россия

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Т-клеточные лимфомы (ТКЛ) представляют собой агрессивные неходжкинские лимфомы, которые не имеют успешных стандартов лечения. Почти у 70% пациентов после первой линии терапии развивается рецидив или рефрактерное течение (р/р). Ряд новых терапевтических подходов нацелены на улучшение результатов лечения у пациентов с р/р ТКЛ. В данной статье обобщен опыт Первого Санкт-Петербургского государственного медицинского университета им. Павлова в лечении пациентов с Т-клеточными лимфомами. Мы проанализировали данные 47 пациентов, которые проходила лечение с 2005 по 2019 год – на момент анализа 44 пациента имеют р/р течение заболевания и 3 пациента находятся в полном ответе после проведенной первой линии терапии. Средний возраст составил 45 лет (от 1 года до 72 лет). Это были преимущественно пациенты с периферическими Т-клеточными лимфомами, неуточненными (41%). Среди всех пациентов n26 (55%) имели первичное химиорезистентное течение, в то время как у остальных n18 (38%) был рецидив после первой линии терапии.

Опыт нашего центра включает в себя использование новых вариантов лечения р/р ТКЛ: антиCD30 моноклональное антитело – брентуксимаб, ингибитор ALK – кризотиниб, ингибитор контрольных точек – ниволумаб и иммунотерапию, включающую проведение трансплантации гемопоэтических стволовых клеток (ТГСК). В общей сложности 24 пациентам выполнена ТГСК: высокодозная химиотерапия с последующей аутологичной ТГСК (ауто-ТГСК) проведена 16 пациентам, 13 пациентам – аллогенная ТГСК (алло-ТГСК) (из них 5 пациентов с рецидивами после ауто-ТГСК). На момент анализа 35 пациентов были живы. Медиана наблюдения за живыми пациентами составила 35 месяцев (6-122 мес.). Медиана общей выживаемости не была достигнута, 5-летняя выживаемость составила 81%, 8-летняя общая выживаемость – 78%. Статус заболевания при последнем наблюдении был следующий: полный ответ у 22 пациентов, частичный ответ у 4 пациентов и прогрессия заболевания у 21. Среди факторов, значительно связанных с неблагоприятным прогнозом, были низкий статус ECOG и B-симптомы на момент постановки диагноза (p=0,06). Пациенты, которые перенесли ТГСК, имели лучший статус заболевания на момент последнего наблюдения: 17/19 (89%) были в полном ответе, по сравнению с 5/16 (31%) у пациентов, которым не проводилась ТГСК. 5-летняя общая выживаемость у пациентов с ТКЛ после ауто-ТГСК и алло-ТГСК составила 87% и 77% соответственно. Результаты анализа показывают, что введение новых агентов и консолидация с помощью высокодозной химиотерапии с последующей ауто-ТГСК или алло-ТГСК в отдельных случаях могут улучшить результаты у пациентов с рецидивирующей или рефрактерной Т-клеточной лимфомой. Схемы, основанные на применении брентуксимаба ведотина и ниволумаба, могут быть успешно использованы в качестве bridge-терапии перед алло-ТГСК.

Ключевые слова

T-клеточные лимфомы, аутологичная трансплантация гемопоэтических стволовых клеток, аллогенная трансплантация гемопоэтических стволовых клеток, брентуксимаб ведотин, ниволумаб.

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Elena E. Lepik¹, Andrey V. Kozlov¹, Evgenia S. Borzenkova¹,
Yury R. Zalyalov¹, Kirill V. Lepik¹, Elena V. Kondakova¹, Vadim V. Baykov¹, Ivan S. Moiseev¹, Tatiana V. Schneider²,
Natalia B. Mikhaylova¹, Boris V. Afanasyev¹

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¹ Raisa Gorbacheva Memorial Research Institute of Pediatric Oncology, Hematology and Transplantation, Pavlov University,
St. Petersburg, Russia
² Leningrad Regional Clinical Hospital, St. Petersburg, Russia

Correspondence
Dr. Elena E. Lepik, Clinical Hematologist, Oncology Department, Raisa Gorbacheva Memorial Research Institute of Pediatric Oncology, Hematology and Transplantation, Pavlov University, L. Tolstoy St. 6-8, 197022, St. Petersburg, Russia
Phone: +7 (905) 226 8922
E-mail: ee.dav@mail.ru

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T-cell lymphomas (TCL) comprise a group of aggressive non-Hodgkin lymphomas, which do not have successful treatment standards. Almost 70% of patients undergoing first-line therapy develop a relapse or refractory (r/r) disease. A number of novel therapy approaches are aimed for improvement of outcomes in patients with r/r TCL. This report summarizes clinical experience of Pavlov Medical University in the treatment of T cell lymphomas. We analyzed data of 47 patients with TCL treated from 2005 to 2019. Of them, 44 had r/r TCL, and 3 patients were in complete response after first line therapy. The median age was 45 years (range 1-72 years). These were predominantly patients with peripheral T-cell lymphomas not otherwise specified (TCL-NOS, 41%). 26 patients (55% of total) had a primary chemoresistant disease, while the remaining 18 patients (38% of total) had a relapse after initial treatment.

Our center has implemented new treatment options for r/r TCL, i.e., anti CD30 monoclonal antibody brentuximab, ALK inhibitor crizotinib, immunotherapy with checkpoint inhibitors nivolumab, and hematopoietic stem cell transplantation (HSCT). A total of 24 patients underwent: high-dose chemotherapy with autologous HSCT (auto-HSCT) was performed in 16 cases, 13 patients were subjected to allogeneic HSCT (allo-HSCT), including 5 relapsed patients after auto-HSCT. At the time of analysis, 35 patients remained alive. The median follow-up of surviving patients was 35 months (6-122 mo). The median overall survival (OS) was not reached, 5-year survival rate was 81%, and 8-year survival rate was 78%. Complete remission (CR) at the last follow-up was diagnosed in 22 patients; partial response (PR), in 4 cases, and progression of the disease (PD) was revealed in 21 patients. Among factors significantly associated with adverse prognosis were lower ECOG performance status and B-symptoms at the time of diagnosis (p=0.06). The patients who underwent HSCT showed significantly better disease status at the moment of last follow up: 17/19 (89%) were in CR, versus 5/16 (31%) among the patients not subjected to HSCT. 5-year overall survival rates after auto-HSCT and allo-HSCT were 87% and 77%, respectively. The results show that implementation of novel therapeutic agents, as well as consolidation with high-dose chemotherapy and auto- or allo-HSCT in selected cases improve outcomes in patients with r/r TCL. Brentuximab vedotin and nivolumab-based regimens may be successfully used as a bridge therapy before HSCT.

Keywords

T-cell lymphoma, autologous hematopoietic stem cells transplantation, allogeneic hematopoietic stem cells transplantation, brentuximab vedotin, nivolumab.

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"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) "26314" ["VALUE"]=> array(2) { ["TEXT"]=> string(622) "<p> Elena E. Lepik¹, Andrey V. Kozlov¹, Evgenia S. Borzenkova¹,<br> Yury R. Zalyalov¹, Kirill V. Lepik¹, Elena V. Kondakova¹, Vadim V. Baykov¹, Ivan S. Moiseev¹, Tatiana V. Schneider², <br> Natalia B. Mikhaylova¹, <span style="border: 1px solid black; margin: 0; padding: 1px 2px;">Boris V. Afanasyev¹</span> </p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(444) "

Elena E. Lepik¹, Andrey V. Kozlov¹, Evgenia S. Borzenkova¹,
Yury R. Zalyalov¹, Kirill V. Lepik¹, Elena V. Kondakova¹, Vadim V. Baykov¹, Ivan S. Moiseev¹, Tatiana V. Schneider²,
Natalia B. Mikhaylova¹, Boris V. Afanasyev¹

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Elena E. Lepik¹, Andrey V. Kozlov¹, Evgenia S. Borzenkova¹,
Yury R. Zalyalov¹, Kirill V. Lepik¹, Elena V. Kondakova¹, Vadim V. Baykov¹, Ivan S. Moiseev¹, Tatiana V. Schneider²,
Natalia B. Mikhaylova¹, Boris V. Afanasyev¹

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T-cell lymphomas (TCL) comprise a group of aggressive non-Hodgkin lymphomas, which do not have successful treatment standards. Almost 70% of patients undergoing first-line therapy develop a relapse or refractory (r/r) disease. A number of novel therapy approaches are aimed for improvement of outcomes in patients with r/r TCL. This report summarizes clinical experience of Pavlov Medical University in the treatment of T cell lymphomas. We analyzed data of 47 patients with TCL treated from 2005 to 2019. Of them, 44 had r/r TCL, and 3 patients were in complete response after first line therapy. The median age was 45 years (range 1-72 years). These were predominantly patients with peripheral T-cell lymphomas not otherwise specified (TCL-NOS, 41%). 26 patients (55% of total) had a primary chemoresistant disease, while the remaining 18 patients (38% of total) had a relapse after initial treatment.

Our center has implemented new treatment options for r/r TCL, i.e., anti CD30 monoclonal antibody brentuximab, ALK inhibitor crizotinib, immunotherapy with checkpoint inhibitors nivolumab, and hematopoietic stem cell transplantation (HSCT). A total of 24 patients underwent: high-dose chemotherapy with autologous HSCT (auto-HSCT) was performed in 16 cases, 13 patients were subjected to allogeneic HSCT (allo-HSCT), including 5 relapsed patients after auto-HSCT. At the time of analysis, 35 patients remained alive. The median follow-up of surviving patients was 35 months (6-122 mo). The median overall survival (OS) was not reached, 5-year survival rate was 81%, and 8-year survival rate was 78%. Complete remission (CR) at the last follow-up was diagnosed in 22 patients; partial response (PR), in 4 cases, and progression of the disease (PD) was revealed in 21 patients. Among factors significantly associated with adverse prognosis were lower ECOG performance status and B-symptoms at the time of diagnosis (p=0.06). The patients who underwent HSCT showed significantly better disease status at the moment of last follow up: 17/19 (89%) were in CR, versus 5/16 (31%) among the patients not subjected to HSCT. 5-year overall survival rates after auto-HSCT and allo-HSCT were 87% and 77%, respectively. The results show that implementation of novel therapeutic agents, as well as consolidation with high-dose chemotherapy and auto- or allo-HSCT in selected cases improve outcomes in patients with r/r TCL. Brentuximab vedotin and nivolumab-based regimens may be successfully used as a bridge therapy before HSCT.

Keywords

T-cell lymphoma, autologous hematopoietic stem cells transplantation, allogeneic hematopoietic stem cells transplantation, brentuximab vedotin, nivolumab.

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T-cell lymphomas (TCL) comprise a group of aggressive non-Hodgkin lymphomas, which do not have successful treatment standards. Almost 70% of patients undergoing first-line therapy develop a relapse or refractory (r/r) disease. A number of novel therapy approaches are aimed for improvement of outcomes in patients with r/r TCL. This report summarizes clinical experience of Pavlov Medical University in the treatment of T cell lymphomas. We analyzed data of 47 patients with TCL treated from 2005 to 2019. Of them, 44 had r/r TCL, and 3 patients were in complete response after first line therapy. The median age was 45 years (range 1-72 years). These were predominantly patients with peripheral T-cell lymphomas not otherwise specified (TCL-NOS, 41%). 26 patients (55% of total) had a primary chemoresistant disease, while the remaining 18 patients (38% of total) had a relapse after initial treatment.

Our center has implemented new treatment options for r/r TCL, i.e., anti CD30 monoclonal antibody brentuximab, ALK inhibitor crizotinib, immunotherapy with checkpoint inhibitors nivolumab, and hematopoietic stem cell transplantation (HSCT). A total of 24 patients underwent: high-dose chemotherapy with autologous HSCT (auto-HSCT) was performed in 16 cases, 13 patients were subjected to allogeneic HSCT (allo-HSCT), including 5 relapsed patients after auto-HSCT. At the time of analysis, 35 patients remained alive. The median follow-up of surviving patients was 35 months (6-122 mo). The median overall survival (OS) was not reached, 5-year survival rate was 81%, and 8-year survival rate was 78%. Complete remission (CR) at the last follow-up was diagnosed in 22 patients; partial response (PR), in 4 cases, and progression of the disease (PD) was revealed in 21 patients. Among factors significantly associated with adverse prognosis were lower ECOG performance status and B-symptoms at the time of diagnosis (p=0.06). The patients who underwent HSCT showed significantly better disease status at the moment of last follow up: 17/19 (89%) were in CR, versus 5/16 (31%) among the patients not subjected to HSCT. 5-year overall survival rates after auto-HSCT and allo-HSCT were 87% and 77%, respectively. The results show that implementation of novel therapeutic agents, as well as consolidation with high-dose chemotherapy and auto- or allo-HSCT in selected cases improve outcomes in patients with r/r TCL. Brentuximab vedotin and nivolumab-based regimens may be successfully used as a bridge therapy before HSCT.

Keywords

T-cell lymphoma, autologous hematopoietic stem cells transplantation, allogeneic hematopoietic stem cells transplantation, brentuximab vedotin, nivolumab.

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¹ Raisa Gorbacheva Memorial Research Institute of Pediatric Oncology, Hematology and Transplantation, Pavlov University,
St. Petersburg, Russia
² Leningrad Regional Clinical Hospital, St. Petersburg, Russia

Correspondence
Dr. Elena E. Lepik, Clinical Hematologist, Oncology Department, Raisa Gorbacheva Memorial Research Institute of Pediatric Oncology, Hematology and Transplantation, Pavlov University, L. Tolstoy St. 6-8, 197022, St. Petersburg, Russia
Phone: +7 (905) 226 8922
E-mail: ee.dav@mail.ru

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¹ Raisa Gorbacheva Memorial Research Institute of Pediatric Oncology, Hematology and Transplantation, Pavlov University,
St. Petersburg, Russia
² Leningrad Regional Clinical Hospital, St. Petersburg, Russia

Correspondence
Dr. Elena E. Lepik, Clinical Hematologist, Oncology Department, Raisa Gorbacheva Memorial Research Institute of Pediatric Oncology, Hematology and Transplantation, Pavlov University, L. Tolstoy St. 6-8, 197022, St. Petersburg, Russia
Phone: +7 (905) 226 8922
E-mail: ee.dav@mail.ru

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Елена Е. Лепик¹, Андрей В. Козлов¹, Евгения С. Борзенкова¹, Юрий Р. Залялов¹, Кирилл В. Лепик¹,
Елена В. Кондакова¹, Вадим В. Байков¹, Иван С. Моисеев¹, Татьяна В. Шнайдер², Наталья Б. Михайлова¹,
Борис В. Афанасьев¹

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Елена Е. Лепик¹, Андрей В. Козлов¹, Евгения С. Борзенкова¹, Юрий Р. Залялов¹, Кирилл В. Лепик¹,
Елена В. Кондакова¹, Вадим В. Байков¹, Иван С. Моисеев¹, Татьяна В. Шнайдер², Наталья Б. Михайлова¹,
Борис В. Афанасьев¹

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Почти у 70% пациентов после первой линии терапии развивается рецидив или рефрактерное течение (р/р). Ряд новых терапевтических подходов нацелены на улучшение результатов лечения у пациентов с р/р ТКЛ. В данной статье обобщен опыт Первого Санкт-Петербургского государственного медицинского университета им. Павлова в лечении пациентов с Т-клеточными лимфомами. Мы проанализировали данные 47 пациентов, которые проходила лечение с 2005 по 2019 год – на момент анализа 44 пациента имеют р/р течение заболевания и 3 пациента находятся в полном ответе после проведенной первой линии терапии. Средний возраст составил 45 лет (от 1 года до 72 лет). Это были преимущественно пациенты с периферическими Т-клеточными лимфомами, неуточненными (41%). Среди всех пациентов n26 (55%) имели первичное химиорезистентное течение, в то время как у остальных n18 (38%) был рецидив после первой линии терапии.</p> <p style="text-align: justify;"> Опыт нашего центра включает в себя использование новых вариантов лечения р/р ТКЛ: антиCD30 моноклональное антитело – брентуксимаб, ингибитор ALK – кризотиниб, ингибитор контрольных точек – ниволумаб и иммунотерапию, включающую проведение трансплантации гемопоэтических стволовых клеток (ТГСК). В общей сложности 24 пациентам выполнена ТГСК: высокодозная химиотерапия с последующей аутологичной ТГСК (ауто-ТГСК) проведена 16 пациентам, 13 пациентам – аллогенная ТГСК (алло-ТГСК) (из них 5 пациентов с рецидивами после ауто-ТГСК). На момент анализа 35 пациентов были живы. Медиана наблюдения за живыми пациентами составила 35 месяцев (6-122 мес.). Медиана общей выживаемости не была достигнута, 5-летняя выживаемость составила 81%, 8-летняя общая выживаемость – 78%. Статус заболевания при последнем наблюдении был следующий: полный ответ у 22 пациентов, частичный ответ у 4 пациентов и прогрессия заболевания у 21. Среди факторов, значительно связанных с неблагоприятным прогнозом, были низкий статус ECOG и B-симптомы на момент постановки диагноза (p=0,06). Пациенты, которые перенесли ТГСК, имели лучший статус заболевания на момент последнего наблюдения: 17/19 (89%) были в полном ответе, по сравнению с 5/16 (31%) у пациентов, которым не проводилась ТГСК. 5-летняя общая выживаемость у пациентов с ТКЛ после ауто-ТГСК и алло-ТГСК составила 87% и 77% соответственно. Результаты анализа показывают, что введение новых агентов и консолидация с помощью высокодозной химиотерапии с последующей ауто-ТГСК или алло-ТГСК в отдельных случаях могут улучшить результаты у пациентов с рецидивирующей или рефрактерной Т-клеточной лимфомой. Схемы, основанные на применении брентуксимаба ведотина и ниволумаба, могут быть успешно использованы в качестве bridge-терапии перед алло-ТГСК.</p> <h2>Ключевые слова</h2> <p style="text-align: justify;"> T-клеточные лимфомы, аутологичная трансплантация гемопоэтических стволовых клеток, аллогенная трансплантация гемопоэтических стволовых клеток, брентуксимаб ведотин, ниволумаб. </p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(5496) "

Т-клеточные лимфомы (ТКЛ) представляют собой агрессивные неходжкинские лимфомы, которые не имеют успешных стандартов лечения. Почти у 70% пациентов после первой линии терапии развивается рецидив или рефрактерное течение (р/р). Ряд новых терапевтических подходов нацелены на улучшение результатов лечения у пациентов с р/р ТКЛ. В данной статье обобщен опыт Первого Санкт-Петербургского государственного медицинского университета им. Павлова в лечении пациентов с Т-клеточными лимфомами. Мы проанализировали данные 47 пациентов, которые проходила лечение с 2005 по 2019 год – на момент анализа 44 пациента имеют р/р течение заболевания и 3 пациента находятся в полном ответе после проведенной первой линии терапии. Средний возраст составил 45 лет (от 1 года до 72 лет). Это были преимущественно пациенты с периферическими Т-клеточными лимфомами, неуточненными (41%). Среди всех пациентов n26 (55%) имели первичное химиорезистентное течение, в то время как у остальных n18 (38%) был рецидив после первой линии терапии.

Опыт нашего центра включает в себя использование новых вариантов лечения р/р ТКЛ: антиCD30 моноклональное антитело – брентуксимаб, ингибитор ALK – кризотиниб, ингибитор контрольных точек – ниволумаб и иммунотерапию, включающую проведение трансплантации гемопоэтических стволовых клеток (ТГСК). В общей сложности 24 пациентам выполнена ТГСК: высокодозная химиотерапия с последующей аутологичной ТГСК (ауто-ТГСК) проведена 16 пациентам, 13 пациентам – аллогенная ТГСК (алло-ТГСК) (из них 5 пациентов с рецидивами после ауто-ТГСК). На момент анализа 35 пациентов были живы. Медиана наблюдения за живыми пациентами составила 35 месяцев (6-122 мес.). Медиана общей выживаемости не была достигнута, 5-летняя выживаемость составила 81%, 8-летняя общая выживаемость – 78%. Статус заболевания при последнем наблюдении был следующий: полный ответ у 22 пациентов, частичный ответ у 4 пациентов и прогрессия заболевания у 21. Среди факторов, значительно связанных с неблагоприятным прогнозом, были низкий статус ECOG и B-симптомы на момент постановки диагноза (p=0,06). Пациенты, которые перенесли ТГСК, имели лучший статус заболевания на момент последнего наблюдения: 17/19 (89%) были в полном ответе, по сравнению с 5/16 (31%) у пациентов, которым не проводилась ТГСК. 5-летняя общая выживаемость у пациентов с ТКЛ после ауто-ТГСК и алло-ТГСК составила 87% и 77% соответственно. Результаты анализа показывают, что введение новых агентов и консолидация с помощью высокодозной химиотерапии с последующей ауто-ТГСК или алло-ТГСК в отдельных случаях могут улучшить результаты у пациентов с рецидивирующей или рефрактерной Т-клеточной лимфомой. Схемы, основанные на применении брентуксимаба ведотина и ниволумаба, могут быть успешно использованы в качестве bridge-терапии перед алло-ТГСК.

Ключевые слова

T-клеточные лимфомы, аутологичная трансплантация гемопоэтических стволовых клеток, аллогенная трансплантация гемопоэтических стволовых клеток, брентуксимаб ведотин, ниволумаб.

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Т-клеточные лимфомы (ТКЛ) представляют собой агрессивные неходжкинские лимфомы, которые не имеют успешных стандартов лечения. Почти у 70% пациентов после первой линии терапии развивается рецидив или рефрактерное течение (р/р). Ряд новых терапевтических подходов нацелены на улучшение результатов лечения у пациентов с р/р ТКЛ. В данной статье обобщен опыт Первого Санкт-Петербургского государственного медицинского университета им. Павлова в лечении пациентов с Т-клеточными лимфомами. Мы проанализировали данные 47 пациентов, которые проходила лечение с 2005 по 2019 год – на момент анализа 44 пациента имеют р/р течение заболевания и 3 пациента находятся в полном ответе после проведенной первой линии терапии. Средний возраст составил 45 лет (от 1 года до 72 лет). Это были преимущественно пациенты с периферическими Т-клеточными лимфомами, неуточненными (41%). Среди всех пациентов n26 (55%) имели первичное химиорезистентное течение, в то время как у остальных n18 (38%) был рецидив после первой линии терапии.

Опыт нашего центра включает в себя использование новых вариантов лечения р/р ТКЛ: антиCD30 моноклональное антитело – брентуксимаб, ингибитор ALK – кризотиниб, ингибитор контрольных точек – ниволумаб и иммунотерапию, включающую проведение трансплантации гемопоэтических стволовых клеток (ТГСК). В общей сложности 24 пациентам выполнена ТГСК: высокодозная химиотерапия с последующей аутологичной ТГСК (ауто-ТГСК) проведена 16 пациентам, 13 пациентам – аллогенная ТГСК (алло-ТГСК) (из них 5 пациентов с рецидивами после ауто-ТГСК). На момент анализа 35 пациентов были живы. Медиана наблюдения за живыми пациентами составила 35 месяцев (6-122 мес.). Медиана общей выживаемости не была достигнута, 5-летняя выживаемость составила 81%, 8-летняя общая выживаемость – 78%. Статус заболевания при последнем наблюдении был следующий: полный ответ у 22 пациентов, частичный ответ у 4 пациентов и прогрессия заболевания у 21. Среди факторов, значительно связанных с неблагоприятным прогнозом, были низкий статус ECOG и B-симптомы на момент постановки диагноза (p=0,06). Пациенты, которые перенесли ТГСК, имели лучший статус заболевания на момент последнего наблюдения: 17/19 (89%) были в полном ответе, по сравнению с 5/16 (31%) у пациентов, которым не проводилась ТГСК. 5-летняя общая выживаемость у пациентов с ТКЛ после ауто-ТГСК и алло-ТГСК составила 87% и 77% соответственно. Результаты анализа показывают, что введение новых агентов и консолидация с помощью высокодозной химиотерапии с последующей ауто-ТГСК или алло-ТГСК в отдельных случаях могут улучшить результаты у пациентов с рецидивирующей или рефрактерной Т-клеточной лимфомой. Схемы, основанные на применении брентуксимаба ведотина и ниволумаба, могут быть успешно использованы в качестве bridge-терапии перед алло-ТГСК.

Ключевые слова

T-клеточные лимфомы, аутологичная трансплантация гемопоэтических стволовых клеток, аллогенная трансплантация гемопоэтических стволовых клеток, брентуксимаб ведотин, ниволумаб.

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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 Ленинградская областная клиническая больница, Санкт-Петербург, 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 Ленинградская областная клиническая больница, Санкт-Петербург, Россия

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Introduction

Peripheral T-cell lymphomas (PTCLs) derived from post-thymic T cells or mature NK cells, are a rare and heterogeneous group of aggressive lymphomas comprising approximately 10% of all non-Hodgkin lymphomas diagnosed in the western world. In 2016, the WHO classification of lymphoid neoplasms recognized more than 20 different T-cell lymphoma entities that broadly segregate into lymphomas with predominant nodal involvement, extra-nodal involvement, leukemic, or cutaneous manifestations [1].

Nodal PTCLs are the most common of the PTCL subtypes and include peripheral T-cell lymphoma not otherwise specified (PTCL-NOS), systemic anaplastic large cell lymphoma (sALCL) and angioimmunoblastic T-cell lymphoma (AITL). Together these 3 subtypes account for about 60% of all PTCL lymphomas. Given their heterogeneity, there is no consensus regarding the best first-line treatment, and the role of autologous/allogeneic (ASCT/alloSCT) stem cell transplantation as consolidation is controversial.

Conventional treatment with CHOP or CHOP-like regimen induces CR in about 50% of cases, with a 5-year survival of 30%-35% [2, 3]. Expected outcomes in terms of 5-year PFS/EFS in PTCL with initial CHOP treatment are based on 2 large retrospective series: the studies performed by the International T-Cell Project (ITCP) and the British Columbia Cancer Agency (BCCA) [4, 5] shown in Table 1.

Although CHOP is the most commonly used first-line regimen for patients with PTCL outcomes are disappointing with the exception of patients with ALK-positive sALCL. The most compelling evidence supporting the benefits of building on CHOP come from studies adding etoposide (CHOEP). It appears to offer an advantage over CHOP in younger patients (<60 years) based on a retrospective analysis of 7 prospective phase 2 or 3 German protocols including 343 patients [6]. CHOEP improved EFS from 51% to 71%. A registry study from Sweden found a superior PFS for CHOEP, also in patients <60 years [7]. This was seen particularly in those with ALCL and normal concentrations of lactate dehydrogenase. However, no improvement in OS was revealed, and greater toxicity was observed in older patients. This is also supported by the data from the COMPLETE study and suggests that any overall survival benefit associated with etoposide use in patients with PTCL is at best modest [8].

Although CHOP is the most commonly used first-line regimen for patients with PTCL outcomes are disappointing with the exception of patients with ALK-positive sALCL. The most compelling evidence supporting the benefits of building on CHOP come from studies adding etoposide (CHOEP). It appears to offer an advantage over CHOP in younger patients (<60 years) based on a retrospective analysis of 7 prospective phase 2 or 3 German protocols including 343 patients [6]. CHOEP improved EFS from 51% to 71%. A registry study from Sweden found a superior PFS for CHOEP, also in patients <60 years [7]. This was seen particularly in those with ALCL and normal concentrations of lactate dehydrogenase. However, no improvement in OS was revealed, and greater toxicity was observed in older patients. This is also supported by the data from the COMPLETE study and suggests that any overall survival benefit associated with etoposide use in patients with PTCL is at best modest [8].

CD30 is expressed in all sALCL and among other nodal variants of PTCL its expression is variable from 58-64% in PTCL NOS and 43-63% in AITL. Brentuximab vedotin (BV, Adcetris) is an antibody-drug conjugate active against CD30-positive lymphomas. The ECHELON-2 trial included a randomized, double-blind, phase 3 study of Brentuximab vedotin and CHP (A+CHP) versus CHOP in the frontline treatment of patients with CD30+ PTCLs [9].

The A+CHP schedule showed superior PFS and significantly longer OS than CHOP in patients with nodal CD30+ PTCLs. The trial also demonstrated improvement in the complete remission rate (68% vs 56%), and overall response rate (83% vs 72%) with A+CHP. Adverse events, including fatal AEs, were similar between groups. Of note, consolidative SCT was given to 22% patients in the A+CHP group and to 17% in the CHOP group. The treatment with ASCT did not affect PFS nor OS rates.

The NCCN guidelines suggest the following treatment regimens as first line therapy: BV+CHP regimen for sALCL cases; in other tumor histologies (PTCL NOS, AITL, nodal PTCL TFH), suggested regimens are as follows: BV+CHP for CD30+ histologies, and CHOP or CHOEP for other histologies, according to the patient’s age and performance status. As first-line consolidation high-dose therapy and stem cell rescue may be considered in appropriate patients [10].

High dose chemotherapy followed by autologous stem cell transplantation (ASCT) is a reasonable treatment option as front-line consolidation with resulting OS rates of 54% to 68% and low non-relapse mortality. A major problem is early relapse/progression in up to 40% of patients starting first-line therapy. In the relapse situation the overall prognosis is dismal, and the best treatment has not been defined yet [11, 12]. Chemorefractory patients should proceed to allogeneic SCT (allo-SCT) whenever possible, and the use of single agents as a bridge to transplant for these patients may be more appropriate because there is a need to sustain response until a compatible donor is identified and worked up [10-13].

Clinical practice recommendations on indication and timing of hematopoietic stem cell transplantation have recently been published by the American Society for Blood and Marrow Transplantation [14]. Registry studies on the role of autologous and allogeneic transplantation in PTCL have also been the subject of recent publications [15-17].

The current EBMT indications for hematopoietic transplantation in PTCL are illustrated in Table 2 [18].

Table 2. EBMT indications for HSCT in PTCL [18]

CO: clinical option; S: standard of care; GNR: generally not recommended; Grade I: at least 1 randomized trial; Grade II: at least 1 well-designed non-randomized CT; Grade III: expert opinion

To examine the real-world outcomes for patients with PTCL who underwent hematopoietic stem cell transplantation in our institution we conducted a retrospective review and report the clinical outcomes of 26 consecutive patients who were treated either as first-line consolidation or in the relapse setting between January 2000 and July 2018.

Patients and methods

Twenty-six patients were identified, with a median age of 46 years. Ninety-two percent of patients presented with advanced-stage at diagnosis (Ann Arbor stage III or IV) and 38% had B symptoms. The age-adjusted IPI (aaIPI) was low-intermediate in 15 patients and intermediate high/high in 11 patients (Table 3).

According to the 2016 revision of the WHO classification of lymphoid neoplasms, the most common PTCL subtypes within our cohort were AILT (46%), ALCL (26%) and PTCL NOS (20%) (1).

Most patients received CHOP chemotherapy as induction treatment regimen, with CHOEP being less frequently used (Table 4).

Twenty-seven transplants were performed in 26 patients (one patient had an ASCT followed by an allo-SCT after relapsing).

Nineteen patients had an ASCT with the BEAM conditioning regimen (Fig. 1). Sixteen patients were given an ASCT upfront as consolidation after induction treatment, with 14 being in CR and 2 in PR. Of these 16 patients, 5 had a relapse after ASCT and none survived, even though one was given an allo-SCT. Of the 3 patients given an ASCT as rescue treatment for relapse, 2 are alive in CR.

Seven patients underwent an allo-SCT, of whom 4 had it upfront and 3 after relapsing from a previous ASCT (Fig. 2). All patients received tacrolimus plus mycophenolate mofetil as GvHD prophylaxis and ATG was added to the conditioning regimen of the 2 patients transplanted with a mismatched unrelated donor. Five patients were conditioned with the Flu Mel protocol, 1 with Flu 2Gy TBI and 1 with the Flu BiCNU Mel protocol. All 4 patients treated upfront were given a transplant from unrelated donors of whom 1 was a 9/10 mismatch, none relapsed and all are alive. Of the 3 patients having a transplant after relapse, 2 are alive with no evidence of disease and one died of transplant related mortality.

Two patients deserve a special mention:
• Patient 19, a 58-y.o. male had a diagnosis of classic Hodgkin’s disease (cHD) in 2009, was treated with 8 cycles of ABVD and relapsed in 2011being treated with ICE followed by ASCT at another institution. In 2013, he presented with PTCL AITL subtype infiltrated with EBV+ B cells and was treated with R-ICE before being submitted to a matched unrelated allo-SCT in CR.
• Patient 21, a 42-y.o. male patient had a diagnosis of cHD in 1995, and achieved complete remission after 6 cycles of ABVD. He had a localized relapse of cHD in 1999, treated with local radiotherapy. He then presented in 2015 with a PTCL AITL subtype infiltrated with EBV+ B cells and CNS infiltration. He was treated with ESHAP followed by the LMB-96 protocol and was then submitted to a mismatched unrelated allo-SCT in CR.

Both patients are alive, one with moderate cGvHD.

Results

We evaluated the overall survival (OS) and progression-free survival (PFS) in our cohort of patients. The median follow-up time was 6.3 years (1-18.1 years). OS was calculated from the date of diagnosis until death due to any cause, and PFS was measured from transplant until relapse, progressive disease or last follow-up. Survival-based analysis were performed with the Kaplan-Meier methodology with censoring as appropriate and were evaluated with a log-rank test, with a 2-tailed P value ≤.05 used to reject the null hypothesis.

Nineteen patients underwent ASCT, of whom 16 (8 AITL, 4 PTCL NOS, 4 ALCL) as upfront consolidation treatment and 3 (2 ALCL, 1 AITL) for relapsed disease. Fifteen of the patients having an ASCT upfront were in CR1 and 4 relapsed, all within 6 months of transplant; the patient transplanted upfront in PR is alive in CR.

Three patients had an ASCT as rescue for recurrent disease, 1 died with relapse and 2 are alive in CR. The OS and RFS at 6-years for the 19 patients having an ASCT are 62% and 59%, respectively.

Seven patients had an allograft. Four (2 AITL, 1 ALCL, 1 NOS) as upfront consolidation, of whom 3 with a matched unrelated donor and 1 with a mismatched unrelated donor. They all are alive in CR.

Three patients (2 AITL, 1 PTCL NOS) had an alloSCT after relapsing. Two with an unrelated donor, after having failed an ASCT, and 1 with a matched sibling. Two are alive in CR and 1 died due to transplant-related complications.

Chronic GvHD was the most relevant complication observed in 50% of patients submitted to allo-SCT. It resolved in all except 2 patients who still have cGvHD needing immunosuppression.

The OS and RFS at 6-years for the 7 patients submitted to allo-SCT are 87% and 85%, respectively. Transplant-related mortality (TRM) was 3.7% for the entire population. Out of the 26 patients, seven patients died, 6 with progressive disease after auto HSCT and 1 with multiorgan failure after allo-HSCT. The 6-year OS and PFS for the entire population were 74% and 69% respectively (Fig. 3). Overall survival and PFS for patients submitted to ASCT and allo-SCT were similar, as shown in Fig. 4.

Figure 3. Kaplan-Meier estimates of 6-year OS (A) and PFS (B) for the entire patient population

Figure 4. Kaplan-Meier estimates of overall survival and relapse free survival of PTCL patient cohorts submitted to autologous and allogeneic transplantation

Conclusions

The results of this retrospective study, taking into account the adverse risk profile of the population, suggest that autologous/allogeneic stem cell transplantation is an effective and safe option for the consolidation of patients with PTCLs.

The recently published results of the COMPLETE consortium analyzed the impact of ASCT on the clinical outcomes of patients with newly diagnosed nodal PTCL in CR1 patients. They suggested that certain subgroups of patients with PTCL, i.e. those with AITL and/or high-risk features (advanced-stage disease or intermediate-to-high IPI scores) might benefit from consolidative ASCT in CR1 [19]. Still they concluded that the broader applicability of this strategy should be determined in prospective, randomized trials.

In our small study, some key questions remain on the real role of ASCT and allo-SCT in PTCL. Notwithstanding these limitations our study shows that HSCT is feasible and may benefit patients with high risk PTCL. The outcomes did not differ significantly between ASCT and allo-SCT approaches, but the latter is probably more effective in patients with refractory disease.

These results need to be validated in prospective studies, including a larger number of patients and may provide a platform for designing future and larger studies on the role of HSCT in PTCL.

Conflict of interest

M. Abecasis is in the speakers bureau of Takeda.

References

1. Swerdlow SH, Campo E, Pileri SA, Harris NL et al. The 2016 revision of the World Health Organization classification of lymphoid neoplasms. Blood 2016; 127: 2375-2390.
2. Moskowitz AJ, Lunning MA, Horwitz SM. How I treat the peripheral T-cell lymphomas. Blood 2014; 123: 2636-2644.
3. Wilcox RA. Optimising initial treatment for peripheral T-cell lymphoma: a tough nut to CHOP. Lancet Haematol. 2018; 5: e182-e183.
4. Savage KJ, Chhanabhai M, Gascoyne RD, Connors JM. Characterization of peripheral T-cell lymphomas in a single North American institution by the WHO classification. Ann Oncol 2004; 15: 1467-1475.
5. Vose J, Armitage J, Weisenburger D. International peripheral T-cell and natural killer/T-cell lymphoma study: pathology findings and clinical outcomes. J Clin Oncol 2006; 24: 2472-2479.
6. Schmitz N, Trumper L, Ziepert M, Nickelsen M et al. of mature T-cell and NK-cell lymphoma: an analysis of patients with T-cell lymphoma treated in studies of the German High-Grade Non Hodgkin Lymphoma Study Group. Blood 2010; 116: 3418-3425.
7. Ellin F, Landstrom J, Jerkeman M, Relander T. Real-world data on prognostic factors and treatment in peripheral T- cell lymphomas: a study from the Swedish Lymphoma Registry. Blood 2014; 124: 1570-1577.
8. Carson KR, Horwitz SM, Pinter-Brown LC, Rosen ST et al. A prospective cohort study of patients with peripheral T-cell lymphoma in the United States. Cancer 2017; 123: 1174-1183.
9. Horwitz S, O'Connor OA, Pro B, Illidge T, Fanale M et al. ECHELON-2 Study Group. Brentuximab vedotin with chemotherapy for CD30-positive peripheral T-cell lymphoma(ECHELON-2): a global, double-blind, randomised, phase 3 trial. Lancet. 2019; 393:229-240.
10. National Comprehensive Cancer Network. NCCN Clinical practice guidelines in oncology for Non-Hodgkin’s Lymphomas. Version 2.2019.
11. Schmitz N, de Leval L. How I manage peripheral T-cell lymphoma, not otherwise specified and angioimmunoblastic T-cell lymphoma: current practice and a glimpse into the future. Br J Haematol 2017; 176: 851-866.
12. Zain JM. Aggressive T-cell lymphomas: 2019 updates on diagnosis, risk stratification, and management. Am J Hematol 2019; 94: 929-946.
13. Schmitz N, Lenz G, Stelljes M. Allogeneic hematopoietic stem cell transplantation for T-cell lymphomas. Blood 2018; 132: 245-253.
14. Kharfan-Dabaja MA, Kumar A, Ayala E, Hamadani M, et al. Clinical practice recommendations on indication and timing of hematopoietic cell transplantation in mature T cell and NK/T cell lymphomas: an international collaborative effort on behalf of the guidelines committee of the American Society for Blood and Marrow Transplantation. Biol Blood Marrow Transplant. 2017; 23(11):1826-1838.
15. Rohlfing S, Dietrich S, Witzens-Harig M, Hegenbart U et al. The impact of stem cell transplantation on the natural course of peripheral T-cell lymphoma: a real-world experience. Ann Hematol 2018; 97: 1241-1250.
16. Fossard G, Broussais F, Coelho I, Bailly S et al. Role of up-front autologous stem-cell transplantation in peripheral T-cell lymphoma for patients in response after induction: an analysis of patients from LYSA centers. Ann Oncology 2018; 29: 715-723.
17. Epperla N, Ahn KW, Litovich C, Ahmed A et al. Allogeneic hematopoietic cell transplantation provides effective salvage despite refractory disease or failed prior autologous transplant in angioimmunoblastic T-cell lymphoma: a CIBMTR analysis. J Hematol Oncol 2019; 6: doi: 10.1186/s13045-018-0696-z.
18. Duarte R, Labopin M, Bader P, Basak GW et al. Indications for haematopoietic stem cell transplantation for haematological diseases, solid tumors and immune disorders; current practice in Europe, 2019. Bone Marrow Transplant 2019; 54: 1525-15.
19. Park SI, Horwitz SM, Foss FM, Pinter-Brown LC, Carson KR et al. The role of autologous stem cell transplantation in patients with nodal peripheral T-cell lymphomas in first complete remission: report from COMPLETE, a prospective, multicenter cohort study. Cancer 2019; 125:1507-1517.

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Introduction

Peripheral T-cell lymphomas (PTCLs) derived from post-thymic T cells or mature NK cells, are a rare and heterogeneous group of aggressive lymphomas comprising approximately 10% of all non-Hodgkin lymphomas diagnosed in the western world. In 2016, the WHO classification of lymphoid neoplasms recognized more than 20 different T-cell lymphoma entities that broadly segregate into lymphomas with predominant nodal involvement, extra-nodal involvement, leukemic, or cutaneous manifestations [1].

Nodal PTCLs are the most common of the PTCL subtypes and include peripheral T-cell lymphoma not otherwise specified (PTCL-NOS), systemic anaplastic large cell lymphoma (sALCL) and angioimmunoblastic T-cell lymphoma (AITL). Together these 3 subtypes account for about 60% of all PTCL lymphomas. Given their heterogeneity, there is no consensus regarding the best first-line treatment, and the role of autologous/allogeneic (ASCT/alloSCT) stem cell transplantation as consolidation is controversial.

Conventional treatment with CHOP or CHOP-like regimen induces CR in about 50% of cases, with a 5-year survival of 30%-35% [2, 3]. Expected outcomes in terms of 5-year PFS/EFS in PTCL with initial CHOP treatment are based on 2 large retrospective series: the studies performed by the International T-Cell Project (ITCP) and the British Columbia Cancer Agency (BCCA) [4, 5] shown in Table 1.

Although CHOP is the most commonly used first-line regimen for patients with PTCL outcomes are disappointing with the exception of patients with ALK-positive sALCL. The most compelling evidence supporting the benefits of building on CHOP come from studies adding etoposide (CHOEP). It appears to offer an advantage over CHOP in younger patients (<60 years) based on a retrospective analysis of 7 prospective phase 2 or 3 German protocols including 343 patients [6]. CHOEP improved EFS from 51% to 71%. A registry study from Sweden found a superior PFS for CHOEP, also in patients <60 years [7]. This was seen particularly in those with ALCL and normal concentrations of lactate dehydrogenase. However, no improvement in OS was revealed, and greater toxicity was observed in older patients. This is also supported by the data from the COMPLETE study and suggests that any overall survival benefit associated with etoposide use in patients with PTCL is at best modest [8].

Although CHOP is the most commonly used first-line regimen for patients with PTCL outcomes are disappointing with the exception of patients with ALK-positive sALCL. The most compelling evidence supporting the benefits of building on CHOP come from studies adding etoposide (CHOEP). It appears to offer an advantage over CHOP in younger patients (<60 years) based on a retrospective analysis of 7 prospective phase 2 or 3 German protocols including 343 patients [6]. CHOEP improved EFS from 51% to 71%. A registry study from Sweden found a superior PFS for CHOEP, also in patients <60 years [7]. This was seen particularly in those with ALCL and normal concentrations of lactate dehydrogenase. However, no improvement in OS was revealed, and greater toxicity was observed in older patients. This is also supported by the data from the COMPLETE study and suggests that any overall survival benefit associated with etoposide use in patients with PTCL is at best modest [8].

CD30 is expressed in all sALCL and among other nodal variants of PTCL its expression is variable from 58-64% in PTCL NOS and 43-63% in AITL. Brentuximab vedotin (BV, Adcetris) is an antibody-drug conjugate active against CD30-positive lymphomas. The ECHELON-2 trial included a randomized, double-blind, phase 3 study of Brentuximab vedotin and CHP (A+CHP) versus CHOP in the frontline treatment of patients with CD30+ PTCLs [9].

The A+CHP schedule showed superior PFS and significantly longer OS than CHOP in patients with nodal CD30+ PTCLs. The trial also demonstrated improvement in the complete remission rate (68% vs 56%), and overall response rate (83% vs 72%) with A+CHP. Adverse events, including fatal AEs, were similar between groups. Of note, consolidative SCT was given to 22% patients in the A+CHP group and to 17% in the CHOP group. The treatment with ASCT did not affect PFS nor OS rates.

The NCCN guidelines suggest the following treatment regimens as first line therapy: BV+CHP regimen for sALCL cases; in other tumor histologies (PTCL NOS, AITL, nodal PTCL TFH), suggested regimens are as follows: BV+CHP for CD30+ histologies, and CHOP or CHOEP for other histologies, according to the patient’s age and performance status. As first-line consolidation high-dose therapy and stem cell rescue may be considered in appropriate patients [10].

High dose chemotherapy followed by autologous stem cell transplantation (ASCT) is a reasonable treatment option as front-line consolidation with resulting OS rates of 54% to 68% and low non-relapse mortality. A major problem is early relapse/progression in up to 40% of patients starting first-line therapy. In the relapse situation the overall prognosis is dismal, and the best treatment has not been defined yet [11, 12]. Chemorefractory patients should proceed to allogeneic SCT (allo-SCT) whenever possible, and the use of single agents as a bridge to transplant for these patients may be more appropriate because there is a need to sustain response until a compatible donor is identified and worked up [10-13].

Clinical practice recommendations on indication and timing of hematopoietic stem cell transplantation have recently been published by the American Society for Blood and Marrow Transplantation [14]. Registry studies on the role of autologous and allogeneic transplantation in PTCL have also been the subject of recent publications [15-17].

The current EBMT indications for hematopoietic transplantation in PTCL are illustrated in Table 2 [18].

Table 2. EBMT indications for HSCT in PTCL [18]

CO: clinical option; S: standard of care; GNR: generally not recommended; Grade I: at least 1 randomized trial; Grade II: at least 1 well-designed non-randomized CT; Grade III: expert opinion

To examine the real-world outcomes for patients with PTCL who underwent hematopoietic stem cell transplantation in our institution we conducted a retrospective review and report the clinical outcomes of 26 consecutive patients who were treated either as first-line consolidation or in the relapse setting between January 2000 and July 2018.

Patients and methods

Twenty-six patients were identified, with a median age of 46 years. Ninety-two percent of patients presented with advanced-stage at diagnosis (Ann Arbor stage III or IV) and 38% had B symptoms. The age-adjusted IPI (aaIPI) was low-intermediate in 15 patients and intermediate high/high in 11 patients (Table 3).

According to the 2016 revision of the WHO classification of lymphoid neoplasms, the most common PTCL subtypes within our cohort were AILT (46%), ALCL (26%) and PTCL NOS (20%) (1).

Most patients received CHOP chemotherapy as induction treatment regimen, with CHOEP being less frequently used (Table 4).

Twenty-seven transplants were performed in 26 patients (one patient had an ASCT followed by an allo-SCT after relapsing).

Nineteen patients had an ASCT with the BEAM conditioning regimen (Fig. 1). Sixteen patients were given an ASCT upfront as consolidation after induction treatment, with 14 being in CR and 2 in PR. Of these 16 patients, 5 had a relapse after ASCT and none survived, even though one was given an allo-SCT. Of the 3 patients given an ASCT as rescue treatment for relapse, 2 are alive in CR.

Seven patients underwent an allo-SCT, of whom 4 had it upfront and 3 after relapsing from a previous ASCT (Fig. 2). All patients received tacrolimus plus mycophenolate mofetil as GvHD prophylaxis and ATG was added to the conditioning regimen of the 2 patients transplanted with a mismatched unrelated donor. Five patients were conditioned with the Flu Mel protocol, 1 with Flu 2Gy TBI and 1 with the Flu BiCNU Mel protocol. All 4 patients treated upfront were given a transplant from unrelated donors of whom 1 was a 9/10 mismatch, none relapsed and all are alive. Of the 3 patients having a transplant after relapse, 2 are alive with no evidence of disease and one died of transplant related mortality.

Two patients deserve a special mention:
• Patient 19, a 58-y.o. male had a diagnosis of classic Hodgkin’s disease (cHD) in 2009, was treated with 8 cycles of ABVD and relapsed in 2011being treated with ICE followed by ASCT at another institution. In 2013, he presented with PTCL AITL subtype infiltrated with EBV+ B cells and was treated with R-ICE before being submitted to a matched unrelated allo-SCT in CR.
• Patient 21, a 42-y.o. male patient had a diagnosis of cHD in 1995, and achieved complete remission after 6 cycles of ABVD. He had a localized relapse of cHD in 1999, treated with local radiotherapy. He then presented in 2015 with a PTCL AITL subtype infiltrated with EBV+ B cells and CNS infiltration. He was treated with ESHAP followed by the LMB-96 protocol and was then submitted to a mismatched unrelated allo-SCT in CR.

Both patients are alive, one with moderate cGvHD.

Results

We evaluated the overall survival (OS) and progression-free survival (PFS) in our cohort of patients. The median follow-up time was 6.3 years (1-18.1 years). OS was calculated from the date of diagnosis until death due to any cause, and PFS was measured from transplant until relapse, progressive disease or last follow-up. Survival-based analysis were performed with the Kaplan-Meier methodology with censoring as appropriate and were evaluated with a log-rank test, with a 2-tailed P value ≤.05 used to reject the null hypothesis.

Nineteen patients underwent ASCT, of whom 16 (8 AITL, 4 PTCL NOS, 4 ALCL) as upfront consolidation treatment and 3 (2 ALCL, 1 AITL) for relapsed disease. Fifteen of the patients having an ASCT upfront were in CR1 and 4 relapsed, all within 6 months of transplant; the patient transplanted upfront in PR is alive in CR.

Three patients had an ASCT as rescue for recurrent disease, 1 died with relapse and 2 are alive in CR. The OS and RFS at 6-years for the 19 patients having an ASCT are 62% and 59%, respectively.

Seven patients had an allograft. Four (2 AITL, 1 ALCL, 1 NOS) as upfront consolidation, of whom 3 with a matched unrelated donor and 1 with a mismatched unrelated donor. They all are alive in CR.

Three patients (2 AITL, 1 PTCL NOS) had an alloSCT after relapsing. Two with an unrelated donor, after having failed an ASCT, and 1 with a matched sibling. Two are alive in CR and 1 died due to transplant-related complications.

Chronic GvHD was the most relevant complication observed in 50% of patients submitted to allo-SCT. It resolved in all except 2 patients who still have cGvHD needing immunosuppression.

The OS and RFS at 6-years for the 7 patients submitted to allo-SCT are 87% and 85%, respectively. Transplant-related mortality (TRM) was 3.7% for the entire population. Out of the 26 patients, seven patients died, 6 with progressive disease after auto HSCT and 1 with multiorgan failure after allo-HSCT. The 6-year OS and PFS for the entire population were 74% and 69% respectively (Fig. 3). Overall survival and PFS for patients submitted to ASCT and allo-SCT were similar, as shown in Fig. 4.

Figure 3. Kaplan-Meier estimates of 6-year OS (A) and PFS (B) for the entire patient population

Figure 4. Kaplan-Meier estimates of overall survival and relapse free survival of PTCL patient cohorts submitted to autologous and allogeneic transplantation

Conclusions

The results of this retrospective study, taking into account the adverse risk profile of the population, suggest that autologous/allogeneic stem cell transplantation is an effective and safe option for the consolidation of patients with PTCLs.

The recently published results of the COMPLETE consortium analyzed the impact of ASCT on the clinical outcomes of patients with newly diagnosed nodal PTCL in CR1 patients. They suggested that certain subgroups of patients with PTCL, i.e. those with AITL and/or high-risk features (advanced-stage disease or intermediate-to-high IPI scores) might benefit from consolidative ASCT in CR1 [19]. Still they concluded that the broader applicability of this strategy should be determined in prospective, randomized trials.

In our small study, some key questions remain on the real role of ASCT and allo-SCT in PTCL. Notwithstanding these limitations our study shows that HSCT is feasible and may benefit patients with high risk PTCL. The outcomes did not differ significantly between ASCT and allo-SCT approaches, but the latter is probably more effective in patients with refractory disease.

These results need to be validated in prospective studies, including a larger number of patients and may provide a platform for designing future and larger studies on the role of HSCT in PTCL.

Conflict of interest

M. Abecasis is in the speakers bureau of Takeda.

References

1. Swerdlow SH, Campo E, Pileri SA, Harris NL et al. The 2016 revision of the World Health Organization classification of lymphoid neoplasms. Blood 2016; 127: 2375-2390.
2. Moskowitz AJ, Lunning MA, Horwitz SM. How I treat the peripheral T-cell lymphomas. Blood 2014; 123: 2636-2644.
3. Wilcox RA. Optimising initial treatment for peripheral T-cell lymphoma: a tough nut to CHOP. Lancet Haematol. 2018; 5: e182-e183.
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Учитывая их гетерогенность, отсутствует консенсус, касающийся наилучшего лечения первой линии, роль аутологичной или аллогенной трансплантации гемопоэтических клеток (ТГСК) в качестве консолидации пока противоречива. Чтобы изучить реальные исходы у пациентов с ПТКЛ, направленных для ТГСК в наше учреждение, мы ретроспективно изучили клинические исходы у 26 пациентов, которым выполняли трансплантацию либо в качестве консолидирующей терапии первой линии или при рецидиве заболевания в период с января 2000 по июль 2018 г. Медианный срок наблюдения составлял 6,3 года; 19 больных получили ауто-ТГСК, 16 – в качестве первой консолидации и 3 – по поводу рецидива болезни. Общая выживаемость (ОВ) и безрецидивная выживаемость (БРВ) были, соответственно, 62% и 59%. Семи больным было проведена алло-ТГСК, четыре – консолидация первой линии и трем – после рецидива. Шесть больных живы и один умер в связи с процедурой ТГСК. Этот вид летальности составил 3.7% для всей группы, а 6-летние показатели ОВ и БРВ были, соответственно, 74% и 69%. Наши результаты предполагают, что аутологичные и аллогенные ТГСК являются эффективным и безопасным вариантом в целях консолидации больных ПТКЛ с неблагоприятным профилем риска, но нужна их валидация в проспективных исследованиях, включающих большое число пациентов.</p> <h2>Ключевые слова</h2> <p style="text-align: justify;">Периферические Т-клеточные лимфомы, терапия первой линии, CHOP, Брентуксимаб ведотин, трансплантация гемопоэтических клеток, аллогенная, аутологичная. </p> " ["ELEMENT_PREVIEW_PICTURE_FILE_TITLE"]=> string(188) "Трансплантация стволовых клеток как консолидирующее лечение при периферических Т-клеточных лимфомах" ["ELEMENT_DETAIL_PICTURE_FILE_ALT"]=> string(188) "Трансплантация стволовых клеток как консолидирующее лечение при периферических Т-клеточных лимфомах" ["ELEMENT_DETAIL_PICTURE_FILE_TITLE"]=> string(188) "Трансплантация стволовых клеток как консолидирующее лечение при периферических Т-клеточных лимфомах" ["SECTION_META_TITLE"]=> string(188) "Трансплантация 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Мануэль Абекасис, Каталина Гомез, Изабелина Феррейра, Мария Гомес да Силва, Нуньо Миранда, Гилда Тейксейра, Фернандо Леаль да Коста, Мария Жоао Гутьеррез

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Португальский институт онкологии Франциско Жентиль, Лиссабон, Португалия

" ["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) "26147" ["VALUE"]=> array(2) { ["TEXT"]=> string(3244) "<p style="text-align: justify;">Периферические Т-клеточные лимфомы (ПТКЛ) являются гетерогенной группой редких агрессивных лимфом, состоящей из более чем 20 различных клинических форм и представляющих около 10% всех неходжкинских лимфом, диагностированных в Западном мире. Учитывая их гетерогенность, отсутствует консенсус, касающийся наилучшего лечения первой линии, роль аутологичной или аллогенной трансплантации гемопоэтических клеток (ТГСК) в качестве консолидации пока противоречива. Чтобы изучить реальные исходы у пациентов с ПТКЛ, направленных для ТГСК в наше учреждение, мы ретроспективно изучили клинические исходы у 26 пациентов, которым выполняли трансплантацию либо в качестве консолидирующей терапии первой линии или при рецидиве заболевания в период с января 2000 по июль 2018 г. Медианный срок наблюдения составлял 6,3 года; 19 больных получили ауто-ТГСК, 16 – в качестве первой консолидации и 3 – по поводу рецидива болезни. Общая выживаемость (ОВ) и безрецидивная выживаемость (БРВ) были, соответственно, 62% и 59%. Семи больным было проведена алло-ТГСК, четыре – консолидация первой линии и трем – после рецидива. Шесть больных живы и один умер в связи с процедурой ТГСК. Этот вид летальности составил 3.7% для всей группы, а 6-летние показатели ОВ и БРВ были, соответственно, 74% и 69%. Наши результаты предполагают, что аутологичные и аллогенные ТГСК являются эффективным и безопасным вариантом в целях консолидации больных ПТКЛ с неблагоприятным профилем риска, но нужна их валидация в проспективных исследованиях, включающих большое число пациентов.</p> <h2>Ключевые слова</h2> <p style="text-align: justify;">Периферические Т-клеточные лимфомы, терапия первой линии, CHOP, Брентуксимаб ведотин, трансплантация гемопоэтических клеток, аллогенная, аутологичная. </p> " ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(3188) "

Периферические Т-клеточные лимфомы (ПТКЛ) являются гетерогенной группой редких агрессивных лимфом, состоящей из более чем 20 различных клинических форм и представляющих около 10% всех неходжкинских лимфом, диагностированных в Западном мире. Учитывая их гетерогенность, отсутствует консенсус, касающийся наилучшего лечения первой линии, роль аутологичной или аллогенной трансплантации гемопоэтических клеток (ТГСК) в качестве консолидации пока противоречива. Чтобы изучить реальные исходы у пациентов с ПТКЛ, направленных для ТГСК в наше учреждение, мы ретроспективно изучили клинические исходы у 26 пациентов, которым выполняли трансплантацию либо в качестве консолидирующей терапии первой линии или при рецидиве заболевания в период с января 2000 по июль 2018 г. Медианный срок наблюдения составлял 6,3 года; 19 больных получили ауто-ТГСК, 16 – в качестве первой консолидации и 3 – по поводу рецидива болезни. Общая выживаемость (ОВ) и безрецидивная выживаемость (БРВ) были, соответственно, 62% и 59%. Семи больным было проведена алло-ТГСК, четыре – консолидация первой линии и трем – после рецидива. Шесть больных живы и один умер в связи с процедурой ТГСК. Этот вид летальности составил 3.7% для всей группы, а 6-летние показатели ОВ и БРВ были, соответственно, 74% и 69%. Наши результаты предполагают, что аутологичные и аллогенные ТГСК являются эффективным и безопасным вариантом в целях консолидации больных ПТКЛ с неблагоприятным профилем риска, но нужна их валидация в проспективных исследованиях, включающих большое число пациентов.

Ключевые слова

Периферические Т-клеточные лимфомы, терапия первой линии, CHOP, Брентуксимаб ведотин, трансплантация гемопоэтических клеток, аллогенная, аутологичная.

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Manuel Abecasis, Catalina Gomez, Isabelina Ferreira, Maria Gomes da Silva, Nuno Miranda, Gilda Teixeira, Fernando Leal da Costa, Maria João Gutierrez

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Instituto Português Oncologia de Lisboa Francisco Gentil, Lisboa, Portugal

Correspondence
Prof. Dr. Manuel Abecasis, Director, Hematology Department, Instituto Português Oncologia,
R. Professor Lima Basto 1099-093, Lisboa, Portugal

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Peripheral T-cell lymphomas (PTCLs) are a rare and heterogeneous group of aggressive lymphomas comprising more than 20 different entities and representing about 10% of all non-Hodgkin lymphomas diagnosed in the Western World. Given their heterogeneity, there is no consensus regarding the best first-line treatment and the role of autologous/allogeneic hematopoietic stem cell transplantation (HSCT) as consolidation is controversial. To examine the real-world outcomes for patients with PTCL submitted to HSCT in our institution we retrospectively reviewed the clinical outcomes of 26 patients who were given a transplant either as first-line consolidation or in relapse between January 2000 and July 2018. The median follow-up is 6.3 years; 19 patients had an autologous HSCT, 16 as upfront consolidation and 3, for relapsed disease. Overall survival (OS) and relapse free survival (RFS) were, respectively, 62% and 59%. Seven patients had an allograft, 4 as upfront consolidation and 3 after relapse; 6 are alive and 1 died due to transplant-related mortality (TRM). TRM was 3.7% for the entire population and the 6-year OS and PFS were 74% and 69%, respectively. Our results suggest that autologous/allogeneic HSCT is an effective and safe option for the consolidation of adverse-risk profile patients with PTCL, but they need to be validated in prospective studies including a larger number of patients.

Keywords

Peripheral T-cell lymphomas, first-line therapy, CHOP, Brentuximab vedotin, hematopoietic stem cell transplantation, allogeneic, autologous.

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Manuel Abecasis, Catalina Gomez, Isabelina Ferreira, Maria Gomes da Silva, Nuno Miranda, Gilda Teixeira, Fernando Leal da Costa, Maria João Gutierrez

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Manuel Abecasis, Catalina Gomez, Isabelina Ferreira, Maria Gomes da Silva, Nuno Miranda, Gilda Teixeira, Fernando Leal da Costa, Maria João Gutierrez

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Peripheral T-cell lymphomas (PTCLs) are a rare and heterogeneous group of aggressive lymphomas comprising more than 20 different entities and representing about 10% of all non-Hodgkin lymphomas diagnosed in the Western World. Given their heterogeneity, there is no consensus regarding the best first-line treatment and the role of autologous/allogeneic hematopoietic stem cell transplantation (HSCT) as consolidation is controversial. To examine the real-world outcomes for patients with PTCL submitted to HSCT in our institution we retrospectively reviewed the clinical outcomes of 26 patients who were given a transplant either as first-line consolidation or in relapse between January 2000 and July 2018. The median follow-up is 6.3 years; 19 patients had an autologous HSCT, 16 as upfront consolidation and 3, for relapsed disease. Overall survival (OS) and relapse free survival (RFS) were, respectively, 62% and 59%. Seven patients had an allograft, 4 as upfront consolidation and 3 after relapse; 6 are alive and 1 died due to transplant-related mortality (TRM). TRM was 3.7% for the entire population and the 6-year OS and PFS were 74% and 69%, respectively. Our results suggest that autologous/allogeneic HSCT is an effective and safe option for the consolidation of adverse-risk profile patients with PTCL, but they need to be validated in prospective studies including a larger number of patients.

Keywords

Peripheral T-cell lymphomas, first-line therapy, CHOP, Brentuximab vedotin, hematopoietic stem cell transplantation, allogeneic, autologous.

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Peripheral T-cell lymphomas (PTCLs) are a rare and heterogeneous group of aggressive lymphomas comprising more than 20 different entities and representing about 10% of all non-Hodgkin lymphomas diagnosed in the Western World. Given their heterogeneity, there is no consensus regarding the best first-line treatment and the role of autologous/allogeneic hematopoietic stem cell transplantation (HSCT) as consolidation is controversial. To examine the real-world outcomes for patients with PTCL submitted to HSCT in our institution we retrospectively reviewed the clinical outcomes of 26 patients who were given a transplant either as first-line consolidation or in relapse between January 2000 and July 2018. The median follow-up is 6.3 years; 19 patients had an autologous HSCT, 16 as upfront consolidation and 3, for relapsed disease. Overall survival (OS) and relapse free survival (RFS) were, respectively, 62% and 59%. Seven patients had an allograft, 4 as upfront consolidation and 3 after relapse; 6 are alive and 1 died due to transplant-related mortality (TRM). TRM was 3.7% for the entire population and the 6-year OS and PFS were 74% and 69%, respectively. Our results suggest that autologous/allogeneic HSCT is an effective and safe option for the consolidation of adverse-risk profile patients with PTCL, but they need to be validated in prospective studies including a larger number of patients.

Keywords

Peripheral T-cell lymphomas, first-line therapy, CHOP, Brentuximab vedotin, hematopoietic stem cell transplantation, allogeneic, autologous.

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Instituto Português Oncologia de Lisboa Francisco Gentil, Lisboa, Portugal

Correspondence
Prof. Dr. Manuel Abecasis, Director, Hematology Department, Instituto Português Oncologia,
R. Professor Lima Basto 1099-093, Lisboa, Portugal

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Instituto Português Oncologia de Lisboa Francisco Gentil, Lisboa, Portugal

Correspondence
Prof. Dr. Manuel Abecasis, Director, Hematology Department, Instituto Português Oncologia,
R. Professor Lima Basto 1099-093, Lisboa, Portugal

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Мануэль Абекасис, Каталина Гомез, Изабелина Феррейра, Мария Гомес да Силва, Нуньо Миранда, Гилда Тейксейра, Фернандо Леаль да Коста, Мария Жоао Гутьеррез

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Мануэль Абекасис, Каталина Гомез, Изабелина Феррейра, Мария Гомес да Силва, Нуньо Миранда, Гилда Тейксейра, Фернандо Леаль да Коста, Мария Жоао Гутьеррез

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Учитывая их гетерогенность, отсутствует консенсус, касающийся наилучшего лечения первой линии, роль аутологичной или аллогенной трансплантации гемопоэтических клеток (ТГСК) в качестве консолидации пока противоречива. Чтобы изучить реальные исходы у пациентов с ПТКЛ, направленных для ТГСК в наше учреждение, мы ретроспективно изучили клинические исходы у 26 пациентов, которым выполняли трансплантацию либо в качестве консолидирующей терапии первой линии или при рецидиве заболевания в период с января 2000 по июль 2018 г. Медианный срок наблюдения составлял 6,3 года; 19 больных получили ауто-ТГСК, 16 – в качестве первой консолидации и 3 – по поводу рецидива болезни. Общая выживаемость (ОВ) и безрецидивная выживаемость (БРВ) были, соответственно, 62% и 59%. Семи больным было проведена алло-ТГСК, четыре – консолидация первой линии и трем – после рецидива. Шесть больных живы и один умер в связи с процедурой ТГСК. Этот вид летальности составил 3.7% для всей группы, а 6-летние показатели ОВ и БРВ были, соответственно, 74% и 69%. Наши результаты предполагают, что аутологичные и аллогенные ТГСК являются эффективным и безопасным вариантом в целях консолидации больных ПТКЛ с неблагоприятным профилем риска, но нужна их валидация в проспективных исследованиях, включающих большое число пациентов.</p> <h2>Ключевые слова</h2> <p style="text-align: justify;">Периферические Т-клеточные лимфомы, терапия первой линии, CHOP, Брентуксимаб ведотин, трансплантация гемопоэтических клеток, аллогенная, аутологичная. </p> " ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(3188) "

Периферические Т-клеточные лимфомы (ПТКЛ) являются гетерогенной группой редких агрессивных лимфом, состоящей из более чем 20 различных клинических форм и представляющих около 10% всех неходжкинских лимфом, диагностированных в Западном мире. Учитывая их гетерогенность, отсутствует консенсус, касающийся наилучшего лечения первой линии, роль аутологичной или аллогенной трансплантации гемопоэтических клеток (ТГСК) в качестве консолидации пока противоречива. Чтобы изучить реальные исходы у пациентов с ПТКЛ, направленных для ТГСК в наше учреждение, мы ретроспективно изучили клинические исходы у 26 пациентов, которым выполняли трансплантацию либо в качестве консолидирующей терапии первой линии или при рецидиве заболевания в период с января 2000 по июль 2018 г. Медианный срок наблюдения составлял 6,3 года; 19 больных получили ауто-ТГСК, 16 – в качестве первой консолидации и 3 – по поводу рецидива болезни. Общая выживаемость (ОВ) и безрецидивная выживаемость (БРВ) были, соответственно, 62% и 59%. Семи больным было проведена алло-ТГСК, четыре – консолидация первой линии и трем – после рецидива. Шесть больных живы и один умер в связи с процедурой ТГСК. Этот вид летальности составил 3.7% для всей группы, а 6-летние показатели ОВ и БРВ были, соответственно, 74% и 69%. Наши результаты предполагают, что аутологичные и аллогенные ТГСК являются эффективным и безопасным вариантом в целях консолидации больных ПТКЛ с неблагоприятным профилем риска, но нужна их валидация в проспективных исследованиях, включающих большое число пациентов.

Ключевые слова

Периферические Т-клеточные лимфомы, терапия первой линии, CHOP, Брентуксимаб ведотин, трансплантация гемопоэтических клеток, аллогенная, аутологичная.

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Периферические Т-клеточные лимфомы (ПТКЛ) являются гетерогенной группой редких агрессивных лимфом, состоящей из более чем 20 различных клинических форм и представляющих около 10% всех неходжкинских лимфом, диагностированных в Западном мире. Учитывая их гетерогенность, отсутствует консенсус, касающийся наилучшего лечения первой линии, роль аутологичной или аллогенной трансплантации гемопоэтических клеток (ТГСК) в качестве консолидации пока противоречива. Чтобы изучить реальные исходы у пациентов с ПТКЛ, направленных для ТГСК в наше учреждение, мы ретроспективно изучили клинические исходы у 26 пациентов, которым выполняли трансплантацию либо в качестве консолидирующей терапии первой линии или при рецидиве заболевания в период с января 2000 по июль 2018 г. Медианный срок наблюдения составлял 6,3 года; 19 больных получили ауто-ТГСК, 16 – в качестве первой консолидации и 3 – по поводу рецидива болезни. Общая выживаемость (ОВ) и безрецидивная выживаемость (БРВ) были, соответственно, 62% и 59%. Семи больным было проведена алло-ТГСК, четыре – консолидация первой линии и трем – после рецидива. Шесть больных живы и один умер в связи с процедурой ТГСК. Этот вид летальности составил 3.7% для всей группы, а 6-летние показатели ОВ и БРВ были, соответственно, 74% и 69%. Наши результаты предполагают, что аутологичные и аллогенные ТГСК являются эффективным и безопасным вариантом в целях консолидации больных ПТКЛ с неблагоприятным профилем риска, но нужна их валидация в проспективных исследованиях, включающих большое число пациентов.

Ключевые слова

Периферические Т-клеточные лимфомы, терапия первой линии, CHOP, Брентуксимаб ведотин, трансплантация гемопоэтических клеток, аллогенная, аутологичная.

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Португальский институт онкологии Франциско Жентиль, Лиссабон, Португалия

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Португальский институт онкологии Франциско Жентиль, Лиссабон, Португалия

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Introduction

Bispecific monoclonal antibodies for targeting tumor cells have a long story from 1980's to produce approved drug in 2014 [1-3]. Several trials for relapsed/refractory acute lymphoblastic leukemia (R/R ALL) treatment including ALCANTARA for Philadelphia chromosome-positive (Ph-positive) R/R ALL were performed and showed clinical effectiveness and even an advantage over chemotherapy (TOWER Study) [4-8]. Recently published results on blinatumomab combined with TKI for therapy of Ph-positive R/R ALL characterized this approach to be safe and effective [11]. Combination of Blinatumomab and TKI could elicit lower toxicity and improve primary results in managing heavily pretreated R/R ALL patients. In preclinical studies, retinoids have shown antileukemic activity in IKZF-deleted ALL [12]. We previously reported about effective combination of blinatumomab with tyrosine kinase inhibitors (TKI) for the treatment of Ph-positive and FLT3-ITD R/R ALL and blinatumomab with TKI and all-trans retinoic acid in IKZF-deleted R/R ALL patients [9, 10]. The aim of our study was to present the data on 11 R/R ALL patients treated with Blinatumomab and TKI+/-ATRA, omitting simultaneous standard chemotherapy.

Patients and methods

Eleven patients (pts) with R/R ALL were treated with Blinatumomab + TKI/TKI+ATRA at the National Research Center for Hematology, Moscow, Russia, and in Raisa Gorbacheva Memorial Institute of Pediatric Oncology, Hematology and Transplantation, Saint Petersburg, Russia, from October 2015 to October 2018. The study was approved by the Institutional Review Board. The treatment was administered after the patient has signed informed consent. Blinatumomab was provided by Amgen as part of the expanded access program. The treatment consisted of 4-5 cycles of blinatumomab 28 mcg/day by continuous infusion for 4 weeks each cycle. Over 1^st week of 1^st cycle, Blinatumomab was administered at the dose of 9 mcg/day. The 2-week intervals followed between the rounds of blinatumomab treatment. All the patients were administered one of TKIs: 7 Ph-positive and 2 IKZF1-deleted ALL pts were initially treated with dasatinib (140 mg/day) per os, 1 FLT3-ITD ALL patient received sorafenib (800 mg/day) per os, and one Ph-positive ALL patient with a T315I mutation received ponatinib (45 mg/day). All the TKIs were administered continuously, from the 1^st day of starting blinatumomab. All-trans-retinoic acid (ATRA) at a dose of 45 mg/m²/day was administered per os in the IKZF1-deleted pts during 4 weeks of the 1^st blinatumomab cycle, and during first two weeks of subsequent blinatumomab cycles.

Complete remission (CR) was diagnosed if less than 5% of blasts were present in bone marrow. Cytogenetic remission (CyR) was diagnosed in the absence of BCR-ABL positive nuclei per 200 nuclei by fluorescence in situ hybridization (FISH). Molecular CR (MolCR) was diagnosed if BCR-ABL/ABL at a ratio of <0.01 was detected in bone marrow samples by RT-qPCR. The CD3+/CD4+/CD8- T-helper, CD3+/CD4-/CD8+ T-cytotoxic, CD3+/CD4-/CD8- T-Double-negative, CD3+/CD4+/CD25+ T-regulatory, CD3-/CD56+ NK subpopulations were measured in peripheral blood lymphocytes by flow cytometry weekly during blinatumomab treatment in all the pts (1 to 16 samples, 4 points per each blinatumomab cycle). Serum immunoglobulins (Ig) G, M and A were measured during each cycle of blinatumomab (a total of 4 sampling points).

The SAS software was used for statistical evaluation using regression analysis. The MIXED SAS procedure was used to perform repeated measures analysis and to estimate parameters of linear regression of average time-dependent trend.

Results

Median follow-up was 23 months (19 to 36 months). Median age is 32 years (24 to 49 years). Eight pts were females and 3, males. 7 pts received 4 cycles; 1 pt, 5 cycles; 2 pts underwent 2 cycles, and 1 pt was subjected to 1 cycle of blinatumomab treatment. Nine patients had febrile reactions during first two weeks at the 1^st cycle of blinatumomab. No one cycle of blinatumomab therapy was not interrupted. Neurological toxicity (1-2 grades) was observed in 2 cases manifesting as headaches in 1 patient, and ulnar neuropathy in 1 case. One patient treated with sorafenib has hand-foot skin syndrome. The syndrome completely resolved after 2 weeks interruption of sorafenib treatment.

Pulmonary infiltrates and pleural effusion in one dasatinib-treated case were completely resolved after switching to nilotinib. Diarrhea associated with dasatinib therapy was observed in 3 patients and resolved after its replacement with bosutinib in 2 cases, and with nilotinib in 1 patient. CMV-associated colitis was diagnosed in 2 cases using virus-specific PCR in stool samples. Massive intestinal bleeding and multiple intestinal ulceration were observed in one patient with CMV colitis, as confirmed by colonoscopy. Facial edema and hyperemia were evident in 1 patient upon dasatinib treatment. These symptoms resolved after passage from dasatinib to nilotinib. Greyness of hair was detected in one patient treated with ponatinib. The main clinical characteristics of individual patients and the events are listed in Table 1.

Table 1. Basic clinical characteristics of blinatumomab + TKI-treated ALL patients, response to therapy, and adverse effects

The weekly performed counts of T-cytotoxic, NK, T-helper and T-regulatory cells in peripheral blood were decreased during the 1^st blinatumomab cycle. T-cytotoxic and NK cells returned to normal ranges over the 2^nd to 4^th blinatumomab cycles. T-regulatory cell counts remained decreased or approached low-normal limits at all terms, except of 2^nd blinatumomab cycle (Fig. 1).

Regression analysis (the MIXED procedure in SAS system) was performed for each cell subpopulation, in order to detect significant changes of the T cell subpopulation kinetics (Table 2 and Fig. 2 a-e). As seen in table 2 in T-helper, T-cytotoxic and NK-subpopulations the weekly gaining effect was statistically significant.

Hypogammaglobulinemia during blinatumomab treatment was frequently observed (Fig. 3), and, in eight patients, treatment with intravenous human normal immunoglobulin was used. To check if the IgG, IgA and IgM kinetics were statistically significant, the regression analysis (the MIXED procedure in SAS system) was performed for each Ig (Table 3 and Fig. 4). As seen in Table 3, a gradual decrease in immunoglobulins with each cycle of blinatumomab was statistically significant for IgG, IgA and IgM. Fig. 4 shows the statistically significant effects of Blinatumomab treatment upon IgG (p=0.0446), IgA (p<.0001), and IgM (p=0.0186) (Table 3).

In 10 cases of 11, complete remission (CR) was achieved after 1^st blimatumomab cycle. Progression of the disease was observed in 1 patient during 1^st cycle of blinatumomab treatment, thus urging us to stop this therapy. Molecular CR (MolCR) was achieved in 9 cases, and cytogenetic CR was detected in 1 patient during consequent blinatumomab cycles. Allogeneic BMT was performed in 9 cases, and auto-BMT, in 1 patient with MolCR. Overt rapid hematological relapse was diagnosed in 1 patient under bosutinib maintenance therapy while waiting for alloBMT. Subsequent MolCR was achieved in the patient with bortezomib-based chemotherapy + dasatinib. One cytogenetic relapse was observed in 1 patient with complete cytogenetic remission before alloBMT. One patient treated with dasatinib as maintenance therapy after auto-BMT had molecular relapse, and second MolCR was achieved after Blinatumomab retreatment + dasatinib + ATRA. Allo-BMT from haploidentical donor was performed in this case. One patient treated with ponatinib and one patient receiving dasatinib maintenance after allo-BMT had CNS relapse and CNS lesions that regressed after intrathecal chemotherapy and cranial irradiation. One patient in MolCR died from septic shock 5 months after allo-BMT.

Discussion

Each patient in the study received combined treatment with blimatumomab immunotherapy and TKI target therapy. The treatment was well tolerated and complications were rare and curable. Hypogammaglobulinemia was common during blinatumomab treatment reflecting strong mature B-cell depletion on anti CD19 treatment. High rate of hypogammaglobulinemia lead to high rate of CMV infection, that was severe in 1 case. Rapid CR achievement and granulocyte recovery permits to treat almost all patients from 2^nd to 4^th cycles in outpatient settings. Nine molCR and one CyR with only one case of progressive disease permit to recognize this approach as highly effective, with low toxicity profile. Complementary treatment with ATRA in IKZF-deleted pts was also effective strategy though the number of such cases is too small. TKI treatment allows to perform prolonged maintenance, in order to control remaining leukemic populations in some cases. Though the rate of relapses is high, i.e., one half of the pts. However, a cohort of patients had extremely high risk of subsequent relapses and our approach did not exclude this risk entirely. In a single case, replacement of effective TKIs due to toxicity resulted in overt hematological relapse.

Prolonged neutropenia after Allo-BMT resulted in postponing of TKI maintenance and, in all these cases, the dose of eventually administered TKI was lowered by half. Heavily pre-treated patients have higher post-Allo-BMT toxicity, and the maintenance therapy after BMT was not proper. Auto-BMT in Ph-positive patient was not a curative strategy, though in IKZF-deleted patient, AutoBMT with lower toxicity regimen enables us to perform adequate maintenance with two agents, i.e., TKI and ATRA. Recently published results of combined treatment with blinatumomab and TKIs in Ph-positive relapsed ALL had also shown high rates of subsequent remissions and OS values (73% to 75%) in a small cohort of patients [11]. Statistical evaluation of changes observed for different lymphoid subpopulations revealed a strong evidence for T-cytotoxic and NK cells recovery in the course of effective combined treatment with blinatumomab and TKI. Duell et al. have demonstrated that lower frequency of T-regulatory cells correlates with higher response to blinatumomab in B-ALL patients [13]. T-regulatory and double-negative cells may potentially inhibit cytotoxic and other effector lymphocytes subpopulations and we observed their fluctuation within lower values of absolute peripheral blood counts in responders to the drug. Rapid and strong B-cell depletion as demonstrated by Zugmaier et al. [14], could explain the dropping immunoglobulin synthesis and prolonged hypogammaglobulinemia in most patients treated with blinatumomab.

Conclusion

Combined treatment with blinatumomab and TKI has acceptable and curable toxicity and demonstrates high rate of MolCR in high risk R/R ALL pts. The results are promising, with respect of using this treatment as induction and consolidation therapy without standard chemotherapy. IKZF deletions and FLT3-ITD are the new targets for chemo-free combined immunotherapy and TKI in ALL patients.

Acknowledgements

We thank Amgen for blinatumomab providing. We thank the Russian Acute Leukemia Study Group, National Hematology Society of Russia and also Margarita Anukhina for data management.

References

1. Perez P, Hoffman RW, Shaw S, Bluestone JA, Segal DM. Specific targeting of cytotoxic T cells by anti-T3 linked to anti-target cell antibody. Nature. 1985; 316:354-356.
2. Baagen A, Van De Griend R, Clark M, Geerars A, Bast B, De Gast B. Killing of human leukaemia/lymphoma B cells by activated cytotoxic T lymphocytes in the presence of a bispecific monoclonal antibody (mCD3/mCD19). Clin Exp Immunol. 1992; 90: 368-375.
3. Przepiorka D, Ko C-W, Deisseroth A, Yancey CL, Candau-Chacon R, Chiu H-J, Gehrke BJ, Gomez-Broughton C, Kane RC, Kirshner S, Mehrotra N, Ricks TK, Schmiel D, Song P, Zhao P, Zhou Q, Farrell AT, Pazdur R. FDA Approval: Blinatumomab. Clin Cancer Res. 2015; 21(18):4035-4039.
4. Topp MS, Gokbuget N, Stein AS, Zugmaier G, O'Brien S, Bargou RC, Dombret H, Fielding AK, Heffner L, Larson RA, Neumann S, Foà R, Litzow M, Ribera JM, Rambaldi A, Schiller G. Safety and activity of Blinatumomab for adult patients with relapsed or refractory B-precursor acute lymphoblastic leukaemia: A multicentre, single-arm phase 2 study. Lancet Oncol. 2015;16:57-66.
5. Kantarjian H, Stein A, Gokbuget N, Fielding AK, Schuh AC, Ribera J-M, Wei A, Dombret H, Foà R, Bassan R, Arslan Ö, Sanz MA, et al. Blinatumomab versus chemotherapy for advanced acute lymphoblastic leukemia. N Eng J Med. 2017;376:836-847.
6. Martinelli G, Boissel N, Chevallier P, Ottmann O, Gökbuget N, Topp MS, Fielding AK, Rambaldi A, Ritchie EK, Papayannidis C, Sterling LR, Benjamin J, Stein A. Complete hematologic and molecular response in adult patients with relapsed/refractory Philadelphia chromosome-positive B-precursor acute lymphoblastic leukemia following treatment with Blinatumomab: Results from a phase II, single-arm, multicenter study. J Clin Oncol. 2017;35:1795-1802.
7. von Stackelberg A, Locatelli F, Zugmaier G, Handgretinger R, Trippett TM, Rizzari C, Bader P, O'Brien MM, Brethon B, Bhojwani D, Schlegel PG, Borkhardt A, Rheingold SR, Cooper TM, Zwaan CM et al. Phase I/phase II study of Blinatumomab in pediatric patients with relapsed/refractory acute lymphoblastic leukemia. J Clin Oncol. 2016;34(36):4381-4389.
8. Gokbuget N, Dombret H, Ribera JM, Fielding AK, Advani A, Bassan R, Chia V, Doubek M, Giebel S, Hoelzer D, Ifrah N, Katz A, Kelsh M, Martinelli G, Morgades M, O'Brien S et al. International reference analysis of outcomes in adults with B-precursor Ph-negative relapsed/refractory acute lymphoblastic leukemia. Haematologica. 2016; 101:1524-1533.
9. Sokolov A, Parovichnikova E, Troitskaya V, Galtseva I, Firsova M, Davidova J, Kapranov N, Savchenko V. Combined Blinatumomab + Dasatinib/Ibrutinib therapy of relapsed acute lymphoblastic leukemia patients – antileukemic effect on the T-helper and T-regulatory cells reduction background. Haematologica. 2016; 101: 354-355 (E867).
10. Sokolov AN, Parovichnikova EN, Troitskaya VV, Kuzmina LA, Galtseva IV, Kulikov SM, Bondarenko SN, Davidova JO, Kapranov NM, Lukyanova IA, Lobanova TI, Usikova EI, Zarubina KI, Savchenko VG. Blinatumomab + tyrosine kinase inhibitors with no chemotherapy in BCR-ABL-positive or IKZF1-deleted or FLT3-ITD-positive relapsed/refractory acute lymphoblastic leukemia patients: high molecular remission rate and toxicity profile. Blood. 2017;130:3884.
11. Assi R, Kantarjian H, Short NJ, Daver N, Takahashi K, Garcia-Manero G, DiNardo C, Burger J, Cortes J, Jain N, Wierda W, Chamoun S, Konopleva M, Jabbour E. Safety and efficacy of blinatumomab in combination with a tyrosine kinase inhibitor for the treatment of relapsed Philadelphia chromosome-positive leukemia. Clin Lymphoma Myeloma Leuk. 2017;17(12):897-901.
12. Churchman ML, Low J, Qu C, Paietta EM, Kasper LH, Chang Y, Payne-Turner D, Althoff MJ, Song G, Chen SC, Ma J, Rusch M, McGoldrick D, Edmonson M, Gupta P, Wang YD et al. Efficacy of retinoids in IKZF1-mutated BCR-ABL1 acute lymphoblastic leukemia. Cancer Cell. 2015;28(3):343-356.
13. Duell J, Dittrich M, Bedke T, Mueller T, Eisele F, Rosenwald A, Rasche L, Hartmann E, Dandekar T, Einsele H, Topp MS. Frequency of regulatory T cells determines the outcome of the T-cell-engaging antibody blinatumomab in patients with B-precursor ALL. Leukemia. (2017);31, 2181-2190.
14. Zugmaier G, Gokbuget N, Klinger M, Viardot A, Stelljes M, Neumann S, Horst H-A, Marks R, Faul C, Diedrich H, Reichle A, Brüggemann M, Holland C, Schmidt M, Einsele H, Bargou RC, Topp MS. Long-term survival and T-cell kinetics in relapsed/refractory ALL patients who achieved MRD response after blinatumomab treatment. Blood. 2015;126(24):2578-2584.

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Introduction

Bispecific monoclonal antibodies for targeting tumor cells have a long story from 1980's to produce approved drug in 2014 [1-3]. Several trials for relapsed/refractory acute lymphoblastic leukemia (R/R ALL) treatment including ALCANTARA for Philadelphia chromosome-positive (Ph-positive) R/R ALL were performed and showed clinical effectiveness and even an advantage over chemotherapy (TOWER Study) [4-8]. Recently published results on blinatumomab combined with TKI for therapy of Ph-positive R/R ALL characterized this approach to be safe and effective [11]. Combination of Blinatumomab and TKI could elicit lower toxicity and improve primary results in managing heavily pretreated R/R ALL patients. In preclinical studies, retinoids have shown antileukemic activity in IKZF-deleted ALL [12]. We previously reported about effective combination of blinatumomab with tyrosine kinase inhibitors (TKI) for the treatment of Ph-positive and FLT3-ITD R/R ALL and blinatumomab with TKI and all-trans retinoic acid in IKZF-deleted R/R ALL patients [9, 10]. The aim of our study was to present the data on 11 R/R ALL patients treated with Blinatumomab and TKI+/-ATRA, omitting simultaneous standard chemotherapy.

Patients and methods

Eleven patients (pts) with R/R ALL were treated with Blinatumomab + TKI/TKI+ATRA at the National Research Center for Hematology, Moscow, Russia, and in Raisa Gorbacheva Memorial Institute of Pediatric Oncology, Hematology and Transplantation, Saint Petersburg, Russia, from October 2015 to October 2018. The study was approved by the Institutional Review Board. The treatment was administered after the patient has signed informed consent. Blinatumomab was provided by Amgen as part of the expanded access program. The treatment consisted of 4-5 cycles of blinatumomab 28 mcg/day by continuous infusion for 4 weeks each cycle. Over 1^st week of 1^st cycle, Blinatumomab was administered at the dose of 9 mcg/day. The 2-week intervals followed between the rounds of blinatumomab treatment. All the patients were administered one of TKIs: 7 Ph-positive and 2 IKZF1-deleted ALL pts were initially treated with dasatinib (140 mg/day) per os, 1 FLT3-ITD ALL patient received sorafenib (800 mg/day) per os, and one Ph-positive ALL patient with a T315I mutation received ponatinib (45 mg/day). All the TKIs were administered continuously, from the 1^st day of starting blinatumomab. All-trans-retinoic acid (ATRA) at a dose of 45 mg/m²/day was administered per os in the IKZF1-deleted pts during 4 weeks of the 1^st blinatumomab cycle, and during first two weeks of subsequent blinatumomab cycles.

Complete remission (CR) was diagnosed if less than 5% of blasts were present in bone marrow. Cytogenetic remission (CyR) was diagnosed in the absence of BCR-ABL positive nuclei per 200 nuclei by fluorescence in situ hybridization (FISH). Molecular CR (MolCR) was diagnosed if BCR-ABL/ABL at a ratio of <0.01 was detected in bone marrow samples by RT-qPCR. The CD3+/CD4+/CD8- T-helper, CD3+/CD4-/CD8+ T-cytotoxic, CD3+/CD4-/CD8- T-Double-negative, CD3+/CD4+/CD25+ T-regulatory, CD3-/CD56+ NK subpopulations were measured in peripheral blood lymphocytes by flow cytometry weekly during blinatumomab treatment in all the pts (1 to 16 samples, 4 points per each blinatumomab cycle). Serum immunoglobulins (Ig) G, M and A were measured during each cycle of blinatumomab (a total of 4 sampling points).

The SAS software was used for statistical evaluation using regression analysis. The MIXED SAS procedure was used to perform repeated measures analysis and to estimate parameters of linear regression of average time-dependent trend.

Results

Median follow-up was 23 months (19 to 36 months). Median age is 32 years (24 to 49 years). Eight pts were females and 3, males. 7 pts received 4 cycles; 1 pt, 5 cycles; 2 pts underwent 2 cycles, and 1 pt was subjected to 1 cycle of blinatumomab treatment. Nine patients had febrile reactions during first two weeks at the 1^st cycle of blinatumomab. No one cycle of blinatumomab therapy was not interrupted. Neurological toxicity (1-2 grades) was observed in 2 cases manifesting as headaches in 1 patient, and ulnar neuropathy in 1 case. One patient treated with sorafenib has hand-foot skin syndrome. The syndrome completely resolved after 2 weeks interruption of sorafenib treatment.

Pulmonary infiltrates and pleural effusion in one dasatinib-treated case were completely resolved after switching to nilotinib. Diarrhea associated with dasatinib therapy was observed in 3 patients and resolved after its replacement with bosutinib in 2 cases, and with nilotinib in 1 patient. CMV-associated colitis was diagnosed in 2 cases using virus-specific PCR in stool samples. Massive intestinal bleeding and multiple intestinal ulceration were observed in one patient with CMV colitis, as confirmed by colonoscopy. Facial edema and hyperemia were evident in 1 patient upon dasatinib treatment. These symptoms resolved after passage from dasatinib to nilotinib. Greyness of hair was detected in one patient treated with ponatinib. The main clinical characteristics of individual patients and the events are listed in Table 1.

Table 1. Basic clinical characteristics of blinatumomab + TKI-treated ALL patients, response to therapy, and adverse effects

The weekly performed counts of T-cytotoxic, NK, T-helper and T-regulatory cells in peripheral blood were decreased during the 1^st blinatumomab cycle. T-cytotoxic and NK cells returned to normal ranges over the 2^nd to 4^th blinatumomab cycles. T-regulatory cell counts remained decreased or approached low-normal limits at all terms, except of 2^nd blinatumomab cycle (Fig. 1).

Regression analysis (the MIXED procedure in SAS system) was performed for each cell subpopulation, in order to detect significant changes of the T cell subpopulation kinetics (Table 2 and Fig. 2 a-e). As seen in table 2 in T-helper, T-cytotoxic and NK-subpopulations the weekly gaining effect was statistically significant.

Hypogammaglobulinemia during blinatumomab treatment was frequently observed (Fig. 3), and, in eight patients, treatment with intravenous human normal immunoglobulin was used. To check if the IgG, IgA and IgM kinetics were statistically significant, the regression analysis (the MIXED procedure in SAS system) was performed for each Ig (Table 3 and Fig. 4). As seen in Table 3, a gradual decrease in immunoglobulins with each cycle of blinatumomab was statistically significant for IgG, IgA and IgM. Fig. 4 shows the statistically significant effects of Blinatumomab treatment upon IgG (p=0.0446), IgA (p<.0001), and IgM (p=0.0186) (Table 3).

In 10 cases of 11, complete remission (CR) was achieved after 1^st blimatumomab cycle. Progression of the disease was observed in 1 patient during 1^st cycle of blinatumomab treatment, thus urging us to stop this therapy. Molecular CR (MolCR) was achieved in 9 cases, and cytogenetic CR was detected in 1 patient during consequent blinatumomab cycles. Allogeneic BMT was performed in 9 cases, and auto-BMT, in 1 patient with MolCR. Overt rapid hematological relapse was diagnosed in 1 patient under bosutinib maintenance therapy while waiting for alloBMT. Subsequent MolCR was achieved in the patient with bortezomib-based chemotherapy + dasatinib. One cytogenetic relapse was observed in 1 patient with complete cytogenetic remission before alloBMT. One patient treated with dasatinib as maintenance therapy after auto-BMT had molecular relapse, and second MolCR was achieved after Blinatumomab retreatment + dasatinib + ATRA. Allo-BMT from haploidentical donor was performed in this case. One patient treated with ponatinib and one patient receiving dasatinib maintenance after allo-BMT had CNS relapse and CNS lesions that regressed after intrathecal chemotherapy and cranial irradiation. One patient in MolCR died from septic shock 5 months after allo-BMT.

Discussion

Each patient in the study received combined treatment with blimatumomab immunotherapy and TKI target therapy. The treatment was well tolerated and complications were rare and curable. Hypogammaglobulinemia was common during blinatumomab treatment reflecting strong mature B-cell depletion on anti CD19 treatment. High rate of hypogammaglobulinemia lead to high rate of CMV infection, that was severe in 1 case. Rapid CR achievement and granulocyte recovery permits to treat almost all patients from 2^nd to 4^th cycles in outpatient settings. Nine molCR and one CyR with only one case of progressive disease permit to recognize this approach as highly effective, with low toxicity profile. Complementary treatment with ATRA in IKZF-deleted pts was also effective strategy though the number of such cases is too small. TKI treatment allows to perform prolonged maintenance, in order to control remaining leukemic populations in some cases. Though the rate of relapses is high, i.e., one half of the pts. However, a cohort of patients had extremely high risk of subsequent relapses and our approach did not exclude this risk entirely. In a single case, replacement of effective TKIs due to toxicity resulted in overt hematological relapse.

Prolonged neutropenia after Allo-BMT resulted in postponing of TKI maintenance and, in all these cases, the dose of eventually administered TKI was lowered by half. Heavily pre-treated patients have higher post-Allo-BMT toxicity, and the maintenance therapy after BMT was not proper. Auto-BMT in Ph-positive patient was not a curative strategy, though in IKZF-deleted patient, AutoBMT with lower toxicity regimen enables us to perform adequate maintenance with two agents, i.e., TKI and ATRA. Recently published results of combined treatment with blinatumomab and TKIs in Ph-positive relapsed ALL had also shown high rates of subsequent remissions and OS values (73% to 75%) in a small cohort of patients [11]. Statistical evaluation of changes observed for different lymphoid subpopulations revealed a strong evidence for T-cytotoxic and NK cells recovery in the course of effective combined treatment with blinatumomab and TKI. Duell et al. have demonstrated that lower frequency of T-regulatory cells correlates with higher response to blinatumomab in B-ALL patients [13]. T-regulatory and double-negative cells may potentially inhibit cytotoxic and other effector lymphocytes subpopulations and we observed their fluctuation within lower values of absolute peripheral blood counts in responders to the drug. Rapid and strong B-cell depletion as demonstrated by Zugmaier et al. [14], could explain the dropping immunoglobulin synthesis and prolonged hypogammaglobulinemia in most patients treated with blinatumomab.

Conclusion

Combined treatment with blinatumomab and TKI has acceptable and curable toxicity and demonstrates high rate of MolCR in high risk R/R ALL pts. The results are promising, with respect of using this treatment as induction and consolidation therapy without standard chemotherapy. IKZF deletions and FLT3-ITD are the new targets for chemo-free combined immunotherapy and TKI in ALL patients.

Acknowledgements

We thank Amgen for blinatumomab providing. We thank the Russian Acute Leukemia Study Group, National Hematology Society of Russia and also Margarita Anukhina for data management.

References

1. Perez P, Hoffman RW, Shaw S, Bluestone JA, Segal DM. Specific targeting of cytotoxic T cells by anti-T3 linked to anti-target cell antibody. Nature. 1985; 316:354-356.
2. Baagen A, Van De Griend R, Clark M, Geerars A, Bast B, De Gast B. Killing of human leukaemia/lymphoma B cells by activated cytotoxic T lymphocytes in the presence of a bispecific monoclonal antibody (mCD3/mCD19). Clin Exp Immunol. 1992; 90: 368-375.
3. Przepiorka D, Ko C-W, Deisseroth A, Yancey CL, Candau-Chacon R, Chiu H-J, Gehrke BJ, Gomez-Broughton C, Kane RC, Kirshner S, Mehrotra N, Ricks TK, Schmiel D, Song P, Zhao P, Zhou Q, Farrell AT, Pazdur R. FDA Approval: Blinatumomab. Clin Cancer Res. 2015; 21(18):4035-4039.
4. Topp MS, Gokbuget N, Stein AS, Zugmaier G, O'Brien S, Bargou RC, Dombret H, Fielding AK, Heffner L, Larson RA, Neumann S, Foà R, Litzow M, Ribera JM, Rambaldi A, Schiller G. Safety and activity of Blinatumomab for adult patients with relapsed or refractory B-precursor acute lymphoblastic leukaemia: A multicentre, single-arm phase 2 study. Lancet Oncol. 2015;16:57-66.
5. Kantarjian H, Stein A, Gokbuget N, Fielding AK, Schuh AC, Ribera J-M, Wei A, Dombret H, Foà R, Bassan R, Arslan Ö, Sanz MA, et al. Blinatumomab versus chemotherapy for advanced acute lymphoblastic leukemia. N Eng J Med. 2017;376:836-847.
6. Martinelli G, Boissel N, Chevallier P, Ottmann O, Gökbuget N, Topp MS, Fielding AK, Rambaldi A, Ritchie EK, Papayannidis C, Sterling LR, Benjamin J, Stein A. Complete hematologic and molecular response in adult patients with relapsed/refractory Philadelphia chromosome-positive B-precursor acute lymphoblastic leukemia following treatment with Blinatumomab: Results from a phase II, single-arm, multicenter study. J Clin Oncol. 2017;35:1795-1802.
7. von Stackelberg A, Locatelli F, Zugmaier G, Handgretinger R, Trippett TM, Rizzari C, Bader P, O'Brien MM, Brethon B, Bhojwani D, Schlegel PG, Borkhardt A, Rheingold SR, Cooper TM, Zwaan CM et al. Phase I/phase II study of Blinatumomab in pediatric patients with relapsed/refractory acute lymphoblastic leukemia. J Clin Oncol. 2016;34(36):4381-4389.
8. Gokbuget N, Dombret H, Ribera JM, Fielding AK, Advani A, Bassan R, Chia V, Doubek M, Giebel S, Hoelzer D, Ifrah N, Katz A, Kelsh M, Martinelli G, Morgades M, O'Brien S et al. International reference analysis of outcomes in adults with B-precursor Ph-negative relapsed/refractory acute lymphoblastic leukemia. Haematologica. 2016; 101:1524-1533.
9. Sokolov A, Parovichnikova E, Troitskaya V, Galtseva I, Firsova M, Davidova J, Kapranov N, Savchenko V. Combined Blinatumomab + Dasatinib/Ibrutinib therapy of relapsed acute lymphoblastic leukemia patients – antileukemic effect on the T-helper and T-regulatory cells reduction background. Haematologica. 2016; 101: 354-355 (E867).
10. Sokolov AN, Parovichnikova EN, Troitskaya VV, Kuzmina LA, Galtseva IV, Kulikov SM, Bondarenko SN, Davidova JO, Kapranov NM, Lukyanova IA, Lobanova TI, Usikova EI, Zarubina KI, Savchenko VG. Blinatumomab + tyrosine kinase inhibitors with no chemotherapy in BCR-ABL-positive or IKZF1-deleted or FLT3-ITD-positive relapsed/refractory acute lymphoblastic leukemia patients: high molecular remission rate and toxicity profile. Blood. 2017;130:3884.
11. Assi R, Kantarjian H, Short NJ, Daver N, Takahashi K, Garcia-Manero G, DiNardo C, Burger J, Cortes J, Jain N, Wierda W, Chamoun S, Konopleva M, Jabbour E. Safety and efficacy of blinatumomab in combination with a tyrosine kinase inhibitor for the treatment of relapsed Philadelphia chromosome-positive leukemia. Clin Lymphoma Myeloma Leuk. 2017;17(12):897-901.
12. Churchman ML, Low J, Qu C, Paietta EM, Kasper LH, Chang Y, Payne-Turner D, Althoff MJ, Song G, Chen SC, Ma J, Rusch M, McGoldrick D, Edmonson M, Gupta P, Wang YD et al. Efficacy of retinoids in IKZF1-mutated BCR-ABL1 acute lymphoblastic leukemia. Cancer Cell. 2015;28(3):343-356.
13. Duell J, Dittrich M, Bedke T, Mueller T, Eisele F, Rosenwald A, Rasche L, Hartmann E, Dandekar T, Einsele H, Topp MS. Frequency of regulatory T cells determines the outcome of the T-cell-engaging antibody blinatumomab in patients with B-precursor ALL. Leukemia. (2017);31, 2181-2190.
14. Zugmaier G, Gokbuget N, Klinger M, Viardot A, Stelljes M, Neumann S, Horst H-A, Marks R, Faul C, Diedrich H, Reichle A, Brüggemann M, Holland C, Schmidt M, Einsele H, Bargou RC, Topp MS. Long-term survival and T-cell kinetics in relapsed/refractory ALL patients who achieved MRD response after blinatumomab treatment. Blood. 2015;126(24):2578-2584.

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Несколько дополнительных молекулярных мишеней могут быть использованы для комбинированного лечения без обычной химиотерапии, а именно ингибиторы тирозинкиназ, в т.ч. BCR-ABL, FLT3 и делеции IKZF1. Целью данного исследования было определение токсичности и клинической эффективности комбинированного лечения блинатумомабом и несколькими ингибиторами тирозинкиназы. </p> <h3>Пациенты и методы</h3> <p style="text-align: justify;"> С октября 2015 по октябрь 2018 г. нами пролечены 11 пациентов с рецидивируюшим/рефрактерным течением ОЛЛ. Терапия блинатумомабом состояла из 4-5 циклов с 2-недельными интервалами (28 мкг/день посредством постоянной инфузии в течение 28 дней, при дозе 9 мкг/день в течении 1-й недели 1-го цикла). Семь BCR-ABL-позитивных больных и 2 пациента с делецией IKZF1 получали исходно дазатиниб (140 мг/день), один пациент с FLT3-ITD – сорафениб (800 мг/день). Один BCR-ABL-позитивный больной с мутацией T315I получал понатиниб (45 мг/день). Пациентам с делециями IKZF1 назначалась ATRA (45 мг/м²/день в течение 4 недель) на 1-м цикле блинатумомаба и в первые 2 недели последующих циклов лечения антителом.</p> <h3>Результаты</h3> <p style="text-align: justify;"> У пациентов, отвечающих на лечение блинатумомабом, отмечалось статистически достоверное повышение абсолютного количества Т-хелперных лимфоцитов (p=0.0034), T-цитотоксических клеток (p<0.0001) и субпопуляций естественных киллеров (p=0.0006) в периферической крови на протяжении всего периода лечения. T-регуляторные и дубль-негативные T-клетки – потенциальные ингибиторы Т-клеточного ответа на блинатумомаб оставались в пределах нижних значений нормы. Гипогаммаглобулинемия наблюдалась у 8 из 11 пациентов. Полная ремиссия (ПР) была получена у 10 больных после 1-го цикла блинатумомаба, прогрессия заболевания – в одном случае. Из 10 пациентов, в 9 случаях достигнута полная молекулярная ремиссия (ПМР) и в одном – полная цитогенетическая ремиссия. Выполнены девять аллогенных трансплантаций гемопоэтических стволовых клеток (ТГСК) и одна аутологичная ТГСК в 10 случаях ПР. Выявлены три рецидива в ЦНС после алло-ТГСК и один молекулярный рецидив после ауто-ТГСК. Один пациент скончался от септического шока после алло-ТГСК. </p> <h3>Выводы</h3> <p style="text-align: justify;"> Блинатомомаб в коимбинации с ингибиторами тирозинкиназ имеет высокий терапевтический потенциал для индукции ремиссии в определенных случаях ОЛЛ без применения обычной химиотерапии. 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Соколов¹, Елена Н. Паровичникова¹, Вера В. Троицкая¹, Лариса А. Кузьмина¹, Ирина В. Гальцева¹, Сергей М. Куликов¹, Сергей Н. Бондаренко², Ирина А. Лукьянова¹, Татьяна И. Лобанова¹, Екатерина И. Усикова¹, Ксения И. Зарубина¹, Ольга А. Гаврилина¹, Юлия О. Давыдова¹, Николай М. Капранов¹, Валерий Г. Савченко¹</p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(718) "

Андрей Н. Соколов¹, Елена Н. Паровичникова¹, Вера В. Троицкая¹, Лариса А. Кузьмина¹, Ирина В. Гальцева¹, Сергей М. Куликов¹, Сергей Н. Бондаренко², Ирина А. Лукьянова¹, Татьяна И. Лобанова¹, Екатерина И. Усикова¹, Ксения И. Зарубина¹, Ольга А. Гаврилина¹, Юлия О. Давыдова¹, Николай М. Капранов¹, Валерий Г. Савченко¹

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¹ Федеральное государственное бюджетное учреждение научный медицинский исследовательский центр гематологии Минздрава России, Москва, Россия
² НИИ детской онкологии, гематологии и трансплантологии им. Р. М. Горбачевой, Первый Санкт-Петербургский государственный медицинский университет им. И. П. Павлова, Санкт-Петербург, Россия

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Биспецифическое моноклональное антитело блинатумомаб против антигена CD19 используется для лечения острого лимфобластного лейкоза (ОЛЛ). Несколько дополнительных молекулярных мишеней могут быть использованы для комбинированного лечения без обычной химиотерапии, а именно ингибиторы тирозинкиназ, в т.ч. BCR-ABL, FLT3 и делеции IKZF1. Целью данного исследования было определение токсичности и клинической эффективности комбинированного лечения блинатумомабом и несколькими ингибиторами тирозинкиназы.

Пациенты и методы

С октября 2015 по октябрь 2018 г. нами пролечены 11 пациентов с рецидивируюшим/рефрактерным течением ОЛЛ. Терапия блинатумомабом состояла из 4-5 циклов с 2-недельными интервалами (28 мкг/день посредством постоянной инфузии в течение 28 дней, при дозе 9 мкг/день в течении 1-й недели 1-го цикла). Семь BCR-ABL-позитивных больных и 2 пациента с делецией IKZF1 получали исходно дазатиниб (140 мг/день), один пациент с FLT3-ITD – сорафениб (800 мг/день). Один BCR-ABL-позитивный больной с мутацией T315I получал понатиниб (45 мг/день). Пациентам с делециями IKZF1 назначалась ATRA (45 мг/м²/день в течение 4 недель) на 1-м цикле блинатумомаба и в первые 2 недели последующих циклов лечения антителом.

Результаты

У пациентов, отвечающих на лечение блинатумомабом, отмечалось статистически достоверное повышение абсолютного количества Т-хелперных лимфоцитов (p=0.0034), T-цитотоксических клеток (p<0.0001) и субпопуляций естественных киллеров (p=0.0006) в периферической крови на протяжении всего периода лечения. T-регуляторные и дубль-негативные T-клетки – потенциальные ингибиторы Т-клеточного ответа на блинатумомаб оставались в пределах нижних значений нормы. Гипогаммаглобулинемия наблюдалась у 8 из 11 пациентов. Полная ремиссия (ПР) была получена у 10 больных после 1-го цикла блинатумомаба, прогрессия заболевания – в одном случае. Из 10 пациентов, в 9 случаях достигнута полная молекулярная ремиссия (ПМР) и в одном – полная цитогенетическая ремиссия. Выполнены девять аллогенных трансплантаций гемопоэтических стволовых клеток (ТГСК) и одна аутологичная ТГСК в 10 случаях ПР. Выявлены три рецидива в ЦНС после алло-ТГСК и один молекулярный рецидив после ауто-ТГСК. Один пациент скончался от септического шока после алло-ТГСК.

Выводы

Блинатомомаб в коимбинации с ингибиторами тирозинкиназ имеет высокий терапевтический потенциал для индукции ремиссии в определенных случаях ОЛЛ без применения обычной химиотерапии. Высокая частота потенциальных рецидивов в ЦНС может быть снижена за счет более интенсивной интратекальной профилактики.

Ключевые слова

Острый лимфобластный лейкоз, блинатумомаб, ингибиторы тирозинкиназ.

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Andrey N. Sokolov¹, Elena N. Parovichnikova¹, Vera V. Troitskaya¹, Larisa A. Kuzmina¹, Irina V. Galtseva¹, Sergei M. Kulikov¹, Sergey N. Bondarenko², Irina A. Lukyanova¹, Tatiana I. Lobanova¹, Ekaterina I. Usikova¹, Ksenia I. Zarubina¹, Olga A. Gavrilina¹, Julia O. Davidova¹, Nikolai M. Kapranov¹, Valeriy G. Savchenko¹

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¹ National Research Center for Hematology of the Ministry of Healthcare of the Russian Federation, Moscow, Russia
² Raisa Gorbacheva Memorial Research Institute of Pediatric Oncology, Hematology and Transplantation, Pavlov University,
St. Petersburg, Russia

Correspondence
Dr. Andrey N. Sokolov, National Research Center for Hematology, 4A Novyi Zykovskii Lane, 125167, Moscow, Russia
Phone: +7 (495) 612 4592
E-mail: sokolov.a@blood.ru

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Bispecific monoclonal antibody blinatumomab is targeting CD19, being applied for treatment of acute lymphoblastic leukemia (ALL). Several additional targets could be used for combined chemo-free treatment with thyrosine kinase inhibitors: BCR-ABL, FLT3 and IKZF1 deletions are amongst them. In the following study, we aimed to assess toxicity and clinical effectiveness of the combination of blinatumomab and several thyrosine kinase inhibitors.

Patients and methods

From October 2015 to October 2018, we treated 11 relapsed/refractory (R/R) ALL patients (pts). The blinatumomab treatment consisted of 4-5 cycles with 2-week intervals (28 mcg/day by continuous infusion during 28 days per cycle with 9 mcg/day during the first week of the first cycle). Seven BCR-ABL-positive and 2 IKZF1-deleted pts received initially dasatinib at 140 mg/day, one case, with FLT3-ITD received sorafenib (800 mg/day). One BCR-ABL-positive pt with T315I mutation was administered ponatinib (45 mg/day). Pts with IKZF1 deletions received ATRA (45 mg/m²/day for 4 weeks) of the 1^st blinatumomab cycle and during first 2 weeks of subsequent blinatumomab cycles.

Results

In the patients responding to blinatumomab treatment, we observed a statistically significant increment of absolute values in T-helper (p=0.0034), T-cytotoxic (p<0.0001) and NK (p=0.0006) cell subpopulations in peripheral blood over the entire treatment period. T-regulatory and double-negative T-cells as potentially inhibitors of T cell response to blinatumomab remained within low values of normal ranges. Hypogammaglobulinemia was observed in 8 of 11 pts. CR was achieved in 10 pts after 1st cycle of blinatumomab, progressive disease was detected in 1 pt. Nine cases of complete molecular remissions (MolCR) and one cytogenetic complete remission were achieved in ten CR pts. Nine allo-BMT and one auto-BMT were performed in 10 CR pts. Three CNS relapses after allo-BMT and one molecular relapse after auto-BMT were diagnosed. One pt died from septic shock after allo-BMT.

Conclusion

Blinatumomab combined with TKI has high therapeutic potential as induction remission treatment in targeted ALL population without conventional chemotherapy. High rate of potential CNS relapses could be decreased with more intensive intrathecal prophylaxis.

Keywords

Acute lymphoblastic leukemia, blinatumomab, tyrosine kinase inhibitors.

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Sokolov¹, Elena N. Parovichnikova¹, Vera V. Troitskaya¹, Larisa A. Kuzmina¹, Irina V. Galtseva¹, Sergei M. Kulikov¹, Sergey N. Bondarenko², Irina A. Lukyanova¹, Tatiana I. Lobanova¹, Ekaterina I. Usikova¹, Ksenia I. Zarubina¹, Olga A. Gavrilina¹, Julia O. Davidova¹, Nikolai M. Kapranov¹, Valeriy G. Savchenko¹</p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(492) "

Andrey N. Sokolov¹, Elena N. Parovichnikova¹, Vera V. Troitskaya¹, Larisa A. Kuzmina¹, Irina V. Galtseva¹, Sergei M. Kulikov¹, Sergey N. Bondarenko², Irina A. Lukyanova¹, Tatiana I. Lobanova¹, Ekaterina I. Usikova¹, Ksenia I. Zarubina¹, Olga A. Gavrilina¹, Julia O. Davidova¹, Nikolai M. Kapranov¹, Valeriy G. Savchenko¹

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Andrey N. Sokolov¹, Elena N. Parovichnikova¹, Vera V. Troitskaya¹, Larisa A. Kuzmina¹, Irina V. Galtseva¹, Sergei M. Kulikov¹, Sergey N. Bondarenko², Irina A. Lukyanova¹, Tatiana I. Lobanova¹, Ekaterina I. Usikova¹, Ksenia I. Zarubina¹, Olga A. Gavrilina¹, Julia O. Davidova¹, Nikolai M. Kapranov¹, Valeriy G. Savchenko¹

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Bispecific monoclonal antibody blinatumomab is targeting CD19, being applied for treatment of acute lymphoblastic leukemia (ALL). Several additional targets could be used for combined chemo-free treatment with thyrosine kinase inhibitors: BCR-ABL, FLT3 and IKZF1 deletions are amongst them. In the following study, we aimed to assess toxicity and clinical effectiveness of the combination of blinatumomab and several thyrosine kinase inhibitors.

Patients and methods

From October 2015 to October 2018, we treated 11 relapsed/refractory (R/R) ALL patients (pts). The blinatumomab treatment consisted of 4-5 cycles with 2-week intervals (28 mcg/day by continuous infusion during 28 days per cycle with 9 mcg/day during the first week of the first cycle). Seven BCR-ABL-positive and 2 IKZF1-deleted pts received initially dasatinib at 140 mg/day, one case, with FLT3-ITD received sorafenib (800 mg/day). One BCR-ABL-positive pt with T315I mutation was administered ponatinib (45 mg/day). Pts with IKZF1 deletions received ATRA (45 mg/m²/day for 4 weeks) of the 1^st blinatumomab cycle and during first 2 weeks of subsequent blinatumomab cycles.

Results

In the patients responding to blinatumomab treatment, we observed a statistically significant increment of absolute values in T-helper (p=0.0034), T-cytotoxic (p<0.0001) and NK (p=0.0006) cell subpopulations in peripheral blood over the entire treatment period. T-regulatory and double-negative T-cells as potentially inhibitors of T cell response to blinatumomab remained within low values of normal ranges. Hypogammaglobulinemia was observed in 8 of 11 pts. CR was achieved in 10 pts after 1st cycle of blinatumomab, progressive disease was detected in 1 pt. Nine cases of complete molecular remissions (MolCR) and one cytogenetic complete remission were achieved in ten CR pts. Nine allo-BMT and one auto-BMT were performed in 10 CR pts. Three CNS relapses after allo-BMT and one molecular relapse after auto-BMT were diagnosed. One pt died from septic shock after allo-BMT.

Conclusion

Blinatumomab combined with TKI has high therapeutic potential as induction remission treatment in targeted ALL population without conventional chemotherapy. High rate of potential CNS relapses could be decreased with more intensive intrathecal prophylaxis.

Keywords

Acute lymphoblastic leukemia, blinatumomab, tyrosine kinase inhibitors.

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Bispecific monoclonal antibody blinatumomab is targeting CD19, being applied for treatment of acute lymphoblastic leukemia (ALL). Several additional targets could be used for combined chemo-free treatment with thyrosine kinase inhibitors: BCR-ABL, FLT3 and IKZF1 deletions are amongst them. In the following study, we aimed to assess toxicity and clinical effectiveness of the combination of blinatumomab and several thyrosine kinase inhibitors.

Patients and methods

From October 2015 to October 2018, we treated 11 relapsed/refractory (R/R) ALL patients (pts). The blinatumomab treatment consisted of 4-5 cycles with 2-week intervals (28 mcg/day by continuous infusion during 28 days per cycle with 9 mcg/day during the first week of the first cycle). Seven BCR-ABL-positive and 2 IKZF1-deleted pts received initially dasatinib at 140 mg/day, one case, with FLT3-ITD received sorafenib (800 mg/day). One BCR-ABL-positive pt with T315I mutation was administered ponatinib (45 mg/day). Pts with IKZF1 deletions received ATRA (45 mg/m²/day for 4 weeks) of the 1^st blinatumomab cycle and during first 2 weeks of subsequent blinatumomab cycles.

Results

In the patients responding to blinatumomab treatment, we observed a statistically significant increment of absolute values in T-helper (p=0.0034), T-cytotoxic (p<0.0001) and NK (p=0.0006) cell subpopulations in peripheral blood over the entire treatment period. T-regulatory and double-negative T-cells as potentially inhibitors of T cell response to blinatumomab remained within low values of normal ranges. Hypogammaglobulinemia was observed in 8 of 11 pts. CR was achieved in 10 pts after 1st cycle of blinatumomab, progressive disease was detected in 1 pt. Nine cases of complete molecular remissions (MolCR) and one cytogenetic complete remission were achieved in ten CR pts. Nine allo-BMT and one auto-BMT were performed in 10 CR pts. Three CNS relapses after allo-BMT and one molecular relapse after auto-BMT were diagnosed. One pt died from septic shock after allo-BMT.

Conclusion

Blinatumomab combined with TKI has high therapeutic potential as induction remission treatment in targeted ALL population without conventional chemotherapy. High rate of potential CNS relapses could be decreased with more intensive intrathecal prophylaxis.

Keywords

Acute lymphoblastic leukemia, blinatumomab, tyrosine kinase inhibitors.

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¹ National Research Center for Hematology of the Ministry of Healthcare of the Russian Federation, Moscow, Russia
² Raisa Gorbacheva Memorial Research Institute of Pediatric Oncology, Hematology and Transplantation, Pavlov University,
St. Petersburg, Russia

Correspondence
Dr. Andrey N. Sokolov, National Research Center for Hematology, 4A Novyi Zykovskii Lane, 125167, Moscow, Russia
Phone: +7 (495) 612 4592
E-mail: sokolov.a@blood.ru

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¹ National Research Center for Hematology of the Ministry of Healthcare of the Russian Federation, Moscow, Russia
² Raisa Gorbacheva Memorial Research Institute of Pediatric Oncology, Hematology and Transplantation, Pavlov University,
St. Petersburg, Russia

Correspondence
Dr. Andrey N. Sokolov, National Research Center for Hematology, 4A Novyi Zykovskii Lane, 125167, Moscow, Russia
Phone: +7 (495) 612 4592
E-mail: sokolov.a@blood.ru

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Андрей Н. Соколов¹, Елена Н. Паровичникова¹, Вера В. Троицкая¹, Лариса А. Кузьмина¹, Ирина В. Гальцева¹, Сергей М. Куликов¹, Сергей Н. Бондаренко², Ирина А. Лукьянова¹, Татьяна И. Лобанова¹, Екатерина И. Усикова¹, Ксения И. Зарубина¹, Ольга А. Гаврилина¹, Юлия О. Давыдова¹, Николай М. Капранов¹, Валерий Г. Савченко¹

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Андрей Н. Соколов¹, Елена Н. Паровичникова¹, Вера В. Троицкая¹, Лариса А. Кузьмина¹, Ирина В. Гальцева¹, Сергей М. Куликов¹, Сергей Н. Бондаренко², Ирина А. Лукьянова¹, Татьяна И. Лобанова¹, Екатерина И. Усикова¹, Ксения И. Зарубина¹, Ольга А. Гаврилина¹, Юлия О. Давыдова¹, Николай М. Капранов¹, Валерий Г. Савченко¹

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Несколько дополнительных молекулярных мишеней могут быть использованы для комбинированного лечения без обычной химиотерапии, а именно ингибиторы тирозинкиназ, в т.ч. BCR-ABL, FLT3 и делеции IKZF1. Целью данного исследования было определение токсичности и клинической эффективности комбинированного лечения блинатумомабом и несколькими ингибиторами тирозинкиназы. </p> <h3>Пациенты и методы</h3> <p style="text-align: justify;"> С октября 2015 по октябрь 2018 г. нами пролечены 11 пациентов с рецидивируюшим/рефрактерным течением ОЛЛ. Терапия блинатумомабом состояла из 4-5 циклов с 2-недельными интервалами (28 мкг/день посредством постоянной инфузии в течение 28 дней, при дозе 9 мкг/день в течении 1-й недели 1-го цикла). Семь BCR-ABL-позитивных больных и 2 пациента с делецией IKZF1 получали исходно дазатиниб (140 мг/день), один пациент с FLT3-ITD – сорафениб (800 мг/день). Один BCR-ABL-позитивный больной с мутацией T315I получал понатиниб (45 мг/день). Пациентам с делециями IKZF1 назначалась ATRA (45 мг/м²/день в течение 4 недель) на 1-м цикле блинатумомаба и в первые 2 недели последующих циклов лечения антителом.</p> <h3>Результаты</h3> <p style="text-align: justify;"> У пациентов, отвечающих на лечение блинатумомабом, отмечалось статистически достоверное повышение абсолютного количества Т-хелперных лимфоцитов (p=0.0034), T-цитотоксических клеток (p<0.0001) и субпопуляций естественных киллеров (p=0.0006) в периферической крови на протяжении всего периода лечения. T-регуляторные и дубль-негативные T-клетки – потенциальные ингибиторы Т-клеточного ответа на блинатумомаб оставались в пределах нижних значений нормы. Гипогаммаглобулинемия наблюдалась у 8 из 11 пациентов. Полная ремиссия (ПР) была получена у 10 больных после 1-го цикла блинатумомаба, прогрессия заболевания – в одном случае. Из 10 пациентов, в 9 случаях достигнута полная молекулярная ремиссия (ПМР) и в одном – полная цитогенетическая ремиссия. Выполнены девять аллогенных трансплантаций гемопоэтических стволовых клеток (ТГСК) и одна аутологичная ТГСК в 10 случаях ПР. Выявлены три рецидива в ЦНС после алло-ТГСК и один молекулярный рецидив после ауто-ТГСК. Один пациент скончался от септического шока после алло-ТГСК. </p> <h3>Выводы</h3> <p style="text-align: justify;"> Блинатомомаб в коимбинации с ингибиторами тирозинкиназ имеет высокий терапевтический потенциал для индукции ремиссии в определенных случаях ОЛЛ без применения обычной химиотерапии. Высокая частота потенциальных рецидивов в ЦНС может быть снижена за счет более интенсивной интратекальной профилактики. </p> <h2>Ключевые слова</h2> <p style="text-align: justify;"> Острый лимфобластный лейкоз, блинатумомаб, ингибиторы тирозинкиназ. </p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(4986) "

Биспецифическое моноклональное антитело блинатумомаб против антигена CD19 используется для лечения острого лимфобластного лейкоза (ОЛЛ). Несколько дополнительных молекулярных мишеней могут быть использованы для комбинированного лечения без обычной химиотерапии, а именно ингибиторы тирозинкиназ, в т.ч. BCR-ABL, FLT3 и делеции IKZF1. Целью данного исследования было определение токсичности и клинической эффективности комбинированного лечения блинатумомабом и несколькими ингибиторами тирозинкиназы.

Пациенты и методы

С октября 2015 по октябрь 2018 г. нами пролечены 11 пациентов с рецидивируюшим/рефрактерным течением ОЛЛ. Терапия блинатумомабом состояла из 4-5 циклов с 2-недельными интервалами (28 мкг/день посредством постоянной инфузии в течение 28 дней, при дозе 9 мкг/день в течении 1-й недели 1-го цикла). Семь BCR-ABL-позитивных больных и 2 пациента с делецией IKZF1 получали исходно дазатиниб (140 мг/день), один пациент с FLT3-ITD – сорафениб (800 мг/день). Один BCR-ABL-позитивный больной с мутацией T315I получал понатиниб (45 мг/день). Пациентам с делециями IKZF1 назначалась ATRA (45 мг/м²/день в течение 4 недель) на 1-м цикле блинатумомаба и в первые 2 недели последующих циклов лечения антителом.

Результаты

У пациентов, отвечающих на лечение блинатумомабом, отмечалось статистически достоверное повышение абсолютного количества Т-хелперных лимфоцитов (p=0.0034), T-цитотоксических клеток (p<0.0001) и субпопуляций естественных киллеров (p=0.0006) в периферической крови на протяжении всего периода лечения. T-регуляторные и дубль-негативные T-клетки – потенциальные ингибиторы Т-клеточного ответа на блинатумомаб оставались в пределах нижних значений нормы. Гипогаммаглобулинемия наблюдалась у 8 из 11 пациентов. Полная ремиссия (ПР) была получена у 10 больных после 1-го цикла блинатумомаба, прогрессия заболевания – в одном случае. Из 10 пациентов, в 9 случаях достигнута полная молекулярная ремиссия (ПМР) и в одном – полная цитогенетическая ремиссия. Выполнены девять аллогенных трансплантаций гемопоэтических стволовых клеток (ТГСК) и одна аутологичная ТГСК в 10 случаях ПР. Выявлены три рецидива в ЦНС после алло-ТГСК и один молекулярный рецидив после ауто-ТГСК. Один пациент скончался от септического шока после алло-ТГСК.

Выводы

Блинатомомаб в коимбинации с ингибиторами тирозинкиназ имеет высокий терапевтический потенциал для индукции ремиссии в определенных случаях ОЛЛ без применения обычной химиотерапии. Высокая частота потенциальных рецидивов в ЦНС может быть снижена за счет более интенсивной интратекальной профилактики.

Ключевые слова

Острый лимфобластный лейкоз, блинатумомаб, ингибиторы тирозинкиназ.

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Биспецифическое моноклональное антитело блинатумомаб против антигена CD19 используется для лечения острого лимфобластного лейкоза (ОЛЛ). Несколько дополнительных молекулярных мишеней могут быть использованы для комбинированного лечения без обычной химиотерапии, а именно ингибиторы тирозинкиназ, в т.ч. BCR-ABL, FLT3 и делеции IKZF1. Целью данного исследования было определение токсичности и клинической эффективности комбинированного лечения блинатумомабом и несколькими ингибиторами тирозинкиназы.

Пациенты и методы

С октября 2015 по октябрь 2018 г. нами пролечены 11 пациентов с рецидивируюшим/рефрактерным течением ОЛЛ. Терапия блинатумомабом состояла из 4-5 циклов с 2-недельными интервалами (28 мкг/день посредством постоянной инфузии в течение 28 дней, при дозе 9 мкг/день в течении 1-й недели 1-го цикла). Семь BCR-ABL-позитивных больных и 2 пациента с делецией IKZF1 получали исходно дазатиниб (140 мг/день), один пациент с FLT3-ITD – сорафениб (800 мг/день). Один BCR-ABL-позитивный больной с мутацией T315I получал понатиниб (45 мг/день). Пациентам с делециями IKZF1 назначалась ATRA (45 мг/м²/день в течение 4 недель) на 1-м цикле блинатумомаба и в первые 2 недели последующих циклов лечения антителом.

Результаты

У пациентов, отвечающих на лечение блинатумомабом, отмечалось статистически достоверное повышение абсолютного количества Т-хелперных лимфоцитов (p=0.0034), T-цитотоксических клеток (p<0.0001) и субпопуляций естественных киллеров (p=0.0006) в периферической крови на протяжении всего периода лечения. T-регуляторные и дубль-негативные T-клетки – потенциальные ингибиторы Т-клеточного ответа на блинатумомаб оставались в пределах нижних значений нормы. Гипогаммаглобулинемия наблюдалась у 8 из 11 пациентов. Полная ремиссия (ПР) была получена у 10 больных после 1-го цикла блинатумомаба, прогрессия заболевания – в одном случае. Из 10 пациентов, в 9 случаях достигнута полная молекулярная ремиссия (ПМР) и в одном – полная цитогенетическая ремиссия. Выполнены девять аллогенных трансплантаций гемопоэтических стволовых клеток (ТГСК) и одна аутологичная ТГСК в 10 случаях ПР. Выявлены три рецидива в ЦНС после алло-ТГСК и один молекулярный рецидив после ауто-ТГСК. Один пациент скончался от септического шока после алло-ТГСК.

Выводы

Блинатомомаб в коимбинации с ингибиторами тирозинкиназ имеет высокий терапевтический потенциал для индукции ремиссии в определенных случаях ОЛЛ без применения обычной химиотерапии. Высокая частота потенциальных рецидивов в ЦНС может быть снижена за счет более интенсивной интратекальной профилактики.

Ключевые слова

Острый лимфобластный лейкоз, блинатумомаб, ингибиторы тирозинкиназ.

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² НИИ детской онкологии, гематологии и трансплантологии им. Р. М. Горбачевой, Первый Санкт-Петербургский государственный медицинский университет им. И. П. Павлова, Санкт-Петербург, Россия

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Introduction

In recent years, the outcome of patients with B-cell acute lymphoblastic leukemia (B-ALL) has improved dramatically due to the use of modern chemotherapy regimens. In children with B- ALL cure rate varies within 70%-80%, while in adults – within 15%-40% [1, 2] However, primary resistance and relapses that do occur in 15%-25% of children, and in 50%-70% of adults, and significantly impact survival [3, 4]. In relapsed patients, the prognosis is adverse and after each relapse, the outcome is deteriorating. In case of third and further relapses the probability to achieve remission by salvage high-dose chemotherapy is decreasing. In addition, when using intensive chemotherapy, commutative toxicity is accumulating which is an additional risk factor for increasing the incidence of non-relapse mortality during allogeneic hematopoietic stem cells transplantation (allo-HSCT) [5, 6, 7]. The depth of the response is another factor which impacts the allo-HSCT efficacy, and salvage chemotherapy rarely induces molecular remissions [7, 8, 9, 10].

The emergency of different monoclonal antibodies (BITE, conjugated) has significantly expanded our options for treatment of the patients with relapsed/refractory (r/r) B-cell ALL.

Currently blinatumomab, a bispecific T-cells engager monoclonal antibody (anti-CD19), and inotusumab ozogamicin, a conjugate monoclonal antibody (anti-CD22), are the most promising in treatment of r/r B-ALL in children and adults, which has been shown in a large number of studies [11, 12, 13, 14, 15, 16]. Their pharmacokinetics and pharmacodynamics have been well studied to date. But there are still many unresolved questions concerning use of these monoclonal antibodies in real clinical practice. Various pilot studies and randomized clinical trials have shown the advantages of blinatumomab and inotuzumab over standard and salvage chemotherapy [17, 18].

Our aim was to summarize the results of a single-center non-randomized study in order to investigate in real clinical practice the results of treatment with blinatumomab and inotuzumab ozogamicin in children and adults in heterogeneous cohort of r/r B-ALL.

Patients and methods

The study included patients, both children and adults, with different types of r/r B-ALL who were treated with monoclonal antibodies – blinatumomab and inotuzumab ozogamicin in real clinical setting. The patients were treated in Raisa Gorbacheva Memorial Institute of Pediatric Oncology, Hematology and Transplantation, Pavlov University, Saint-Petersburg from April 2015 to October 2019. All the patients gave informed consent for the treatment, each case was approved by the Russian Ministry of Health for individual use of investigational product.

The group of patients in our study was heterogenous for different parameters. The heterogeneity was due to genetic markers of r/r B-ALL patients, age differences, as well as different types of relapses, previous therapy and clinical state of the disease (hematological or molecular relapses) at the moment of starting therapy by blinatumomab or inotuzumab (Table 1). Hematological relapse (HR) was determined in cases with more than 5% blasts in bone marrow.

Table 1. Clinical characteristics of B-ALL patients included into the study

Molecular relapse (MR) was diagnosed if minimal reduced disease (MRD) was defined as presence of leukemia blasts not detectable by microscope, being, however, revealed by mutation-specific polymerase chain reaction (PCR) or flow cytometry, if the relevant result was >1 malignant cell per 10^-4 normal counterparts.

The patients received blinatumomab by continuous intravenous infusions. One course included 4-week treatment followed by 2-weeks pause in treatment. The doses were as follows: in adult patients with hematologic relapse and children with hematologic and molecular relapses weighing >45 kg, at the dose of 9 mcg/d for the first week in cycle, and 28 mcg/d over the remaining 3 weeks. The patients with body mass of <45 kg received 5 mcg/m²/d during first week, and 15 mcg/m²/d over following 3 weeks. Adult patients with molecular relapses received 15 mcg/m2/d during 4 weeks. Inotuzumab ozogamycin was administered in adult and children groups at the same dosage: one cycle consisted of 3 dose regimens, i.e., 0.8 mg/m² on week 1, and 0.5 mg/m² on week 2 and week 3.

Patients with r/r Ph-positive B-ALL were treated with combination of blinatumomab or inotuzumab with different tyrosine kinase inhibitors at recommended doses administered during therapeutic cycles. Next types of response were registered: complete remission without MRD, i.e., molecular remission, and complete remission with MRD termed as hematological remission. Complete remission (CR) included variants with recovery and partial recovery of hemopoiesis. In several patients, complete remission was registered in bone marrow, but extramedullary lesions were found in them.

Statistical evaluation

Descriptive statistics were used for the patients’ characteristics and response to treatment using. Differences in response to treatment were evaluated with chi-square test. The variables with a significance levels of <=0.1 in the univariate analysis were selected for evaluation with logistic regression. The analyses were performed in SPSS ver. 17.0.

Results

The entire group of patients consisted of 182 children and adults at the age of 1 to 72 years old, including 78 children and adolescents up to 18 years, and 104 adults. 128 patients were treated with blinatumomab, 54 patients received inotuzumab ozogamicin. Baseline characteristics of the patients are shown in Table 1. The patients were classified by their mutational status at the time of onset of the disease, i.e., 161 (88%) cases of Ph-negative B-ALL and 21 (12%) patients with Ph-positive B-ALL. The mixed-lineage leukemia (MLL1) gene was detected in 17 (9%) patients: 9 with infant ALL, 2 in children over 1 year at the time of onset of disease and 6 in adults. Depending on occurrence of past relapses, the patients were divided into those who developed relapses after previous allo-HSCT 46 (25%) cases, or after chemotherapy (n=127, 70%) and primary resistance cases (n=9, i.e., 5%). Before blinatumomab treatment, 69 (54%) patients had molecular relapses, i.e., minimal residual disease (MRD), and 59 (46%) patients from this group. All the patients (n=54) who received inotuzumab had hematological relapses. Time of observation was from 23 to 730 days (median 244 days). In our study, most patients received 1-2 courses of blinatumomab and most patients received one cycle of inotuzumab ozogomicin. Patients with r/r Ph-positive B-ALL received different tyrosine kinase inhibitors (dasatinib 13, imatinib 6, nilotinib 2).

Clinical response in the whole group patients who received blinatumomab or inotuzumab was high both in adult and children groups, 83% and 69%, respectively, and most patients achieved complete remission (CR). In blinatumomab group, CR was registered in 57 adult patients (76%) and in 28 patients (52%) under 18 y.o. In inotuzumab group, overall response rate in adults was 82%, in children and adolescents, 81%; CR was achieved in 14 adult patients (50%), and in 14 children (58%) as seen from Fig. 1, A. The patients with cytogenetic or molecular genetics prognostic factors had high responses as well. Ph+ B-ALL in blinatumomab group had overall response in 84%, including 67% with CR. All Ph+ B-ALL patients in the inotuzumab group had hematological remission. The patients with MLL translocation had worst overall response compared to patients without MLL translocation, i.e., 41% and 65% of general group, respectively (Fig. 1, D). Overall responses in patients with relapses after previous HSCT and relapses after CT were comparable, 28 (63%) and 85 cases (63%) (Fig. 1, B). The patients who had molecular relapses before therapy with blinatumomab had higher response than patients with hematological relapses (90% vs 58%), as shown in Fig. 1, C. Multivariate analysis in our study showed that only age (p=0.001) and disease status (p=0.01) before blinatumomab or inotuzumab therapy showed statistical significance (Table 2). Previous exposition on blinatumab did not influence the response to inotuzumab ozogamicin, i.e., 89% vs 81% of responding patients (p=0.46) in blinatumomab-naïve versus blinatumomab-exposed cases.

Figure 1. Types of responses to antibody-based drug treatment in r/r B-ALL patients. A, Children vs adults; B, Patients with relapses following previous HSCT vs preceding CT; C, Patients with molecular relapses vs hematological relapses; D, Cases with MLL translocation vs patients without MLL translocation. The patients were classified by different types of minimal residual disease (bottom line of the pictures)

Table 2. Multivariate analysis of some factors predictive for treatment response

Discussion

We have assessed high efficacy of blinatumomab and inotuzumab ozogamicin in a heterogeneous cohort of r/r B-cell ALL of children and adults in real clinical practice. After these therapies, high rate of complete remission (CR) was observed in all subgroups, including patients with cytogenetics/ molecular genetic prognostic factors, e.g., in the cases with Ph-positive r/r B-ALL. If comparing our study with recent work that used combination of TKI and blinatumomab in patients with Ph-positive r/r B-ALL [19], our results seem to be something better. In our study, CR was achieved in 57% versus 36%, probably, due to high proportion of patients treated for MRD unlike in the previous study where majority of patients had hematological relapse. Patients with r/r B-ALL and MLL translocation achieved CR in 41% cases. These data demonstrate an opportunity of using this treatment in patients from high-risk group, but further studies are required to demonstrate whether the response rate is significantly lower than in general cohort.

Overall response in pediatric subgroup in our study differed significantly from adult patients because of probable differences in biology, e.g., genomic profiling in pediatric B-ALL more often reveals mutations in NRAS, KRAS genes, and MLL rearrangement. ETV6/RUNX1 (E/R) was the most common fusion gene in pediatric B-ALL as well [20]. Differences in immune system may also play a role in response rates [21] The observation that blinatumomab works better in MRD setting than in hematological remission confirms the previous report on clinical trials of Germany group, where 80% of molecular CR was documented [22]. Inotuzumab ozogamicin is effective, regardless the tumor burden: the overall response was 81%. The response rate was comparable to results of adult and pediatric registration study [11, 12, 13, 14]. Monoclonal antibodies present such opportunity, providing reliable approach to achieve CR in r/r B-ALL patients before sequential HSCT.

Conclusion

1. Both blinatumomab and inotuzumab ozogomicin are effective in patients with r/r B-ALL.

2. Blinatumomab is more effective in patients with molecular relapses.

3. Blinatumomab-refractory patients can be salvaged with inotuzumab ozogamicin.

4. Results in real-life clinical practice are comparable to extensive registration studies.

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Introduction

In recent years, the outcome of patients with B-cell acute lymphoblastic leukemia (B-ALL) has improved dramatically due to the use of modern chemotherapy regimens. In children with B- ALL cure rate varies within 70%-80%, while in adults – within 15%-40% [1, 2] However, primary resistance and relapses that do occur in 15%-25% of children, and in 50%-70% of adults, and significantly impact survival [3, 4]. In relapsed patients, the prognosis is adverse and after each relapse, the outcome is deteriorating. In case of third and further relapses the probability to achieve remission by salvage high-dose chemotherapy is decreasing. In addition, when using intensive chemotherapy, commutative toxicity is accumulating which is an additional risk factor for increasing the incidence of non-relapse mortality during allogeneic hematopoietic stem cells transplantation (allo-HSCT) [5, 6, 7]. The depth of the response is another factor which impacts the allo-HSCT efficacy, and salvage chemotherapy rarely induces molecular remissions [7, 8, 9, 10].

The emergency of different monoclonal antibodies (BITE, conjugated) has significantly expanded our options for treatment of the patients with relapsed/refractory (r/r) B-cell ALL.

Currently blinatumomab, a bispecific T-cells engager monoclonal antibody (anti-CD19), and inotusumab ozogamicin, a conjugate monoclonal antibody (anti-CD22), are the most promising in treatment of r/r B-ALL in children and adults, which has been shown in a large number of studies [11, 12, 13, 14, 15, 16]. Their pharmacokinetics and pharmacodynamics have been well studied to date. But there are still many unresolved questions concerning use of these monoclonal antibodies in real clinical practice. Various pilot studies and randomized clinical trials have shown the advantages of blinatumomab and inotuzumab over standard and salvage chemotherapy [17, 18].

Our aim was to summarize the results of a single-center non-randomized study in order to investigate in real clinical practice the results of treatment with blinatumomab and inotuzumab ozogamicin in children and adults in heterogeneous cohort of r/r B-ALL.

Patients and methods

The study included patients, both children and adults, with different types of r/r B-ALL who were treated with monoclonal antibodies – blinatumomab and inotuzumab ozogamicin in real clinical setting. The patients were treated in Raisa Gorbacheva Memorial Institute of Pediatric Oncology, Hematology and Transplantation, Pavlov University, Saint-Petersburg from April 2015 to October 2019. All the patients gave informed consent for the treatment, each case was approved by the Russian Ministry of Health for individual use of investigational product.

The group of patients in our study was heterogenous for different parameters. The heterogeneity was due to genetic markers of r/r B-ALL patients, age differences, as well as different types of relapses, previous therapy and clinical state of the disease (hematological or molecular relapses) at the moment of starting therapy by blinatumomab or inotuzumab (Table 1). Hematological relapse (HR) was determined in cases with more than 5% blasts in bone marrow.

Table 1. Clinical characteristics of B-ALL patients included into the study

Molecular relapse (MR) was diagnosed if minimal reduced disease (MRD) was defined as presence of leukemia blasts not detectable by microscope, being, however, revealed by mutation-specific polymerase chain reaction (PCR) or flow cytometry, if the relevant result was >1 malignant cell per 10^-4 normal counterparts.

The patients received blinatumomab by continuous intravenous infusions. One course included 4-week treatment followed by 2-weeks pause in treatment. The doses were as follows: in adult patients with hematologic relapse and children with hematologic and molecular relapses weighing >45 kg, at the dose of 9 mcg/d for the first week in cycle, and 28 mcg/d over the remaining 3 weeks. The patients with body mass of <45 kg received 5 mcg/m²/d during first week, and 15 mcg/m²/d over following 3 weeks. Adult patients with molecular relapses received 15 mcg/m2/d during 4 weeks. Inotuzumab ozogamycin was administered in adult and children groups at the same dosage: one cycle consisted of 3 dose regimens, i.e., 0.8 mg/m² on week 1, and 0.5 mg/m² on week 2 and week 3.

Patients with r/r Ph-positive B-ALL were treated with combination of blinatumomab or inotuzumab with different tyrosine kinase inhibitors at recommended doses administered during therapeutic cycles. Next types of response were registered: complete remission without MRD, i.e., molecular remission, and complete remission with MRD termed as hematological remission. Complete remission (CR) included variants with recovery and partial recovery of hemopoiesis. In several patients, complete remission was registered in bone marrow, but extramedullary lesions were found in them.

Statistical evaluation

Descriptive statistics were used for the patients’ characteristics and response to treatment using. Differences in response to treatment were evaluated with chi-square test. The variables with a significance levels of <=0.1 in the univariate analysis were selected for evaluation with logistic regression. The analyses were performed in SPSS ver. 17.0.

Results

The entire group of patients consisted of 182 children and adults at the age of 1 to 72 years old, including 78 children and adolescents up to 18 years, and 104 adults. 128 patients were treated with blinatumomab, 54 patients received inotuzumab ozogamicin. Baseline characteristics of the patients are shown in Table 1. The patients were classified by their mutational status at the time of onset of the disease, i.e., 161 (88%) cases of Ph-negative B-ALL and 21 (12%) patients with Ph-positive B-ALL. The mixed-lineage leukemia (MLL1) gene was detected in 17 (9%) patients: 9 with infant ALL, 2 in children over 1 year at the time of onset of disease and 6 in adults. Depending on occurrence of past relapses, the patients were divided into those who developed relapses after previous allo-HSCT 46 (25%) cases, or after chemotherapy (n=127, 70%) and primary resistance cases (n=9, i.e., 5%). Before blinatumomab treatment, 69 (54%) patients had molecular relapses, i.e., minimal residual disease (MRD), and 59 (46%) patients from this group. All the patients (n=54) who received inotuzumab had hematological relapses. Time of observation was from 23 to 730 days (median 244 days). In our study, most patients received 1-2 courses of blinatumomab and most patients received one cycle of inotuzumab ozogomicin. Patients with r/r Ph-positive B-ALL received different tyrosine kinase inhibitors (dasatinib 13, imatinib 6, nilotinib 2).

Clinical response in the whole group patients who received blinatumomab or inotuzumab was high both in adult and children groups, 83% and 69%, respectively, and most patients achieved complete remission (CR). In blinatumomab group, CR was registered in 57 adult patients (76%) and in 28 patients (52%) under 18 y.o. In inotuzumab group, overall response rate in adults was 82%, in children and adolescents, 81%; CR was achieved in 14 adult patients (50%), and in 14 children (58%) as seen from Fig. 1, A. The patients with cytogenetic or molecular genetics prognostic factors had high responses as well. Ph+ B-ALL in blinatumomab group had overall response in 84%, including 67% with CR. All Ph+ B-ALL patients in the inotuzumab group had hematological remission. The patients with MLL translocation had worst overall response compared to patients without MLL translocation, i.e., 41% and 65% of general group, respectively (Fig. 1, D). Overall responses in patients with relapses after previous HSCT and relapses after CT were comparable, 28 (63%) and 85 cases (63%) (Fig. 1, B). The patients who had molecular relapses before therapy with blinatumomab had higher response than patients with hematological relapses (90% vs 58%), as shown in Fig. 1, C. Multivariate analysis in our study showed that only age (p=0.001) and disease status (p=0.01) before blinatumomab or inotuzumab therapy showed statistical significance (Table 2). Previous exposition on blinatumab did not influence the response to inotuzumab ozogamicin, i.e., 89% vs 81% of responding patients (p=0.46) in blinatumomab-naïve versus blinatumomab-exposed cases.

Figure 1. Types of responses to antibody-based drug treatment in r/r B-ALL patients. A, Children vs adults; B, Patients with relapses following previous HSCT vs preceding CT; C, Patients with molecular relapses vs hematological relapses; D, Cases with MLL translocation vs patients without MLL translocation. The patients were classified by different types of minimal residual disease (bottom line of the pictures)

Table 2. Multivariate analysis of some factors predictive for treatment response

Discussion

We have assessed high efficacy of blinatumomab and inotuzumab ozogamicin in a heterogeneous cohort of r/r B-cell ALL of children and adults in real clinical practice. After these therapies, high rate of complete remission (CR) was observed in all subgroups, including patients with cytogenetics/ molecular genetic prognostic factors, e.g., in the cases with Ph-positive r/r B-ALL. If comparing our study with recent work that used combination of TKI and blinatumomab in patients with Ph-positive r/r B-ALL [19], our results seem to be something better. In our study, CR was achieved in 57% versus 36%, probably, due to high proportion of patients treated for MRD unlike in the previous study where majority of patients had hematological relapse. Patients with r/r B-ALL and MLL translocation achieved CR in 41% cases. These data demonstrate an opportunity of using this treatment in patients from high-risk group, but further studies are required to demonstrate whether the response rate is significantly lower than in general cohort.

Overall response in pediatric subgroup in our study differed significantly from adult patients because of probable differences in biology, e.g., genomic profiling in pediatric B-ALL more often reveals mutations in NRAS, KRAS genes, and MLL rearrangement. ETV6/RUNX1 (E/R) was the most common fusion gene in pediatric B-ALL as well [20]. Differences in immune system may also play a role in response rates [21] The observation that blinatumomab works better in MRD setting than in hematological remission confirms the previous report on clinical trials of Germany group, where 80% of molecular CR was documented [22]. Inotuzumab ozogamicin is effective, regardless the tumor burden: the overall response was 81%. The response rate was comparable to results of adult and pediatric registration study [11, 12, 13, 14]. Monoclonal antibodies present such opportunity, providing reliable approach to achieve CR in r/r B-ALL patients before sequential HSCT.

Conclusion

1. Both blinatumomab and inotuzumab ozogomicin are effective in patients with r/r B-ALL.

2. Blinatumomab is more effective in patients with molecular relapses.

3. Blinatumomab-refractory patients can be salvaged with inotuzumab ozogamicin.

4. Results in real-life clinical practice are comparable to extensive registration studies.

References

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"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) "26374" 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Маркова, Сергей Н. Бондаренко, Олеся В. Паина, Белла И. Аюбова, Полина В. Кожокарь, Анастасия С. Фролова, Ильдар М. Бархатов, Елена В. Бабенко, Александр А. Алянский, Кирилл А. Екушов, Татьяна Л. Гиндина, Елена В. Семенова, Иван С. Моисеев, Людмила С. Зубаровская, <span style="border: 1px solid black; margin: 0; padding: 2px 2px;">Борис В. Афанасьев</span></p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(591) "

Инна В. Маркова, Сергей Н. Бондаренко, Олеся В. Паина, Белла И. Аюбова, Полина В. Кожокарь, Анастасия С. Фролова, Ильдар М. Бархатов, Елена В. Бабенко, Александр А. Алянский, Кирилл А. Екушов, Татьяна Л. Гиндина, Елена В. Семенова, Иван С. Моисеев, Людмила С. Зубаровская, Борис В. Афанасьев

" ["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) "26375" ["VALUE"]=> array(2) { ["TEXT"]=> string(367) "<p>НИИ детской онкологии, гематологии и трансплантологии им. Р. М. Горбачевой, 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(355) "

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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Аллогенная трансплантация гемопоэтических стволовых клеток остается наиболее эффективным методом излечения пациентов с рефрактерным течением/рецидивами В-клеточного острого лимфобластного лейкоза (р/р В-ОЛЛ). Полная ремиссия заболевания без признаков минимальной остаточной болезни является ключевым фактором успешного исхода. Моноклональные антитела (биспецифические и коньюгаты) представляют собой эффективные опции в достижении ремиссии у этих пациентов. Нашей целью было обобщение результатов одноцентрового нерандомизированного исследовапния для изучения результатов терапии блинатумамобом и инотузумаб-озогамицином у детей и взрослых в гетерогенной когорте больных р/р В-ОЛЛ. Результаты одноцентрового, нерандомизированного пилотного исследования в реальной клинической практике продемонстрировали высокий уровень ответа на данный вид терапии в гетерогенной когорте пациентов с р/р В-ОЛЛ. Исследуемая группа включала 182 пациента р/р В-ОЛЛ, возраст от одного года до 72 лет, 128 пациентов получали блинатумомаб, 54 пациента получали инотузумаб озогамицин. Уровень общего ответа был высоким в обеих группах – 96 (75%) и 44 случая (82%), соответственно. Главными предикторами ответа были взрослый возраст (OR=3,819, 95% CI=1,744-8,223, p=0,001) и показания к терапии – гематологический рецидив или персистенция минимальной остаточной болезни (OR=0,018, 95% CI=0,153-0,841, p=0,01). Другие клинические или патологические параметры не оказывали существенного влияния на ответы на терапию.

Ключевые слова

В-клеточный острый лимфобластный лейкоз, рефрактерный и рецидивирующий, моноклональные антитела, блинатумомаб, инотузумаб озогамицин, общий ответ.

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Inna V. Markova, Sergey N. Bondarenko, Olesya V. Paina, Bella I. Aubova, Polina V. Kozhokar, Anastasia S. Frolova,
Ildar M. Barkhatov, Elena V. Babenko, Alexander A. Alyanskiy, Kirill A. Ekushov, Tatyana L. Gindina, Elena V. Semenova, Ivan S. Moiseev, Ludmila S. Zubarovskaya, Boris V. Afanasyev

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Raisa Gorbacheva Memorial Research Institute of Pediatric Oncology, Hematology and Transplantation, Pavlov University,
St. Petersburg, Russia

Correspondence Dr. Inna V. Markova, Raisa Gorbacheva Memorial Research Institute of Pediatric Oncology, Hematology and Transplantation, Pavlov University, L. Tolstoy St. 6-8, 197022, St. Petersburg, Russia
Phone: +7 (911) 964 6745

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Allogeneic hematopoietic stem cell transplantation is an effective method to cure patients with relapse/refractory (r/r) B-cell acute lymphoblastic leukemia, and deep remission without minimal residual disease is the key factor for the favorable outcome. Monoclonal antibodies (bispecific T-cells engager and conjugates) are the promising option to achieve complete remission in these patients. Our aim was to summarize the results of a single-center non-randomized study in order to investigate in real clinical practice the results of treatment with blinatumomab and inotuzumab ozogamicin in children and adults in heterogeneous cohort of r/r B- ALL.

Results of the single-center non-randomized pilot study in real clinical practice showed high response rate in heterogeneous cohort of r/r B- ALL. The study group included 182 patients with r/r B-ALL, their age was from one to 72 years old. 128 patients were treated with blinatumomab, 54 patients received inotuzumab ozogamicin. Overall response was high in both groups, 96 (75%) and 44 (82%). The major predictors of response were adult age (OR= 3.819; 95% CI, 1.744-8.223; p=0.001) and clinical indications, i.e., active disease or measurable residual disease (OR= 0.018; 95% CI, 0.153-0.841; p=0.01). The other clinical or disease parameters had no significant impact on response.

Keywords

B-cell acute lymphoblastic leukemia, relapse/refractory, monoclonal antibodies, blinatumomab, inotuzumab ozogamicin, overall response.

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"HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(80) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> NULL ["VALUE"]=> string(0) "" ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> string(0) "" ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(72) "Название (для очень длинных заголовков)" ["~DEFAULT_VALUE"]=> array(2) { ["TYPE"]=> string(4) "HTML" ["TEXT"]=> string(0) "" } } } ["DISPLAY_PROPERTIES"]=> array(10) { ["AUTHOR_EN"]=> array(37) { ["ID"]=> string(2) "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) "26380" ["VALUE"]=> array(2) { ["TEXT"]=> string(421) "<p>Inna V. Markova, Sergey N. Bondarenko, Olesya V. Paina, Bella I. Aubova, Polina V. Kozhokar, Anastasia S. Frolova, <br>Ildar M. Barkhatov, Elena V. Babenko, Alexander A. Alyanskiy, Kirill A. Ekushov, Tatyana L. Gindina, Elena V. Semenova, Ivan S. Moiseev, Ludmila S. Zubarovskaya, <span style="border: 1px solid black; margin: 0; padding: 2px 2px;">Boris V. Afanasyev</span></p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(381) "

Inna V. Markova, Sergey N. Bondarenko, Olesya V. Paina, Bella I. Aubova, Polina V. Kozhokar, Anastasia S. Frolova,
Ildar M. Barkhatov, Elena V. Babenko, Alexander A. Alyanskiy, Kirill A. Ekushov, Tatyana L. Gindina, Elena V. Semenova, Ivan S. Moiseev, Ludmila S. Zubarovskaya, Boris V. Afanasyev

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Inna V. Markova, Sergey N. Bondarenko, Olesya V. Paina, Bella I. Aubova, Polina V. Kozhokar, Anastasia S. Frolova,
Ildar M. Barkhatov, Elena V. Babenko, Alexander A. Alyanskiy, Kirill A. Ekushov, Tatyana L. Gindina, Elena V. Semenova, Ivan S. Moiseev, Ludmila S. Zubarovskaya, Boris V. Afanasyev

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Allogeneic hematopoietic stem cell transplantation is an effective method to cure patients with relapse/refractory (r/r) B-cell acute lymphoblastic leukemia, and deep remission without minimal residual disease is the key factor for the favorable outcome. Monoclonal antibodies (bispecific T-cells engager and conjugates) are the promising option to achieve complete remission in these patients. Our aim was to summarize the results of a single-center non-randomized study in order to investigate in real clinical practice the results of treatment with blinatumomab and inotuzumab ozogamicin in children and adults in heterogeneous cohort of r/r B- ALL.

Results of the single-center non-randomized pilot study in real clinical practice showed high response rate in heterogeneous cohort of r/r B- ALL. The study group included 182 patients with r/r B-ALL, their age was from one to 72 years old. 128 patients were treated with blinatumomab, 54 patients received inotuzumab ozogamicin. Overall response was high in both groups, 96 (75%) and 44 (82%). The major predictors of response were adult age (OR= 3.819; 95% CI, 1.744-8.223; p=0.001) and clinical indications, i.e., active disease or measurable residual disease (OR= 0.018; 95% CI, 0.153-0.841; p=0.01). The other clinical or disease parameters had no significant impact on response.

Keywords

B-cell acute lymphoblastic leukemia, relapse/refractory, monoclonal antibodies, blinatumomab, inotuzumab ozogamicin, overall response.

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Allogeneic hematopoietic stem cell transplantation is an effective method to cure patients with relapse/refractory (r/r) B-cell acute lymphoblastic leukemia, and deep remission without minimal residual disease is the key factor for the favorable outcome. Monoclonal antibodies (bispecific T-cells engager and conjugates) are the promising option to achieve complete remission in these patients. Our aim was to summarize the results of a single-center non-randomized study in order to investigate in real clinical practice the results of treatment with blinatumomab and inotuzumab ozogamicin in children and adults in heterogeneous cohort of r/r B- ALL.

Results of the single-center non-randomized pilot study in real clinical practice showed high response rate in heterogeneous cohort of r/r B- ALL. The study group included 182 patients with r/r B-ALL, their age was from one to 72 years old. 128 patients were treated with blinatumomab, 54 patients received inotuzumab ozogamicin. Overall response was high in both groups, 96 (75%) and 44 (82%). The major predictors of response were adult age (OR= 3.819; 95% CI, 1.744-8.223; p=0.001) and clinical indications, i.e., active disease or measurable residual disease (OR= 0.018; 95% CI, 0.153-0.841; p=0.01). The other clinical or disease parameters had no significant impact on response.

Keywords

B-cell acute lymphoblastic leukemia, relapse/refractory, monoclonal antibodies, blinatumomab, inotuzumab ozogamicin, overall response.

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Raisa Gorbacheva Memorial Research Institute of Pediatric Oncology, Hematology and Transplantation, Pavlov University,
St. Petersburg, Russia

Correspondence Dr. Inna V. Markova, Raisa Gorbacheva Memorial Research Institute of Pediatric Oncology, Hematology and Transplantation, Pavlov University, L. Tolstoy St. 6-8, 197022, St. Petersburg, Russia
Phone: +7 (911) 964 6745

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Raisa Gorbacheva Memorial Research Institute of Pediatric Oncology, Hematology and Transplantation, Pavlov University,
St. Petersburg, Russia

Correspondence Dr. Inna V. Markova, Raisa Gorbacheva Memorial Research Institute of Pediatric Oncology, Hematology and Transplantation, Pavlov University, L. Tolstoy St. 6-8, 197022, St. Petersburg, Russia
Phone: +7 (911) 964 6745

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Инна В. Маркова, Сергей Н. Бондаренко, Олеся В. Паина, Белла И. Аюбова, Полина В. Кожокарь, Анастасия С. Фролова, Ильдар М. Бархатов, Елена В. Бабенко, Александр А. Алянский, Кирилл А. Екушов, Татьяна Л. Гиндина, Елена В. Семенова, Иван С. Моисеев, Людмила С. Зубаровская, Борис В. Афанасьев

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Инна В. Маркова, Сергей Н. Бондаренко, Олеся В. Паина, Белла И. Аюбова, Полина В. Кожокарь, Анастасия С. Фролова, Ильдар М. Бархатов, Елена В. Бабенко, Александр А. Алянский, Кирилл А. Екушов, Татьяна Л. Гиндина, Елена В. Семенова, Иван С. Моисеев, Людмила С. Зубаровская, Борис В. Афанасьев

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Полная ремиссия заболевания без признаков минимальной остаточной болезни является ключевым фактором успешного исхода. Моноклональные антитела (биспецифические и коньюгаты) представляют собой эффективные опции в достижении ремиссии у этих пациентов. Нашей целью было обобщение результатов одноцентрового нерандомизированного исследовапния для изучения результатов терапии блинатумамобом и инотузумаб-озогамицином у детей и взрослых в гетерогенной когорте больных р/р В-ОЛЛ. Результаты одноцентрового, нерандомизированного пилотного исследования в реальной клинической практике продемонстрировали высокий уровень ответа на данный вид терапии в гетерогенной когорте пациентов с р/р В-ОЛЛ. Исследуемая группа включала 182 пациента р/р В-ОЛЛ, возраст от одного года до 72 лет, 128 пациентов получали блинатумомаб, 54 пациента получали инотузумаб озогамицин. Уровень общего ответа был высоким в обеих группах – 96 (75%) и 44 случая (82%), соответственно. Главными предикторами ответа были взрослый возраст (OR=3,819, 95% CI=1,744-8,223, p=0,001) и показания к терапии – гематологический рецидив или персистенция минимальной остаточной болезни (OR=0,018, 95% CI=0,153-0,841, p=0,01). Другие клинические или патологические параметры не оказывали существенного влияния на ответы на терапию. </p> <h2>Ключевые слова</h2> <p style="text-align: justify;"> В-клеточный острый лимфобластный лейкоз, рефрактерный и рецидивирующий, моноклональные антитела, блинатумомаб, инотузумаб озогамицин, общий ответ.</p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(3073) "

Аллогенная трансплантация гемопоэтических стволовых клеток остается наиболее эффективным методом излечения пациентов с рефрактерным течением/рецидивами В-клеточного острого лимфобластного лейкоза (р/р В-ОЛЛ). Полная ремиссия заболевания без признаков минимальной остаточной болезни является ключевым фактором успешного исхода. Моноклональные антитела (биспецифические и коньюгаты) представляют собой эффективные опции в достижении ремиссии у этих пациентов. Нашей целью было обобщение результатов одноцентрового нерандомизированного исследовапния для изучения результатов терапии блинатумамобом и инотузумаб-озогамицином у детей и взрослых в гетерогенной когорте больных р/р В-ОЛЛ. Результаты одноцентрового, нерандомизированного пилотного исследования в реальной клинической практике продемонстрировали высокий уровень ответа на данный вид терапии в гетерогенной когорте пациентов с р/р В-ОЛЛ. Исследуемая группа включала 182 пациента р/р В-ОЛЛ, возраст от одного года до 72 лет, 128 пациентов получали блинатумомаб, 54 пациента получали инотузумаб озогамицин. Уровень общего ответа был высоким в обеих группах – 96 (75%) и 44 случая (82%), соответственно. Главными предикторами ответа были взрослый возраст (OR=3,819, 95% CI=1,744-8,223, p=0,001) и показания к терапии – гематологический рецидив или персистенция минимальной остаточной болезни (OR=0,018, 95% CI=0,153-0,841, p=0,01). Другие клинические или патологические параметры не оказывали существенного влияния на ответы на терапию.

Ключевые слова

В-клеточный острый лимфобластный лейкоз, рефрактерный и рецидивирующий, моноклональные антитела, блинатумомаб, инотузумаб озогамицин, общий ответ.

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Аллогенная трансплантация гемопоэтических стволовых клеток остается наиболее эффективным методом излечения пациентов с рефрактерным течением/рецидивами В-клеточного острого лимфобластного лейкоза (р/р В-ОЛЛ). Полная ремиссия заболевания без признаков минимальной остаточной болезни является ключевым фактором успешного исхода. Моноклональные антитела (биспецифические и коньюгаты) представляют собой эффективные опции в достижении ремиссии у этих пациентов. Нашей целью было обобщение результатов одноцентрового нерандомизированного исследовапния для изучения результатов терапии блинатумамобом и инотузумаб-озогамицином у детей и взрослых в гетерогенной когорте больных р/р В-ОЛЛ. Результаты одноцентрового, нерандомизированного пилотного исследования в реальной клинической практике продемонстрировали высокий уровень ответа на данный вид терапии в гетерогенной когорте пациентов с р/р В-ОЛЛ. Исследуемая группа включала 182 пациента р/р В-ОЛЛ, возраст от одного года до 72 лет, 128 пациентов получали блинатумомаб, 54 пациента получали инотузумаб озогамицин. Уровень общего ответа был высоким в обеих группах – 96 (75%) и 44 случая (82%), соответственно. Главными предикторами ответа были взрослый возраст (OR=3,819, 95% CI=1,744-8,223, p=0,001) и показания к терапии – гематологический рецидив или персистенция минимальной остаточной болезни (OR=0,018, 95% CI=0,153-0,841, p=0,01). Другие клинические или патологические параметры не оказывали существенного влияния на ответы на терапию.

Ключевые слова

В-клеточный острый лимфобластный лейкоз, рефрактерный и рецидивирующий, моноклональные антитела, блинатумомаб, инотузумаб озогамицин, общий ответ.

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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

Myelodysplastic syndrome (MDS), chronic myeloproliferative neoplasms (MPN) and chronic myeloid leukemia (CML) comprise about 15% of patients with indication for allogeneic stem cell transplantation (SCT) [1]. Nonetheless SCT in this group of patients is associated with significant non-relapse mortality reaching 26% in advanced chronic myeloid leukemia [2], 32% in myelodysplastic syndrome [3] and 25-36% in various types of MPN [4, 5]. The main reasons of mortality in these diseases are infectious complications, graft-versus-host disease and primary graft failure which is significantly more frequent than in other hematological malignancies [6].

Posttransplant cyclophosphamide (PTCY) is an approach which is gaining popularity for haploidentical (Haplo) and mismatched unrelated donor (MUD) transplantation. This approach in the large retrospective study demonstrated reduced incidence of GvHD, reduced non-relapse mortality and improved GvHD-relapse-free survival (GFRS) compared to in vivo T-cell depletion methods both in Haplo and MUD settings [7, 8]. But most of the supportive data describes acute leukemia patients [9] or MDS/ MPN patients are combined in the analysis with acute leukemia [10]. Thus there is limited data whether PTCY in the group of chronic myeloid neoplasms provide the same benefit as in acute leukemias. Also there was a concern that in the setting of MDS/CML/MPN PTCy might increase the primary graft failure incidence.

The majority of SCTs in MDS and CML patients are unrelated, because of older age and comorbidities of the related donors and better outcomes after transplantation from a young donor [11]. So we conducted a single-center prospective randomized study in unrelated SCT recipients between the standard approach of GvHD prophylaxis with thymoglobulin and PTCY. The other components of GvHD prophylaxis was the same as well as the conditioning and supportive care.

Patients and methods

General parameters of the patients and transplants

The prospective single-center randomized study was conducted in the First Pavlov Medical university. The study was approved by the local Ethical committee and was conducted according to the good clinical practices and Helsinki declaration. All patients signed informed consent to participate in the study and processing of the personal data. The study was registered at clinicaltrials.gov, NCT02627573. The conclusion criteria were the diagnosis of chronic myeloid leukemia or myelodysplastic Syndrome or myeloprolipherative neoplasm unclassified or atypical chronic myelogenous leukemia with indications for SCT and presence of 10/10 HLA-matched unrelated donor. The donor and recipient must be identical by the following genetic loci: HLA-A, HLA-B, HLA-Cw, HLA-DRB1, and HLA-DQB1. Mismatches in these loci were not allowed. Also only patients were included in whom the donor agreed to donate peripheral blood stem cells (PBSC). The exclusion criteria were the presence of severe concurrent illness, prior history of anaphylaxis to thymoglobulin, moderate or severe cardiac dysfunction, left ventricular ejection fraction <50%, moderate or severe decrease in pulmonary function, FEV1 <70% or DLCO <70% of predicted, respiratory distress at least grade I, severe organ dysfunction: AST or ALT >5 upper normal limits, bilirubin >1.5 upper normal limits, creatinine >2 upper normal limits, creatinine clearance <60 mL/min., uncontrolled bacterial or fungal infection at the time of enrollment, requirement for vasopressor support at the time of enrollment, Karnofsky index <30%, pregnancy, and somatic or psychiatric disorder making the patient unable to sign informed consent. The study during 2015-2019 has enrolled 33 patients: 16 in the thymoglobulin arm and 17 in the PTCY arm. The study was terminated prematurely due to poor recruitment. All recruited patients were included in the analysis. The study group was well balanced with no significant differences in characteristics of patients (Table 1).

Table 1. Characteristics of patients

CML = chronic myeloid leukemia, MDS = myelodysplastic syndrome, MPN = myeloproliferative neoplasm, CP = chronic phase, AP = acceleration phase, BC = blast crisis, AEB – access blasts, MLD – multileaneage dysplasia.

Study procedures

All patients received conditioning with fludarabine 180 mg/m² over 6 days and oral busulfan 10 mg/kg over 3 days. Patients in the thymoglobulin group received GvHD prophylaxis with thymoglobulin 2.5 mg/kg on days -3 and -2, tacrolimus 0.03 mg/kg/day starting day -1 with target concentration 5-15 ng/ml and mycophenolate mofetil (MMF) 30 mg/kg/day starting. The MMF was continued until day +30. Tacrolimus was continued until day +100 and gradually tapered over 1 month in absence of GvHD. Steroids were used in this group as the pre-medication to thymoglobulin and graft infusion. In the PTCy group patients received cyclophosphamide 50 mg/kg on days +3 and +4. Mesna 50 mg/kg was administered as 24-hour infusion on the days of cyclophosphamide administration. MMF 30 mg/kg/day was started on day +5 and continued until day +35. Tacrolimus 0.03 mg/kg/day was started on day +5 with target concentration 5-15 ng/ml. Tacrolimus in this arm was in the same way continued until day +100 and gradually tapered over 1 month in absence of GvHD. Use of steroids was prohibited from day-5 to day+5. The rest of the supportive care was the same in both arms. The standard antifungal prophylaxis was fluconazole starting on day 0 and continued until engraftment.

Clinical outcomes

Time to disease relapse, acute GvHD (GvHD), moderate to severe chronic GvHD (cGvHD), non-relapse mortality (NRM), overall survival (OS), event-free survival (EFS), and GvHD-relapse free survival (GRFS) were defined as the time from transplantation to the event. Incidence of aGvHD was calculated at 125 days after HSCT, and the time frame for the other outcomes was free years. Events for EFS were relapse or death. Events for GRFS were either death, relapse, grades III-IV acute GvHD or systemic therapy-requiring chronic GvHD [12]. Patients were censored at the time of last contact or a second transplantation for all outcomes. Disease relapse was defined as morphologic or cytogenetic evidence of disease with pre-transplantation characteristics. Disease staging, including bone marrow biopsies, was routinely performed on days +30,+60,+100, +180, +365 post-transplant. The Consensus Conference criteria and National Institutes of Health criteria were used for aGvHD and cGvHD grading [13, 14]. Primary graft failure was defined as the complete absence of donor chimerism in bone marrow biopsy by day +40. Time to engraftment was calculated as time from HSCT to unsupported neutrophil count > 500/µl and white blood cell count >1000/µl for 3 consecutive days. Toxicity was assessed with CTCAE ver. 4.03. Sepsis and severe sepsis were diagnosed based on International Guidelines for Management of Severe Sepsis and Septic Shock [15]. Invasive mycosis was diagnosed in case of probable or proven infection according to EORTC/MSG guidelines [16]. The threshold for cytomegalovirus (CMV) reactivation was >500 copies/ml. Clinically significant CMV reactivation was defined as >10000 copies/mL. Veno-occlusive disease was diagnosed and graded based on EBMT criteria [17].

Statistical evaluation

The study primary endpoint was the incidence of primary graft failure. The study was planned to enroll 60 patients, 30 patients in each arm. With the study group size was calculated with 30% margin, 0.65 study power and 0.05 significance using Fisher’s criterion. Secondary endpoints were incidence of acute grade II-IV acute GvHD, incidence moderate and severe chronic GvHD, non-relapse mortality, OS, EFS, GFRS, relapse incidence, toxicity and infectious complications. The strata for randomization was a pretransplant assessment of mortality (PAM) score [18]. The stratification was performed using Mann-Whitney U-criterion to achieve the minimal differences in PAM between the study groups. The final median PAM values were 14.1 (range 7.8-25.2) and 14.1 (6.9-21.9) in the thymoglobulin and PTCY groups, respectively (p=0.98).

Comparison of patient characteristics was performed by Mann-Whitney test. The survival distributions for OS, EFS, GRFS were calculated using Kaplan-Meier methodology. The comparisons were made using the log-rank test. Cumulative incidence analysis with competing risks for aGvHD, cGvHD, relapse incidence and NRM was performed using Gray test. Relapse and NRM were accounted as competing risks. Incidence and severity of complications was compared using Chi-square and Mann-Whitney test. Analyses were conducted in SAS 9.3 (SAS Institute, Inc.).

Results

Median follow up in the study was 29 months (range 7-48). There was no difference in the incidence of primary graft failure: 12.50% (95%CI 2%-38%) in the thymoglobulin arm and 11.8% (95%CI 1%-36%) in the PTCY arm, p=0.95. Three out of four patients with primary graft failure died, one was salvaged with second transplantation. All patients without primary graft failure survived to the day of engraftment. Median time to neutrophil engraftment was longer in the PTCY group: 20 (16-33) vs 16 (11-30) days, p=0.0017. Time to white blood cell engraftment was also significantly longer: 21 (16-33) vs 15 (11-30) days, p=0.0016. No differences were observed in the time to platelet engraftment: median 12 (8-40) vs 15 (11-45) days, p=0.1482.

Acute GvHD grade II-IV was documented in 3 (23%) patients in the thymoglobulin group and 1 (6%) patients in the PTCY group (p=0.20). No cases of acute GvHD grade III-IV were documented. Moderate and severe chronic GvHD was diagnosed in 3 (23%) patient after thymoglobulin and 4 (25%) patients after PTCY (p=0.41). Median time to chronic GvHD was a little shorter after thymoglobulin (5.5 months) compared to PTCY (15 months), p=0.11. One patient in thymoglobulin and 2 patients in the PTCY group had mild chronic GvHD.

Patients after PTCY prophylaxis had significantly better outcomes of transplantation. 4-year OS was 82% (95%CI 55-94%) vs 30% (95%CI 6-59%), p=0.0126; EFS was 61% (95%CI 31-81%) vs 26% (95%CI 5-54%), p=0.0335, GFRS 61% 95%CI (31-81%) vs 16% (95%CI 1-46%), p=0.0072 (Figure 1). There was a comparable incidence of relapse between the groups (25% vs 29%, p=0.77), but significantly reduced non-relapse mortality in the PTCY group (6% vs 38%, p=0.0264), which was main cause of the differences in survival outcomes. Primary graft failure and infectious complications were the only causes of non-relapse mortality in the study groups.

Figure 1. Overall (A), event-free (B) and GvHD-relapse-free (C) survival. The percentages shown are 4-year Kaplan-Mayer estimates

No unexpected toxicity was observed during the study. There was no significant difference in the incidence of early complications (Table 2). No cases of neurotoxicity or veno-occlusive disease were documented during the study. The infusion reactions in the thymoglobulin group were allergic reactions and in the PTCY group – one case of cystalgia.

Table 2. Toxicity and complications observed in ATG and PTCY groups

Note: TA-TMA = transplant-associated microangiopathy. Infusion reaction is defined as any reaction during or immediately after infusion that required change in the systemic therapy

Discussion

The study was originally developed to demonstrate if there is a difference in primary graft failure after PTCY. Despite it was terminated prematurely due to poor recruitment, several approximations could be made. We have observed identical number of graft failures in the thymoglobulin and PTCY group. According to CIBMTR data the average number of primary graft failure is 5.5% and CML and MDS patients have the double risk. So the incidence in the current study was not only the same between groups, but almost identical to the one reported by large registry studies [6]. So it is likely that there is no impact of PTCY on the incidence of primary graft failure. On the other hand, we have not observed any positive impact of PTCY on engraftment in this patient population despite previous preclinical data [19]. Unlike primary graft failure engraftment of neutrophils is delayed by several days which in concordance with previously published data [7].

The study was not powered to capture the significance and survival and recruitment was not completed, but most striking results were obtained in terms of survival outcomes. PTCY prophylaxis was associated with significantly higher incidence of OS, EFS and GRFS. The differences were due to reduced non-relapse mortality, it was only 6% in the PTCY group. These extremely low incidence of NRM was recently confirmed in the retrospective [7] and prospective randomized [20] studies. Despite the situation in haploidentical transplantation where PTCY reduces mortality through more effective prevention of acute and chronic GvHD [8], here we observed identical incidence of both acute and chronic GvHD, but the difference was due to late severe bacterial infections. In this study 5 mg/kg dose of thymoglobulin was used which is reported to cause less profound immunosuppression and promote graft-versus-leukemia effect [21, 22]. However the population of MDS and MPN patients is different from acute leukemia. There is a significant iron overload, which may increase the risk of infections after SCT and thymoglobulin effects might overlap with these negative impacts of iron overload [23]. Otherwise this might be an indication of better immunological recovery after unrelated transplantation with PTCY. Additional studies are required to confirm these assumptions.

Conclusion

Despite incomplete recruitment, this study provides some evidence on the use of PTCY-based prophylaxis for unrelated transplantations in patients with CML, MDS and MPN. The study has demonstrated that there is likely no impact of PTCY on the incidence of primary graft failure. Also it creates the basis for future studies to evaluate survival and immunological recovery in this patient population.

Conflict of interest

No conflict of interest reported.

References

1. Passweg JR, Baldomero H, Bader P, Basak GW, Bonini C, Duarte R et al. Is the use of unrelated donor transplantation leveling off in Europe? The 2016 European Society for Blood and Marrow Transplant activity survey report. Bone Marrow Transplant. 2018;53(9):1139-1148.
2. Radujkovic A, Dietrich S, Blok HJ, Nagler A, Ayuk F, Finke J et al. Allogeneic Stem Cell Transplantation for Blast Crisis Chronic Myeloid Leukemia in the Era of Tyrosine Kinase Inhibitors: A Retrospective Study by the EBMT Chronic Malignancies Working Party. Biol Blood Marrow Transplant. 2019;25(10):2008-2016.
3. Carré M, Porcher R, Finke J, Ehninger G, Koster L, Beelen D et al. Role of age and hematopoietic cell transplantation-specific comorbidity index in myelodysplastic patients undergoing an allotransplant. A retrospective study from the CMWP (Chronic Malignancies Working Party) of the EBMT. Biol Blood Marrow Transplant. 2019 Oct 21. pii: S1083-8791(19)30672-X. doi: 10.1016/j.bbmt.2019.10.015.
4. Onida F, de Wreede LC, van Biezen A, Eikema DJ, Byrne JL, Iori AP et al. Allogeneic stem cell transplantation in patients with atypical chronic myeloid leukaemia: a retrospective study from the Chronic Malignancies Working Party of the European Society for Blood and Marrow Transplantation. Br J Haematol. 2017;177(5):759-765.
5. Sharma P, Shinde SS, Damlaj M, Hefazi Rorghabeh M, Hashmi SK, Litzow MR et al. Allogeneic hematopoietic stem cell transplant in adult patients with myelodysplastic syndrome/myeloproliferative neoplasm (MDS/MPN) overlap syndromes. Leuk Lymphoma. 2017;58(4):872-881.
6. Olsson RF, Logan BR, Chaudhury S, Zhu X, Akpek G, Bolwell BJ et al. Primary graft failure after myeloablative allogeneic hematopoietic cell transplantation for hematologic malignancies. Leukemia. 2015;29(8):1754-62.
7. Battipaglia G, Labopin M, Kröger N, Vitek A, Afanasyev B, Hilgendorf I et al. Posttransplant cyclophosphamide vs antithymocyte globulin in HLA-mismatched unrelated donor transplantation. Blood. 2019;134(11):892-899.
8. Piemontese S, Ciceri F, Labopin M, Bacigalupo A, Huang H, Santarone S et al. A survey on unmanipulated haploidentical hematopoietic stem cell transplantation in adults with acute leukemia. Leukemia. 2015;29(5):1069-75.
9. Brissot E, Labopin M, Ehninger G, Stelljes M, Brecht A, Ganser A et al. Haploidentical versus unrelated allogeneic stem cell transplantation for relapsed/refractory acute myeloid leukemia: a report on 1578 patients from the Acute Leukemia Working Party of the EBMT. Haematologica. 2019;104(3):524-532.
10. Shah MV, Saliba RM, Rondon G, Chen J, Soebbing D, Rus I et al. Pilot study using post-transplant cyclophosphamide (PTCy), tacrolimus and mycophenolate GvHD prophylaxis for older patients receiving 10/10 HLA-matched unrelated donor hematopoietic stem cell transplantation. Bone Marrow Transplant. 2019;54(4):601-606.
11. Ayuk F, Beelen DW, Bornhäuser M, Stelljes M, Zabelina T, Finke J et al. Relative Impact of HLA Matching and Non-HLA Donor Characteristics on Outcomes of Allogeneic Stem Cell Transplantation for Acute Myeloid Leukemia and Myelodysplastic Syndrome. Biol Blood Marrow Transplant. 2018;24(12):2558-2567.
12. Holtan SG, DeFor TE, Lazaryan A, Bejanyan N, Arora M, Brunstein CG et al. Composite end point of graft-versus-host disease-free, relapse-free survival after allogeneic hematopoietic cell transplantation. Blood. 2015;125(8):1333-1338.
13. Przepiorka D1, Weisdorf D, Martin P, Klingemann HG, Beatty P, Hows J, Thomas ED. 1994 Consensus Conference on Acute GvHD Grading. Bone Marrow Transplant. 1995;15:825-828.
14. Filipovich AH, Weisdorf D, Pavletic S, Socie G, Wingard JR, Lee SJ et al. National Institutes of Health consensus development project on criteria for clinical trials in chronic graft-versus-host disease: I. Diagnosis and staging working group report. Biol Blood Marrow Transplant. 2005;11:945-956.
15. Dellinger RP, Levy MM, Rhodes A, Annane D, Gerlach H, Opal SM et al. Surviving Sepsis Campaign: international guidelines for management of severe sepsis and septic shock, 2012. Intensive Care Med. 2013;39(2):165-228.
16. De Pauw B, Walsh TJ, Donnelly JP, Stevens DA, Edwards JE, Calandra T et al. Revised definitions of invasive fungal disease from the European Organization for Research and Treatment of Cancer/Invasive Fungal Infections Cooperative Group and the National Institute of Allergy and Infectious Diseases Mycoses Study Group (EORTC/MSG) Consensus Group. Clin Infect Dis. 2008;46(12):1813-1821.
17. Mohty M, Malard F, Abecassis M, Aerts E, Alaskar AS, Aljurf M et al. Sinusoidal obstruction syndrome/veno-occlusive disease: current situation and perspectives – a position statement from the European Society for Blood and Marrow Transplantation (EBMT). Bone Marrow Transplant. 2015;50(6):781-789.
19. Parimon T, Au DH, Martin PJ, Chien JW. A risk score for mortality after allogeneic hematopoietic cell transplantation. Ann Intern Med. 2006;144(6):407-414. Luznik L, O'Donnell PV, Fuchs EJ. Post-transplantation cyclophosphamide for tolerance induction in HLA-haploidentical bone marrow transplantation. Semin Oncol. 2012;39(6):683-693.
20. Bolaños-Meade J, Reshef R, Fraser R, Fei M, Abhyankar S, Al-Kadhimi Z et al. Three prophylaxis regimens (tacrolimus, mycophenolate mofetil, and cyclophosphamide; tacrolimus, methotrexate, and bortezomib; or tacrolimus, methotrexate, and maraviroc) versus tacrolimus and methotrexate for prevention of graft-versus-host disease with haemopoietic cell transplantation with reduced-intensity conditioning: a randomised phase 2 trial with a non-randomised contemporaneous control group (BMT CTN 1203). Lancet Haematol. 2019;6(3):e132-e143.
21. Bryant A, Mallick R, Huebsch L, Allan D, Atkins H, Anstee G et al. Low-Dose Antithymocyte Globulin for Graft-versus-Host-Disease Prophylaxis in Matched Unrelated Allogeneic Hematopoietic Stem Cell Transplantation. Biol Blood Marrow Transplant. 2017;23(12):2096-2101.
22. Kennedy VE, Chen H, Savani BN, Greer J, Kassim AA, Engelhardt BG et al. Optimizing Antithymocyte Globulin Dosing for Unrelated Donor Allogeneic Hematopoietic Cell Transplantation Based on Recipient Absolute Lymphocyte Count. Biol Blood Marrow Transplant. 2018;24(1):150-155.
23. Alessandrino EP, Della Porta MG, Bacigalupo A, Malcovati L, Angelucci E, Van Lint MT et al. Prognostic impact of pre-transplantation transfusion history and secondary iron overload in patients with myelodysplastic syndrome undergoing allogeneic stem cell transplantation: a GITMO study. Haematologica. 2010;95(3):476-484.

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Introduction

Myelodysplastic syndrome (MDS), chronic myeloproliferative neoplasms (MPN) and chronic myeloid leukemia (CML) comprise about 15% of patients with indication for allogeneic stem cell transplantation (SCT) [1]. Nonetheless SCT in this group of patients is associated with significant non-relapse mortality reaching 26% in advanced chronic myeloid leukemia [2], 32% in myelodysplastic syndrome [3] and 25-36% in various types of MPN [4, 5]. The main reasons of mortality in these diseases are infectious complications, graft-versus-host disease and primary graft failure which is significantly more frequent than in other hematological malignancies [6].

Posttransplant cyclophosphamide (PTCY) is an approach which is gaining popularity for haploidentical (Haplo) and mismatched unrelated donor (MUD) transplantation. This approach in the large retrospective study demonstrated reduced incidence of GvHD, reduced non-relapse mortality and improved GvHD-relapse-free survival (GFRS) compared to in vivo T-cell depletion methods both in Haplo and MUD settings [7, 8]. But most of the supportive data describes acute leukemia patients [9] or MDS/ MPN patients are combined in the analysis with acute leukemia [10]. Thus there is limited data whether PTCY in the group of chronic myeloid neoplasms provide the same benefit as in acute leukemias. Also there was a concern that in the setting of MDS/CML/MPN PTCy might increase the primary graft failure incidence.

The majority of SCTs in MDS and CML patients are unrelated, because of older age and comorbidities of the related donors and better outcomes after transplantation from a young donor [11]. So we conducted a single-center prospective randomized study in unrelated SCT recipients between the standard approach of GvHD prophylaxis with thymoglobulin and PTCY. The other components of GvHD prophylaxis was the same as well as the conditioning and supportive care.

Patients and methods

General parameters of the patients and transplants

The prospective single-center randomized study was conducted in the First Pavlov Medical university. The study was approved by the local Ethical committee and was conducted according to the good clinical practices and Helsinki declaration. All patients signed informed consent to participate in the study and processing of the personal data. The study was registered at clinicaltrials.gov, NCT02627573. The conclusion criteria were the diagnosis of chronic myeloid leukemia or myelodysplastic Syndrome or myeloprolipherative neoplasm unclassified or atypical chronic myelogenous leukemia with indications for SCT and presence of 10/10 HLA-matched unrelated donor. The donor and recipient must be identical by the following genetic loci: HLA-A, HLA-B, HLA-Cw, HLA-DRB1, and HLA-DQB1. Mismatches in these loci were not allowed. Also only patients were included in whom the donor agreed to donate peripheral blood stem cells (PBSC). The exclusion criteria were the presence of severe concurrent illness, prior history of anaphylaxis to thymoglobulin, moderate or severe cardiac dysfunction, left ventricular ejection fraction <50%, moderate or severe decrease in pulmonary function, FEV1 <70% or DLCO <70% of predicted, respiratory distress at least grade I, severe organ dysfunction: AST or ALT >5 upper normal limits, bilirubin >1.5 upper normal limits, creatinine >2 upper normal limits, creatinine clearance <60 mL/min., uncontrolled bacterial or fungal infection at the time of enrollment, requirement for vasopressor support at the time of enrollment, Karnofsky index <30%, pregnancy, and somatic or psychiatric disorder making the patient unable to sign informed consent. The study during 2015-2019 has enrolled 33 patients: 16 in the thymoglobulin arm and 17 in the PTCY arm. The study was terminated prematurely due to poor recruitment. All recruited patients were included in the analysis. The study group was well balanced with no significant differences in characteristics of patients (Table 1).

Table 1. Characteristics of patients

CML = chronic myeloid leukemia, MDS = myelodysplastic syndrome, MPN = myeloproliferative neoplasm, CP = chronic phase, AP = acceleration phase, BC = blast crisis, AEB – access blasts, MLD – multileaneage dysplasia.

Study procedures

All patients received conditioning with fludarabine 180 mg/m² over 6 days and oral busulfan 10 mg/kg over 3 days. Patients in the thymoglobulin group received GvHD prophylaxis with thymoglobulin 2.5 mg/kg on days -3 and -2, tacrolimus 0.03 mg/kg/day starting day -1 with target concentration 5-15 ng/ml and mycophenolate mofetil (MMF) 30 mg/kg/day starting. The MMF was continued until day +30. Tacrolimus was continued until day +100 and gradually tapered over 1 month in absence of GvHD. Steroids were used in this group as the pre-medication to thymoglobulin and graft infusion. In the PTCy group patients received cyclophosphamide 50 mg/kg on days +3 and +4. Mesna 50 mg/kg was administered as 24-hour infusion on the days of cyclophosphamide administration. MMF 30 mg/kg/day was started on day +5 and continued until day +35. Tacrolimus 0.03 mg/kg/day was started on day +5 with target concentration 5-15 ng/ml. Tacrolimus in this arm was in the same way continued until day +100 and gradually tapered over 1 month in absence of GvHD. Use of steroids was prohibited from day-5 to day+5. The rest of the supportive care was the same in both arms. The standard antifungal prophylaxis was fluconazole starting on day 0 and continued until engraftment.

Clinical outcomes

Time to disease relapse, acute GvHD (GvHD), moderate to severe chronic GvHD (cGvHD), non-relapse mortality (NRM), overall survival (OS), event-free survival (EFS), and GvHD-relapse free survival (GRFS) were defined as the time from transplantation to the event. Incidence of aGvHD was calculated at 125 days after HSCT, and the time frame for the other outcomes was free years. Events for EFS were relapse or death. Events for GRFS were either death, relapse, grades III-IV acute GvHD or systemic therapy-requiring chronic GvHD [12]. Patients were censored at the time of last contact or a second transplantation for all outcomes. Disease relapse was defined as morphologic or cytogenetic evidence of disease with pre-transplantation characteristics. Disease staging, including bone marrow biopsies, was routinely performed on days +30,+60,+100, +180, +365 post-transplant. The Consensus Conference criteria and National Institutes of Health criteria were used for aGvHD and cGvHD grading [13, 14]. Primary graft failure was defined as the complete absence of donor chimerism in bone marrow biopsy by day +40. Time to engraftment was calculated as time from HSCT to unsupported neutrophil count > 500/µl and white blood cell count >1000/µl for 3 consecutive days. Toxicity was assessed with CTCAE ver. 4.03. Sepsis and severe sepsis were diagnosed based on International Guidelines for Management of Severe Sepsis and Septic Shock [15]. Invasive mycosis was diagnosed in case of probable or proven infection according to EORTC/MSG guidelines [16]. The threshold for cytomegalovirus (CMV) reactivation was >500 copies/ml. Clinically significant CMV reactivation was defined as >10000 copies/mL. Veno-occlusive disease was diagnosed and graded based on EBMT criteria [17].

Statistical evaluation

The study primary endpoint was the incidence of primary graft failure. The study was planned to enroll 60 patients, 30 patients in each arm. With the study group size was calculated with 30% margin, 0.65 study power and 0.05 significance using Fisher’s criterion. Secondary endpoints were incidence of acute grade II-IV acute GvHD, incidence moderate and severe chronic GvHD, non-relapse mortality, OS, EFS, GFRS, relapse incidence, toxicity and infectious complications. The strata for randomization was a pretransplant assessment of mortality (PAM) score [18]. The stratification was performed using Mann-Whitney U-criterion to achieve the minimal differences in PAM between the study groups. The final median PAM values were 14.1 (range 7.8-25.2) and 14.1 (6.9-21.9) in the thymoglobulin and PTCY groups, respectively (p=0.98).

Comparison of patient characteristics was performed by Mann-Whitney test. The survival distributions for OS, EFS, GRFS were calculated using Kaplan-Meier methodology. The comparisons were made using the log-rank test. Cumulative incidence analysis with competing risks for aGvHD, cGvHD, relapse incidence and NRM was performed using Gray test. Relapse and NRM were accounted as competing risks. Incidence and severity of complications was compared using Chi-square and Mann-Whitney test. Analyses were conducted in SAS 9.3 (SAS Institute, Inc.).

Results

Median follow up in the study was 29 months (range 7-48). There was no difference in the incidence of primary graft failure: 12.50% (95%CI 2%-38%) in the thymoglobulin arm and 11.8% (95%CI 1%-36%) in the PTCY arm, p=0.95. Three out of four patients with primary graft failure died, one was salvaged with second transplantation. All patients without primary graft failure survived to the day of engraftment. Median time to neutrophil engraftment was longer in the PTCY group: 20 (16-33) vs 16 (11-30) days, p=0.0017. Time to white blood cell engraftment was also significantly longer: 21 (16-33) vs 15 (11-30) days, p=0.0016. No differences were observed in the time to platelet engraftment: median 12 (8-40) vs 15 (11-45) days, p=0.1482.

Acute GvHD grade II-IV was documented in 3 (23%) patients in the thymoglobulin group and 1 (6%) patients in the PTCY group (p=0.20). No cases of acute GvHD grade III-IV were documented. Moderate and severe chronic GvHD was diagnosed in 3 (23%) patient after thymoglobulin and 4 (25%) patients after PTCY (p=0.41). Median time to chronic GvHD was a little shorter after thymoglobulin (5.5 months) compared to PTCY (15 months), p=0.11. One patient in thymoglobulin and 2 patients in the PTCY group had mild chronic GvHD.

Patients after PTCY prophylaxis had significantly better outcomes of transplantation. 4-year OS was 82% (95%CI 55-94%) vs 30% (95%CI 6-59%), p=0.0126; EFS was 61% (95%CI 31-81%) vs 26% (95%CI 5-54%), p=0.0335, GFRS 61% 95%CI (31-81%) vs 16% (95%CI 1-46%), p=0.0072 (Figure 1). There was a comparable incidence of relapse between the groups (25% vs 29%, p=0.77), but significantly reduced non-relapse mortality in the PTCY group (6% vs 38%, p=0.0264), which was main cause of the differences in survival outcomes. Primary graft failure and infectious complications were the only causes of non-relapse mortality in the study groups.

Figure 1. Overall (A), event-free (B) and GvHD-relapse-free (C) survival. The percentages shown are 4-year Kaplan-Mayer estimates

No unexpected toxicity was observed during the study. There was no significant difference in the incidence of early complications (Table 2). No cases of neurotoxicity or veno-occlusive disease were documented during the study. The infusion reactions in the thymoglobulin group were allergic reactions and in the PTCY group – one case of cystalgia.

Table 2. Toxicity and complications observed in ATG and PTCY groups

Note: TA-TMA = transplant-associated microangiopathy. Infusion reaction is defined as any reaction during or immediately after infusion that required change in the systemic therapy

Discussion

The study was originally developed to demonstrate if there is a difference in primary graft failure after PTCY. Despite it was terminated prematurely due to poor recruitment, several approximations could be made. We have observed identical number of graft failures in the thymoglobulin and PTCY group. According to CIBMTR data the average number of primary graft failure is 5.5% and CML and MDS patients have the double risk. So the incidence in the current study was not only the same between groups, but almost identical to the one reported by large registry studies [6]. So it is likely that there is no impact of PTCY on the incidence of primary graft failure. On the other hand, we have not observed any positive impact of PTCY on engraftment in this patient population despite previous preclinical data [19]. Unlike primary graft failure engraftment of neutrophils is delayed by several days which in concordance with previously published data [7].

The study was not powered to capture the significance and survival and recruitment was not completed, but most striking results were obtained in terms of survival outcomes. PTCY prophylaxis was associated with significantly higher incidence of OS, EFS and GRFS. The differences were due to reduced non-relapse mortality, it was only 6% in the PTCY group. These extremely low incidence of NRM was recently confirmed in the retrospective [7] and prospective randomized [20] studies. Despite the situation in haploidentical transplantation where PTCY reduces mortality through more effective prevention of acute and chronic GvHD [8], here we observed identical incidence of both acute and chronic GvHD, but the difference was due to late severe bacterial infections. In this study 5 mg/kg dose of thymoglobulin was used which is reported to cause less profound immunosuppression and promote graft-versus-leukemia effect [21, 22]. However the population of MDS and MPN patients is different from acute leukemia. There is a significant iron overload, which may increase the risk of infections after SCT and thymoglobulin effects might overlap with these negative impacts of iron overload [23]. Otherwise this might be an indication of better immunological recovery after unrelated transplantation with PTCY. Additional studies are required to confirm these assumptions.

Conclusion

Despite incomplete recruitment, this study provides some evidence on the use of PTCY-based prophylaxis for unrelated transplantations in patients with CML, MDS and MPN. The study has demonstrated that there is likely no impact of PTCY on the incidence of primary graft failure. Also it creates the basis for future studies to evaluate survival and immunological recovery in this patient population.

Conflict of interest

No conflict of interest reported.

References

1. Passweg JR, Baldomero H, Bader P, Basak GW, Bonini C, Duarte R et al. Is the use of unrelated donor transplantation leveling off in Europe? The 2016 European Society for Blood and Marrow Transplant activity survey report. Bone Marrow Transplant. 2018;53(9):1139-1148.
2. Radujkovic A, Dietrich S, Blok HJ, Nagler A, Ayuk F, Finke J et al. Allogeneic Stem Cell Transplantation for Blast Crisis Chronic Myeloid Leukemia in the Era of Tyrosine Kinase Inhibitors: A Retrospective Study by the EBMT Chronic Malignancies Working Party. Biol Blood Marrow Transplant. 2019;25(10):2008-2016.
3. Carré M, Porcher R, Finke J, Ehninger G, Koster L, Beelen D et al. Role of age and hematopoietic cell transplantation-specific comorbidity index in myelodysplastic patients undergoing an allotransplant. A retrospective study from the CMWP (Chronic Malignancies Working Party) of the EBMT. Biol Blood Marrow Transplant. 2019 Oct 21. pii: S1083-8791(19)30672-X. doi: 10.1016/j.bbmt.2019.10.015.
4. Onida F, de Wreede LC, van Biezen A, Eikema DJ, Byrne JL, Iori AP et al. Allogeneic stem cell transplantation in patients with atypical chronic myeloid leukaemia: a retrospective study from the Chronic Malignancies Working Party of the European Society for Blood and Marrow Transplantation. Br J Haematol. 2017;177(5):759-765.
5. Sharma P, Shinde SS, Damlaj M, Hefazi Rorghabeh M, Hashmi SK, Litzow MR et al. Allogeneic hematopoietic stem cell transplant in adult patients with myelodysplastic syndrome/myeloproliferative neoplasm (MDS/MPN) overlap syndromes. Leuk Lymphoma. 2017;58(4):872-881.
6. Olsson RF, Logan BR, Chaudhury S, Zhu X, Akpek G, Bolwell BJ et al. Primary graft failure after myeloablative allogeneic hematopoietic cell transplantation for hematologic malignancies. Leukemia. 2015;29(8):1754-62.
7. Battipaglia G, Labopin M, Kröger N, Vitek A, Afanasyev B, Hilgendorf I et al. Posttransplant cyclophosphamide vs antithymocyte globulin in HLA-mismatched unrelated donor transplantation. Blood. 2019;134(11):892-899.
8. Piemontese S, Ciceri F, Labopin M, Bacigalupo A, Huang H, Santarone S et al. A survey on unmanipulated haploidentical hematopoietic stem cell transplantation in adults with acute leukemia. Leukemia. 2015;29(5):1069-75.
9. Brissot E, Labopin M, Ehninger G, Stelljes M, Brecht A, Ganser A et al. Haploidentical versus unrelated allogeneic stem cell transplantation for relapsed/refractory acute myeloid leukemia: a report on 1578 patients from the Acute Leukemia Working Party of the EBMT. Haematologica. 2019;104(3):524-532.
10. Shah MV, Saliba RM, Rondon G, Chen J, Soebbing D, Rus I et al. Pilot study using post-transplant cyclophosphamide (PTCy), tacrolimus and mycophenolate GvHD prophylaxis for older patients receiving 10/10 HLA-matched unrelated donor hematopoietic stem cell transplantation. Bone Marrow Transplant. 2019;54(4):601-606.
11. Ayuk F, Beelen DW, Bornhäuser M, Stelljes M, Zabelina T, Finke J et al. Relative Impact of HLA Matching and Non-HLA Donor Characteristics on Outcomes of Allogeneic Stem Cell Transplantation for Acute Myeloid Leukemia and Myelodysplastic Syndrome. Biol Blood Marrow Transplant. 2018;24(12):2558-2567.
12. Holtan SG, DeFor TE, Lazaryan A, Bejanyan N, Arora M, Brunstein CG et al. Composite end point of graft-versus-host disease-free, relapse-free survival after allogeneic hematopoietic cell transplantation. Blood. 2015;125(8):1333-1338.
13. Przepiorka D1, Weisdorf D, Martin P, Klingemann HG, Beatty P, Hows J, Thomas ED. 1994 Consensus Conference on Acute GvHD Grading. Bone Marrow Transplant. 1995;15:825-828.
14. Filipovich AH, Weisdorf D, Pavletic S, Socie G, Wingard JR, Lee SJ et al. National Institutes of Health consensus development project on criteria for clinical trials in chronic graft-versus-host disease: I. Diagnosis and staging working group report. Biol Blood Marrow Transplant. 2005;11:945-956.
15. Dellinger RP, Levy MM, Rhodes A, Annane D, Gerlach H, Opal SM et al. Surviving Sepsis Campaign: international guidelines for management of severe sepsis and septic shock, 2012. Intensive Care Med. 2013;39(2):165-228.
16. De Pauw B, Walsh TJ, Donnelly JP, Stevens DA, Edwards JE, Calandra T et al. Revised definitions of invasive fungal disease from the European Organization for Research and Treatment of Cancer/Invasive Fungal Infections Cooperative Group and the National Institute of Allergy and Infectious Diseases Mycoses Study Group (EORTC/MSG) Consensus Group. Clin Infect Dis. 2008;46(12):1813-1821.
17. Mohty M, Malard F, Abecassis M, Aerts E, Alaskar AS, Aljurf M et al. Sinusoidal obstruction syndrome/veno-occlusive disease: current situation and perspectives – a position statement from the European Society for Blood and Marrow Transplantation (EBMT). Bone Marrow Transplant. 2015;50(6):781-789.
19. Parimon T, Au DH, Martin PJ, Chien JW. A risk score for mortality after allogeneic hematopoietic cell transplantation. Ann Intern Med. 2006;144(6):407-414. Luznik L, O'Donnell PV, Fuchs EJ. Post-transplantation cyclophosphamide for tolerance induction in HLA-haploidentical bone marrow transplantation. Semin Oncol. 2012;39(6):683-693.
20. Bolaños-Meade J, Reshef R, Fraser R, Fei M, Abhyankar S, Al-Kadhimi Z et al. Three prophylaxis regimens (tacrolimus, mycophenolate mofetil, and cyclophosphamide; tacrolimus, methotrexate, and bortezomib; or tacrolimus, methotrexate, and maraviroc) versus tacrolimus and methotrexate for prevention of graft-versus-host disease with haemopoietic cell transplantation with reduced-intensity conditioning: a randomised phase 2 trial with a non-randomised contemporaneous control group (BMT CTN 1203). Lancet Haematol. 2019;6(3):e132-e143.
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22. Kennedy VE, Chen H, Savani BN, Greer J, Kassim AA, Engelhardt BG et al. Optimizing Antithymocyte Globulin Dosing for Unrelated Donor Allogeneic Hematopoietic Cell Transplantation Based on Recipient Absolute Lymphocyte Count. Biol Blood Marrow Transplant. 2018;24(1):150-155.
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Тем не менее, большинство этих публикаций включают только пациентов с острыми лейкозами. Данные о возможности применения ПТЦФ при хроническом миелолейкозе (ХМЛ), миелодиспластическом синдроме (МДС) и хронических миелопролиферативных заболеваниях (ХМПЗ) практически отсутствуют, поэтому в данной популяции пациентов было инициировано проспективное рандомизированное сравнение тимоглобулина и ПТЦФ в профилактики РТПХ при 10/10- HLA совместимой неродственной трансплантации (NCT02627573, clinicaltrials.gov). Стратой для рандомизации был индекс pretransplant assessment of mortality. Исследование было прекращено преждевременно в связи с медленным набором пациентов, тем не менее, за время исследования было включено 33 пациента, 16 пациентов в группу тимоглобулина и 17 пациентов в группу ПТЦФ. Медиана наблюдения составила 29 месяцев. Не было выявлено различий ни в частоте первичного неприживления трансплантата (12,50% против 11,8%, p=0,9), ни острой РТПХ II-IV степени (23% <i>vs</i> 6%, p=0,2), ни хронической РТПХ средней и тяжелой степени (25% <i>vs</i> 23%, p=0,4) в группах тимоглобулина и ПТЦФ, соответственно. Однако, было в группе ПТЦФ наблюдалась достоверно лучшая общая (82% <i>vs</i> 30%, p=0,0126) и бессобытийная (61% <i>vs</i> 26%, p=0,0335) выживаемость, а также выживаемость без рецидива и РТПХ (61% <i>vs</i> 16%, p=0,0072). Различия были связаны с поздней инфекционной летальностью. Никак достоверных различий в токсичности 2 режимов выявлено не было. Подводя итоги, данное исследование дает обоснование для применения ПТЦФ при неродственных трансплантациях у пациентов с ХМЛ и МДС. 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Морозова, Иван С. Моисеев, Юлия Ю. Власова, Николай Ю. Цветков, Юлия В. Рудницкая, Мария В. Барабанщикова, Анна Г. Смирнова, Елена И. Дарская, Сергей Н. Бондаренко, <span style="border: 1px solid black; margin: 0; padding: 2px 2px;">Борис В. Афанасьев</span></p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(418) "

Елена В. Морозова, Иван С. Моисеев, Юлия Ю. Власова, Николай Ю. Цветков, Юлия В. Рудницкая, Мария В. Барабанщикова, Анна Г. Смирнова, Елена И. Дарская, Сергей Н. Бондаренко, Борис В. Афанасьев

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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"]=> 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) "26388" ["VALUE"]=> array(2) { ["TEXT"]=> string(3984) "<p style="text-align: justify;">В настоящий момент отмечается рост числа публикаций по поводу использования посттрансплантационного циклофосфана (ПТЦФ) в профилактике реакции «трансплантат против хозяина» при неродственной трансплантации гемопоэтических стволовых клеток. Тем не менее, большинство этих публикаций включают только пациентов с острыми лейкозами. Данные о возможности применения ПТЦФ при хроническом миелолейкозе (ХМЛ), миелодиспластическом синдроме (МДС) и хронических миелопролиферативных заболеваниях (ХМПЗ) практически отсутствуют, поэтому в данной популяции пациентов было инициировано проспективное рандомизированное сравнение тимоглобулина и ПТЦФ в профилактики РТПХ при 10/10- HLA совместимой неродственной трансплантации (NCT02627573, clinicaltrials.gov). Стратой для рандомизации был индекс pretransplant assessment of mortality. Исследование было прекращено преждевременно в связи с медленным набором пациентов, тем не менее, за время исследования было включено 33 пациента, 16 пациентов в группу тимоглобулина и 17 пациентов в группу ПТЦФ. Медиана наблюдения составила 29 месяцев. Не было выявлено различий ни в частоте первичного неприживления трансплантата (12,50% против 11,8%, p=0,9), ни острой РТПХ II-IV степени (23% <i>vs</i> 6%, p=0,2), ни хронической РТПХ средней и тяжелой степени (25% <i>vs</i> 23%, p=0,4) в группах тимоглобулина и ПТЦФ, соответственно. Однако, было в группе ПТЦФ наблюдалась достоверно лучшая общая (82% <i>vs</i> 30%, p=0,0126) и бессобытийная (61% <i>vs</i> 26%, p=0,0335) выживаемость, а также выживаемость без рецидива и РТПХ (61% <i>vs</i> 16%, p=0,0072). Различия были связаны с поздней инфекционной летальностью. Никак достоверных различий в токсичности 2 режимов выявлено не было. Подводя итоги, данное исследование дает обоснование для применения ПТЦФ при неродственных трансплантациях у пациентов с ХМЛ и МДС. Требуются дальнейшие исследования для подтверждения преимущества ПТЦФ над классической профилактикой с тимоглобулином. </p> <h2>Ключевые слова</h2> <p style="text-align: justify;"> Посттрансплантационный циклофосфан, миелодиспластический синдром, хронический миелоидный лейкоз, хроническая миелопролиферативная неоплазия, совместимый неродственный донор. </p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(3868) "

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Ключевые слова

Посттрансплантационный циклофосфан, миелодиспластический синдром, хронический миелоидный лейкоз, хроническая миелопролиферативная неоплазия, совместимый неродственный донор.

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Elena V. Morozova, Ivan S. Moiseev, Yulia Yu. Vlasova, Nikolay Yu. Tcvetkov, Yulia V. Rudnitskaya, Maria V. Barabanschikova, Anna G. Smirnova, Elena I. Darskaya, Sergey N. Bondarenko, Boris V. Afanasyev

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Raisa Gorbacheva Memorial Research Institute of Pediatric Oncology, Hematology and Transplantation, Pavlov University,
St. Petersburg, Russia

Correspondence
Dr. Elena V. Morozova, PhD, Raisa Gorbacheva Memorial Research Institute of Pediatric Oncology, Hematology and Transplantation, Pavlov University, L. Tolstoy St. 6-8, 197022, St. Petersburg, Russia
Phone: +7 (911) 927 8229
E-mail: dr_morozova@mail.ru

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Despite growing evidence on the use of posttransplantation cyclophosphamide (PTCY) in matched unrelated transplantation in acute leukemia patients, prospective evidence to support this type of prophylaxis in myelodysplastic syndrome (MDS), chronic myeloproliferative neoplasms and chronic myeloid leukemia (CML) patients is lacking. In this patient population we conducted a prospective randomized study of PTCY vs thymoglobulin for graft-versus-host disease (GvHD) prophylaxis in the setting of 10/10 HLA-matched unrelated transplantation (NCT02627573, clinicaltrials.gov). The strata for randomization was pretransplant assessment of mortality score. The study was terminated prematurely due to poor recruitment, but 33 patients were enrolled, 17 in the PTCY and 16 in the thymoglobulin group. Median follow up was 29 months. There was no difference between groups in the incidence primary graft failure (12.50% vs 11.8%, p=0.9), acute GvHD grade II-IV (23% vs 6%, p=0.2), moderate and severe chronic GvHD (25% vs 23%, p=0.4) in the thymoglobulin and PTCY arms, respectively. However there was a significantly higher overall survival (82% vs 30%, p=0.0126), event-free survival (61% vs 26%, p=0.0335), and GvHD-relapse free survival (61% vs 16%, p=0.0072) in the PTCY group due to reduced late infection-related mortality. No differences was observed in terms of toxicity. In conclusion, despite incomplete recruitment, the study created the basis for the use of PTCY in unrelated transplantations from fully matched unrelated donors in CML and MDS. Future studies are required to confirm if there is a benefit of PTCY-based prophylaxis over thymoglobulin.

Keywords

Posttransplant cyclophosphamide, myelodysplastic syndrome, chronic myeloid leukemia, chronic myeloproliferative neoplasm, matched unrelated donor.

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Morozova, Ivan S. Moiseev, Yulia Yu. Vlasova, Nikolay Yu. Tcvetkov, Yulia V. Rudnitskaya, Maria V. Barabanschikova, Anna G. Smirnova, Elena I. Darskaya, Sergey N. Bondarenko, <span style="border: 1px solid black; margin: 0; padding: 2px 2px;">Boris V. Afanasyev</span> </p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(286) "

Elena V. Morozova, Ivan S. Moiseev, Yulia Yu. Vlasova, Nikolay Yu. Tcvetkov, Yulia V. Rudnitskaya, Maria V. Barabanschikova, Anna G. Smirnova, Elena I. Darskaya, Sergey N. Bondarenko, Boris V. Afanasyev

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Elena V. Morozova, Ivan S. Moiseev, Yulia Yu. Vlasova, Nikolay Yu. Tcvetkov, Yulia V. Rudnitskaya, Maria V. Barabanschikova, Anna G. Smirnova, Elena I. Darskaya, Sergey N. Bondarenko, Boris V. Afanasyev

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Despite growing evidence on the use of posttransplantation cyclophosphamide (PTCY) in matched unrelated transplantation in acute leukemia patients, prospective evidence to support this type of prophylaxis in myelodysplastic syndrome (MDS), chronic myeloproliferative neoplasms and chronic myeloid leukemia (CML) patients is lacking. In this patient population we conducted a prospective randomized study of PTCY vs thymoglobulin for graft-versus-host disease (GvHD) prophylaxis in the setting of 10/10 HLA-matched unrelated transplantation (NCT02627573, clinicaltrials.gov). The strata for randomization was pretransplant assessment of mortality score. The study was terminated prematurely due to poor recruitment, but 33 patients were enrolled, 17 in the PTCY and 16 in the thymoglobulin group. Median follow up was 29 months. There was no difference between groups in the incidence primary graft failure (12.50% vs 11.8%, p=0.9), acute GvHD grade II-IV (23% vs 6%, p=0.2), moderate and severe chronic GvHD (25% vs 23%, p=0.4) in the thymoglobulin and PTCY arms, respectively. However there was a significantly higher overall survival (82% vs 30%, p=0.0126), event-free survival (61% vs 26%, p=0.0335), and GvHD-relapse free survival (61% vs 16%, p=0.0072) in the PTCY group due to reduced late infection-related mortality. No differences was observed in terms of toxicity. In conclusion, despite incomplete recruitment, the study created the basis for the use of PTCY in unrelated transplantations from fully matched unrelated donors in CML and MDS. Future studies are required to confirm if there is a benefit of PTCY-based prophylaxis over thymoglobulin.

Keywords

Posttransplant cyclophosphamide, myelodysplastic syndrome, chronic myeloid leukemia, chronic myeloproliferative neoplasm, matched unrelated donor.

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Despite growing evidence on the use of posttransplantation cyclophosphamide (PTCY) in matched unrelated transplantation in acute leukemia patients, prospective evidence to support this type of prophylaxis in myelodysplastic syndrome (MDS), chronic myeloproliferative neoplasms and chronic myeloid leukemia (CML) patients is lacking. In this patient population we conducted a prospective randomized study of PTCY vs thymoglobulin for graft-versus-host disease (GvHD) prophylaxis in the setting of 10/10 HLA-matched unrelated transplantation (NCT02627573, clinicaltrials.gov). The strata for randomization was pretransplant assessment of mortality score. The study was terminated prematurely due to poor recruitment, but 33 patients were enrolled, 17 in the PTCY and 16 in the thymoglobulin group. Median follow up was 29 months. There was no difference between groups in the incidence primary graft failure (12.50% vs 11.8%, p=0.9), acute GvHD grade II-IV (23% vs 6%, p=0.2), moderate and severe chronic GvHD (25% vs 23%, p=0.4) in the thymoglobulin and PTCY arms, respectively. However there was a significantly higher overall survival (82% vs 30%, p=0.0126), event-free survival (61% vs 26%, p=0.0335), and GvHD-relapse free survival (61% vs 16%, p=0.0072) in the PTCY group due to reduced late infection-related mortality. No differences was observed in terms of toxicity. In conclusion, despite incomplete recruitment, the study created the basis for the use of PTCY in unrelated transplantations from fully matched unrelated donors in CML and MDS. Future studies are required to confirm if there is a benefit of PTCY-based prophylaxis over thymoglobulin.

Keywords

Posttransplant cyclophosphamide, myelodysplastic syndrome, chronic myeloid leukemia, chronic myeloproliferative neoplasm, matched unrelated donor.

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Raisa Gorbacheva Memorial Research Institute of Pediatric Oncology, Hematology and Transplantation, Pavlov University,
St. Petersburg, Russia

Correspondence
Dr. Elena V. Morozova, PhD, Raisa Gorbacheva Memorial Research Institute of Pediatric Oncology, Hematology and Transplantation, Pavlov University, L. Tolstoy St. 6-8, 197022, St. Petersburg, Russia
Phone: +7 (911) 927 8229
E-mail: dr_morozova@mail.ru

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Raisa Gorbacheva Memorial Research Institute of Pediatric Oncology, Hematology and Transplantation, Pavlov University,
St. Petersburg, Russia

Correspondence
Dr. Elena V. Morozova, PhD, Raisa Gorbacheva Memorial Research Institute of Pediatric Oncology, Hematology and Transplantation, Pavlov University, L. Tolstoy St. 6-8, 197022, St. Petersburg, Russia
Phone: +7 (911) 927 8229
E-mail: dr_morozova@mail.ru

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Елена В. Морозова, Иван С. Моисеев, Юлия Ю. Власова, Николай Ю. Цветков, Юлия В. Рудницкая, Мария В. Барабанщикова, Анна Г. Смирнова, Елена И. Дарская, Сергей Н. Бондаренко, Борис В. Афанасьев

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Елена В. Морозова, Иван С. Моисеев, Юлия Ю. Власова, Николай Ю. Цветков, Юлия В. Рудницкая, Мария В. Барабанщикова, Анна Г. Смирнова, Елена И. Дарская, Сергей Н. Бондаренко, Борис В. Афанасьев

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Тем не менее, большинство этих публикаций включают только пациентов с острыми лейкозами. Данные о возможности применения ПТЦФ при хроническом миелолейкозе (ХМЛ), миелодиспластическом синдроме (МДС) и хронических миелопролиферативных заболеваниях (ХМПЗ) практически отсутствуют, поэтому в данной популяции пациентов было инициировано проспективное рандомизированное сравнение тимоглобулина и ПТЦФ в профилактики РТПХ при 10/10- HLA совместимой неродственной трансплантации (NCT02627573, clinicaltrials.gov). Стратой для рандомизации был индекс pretransplant assessment of mortality. Исследование было прекращено преждевременно в связи с медленным набором пациентов, тем не менее, за время исследования было включено 33 пациента, 16 пациентов в группу тимоглобулина и 17 пациентов в группу ПТЦФ. Медиана наблюдения составила 29 месяцев. Не было выявлено различий ни в частоте первичного неприживления трансплантата (12,50% против 11,8%, p=0,9), ни острой РТПХ II-IV степени (23% <i>vs</i> 6%, p=0,2), ни хронической РТПХ средней и тяжелой степени (25% <i>vs</i> 23%, p=0,4) в группах тимоглобулина и ПТЦФ, соответственно. Однако, было в группе ПТЦФ наблюдалась достоверно лучшая общая (82% <i>vs</i> 30%, p=0,0126) и бессобытийная (61% <i>vs</i> 26%, p=0,0335) выживаемость, а также выживаемость без рецидива и РТПХ (61% <i>vs</i> 16%, p=0,0072). Различия были связаны с поздней инфекционной летальностью. Никак достоверных различий в токсичности 2 режимов выявлено не было. Подводя итоги, данное исследование дает обоснование для применения ПТЦФ при неродственных трансплантациях у пациентов с ХМЛ и МДС. Требуются дальнейшие исследования для подтверждения преимущества ПТЦФ над классической профилактикой с тимоглобулином. </p> <h2>Ключевые слова</h2> <p style="text-align: justify;"> Посттрансплантационный циклофосфан, миелодиспластический синдром, хронический миелоидный лейкоз, хроническая миелопролиферативная неоплазия, совместимый неродственный донор. </p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(3868) "

В настоящий момент отмечается рост числа публикаций по поводу использования посттрансплантационного циклофосфана (ПТЦФ) в профилактике реакции «трансплантат против хозяина» при неродственной трансплантации гемопоэтических стволовых клеток. Тем не менее, большинство этих публикаций включают только пациентов с острыми лейкозами. Данные о возможности применения ПТЦФ при хроническом миелолейкозе (ХМЛ), миелодиспластическом синдроме (МДС) и хронических миелопролиферативных заболеваниях (ХМПЗ) практически отсутствуют, поэтому в данной популяции пациентов было инициировано проспективное рандомизированное сравнение тимоглобулина и ПТЦФ в профилактики РТПХ при 10/10- HLA совместимой неродственной трансплантации (NCT02627573, clinicaltrials.gov). Стратой для рандомизации был индекс pretransplant assessment of mortality. Исследование было прекращено преждевременно в связи с медленным набором пациентов, тем не менее, за время исследования было включено 33 пациента, 16 пациентов в группу тимоглобулина и 17 пациентов в группу ПТЦФ. Медиана наблюдения составила 29 месяцев. Не было выявлено различий ни в частоте первичного неприживления трансплантата (12,50% против 11,8%, p=0,9), ни острой РТПХ II-IV степени (23% vs 6%, p=0,2), ни хронической РТПХ средней и тяжелой степени (25% vs 23%, p=0,4) в группах тимоглобулина и ПТЦФ, соответственно. Однако, было в группе ПТЦФ наблюдалась достоверно лучшая общая (82% vs 30%, p=0,0126) и бессобытийная (61% vs 26%, p=0,0335) выживаемость, а также выживаемость без рецидива и РТПХ (61% vs 16%, p=0,0072). Различия были связаны с поздней инфекционной летальностью. Никак достоверных различий в токсичности 2 режимов выявлено не было. Подводя итоги, данное исследование дает обоснование для применения ПТЦФ при неродственных трансплантациях у пациентов с ХМЛ и МДС. Требуются дальнейшие исследования для подтверждения преимущества ПТЦФ над классической профилактикой с тимоглобулином.

Ключевые слова

Посттрансплантационный циклофосфан, миелодиспластический синдром, хронический миелоидный лейкоз, хроническая миелопролиферативная неоплазия, совместимый неродственный донор.

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В настоящий момент отмечается рост числа публикаций по поводу использования посттрансплантационного циклофосфана (ПТЦФ) в профилактике реакции «трансплантат против хозяина» при неродственной трансплантации гемопоэтических стволовых клеток. Тем не менее, большинство этих публикаций включают только пациентов с острыми лейкозами. Данные о возможности применения ПТЦФ при хроническом миелолейкозе (ХМЛ), миелодиспластическом синдроме (МДС) и хронических миелопролиферативных заболеваниях (ХМПЗ) практически отсутствуют, поэтому в данной популяции пациентов было инициировано проспективное рандомизированное сравнение тимоглобулина и ПТЦФ в профилактики РТПХ при 10/10- HLA совместимой неродственной трансплантации (NCT02627573, clinicaltrials.gov). Стратой для рандомизации был индекс pretransplant assessment of mortality. Исследование было прекращено преждевременно в связи с медленным набором пациентов, тем не менее, за время исследования было включено 33 пациента, 16 пациентов в группу тимоглобулина и 17 пациентов в группу ПТЦФ. Медиана наблюдения составила 29 месяцев. Не было выявлено различий ни в частоте первичного неприживления трансплантата (12,50% против 11,8%, p=0,9), ни острой РТПХ II-IV степени (23% vs 6%, p=0,2), ни хронической РТПХ средней и тяжелой степени (25% vs 23%, p=0,4) в группах тимоглобулина и ПТЦФ, соответственно. Однако, было в группе ПТЦФ наблюдалась достоверно лучшая общая (82% vs 30%, p=0,0126) и бессобытийная (61% vs 26%, p=0,0335) выживаемость, а также выживаемость без рецидива и РТПХ (61% vs 16%, p=0,0072). Различия были связаны с поздней инфекционной летальностью. Никак достоверных различий в токсичности 2 режимов выявлено не было. Подводя итоги, данное исследование дает обоснование для применения ПТЦФ при неродственных трансплантациях у пациентов с ХМЛ и МДС. Требуются дальнейшие исследования для подтверждения преимущества ПТЦФ над классической профилактикой с тимоглобулином.

Ключевые слова

Посттрансплантационный циклофосфан, миелодиспластический синдром, хронический миелоидный лейкоз, хроническая миелопролиферативная неоплазия, совместимый неродственный донор.

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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

Hemorrhagic cystitis (HC) is a frequent complication in allogeneic hematopoietic stem cell transplantation (allo-HSCT) with incidence of 9% to 31% for different cohorts [1-7]. Early clinical form of HC usually develops within ten days post allo-HSCT. In this cases HC is considered a direct consequence of cytotoxic conditioning therapy and graft-versus-host disease (GvHD) prophylaxis [8]. Along with cytotoxic drugs, some viral agents, e.g., BK- and JC- polyomaviruses, adenovirus and cytomegalovirus may be also involved in HC pathogenesis. Among them, human BK-polyomavirus (BKPyV) is the most frequently activated virus in urological setting, and, therefore, its elimination is a primary aim in HC treatment [8-12].

Some preclinical evidence for intravenous immunoglobulin (IVIG) effectiveness was reported earlier. Parmjeet S Randhawa et al. have demonstrated an ability of commercially available IVIG to neutralize BKPyV in human and mice cell cultures [13]. E.g., a 5-gram IVIG volume (one standard bottle) was able to inactivate 1.9*106 BKPyV/mL of plasma in 5.000 ml of blood, thus roughly corresponding to mean circulating blood volume in adults. It was, therefore, supposed that these preparations contain sufficient amounts of BKPyV-specific antibodies to neutralize clinically significant viral loads.

There is also some clinical evidence of IVIG effectiveness in BK virus nephropathy following renal transplantation. The latter condition has much common in origin with HC post allo-HSCT since it also occurs in immunocompromised host with preexisting urinary system lesions. The current treatment approaches for BKPyV nephropathy are immunosuppression reduction and IVIG administration at a total dose of 2 g/kg over 2-5 consecutive days [14, 15].

No standard strategy is, however, developed for HC treatment after allo-HSCT, as all the published data on IVIG treatment in these settings are limited to several case reports [16]. Despite the lack of available data, IVIG may be regarded as a feasible option based on its favorable safety profile and potential clinical efficiency [6].

It is even more notable, since some other established treatment options, e.g. intravenous Cidofovir infusions (CII evidence level) are, besides being potentially nephrotoxic, not currently available in Russian Federation. Meanwhile, the IVIG efficiency in HC has not been previously evaluated, although it is routinely used in our practice.

The current study is, therefore, aimed at evaluating the efficiency of IVIG infusions in HC patients after allo-HSCT, taking into account such additional clinical variables as conditioning regimen intensity and GvHD prophylaxis used.

Materials and methods

A total of 1037 allo-HSCT recipients transplanted in R. M. Gor- bacheva Memorial institute for Pediatric Oncology, Hematology and Transplantation in 2013-2018 were included to the retrospective open single-center cohort study. Hemorrhagic cystitis (HC) was registered in 118 cases (11.4%). According to inclusion criteria, only 90 patients were enrolled to the final analysis. This cohort was divided into two groups based on HC therapy used: the intervention group (n=42) included the patients with standard HC treatment with addition of IVIG; the control group (n=48) received standard HC therapy only. Patients developing allegedly cytotoxic HC before Day+7 post allo-HSCT and second allo-HSCT recipients were excluded from the analysis. Patients in the intervention group were also subdivided based on IVIG therapy timing, dose and duration. Only those patients were included who received IVIG for at least 3 days at the doses of >400 mg per kg, being administered not later than three days since HC onset.

HC diagnosis was based on the presence of hematuria and dysuria. The laboratory criteria included at least one episode of high-grade hematuria (>50 red blood cells per high-power field). The presence of GvHD I-IV was considered as an additional risk factor in statistical evaluation. The standard HC treatment, which all patients received, consisted of intensive iv fluids with forced diuresis, NSAIDs and antispasmodics. Elastic urinary catheters were used in cases of high-risk bladder tamponade, in order to provide bladder washing and evacuation of blood clots.

In the intervention group, we used a commercially available IVIG (Immunovenin® 5%, 50 mg/mL), manufactured by Microgen, Russia. The IVIG treatment began within the first three days since the HC onset, in most patients it was started within 24 hours. Estimation of treatment effectiveness was based on HC symptoms duration. These results were compared to the ones in the control group, which did not receive IVIG. Additional risk factors included conditioning regimen intensity, GvHD prophylaxis, and presence of GvHD.

Statistical evaluation

The data was analyzed with SPSS Statistics v.23 software. The groups were characterized via qualitative characteristics, which were grouped for comparison via chi-square test in conjugated tables. One sample Kolmogorov-Smirnov test used for testing if a variable follows a given distribution in a population. Mann-Whitney U test was used to compare outcomes between two independent groups. To compare HC duration depending on different factors (IVIG therapy, conditioning regimen intensity, and presence of GvHD) Kaplan-Meier curves were used. HC duration was a median (95% CI) according Kaplan-Meier test. The correlation strength was evaluated via log rank test. All values with significant correlation were combined as Cox regression model for multivariate analysis. The p values of ≤0.05 were considered statistically significant.

Results

The HC development rate in the total allo-HSCT recipient group (intervention and control) was 11.4% (n=118). Only 90 patients matched all the above clinical criteria and were included in the analysis, 42 of them (46.7%) fell into the intervention group (with IVIG), and 48 (53.3%), into control group. The median HC duration in common group was 21 days.

Both groups were balanced by gender, diagnosis (malignant and non-malignant conditions), donor type, hematopoietic stem cells (HSC) source, number of patients with clinical signs of GvHD at first signs of HC. The groups were different by two parameters: median age (17 in the intervention group, and 23 in control group, p=0.02), and underlying malignant conditions spectrum (more ALL patients among IVIG recipients, and more AML patients in control group).

The majority of patients received allo-HSCT from unrelated donor (70.8% in the intervention group, and 71% in control group, respectively). There was no significant difference in HSC source between the groups. Bone marrow (BM) and peripheral blood stem cells (PBSC) were used 43.7% and 56.3% in the intervention group, and 45.2% and 54.8% allo-HSCT cases in control group, respectively. The patients’ characteristics are presented in Table 1.

Table 1. Characteristics of patients with hemorrhagic cystitis in IVIG-treated and control groups

A total IVIG dose ranged from 1.2 g/kg to 4 g/kg was used (usually 400 mg/kg/day for 3 consecutive days, except one patient with 10-days IVIG treatment) with a median single dose of 1.2 g/kg and a median total dose of 35 g per patient. There was no statistically significant difference in HC duration between groups with the median of 24 days (16, 32; 95% CI) in the intervention group and 24 days (2, 46; 95% CI) in control group, respectively (p=0.39; Fig. 1).

The main factors affecting HC duration were conditioning regimen intensity, presence of GvHD at the moment of the first HC signs. The median HC duration in MAC and RIC recipients were 35 days (18, 52; 95% CI) and 17 days (14, 20; 95% CI), respectively (p<0.01; Fig. 1).

The presence of GvHD I-IV at the time of HC symptoms manifestation was also characterized by positive correlation with HC duration. It was 36 days (22, 50; 95% CI) in patients with, and 18 days (15, 21; 95% CI) in patients without active GvHD (p=0.013).

Figure 1. Univariate analysis (Kaplan-Meier method) of HC cumulative incidence in the intervention group and control group, then based on conditioning regimen intensity (MAC vs RIC), and presence of GvHD I-IV at the time of HC manifestation

The multivariate analysis was performed by Cox proportional hazard regression model including the following factors: IVIG vs no IVIG in therapy regimen, conditioning regimen intensity (MAC vs RIC), and presence of HC at the time of HC symptoms onset. It has shown MAC and GvHD presence to be independent risk factors associated with longer HC duration (Table 2).

Table 2. Cox proportional hazard regression model data for the three studied clinical parameters in HSCT patients with hemorrhagic cystitis

Discussion

While there was no statistically significant difference between cohorts in our study, it had some significant limitations, which could compromise the results: the retrospective design of the study, single-center experience and unknown HC etiology; varied IVIG doses – the median single dose was 1.2 g/kg, which is significantly lower than dose recommended for patients with BKPyV-associated nephropathy (2 g/kg) [14, 15]. Therefore, the IVIG therapy at the dose recommended for BKPyV-associated nephropathy may still be effective.

According to World Health Organization Model Formulary 2008, Chapter – IVIG: "Formulations from different manufacturers vary and should not be regarded as equivalent" [17]. IVIG can have significant differences not only between manufacturers and commercial brands, but also between series of the same drug, which is well discussed by Nathaniel Washburn et al. It is a challenge to assess the influence of these data on clinical effectiveness, especially when IVIG mechanism of action in HC is partly unclear. Also there is lack of data in drug’s instructions for use, given by manufacturers about IVIG class and mechanism of action [18]. The prospective study design involving higher IVIG doses (at least 2 g/kg) and from different manufactures could be more exemplary.

According to ECIL (European Conference on Infections in Leukaemia) 2018 guidelines on post allo-HSCT BK-associated HC, IVIG therapy is not recommended as a routine treatment option and graded experimental among such methods as intravesical Cidofovir or Sodium Hyaluronate infusions, iv estrogens, mesenchymal cells etc. This is explained by current lack of evidence with most evident-based method (AIII level) being best supportive care consisting of hydratation, platelets transfusion and pain control [6]. Our data is also not yet sufficient to recommend IVIG as a standard treatment option.

Many researches have demonstrated the association between conditioning regimen intensity and HC incidence, some of them presumed cyclophosphamide toxicity, but this link has not always been confirmed [19-25]. The reasons for GvHD association with HC development are not yet completely clear. The direct immune damage hypothesis has not been proved [26, 27]. However, as GvHD treatment causes additional severe immunosuppression, viral reactivation and active replication may appear which may be a direct cause of HC [28]. We demonstrated the association between certain risk factors (condition regimen intensity and concurrent GvHD) and not only HC incidence, but also its duration, which may be due to stronger immunosuppression in these conditions.

Conclusions

Our data didn’t prove superior therapeutic effect of 1.2 g/kg IVIG (Immunovenin® 5% (50mg/ml) by Microgen) in post allo-HSCT HC patients. Conditioning regimen intensity and GvHD I-IV are the risk factors for HC longer duration. A further prospective study is needed to make final conclusions on method’s effectiveness.

Conflict of interest

None declared.

References

1. Moiseev IS, Pirogova OV, Alyanski AL, Babenko EV, Gindina TL, Darskaya EI, Slesarchuk OA, Bondarenko SN, Afanasyev BV. Graft-versus-host disease prophylaxis in unrelated peripheral blood stem cell transplantation with post-transplantation cyclophosphamide, tacrolimus and mycophenalate mofetil. Biol Blood Marrow Transplant. 2016; 22(6):1037-1042.
2. Shaheen M, Ivanova MO, Moiseev IS, Bondarchuk SV, Afanasyev BV. Impact of initial serum ferritin on early post-HSCT complications: a single center study. Cell Ther Transplant. 2016;5(2): 40-49.
3. Morozova EV, Moiseev IS, Barabanshikova MV, Darskaya EI, Bondarenko SN, Zubarovskaya LS, Baykov VV, Alyanski AL, Barkhatov IM, Zander AR, Afanasyev BV. Graft-versus-host disease prophylaxis with posttransplantation cyclophosphamide and ruxolitinib in patients with myelofibrosis. Blood 2017; 130 (Supplement 1): 4492.
4. Afanasyev BV, Zubarovskaya LS, Semenova EV, Ivanova NE, Alyanskyi AL, Morozova EV, Mikhailova N.B, Darskaya EI, Estrina MA, Golovacheva AA, Babenko EV, Bondarenko SN, Ganapiev AA, Bogomolny MP. Experience with unrelated allogeneic transplantation of hematopoietic stem cells in bone marrow transplantation clinic. Terap Arkhiv. 2007; 7: 35-42 (In Russian).
5. Shcherbakov AA, Kucher AA, Shvetcov AN, Paina OV, Slesarchuk OA, Klementeva RV, Goloshchapov AV, Zubarovskaya LS, Afanasyev BV. Hemorrhagic cystitis after allogeneic transplantation of hematopoietic stem cells in children with hematological, oncological and hereditary diseases. Pediatriya – Zhurnal im G.N. Speranskogo 2018; 97(5): 41-46 (In Russian).
6. Cesaro S, Dalianis T, Hanssen Rinaldo C, Koskenvuo M, Pegoraro A, Einsele H, Cordonnier C, Hirsch HH, Members of the ECIL-6 Group, ECIL guidelines for the prevention, diagnosis and treatment of BK polyomavirus-associated haemorrhagic cystitis in haematopoietic stem cell transplant recipients. J Antimicrob Chemother. 2018; 73(1):12-21.
7. Han SB, Cho B, Kang JH. BK virus-associated hemorrhagic cystitis after pediatric stem cell. Korean J Pediatr. 2014; 57(12):514-519.
8. Silva Lde P, Patah PA, Saliba RM, Szewczyk NA, Gilman L, Neumann J, Han XY, Tarrand J, Ribeiro R, Gulbis A, Shpall EJ, Jones R, Popat U, Walker JA, Petropoulos D, Chiattone A, Stewart J, El-Zimaity M, Anderlini P, Giralt S, Champlin RE, de Lima M. Hemorrhagic cystitis after allogeneic hematopoietic stem cell transplants is the complex result of BK virus infection, preparative regimen intensity and donor type. Haematologica. 2010;95(7):1183-1190.
9. Bogdanovic G, Priftakis P, Giraud G, Kuzniar M, Ferraldeschi R, Kokhaei P, Mellstedt H, Remberger M, Ljungman P, Winiarski J, Dalianis T. Association between a high BK virus load in urine samples of patients with graft-versus-host disease and development of hemorrhagic cystitis after hematopoietic stem cell transplantation. J Clin Microbiol. 2004;42(11):5394-5396.
10. Mori T, Aisa Y, Shimizu T, Ikeda Y, Okamoto S, Okada K, Kazuyama Y. Hemorrhagic cystitis caused by adenovirus type 34 after allogeneic bone marrow transplantation. Transplantation. 2005;79(5):624.
11. Dropulic LK, Jones RJ. Polyomavirus BK infection in blood and marrow transplant recipients. Bone Marrow Transplant. 2008;41(1):11-18.
12. Chukhlovin AB, Eismont YuA, Vavilov VN, Zubarovskaya LS, Afanasyev BV. Time- and sample-dependent differences in polyomavirus incidence following hematopoietic stem cell transplantation. Cell Ther Transplant. 2016; 5(1):26-30.
13. Randhawa PS, Schonder K, Shapiro R, Farasati N, Huang Y. Polyomavirus BK neutralizing activity in human immunoglobulin preparations. Transplantation. 2010;89(12):1462-1465.
14. Sener A, House AA, Jevnikar AM, Boudville N, McAlister VC, Muirhead N, Rehman F, Luke PP. Intravenous immunoglobulin as a treatment for BK virus associated nephropathy: one-year follow-up of renal allograft recipients. Transplantation. 2006;81(1):117-120.
15. Anyaegbu EI, Almond PS, Milligan T, Allen WR, Gharaybeh S, Al-Akash SI. Intravenous immunoglobulin therapy in the treatment of BK viremia and nephropathy in pediatric renal transplant recipients. Pediatr Transplant. 2012 Feb; 16(1): E19-E24.
16. Mert D, Batgi H, Merdin A, Çeken S, Dal MS, Tekgündüz E, Altuntaş F, Ertek M. BK Virus-associated hemorrhagic cystitis in patients with allogeneic hematopoietic cell transplantation: report of three cases. Hematol Rep. 2017;9(2):7205. 2017 Jun 26.
17. World Health Organization. WHO model formulary 2008, Editors: Marc C. Stuart, Maria Kouimtzi, Suzanne R. Hill.
18. Washburn N, Meccariello R, Hu S, Hains M, Bhatnagar N, Sarvaiya H, et al. High-resolution physicochemical characterization of different intravenous immunoglobulin products. PLoS ONE. 2017; 12(7): e0181251. https://doi.org/10.1371/journal.pone.0181251.
19. Kopterides P, Theodorakopoulou M, Mentzelopoulos S, Armaganidis A. Cyclophosphamide-induced hemorrhagic cystitis successfully treated with conjugated estrogens. Am J Hematol. 2005;80(2):166-167.
20. Walker RD. Cyclophosphamide-induced hemorrhagic cystitis. J Urol. 1999;161(6):1747.
21. Haselberger MB, Schwinghammer TL. Efficacy of Mesna for prevention of hemorrhagic cystitis after high-dose cyclophosphamide therapy. Ann Pharmacother. 1995;29(9):918-921.
22. Wang CC, Weng TI, Wu ET, Wu MH, Yang RS, Liu SH. Involvement of interleukin-6-regulated nitric oxide synthase in hemorrhagic cystitis and impaired bladder contractions in young rats induced by acrolein, a urinary metabolite of cyclophosphamide. Toxicol Sci. 2013;131(1):302-310.
23. Gilis L, Morisset S, Billaud G, Ducastelle-Leprêtre S, Labussière-Wallet H, Nicolini F-E, Barraco F, Detrait M, Thomas X, Tedone N. High burden of BK virus-associated hemorrhagic cystitis in patients undergoing allogeneic hematopoietic stem cell transplantation. Bone Marrow Transplant. 2014;49(5):664-670.
24. Zubarovskaya LS. Efficiency evaluation of high-dose cytostatic therapy with hematopoietic stem cell transplantation in treatment of hematological and oncological disorders in children and adolescents. Doctoral Thesis. St.Petersburg, 2005:1-31 (In Russian).
25. Vitrischak A, Semenova E, Ovsyannikova M, Pugachev A, Morozova E, Mikhailova N, Zubarovskaya L, Afanasyev B. Risk factors for acute GvHD after allogeneic stem cell transplantation in children. 30th Annual EBMT Meeting, Barcelona, 2004. Bone Marrow Transplant; 33 (Suppl 1 R1117): S312.
26. Uhm J, Hamad N, Michelis FV, Shanavas M, Kuruvilla J, Gupta V, Lipton JH, Messner HA, Seftel M, Kim DD. The risk of polyomavirus BK-associated hemorrhagic cystitis after allogeneic hematopoietic SCT is associated with myeloablative conditioning, CMV viremia and severe acute GvHD. Bone Marrow Transplant. 2014; 49 (12): 1528-1534.
27. Dalianis T, Ljungman P. Full myeloablative conditioning and an unrelated HLA-mismatched donor increase the risk for BK virus-positive hemorrhagic cystitis in allogeneic hematopoetic stem cell transplanted patients. Anticancer Res. 2011;31(3):939-944.
28. Lunde LE, Dasaraju S, Cao Q, Cohn CS, Reding M, Bejanyan N, Trottier B, Rogosheske J, Brunstein C, Warlick E, Young JA, Weisdorf DJ, Ustun C. Hemorrhagic cystitis after allogeneic hematopoietic cell transplantation: risk factors, graft source and survival. Bone Marrow Transplant. 2015;50(11):1432-1437.

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Introduction

Hemorrhagic cystitis (HC) is a frequent complication in allogeneic hematopoietic stem cell transplantation (allo-HSCT) with incidence of 9% to 31% for different cohorts [1-7]. Early clinical form of HC usually develops within ten days post allo-HSCT. In this cases HC is considered a direct consequence of cytotoxic conditioning therapy and graft-versus-host disease (GvHD) prophylaxis [8]. Along with cytotoxic drugs, some viral agents, e.g., BK- and JC- polyomaviruses, adenovirus and cytomegalovirus may be also involved in HC pathogenesis. Among them, human BK-polyomavirus (BKPyV) is the most frequently activated virus in urological setting, and, therefore, its elimination is a primary aim in HC treatment [8-12].

Some preclinical evidence for intravenous immunoglobulin (IVIG) effectiveness was reported earlier. Parmjeet S Randhawa et al. have demonstrated an ability of commercially available IVIG to neutralize BKPyV in human and mice cell cultures [13]. E.g., a 5-gram IVIG volume (one standard bottle) was able to inactivate 1.9*106 BKPyV/mL of plasma in 5.000 ml of blood, thus roughly corresponding to mean circulating blood volume in adults. It was, therefore, supposed that these preparations contain sufficient amounts of BKPyV-specific antibodies to neutralize clinically significant viral loads.

There is also some clinical evidence of IVIG effectiveness in BK virus nephropathy following renal transplantation. The latter condition has much common in origin with HC post allo-HSCT since it also occurs in immunocompromised host with preexisting urinary system lesions. The current treatment approaches for BKPyV nephropathy are immunosuppression reduction and IVIG administration at a total dose of 2 g/kg over 2-5 consecutive days [14, 15].

No standard strategy is, however, developed for HC treatment after allo-HSCT, as all the published data on IVIG treatment in these settings are limited to several case reports [16]. Despite the lack of available data, IVIG may be regarded as a feasible option based on its favorable safety profile and potential clinical efficiency [6].

It is even more notable, since some other established treatment options, e.g. intravenous Cidofovir infusions (CII evidence level) are, besides being potentially nephrotoxic, not currently available in Russian Federation. Meanwhile, the IVIG efficiency in HC has not been previously evaluated, although it is routinely used in our practice.

The current study is, therefore, aimed at evaluating the efficiency of IVIG infusions in HC patients after allo-HSCT, taking into account such additional clinical variables as conditioning regimen intensity and GvHD prophylaxis used.

Materials and methods

A total of 1037 allo-HSCT recipients transplanted in R. M. Gor- bacheva Memorial institute for Pediatric Oncology, Hematology and Transplantation in 2013-2018 were included to the retrospective open single-center cohort study. Hemorrhagic cystitis (HC) was registered in 118 cases (11.4%). According to inclusion criteria, only 90 patients were enrolled to the final analysis. This cohort was divided into two groups based on HC therapy used: the intervention group (n=42) included the patients with standard HC treatment with addition of IVIG; the control group (n=48) received standard HC therapy only. Patients developing allegedly cytotoxic HC before Day+7 post allo-HSCT and second allo-HSCT recipients were excluded from the analysis. Patients in the intervention group were also subdivided based on IVIG therapy timing, dose and duration. Only those patients were included who received IVIG for at least 3 days at the doses of >400 mg per kg, being administered not later than three days since HC onset.

HC diagnosis was based on the presence of hematuria and dysuria. The laboratory criteria included at least one episode of high-grade hematuria (>50 red blood cells per high-power field). The presence of GvHD I-IV was considered as an additional risk factor in statistical evaluation. The standard HC treatment, which all patients received, consisted of intensive iv fluids with forced diuresis, NSAIDs and antispasmodics. Elastic urinary catheters were used in cases of high-risk bladder tamponade, in order to provide bladder washing and evacuation of blood clots.

In the intervention group, we used a commercially available IVIG (Immunovenin® 5%, 50 mg/mL), manufactured by Microgen, Russia. The IVIG treatment began within the first three days since the HC onset, in most patients it was started within 24 hours. Estimation of treatment effectiveness was based on HC symptoms duration. These results were compared to the ones in the control group, which did not receive IVIG. Additional risk factors included conditioning regimen intensity, GvHD prophylaxis, and presence of GvHD.

Statistical evaluation

The data was analyzed with SPSS Statistics v.23 software. The groups were characterized via qualitative characteristics, which were grouped for comparison via chi-square test in conjugated tables. One sample Kolmogorov-Smirnov test used for testing if a variable follows a given distribution in a population. Mann-Whitney U test was used to compare outcomes between two independent groups. To compare HC duration depending on different factors (IVIG therapy, conditioning regimen intensity, and presence of GvHD) Kaplan-Meier curves were used. HC duration was a median (95% CI) according Kaplan-Meier test. The correlation strength was evaluated via log rank test. All values with significant correlation were combined as Cox regression model for multivariate analysis. The p values of ≤0.05 were considered statistically significant.

Results

The HC development rate in the total allo-HSCT recipient group (intervention and control) was 11.4% (n=118). Only 90 patients matched all the above clinical criteria and were included in the analysis, 42 of them (46.7%) fell into the intervention group (with IVIG), and 48 (53.3%), into control group. The median HC duration in common group was 21 days.

Both groups were balanced by gender, diagnosis (malignant and non-malignant conditions), donor type, hematopoietic stem cells (HSC) source, number of patients with clinical signs of GvHD at first signs of HC. The groups were different by two parameters: median age (17 in the intervention group, and 23 in control group, p=0.02), and underlying malignant conditions spectrum (more ALL patients among IVIG recipients, and more AML patients in control group).

The majority of patients received allo-HSCT from unrelated donor (70.8% in the intervention group, and 71% in control group, respectively). There was no significant difference in HSC source between the groups. Bone marrow (BM) and peripheral blood stem cells (PBSC) were used 43.7% and 56.3% in the intervention group, and 45.2% and 54.8% allo-HSCT cases in control group, respectively. The patients’ characteristics are presented in Table 1.

Table 1. Characteristics of patients with hemorrhagic cystitis in IVIG-treated and control groups

A total IVIG dose ranged from 1.2 g/kg to 4 g/kg was used (usually 400 mg/kg/day for 3 consecutive days, except one patient with 10-days IVIG treatment) with a median single dose of 1.2 g/kg and a median total dose of 35 g per patient. There was no statistically significant difference in HC duration between groups with the median of 24 days (16, 32; 95% CI) in the intervention group and 24 days (2, 46; 95% CI) in control group, respectively (p=0.39; Fig. 1).

The main factors affecting HC duration were conditioning regimen intensity, presence of GvHD at the moment of the first HC signs. The median HC duration in MAC and RIC recipients were 35 days (18, 52; 95% CI) and 17 days (14, 20; 95% CI), respectively (p<0.01; Fig. 1).

The presence of GvHD I-IV at the time of HC symptoms manifestation was also characterized by positive correlation with HC duration. It was 36 days (22, 50; 95% CI) in patients with, and 18 days (15, 21; 95% CI) in patients without active GvHD (p=0.013).

Figure 1. Univariate analysis (Kaplan-Meier method) of HC cumulative incidence in the intervention group and control group, then based on conditioning regimen intensity (MAC vs RIC), and presence of GvHD I-IV at the time of HC manifestation

The multivariate analysis was performed by Cox proportional hazard regression model including the following factors: IVIG vs no IVIG in therapy regimen, conditioning regimen intensity (MAC vs RIC), and presence of HC at the time of HC symptoms onset. It has shown MAC and GvHD presence to be independent risk factors associated with longer HC duration (Table 2).

Table 2. Cox proportional hazard regression model data for the three studied clinical parameters in HSCT patients with hemorrhagic cystitis

Discussion

While there was no statistically significant difference between cohorts in our study, it had some significant limitations, which could compromise the results: the retrospective design of the study, single-center experience and unknown HC etiology; varied IVIG doses – the median single dose was 1.2 g/kg, which is significantly lower than dose recommended for patients with BKPyV-associated nephropathy (2 g/kg) [14, 15]. Therefore, the IVIG therapy at the dose recommended for BKPyV-associated nephropathy may still be effective.

According to World Health Organization Model Formulary 2008, Chapter – IVIG: "Formulations from different manufacturers vary and should not be regarded as equivalent" [17]. IVIG can have significant differences not only between manufacturers and commercial brands, but also between series of the same drug, which is well discussed by Nathaniel Washburn et al. It is a challenge to assess the influence of these data on clinical effectiveness, especially when IVIG mechanism of action in HC is partly unclear. Also there is lack of data in drug’s instructions for use, given by manufacturers about IVIG class and mechanism of action [18]. The prospective study design involving higher IVIG doses (at least 2 g/kg) and from different manufactures could be more exemplary.

According to ECIL (European Conference on Infections in Leukaemia) 2018 guidelines on post allo-HSCT BK-associated HC, IVIG therapy is not recommended as a routine treatment option and graded experimental among such methods as intravesical Cidofovir or Sodium Hyaluronate infusions, iv estrogens, mesenchymal cells etc. This is explained by current lack of evidence with most evident-based method (AIII level) being best supportive care consisting of hydratation, platelets transfusion and pain control [6]. Our data is also not yet sufficient to recommend IVIG as a standard treatment option.

Many researches have demonstrated the association between conditioning regimen intensity and HC incidence, some of them presumed cyclophosphamide toxicity, but this link has not always been confirmed [19-25]. The reasons for GvHD association with HC development are not yet completely clear. The direct immune damage hypothesis has not been proved [26, 27]. However, as GvHD treatment causes additional severe immunosuppression, viral reactivation and active replication may appear which may be a direct cause of HC [28]. We demonstrated the association between certain risk factors (condition regimen intensity and concurrent GvHD) and not only HC incidence, but also its duration, which may be due to stronger immunosuppression in these conditions.

Conclusions

Our data didn’t prove superior therapeutic effect of 1.2 g/kg IVIG (Immunovenin® 5% (50mg/ml) by Microgen) in post allo-HSCT HC patients. Conditioning regimen intensity and GvHD I-IV are the risk factors for HC longer duration. A further prospective study is needed to make final conclusions on method’s effectiveness.

Conflict of interest

None declared.

References

1. Moiseev IS, Pirogova OV, Alyanski AL, Babenko EV, Gindina TL, Darskaya EI, Slesarchuk OA, Bondarenko SN, Afanasyev BV. Graft-versus-host disease prophylaxis in unrelated peripheral blood stem cell transplantation with post-transplantation cyclophosphamide, tacrolimus and mycophenalate mofetil. Biol Blood Marrow Transplant. 2016; 22(6):1037-1042.
2. Shaheen M, Ivanova MO, Moiseev IS, Bondarchuk SV, Afanasyev BV. Impact of initial serum ferritin on early post-HSCT complications: a single center study. Cell Ther Transplant. 2016;5(2): 40-49.
3. Morozova EV, Moiseev IS, Barabanshikova MV, Darskaya EI, Bondarenko SN, Zubarovskaya LS, Baykov VV, Alyanski AL, Barkhatov IM, Zander AR, Afanasyev BV. Graft-versus-host disease prophylaxis with posttransplantation cyclophosphamide and ruxolitinib in patients with myelofibrosis. Blood 2017; 130 (Supplement 1): 4492.
4. Afanasyev BV, Zubarovskaya LS, Semenova EV, Ivanova NE, Alyanskyi AL, Morozova EV, Mikhailova N.B, Darskaya EI, Estrina MA, Golovacheva AA, Babenko EV, Bondarenko SN, Ganapiev AA, Bogomolny MP. Experience with unrelated allogeneic transplantation of hematopoietic stem cells in bone marrow transplantation clinic. Terap Arkhiv. 2007; 7: 35-42 (In Russian).
5. Shcherbakov AA, Kucher AA, Shvetcov AN, Paina OV, Slesarchuk OA, Klementeva RV, Goloshchapov AV, Zubarovskaya LS, Afanasyev BV. Hemorrhagic cystitis after allogeneic transplantation of hematopoietic stem cells in children with hematological, oncological and hereditary diseases. Pediatriya – Zhurnal im G.N. Speranskogo 2018; 97(5): 41-46 (In Russian).
6. Cesaro S, Dalianis T, Hanssen Rinaldo C, Koskenvuo M, Pegoraro A, Einsele H, Cordonnier C, Hirsch HH, Members of the ECIL-6 Group, ECIL guidelines for the prevention, diagnosis and treatment of BK polyomavirus-associated haemorrhagic cystitis in haematopoietic stem cell transplant recipients. J Antimicrob Chemother. 2018; 73(1):12-21.
7. Han SB, Cho B, Kang JH. BK virus-associated hemorrhagic cystitis after pediatric stem cell. Korean J Pediatr. 2014; 57(12):514-519.
8. Silva Lde P, Patah PA, Saliba RM, Szewczyk NA, Gilman L, Neumann J, Han XY, Tarrand J, Ribeiro R, Gulbis A, Shpall EJ, Jones R, Popat U, Walker JA, Petropoulos D, Chiattone A, Stewart J, El-Zimaity M, Anderlini P, Giralt S, Champlin RE, de Lima M. Hemorrhagic cystitis after allogeneic hematopoietic stem cell transplants is the complex result of BK virus infection, preparative regimen intensity and donor type. Haematologica. 2010;95(7):1183-1190.
9. Bogdanovic G, Priftakis P, Giraud G, Kuzniar M, Ferraldeschi R, Kokhaei P, Mellstedt H, Remberger M, Ljungman P, Winiarski J, Dalianis T. Association between a high BK virus load in urine samples of patients with graft-versus-host disease and development of hemorrhagic cystitis after hematopoietic stem cell transplantation. J Clin Microbiol. 2004;42(11):5394-5396.
10. Mori T, Aisa Y, Shimizu T, Ikeda Y, Okamoto S, Okada K, Kazuyama Y. Hemorrhagic cystitis caused by adenovirus type 34 after allogeneic bone marrow transplantation. Transplantation. 2005;79(5):624.
11. Dropulic LK, Jones RJ. Polyomavirus BK infection in blood and marrow transplant recipients. Bone Marrow Transplant. 2008;41(1):11-18.
12. Chukhlovin AB, Eismont YuA, Vavilov VN, Zubarovskaya LS, Afanasyev BV. Time- and sample-dependent differences in polyomavirus incidence following hematopoietic stem cell transplantation. Cell Ther Transplant. 2016; 5(1):26-30.
13. Randhawa PS, Schonder K, Shapiro R, Farasati N, Huang Y. Polyomavirus BK neutralizing activity in human immunoglobulin preparations. Transplantation. 2010;89(12):1462-1465.
14. Sener A, House AA, Jevnikar AM, Boudville N, McAlister VC, Muirhead N, Rehman F, Luke PP. Intravenous immunoglobulin as a treatment for BK virus associated nephropathy: one-year follow-up of renal allograft recipients. Transplantation. 2006;81(1):117-120.
15. Anyaegbu EI, Almond PS, Milligan T, Allen WR, Gharaybeh S, Al-Akash SI. Intravenous immunoglobulin therapy in the treatment of BK viremia and nephropathy in pediatric renal transplant recipients. Pediatr Transplant. 2012 Feb; 16(1): E19-E24.
16. Mert D, Batgi H, Merdin A, Çeken S, Dal MS, Tekgündüz E, Altuntaş F, Ertek M. BK Virus-associated hemorrhagic cystitis in patients with allogeneic hematopoietic cell transplantation: report of three cases. Hematol Rep. 2017;9(2):7205. 2017 Jun 26.
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19. Kopterides P, Theodorakopoulou M, Mentzelopoulos S, Armaganidis A. Cyclophosphamide-induced hemorrhagic cystitis successfully treated with conjugated estrogens. Am J Hematol. 2005;80(2):166-167.
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Персистирование BK полиомавируса (BKPyV) является одной из основных предполагаемых причин, приводящих к развитию позднего ГЦ после алло-ТГСК. Имеются доклинические данные об эффективной нейтрализации BKPyV внутривенным иммуноглобулином G (ВВИГ) в клеточных культурах, а также при BK вирусной нефропатии при трансплантации почки. </p> <h3>Пациенты и методы</h3> <p style="text-align: justify;"> Ретроспективно было изучено 1037 пациентов получивших алло-ТГСК в НИИ детской онкологии, гематологии и трансплантологии им. Р.М. Горбачевой с 2013 по 2018 год. ГЦ был зарегистрирован в 118 (11,4%) случаях, из них, согласно критериям включения, 90 пациентов включены в анализ: группа сравнения с ВВИГ (n=42) и контрольная группа (n=48) со стандартной терапией ГЦ. </p> <h3>Результаты</h3> <p style="text-align: justify;"> Продолжительность ГЦ в общей группе составила 21 день. Не было статистически значимой разницы в продолжительности ГЦ между группой сравнения и контрольной группой – медиана 24 дня (16, 32; 95% CI) и 24 дня (2, 46; 95% CI), соответственно (p=0,39). Продолжительность ГЦ при миелоаблативном режиме кондиционирования составила 35 дней (18, 52; 95% ДИ) и 17 дней (14, 20; 95% ДИ) при немиелоаблативном режиме кондиционирования, р &lt;0,01. Одновременное наличие симптомов ГЦ и РТПХ I-IV степени, также характеризовалось положительной корреляцией с длительностью ГЦ – 36 дней (22, 50; 95% ДИ) у пациентов с РТПХ и 18 дней (15, 21; 95% ДИ) у пациентов без РТПХ, р=0,013. </p> <h3>Выводы</h3> <p style="text-align: justify;"> Настоящее исследование не подтвердило клиническую эффективность ВВИГ (Иммуновенин 5% (50мг/мл) Микроген) в дозе 1,2 гр/кг у пациентов с ГЦ после алло-ТГСК. Факторами риска более длительного течения ГЦ были интенсивность режима кондиционирования и наличие РТПХ I-IV степени. 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Щербаков, Алена Н. Зайцева, Максим А. Кучер, Ирина С. Ярушкина, Ольга Н. Зацепина, Екатерина С. Кульнева, Олеся В. Паина, Руслана В. Клементьева, Олег В. Голощапов, Иван С. Моисеев, Людмила С. Зубаровская, <span style="border: 1px solid black; margin: 0; padding: 2px 2px;">Борис В. Афанасьев</span> </p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(504) "

Александр А. Щербаков, Алена Н. Зайцева, Максим А. Кучер, Ирина С. Ярушкина, Ольга Н. Зацепина, Екатерина С. Кульнева, Олеся В. Паина, Руслана В. Клементьева, Олег В. Голощапов, Иван С. Моисеев, Людмила С. Зубаровская, Борис В. Афанасьев

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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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Геморрагический цистит (ГЦ) – это частое осложнение при аллогенной трансплантации гемопоэтических стволовых клеток (алло-ТГСК). Персистирование BK полиомавируса (BKPyV) является одной из основных предполагаемых причин, приводящих к развитию позднего ГЦ после алло-ТГСК. Имеются доклинические данные об эффективной нейтрализации BKPyV внутривенным иммуноглобулином G (ВВИГ) в клеточных культурах, а также при BK вирусной нефропатии при трансплантации почки.

Пациенты и методы

Ретроспективно было изучено 1037 пациентов получивших алло-ТГСК в НИИ детской онкологии, гематологии и трансплантологии им. Р.М. Горбачевой с 2013 по 2018 год. ГЦ был зарегистрирован в 118 (11,4%) случаях, из них, согласно критериям включения, 90 пациентов включены в анализ: группа сравнения с ВВИГ (n=42) и контрольная группа (n=48) со стандартной терапией ГЦ.

Результаты

Продолжительность ГЦ в общей группе составила 21 день. Не было статистически значимой разницы в продолжительности ГЦ между группой сравнения и контрольной группой – медиана 24 дня (16, 32; 95% CI) и 24 дня (2, 46; 95% CI), соответственно (p=0,39). Продолжительность ГЦ при миелоаблативном режиме кондиционирования составила 35 дней (18, 52; 95% ДИ) и 17 дней (14, 20; 95% ДИ) при немиелоаблативном режиме кондиционирования, р <0,01. Одновременное наличие симптомов ГЦ и РТПХ I-IV степени, также характеризовалось положительной корреляцией с длительностью ГЦ – 36 дней (22, 50; 95% ДИ) у пациентов с РТПХ и 18 дней (15, 21; 95% ДИ) у пациентов без РТПХ, р=0,013.

Выводы

Настоящее исследование не подтвердило клиническую эффективность ВВИГ (Иммуновенин 5% (50мг/мл) Микроген) в дозе 1,2 гр/кг у пациентов с ГЦ после алло-ТГСК. Факторами риска более длительного течения ГЦ были интенсивность режима кондиционирования и наличие РТПХ I-IV степени. Требуется проведение проспективного исследования для определения эффективности ВВИГ в качестве терапии позднего ГЦ после алло-ТГСК.

Ключевые слова

Аллогенная трансплантация гемопоэтических стволовых клеток, геморрагический цистит, внутривенный иммуноглобулин, ВВИГ, факторы риска, реакция «трансплантат против хозяина» (РТПХ).

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Alexander A. Shcherbakov, Alena N. Zaytseva, Maksim A. Kucher, Irina S. Iarushkina, Olga N. Zatsepina, Ekaterina S. Kulneva, Olesya V. Paina, Ruslana V. Klementeva, Оleg V. Goloshchapov, Ivan S. Moiseev, Ludmila S. Zubarovskaya,
Boris V. Afanasyev

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Raisa Gorbacheva Memorial Research Institute of Pediatric Oncology, Hematology and Transplantation, Pavlov University,
St. Petersburg, Russia

Correspondence
Dr. Alexander A. Shcherbakov, Raisa Gorbacheva Memorial Research Institute of Pediatric Oncology, Hematology and Transplantation, Pavlov University, L. Tolstoy St. 6-8, 197022, St. Petersburg, Russia
Phone: +7(904) 604 0884
E-mail: xihmrx@gmail.com

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Hemorrhagic cystitis (HC) is a frequent complication in allogeneic hematopoietic stem cell transplantation (allo- HSCT). Human BK-polyomavirus (BKPyV) may be one of the main agents found in late HC developing after allo-HSCT. In previous studies, intravenous immunoglobulin (IVIG) preparations were shown to neutralize BKPyV in mice cell cultures and to reduce BK virus nephropathy in kidney transplantation. The aim of current study was to evaluate efficiency of HC treatment with IVIG in allo-HSCT recipients, with respect to conditioning regimen intensity and presence of graft-versus-host disease (GvHD).

Patients and methods

A total of 1037 allo-HSCT recipients transplanted in R. M. Gorbacheva Memorial institute for Pediatric Oncology, Hematology and Transplantation in 2013-2018 were included into retrospective open single-center cohort study. HC was registered in 118 (11.4%) cases. According to inclusion criteria, only 90 patients were enrolled to the final analysis. This cohort was divided into two groups based on HC therapy used: the intervention group (n=42) included patients with standard HC treatment with addition of IVIG; the control group (n=48) – with standard HC therapy only.

Results

The median HC duration in common group (IVIG and control) was 21 days. There was no statistically significant difference in HC duration between the two groups, with the median of 24 days (16, 32; 95% CI) in the intervention group (standard therapy + IVIG), and 24 days (2, 46; 95% CI) in control group, respectively (p=0.39). The median HC duration in MAC and RIC was 35 days (18, 52; 95% CI) versus 17 days (14, 20; 95% CI), respectively (p<0.01). The presence of GvHD I-IV at the time of HC symptoms manifestation was also characterized by positive correlation with HC duration. It was 36 days (22, 50; 95% CI) in patients with GvHD and 18 days (15, 21; 95% CI) in patients without GvHD (p=0.013).

Conclusions

Our data didn’t show any clinical efficiency of 1.2 g/kg IVIG (Immunovenin® 5%, 50mg/mL by Microgen) effectiveness in post allo-HSCT HC patients. Conditioning regimen intensity and GvHD I-IV are the risk factors for HC longer duration. The further prospective study is needed to make final conclusions on method’s effectiveness.

Keywords

Allogeneic hematopoietic stem cell transplantation, hemorrhagic cystitis, intravenous immunoglobulin, IVIG, risk factors, graft-versus-host disease (GvHD).

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["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) "26404" ["VALUE"]=> array(2) { ["TEXT"]=> string(378) "<p>Alexander A. Shcherbakov, Alena N. Zaytseva, Maksim A. Kucher, Irina S. Iarushkina, Olga N. Zatsepina, Ekaterina S. Kulneva, Olesya V. Paina, Ruslana V. Klementeva, Оleg V. Goloshchapov, Ivan S. Moiseev, Ludmila S. Zubarovskaya,<br> <span style="border: 1px solid black; margin: 0; padding: 2px 2px;">Boris V. Afanasyev</span> </p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(338) "

Alexander A. Shcherbakov, Alena N. Zaytseva, Maksim A. Kucher, Irina S. Iarushkina, Olga N. Zatsepina, Ekaterina S. Kulneva, Olesya V. Paina, Ruslana V. Klementeva, Оleg V. Goloshchapov, Ivan S. Moiseev, Ludmila S. Zubarovskaya,
Boris V. Afanasyev

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Alexander A. Shcherbakov, Alena N. Zaytseva, Maksim A. Kucher, Irina S. Iarushkina, Olga N. Zatsepina, Ekaterina S. Kulneva, Olesya V. Paina, Ruslana V. Klementeva, Оleg V. Goloshchapov, Ivan S. Moiseev, Ludmila S. Zubarovskaya,
Boris V. Afanasyev

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Hemorrhagic cystitis (HC) is a frequent complication in allogeneic hematopoietic stem cell transplantation (allo- HSCT). Human BK-polyomavirus (BKPyV) may be one of the main agents found in late HC developing after allo-HSCT. In previous studies, intravenous immunoglobulin (IVIG) preparations were shown to neutralize BKPyV in mice cell cultures and to reduce BK virus nephropathy in kidney transplantation. The aim of current study was to evaluate efficiency of HC treatment with IVIG in allo-HSCT recipients, with respect to conditioning regimen intensity and presence of graft-versus-host disease (GvHD).

Patients and methods

A total of 1037 allo-HSCT recipients transplanted in R. M. Gorbacheva Memorial institute for Pediatric Oncology, Hematology and Transplantation in 2013-2018 were included into retrospective open single-center cohort study. HC was registered in 118 (11.4%) cases. According to inclusion criteria, only 90 patients were enrolled to the final analysis. This cohort was divided into two groups based on HC therapy used: the intervention group (n=42) included patients with standard HC treatment with addition of IVIG; the control group (n=48) – with standard HC therapy only.

Results

The median HC duration in common group (IVIG and control) was 21 days. There was no statistically significant difference in HC duration between the two groups, with the median of 24 days (16, 32; 95% CI) in the intervention group (standard therapy + IVIG), and 24 days (2, 46; 95% CI) in control group, respectively (p=0.39). The median HC duration in MAC and RIC was 35 days (18, 52; 95% CI) versus 17 days (14, 20; 95% CI), respectively (p<0.01). The presence of GvHD I-IV at the time of HC symptoms manifestation was also characterized by positive correlation with HC duration. It was 36 days (22, 50; 95% CI) in patients with GvHD and 18 days (15, 21; 95% CI) in patients without GvHD (p=0.013).

Conclusions

Our data didn’t show any clinical efficiency of 1.2 g/kg IVIG (Immunovenin® 5%, 50mg/mL by Microgen) effectiveness in post allo-HSCT HC patients. Conditioning regimen intensity and GvHD I-IV are the risk factors for HC longer duration. The further prospective study is needed to make final conclusions on method’s effectiveness.

Keywords

Allogeneic hematopoietic stem cell transplantation, hemorrhagic cystitis, intravenous immunoglobulin, IVIG, risk factors, graft-versus-host disease (GvHD).

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Hemorrhagic cystitis (HC) is a frequent complication in allogeneic hematopoietic stem cell transplantation (allo- HSCT). Human BK-polyomavirus (BKPyV) may be one of the main agents found in late HC developing after allo-HSCT. In previous studies, intravenous immunoglobulin (IVIG) preparations were shown to neutralize BKPyV in mice cell cultures and to reduce BK virus nephropathy in kidney transplantation. The aim of current study was to evaluate efficiency of HC treatment with IVIG in allo-HSCT recipients, with respect to conditioning regimen intensity and presence of graft-versus-host disease (GvHD).

Patients and methods

A total of 1037 allo-HSCT recipients transplanted in R. M. Gorbacheva Memorial institute for Pediatric Oncology, Hematology and Transplantation in 2013-2018 were included into retrospective open single-center cohort study. HC was registered in 118 (11.4%) cases. According to inclusion criteria, only 90 patients were enrolled to the final analysis. This cohort was divided into two groups based on HC therapy used: the intervention group (n=42) included patients with standard HC treatment with addition of IVIG; the control group (n=48) – with standard HC therapy only.

Results

The median HC duration in common group (IVIG and control) was 21 days. There was no statistically significant difference in HC duration between the two groups, with the median of 24 days (16, 32; 95% CI) in the intervention group (standard therapy + IVIG), and 24 days (2, 46; 95% CI) in control group, respectively (p=0.39). The median HC duration in MAC and RIC was 35 days (18, 52; 95% CI) versus 17 days (14, 20; 95% CI), respectively (p<0.01). The presence of GvHD I-IV at the time of HC symptoms manifestation was also characterized by positive correlation with HC duration. It was 36 days (22, 50; 95% CI) in patients with GvHD and 18 days (15, 21; 95% CI) in patients without GvHD (p=0.013).

Conclusions

Our data didn’t show any clinical efficiency of 1.2 g/kg IVIG (Immunovenin® 5%, 50mg/mL by Microgen) effectiveness in post allo-HSCT HC patients. Conditioning regimen intensity and GvHD I-IV are the risk factors for HC longer duration. The further prospective study is needed to make final conclusions on method’s effectiveness.

Keywords

Allogeneic hematopoietic stem cell transplantation, hemorrhagic cystitis, intravenous immunoglobulin, IVIG, risk factors, graft-versus-host disease (GvHD).

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Raisa Gorbacheva Memorial Research Institute of Pediatric Oncology, Hematology and Transplantation, Pavlov University,
St. Petersburg, Russia

Correspondence
Dr. Alexander A. Shcherbakov, Raisa Gorbacheva Memorial Research Institute of Pediatric Oncology, Hematology and Transplantation, Pavlov University, L. Tolstoy St. 6-8, 197022, St. Petersburg, Russia
Phone: +7(904) 604 0884
E-mail: xihmrx@gmail.com

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Raisa Gorbacheva Memorial Research Institute of Pediatric Oncology, Hematology and Transplantation, Pavlov University,
St. Petersburg, Russia

Correspondence
Dr. Alexander A. Shcherbakov, Raisa Gorbacheva Memorial Research Institute of Pediatric Oncology, Hematology and Transplantation, Pavlov University, L. Tolstoy St. 6-8, 197022, St. Petersburg, Russia
Phone: +7(904) 604 0884
E-mail: xihmrx@gmail.com

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Александр А. Щербаков, Алена Н. Зайцева, Максим А. Кучер, Ирина С. Ярушкина, Ольга Н. Зацепина, Екатерина С. Кульнева, Олеся В. Паина, Руслана В. Клементьева, Олег В. Голощапов, Иван С. Моисеев, Людмила С. Зубаровская, Борис В. Афанасьев

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Александр А. Щербаков, Алена Н. Зайцева, Максим А. Кучер, Ирина С. Ярушкина, Ольга Н. Зацепина, Екатерина С. Кульнева, Олеся В. Паина, Руслана В. Клементьева, Олег В. Голощапов, Иван С. Моисеев, Людмила С. Зубаровская, Борис В. Афанасьев

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Персистирование BK полиомавируса (BKPyV) является одной из основных предполагаемых причин, приводящих к развитию позднего ГЦ после алло-ТГСК. Имеются доклинические данные об эффективной нейтрализации BKPyV внутривенным иммуноглобулином G (ВВИГ) в клеточных культурах, а также при BK вирусной нефропатии при трансплантации почки. </p> <h3>Пациенты и методы</h3> <p style="text-align: justify;"> Ретроспективно было изучено 1037 пациентов получивших алло-ТГСК в НИИ детской онкологии, гематологии и трансплантологии им. Р.М. Горбачевой с 2013 по 2018 год. ГЦ был зарегистрирован в 118 (11,4%) случаях, из них, согласно критериям включения, 90 пациентов включены в анализ: группа сравнения с ВВИГ (n=42) и контрольная группа (n=48) со стандартной терапией ГЦ. </p> <h3>Результаты</h3> <p style="text-align: justify;"> Продолжительность ГЦ в общей группе составила 21 день. Не было статистически значимой разницы в продолжительности ГЦ между группой сравнения и контрольной группой – медиана 24 дня (16, 32; 95% CI) и 24 дня (2, 46; 95% CI), соответственно (p=0,39). Продолжительность ГЦ при миелоаблативном режиме кондиционирования составила 35 дней (18, 52; 95% ДИ) и 17 дней (14, 20; 95% ДИ) при немиелоаблативном режиме кондиционирования, р &lt;0,01. Одновременное наличие симптомов ГЦ и РТПХ I-IV степени, также характеризовалось положительной корреляцией с длительностью ГЦ – 36 дней (22, 50; 95% ДИ) у пациентов с РТПХ и 18 дней (15, 21; 95% ДИ) у пациентов без РТПХ, р=0,013. </p> <h3>Выводы</h3> <p style="text-align: justify;"> Настоящее исследование не подтвердило клиническую эффективность ВВИГ (Иммуновенин 5% (50мг/мл) Микроген) в дозе 1,2 гр/кг у пациентов с ГЦ после алло-ТГСК. Факторами риска более длительного течения ГЦ были интенсивность режима кондиционирования и наличие РТПХ I-IV степени. Требуется проведение проспективного исследования для определения эффективности ВВИГ в качестве терапии позднего ГЦ после алло-ТГСК. </p> <h2>Ключевые слова</h2> <p style="text-align: justify;"> Аллогенная трансплантация гемопоэтических стволовых клеток, геморрагический цистит, внутривенный иммуноглобулин, ВВИГ, факторы риска, реакция «трансплантат против хозяина» (РТПХ). </p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(3992) "

Геморрагический цистит (ГЦ) – это частое осложнение при аллогенной трансплантации гемопоэтических стволовых клеток (алло-ТГСК). Персистирование BK полиомавируса (BKPyV) является одной из основных предполагаемых причин, приводящих к развитию позднего ГЦ после алло-ТГСК. Имеются доклинические данные об эффективной нейтрализации BKPyV внутривенным иммуноглобулином G (ВВИГ) в клеточных культурах, а также при BK вирусной нефропатии при трансплантации почки.

Пациенты и методы

Ретроспективно было изучено 1037 пациентов получивших алло-ТГСК в НИИ детской онкологии, гематологии и трансплантологии им. Р.М. Горбачевой с 2013 по 2018 год. ГЦ был зарегистрирован в 118 (11,4%) случаях, из них, согласно критериям включения, 90 пациентов включены в анализ: группа сравнения с ВВИГ (n=42) и контрольная группа (n=48) со стандартной терапией ГЦ.

Результаты

Продолжительность ГЦ в общей группе составила 21 день. Не было статистически значимой разницы в продолжительности ГЦ между группой сравнения и контрольной группой – медиана 24 дня (16, 32; 95% CI) и 24 дня (2, 46; 95% CI), соответственно (p=0,39). Продолжительность ГЦ при миелоаблативном режиме кондиционирования составила 35 дней (18, 52; 95% ДИ) и 17 дней (14, 20; 95% ДИ) при немиелоаблативном режиме кондиционирования, р <0,01. Одновременное наличие симптомов ГЦ и РТПХ I-IV степени, также характеризовалось положительной корреляцией с длительностью ГЦ – 36 дней (22, 50; 95% ДИ) у пациентов с РТПХ и 18 дней (15, 21; 95% ДИ) у пациентов без РТПХ, р=0,013.

Выводы

Настоящее исследование не подтвердило клиническую эффективность ВВИГ (Иммуновенин 5% (50мг/мл) Микроген) в дозе 1,2 гр/кг у пациентов с ГЦ после алло-ТГСК. Факторами риска более длительного течения ГЦ были интенсивность режима кондиционирования и наличие РТПХ I-IV степени. Требуется проведение проспективного исследования для определения эффективности ВВИГ в качестве терапии позднего ГЦ после алло-ТГСК.

Ключевые слова

Аллогенная трансплантация гемопоэтических стволовых клеток, геморрагический цистит, внутривенный иммуноглобулин, ВВИГ, факторы риска, реакция «трансплантат против хозяина» (РТПХ).

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Геморрагический цистит (ГЦ) – это частое осложнение при аллогенной трансплантации гемопоэтических стволовых клеток (алло-ТГСК). Персистирование BK полиомавируса (BKPyV) является одной из основных предполагаемых причин, приводящих к развитию позднего ГЦ после алло-ТГСК. Имеются доклинические данные об эффективной нейтрализации BKPyV внутривенным иммуноглобулином G (ВВИГ) в клеточных культурах, а также при BK вирусной нефропатии при трансплантации почки.

Пациенты и методы

Ретроспективно было изучено 1037 пациентов получивших алло-ТГСК в НИИ детской онкологии, гематологии и трансплантологии им. Р.М. Горбачевой с 2013 по 2018 год. ГЦ был зарегистрирован в 118 (11,4%) случаях, из них, согласно критериям включения, 90 пациентов включены в анализ: группа сравнения с ВВИГ (n=42) и контрольная группа (n=48) со стандартной терапией ГЦ.

Результаты

Продолжительность ГЦ в общей группе составила 21 день. Не было статистически значимой разницы в продолжительности ГЦ между группой сравнения и контрольной группой – медиана 24 дня (16, 32; 95% CI) и 24 дня (2, 46; 95% CI), соответственно (p=0,39). Продолжительность ГЦ при миелоаблативном режиме кондиционирования составила 35 дней (18, 52; 95% ДИ) и 17 дней (14, 20; 95% ДИ) при немиелоаблативном режиме кондиционирования, р <0,01. Одновременное наличие симптомов ГЦ и РТПХ I-IV степени, также характеризовалось положительной корреляцией с длительностью ГЦ – 36 дней (22, 50; 95% ДИ) у пациентов с РТПХ и 18 дней (15, 21; 95% ДИ) у пациентов без РТПХ, р=0,013.

Выводы

Настоящее исследование не подтвердило клиническую эффективность ВВИГ (Иммуновенин 5% (50мг/мл) Микроген) в дозе 1,2 гр/кг у пациентов с ГЦ после алло-ТГСК. Факторами риска более длительного течения ГЦ были интенсивность режима кондиционирования и наличие РТПХ I-IV степени. Требуется проведение проспективного исследования для определения эффективности ВВИГ в качестве терапии позднего ГЦ после алло-ТГСК.

Ключевые слова

Аллогенная трансплантация гемопоэтических стволовых клеток, геморрагический цистит, внутривенный иммуноглобулин, ВВИГ, факторы риска, реакция «трансплантат против хозяина» (РТПХ).

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	 Елена Е. Лепик<sup>1</sup>, Андрей В. Козлов<sup>1</sup>, Евгения С. Борзенкова<sup>1</sup>, Юрий Р. Залялов<sup>1</sup>, Кирилл В. Лепик<sup>1</sup>, <br>
	 Елена В. Кондакова<sup>1</sup>, Вадим В. Байков<sup>1</sup>, Иван С. Моисеев<sup>1</sup>, Татьяна В. Шнайдер<sup>2</sup>, Наталья Б. Михайлова<sup>1</sup>, <br>
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<sup>2</sup> Ленинградская областная клиническая больница, Санкт-Петербург, Россия</p>
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2 Ленинградская областная клиническая больница, Санкт-Петербург, Россия
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                    [TEXT] => <p style="text-align: justify;">Т-клеточные лимфомы (ТКЛ) представляют собой агрессивные неходжкинские лимфомы, которые не имеют успешных стандартов лечения. Почти у 70% пациентов после первой линии терапии развивается рецидив или рефрактерное течение (р/р). Ряд новых терапевтических подходов нацелены на улучшение результатов лечения у пациентов с р/р ТКЛ.
В данной статье обобщен опыт Первого Санкт-Петербургского государственного медицинского университета им. Павлова в лечении пациентов с Т-клеточными лимфомами. Мы проанализировали данные 47 пациентов, которые проходила лечение с 2005 по 2019 год – на момент анализа 44 пациента имеют р/р течение заболевания и 3 пациента находятся в полном ответе после проведенной первой линии терапии. Средний возраст составил 45 лет (от 1 года до 72 лет). Это были преимущественно пациенты с периферическими Т-клеточными лимфомами, неуточненными (41%). Среди всех пациентов n26 (55%) имели первичное химиорезистентное течение, в то время как у остальных n18 (38%) был рецидив после первой линии терапии.</p>
<p style="text-align: justify;">
Опыт нашего центра включает в себя использование новых вариантов лечения р/р ТКЛ: антиCD30 моноклональное антитело – брентуксимаб, ингибитор ALK – кризотиниб, ингибитор контрольных точек – ниволумаб и иммунотерапию, включающую проведение трансплантации гемопоэтических стволовых клеток (ТГСК). В общей сложности 24 пациентам выполнена ТГСК: высокодозная химиотерапия с последующей аутологичной ТГСК (ауто-ТГСК) проведена 16 пациентам, 13 пациентам – аллогенная ТГСК (алло-ТГСК) (из них 5 пациентов с рецидивами после ауто-ТГСК).
На момент анализа 35 пациентов были живы. Медиана наблюдения за живыми пациентами составила 35 месяцев (6-122 мес.). Медиана общей выживаемости не была достигнута, 5-летняя выживаемость составила 81%, 8-летняя общая выживаемость – 78%. Статус заболевания при последнем наблюдении был следующий: полный ответ у 22 пациентов, частичный ответ у 4 пациентов и прогрессия заболевания у 21. Среди факторов, значительно связанных с неблагоприятным прогнозом, были низкий статус ECOG и B-симптомы на момент постановки диагноза (p=0,06). Пациенты, которые перенесли ТГСК, имели лучший статус заболевания на момент последнего наблюдения: 17/19 (89%) были в полном ответе, по сравнению с 5/16 (31%) у пациентов, которым не проводилась ТГСК. 5-летняя общая выживаемость у пациентов с ТКЛ после ауто-ТГСК и алло-ТГСК составила 87% и 77% соответственно. Результаты анализа показывают, что введение новых агентов и консолидация с помощью высокодозной химиотерапии с последующей ауто-ТГСК или алло-ТГСК в отдельных случаях могут улучшить результаты у пациентов с рецидивирующей или рефрактерной Т-клеточной лимфомой. Схемы, основанные на применении брентуксимаба ведотина и ниволумаба, могут быть успешно использованы в качестве bridge-терапии перед алло-ТГСК.</p>
<h2>Ключевые слова</h2>
<p style="text-align: justify;">
T-клеточные лимфомы, аутологичная трансплантация гемопоэтических стволовых клеток, аллогенная трансплантация гемопоэтических стволовых клеток, брентуксимаб ведотин, ниволумаб.    </p>
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Т-клеточные лимфомы (ТКЛ) представляют собой агрессивные неходжкинские лимфомы, которые не имеют успешных стандартов лечения. Почти у 70% пациентов после первой линии терапии развивается рецидив или рефрактерное течение (р/р). Ряд новых терапевтических подходов нацелены на улучшение результатов лечения у пациентов с р/р ТКЛ.
В данной статье обобщен опыт Первого Санкт-Петербургского государственного медицинского университета им. Павлова в лечении пациентов с Т-клеточными лимфомами. Мы проанализировали данные 47 пациентов, которые проходила лечение с 2005 по 2019 год – на момент анализа 44 пациента имеют р/р течение заболевания и 3 пациента находятся в полном ответе после проведенной первой линии терапии. Средний возраст составил 45 лет (от 1 года до 72 лет). Это были преимущественно пациенты с периферическими Т-клеточными лимфомами, неуточненными (41%). Среди всех пациентов n26 (55%) имели первичное химиорезистентное течение, в то время как у остальных n18 (38%) был рецидив после первой линии терапии.

Опыт нашего центра включает в себя использование новых вариантов лечения р/р ТКЛ: антиCD30 моноклональное антитело – брентуксимаб, ингибитор ALK – кризотиниб, ингибитор контрольных точек – ниволумаб и иммунотерапию, включающую проведение трансплантации гемопоэтических стволовых клеток (ТГСК). В общей сложности 24 пациентам выполнена ТГСК: высокодозная химиотерапия с последующей аутологичной ТГСК (ауто-ТГСК) проведена 16 пациентам, 13 пациентам – аллогенная ТГСК (алло-ТГСК) (из них 5 пациентов с рецидивами после ауто-ТГСК).
На момент анализа 35 пациентов были живы. Медиана наблюдения за живыми пациентами составила 35 месяцев (6-122 мес.). Медиана общей выживаемости не была достигнута, 5-летняя выживаемость составила 81%, 8-летняя общая выживаемость – 78%. Статус заболевания при последнем наблюдении был следующий: полный ответ у 22 пациентов, частичный ответ у 4 пациентов и прогрессия заболевания у 21. Среди факторов, значительно связанных с неблагоприятным прогнозом, были низкий статус ECOG и B-симптомы на момент постановки диагноза (p=0,06). Пациенты, которые перенесли ТГСК, имели лучший статус заболевания на момент последнего наблюдения: 17/19 (89%) были в полном ответе, по сравнению с 5/16 (31%) у пациентов, которым не проводилась ТГСК. 5-летняя общая выживаемость у пациентов с ТКЛ после ауто-ТГСК и алло-ТГСК составила 87% и 77% соответственно. Результаты анализа показывают, что введение новых агентов и консолидация с помощью высокодозной химиотерапии с последующей ауто-ТГСК или алло-ТГСК в отдельных случаях могут улучшить результаты у пациентов с рецидивирующей или рефрактерной Т-клеточной лимфомой. Схемы, основанные на применении брентуксимаба ведотина и ниволумаба, могут быть успешно использованы в качестве bridge-терапии перед алло-ТГСК.
Ключевые слова

T-клеточные лимфомы, аутологичная трансплантация гемопоэтических стволовых клеток, аллогенная трансплантация гемопоэтических стволовых клеток, брентуксимаб ведотин, ниволумаб.    
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	 Elena E. Lepik<sup>1</sup>, Andrey V. Kozlov<sup>1</sup>, Evgenia S. Borzenkova<sup>1</sup>,<br>
	 Yury R. Zalyalov<sup>1</sup>, Kirill V. Lepik<sup>1</sup>, Elena V. Kondakova<sup>1</sup>, Vadim V. Baykov<sup>1</sup>, Ivan S. Moiseev<sup>1</sup>, Tatiana V. Schneider<sup>2</sup>, <br>
	 Natalia B. Mikhaylova<sup>1</sup>, <span style="border: 1px solid black; margin: 0; padding: 1px 2px;">Boris V. Afanasyev<sup>1</sup></span>
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	 Elena E. Lepik1, Andrey V. Kozlov1, Evgenia S. Borzenkova1,

	 Yury R. Zalyalov1, Kirill V. Lepik1, Elena V. Kondakova1, Vadim V. Baykov1, Ivan S. Moiseev1, Tatiana V. Schneider2, 

	 Natalia B. Mikhaylova1, Boris V. Afanasyev1

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                    [TEXT] => <p><sup>1</sup> Raisa Gorbacheva Memorial Research Institute of Pediatric Oncology, Hematology and Transplantation, Pavlov University,<br> St. Petersburg, Russia<br>
<sup>2</sup> Leningrad Regional Clinical Hospital, St. Petersburg, Russia </p>
<br>
<p><b>Correspondence</b><br>
Dr. Elena E. Lepik, Clinical Hematologist, Oncology Department, Raisa Gorbacheva Memorial Research Institute of Pediatric Oncology, Hematology and Transplantation, Pavlov University, L. Tolstoy St. 6-8, 197022, St. Petersburg, Russia<br>
Phone: +7 (905) 226 8922<br>
E-mail: ee.dav@mail.ru</p>

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1 Raisa Gorbacheva Memorial Research Institute of Pediatric Oncology, Hematology and Transplantation, Pavlov University,
 St. Petersburg, Russia

2 Leningrad Regional Clinical Hospital, St. Petersburg, Russia 


Correspondence

Dr. Elena E. Lepik, Clinical Hematologist, Oncology Department, Raisa Gorbacheva Memorial Research Institute of Pediatric Oncology, Hematology and Transplantation, Pavlov University, L. Tolstoy St. 6-8, 197022, St. Petersburg, Russia

Phone: +7 (905) 226 8922

E-mail: ee.dav@mail.ru

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                    [TEXT] => <p style="text-align: justify;">T-cell lymphomas (TCL) comprise a group of aggressive non-Hodgkin lymphomas, which do not have successful treatment standards. Almost 70% of patients undergoing first-line therapy develop a relapse or refractory (r/r) disease. A number of novel therapy approaches are aimed for improvement of outcomes in patients with r/r TCL. This report summarizes clinical experience of Pavlov Medical University in the treatment of T cell lymphomas. We analyzed data of 47 patients with TCL treated from 2005 to 2019. Of them, 44 had r/r TCL, and 3 patients were in complete response after first line therapy. The median age was 45 years (range 1-72 years). These were predominantly patients with peripheral T-cell lymphomas not otherwise specified (TCL-NOS, 41%).
26 patients (55% of total) had a primary chemoresistant disease, while the remaining 18 patients (38% of total) had a relapse after initial treatment. </p>
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Our center has implemented new treatment options for r/r TCL, i.e., anti CD30 monoclonal antibody brentuximab, ALK inhibitor crizotinib, immunotherapy with checkpoint inhibitors nivolumab, and hematopoietic stem cell transplantation (HSCT). A total of 24 patients underwent: high-dose chemotherapy with autologous HSCT (auto-HSCT) was performed in 16 cases, 13 patients were subjected to allogeneic HSCT (allo-HSCT), including 5 relapsed patients after auto-HSCT. At the time of analysis, 35 patients remained alive. The median follow-up of surviving patients was 35 months (6-122 mo). The median overall survival (OS) was not reached, 5-year survival rate was 81%, and 8-year survival rate was 78%. Complete remission (CR) at the last follow-up was diagnosed in 22 patients; partial response (PR), in 4 cases, and progression of the disease (PD) was revealed in 21 patients. Among factors significantly associated with adverse prognosis were lower ECOG performance status and B-symptoms at the time of diagnosis (p=0.06). The patients who underwent HSCT showed significantly better disease status at the moment of last follow up: 17/19 (89%) were in CR, versus 5/16 (31%) among the patients not subjected to HSCT. 5-year overall survival rates after auto-HSCT and allo-HSCT were 87% and 77%, respectively. The results show that implementation of novel therapeutic agents, as well as consolidation with high-dose chemotherapy and auto- or allo-HSCT in selected cases improve outcomes in patients with r/r TCL. Brentuximab vedotin and nivolumab-based regimens may be successfully used as a bridge therapy before HSCT.   </p>
<h2>Keywords</h2>
<p style="text-align: justify;">
T-cell lymphoma, autologous hematopoietic stem cells transplantation, allogeneic hematopoietic stem cells transplantation, brentuximab vedotin, nivolumab. </p>
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T-cell lymphomas (TCL) comprise a group of aggressive non-Hodgkin lymphomas, which do not have successful treatment standards. Almost 70% of patients undergoing first-line therapy develop a relapse or refractory (r/r) disease. A number of novel therapy approaches are aimed for improvement of outcomes in patients with r/r TCL. This report summarizes clinical experience of Pavlov Medical University in the treatment of T cell lymphomas. We analyzed data of 47 patients with TCL treated from 2005 to 2019. Of them, 44 had r/r TCL, and 3 patients were in complete response after first line therapy. The median age was 45 years (range 1-72 years). These were predominantly patients with peripheral T-cell lymphomas not otherwise specified (TCL-NOS, 41%).
26 patients (55% of total) had a primary chemoresistant disease, while the remaining 18 patients (38% of total) had a relapse after initial treatment. 

Our center has implemented new treatment options for r/r TCL, i.e., anti CD30 monoclonal antibody brentuximab, ALK inhibitor crizotinib, immunotherapy with checkpoint inhibitors nivolumab, and hematopoietic stem cell transplantation (HSCT). A total of 24 patients underwent: high-dose chemotherapy with autologous HSCT (auto-HSCT) was performed in 16 cases, 13 patients were subjected to allogeneic HSCT (allo-HSCT), including 5 relapsed patients after auto-HSCT. At the time of analysis, 35 patients remained alive. The median follow-up of surviving patients was 35 months (6-122 mo). The median overall survival (OS) was not reached, 5-year survival rate was 81%, and 8-year survival rate was 78%. Complete remission (CR) at the last follow-up was diagnosed in 22 patients; partial response (PR), in 4 cases, and progression of the disease (PD) was revealed in 21 patients. Among factors significantly associated with adverse prognosis were lower ECOG performance status and B-symptoms at the time of diagnosis (p=0.06). The patients who underwent HSCT showed significantly better disease status at the moment of last follow up: 17/19 (89%) were in CR, versus 5/16 (31%) among the patients not subjected to HSCT. 5-year overall survival rates after auto-HSCT and allo-HSCT were 87% and 77%, respectively. The results show that implementation of novel therapeutic agents, as well as consolidation with high-dose chemotherapy and auto- or allo-HSCT in selected cases improve outcomes in patients with r/r TCL. Brentuximab vedotin and nivolumab-based regimens may be successfully used as a bridge therapy before HSCT.   
Keywords

T-cell lymphoma, autologous hematopoietic stem cells transplantation, allogeneic hematopoietic stem cells transplantation, brentuximab vedotin, nivolumab. 
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                    [TEXT] => <p style="text-align: justify;">Периферические Т-клеточные лимфомы (ПТКЛ) являются гетерогенной группой редких агрессивных лимфом, состоящей из более чем 20 различных клинических форм и представляющих около 10% всех неходжкинских лимфом, диагностированных в Западном мире. Учитывая их гетерогенность, отсутствует консенсус, касающийся наилучшего лечения первой линии, роль аутологичной или аллогенной трансплантации гемопоэтических клеток (ТГСК) в качестве консолидации пока противоречива. Чтобы изучить реальные исходы у пациентов с ПТКЛ, направленных для ТГСК в наше учреждение, мы ретроспективно изучили клинические исходы у 26 пациентов, которым выполняли трансплантацию либо в качестве консолидирующей терапии первой линии или при рецидиве заболевания в период с января 2000 по июль 2018 г. Медианный срок наблюдения составлял 6,3 года; 19 больных получили ауто-ТГСК, 16 – в качестве первой консолидации и 3 – по поводу рецидива болезни. Общая выживаемость (ОВ) и безрецидивная выживаемость (БРВ) были, соответственно, 62% и 59%. Семи больным было проведена алло-ТГСК, четыре – консолидация первой линии и трем – после рецидива. Шесть больных живы и один умер в связи с процедурой ТГСК. Этот вид летальности составил 3.7% для всей группы, а 6-летние показатели ОВ и БРВ были, соответственно, 74% и 69%. Наши результаты предполагают, что аутологичные и аллогенные ТГСК являются эффективным и безопасным вариантом в целях консолидации больных ПТКЛ с неблагоприятным профилем риска, но нужна их валидация в проспективных исследованиях, включающих большое число пациентов.</p>
<h2>Ключевые слова</h2>
<p style="text-align: justify;">Периферические Т-клеточные лимфомы, терапия первой линии, CHOP, Брентуксимаб ведотин, трансплантация гемопоэтических клеток, аллогенная, аутологичная.  </p>  
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Ключевые слова
Периферические Т-клеточные лимфомы, терапия первой линии, CHOP, Брентуксимаб ведотин, трансплантация гемопоэтических клеток, аллогенная, аутологичная.  
  
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<br>
<p><b>Correspondence</b><br>
Prof. Dr. Manuel Abecasis, Director, Hematology Department, Instituto Português Oncologia, <br>R. Professor Lima Basto 1099-093, Lisboa, Portugal</p>
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Instituto Português Oncologia de Lisboa Francisco Gentil, Lisboa, Portugal


Correspondence

Prof. Dr. Manuel Abecasis, Director, Hematology Department, Instituto Português Oncologia, 
R. Professor Lima Basto 1099-093, Lisboa, Portugal
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                    [TEXT] => <p style="text-align: justify;">Peripheral T-cell lymphomas (PTCLs) are a rare and heterogeneous group of aggressive lymphomas comprising more than 20 different entities and representing about 10% of all non-Hodgkin lymphomas diagnosed in the Western World. Given their heterogeneity, there is no consensus regarding the best first-line treatment and the role of autologous/allogeneic hematopoietic stem cell transplantation (HSCT) as consolidation is controversial. To examine the real-world outcomes for patients with PTCL submitted to HSCT in our institution we retrospectively reviewed the clinical outcomes of 26 patients who were given a transplant either as first-line consolidation or in relapse between January 2000 and July 2018. The median follow-up is 6.3 years; 19 patients had an autologous HSCT, 16 as upfront consolidation and 3, for relapsed disease. Overall survival (OS) and relapse free survival (RFS) were, respectively, 62% and 59%. Seven patients had an allograft, 4 as upfront consolidation and 3 after relapse; 6 are alive and 1 died due to transplant-related mortality (TRM). TRM was 3.7% for the entire population and the 6-year OS and PFS were 74% and 69%, respectively. Our results suggest that autologous/allogeneic HSCT is an effective and safe option for the consolidation of adverse-risk profile patients with PTCL, but they need to be validated in prospective studies including a larger number of patients.</p>
<h2>Keywords</h2>
<p style="text-align: justify;">Peripheral T-cell lymphomas, first-line therapy, CHOP, Brentuximab vedotin, hematopoietic stem cell transplantation, allogeneic, autologous. </p>
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Peripheral T-cell lymphomas (PTCLs) are a rare and heterogeneous group of aggressive lymphomas comprising more than 20 different entities and representing about 10% of all non-Hodgkin lymphomas diagnosed in the Western World. Given their heterogeneity, there is no consensus regarding the best first-line treatment and the role of autologous/allogeneic hematopoietic stem cell transplantation (HSCT) as consolidation is controversial. To examine the real-world outcomes for patients with PTCL submitted to HSCT in our institution we retrospectively reviewed the clinical outcomes of 26 patients who were given a transplant either as first-line consolidation or in relapse between January 2000 and July 2018. The median follow-up is 6.3 years; 19 patients had an autologous HSCT, 16 as upfront consolidation and 3, for relapsed disease. Overall survival (OS) and relapse free survival (RFS) were, respectively, 62% and 59%. Seven patients had an allograft, 4 as upfront consolidation and 3 after relapse; 6 are alive and 1 died due to transplant-related mortality (TRM). TRM was 3.7% for the entire population and the 6-year OS and PFS were 74% and 69%, respectively. Our results suggest that autologous/allogeneic HSCT is an effective and safe option for the consolidation of adverse-risk profile patients with PTCL, but they need to be validated in prospective studies including a larger number of patients.
Keywords
Peripheral T-cell lymphomas, first-line therapy, CHOP, Brentuximab vedotin, hematopoietic stem cell transplantation, allogeneic, autologous. 
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<sup>2</sup> НИИ детской онкологии, гематологии и трансплантологии им. Р. М. Горбачевой, Первый Санкт-Петербургский государственный медицинский университет им. И. П. Павлова, Санкт-Петербург, Россия</p>
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2 НИИ детской онкологии, гематологии и трансплантологии им. Р. М. Горбачевой, Первый Санкт-Петербургский государственный медицинский университет им. И. П. Павлова, Санкт-Петербург, Россия
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                    [TEXT] => <p style="text-align: justify;">Биспецифическое моноклональное антитело блинатумомаб против антигена CD19 используется для лечения острого лимфобластного лейкоза (ОЛЛ). Несколько дополнительных молекулярных мишеней могут быть использованы для комбинированного лечения без обычной химиотерапии, а именно ингибиторы тирозинкиназ, в т.ч. BCR-ABL, FLT3 и делеции IKZF1. Целью данного исследования было определение токсичности и клинической эффективности  комбинированного лечения блинатумомабом и несколькими ингибиторами тирозинкиназы. </p>
<h3>Пациенты и методы</h3>
<p style="text-align: justify;">
С октября 2015 по октябрь 2018 г. нами пролечены 11 пациентов с рецидивируюшим/рефрактерным течением ОЛЛ. Терапия блинатумомабом состояла из 4-5 циклов с 2-недельными интервалами (28 мкг/день посредством постоянной инфузии в течение 28 дней, при дозе 9 мкг/день в течении 1-й недели 1-го цикла). Семь BCR-ABL-позитивных больных и 2 пациента с делецией IKZF1 получали исходно дазатиниб (140 мг/день), один пациент с FLT3-ITD – сорафениб (800 мг/день). Один BCR-ABL-позитивный больной с мутацией T315I получал понатиниб (45 мг/день). Пациентам с делециями IKZF1 назначалась ATRA (45 мг/м<sup>2</sup>/день в течение 4 недель) на 1-м цикле блинатумомаба и в первые 2 недели последующих циклов лечения антителом.</p>
<h3>Результаты</h3>
<p style="text-align: justify;">
У пациентов, отвечающих на лечение блинатумомабом, отмечалось статистически достоверное повышение абсолютного количества Т-хелперных лимфоцитов (p=0.0034), T-цитотоксических клеток (p<0.0001) и субпопуляций естественных киллеров (p=0.0006) в периферической крови на протяжении всего периода лечения. T-регуляторные и дубль-негативные T-клетки – потенциальные ингибиторы Т-клеточного ответа на блинатумомаб оставались в пределах нижних значений нормы. Гипогаммаглобулинемия наблюдалась у 8 из 11 пациентов. Полная ремиссия (ПР) была получена у 10 больных после 1-го цикла блинатумомаба, прогрессия заболевания – в одном случае. Из 10 пациентов, в 9 случаях достигнута полная молекулярная ремиссия (ПМР) и в одном – полная цитогенетическая ремиссия. Выполнены девять аллогенных трансплантаций гемопоэтических стволовых клеток (ТГСК) и одна аутологичная ТГСК в 10 случаях ПР. Выявлены три рецидива в ЦНС после алло-ТГСК и один молекулярный рецидив после ауто-ТГСК. Один пациент скончался от септического шока после алло-ТГСК. </p>
<h3>Выводы</h3>
<p style="text-align: justify;">
Блинатомомаб в коимбинации с ингибиторами тирозинкиназ имеет высокий терапевтический потенциал для индукции ремиссии в определенных случаях ОЛЛ без применения обычной химиотерапии. Высокая частота потенциальных рецидивов в ЦНС может быть снижена за счет более интенсивной интратекальной профилактики. </p>  
<h2>Ключевые слова</h2>
<p style="text-align: justify;">
Острый лимфобластный лейкоз, блинатумомаб, ингибиторы тирозинкиназ.  </p>
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Биспецифическое моноклональное антитело блинатумомаб против антигена CD19 используется для лечения острого лимфобластного лейкоза (ОЛЛ). Несколько дополнительных молекулярных мишеней могут быть использованы для комбинированного лечения без обычной химиотерапии, а именно ингибиторы тирозинкиназ, в т.ч. BCR-ABL, FLT3 и делеции IKZF1. Целью данного исследования было определение токсичности и клинической эффективности  комбинированного лечения блинатумомабом и несколькими ингибиторами тирозинкиназы. 
Пациенты и методы

С октября 2015 по октябрь 2018 г. нами пролечены 11 пациентов с рецидивируюшим/рефрактерным течением ОЛЛ. Терапия блинатумомабом состояла из 4-5 циклов с 2-недельными интервалами (28 мкг/день посредством постоянной инфузии в течение 28 дней, при дозе 9 мкг/день в течении 1-й недели 1-го цикла). Семь BCR-ABL-позитивных больных и 2 пациента с делецией IKZF1 получали исходно дазатиниб (140 мг/день), один пациент с FLT3-ITD – сорафениб (800 мг/день). Один BCR-ABL-позитивный больной с мутацией T315I получал понатиниб (45 мг/день). Пациентам с делециями IKZF1 назначалась ATRA (45 мг/м2/день в течение 4 недель) на 1-м цикле блинатумомаба и в первые 2 недели последующих циклов лечения антителом.
Результаты

У пациентов, отвечающих на лечение блинатумомабом, отмечалось статистически достоверное повышение абсолютного количества Т-хелперных лимфоцитов (p=0.0034), T-цитотоксических клеток (p<0.0001) и субпопуляций естественных киллеров (p=0.0006) в периферической крови на протяжении всего периода лечения. T-регуляторные и дубль-негативные T-клетки – потенциальные ингибиторы Т-клеточного ответа на блинатумомаб оставались в пределах нижних значений нормы. Гипогаммаглобулинемия наблюдалась у 8 из 11 пациентов. Полная ремиссия (ПР) была получена у 10 больных после 1-го цикла блинатумомаба, прогрессия заболевания – в одном случае. Из 10 пациентов, в 9 случаях достигнута полная молекулярная ремиссия (ПМР) и в одном – полная цитогенетическая ремиссия. Выполнены девять аллогенных трансплантаций гемопоэтических стволовых клеток (ТГСК) и одна аутологичная ТГСК в 10 случаях ПР. Выявлены три рецидива в ЦНС после алло-ТГСК и один молекулярный рецидив после ауто-ТГСК. Один пациент скончался от септического шока после алло-ТГСК. 
Выводы

Блинатомомаб в коимбинации с ингибиторами тирозинкиназ имеет высокий терапевтический потенциал для индукции ремиссии в определенных случаях ОЛЛ без применения обычной химиотерапии. Высокая частота потенциальных рецидивов в ЦНС может быть снижена за счет более интенсивной интратекальной профилактики. 
  
Ключевые слова

Острый лимфобластный лейкоз, блинатумомаб, ингибиторы тирозинкиназ.  
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                    [TEXT] => <p>Andrey N. Sokolov<sup>1</sup>, Elena N. Parovichnikova<sup>1</sup>, Vera V. Troitskaya<sup>1</sup>, Larisa A. Kuzmina<sup>1</sup>, Irina V. Galtseva<sup>1</sup>, Sergei M. Kulikov<sup>1</sup>, Sergey N. Bondarenko<sup>2</sup>, Irina A. Lukyanova<sup>1</sup>, Tatiana I. Lobanova<sup>1</sup>, Ekaterina I. Usikova<sup>1</sup>, Ksenia I. Zarubina<sup>1</sup>, Olga A. Gavrilina<sup>1</sup>, Julia O. Davidova<sup>1</sup>, Nikolai M. Kapranov<sup>1</sup>, Valeriy G. Savchenko<sup>1</sup></p>
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Andrey N. Sokolov1, Elena N. Parovichnikova1, Vera V. Troitskaya1, Larisa A. Kuzmina1, Irina V. Galtseva1, Sergei M. Kulikov1, Sergey N. Bondarenko2, Irina A. Lukyanova1, Tatiana I. Lobanova1, Ekaterina I. Usikova1, Ksenia I. Zarubina1, Olga A. Gavrilina1, Julia O. Davidova1, Nikolai M. Kapranov1, Valeriy G. Savchenko1
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                    [TEXT] => <p><sup>1</sup> National Research Center for Hematology of the Ministry of Healthcare of the Russian Federation, Moscow, Russia<br>
<sup>2</sup> Raisa Gorbacheva Memorial Research Institute of Pediatric Oncology, Hematology and Transplantation, Pavlov University,<br>
St. Petersburg, Russia</p><br>
<p><b>Correspondence</b><br>
Dr. Andrey N. Sokolov, National Research Center for Hematology, 4A Novyi Zykovskii Lane, 125167, Moscow, Russia<br>
Phone: +7 (495) 612 4592<br>
E-mail: sokolov.a@blood.ru</p>

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1 National Research Center for Hematology of the Ministry of Healthcare of the Russian Federation, Moscow, Russia

2 Raisa Gorbacheva Memorial Research Institute of Pediatric Oncology, Hematology and Transplantation, Pavlov University,

St. Petersburg, Russia


Correspondence

Dr. Andrey N. Sokolov, National Research Center for Hematology, 4A Novyi Zykovskii Lane, 125167, Moscow, Russia

Phone: +7 (495) 612 4592

E-mail: sokolov.a@blood.ru

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                    [TEXT] => <p style="text-align: justify;">Bispecific monoclonal antibody blinatumomab is targeting CD19, being applied for treatment of acute lymphoblastic leukemia (ALL). Several additional targets could be used for combined chemo-free treatment with thyrosine kinase inhibitors: BCR-ABL, FLT3 and IKZF1 deletions are amongst them. In the following study, we aimed to assess toxicity and clinical effectiveness of the combination of blinatumomab and several thyrosine kinase inhibitors. </p>
<h3>Patients and methods</h3>
<p style="text-align: justify;">
From October 2015 to October 2018, we treated 11 relapsed/refractory (R/R) ALL patients (pts). The blinatumomab treatment consisted of 4-5 cycles with 2-week intervals (28 mcg/day by continuous infusion during 28 days per cycle with 9 mcg/day during the first week of the first cycle). Seven BCR-ABL-positive and 2 IKZF1-deleted pts received initially dasatinib at 140 mg/day, one case, with FLT3-ITD received sorafenib (800 mg/day). One BCR-ABL-positive pt with T315I mutation was administered ponatinib (45 mg/day). Pts with IKZF1 deletions received ATRA (45 mg/m<sup>2</sup>/day for 4 weeks) of the 1<sup>st</sup> blinatumomab cycle and during first 2 weeks of subsequent blinatumomab cycles. </p>
<h3>Results</h3>
<p style="text-align: justify;">
In the patients responding to blinatumomab treatment, we observed a statistically significant increment of absolute values in T-helper (p=0.0034), T-cytotoxic (p<0.0001) and NK (p=0.0006) cell subpopulations in peripheral blood over the entire treatment period. T-regulatory and double-negative T-cells as potentially inhibitors of T cell response to blinatumomab remained within low values of normal ranges. Hypogammaglobulinemia was observed in 8 of 11 pts. CR was achieved in 10 pts after 1st cycle of blinatumomab, progressive disease was detected in 1 pt. Nine cases of complete molecular remissions (MolCR) and one cytogenetic complete remission were achieved in ten CR pts. Nine allo-BMT and one auto-BMT were performed in 10 CR pts. Three CNS relapses after allo-BMT and one molecular relapse after auto-BMT were diagnosed. One pt died from septic shock after allo-BMT.  </p>
<h3>Conclusion</h3>
<p style="text-align: justify;">
Blinatumomab combined with TKI has high therapeutic potential as induction remission treatment in targeted ALL population without conventional chemotherapy. High rate of potential CNS relapses could be decreased with more intensive intrathecal prophylaxis.</p>
<h2>Keywords</h2>
<p style="text-align: justify;">
Acute lymphoblastic leukemia, blinatumomab, tyrosine kinase inhibitors.   </p>
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Bispecific monoclonal antibody blinatumomab is targeting CD19, being applied for treatment of acute lymphoblastic leukemia (ALL). Several additional targets could be used for combined chemo-free treatment with thyrosine kinase inhibitors: BCR-ABL, FLT3 and IKZF1 deletions are amongst them. In the following study, we aimed to assess toxicity and clinical effectiveness of the combination of blinatumomab and several thyrosine kinase inhibitors. 
Patients and methods

From October 2015 to October 2018, we treated 11 relapsed/refractory (R/R) ALL patients (pts). The blinatumomab treatment consisted of 4-5 cycles with 2-week intervals (28 mcg/day by continuous infusion during 28 days per cycle with 9 mcg/day during the first week of the first cycle). Seven BCR-ABL-positive and 2 IKZF1-deleted pts received initially dasatinib at 140 mg/day, one case, with FLT3-ITD received sorafenib (800 mg/day). One BCR-ABL-positive pt with T315I mutation was administered ponatinib (45 mg/day). Pts with IKZF1 deletions received ATRA (45 mg/m2/day for 4 weeks) of the 1st blinatumomab cycle and during first 2 weeks of subsequent blinatumomab cycles. 
Results

In the patients responding to blinatumomab treatment, we observed a statistically significant increment of absolute values in T-helper (p=0.0034), T-cytotoxic (p<0.0001) and NK (p=0.0006) cell subpopulations in peripheral blood over the entire treatment period. T-regulatory and double-negative T-cells as potentially inhibitors of T cell response to blinatumomab remained within low values of normal ranges. Hypogammaglobulinemia was observed in 8 of 11 pts. CR was achieved in 10 pts after 1st cycle of blinatumomab, progressive disease was detected in 1 pt. Nine cases of complete molecular remissions (MolCR) and one cytogenetic complete remission were achieved in ten CR pts. Nine allo-BMT and one auto-BMT were performed in 10 CR pts. Three CNS relapses after allo-BMT and one molecular relapse after auto-BMT were diagnosed. One pt died from septic shock after allo-BMT.  
Conclusion

Blinatumomab combined with TKI has high therapeutic potential as induction remission treatment in targeted ALL population without conventional chemotherapy. High rate of potential CNS relapses could be decreased with more intensive intrathecal prophylaxis.
Keywords

Acute lymphoblastic leukemia, blinatumomab, tyrosine kinase inhibitors.   
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<h2>Ключевые слова</h2>
<p style="text-align: justify;">
В-клеточный острый лимфобластный лейкоз, рефрактерный и рецидивирующий, моноклональные антитела, блинатумомаб, инотузумаб озогамицин, общий ответ.</p>
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Ключевые слова

В-клеточный острый лимфобластный лейкоз, рефрактерный и рецидивирующий, моноклональные антитела, блинатумомаб, инотузумаб озогамицин, общий ответ.
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Inna V. Markova, Sergey N. Bondarenko, Olesya V. Paina, Bella I. Aubova, Polina V. Kozhokar, Anastasia S. Frolova, 
Ildar M. Barkhatov, Elena V. Babenko, Alexander A. Alyanskiy, Kirill A. Ekushov, Tatyana L. Gindina, Elena V. Semenova, Ivan S. Moiseev, Ludmila S. Zubarovskaya, Boris V. Afanasyev
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                    [TEXT] => <p>Raisa Gorbacheva Memorial Research Institute of Pediatric Oncology, Hematology and Transplantation, Pavlov University,
<br>St. Petersburg, Russia</p><br>
<p><b>Correspondence</b>
Dr. Inna V. Markova, Raisa Gorbacheva Memorial Research Institute of Pediatric Oncology, Hematology and Transplantation, Pavlov University, L. Tolstoy St. 6-8, 197022, St. Petersburg, Russia<br>
Phone: +7 (911) 964 6745</p>
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Raisa Gorbacheva Memorial Research Institute of Pediatric Oncology, Hematology and Transplantation, Pavlov University,

St. Petersburg, Russia


Correspondence
Dr. Inna V. Markova, Raisa Gorbacheva Memorial Research Institute of Pediatric Oncology, Hematology and Transplantation, Pavlov University, L. Tolstoy St. 6-8, 197022, St. Petersburg, Russia

Phone: +7 (911) 964 6745
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                    [TEXT] => <p style="text-align: justify;">Allogeneic hematopoietic stem cell transplantation is an effective method to cure patients with relapse/refractory (r/r) B-cell acute lymphoblastic leukemia, and deep remission without minimal residual disease is the key factor for the favorable outcome. Monoclonal antibodies (bispecific T-cells engager and conjugates) are the promising option to achieve complete remission in these patients. Our aim was to summarize the results of a single-center non-randomized study in order to investigate in real clinical practice the results of treatment with blinatumomab and inotuzumab ozogamicin in children and adults in heterogeneous cohort of r/r B- ALL.</p>
<p style="text-align: justify;">Results of the single-center non-randomized pilot study in real clinical practice showed high response rate in heterogeneous cohort of r/r B- ALL. The study group included 182 patients with r/r B-ALL, their age was from one to 72 years old. 128 patients were treated with blinatumomab, 54 patients received inotuzumab ozogamicin. Overall response was high in both groups, 96 (75%) and 44 (82%). The major predictors of response were adult age (OR= 3.819; 95% CI, 1.744-8.223; p=0.001) and clinical indications, i.e., active disease or measurable residual disease (OR= 0.018; 95% CI, 0.153-0.841; p=0.01). The other clinical or disease parameters had no significant impact on response.</p>
<h2>Keywords</h2>
<p style="text-align: justify;">
B-cell acute lymphoblastic leukemia, relapse/refractory, monoclonal antibodies, blinatumomab, inotuzumab ozogamicin, overall response.</p>
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Allogeneic hematopoietic stem cell transplantation is an effective method to cure patients with relapse/refractory (r/r) B-cell acute lymphoblastic leukemia, and deep remission without minimal residual disease is the key factor for the favorable outcome. Monoclonal antibodies (bispecific T-cells engager and conjugates) are the promising option to achieve complete remission in these patients. Our aim was to summarize the results of a single-center non-randomized study in order to investigate in real clinical practice the results of treatment with blinatumomab and inotuzumab ozogamicin in children and adults in heterogeneous cohort of r/r B- ALL.
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Keywords

B-cell acute lymphoblastic leukemia, relapse/refractory, monoclonal antibodies, blinatumomab, inotuzumab ozogamicin, overall response.
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                    [TEXT] => <p style="text-align: justify;">В настоящий момент отмечается рост числа публикаций по поводу использования посттрансплантационного циклофосфана (ПТЦФ) в профилактике реакции «трансплантат против хозяина» при неродственной трансплантации гемопоэтических стволовых клеток. Тем не менее, большинство этих публикаций включают только пациентов с острыми лейкозами. Данные о возможности применения ПТЦФ при хроническом миелолейкозе (ХМЛ), миелодиспластическом синдроме (МДС) и хронических миелопролиферативных заболеваниях (ХМПЗ) практически отсутствуют, поэтому в данной популяции пациентов было инициировано проспективное рандомизированное сравнение тимоглобулина и ПТЦФ в профилактики РТПХ при 10/10- HLA совместимой неродственной трансплантации (NCT02627573, clinicaltrials.gov). Стратой для рандомизации был индекс pretransplant assessment of mortality. Исследование было прекращено преждевременно в связи с медленным набором пациентов, тем не менее, за время исследования было включено 33 пациента, 16 пациентов в группу тимоглобулина и 17 пациентов в группу ПТЦФ. Медиана наблюдения составила 29 месяцев. Не было выявлено различий ни в частоте первичного неприживления трансплантата (12,50% против 11,8%, p=0,9), ни острой РТПХ II-IV степени (23% <i>vs</i> 6%, p=0,2), ни хронической РТПХ средней и тяжелой степени (25% <i>vs</i> 23%, p=0,4) в группах тимоглобулина и ПТЦФ, соответственно. Однако, было в группе ПТЦФ наблюдалась достоверно лучшая общая (82% <i>vs</i> 30%, p=0,0126) и бессобытийная (61% <i>vs</i> 26%, p=0,0335) выживаемость, а также выживаемость без рецидива и РТПХ (61% <i>vs</i> 16%, p=0,0072). Различия были связаны с поздней инфекционной летальностью. Никак достоверных различий в токсичности 2 режимов выявлено не было. Подводя итоги, данное исследование дает обоснование для применения ПТЦФ при неродственных трансплантациях у пациентов с ХМЛ и МДС. Требуются дальнейшие исследования для подтверждения преимущества ПТЦФ над классической профилактикой с тимоглобулином.    </p> 
<h2>Ключевые слова</h2>
<p style="text-align: justify;">
Посттрансплантационный циклофосфан, миелодиспластический синдром, хронический миелоидный лейкоз, хроническая миелопролиферативная неоплазия, совместимый неродственный донор. </p>
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В настоящий момент отмечается рост числа публикаций по поводу использования посттрансплантационного циклофосфана (ПТЦФ) в профилактике реакции «трансплантат против хозяина» при неродственной трансплантации гемопоэтических стволовых клеток. Тем не менее, большинство этих публикаций включают только пациентов с острыми лейкозами. Данные о возможности применения ПТЦФ при хроническом миелолейкозе (ХМЛ), миелодиспластическом синдроме (МДС) и хронических миелопролиферативных заболеваниях (ХМПЗ) практически отсутствуют, поэтому в данной популяции пациентов было инициировано проспективное рандомизированное сравнение тимоглобулина и ПТЦФ в профилактики РТПХ при 10/10- HLA совместимой неродственной трансплантации (NCT02627573, clinicaltrials.gov). Стратой для рандомизации был индекс pretransplant assessment of mortality. Исследование было прекращено преждевременно в связи с медленным набором пациентов, тем не менее, за время исследования было включено 33 пациента, 16 пациентов в группу тимоглобулина и 17 пациентов в группу ПТЦФ. Медиана наблюдения составила 29 месяцев. Не было выявлено различий ни в частоте первичного неприживления трансплантата (12,50% против 11,8%, p=0,9), ни острой РТПХ II-IV степени (23% vs 6%, p=0,2), ни хронической РТПХ средней и тяжелой степени (25% vs 23%, p=0,4) в группах тимоглобулина и ПТЦФ, соответственно. Однако, было в группе ПТЦФ наблюдалась достоверно лучшая общая (82% vs 30%, p=0,0126) и бессобытийная (61% vs 26%, p=0,0335) выживаемость, а также выживаемость без рецидива и РТПХ (61% vs 16%, p=0,0072). Различия были связаны с поздней инфекционной летальностью. Никак достоверных различий в токсичности 2 режимов выявлено не было. Подводя итоги, данное исследование дает обоснование для применения ПТЦФ при неродственных трансплантациях у пациентов с ХМЛ и МДС. Требуются дальнейшие исследования для подтверждения преимущества ПТЦФ над классической профилактикой с тимоглобулином.    
 
Ключевые слова

Посттрансплантационный циклофосфан, миелодиспластический синдром, хронический миелоидный лейкоз, хроническая миелопролиферативная неоплазия, совместимый неродственный донор. 
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Elena V. Morozova, Ivan S. Moiseev, Yulia Yu. Vlasova, Nikolay Yu. Tcvetkov, Yulia V. Rudnitskaya, Maria V. Barabanschikova, Anna G. Smirnova, Elena I. Darskaya, Sergey N. Bondarenko, Boris V. Afanasyev

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                    [TEXT] => <p>Raisa Gorbacheva Memorial Research Institute of Pediatric Oncology, Hematology and Transplantation, Pavlov University,<br>
St. Petersburg, Russia </p><br>
<p><b>Correspondence</b><br>
Dr. Elena V. Morozova, PhD, Raisa Gorbacheva Memorial Research Institute of Pediatric Oncology, Hematology and Transplantation, Pavlov University, L. Tolstoy St. 6-8, 197022, St. Petersburg, Russia<br>
Phone: +7 (911) 927 8229<br>
E-mail: dr_morozova@mail.ru</p>
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Raisa Gorbacheva Memorial Research Institute of Pediatric Oncology, Hematology and Transplantation, Pavlov University,

St. Petersburg, Russia 


Correspondence

Dr. Elena V. Morozova, PhD, Raisa Gorbacheva Memorial Research Institute of Pediatric Oncology, Hematology and Transplantation, Pavlov University, L. Tolstoy St. 6-8, 197022, St. Petersburg, Russia

Phone: +7 (911) 927 8229

E-mail: dr_morozova@mail.ru
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                    [TEXT] => <p style="text-align: justify;">Despite growing evidence on the use of posttransplantation cyclophosphamide (PTCY) in matched unrelated transplantation in acute leukemia patients, prospective evidence to support this type of prophylaxis in myelodysplastic syndrome (MDS), chronic myeloproliferative neoplasms and chronic myeloid leukemia (CML) patients is lacking. In this patient population we conducted a prospective randomized study of PTCY vs thymoglobulin for graft-versus-host disease (GvHD) prophylaxis in the setting of 10/10 HLA-matched unrelated transplantation (NCT02627573, clinicaltrials.gov). The strata for randomization was pretransplant assessment of mortality score. The study was terminated prematurely due to poor recruitment, but 33 patients were enrolled, 17 in the PTCY and 16 in the thymoglobulin group. Median follow up was 29 months. There was no difference between groups in the incidence primary graft failure (12.50% <i>vs</i> 11.8%, p=0.9), acute GvHD grade II-IV (23% <i>vs</i> 6%, p=0.2), moderate and severe chronic GvHD (25% <i>vs</i> 23%, p=0.4) in the thymoglobulin and PTCY arms, respectively. However there was a significantly higher overall survival (82% <i>vs</i> 30%, p=0.0126), event-free survival (61% <i>vs</i> 26%, p=0.0335), and GvHD-relapse free survival (61% <i>vs</i> 16%, p=0.0072) in the PTCY group due to reduced late infection-related mortality. No differences was observed in terms of toxicity. In conclusion, despite incomplete recruitment, the study created the basis for the use of PTCY in unrelated transplantations from fully matched unrelated donors in CML and MDS. Future studies are required to confirm if there is a benefit of PTCY-based prophylaxis over thymoglobulin. </p>
<h2>Keywords</h2>
<p style="text-align: justify;">
Posttransplant cyclophosphamide, myelodysplastic syndrome, chronic myeloid leukemia, chronic myeloproliferative neoplasm, matched unrelated donor.  </p>
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Despite growing evidence on the use of posttransplantation cyclophosphamide (PTCY) in matched unrelated transplantation in acute leukemia patients, prospective evidence to support this type of prophylaxis in myelodysplastic syndrome (MDS), chronic myeloproliferative neoplasms and chronic myeloid leukemia (CML) patients is lacking. In this patient population we conducted a prospective randomized study of PTCY vs thymoglobulin for graft-versus-host disease (GvHD) prophylaxis in the setting of 10/10 HLA-matched unrelated transplantation (NCT02627573, clinicaltrials.gov). The strata for randomization was pretransplant assessment of mortality score. The study was terminated prematurely due to poor recruitment, but 33 patients were enrolled, 17 in the PTCY and 16 in the thymoglobulin group. Median follow up was 29 months. There was no difference between groups in the incidence primary graft failure (12.50% vs 11.8%, p=0.9), acute GvHD grade II-IV (23% vs 6%, p=0.2), moderate and severe chronic GvHD (25% vs 23%, p=0.4) in the thymoglobulin and PTCY arms, respectively. However there was a significantly higher overall survival (82% vs 30%, p=0.0126), event-free survival (61% vs 26%, p=0.0335), and GvHD-relapse free survival (61% vs 16%, p=0.0072) in the PTCY group due to reduced late infection-related mortality. No differences was observed in terms of toxicity. In conclusion, despite incomplete recruitment, the study created the basis for the use of PTCY in unrelated transplantations from fully matched unrelated donors in CML and MDS. Future studies are required to confirm if there is a benefit of PTCY-based prophylaxis over thymoglobulin. 
Keywords

Posttransplant cyclophosphamide, myelodysplastic syndrome, chronic myeloid leukemia, chronic myeloproliferative neoplasm, matched unrelated donor.  
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	 Александр А. Щербаков, Алена Н. Зайцева, Максим А. Кучер, Ирина С. Ярушкина, Ольга Н. Зацепина, Екатерина С. Кульнева, Олеся В. Паина, Руслана В. Клементьева, Олег В. Голощапов, Иван С. Моисеев, Людмила С. Зубаровская, <span style="border: 1px solid black; margin: 0; padding: 2px 2px;">Борис В. Афанасьев</span>
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	 Александр А. Щербаков, Алена Н. Зайцева, Максим А. Кучер, Ирина С. Ярушкина, Ольга Н. Зацепина, Екатерина С. Кульнева, Олеся В. Паина, Руслана В. Клементьева, Олег В. Голощапов, Иван С. Моисеев, Людмила С. Зубаровская, Борис В. Афанасьев

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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
</p>
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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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	 Геморрагический цистит (ГЦ) – это частое осложнение при аллогенной трансплантации гемопоэтических стволовых клеток (алло-ТГСК). Персистирование BK полиомавируса (BKPyV) является одной из основных предполагаемых причин, приводящих к развитию позднего ГЦ после алло-ТГСК. Имеются доклинические данные об эффективной нейтрализации BKPyV внутривенным иммуноглобулином G (ВВИГ) в клеточных культурах, а также при BK вирусной нефропатии при трансплантации почки.
</p>
<h3>Пациенты и методы</h3>
<p style="text-align: justify;">
	 Ретроспективно было изучено 1037 пациентов получивших алло-ТГСК в НИИ детской онкологии, гематологии и трансплантологии им. Р.М. Горбачевой с 2013 по 2018 год. ГЦ был зарегистрирован в 118 (11,4%) случаях, из них, согласно критериям включения, 90 пациентов включены в анализ: группа сравнения с ВВИГ (n=42) и контрольная группа (n=48) со стандартной терапией ГЦ.
</p>
<h3>Результаты</h3>
<p style="text-align: justify;">
	 Продолжительность ГЦ в общей группе составила 21 день. Не было статистически значимой разницы в продолжительности ГЦ между группой сравнения и контрольной группой – медиана 24 дня (16, 32; 95% CI) и 24 дня (2, 46; 95% CI), соответственно (p=0,39). Продолжительность ГЦ при миелоаблативном режиме кондиционирования составила 35 дней (18, 52; 95% ДИ) и 17 дней (14, 20; 95% ДИ) при немиелоаблативном режиме кондиционирования, р &lt;0,01. Одновременное наличие симптомов ГЦ и РТПХ I-IV степени, также характеризовалось положительной корреляцией с длительностью ГЦ – 36 дней (22, 50; 95% ДИ) у пациентов с РТПХ и 18 дней (15, 21; 95% ДИ) у пациентов без РТПХ, р=0,013.
</p>
<h3>Выводы</h3>
<p style="text-align: justify;">
	 Настоящее исследование не подтвердило клиническую эффективность ВВИГ (Иммуновенин 5% (50мг/мл) Микроген) в дозе 1,2 гр/кг у пациентов с ГЦ после алло-ТГСК. Факторами риска более длительного течения ГЦ были интенсивность режима кондиционирования и наличие РТПХ I-IV степени. Требуется проведение проспективного исследования для определения эффективности ВВИГ в качестве терапии позднего ГЦ после алло-ТГСК.
</p>
<h2>Ключевые слова</h2>
<p style="text-align: justify;">
	 Аллогенная трансплантация гемопоэтических стволовых клеток, геморрагический цистит, внутривенный иммуноглобулин, ВВИГ, факторы риска, реакция «трансплантат против хозяина» (РТПХ).
</p>
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	 Геморрагический цистит (ГЦ) – это частое осложнение при аллогенной трансплантации гемопоэтических стволовых клеток (алло-ТГСК). Персистирование BK полиомавируса (BKPyV) является одной из основных предполагаемых причин, приводящих к развитию позднего ГЦ после алло-ТГСК. Имеются доклинические данные об эффективной нейтрализации BKPyV внутривенным иммуноглобулином G (ВВИГ) в клеточных культурах, а также при BK вирусной нефропатии при трансплантации почки.

Пациенты и методы

	 Ретроспективно было изучено 1037 пациентов получивших алло-ТГСК в НИИ детской онкологии, гематологии и трансплантологии им. Р.М. Горбачевой с 2013 по 2018 год. ГЦ был зарегистрирован в 118 (11,4%) случаях, из них, согласно критериям включения, 90 пациентов включены в анализ: группа сравнения с ВВИГ (n=42) и контрольная группа (n=48) со стандартной терапией ГЦ.

Результаты

	 Продолжительность ГЦ в общей группе составила 21 день. Не было статистически значимой разницы в продолжительности ГЦ между группой сравнения и контрольной группой – медиана 24 дня (16, 32; 95% CI) и 24 дня (2, 46; 95% CI), соответственно (p=0,39). Продолжительность ГЦ при миелоаблативном режиме кондиционирования составила 35 дней (18, 52; 95% ДИ) и 17 дней (14, 20; 95% ДИ) при немиелоаблативном режиме кондиционирования, р <0,01. Одновременное наличие симптомов ГЦ и РТПХ I-IV степени, также характеризовалось положительной корреляцией с длительностью ГЦ – 36 дней (22, 50; 95% ДИ) у пациентов с РТПХ и 18 дней (15, 21; 95% ДИ) у пациентов без РТПХ, р=0,013.

Выводы

	 Настоящее исследование не подтвердило клиническую эффективность ВВИГ (Иммуновенин 5% (50мг/мл) Микроген) в дозе 1,2 гр/кг у пациентов с ГЦ после алло-ТГСК. Факторами риска более длительного течения ГЦ были интенсивность режима кондиционирования и наличие РТПХ I-IV степени. Требуется проведение проспективного исследования для определения эффективности ВВИГ в качестве терапии позднего ГЦ после алло-ТГСК.

Ключевые слова

	 Аллогенная трансплантация гемопоэтических стволовых клеток, геморрагический цистит, внутривенный иммуноглобулин, ВВИГ, факторы риска, реакция «трансплантат против хозяина» (РТПХ).

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                    [TEXT] => <p>Alexander A. Shcherbakov, Alena N. Zaytseva, Maksim A. Kucher, Irina S. Iarushkina, Olga N. Zatsepina,
Ekaterina S. Kulneva, Olesya V. Paina, Ruslana V. Klementeva, Оleg V. Goloshchapov, Ivan S. Moiseev,
Ludmila S. Zubarovskaya,<br> <span style="border: 1px solid black; margin: 0; padding: 2px 2px;">Boris V. Afanasyev</span>
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Alexander A. Shcherbakov, Alena N. Zaytseva, Maksim A. Kucher, Irina S. Iarushkina, Olga N. Zatsepina,
Ekaterina S. Kulneva, Olesya V. Paina, Ruslana V. Klementeva, Оleg V. Goloshchapov, Ivan S. Moiseev,
Ludmila S. Zubarovskaya,
 Boris V. Afanasyev

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                    [TEXT] => <p>Raisa Gorbacheva Memorial Research Institute of Pediatric Oncology, Hematology and Transplantation, Pavlov University,<br>
St. Petersburg, Russia</p><br>
<p><b>Correspondence</b><br>
Dr. Alexander A. Shcherbakov, Raisa Gorbacheva Memorial Research Institute of Pediatric Oncology, Hematology and Transplantation, Pavlov University, L. Tolstoy St. 6-8, 197022, St. Petersburg, Russia<br>
Phone: +7(904) 604 0884<br>
E-mail: xihmrx@gmail.com</p>


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Raisa Gorbacheva Memorial Research Institute of Pediatric Oncology, Hematology and Transplantation, Pavlov University,

St. Petersburg, Russia


Correspondence

Dr. Alexander A. Shcherbakov, Raisa Gorbacheva Memorial Research Institute of Pediatric Oncology, Hematology and Transplantation, Pavlov University, L. Tolstoy St. 6-8, 197022, St. Petersburg, Russia

Phone: +7(904) 604 0884

E-mail: xihmrx@gmail.com


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                    [TEXT] => <p style="text-align: justify;">Hemorrhagic cystitis (HC) is a frequent complication in allogeneic hematopoietic stem cell transplantation (allo-
HSCT). Human BK-polyomavirus (BKPyV) may be one of the main agents found in late HC developing after allo-HSCT. In previous studies, intravenous immunoglobulin (IVIG) preparations were shown to neutralize BKPyV in mice cell cultures and to reduce BK virus nephropathy in kidney transplantation. The aim of current study was to evaluate efficiency of HC treatment with IVIG in allo-HSCT recipients, with respect to conditioning regimen intensity and presence of graft-versus-host disease (GvHD).</p>
<h3>Patients and methods</h3>
<p style="text-align: justify;">A total of 1037 allo-HSCT recipients transplanted in R. M. Gorbacheva Memorial institute for Pediatric Oncology, Hematology and Transplantation in 2013-2018 were included into retrospective open single-center cohort study. HC was registered in 118 (11.4%) cases. According to inclusion criteria, only 90 patients were enrolled to the final analysis. This cohort was divided into two groups based on HC therapy used: the intervention group (n=42) included patients with standard HC treatment with addition of IVIG; the control group (n=48) – with standard HC therapy only.</p>
<h3>Results</h3>
<p style="text-align: justify;">
The median HC duration in common group (IVIG and control) was 21 days. There was no statistically significant difference in HC duration between the two groups, with the median of 24 days (16, 32; 95% CI) in the intervention group (standard therapy + IVIG), and 24 days (2, 46; 95% CI) in control group, respectively (p=0.39). The median HC duration in MAC and RIC was 35 days (18, 52; 95% CI) versus 17 days (14, 20; 95% CI), respectively (p<0.01). The presence of GvHD I-IV at the time of HC symptoms manifestation was also characterized by positive correlation with HC duration. It was 36 days (22, 50; 95% CI) in patients with GvHD and 18 days (15, 21; 95% CI) in patients without GvHD (p=0.013).</p>
<h3>Conclusions</h3>
<p style="text-align: justify;">Our data didn’t show any clinical efficiency of 1.2 g/kg IVIG (Immunovenin® 5%, 50mg/mL by Microgen) effectiveness in post allo-HSCT HC patients. Conditioning regimen intensity and GvHD I-IV are the risk factors for HC longer duration. The further prospective study is needed to make final conclusions on method’s effectiveness.</p>
<h2>Keywords</h2>
<p style="text-align: justify;">
Allogeneic hematopoietic stem cell transplantation, hemorrhagic cystitis, intravenous immunoglobulin, IVIG, risk factors, graft-versus-host disease (GvHD). </p>
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Hemorrhagic cystitis (HC) is a frequent complication in allogeneic hematopoietic stem cell transplantation (allo-
HSCT). Human BK-polyomavirus (BKPyV) may be one of the main agents found in late HC developing after allo-HSCT. In previous studies, intravenous immunoglobulin (IVIG) preparations were shown to neutralize BKPyV in mice cell cultures and to reduce BK virus nephropathy in kidney transplantation. The aim of current study was to evaluate efficiency of HC treatment with IVIG in allo-HSCT recipients, with respect to conditioning regimen intensity and presence of graft-versus-host disease (GvHD).
Patients and methods
A total of 1037 allo-HSCT recipients transplanted in R. M. Gorbacheva Memorial institute for Pediatric Oncology, Hematology and Transplantation in 2013-2018 were included into retrospective open single-center cohort study. HC was registered in 118 (11.4%) cases. According to inclusion criteria, only 90 patients were enrolled to the final analysis. This cohort was divided into two groups based on HC therapy used: the intervention group (n=42) included patients with standard HC treatment with addition of IVIG; the control group (n=48) – with standard HC therapy only.
Results

The median HC duration in common group (IVIG and control) was 21 days. There was no statistically significant difference in HC duration between the two groups, with the median of 24 days (16, 32; 95% CI) in the intervention group (standard therapy + IVIG), and 24 days (2, 46; 95% CI) in control group, respectively (p=0.39). The median HC duration in MAC and RIC was 35 days (18, 52; 95% CI) versus 17 days (14, 20; 95% CI), respectively (p<0.01). The presence of GvHD I-IV at the time of HC symptoms manifestation was also characterized by positive correlation with HC duration. It was 36 days (22, 50; 95% CI) in patients with GvHD and 18 days (15, 21; 95% CI) in patients without GvHD (p=0.013).
Conclusions
Our data didn’t show any clinical efficiency of 1.2 g/kg IVIG (Immunovenin® 5%, 50mg/mL by Microgen) effectiveness in post allo-HSCT HC patients. Conditioning regimen intensity and GvHD I-IV are the risk factors for HC longer duration. The further prospective study is needed to make final conclusions on method’s effectiveness.
Keywords

Allogeneic hematopoietic stem cell transplantation, hemorrhagic cystitis, intravenous immunoglobulin, IVIG, risk factors, graft-versus-host disease (GvHD). 
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