Clinical studies

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Introduction

Dementia is an incurable loss of mental abilities. Dementia in elderly persons is a frequent condition and presents a large public health problem worldwide [1]. It has many different causes, among them primary genetic factors or the sequelae of other diseases such as vascular disorders. The pathogenesis of these forms of dementia is in general poorly understood, which is the major reason for the helpless attempts at developing therapies. Dementia in children – in contrast – is a rare phenomenon. Its causes are frequently well defined genetically, and its pathogenesis is sometimes well understood, which offers chances to develop a rational therapeutic approach.

The most frequent cause of dementia in young persons is a group of diseases called the Neuronal Ceroid-Lipofuscinoses (NCL). This group comprises more than a dozen diseases that are caused by mutations in different genes. All NCL have characteristic features in common: a variable clinical syndrome of dementia, epilepsy and retinopathy, as well as intracellular storage of an abnormal wax-like material called ceroid lipofuscin. The storage process causes degeneration and death of neuronal and retinal cells. NCL are presently classified according to the responsible mutated genes (CLN1, CLN2 etc.). Some of the gene mutations cause deficiencies of soluble lysosomal enzymes, others lead to dysfunction of lysosomal membrane proteins [2].

CLN2 disease, also called classical late-infantile NCL or Janský-Bielschowsky disease, typically strikes healthy-looking and normally developed 3-year-old toddlers. At this age, the disease manifests itself either strikingly with severe epilepsy, or more gradually with a slowing of further development. This is followed by dramatic loss of all mental and motor abilities and paralleled by severe brain atrophy. At the age of about 6 years, the patients are completely helpless and blind. Death usually occurs at the age of 10 to 15 years. Several cases with later manifestation and slower course of the disease have been described [3].

The disease is caused by a profound deficiency of the lysosomal enzyme tripeptidyl peptidase 1 (TPP1) in the brain. TPP1 is a protease, targeted to lysosomes via a mannose 6-phosphate receptor.

It cleaves tripeptides and is activated by clipping of a prosegment. The natural substrate and function of the enzyme are unknown, but it is clear that the deficiency of the enzyme causes storage of material and neurodegeneration.

Replacing a deficient brain protein

Replacing the missing enzyme in the brain of CLN2 patients became an attractive concept, as many enzymes can now be fabricated, and because free lysosomal enzymes are frequently taken up easily by cells [4]. Human recombinant TPP1 was made by BioMarin. However, as the protein does not cross the blood-brain barrier, injection into the CSF space was used in pre-clinical experiments (Fig. 1). In TPP1-deficient mice this led to attenuation of the disease and extended survival. Important studies were done with a natural dog model of CLN2 disease. These TPP1-deficient dogs received the enzyme by infusion into the lumbar CSF space. Their functional improvement and prolonged survival were impressive compared with untreated dogs, which persuaded us to use the treatment for patients. Studies in monkeys demonstrated that the enzyme, when injected into CSF, reached wide areas of brain.

In a clinical trial, we used the method illustrated in Fig. 2 for the application of TPP1. The enzyme (300 mg of the recombinant human TPP1, cerliponase A, Brineura©) is infused every 2 weeks through the skin into an implanted port, from where it is passed on over a thin tube to a lateral brain ventricle.

Figure 1. Preclinical studies with intrathecal application of TPP1 in various animal species and conclusions from results

Figure 2. Method used to apply TPP1 in patients

Figure 3. Results of clinical scoring of CLN2 patients from 0 to 12 years of age

Note: The score used here is a combined score for the ability of a child to walk and talk. Normal walking and talking abilities result in 3 points for each ability (6 points on this scale). Loss of abilities is scored with 2 points for a minor disturbance, 1 point for a major disturbance, and 0 points for total loss of the respective function. There is a dramatic loss of abilities between 3 and 6 years of age. The course of the disease is very uniform. (Redrawn from [5]).

Measuring efficacy of a new treatment in a rare degenerative brain disease poses the serious problem of control patients. Placebo controls were unacceptable because of the aggressiveness of the procedure and the rarity of the condition. Our solution was to use a clinical scoring system we had specifically developed for CLN2 disease. Scoring of a large number of CLN2 patients over many years had resulted in a rather precise quantitative description of the disease course and its variability [5]. Fig. 3 shows that the clinical course of CLN2 disease is characterized (1) by a dramatic loss of motor and language abilities between the ages of three and six years and (2) by great uniformity in the majority of patients. On this basis it was decided that historical untreated patients could be used as controls.

Clinical trial

A clinical trial with intrathecal TPP1 replacement therapy was performed with international cooperation and Angela Schulz as principal investigator as shown in Fig. 4. This was an open-label phase I/II dose escalation study performed 2013-2016. An extension study is presently ongoing.

Enrolled were twenty-four patients. Of them, 23 completed the study. Efficacy was measured against matched historical controls. Adverse events were relatively minor: We had some infections that could be managed easily, and there were some failures of the intraventricular device. None of the adverse events led to discontinuation of treatment [6].

Results of the trial are illustrated by Fig. 5, which shows the striking capacity of the treatment to halt the expected dramatic loss of motor and language abilities.

Figure 4. Investigators and participant institutions at the clinical trial with enzyme replacement therapy for CLN2 disease

Figure 5. Risk of losing motor and language abilities in 23 children with CLN2 disease treated with intraventricular TPP1 (cerliponase A, Brineura©) over a three-year period (blue line), compared to matched untreated historical controls (red line). Probabilities of no functional decline were calculated on the basis of motor-language scoring (see figure 3). From [6]

Summary and conclusions

Effective treatment of CLN2 disease, a rare childhood dementia, has become possible through a combination of favorable factors:
(1) The pathogenetic mechanism was known (lack of a lysosomal enzyme in brain).
(2) The deficient protein could be synthesized.
(3) For preclinical studies, a large experimental animal (natural dog model) was available.
(4) The blood-brain barrier was overcome by intra-ventricular infusion.
(5) The clinical course of the disease and its variability were sufficiently known. Historical controls could therefore be used and placebo controls avoided.

Many questions remain. We have no long-term results of this treatment. Will life-long treatment be necessary? What will be the further development of the treated patients? Are we creating a chronic disease from a dramatically cruel, relatively acute condition? An additional therapeutic approach to the retinopathy will have to be developed. Will new treatments, such as gene therapy, be safe and more effective than enzyme replacement [7]? At any rate, the results of this trial with replacement of a deficient brain protein has pushed open a door. Some principles underlying this study of a rare childhood disease may be applicable to other, much more frequent forms of dementia.

Conflict of interests

None declared.

References

World Health Organization. Dementia: a public health priority. 2012, Geneva: Publications of the World Health Organization.
Nita DA, Mole SE, Minassian BA. Neuronal ceroid lipofuscinoses. Epileptic Disord, 2016; 18(S2): 73-88.
Kohlschütter A, Schulz A. CLN2 Disease (Classic Late Infantile Neuronal Ceroid Lipofuscinosis). Pediatric Endocrinology (Diabetes, Nutrition, Metabolism) Reviews, 2016; 13(Suppl 1): 682-688.
Neufeld EF. Enzyme replacement therapy – a brief history, in Fabry Disease: Perspectives from 5 Years of FOS, A. Mehta, M. Beck, and G. Sunder-Plassmann, Editors. 2006: Oxford.
Nickel M., Simonati A, Jacoby D, Lezius S, Kilian D, Van de Graaf B, Pagovich OE, Kosofsky B, Yohay K, Downs M, Slasor P, Ajayi T, Crystal RG, Kohlschutter A, Sondhi D, Schulz A. Disease characteristics and progression in patients with late-infantile neuronal ceroid lipofuscinosis type 2 (CLN2) disease: an observational cohort study. Lancet Child Adolesc Health, 2018; 2(8): 582-590.
Schulz A, Ajayi T, Specchio N, de Los Reyes E, Gissen P, Ballon D, Dyke JP, Cahan H, Slasor P, Jacoby D, Kohlschutter A, and CLN Study Group. Study of Intraventricular Cerliponase Alfa for CLN2 Disease. N Engl J Med, 2018; 378(20): 898-1907.
Kohlschütter A, Schulz A, Bartsch U, Storch S. Current and Emerging Treatment Strategies for Neuronal Ceroid Lipofuscinoses. CNS Drugs, 2019; 33(4): 315-325.

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Introduction

The disease is caused by a profound deficiency of the lysosomal enzyme tripeptidyl peptidase 1 (TPP1) in the brain. TPP1 is a protease, targeted to lysosomes via a mannose 6-phosphate receptor.

Replacing a deficient brain protein

Figure 1. Preclinical studies with intrathecal application of TPP1 in various animal species and conclusions from results

Figure 2. Method used to apply TPP1 in patients

Figure 3. Results of clinical scoring of CLN2 patients from 0 to 12 years of age

Clinical trial

Results of the trial are illustrated by Fig. 5, which shows the striking capacity of the treatment to halt the expected dramatic loss of motor and language abilities.

Figure 4. Investigators and participant institutions at the clinical trial with enzyme replacement therapy for CLN2 disease

Summary and conclusions

Conflict of interests

None declared.

References

World Health Organization. Dementia: a public health priority. 2012, Geneva: Publications of the World Health Organization.
Nita DA, Mole SE, Minassian BA. Neuronal ceroid lipofuscinoses. Epileptic Disord, 2016; 18(S2): 73-88.
Kohlschütter A, Schulz A. CLN2 Disease (Classic Late Infantile Neuronal Ceroid Lipofuscinosis). Pediatric Endocrinology (Diabetes, Nutrition, Metabolism) Reviews, 2016; 13(Suppl 1): 682-688.
Neufeld EF. Enzyme replacement therapy – a brief history, in Fabry Disease: Perspectives from 5 Years of FOS, A. Mehta, M. Beck, and G. Sunder-Plassmann, Editors. 2006: Oxford.
Nickel M., Simonati A, Jacoby D, Lezius S, Kilian D, Van de Graaf B, Pagovich OE, Kosofsky B, Yohay K, Downs M, Slasor P, Ajayi T, Crystal RG, Kohlschutter A, Sondhi D, Schulz A. Disease characteristics and progression in patients with late-infantile neuronal ceroid lipofuscinosis type 2 (CLN2) disease: an observational cohort study. Lancet Child Adolesc Health, 2018; 2(8): 582-590.
Schulz A, Ajayi T, Specchio N, de Los Reyes E, Gissen P, Ballon D, Dyke JP, Cahan H, Slasor P, Jacoby D, Kohlschutter A, and CLN Study Group. Study of Intraventricular Cerliponase Alfa for CLN2 Disease. N Engl J Med, 2018; 378(20): 898-1907.
Kohlschütter A, Schulz A, Bartsch U, Storch S. Current and Emerging Treatment Strategies for Neuronal Ceroid Lipofuscinoses. CNS Drugs, 2019; 33(4): 315-325.

Альфред Кольшюттер

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Университетский медицинский центр Гамбург-Эппендорф, Гамбург, Германия

Нейрональный цероидный липофусциноз (CLN2) является наследственным, быстро прогрессирующим заболеванием раннего возраста, ведущим к деменции, резкой утрате всех навыков и ранней гибели пациента. Оно вызывается дефицитом лизосомного фермента трипептидил-пептидазы 1 (ТРР1) в нервной системе. Настоящая статья является обзором разработок по замещению дефектного энзима посредством повторных инфузий рекомбинантного ТРР1 в желудочки головного мозга. Показана эффективность метода в плане сдерживания быстрой прогрессии заболевания.

Ключевые слова

Нейрональный цероидный липофусциноз 2, трипептидил-пептидаза 1, дефицит, деменция, рекомбинантный энзим, локальная инфузия, клинический эффект.

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Alfried Kohlschütter

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University Medical Center Hamburg-Eppendorf, Hamburg, Germany

Neuronal сeroid-lipofuscinosis 2 (CLN2) is a genetic, rapidly progressive brain disorder of young humans. It leads to dementia, dramatic loss of all abilities and early death. It is caused by the deficiency of the lysosomal enzyme tripeptidyl peptidase 1 (TPP1) in the nervous system. This article is an overview of the development of replacing the deficient enzyme by repeated infusion of recombinant TPP1 in a brain ventricle, shown to be effective in halting the rapid progression of the disease.

Keywords

Neuronal сeroid-lipofuscinosis 2, tripeptidyl peptidase 1, deficiency, dementia, recombinant enzyme, local infusion, clinical effect.

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Alfried Kohlschütter

Keywords

Neuronal сeroid-lipofuscinosis 2, tripeptidyl peptidase 1, deficiency, dementia, recombinant enzyme, local infusion, clinical effect.

Keywords

Neuronal сeroid-lipofuscinosis 2, tripeptidyl peptidase 1, deficiency, dementia, recombinant enzyme, local infusion, clinical effect.

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University Medical Center Hamburg-Eppendorf, Hamburg, Germany

Альфред Кольшюттер

Ключевые слова

Университетский медицинский центр Гамбург-Эппендорф, Гамбург, Германия

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Introduction

Allogeneic transplantation of hematopoietic stem cells (allo-HSCT) is among superior advances in treatment of children with hematological and inherited disorders [1]. Improvement of treatment protocols based on the balanced intensification of chemotherapy (ChT) provides an increase in long-term survival of the children with acute myeloid leukemia (AML) to 70%, and acute lymphoblastic leukemia (ALL) in 90% of the cases. Chemotherapy followed by allogeneic HSCT is one of the most effective treatment methods remaining an integral part of programmed therapy for high-risk pediatric AML and ALL [2]. Relapse of acute leukemia remains a main indication for allo-HSCT, due to sufficient worsening of prognosis [17].

Along with high-risk acute leukemia in children, allo-HSCT is the only method of treatment in myelodysplastic syndrome (MDS), including juvenile myelo-monocytic leukemia (JMML) (14). Chronic myeloid leukemia (CML) deserves special indications, i.e., in cases of lost therapeutic response, intolerance to tirosine kinase inhibitors (TKI), or mutations associated with TKI resistance permit us to consider allo-HSCT a therapeutic option, due to high efficiency and individual indication strategy.

Allo-HSCT performance is accompanied by some serious complications associated with conditioning regimens, non-engraftment or graft hypofunction, and especially with relapses. Post-transplant relapse remains the most serious issue, being the main cause of mortality in these patients [1, 2, 9, 12]. Frequency of leukemia relapses after allo-HSCT is from 10 to 70% [1, 3, 4]. Prognosis for relapsing patients posttransplant is dismal, and the patients are planned for salvage therapy requiring personalized treatment approach [2]. Among possible therapies applicable after allo-HSCT, one may consider re-transplantation, the use of target and immunotherapy drugs. However, their efficiency of these options has not proven in randomized trials. Nevertheless, the reported experience of different centers is of sufficient interest for taking strategic clinical decisions. The range of problems associated with re-transplantation due to relapse is as follows – to date, the optimal timing for 2^nd HSCT are not yet determined; there is no clear opinion on the graft source (bone marrow or peripheral stem cells), and donor characteristics (HLA matching, gender, age), as well as conditioning regimens, GVHD prophylaxis, subsequent therapies.

A retrospective analysis was performed at the R. M. Gorbacheva Memorial Research Institute for Children Oncology, Hematology and Transplantation concerning 50 pediatric patients with different malignant hematological diseases who were subjected to repeated allo-HSCT due to relapse or progression, primary or secondary non-engraftment. The aim of our study was to evaluate efficiency of 2^nd allo-HSCT in the patients with acute leukemias, MDS, JMML, and CML in cases of evolving clinical relapse, or associated complications occurring after the 1^st allo-HSCT.

Materials and methods

Table 1. Clinical characteristics of pediatric patients considered for 2^nd allo-HSCT

Abbreviations: BU, Busulfan; Treo, Treosulfan; Flu, Fludarabine; Cy, Cyclophosphamide; GIAC, Bu, Ara-C, CCNU, Cy; MAC, myeloablative conditioning, RIC, reduced-intensity conditioning.

The study included 50 children with a median age of 18 years (1 to 18 y.o.) subjected to 2^nd allo-HSCT at our BMT clinic from 2007 to 2018. Their primary diagnoses were as follows: ALL, 24 patients; AML, 15 cases; mixed-phenotype AML, 2 patients; JMML, 6 patients; CML, 1 patient. Relapse of the primary disease was the most common indication for 2^nd allo-HSCT was diagnosed in 36 cases (72%). Other indications for 2^nd HSCT were as follows: primary non-engraftment in 11 patients (22%); secondary non-engraftment in 2 patients (4%); graft hypofunction in one case (2%) in presence of resistant/refractory clinical course. The disease characteristics and parameters of the 1^st HSCT are presented in Table 1.

For 40% of the patients (n=20), unrelated HLA-matched donors were chosen for allo-HSCT; matched related donor was used in 15 cases (30%); haploidentical graft was used in 14 cases (28%); autologous HSCT was carried out in 1 patient (2%). At the time of 1^st HSCT, myeloablative busulfan-containing regimen (MAC) was applied in 34 patients (68%). Dependent on the stage of disease, 16 patients (32%) achieved 1^st complete hematological remission (CR); 2^nd or 3^rd CR was registered in 18 cases (36%). Sixteen patients (32%) were in resistant relapse state, or showed primary resistance.

Median duration of remission after the 1^st allo-HSCT was 148 days (31 to 1084 days). Donor lymphocyte infusions (DLI) were performed in 20 patients after 1^st allo-HSCT, for relapse prophylaxis. Of them, 17 children (85%) received the therapy due to minimal residual disease (MRD) or clinical relapse, and 3 patients (15%), due to graft hypofunction. The DLI proved to be ineffective in all these patients, thus being indicative for 2^nd allo-HSCT.

The patients with progression or relapse after 1^st HSCT (n=38), have received cytoreductive therapy before 2^nd allo-HSCT by the following schedules:
• chemotherapy (ChT) in 24 patients using FLAG protocol, or ALL-REZ BFM 2002, and AML-BFM 2004 chemotherapy blocks;
• targeted drugs (hypomethylating agents or monoclonal antibodies), in 7 patients;
• combined application of ChT and targeted drugs (hypomethylating or monoclonal antibodies) in 7 cases.

In 10 patients of 38 who underwent ChT or targeted treatment, a remission of the disease was achieved; in 12 cases, cytoreduction was observed (marrow blast count reduction to 20%). In 16 patients, stabilization or progression of the disease was registered.

Ten patients with aplasia of hematopoiesis due to primary non-engraftment, 2 patients with secondary rejection, and 1 patient with severe graft hypofunction did not receive additional therapy. Clinical characteristics of the patients subjected to 2^nd allo-HSCT are shown in Table 2.

Table 2. Clinical characteristics of the patients who underwent 2^nd HSCT

Abbreviations: BU, Busulfan; Treo, Treosulfan; Flu, Fludarabine; Cy, Cyclophosphamide; GIAC: Bu, Ara-C, CCNU, Cy; MAC, myeloablative conditioning, RIC, reduced-intensity conditioning; HSCs, hematopoietic stem cells; PBSC, peripheral blood stem cells.

The median time-lag between 1^st and 2^nd HSCT was 7.5 months. In majority of patients (n=41), the donors were changed to haploidentical HSCs donor. In 9 recipients, allo-HSCT was performed from the same donors, i.e., haploidentical transplants in 3 cases; unrelated grafts in 4 patients, and related matched donors were used in 2 cases. For 2^nd allo-HSCT, the reduced-intensity conditioning regimens (RIC) were chosen for 40 patients, due to heavy pre-treatment and severe condition of the patients. Myeloablative conditioning was performed in 10 cases, because of high blast cell counts in bone marrow. Combined prophylaxis of acute graft-versus-host disease (GvHD) after 2^nd allo-HSCT was based on the following immune suppression therapy, i.e., tacrolimus-based prophylaxis was administered to 38 patients; mTOR inhibitors were used in 31 cases; cyclosporine-A-based was applied in 7 patients. In 31 cases, GvHD prophylaxis was performed with cyclophosphamide (50 mg/kg) on D+3 and D+4 posttransplant. Antithymocyte globulin (ATG) was used for GVHD prophylaxis in 11 cases. Monotherapy with calcineurin inhibitors was applied in 7 children.

The Kaplan-Meier estimates were used to assess probability of OS (overall survival) and RFS (relapse-free survival). OS was defined as number of months from the date of 2^nd allo-HSCT to the date of death. RFS defined as number of months from the date of 2^nd allo-HSCT to the date of first documented relapse or progression. Cumulative incidence was used to estimate the probability of transplant-related mortality (TRM) and relapse. For TRM, the relapse was considered a competing event. These estimates are provided with 95% confidence intervals (CI). We didn’t perform any multivariate analysis, because of relatively small number of patients.

Results

Clinical engraftment after 2^nd HSCT was registered in 44 patients (88% of total), with a median of neutrophil recovery of >500/mcL on D+21 (12 to 41), and documented clinical hematological remission. Primary non-engraftment was registered in 6 patients, including 4 cases with progression of the disease. The median observation term was 3 years 7 months (9 months to 10 years). Overall survival (OS) rate in the total group was 48% (Fig. 1), with relapse-free survival (RFS) of 60% (Fig. 3). OS among ALL patients was 46.2%; among the children with AML, 53.3%; for the group with myeloproliferative disorders (MDS, CML, JMML), 44.4%, as seen from Fig. 1.

OS among the patients with remission or cytoreduction achieved before 2^nd allo-HSCT proved to be, respectively, 73.6% и 50%. Meanwhile, OS values in the patients who did not respond to the therapy, on in absence of remission (active disease) comprised only 17.6% (р=0.006), as shown in Fig. 2.

We could not demonstrate any significant difference in OS between the cases with remission of <5 months, and >5 months after 1^st HSCT (respectively, 41.2% and 42.9%, p=0.7), based on median duration of the remission. Similarly, change of donor at the 2^nd HSCT did not result into significant OS changes (50% versus 47%, p=0.4). Moreover, no statistically significant difference was obtained for the groups who received RIC or MAC conditioning (47% versus 50%, p=0.6).

Figure 1. Five-year OS after 2nd allo-HSCT in the entire cohort (A); in patients with ALL (B); in patients with AML (C); in MPD cases (D) after 2^nd allo-HSCT

Abscissa, months after allo-HSCT, ordinate, cumulative survival.

Figure 2. Overall survival in the patients with different status prior to 2^nd allo-HSCT (red graph, remission; green, cytoreduction; blue curve, no response)

Abscissa, terms after 2^nd HSCT, months; ordinate cumulative survival.

Figure 3. Relapse-free survival in the entire group of patients after 2^nd allo-HSCT

Abscissa, terms after 2^nd HSCT, months; ordinate cumulative survival.

The study also concerned possible effects of acute or chronic GvHD upon OS levels. The 5-year OS in the patients (remission – 18 pts, cytoreduction – 12 pts, progression – 11 pts) who developed acute GVHD grade II-III was 63.6% (n=33), as compared to 9.1% (n=11) among GvHD-free cases (р=0.001). Meanwhile, the 5-year OS rate among patients with mild or moderate chronic GvHD reached 72.4% (n=29) when compared to the cases without chronic GvHD 14.3%, (n=7), p<0.0001).

From patients with high risk of relapse after 2^nd allo-HSCT, 9 patients without acute or chronic GvHD were subjected to immunoadoptive therapy, i.e., infusion of donor lymphocytes (DLI), aiming to prevent potential relapse. Maintenance therapy was performed in 13 patients using 6-MP (mercaptopurine), hypomethylating agents (HMa) (5-azacytidine, dacogen), tyrosine kinase inhibitors (TKI). In summary, for the group of patients (n=13) who did not receive any prophylaxis (DLI) or supporting therapy (6-MP, HMa or TKI) after 2^nd all-HSCT, due to acute or chronic GvHD OS 84.6%, (p=0.089).

Overall survival was 55.6% among the patients treated with DLI only. In the patients on maintenance therapy, the OS values proved to be 46.2%. In 9 cases of molecular recurrence (MRD, molecular or cytogenetic relapse) combined therapy was performed, i.e., chemotherapy, HMa (5-azacytidine, dacogen) and DLI, with OS of 22.2% (p=0.089).

We have analyzed the frequency of complications during early posttransplant period (D+100). The following toxic conditions were observed: severe mucositis (grade 3-4) was documented in 54% of cases (n=26); thrombotic microangiopathy, 22% (n=11); veno-occlusive disease, 16% (n=8); neurotoxicity, 16% (n=8). Among infectious complications, we observed cytomegalovirus reactivation (52%, n=26); SIRS syndrome, including sepsis, 44% (n=22); invasive mycoses, 18% (n=9).

Figure 4. Effects of 2 competing events upon general mortality after 2^nd HSCT, i.e., (1) cumulative relapse rate (34%; 95%CI, 21.6%-48%), and (2) TRM rate (18%; 95%CI, 8.8-29.8%)

Relapse or progression of disease remained the main cause of mortality after 2^nd allo-HSCT (65%, n=17). The median time of the relapse development in these patients comprises 58 days.

Transplant-related mortality in this group was 18%, (95%CI, 8.8-29.8%) and the relapse rate (a competing event) was 34% (95%CI, 21.6% to 48%), as shown in Fig. 4.

Discussion

Hematopoietic stem cell transplantation is the only possible treatment method in the most high-risk malignancies in children (AML, ALL etc.) [2]. Despite significant advances in the area, the posttransplant relapses remain the quite serious and common issue, being the main cause of lethal outcomes posttransplant [1, 2, 9, 12, 15]. The relapse frequency in this cohort may vary from 10 to 70% [3, 4, 15]. Clinical prognosis for post-HSCT relapsing patients remains extremely unfavorable, and these patients were intended for the salvage therapy [2]. So far, there are no clear clinical recommendations for treatment of such patients, and the issue of therapeutic options still remains open for this group [10, 15].

A significant therapeutic effect in allogeneic HSCT is achieved due to immune-mediated reactions, e.g., transplant versus leukemia effect, the main factor able to overcome the resistance of malignant cells [4, 10]. However, subsequent administration of mono- or combined therapy is the most common strategy for treatment of the posttransplant relapses, i.e., reinduction polychemotherapy, immunoadoptive cell therapy (donor lymphocyte infusion), usage of targeted drugs including monoclonal antibodies (MAb) [12]. Intensive chemotherapy results into the disease stabilization with remission achieved in 40 to 60% [4], however, without long-lasting effect in most cases, with 2-year OS of <10% [4].

Therapeutic potential of bispecific anti-CD19 monoclonal antibodies in the patients with ALL relapse was evaluated in a multicenter study of the patients who relapsed after HSCT, with a median observation term of 7.5 months. The one-year overall survival in these patients was 25% following treatment with blinatumomab [7].

According to the study by Markova et al. [11] that included 41 children with posttransplant relapse of ALL, the response to blinatumomab was observed in 24 patients (59%); the two-year OS comprised 37%, 2-year relapse-free survival rate was 71%, with a median observation terms of 222 days (25 to 730 days).

Donor lymphocyte infusion is an effective treatment approach in such conditions [12]. On the ground of a retrospective study which included 171 cases, Shmid et al. have shown efficiency of donor lymphocytes when treating posttransplant relapses in AML patients. The 2-year OS among the patients achieving remission after DLI was 56%, as compared with OS of 21% in the patients that did not reach the remission state (>35% blasts in bone marrow). Meanwhile, the 2-year OS remained at 9% for the patients who did not receive DLI [6].

EBMT Acute Leukemia Working Party (M. A. Kharfan-Dabaja et al, 2018) has published a retrospective study in order to compare efficiency of repeated allo-HSCT and DLI, including 418 adult patients with AML relapse after 1^st allo-HSCT. Repeated allo-HSCT was performed in 137 patients, and DLI, in 281 patients. Two-year survival following repeated allo-HSCT proved to be 26%, 5-year OS comprised 19%. Two-year OS among the DLI-treated patients was 25%, and 5-year OS, 15% [16]. In our study, the 5-year OS was 48% after repeated HSCT in general group.

Similarly, several larger studies have shown that repeated HSCT is a probable therapeutic approach [2]. In 2015, Ruutu et al. have summarized the results of 2632 repeated allo-HSCTs. Their results showed the 1-year OS rates of 40%, 5-year OS of 20% [5]. Another study from USA (Swati Naik et al., 2015) demonstrated results of repeated allo-HSCT in 43 children with relapses of different oncohematological disorders, with overall survival at 1, 5 and 10 years of, respectively, 48%, 24%, and 20% [3].

The results of multicenter retrospective study (EBMT-PDWP) were reported in 2018 [8]. Repeated allo-HSCT was performed in 373 cases; the 2- and 5-year OS values were 38% and 29%, respectively. The relapse-free survival was 30% at 2 years, and 30% at 5 years of observation. The median observation time in ALL group was 36.4 months, being 50.2 months for AML patients [8].

Despite current achievements in the posttransplant relapse treatment following allo-HSCT, using repeated allo-HSCT, the optimal timing of its performance is not yet determined, as well as preferable HSC source, change of donor (his/her gender and age), conditioning regimen, GvHD prophylaxis, posttransplant treatment, thus requiring additional multicenter studies, e.g. under participation of European teams active in oncohematology [18].

Conclusion

1. We have performed retrospective study concerning 50 pediatric patients with different blood malignancies that were subjected to repeated allogeneic HSCT due to different reasons, i.e. relapse/progression, primary or secondary non-engraftment.

2. According to our results, the repeated allo-HSCT in this cohort proved to be an effective treatment approach to the therapy of relapses in pediatric malignancies following failure of first allo-HSCT. The 2^nd allo-HSCT may be effectively performed in stable somatic status, without active infections and toxic complications, upon development of remission or when achieving response to cytoreductive therapy before conditioning.

3. The option of repeated HSCT depends on clinical situation and presence of toxic complications in distinct cases. However, taking into account previous severe treatment, one should prefer reduced-intensity or reduced-toxicity conditioning regimens, despite absence of statistical difference between results from MAC and RIC cases. There is no difference upon donor change and allo-HSCT type, however, haploidentical donor seems to be preferred in this setting, due to availability, motivation and sooner performance of this HSCT mode.

4. With respect to soon development of relapses after repeated allo-HSCT (a median of 58 days), a decision on withdrawal of immune suppressive therapy and commencing posttransplant immunoadoptive treatment should be taken within D+30 to D+60 in absence of clinically significant GvHD. Administration of other therapies (DLI, hypomethylating and targeted drugs) causes a sufficient improvement of OS rates in the patients following repeated SC.

5. With development of novel monoclonal antibodies, as well as future CAR-T cell technologies, we need further studies of these therapeutic options in the posttransplant period for this cohort of patients.

Conflict of interest

Non declared.

References

Afanasyev B, Zubarovskaya L, Moiseev I. Allogeneic hematopoietic stem cell transplantation in children: now, problems and prospects. Russian Journal of Pediatric Hematology and Oncology. 2015;2(2):28-42 (In Russian).
Arellano M, Langston A,Winton E, Flowers C, Walle E. Treatment of relapsed acute leukemia after allogeneic transplantation: a single center experience. Biol Blood Marrow Transplant. 2007; 13:116-123.
Naik S. Martinez C, Leung K, Sasa G, Nguyen N. Outcomes after second hematopoietic stem cell transplantations in pediatric patients with relapsed hematological malignancies. Biol Blood Marrow Transplant. 2015; 21:1266-1272.
Shaw B, Russell N. Treatment options for the management of acute leukemia relapsing following an allogeneic transplant. Bone Marrow Transplantation. 2008; 41: 495-503.
Ruutu T, Wreede L, Biezen A, Brand R, Mohty M, Dreger P, Duarte R, Peters C, Garderet L, Schönland S, Gratwohl A, Niederwieser D, Witte T, Kröger N. for the EBMT. Second allogeneic transplantation for relapse of malignant disease: retrospective analysis of outcome and predictive factors by the EBMT. Bone Marrow Transplantation. 2015;50(12):1542-1550.
Schmid C, Labopin M, Nagler A, Bornhäuser M, Finke J, Fassas A, Volin L, Gürman G, Maertens J, Bordigoni P, Holler E, Ehninger G, Polge E, Gorin N-C, Kolb H-J. Donor lymphocyte infusion in the treatment of first hematological relapse after allogeneic stem-cell Transplantation in Adults With Acute Myeloid Leukemia: A Retrospective Risk Factors analysis and comparison with other strategies by the EBMT Acute Leukemia Working Party. J Clin Oncol. 2007; 25:4938-4945.
Gore L, Locatelli F, Zugmaier G, Handgretinger R, O’Brien M, Bader P, Bhojwani D, Schlegel P, Tuglus C, Stackelberg A. Survival after blinatumomab treatment in pediatric patients with relapsed/refractory B-cell precursor acute lymphoblastic leukemia. Blood Cancer J.2018 8(9):80. doi: 10.1038/s41408-018-0117-0.
Yaniv I, Krauss A, Beohou E, Dalissier A, Corbacioglu S, Zecca M, Afanasyev B, Berger M, Diaz M, Kalwak K, Sedlacek P, Varotto S, Peters C, Bader P. Second hematopoietic stem cell transplantation for post-transplant relapsed acute leukemia in children: a retrospective EBMT-PDWP study. Biol Blood Marrow Transplant. 2018;24(8):1629-1642.
Duncan C, Majhail N, Zhiwei R, Cahn WJY. Long-term survival and late effects among one-year survivors of second allogeneic hematopoietic cell transplantation for relapsed acute leukemia and myelodysplastic syndromes. Biol Blood Marrow Transplant. 2015; 21:151-158.
Blau I, Basara N, Bischoff M, Günzelmann S, Römer E, Kirsten D, Schmetzer B, M Kiehl M, Fauser A. Second allogeneic hematopoietic stem cell transplantation as treatment for leukemia relapsing following a first transplant. Bone Marrow Transplantation. 2000; 25(1): 41-45.
Markova I, Zubarovskaya L, Paina O, Bondarenko S, Kozhokar P, Frolova A, Rakhmanova Zh, Galas M, Ekushov K, Babenko E, Gindina T, Barkhatov I, Semenova E, Moiseev I. Assesment of blinatumomab efficacy and safety in treatment of relapses and refractory forms of B-lineage acute lymphoblastic leukemia in children. Pediatria. 2019; 98(4):158-164 (In Russian).
Semenova E, Stancheva N, Zubarovskaya N, Babenko E, Slesarchuk O, Estrina M, Zubarovskaya L, Afanasyev B. Post-transplant relapses of acute leukemia in children and adolescents. Bone Marrow Transplantation. 2010; 45 (Suppl 2):94.
Semenova E, Stancheva N, Alyanskiy A, Tretyakova M, Razumova S, Borovkova A, Babenko E, Bondarenko S, Shiryaev S, Bykova T, Paina O, Zubarovskaya L, Kozlov A, Afanasyev B. Results of second allogeneic stem cell transplantation for children and adolescents with acute leukaemia. Bone Marrow Transplantation. 2011; 46(Suppl.1): 273.
Sakashita K, Matsuda K, Koike K. Diagnosis and treatment of juvenile myelomonocytic leukemia. Pediatrics Int. 2016; 58, 681-690.
Bosi A Laszlo D, Labopin M, Reffeirs J, Michallet M, Gluckman E, Alessandrino PE, Locatelli F, Vernant JP, Sierra J, Jouet JP, Frassoni F. Acute Leukemia Working Party of the European Blood and Marrow Transplant Group. Second allogeneic bone marrow transplantation in acute leukemia: results of a survey by the European Cooperative Group for Blood and Marrow Transplantation. J Clin Oncol. 2001; 19(16): 3675-3684.
Kharfan-Dabaja AM, Labopin M, Polge E, Nishihori T, Bazarbachi A, Finke J, Stadler M, Ehninger G, Lioure B, Schaap N, Afanasyev B, Yeshurun M, Isaksson C, Maertens J, Chalandon Y, Schmid C, Nagler A, Mohty M. Association of second allogeneic hematopoietic cell transplant vs donor lymphocyte infusion with overall survival in patients with acute myeloid leukemia relapse. JAMA Oncol. 2018; 4(9):1245-1253.
Schrappe M, Hunger SP, Pui CH, Saha V. Outcomes after induction failure in childhood acute lymphoblastic leukemia. New Engl J Med. 2012; 366(15):1371-1381.
Fedorova LV, Lepik KV, Popova MO, VlasovaYY, Kudyasheva OV, Rogacheva YA, Lepik EE, Porunova VV, Osipova AA, Zalyalov YR, Darskaya EI, Markova IV. Highlights of the 24th European Hematology Association Congress, Amsterdam 2019. Cell Ther Transplant 2019; 8(2): 82-90.

" ["~DETAIL_TEXT"]=> string(28172) "

Introduction

Materials and methods

Table 1. Clinical characteristics of pediatric patients considered for 2^nd allo-HSCT

Abbreviations: BU, Busulfan; Treo, Treosulfan; Flu, Fludarabine; Cy, Cyclophosphamide; GIAC, Bu, Ara-C, CCNU, Cy; MAC, myeloablative conditioning, RIC, reduced-intensity conditioning.

Table 2. Clinical characteristics of the patients who underwent 2^nd HSCT

Results

Figure 1. Five-year OS after 2nd allo-HSCT in the entire cohort (A); in patients with ALL (B); in patients with AML (C); in MPD cases (D) after 2^nd allo-HSCT

Abscissa, months after allo-HSCT, ordinate, cumulative survival.

Figure 2. Overall survival in the patients with different status prior to 2^nd allo-HSCT (red graph, remission; green, cytoreduction; blue curve, no response)

Abscissa, terms after 2^nd HSCT, months; ordinate cumulative survival.

Figure 3. Relapse-free survival in the entire group of patients after 2^nd allo-HSCT

Abscissa, terms after 2^nd HSCT, months; ordinate cumulative survival.

Figure 4. Effects of 2 competing events upon general mortality after 2^nd HSCT, i.e., (1) cumulative relapse rate (34%; 95%CI, 21.6%-48%), and (2) TRM rate (18%; 95%CI, 8.8-29.8%)

Relapse or progression of disease remained the main cause of mortality after 2^nd allo-HSCT (65%, n=17). The median time of the relapse development in these patients comprises 58 days.

Transplant-related mortality in this group was 18%, (95%CI, 8.8-29.8%) and the relapse rate (a competing event) was 34% (95%CI, 21.6% to 48%), as shown in Fig. 4.

Discussion

Conclusion

Conflict of interest

Non declared.

References

Afanasyev B, Zubarovskaya L, Moiseev I. Allogeneic hematopoietic stem cell transplantation in children: now, problems and prospects. Russian Journal of Pediatric Hematology and Oncology. 2015;2(2):28-42 (In Russian).
Arellano M, Langston A,Winton E, Flowers C, Walle E. Treatment of relapsed acute leukemia after allogeneic transplantation: a single center experience. Biol Blood Marrow Transplant. 2007; 13:116-123.
Naik S. Martinez C, Leung K, Sasa G, Nguyen N. Outcomes after second hematopoietic stem cell transplantations in pediatric patients with relapsed hematological malignancies. Biol Blood Marrow Transplant. 2015; 21:1266-1272.
Shaw B, Russell N. Treatment options for the management of acute leukemia relapsing following an allogeneic transplant. Bone Marrow Transplantation. 2008; 41: 495-503.
Ruutu T, Wreede L, Biezen A, Brand R, Mohty M, Dreger P, Duarte R, Peters C, Garderet L, Schönland S, Gratwohl A, Niederwieser D, Witte T, Kröger N. for the EBMT. Second allogeneic transplantation for relapse of malignant disease: retrospective analysis of outcome and predictive factors by the EBMT. Bone Marrow Transplantation. 2015;50(12):1542-1550.
Schmid C, Labopin M, Nagler A, Bornhäuser M, Finke J, Fassas A, Volin L, Gürman G, Maertens J, Bordigoni P, Holler E, Ehninger G, Polge E, Gorin N-C, Kolb H-J. Donor lymphocyte infusion in the treatment of first hematological relapse after allogeneic stem-cell Transplantation in Adults With Acute Myeloid Leukemia: A Retrospective Risk Factors analysis and comparison with other strategies by the EBMT Acute Leukemia Working Party. J Clin Oncol. 2007; 25:4938-4945.
Gore L, Locatelli F, Zugmaier G, Handgretinger R, O’Brien M, Bader P, Bhojwani D, Schlegel P, Tuglus C, Stackelberg A. Survival after blinatumomab treatment in pediatric patients with relapsed/refractory B-cell precursor acute lymphoblastic leukemia. Blood Cancer J.2018 8(9):80. doi: 10.1038/s41408-018-0117-0.
Yaniv I, Krauss A, Beohou E, Dalissier A, Corbacioglu S, Zecca M, Afanasyev B, Berger M, Diaz M, Kalwak K, Sedlacek P, Varotto S, Peters C, Bader P. Second hematopoietic stem cell transplantation for post-transplant relapsed acute leukemia in children: a retrospective EBMT-PDWP study. Biol Blood Marrow Transplant. 2018;24(8):1629-1642.
Duncan C, Majhail N, Zhiwei R, Cahn WJY. Long-term survival and late effects among one-year survivors of second allogeneic hematopoietic cell transplantation for relapsed acute leukemia and myelodysplastic syndromes. Biol Blood Marrow Transplant. 2015; 21:151-158.
Blau I, Basara N, Bischoff M, Günzelmann S, Römer E, Kirsten D, Schmetzer B, M Kiehl M, Fauser A. Second allogeneic hematopoietic stem cell transplantation as treatment for leukemia relapsing following a first transplant. Bone Marrow Transplantation. 2000; 25(1): 41-45.
Markova I, Zubarovskaya L, Paina O, Bondarenko S, Kozhokar P, Frolova A, Rakhmanova Zh, Galas M, Ekushov K, Babenko E, Gindina T, Barkhatov I, Semenova E, Moiseev I. Assesment of blinatumomab efficacy and safety in treatment of relapses and refractory forms of B-lineage acute lymphoblastic leukemia in children. Pediatria. 2019; 98(4):158-164 (In Russian).
Semenova E, Stancheva N, Zubarovskaya N, Babenko E, Slesarchuk O, Estrina M, Zubarovskaya L, Afanasyev B. Post-transplant relapses of acute leukemia in children and adolescents. Bone Marrow Transplantation. 2010; 45 (Suppl 2):94.
Semenova E, Stancheva N, Alyanskiy A, Tretyakova M, Razumova S, Borovkova A, Babenko E, Bondarenko S, Shiryaev S, Bykova T, Paina O, Zubarovskaya L, Kozlov A, Afanasyev B. Results of second allogeneic stem cell transplantation for children and adolescents with acute leukaemia. Bone Marrow Transplantation. 2011; 46(Suppl.1): 273.
Sakashita K, Matsuda K, Koike K. Diagnosis and treatment of juvenile myelomonocytic leukemia. Pediatrics Int. 2016; 58, 681-690.
Bosi A Laszlo D, Labopin M, Reffeirs J, Michallet M, Gluckman E, Alessandrino PE, Locatelli F, Vernant JP, Sierra J, Jouet JP, Frassoni F. Acute Leukemia Working Party of the European Blood and Marrow Transplant Group. Second allogeneic bone marrow transplantation in acute leukemia: results of a survey by the European Cooperative Group for Blood and Marrow Transplantation. J Clin Oncol. 2001; 19(16): 3675-3684.
Kharfan-Dabaja AM, Labopin M, Polge E, Nishihori T, Bazarbachi A, Finke J, Stadler M, Ehninger G, Lioure B, Schaap N, Afanasyev B, Yeshurun M, Isaksson C, Maertens J, Chalandon Y, Schmid C, Nagler A, Mohty M. Association of second allogeneic hematopoietic cell transplant vs donor lymphocyte infusion with overall survival in patients with acute myeloid leukemia relapse. JAMA Oncol. 2018; 4(9):1245-1253.
Schrappe M, Hunger SP, Pui CH, Saha V. Outcomes after induction failure in childhood acute lymphoblastic leukemia. New Engl J Med. 2012; 366(15):1371-1381.
Fedorova LV, Lepik KV, Popova MO, VlasovaYY, Kudyasheva OV, Rogacheva YA, Lepik EE, Porunova VV, Osipova AA, Zalyalov YR, Darskaya EI, Markova IV. Highlights of the 24th European Hematology Association Congress, Amsterdam 2019. Cell Ther Transplant 2019; 8(2): 82-90.

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Полина В. Кожокарь¹, Олеся В. Паина¹, Анастасия С. Фролова¹, Джемал З. Рахманова¹, Анастасия C. Боровкова¹, Елена В. Семенова¹, Анна А. Осипова¹, Кирилл А. Екушов¹, Ольга А. Слесарчук¹, Варвара Н. Овечкина¹, Елена В. Бабенко¹, Алина А. Витрищак¹, Борис И. Смирнов², Людмила С. Зубаровская¹, 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. И. П. Павлова, Санкт-Петербург, Россия
² Санкт-Петербургский государственный электротехнический университет, 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) "24579" ["VALUE"]=> array(2) { ["TEXT"]=> string(3538) "Аллогенная трансплантация гемопоэтических стволовых клеток (алло-ТГСК) является стандартом терапии в группе высокого риска онкогематологических заболеваний. Несмотря на это, уровень рецидивов варьирует от 10 до 70%. До сих пор отсутствует оптимальный подход к терапии рецидива после алло-ТГСК. Возможные терапевтические опции включают в себя реиндукцию, иммуноадоптивную терапию, таргетную терапию, иммунотерапию (CAR T-клеточную терапию), повторную трансплантацию. В данной публикации представлено ретроспективное исследование пациентов с рефрактерным течением онкогематологических заболеваний, а также отторжением трансплантата в группе высокого риска, в связи с чем выполнялась повторная алло-ТГСК. Целью нашей работы был анализ результатов повторной алло-ТГСК у 50 детей с различными онкогематологическими заболеваниями: ОЛЛ – 24, ОМЛ – 15, МДС и ХМПЗ – 11 пациентов. Общая выживаемость (ОВ) по методу Каплан-Майер во всей группе составила 48%, безрецидивная выживаемость (БРВ) – 60%. Медиана наблюдения составила 3 года 7 мес. Пятилетняя ОВ в группе ОЛЛ была 46,2%, в группе ОМЛ – 53,3%, в группе МДС и МПЗ – 44,4%. Причины летальности: рецидив/прогрессия в 17 случаях (65%).Трансплантационная летальность составила 18% (95% ДИ, 8,8%-29,8%). Кумулятивная частота рецидива составила 34% (95% ДИ, 21,6%-48%). <h3>Заключение</h3> Повторная алло-ТГСК – эффективный метод терапии у пациентов с рецидивом заболевания после первой ТГСК. Пациенты, достигшие ремиссии или циторедукции перед алло-ТГСК, имеют статистически достоверный лучший прогноз. Развитие хронической РТПХ легкой и средней степени статистически улучшает ОВ. Не получено достоверной разницы между РИК и МАК. Посттрансплантационная терапия может улучшить результаты повторной алло-ТГСК. <h2>Ключевые слова</h2> Рецидив острого лейкоза, повторная алло-ТГСК, посттрансплантационная терапия, дети. " ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(3448) "

Аллогенная трансплантация гемопоэтических стволовых клеток (алло-ТГСК) является стандартом терапии в группе высокого риска онкогематологических заболеваний. Несмотря на это, уровень рецидивов варьирует от 10 до 70%. До сих пор отсутствует оптимальный подход к терапии рецидива после алло-ТГСК. Возможные терапевтические опции включают в себя реиндукцию, иммуноадоптивную терапию, таргетную терапию, иммунотерапию (CAR T-клеточную терапию), повторную трансплантацию. В данной публикации представлено ретроспективное исследование пациентов с рефрактерным течением онкогематологических заболеваний, а также отторжением трансплантата в группе высокого риска, в связи с чем выполнялась повторная алло-ТГСК. Целью нашей работы был анализ результатов повторной алло-ТГСК у 50 детей с различными онкогематологическими заболеваниями: ОЛЛ – 24, ОМЛ – 15, МДС и ХМПЗ – 11 пациентов. Общая выживаемость (ОВ) по методу Каплан-Майер во всей группе составила 48%, безрецидивная выживаемость (БРВ) – 60%. Медиана наблюдения составила 3 года 7 мес. Пятилетняя ОВ в группе ОЛЛ была 46,2%, в группе ОМЛ – 53,3%, в группе МДС и МПЗ – 44,4%. Причины летальности: рецидив/прогрессия в 17 случаях (65%).Трансплантационная летальность составила 18% (95% ДИ, 8,8%-29,8%). Кумулятивная частота рецидива составила 34% (95% ДИ, 21,6%-48%).

Заключение

Повторная алло-ТГСК – эффективный метод терапии у пациентов с рецидивом заболевания после первой ТГСК. Пациенты, достигшие ремиссии или циторедукции перед алло-ТГСК, имеют статистически достоверный лучший прогноз. Развитие хронической РТПХ легкой и средней степени статистически улучшает ОВ. Не получено достоверной разницы между РИК и МАК. Посттрансплантационная терапия может улучшить результаты повторной алло-ТГСК.

Ключевые слова

Рецидив острого лейкоза, повторная алло-ТГСК, посттрансплантационная терапия, дети.

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Polina V. Kozhokar¹, Olesya V. Paina¹, Anastasia S. Frolova¹, Zhemal Z. Rakhmanova¹, Anastasia S. Borovkova¹, Elena V. Semenova¹, Anna A. Osipova¹, Kirill A. Ekushov¹, Olga A. Slesarchuk¹, Varvara N. Ovechkina¹, Elena V. Babenko¹, Alina A. Vitrishchak¹, Boris I. Smirnov², Ludmila S. Zubarovskaya¹, 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 Saint Petersburg State Electrotechnical University, St. Petersburg, Russia

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Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is effective treatment in high risk hematological malignancies. Nevertheless, the relapse rates after allo-HSCT range from 10% to 70%.There is no optimal strategy of the relapse therapy after allo-HSCT. Possible therapeutic options include re-induction chemotherapy, immunoadoptive therapy (DLI), target drugs, immunotherapy (CAR-T) and second allo-HSCT. The presented study is a retrospective single-institution experience of second allo-HSCT in the patients (pts) with acute leukemia relapses or graft failure in high-risk cases. The aim of our study was to analyze the outcomes after second allo-HSCT in 50 children with hematological malignancies, i.e., ALL (n=24), AML (n=15), MPDs/MDS (n=11).

Results

Forty-four patients achieved engraftment, with median neutrophil engraftment time of 21 days (12 to 41). Remission was achieved in 44 pts (88%). Median follow-up period was 3 years 7 months. Overall survival (OS), according to Kaplan-Meier method, was 48% in the whole group. Relapse-free survival (RFS) was 60%. The five-year OS in ALL group was 46.2%; in AML group, 53.3%; in MPDs/MDS, 44.4%. Causes of death were as follows: relapse/progression in 65% (n=17), transplant-related mortality (TRM), in 18% (n=9; 95%CI, 8.8%-29.8%); cumulative relapse rate was 34% (95% CI, 21.6%-48%).

Conclusion

Second allo-HSCT is an effective treatment option in cases of relapse after 1^st allo-HSCT. The patients that achieved remission or even blast cytoreduction prior to 2^nd allo-HSCT had better outcome. Clinical manifestations of acute and chronic GVHD can significantly improve the OS. Results of 2^nd allo-HSCT were comparable when using RIC or MAC conditioning regimens. Posttransplant therapy is required to improve results after 2^nd HSCT.

Keywords

Leukemia relapse, second allogeneic HSCT, posttransplant therapy, children.

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Kozhokar1, Olesya V. Paina1, Anastasia S. Frolova1, Zhemal Z. Rakhmanova1, Anastasia S. Borovkova1, Elena V. Semenova1, Anna A. Osipova1, Kirill A. Ekushov1, Olga A. Slesarchuk1, Varvara N. Ovechkina1, Elena V. Babenko1, Alina A. Vitrishchak1, Boris I. Smirnov2, Ludmila S. Zubarovskaya1, Boris V. Afanasyev1" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(490) "

" } ["SUMMARY_EN"]=> array(37) { ["ID"]=> string(2) "39" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:02:59" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(21) "Description / Summary" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(10) "SUMMARY_EN" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "39" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "24598" ["VALUE"]=> array(2) { ["TEXT"]=> string(2286) "Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is effective treatment in high risk hematological malignancies. Nevertheless, the relapse rates after allo-HSCT range from 10% to 70%.There is no optimal strategy of the relapse therapy after allo-HSCT. Possible therapeutic options include re-induction chemotherapy, immunoadoptive therapy (DLI), target drugs, immunotherapy (CAR-T) and second allo-HSCT. The presented study is a retrospective single-institution experience of second allo-HSCT in the patients (pts) with acute leukemia relapses or graft failure in high-risk cases. The aim of our study was to analyze the outcomes after second allo-HSCT in 50 children with hematological malignancies, i.e., ALL (n=24), AML (n=15), MPDs/MDS (n=11). <h3>Results</h3> Forty-four patients achieved engraftment, with median neutrophil engraftment time of 21 days (12 to 41). Remission was achieved in 44 pts (88%). Median follow-up period was 3 years 7 months. Overall survival (OS), according to Kaplan-Meier method, was 48% in the whole group. Relapse-free survival (RFS) was 60%. The five-year OS in ALL group was 46.2%; in AML group, 53.3%; in MPDs/MDS, 44.4%. Causes of death were as follows: relapse/progression in 65% (n=17), transplant-related mortality (TRM), in 18% (n=9; 95%CI, 8.8%-29.8%); cumulative relapse rate was 34% (95% CI, 21.6%-48%). <h3>Conclusion</h3> Second allo-HSCT is an effective treatment option in cases of relapse after 1st allo-HSCT. The patients that achieved remission or even blast cytoreduction prior to 2nd allo-HSCT had better outcome. Clinical manifestations of acute and chronic GVHD can significantly improve the OS. Results of 2nd allo-HSCT were comparable when using RIC or MAC conditioning regimens. Posttransplant therapy is required to improve results after 2nd HSCT. <h2>Keywords</h2> Leukemia relapse, second allogeneic HSCT, posttransplant therapy, children." ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(2114) "

Results

Conclusion

Keywords

Leukemia relapse, second allogeneic HSCT, posttransplant therapy, children.

Results

Conclusion

Keywords

Leukemia relapse, second allogeneic HSCT, posttransplant therapy, children.

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Несмотря на это, уровень рецидивов варьирует от 10 до 70%. До сих пор отсутствует оптимальный подход к терапии рецидива после алло-ТГСК. Возможные терапевтические опции включают в себя реиндукцию, иммуноадоптивную терапию, таргетную терапию, иммунотерапию (CAR T-клеточную терапию), повторную трансплантацию. В данной публикации представлено ретроспективное исследование пациентов с рефрактерным течением онкогематологических заболеваний, а также отторжением трансплантата в группе высокого риска, в связи с чем выполнялась повторная алло-ТГСК. Целью нашей работы был анализ результатов повторной алло-ТГСК у 50 детей с различными онкогематологическими заболеваниями: ОЛЛ – 24, ОМЛ – 15, МДС и ХМПЗ – 11 пациентов. Общая выживаемость (ОВ) по методу Каплан-Майер во всей группе составила 48%, безрецидивная выживаемость (БРВ) – 60%. Медиана наблюдения составила 3 года 7 мес. Пятилетняя ОВ в группе ОЛЛ была 46,2%, в группе ОМЛ – 53,3%, в группе МДС и МПЗ – 44,4%. Причины летальности: рецидив/прогрессия в 17 случаях (65%).Трансплантационная летальность составила 18% (95% ДИ, 8,8%-29,8%). Кумулятивная частота рецидива составила 34% (95% ДИ, 21,6%-48%). <h3>Заключение</h3> Повторная алло-ТГСК – эффективный метод терапии у пациентов с рецидивом заболевания после первой ТГСК. Пациенты, достигшие ремиссии или циторедукции перед алло-ТГСК, имеют статистически достоверный лучший прогноз. Развитие хронической РТПХ легкой и средней степени статистически улучшает ОВ. Не получено достоверной разницы между РИК и МАК. Посттрансплантационная терапия может улучшить результаты повторной алло-ТГСК. <h2>Ключевые слова</h2> Рецидив острого лейкоза, повторная алло-ТГСК, посттрансплантационная терапия, дети. " ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(3448) "

Заключение

Ключевые слова

Рецидив острого лейкоза, повторная алло-ТГСК, посттрансплантационная терапия, дети.

Заключение

Ключевые слова

Рецидив острого лейкоза, повторная алло-ТГСК, посттрансплантационная терапия, дети.

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Introduction

Discovery and clinical success of ICIs entered a new era in oncology. The 2018 Nobel Prize in Medicine was awarded to James P. Allison and Tasuku Honjo "for their discovery of cancer therapy by inhibition of negative immune regulation". The principal role of immune system in tumor control was understood long ago. Earlier researchers mostly explored the opportunities to activate the immune system by stimulation of effector cells ("pressing gas pedal"). James P. Allison and Tasuku Honjo demonstrated that inhibition of checkpoints ("releasing the brake pedal") may effectively upregulate the immune system.

The ICIs demonstrate substantial efficiency in cHL. Pembrolizumab was approved for the treatment of children with cHL, but the role of other ICIs in pediatrics should only to be elucidated. Despite impressive progress in oncology, the children with refractory or resistant (R-R) cHL still demonstrate suboptimal prognosis if ≥3 lines of therapies have to be used [1]. This group of R-R cHL patients needs new approaches in management, and ICIs are among the most promising candidate drugs. The discovery of CIs introduced principally novel approach to cancer cure. This may convert cancer to one of chronic diseases [2].

The principal feature of immunity is the ability to differ between autoantigens and alloantigens. But the immune system is not ideal and regularly makes mistakes. These errors are often mild and non-significant but sometimes may lead to serious consequences such as oncological, autoimmune or infectious diseases. Studying molecular mechanisms of antigen procession, presentation, co-stimulation and inhibition is crucial for the treatment of patients with tumors.

PD-1 (programmed cell death-1) gene was discovered during the research of cell apoptosis [3]. It took a long journey to understand the function of PD-1 [2]. In terms of physiological role (immune inhibition) the definition of PD-1 is relatively correct, due to fundamental position of apoptosis in tolerance. But, in general, the term PD-1 does not precisely reflect the function of the protein.

Structurally PD-1 is a transmembrane protein and its interaction with ligands (PD-L1 or PD-L2) results in activation of PD-1/PD-L pathway [4, 5]. This effect leads to downregulation of autoreactive T cells and upregulation of T regulatory cells [6]. Development of autoimmune disorders in the model of PD-1 knockout mice proved significance of the pathway for adequate immune regulation [7]. Excessive PD-1 expression due to continuous antigen stimulation results in T-cell exhaustion and tolerance [8]. This mechanism may be realized in tumors.

PD-1 and ligands are expressed constitutive or inducibly on many tissues. PD-1 is expressed on immune cells (T-helpers, cytotoxic T-lymphocytes, natural killers, B cells, monocytes and dendritic cells) [9]. PD-L1 has extensive distribution throughout the body while PD-L2 is only present on macrophages and dendritic cells. PD-L1 can be expressed on non-hematological structures, such as endothelial cells, fibroblasts, mucous, pancreatic islet cells, astrocytes, neurons, trophoblasts, retina, heart, placenta, skeletal muscle, lung and kidney [10, 11]. Presence of PD-1 on endothelial cells may play an important role in the prevention of T cell migration into tissues and establishment of blood-organ immunological barriers [12]. Both PD-1 and PD-L1 are present on T cells, В-cells, macrophages and dendritic cells. These cells possess bimodal opportunity to regulate and to be regulated by the pathway. Some tumors also have PD-L1 on its surface, and it allows them to be "invisible" to immune system [13]. The expression of PD-1 and ligands is controlled by cytokines. For example, interferon 1 and tumor necrosis factor-α stimulate PD-L1 expression. Theoretically, combining these drugs with inducers of PD-1/PD-L1 may improve the efficiency of ICIs.

Nivo and pembro are PD-1 blocking antibodies that have been approved by the U.S. Food and Drug Administration for the treatment of сHL and some solid tumors. They were also registered in Russian Federation for the management of adult patients (nivo and pembro) and children with сHL (pembro). In the majority of сHL patients, ICIs induce durable clinical response. Complete or partial recovery of tumor immune control results in significant attenuation of disease progression. Amplification of 9p24.1 and subsequent overexpression of PD-L1 seems to be the characteristic feature of HL-specific Reed-Sternberg cells [14]. It explains high efficiency of ICIs in cHL. However, most HL patients relapse after treatment with ICIs. Therefore, it is important to improve the results by shifting to combination therapy, incorporation of ICIs earlier in treatment and consolidation with HSCT [15]. We are only in the beginning of CIs era, and appropriate schemes and schedules are only to be discovered. For example, lower dosage of nivolumab could be comparable to standard dosage of 3 mg/kg biweekly [16].

The aim of our work was to assess safety and effectiveness of nivo in childhood R-R cHL.

Patients and methods

Twenty-one children and adolescents with R-R Hodgkin's lymphoma (HL) received nivo-based therapy in Raisa Gorbacheva Memorial Research Institute of Children Oncology, Hematology and Transplantation, Pavlov First St. Petersburg State Medical University (see Table 1 for patient´s characteristics). Median age was 16 years (9 to 18). Histological forms of HL were as follows: nodular sclerosis was diagnosed in 15 patients (71%); mixed cellularity cHL, 4 cases (19%), lymphocyte-rich cHL, 1 (5%) and nodular lymphocyte predominant Hodgkin's lymphoma, 1 (5%). At the onset of the disease, the early-stage favorable status was diagnosed in 4 patients (19%); early-stage unfavorable or advanced disease was diagnosed in 17 cases (81%). B-symptoms were documented in 12 patients (67%). Bulky disease (>7 cm) and extranodal lesions were registered in 12 (57%) and 14 (67%) children, respectively. The disease was refractory in 9 cases (43%), whereas resistant or multiple relapses occurred in 12 patients (57%).

Table 1. Patient´s characteristics (n=21)

Abbreviations: NSCHL (nodular sclerosis classical Hodgkin lymphoma), MCCHL (mixed cellularity classical Hodgkin lymphoma), NLPHL (nodular lymphocyte predominant Hodgkin's lymphoma), LRCHL (lymphocyte-rich classical Hodgkin lymphoma), OEPA/COPDAC (vincristine, etoposide, prednisolone, doxorubicin/cyclophosphamide, vincristine, prednisolone, dacarbazine), RT (radiotherapy), BEACOPP (bleomycin, etoposide, cytarabine, cyclophosphamide, vincristine, prednisolone, procarbazine), GDP (gemcitabine, dexamethasone, cisplatin), ABVD (doxorubicin, bleomycin, vinblastine, dacarbazine), DHAP (dexamethasone, cisplatin, cytarabine), ChVPP (chlorbutine, vinblastine, prednisolone, procarbazine), IEP/ABVD (ifosfamide, etoposide, prednisolone/doxorubicin, bleomycin, vinblastine, dacarbazine), VIGEPP (vinorelbine, gemcitabine, procarbazine, prednisolone), auto-HSCT (autologous hematopoietic stem cell transplantation), GemOx (gemcitabine, oxaliplatin), ICE (ifosfamide, carboplatin, etoposide), OPPA/COPP (vincristine, prednisolone, procarbazine, doxorubicin/cyclophosphamide, vincristine, prednisolone, procarbazine), IEP (ifosfamide, etoposide, prednisolone), IGEV (ifosfamide, gemcitabine, vinorelbine), COPP (cyclophosphamide, vincristine, prednisolone, procarbazine), CEMP (cyclophosphamide, etoposide, mitoxantron, prednisolone), COPP/ABV (cyclophosphamide, vincristine, prednisolone, procarbazine/doxorubicin, bleomycin, vinblastine), BV (brentuximab vedotin), rel (relapse), ref (refractory), mr (multiple relapses), mono/comb (monotherapy/combination therapy), R/R (relapsed/refractory), CR (complete response), PR (partial response), IR (indeterminate response), N/A – not applicable.

Median number of previous therapy lines was 4 (2-7) with radiation therapy in 14 patients (67%), and autologous HSCT in 6 cases (29%). Prior to nivo therapy, 16 children (76%) had progression; 3 (14%), stabilization, and 2 (10%), partial remission according to Lugano criteria [17]. All the patients received nivo in an outpatient setting. Monotherapy was used in 13 (62%) and combination with other drugs in 8 (38%). In 5 children, combination therapy was indicated, based on opinion of attended physician. In 3 cases, other drugs were added after slow clinical response to the first nivo infusions, aiming to achieve faster clinical improvement. Treatment schedule consisted of 3 mg/kg of nivo biweekly in 11 (52%) or 40 mg of nivo biweekly in 10 (48%). Combinations of nivo with following drugs were used: brentuximab vedotin 1.8 mg/kg triweekly (n=4) with median of 5 cycles (4-7), bendamustine 180 mg/m² triweekly (n=3) with median of 5 cycles (5-7) and gemcitabine 1000 mg/m² №5 weekly (n=1). Median number of nivo cycles was 9 (2-28). Response to treatment was evaluated by the LYRIC criteria [18]. They represent modified Lugano recommendations, with the addition of indeterminate response (IR). This category describes possible pseudo-progression and allows to continue ICIs hoping for further best response without discontinuation of treatment in the patients with progressive disease according to previous criterial algorithms. After nivo-based treatment, 8 patients (38%) received auto- or allogeneic hematopoietic stem cell transplantation (HSCT). Conditioning regimen in autologous HSCT (n=4) was BeEAM (bendamustine, etoposide, cytarabine and melphalan). Haploidentical donors were employed in two allo-HSCTs, and two matched related siblings were used in two other cases. The conditioning regimen in allogeneic HSCT consisted of bendamustine 360 mg/m² and Fludarabine 150 mg/m². Graft-versus-host disease prophylaxis was based on posttransplant cyclophosphamide and calcineurin inhibitors. Radiation therapy was applied to consolidate the effect of nivo in 2 cases (10%). Eleven patients (52%) did not receive any consolidation treatment.

Results

Clinical response to nivo-based therapy was assessed in 21 patients (100%). Efficiency of treatment is shown in Table 2. Overall response (ORR) was registered in 18 children (86%); CR, in 12 cases (57%); PR, in 6 patients (29%) and IR, in 3 cases (14%). Among the patients with IR, two children relapsed, and one patient is now in remission with the follow-up of 355 days. Monotherapy resulted in ORR of 92% (12 patients); CR, in 62% (8), and PR, in 30% of cases (4). Combination therapy demonstrated similar effectiveness, i.e., ORR, 6 (75%); CR, 4; (50%); PR, 2 (25%).

Table 2. Efficiency of Nivolumab-based therapy

The three-year OS rates comprised 95%. PFS rates at 1, 2 and 3 years were 69%, 58% and 29%, respectively (Fig. 1A and 1B). Median OS was not reached. With median follow-up of 391 days (47-1137), twenty patients (95%) were alive, and 14 (67%) remained in remission state. Median PFS was 24 months. Consolidation with HSCT (auto- or allo-) resulted in 3-year PFS of 75% (Fig. 2). Only 1 patient died in early posttransplant period due to infectious complications.

The general scheme of nivo-based therapy (mono- vs combined treatment), cHL stage (early vs advanced), tumor size (bulky+ vs bulky-), B symptoms, extranodal lesions, number of prior chemotherapy lines, preceding autoHSCT, number of nivo infusions (10 vs >10, see Fig. 3), and complications of therapy did not affect OS and PFS (p>0.1).

In the monotherapy group, complications of nivo were revealed in one adolescent (7.7%). This patient developed autoimmune thyroiditis which required hormone replacement therapy. It didn't lead to discontinuation of the drug. In combination therapy group, 2 patients (25%) developed transient cytopenias that could not be attributed solely to nivo and were probably associated with cytostatics.

Figure 1. Overall survival (A) and progression-free survival (B) of the patients treated with nivolumab (n=21)

Figure 2. Progression-free survival curves with HSCT vs without following HSCT in the patients treated with nivolumab

Figure 3. Progression-free survival curves among the patients treated with nivolumab (≤10 vs >10 infusions).

Discussion

ICIs have demonstrated high efficiency and acceptable safety profile both in adults and children in large cohorts of patients (Tables 3 and 4). Administration of ICIs in adult R-R HL results in overall response (ORR) of 64-82%, with 2-year PFS of approximately 30%-58.5% [1, 19]. The largest pediatric trial with pembro included 125 children. This study clearly demonstrated safety of ICIs in children. Only 7 (6%) had clinically significant adverse effects (grade 3-5). One patient (0.8%) with renal carcinoma experienced pembro-associated pulmonary edema and died.

Table 3. Efficiency of immune checkpoint inhibitors in adult cHL

Abbreviations: ORR, overall response rate; CR, complete response; PR, partial response; HSCT, hematopoietic stem cell transplantation; PFS, progression-free survival; N/A, not applicable

Table 4. Efficiency of immune checkpoint inhibitors in pediatric cohorts

Abbreviations: HL, Hodgkin's lymphoma; NHL, non- Hodgkin's lymphoma; ORR, overall response rate; CR, complete response; PR, partial response

No major interferences on the developing immune system were observed [20]. Another important trial included children with R-R cHL treated with combination of nivo and brentuximab vedotin. Drug-related complications were registered in 32% (grade 3-4) with neutropenia among the most common. Immune-mediated adverse effects were only grade 1-2 and included rash, hypersensitivity, infusion-related reactions and did not result in discontinuation of therapy [21].

In general, the results of the present study concerning nivo-based therapy in pediatric R-R cHL are in concordance with previously published data in adults and children [22]. Higher rates of CR in children and adolescents (57%) compared to adults (15-36%) may be associated with the differences of response evaluation in these studies, may represent a unique feature of pediatric sensitivity to IСIs or may be explained by limited patient number in the study [23, 24]. Despite similar ORR in mono- and combined therapy arms, the data from other investigators strongly support the opinion that additional drugs improve the effects of nivo [25, 26].

Suboptimal 3-year PFS of 29% in this heavily pretreated group (median number of prior lines – 4) replicates earlier data of CIs administration in adults and children [1, 20]. It is important to note that PFS rates at 1 and 2 years in our study are similar or higher than in above mentioned works and steadily decrease with time. It seems that PFS after nivo does not tend to reach plateau with time.

High ORR (86%) after nivo in R-R cHL solves a challenge of remission induction and bridging to HSCT that is now possible in the majority of children. There is an opinion of principal opportunity of ICIs to cure cHL but declining PFS curve argues it, and longer follow-up is needed to draw firm conclusion. Dissociation between high 3-year OS and low PFS marks a very characteristic feature of ICIs therapy in cHL that repairs immune tumor control and improves somatic status of a patient even in active disease. Slow subclinical progression probably is driven by other non-immune mechanisms of tumor escape. Median PFS in children and adolescents in our study is 24 months and well correlates with data in other publications [20]. Longer median PFS may be explained by combination of nivo with other drugs in 38%. The positive effects of nivo significantly prolong life expectancy with good quality of life. Consolidation of nivo-induced remission with HSCT (auto or allo) results in 3-year PFS of 75%. HSCT is a potential option to improve cure rates after ICIs.

There is no established consensus opinion when to proceed with HSCT after ICIs, and what type of HSCT should be chosen. Allogeneic HSCT may be preferable, due to presumed sensitivity of the patients to immunotherapy. But autologous HSCT still may be effective in chemorefractory cases, since a recovery of chemosensitivity after ICIs treatment is hypothesized [27]. There are investigators that use both allo-HSCT and auto-HSCT to consolidate the ICIs effect [22, 24]. At the same time, an impressively high 3-year OS rate (95%) after nivo in our study, even in patients with progression, questions the need for transplantation at all [28]. Extensive follow-up is required to understand how long this clinical stabilization of cHL will continue in the majority of patients. In other words, can cHL be "cured" with morphologically and visibly obvious tumor, and if these patients may have a near-normal life expectancy similar to heathy people? This proposal seems more fantastic than real, and a longer follow-up is needed to see whether such observations will appear. Despite theoretical importance, the classical prognostic factors did not affect OS and PFS in our study. It may be explained by the domination of chemoresistance in our patients that minimizes the role of all other factors. Higher number of nivo cycles also did not improve outcome in our study. It emphasizes the challenging unsolved problem of optimal nivo treatment duration. Hypothetically, earlier consolidation with HSCT can minimize nivo-associated complications without loss of efficiency.

Only one clinically significant AE of nivo therapy was registered in the study, i.e., autoimmune thyroiditis which is a typical complication of the drug. Other characteristic autoimmune AEs were not encountered, probably due to limited patient number. All children and adolescents received nivo in outpatient setting, thus reflecting high tolerability and technical simplicity of treatment.

Conclusion

Nivo-based therapy is effective in the majority of children and adolescents with R-R cHL. In heavily pretreated patients, long-term PFS remains suboptimal, despite excellent OS levels. Consolidation with HSCT after nivo results in 75% PFS at 3 years and should be considered in the majority of patients. Nivo-based therapy is relatively safe with only one clinically significant adverse effect (autoimmune thyroiditis) observed in our study. Nivo is technically simple and well tolerable treatment that is administered in an outpatient setting.

Conflict of interest

None declared.

References

Armand P, Engert A, Younes A, Fanale M, Santoro A, Zinzani PL, Timmerman JM, Collins GP, Ramchandren R, Cohen JB, De Boer JP, Kuruvilla J, Savage KJ, Trneny M, Shipp MA et al. Nivolumab for relapsed/refractory classic Hodgkin lymphoma after failure of autologous hematopoietic cell transplantation: extended follow-up of the multicohort single-arm phase II CheckMate 205 Trial. J Clin Oncol. 2018;36(14):1428-1439.
Honjo Tasuku – Nobel Lecture. NobelPrize.org. Nobel Media AB 2019. 19 Jul 2019. https://www.nobelprize.org/prizes/medicine/2018/honjo/lecture/
Ishida Y, Agata Y, Shibahara K, Honjo T. Induced expression of PD-1, a novel member of the immunoglobulin gene superfamily, upon programmed cell death. EMBO J. 1992;11(11):3887-3895.
Butte MJ, Keir ME, Phamduy TB, Sharpe AH, Freeman GJ. Programmed death-1 ligand 1 interacts specifically with the B7-1 costimulatory molecule to inhibit T cell responses. Immunity. 2007;27:111-122.
Elezov DS, Kudryavtsev IV. PD-1 receptor on immune cells, its expression and potential role in cancer therapy. Cell Ther Transplant, 2019; 8(2):8-16.
Francisco LM, Sage PT, Sharpe AH. The PD-1 pathway in tolerance and autoimmunity. Immunol Rev. 2010;236:219-242.
Yoshida T, Jiang F, Honjo T, Okazaki T. PD-1 deficiency reveals various tissue-specific autoimmunity by H-2b and dose-dependent requirement of H-2g7 for diabetes in NOD mice. Proc Natl Acad Sci USA. 2008;105(9):3533-3538.
Wherry EJ, Ha SJ, Kaech SM, Haining WN, Sarkar S, Kalia V, Subramaniam S, Blattman J, Barber DL, Ahmed R. Molecular signature of CD8+ T cell exhaustion during chronic viral infection. Immunity. 2007; 27(4):670-684.
Kabir TF, Chauhan A, Anthony L, Hildebrandt GC. Immune checkpoint inhibitors in pediatric solid tumors: status in 2018. Ochsner Journal.2018; 18(4):370-376.
Dong H, Zhu G, Tamada K, Chen L. B7-H1, a third member of the B7 family, co-stimulates T-cell proliferation and interleukin-10 secretion. Nat Med. 1999;5:1365-1369.
Suda T, Takahashi T, Golstein P, Nagata S. Molecular cloning and expression of the Fas ligand, a novel member of the tumor necrosis factor family. Cell. 1993;75:1169-1178.
Pittet CL, Newcombe J, Prat A, Arbour N. Human brain endothelial cells endeavor to immunoregulate CD8 T cells via PD-1 ligand expression in multiple sclerosis. J Neuroinflammation. 2011 Nov 8;8:155.
Meti N, Esfahani K, Johnson NA. The role of immune checkpoint inhibitors in classical Hodgkin lymphoma. Cancers (Basel). 2018;10(6):204. doi:10.3390/cancers10060204.
Lepik KV. Immune checkpoint inhibitors in the treatment of lymphomas. Clinical Oncohematology. 2018;11(4):303-312 (In Russian).
Ansell SM. Beyond checkpoint inhibitors for Hodgkin lymphoma. 2018 Pan Pacific Lymphoma Conference. Invited Lecture. Presented July 19, 2018.
Lepik KV, Kozlov AV, Borzenkova ES, Popova MO, Moiseev IS, Darskaya EI, Gevorgyan AG, Tsvetkova LA, Bondarenko SN, Alyanskiy AL, Kondakova EV, Mikhailova NB, Afanasyev BV. Safety and efficacy of nivolumab applied at different dosage in the patients with relapsing Hodgkin lymphoma after allogeneic hematopoietic stem cell transplantation. Cell Ther Transplant. 2018; 7(2): 28-35.
Cheson BD, Fisher RI, Barrington SF, Cavalli F, Schwartz LH, Zucca E, Lister TA et al. Recommendations for Initial evaluation, staging, and response assessment of Hodgkin and non-Hodgkin lymphoma: the Lugano classification. J Clin Oncol. 2014;32(27):3059-3068.
Cheson BD, Ansell S, Schwartz L, Gordon LI, Advani R, Jacene HA, Hoos A, Barrington SF, Armand P. Refinement of the Lugano Classification lymphoma response criteria in the era of immunomodulatory therapy. 2016;128(21):2489-2496.
Ferhanoglu B, Ozbalak M, Bekoz H et al. Nivolumab for relapsed or refractory Hodgkin lymphoma: long term results of multi-center experience in Turkey. EHA Library. Jun 15, 2019; 266862; PS1245.
Geoerger B, Kang HJ, Yalon-Oren M et al. KEYNOTE-051: An update on the phase 2 results of pembrolizumab (pembro) in pediatric patients (pts) with advanced melanoma or a PD-L1–positive advanced, relapsed or refractory solid tumor or lymphoma. J Clin Oncol. 2018; 36(15, Suppl):10525-10525.
Kelly KM, Daw S, Mauz‐Körholz C , Mascarin M, Michel G, Cooper S, Beishuizen A, Leger KJ, Garaventa A, Buffardi S, Brugières L, Harker‐Murray P, Cole PD. Response-adapted treatment with Nivolumab and brentuximab vedotin in young patients with relapsed/refractory classical Hodgkin lymphoma: CHECKMATE744 Subgroup analyses. Hematol Oncol. 2019;37: 56-57.
Chen R, Zinzani PL, Fanale MA, Armand P, Johnson NA, Brice P, Radford J, Ribrag V, Molin D, Vassilakopoulos TP, Tomita A, von Tresckow B, Shipp MA, Zhang Y, Ricart AD, Balakumaran A, Moskowitz CH et al. Phase II study of the efficacy and safety of pembrolizumab for relapsed/refractory classic Hodgkin lymphoma. J Clin Oncol 2017; 35(19):2125-2132.
Lepik KV, Mikhailova NB, Kondakova EV, Tsvetkova LA, Zalyalov YR, Borzenkova ES, Moiseev IS, Baykov VV, Afanasyev BA. Efficacy and safety of nivolumab in the treatment of relapsed/refractory classical Hodgkin’s lymphoma: Pavlov First Saint Petersburg State Medical University experience. Oncohematology. 2018;13(4):17-26. (In Russian).
Santoro A, D'alo' F, Zinzani PL et al. Real-world data of nivolumab in classical Hodgkin lymphoma: results from the Italian Expanded Access Programme. Blood. 2017; 130:5171.
Herrera AF, Moskowitz AJ, Bartlett NL, Vose JM, Ramchandren R, Feldman TA, LaCasce AS, Ansell SM, Moskowitz CH, Fenton K, Ogden CA, Taft D, Zhang Q, Kato K, Campbell M, Advani RH. Interim results of brentuximab vedotin in combination with nivolumab in patients with relapsed or refractory Hodgkin lymphoma. Blood. 2018;131(11):1183-1194.
Ansell S et al: A phase 1 study of nivolumab in combination with ipilimumab for relapsed or refractory hematologic malignancies (CheckMate 039). 2016 ASH Annual Meeting. Abstract 183. December 5, 2016.
Dwary AD, Master S, Patel A, Cole C, Mansour R, Mills G, Koshy N, Peddi P, Burton G, Hammoud D, Beedupalli K. Excellent response to chemotherapy post immunotherapy. Oncotarget. 2017;8(53):91795-91802. doi:10.18632/oncotarget.20030.
Manson G, Mear JB, Herbaux C, Schiano JM, Casasnovas O, Stamatoullas A, Deau B, Schmitt A, Garnier G, Regny C, Bouabdallah K, Moles-Moreau MP, Ghesquieres H, Tempescul A, Dulery R et al. Long-term efficacy of anti-PD1 therapy in Hodgkin lymphoma with and without allogenic stem cell transplantation. Eur J Cancer. 2019; 115 (1):47-56.

" ["~DETAIL_TEXT"]=> string(27881) "

Introduction

The aim of our work was to assess safety and effectiveness of nivo in childhood R-R cHL.

Patients and methods

Table 1. Patient´s characteristics (n=21)

Results

Table 2. Efficiency of Nivolumab-based therapy

Figure 1. Overall survival (A) and progression-free survival (B) of the patients treated with nivolumab (n=21)

Figure 2. Progression-free survival curves with HSCT vs without following HSCT in the patients treated with nivolumab

Figure 3. Progression-free survival curves among the patients treated with nivolumab (≤10 vs >10 infusions).

Discussion

Table 3. Efficiency of immune checkpoint inhibitors in adult cHL

Abbreviations: ORR, overall response rate; CR, complete response; PR, partial response; HSCT, hematopoietic stem cell transplantation; PFS, progression-free survival; N/A, not applicable

Table 4. Efficiency of immune checkpoint inhibitors in pediatric cohorts

Abbreviations: HL, Hodgkin's lymphoma; NHL, non- Hodgkin's lymphoma; ORR, overall response rate; CR, complete response; PR, partial response

Conclusion

Conflict of interest

None declared.

References

Armand P, Engert A, Younes A, Fanale M, Santoro A, Zinzani PL, Timmerman JM, Collins GP, Ramchandren R, Cohen JB, De Boer JP, Kuruvilla J, Savage KJ, Trneny M, Shipp MA et al. Nivolumab for relapsed/refractory classic Hodgkin lymphoma after failure of autologous hematopoietic cell transplantation: extended follow-up of the multicohort single-arm phase II CheckMate 205 Trial. J Clin Oncol. 2018;36(14):1428-1439.
Honjo Tasuku – Nobel Lecture. NobelPrize.org. Nobel Media AB 2019. 19 Jul 2019. https://www.nobelprize.org/prizes/medicine/2018/honjo/lecture/
Ishida Y, Agata Y, Shibahara K, Honjo T. Induced expression of PD-1, a novel member of the immunoglobulin gene superfamily, upon programmed cell death. EMBO J. 1992;11(11):3887-3895.
Butte MJ, Keir ME, Phamduy TB, Sharpe AH, Freeman GJ. Programmed death-1 ligand 1 interacts specifically with the B7-1 costimulatory molecule to inhibit T cell responses. Immunity. 2007;27:111-122.
Elezov DS, Kudryavtsev IV. PD-1 receptor on immune cells, its expression and potential role in cancer therapy. Cell Ther Transplant, 2019; 8(2):8-16.
Francisco LM, Sage PT, Sharpe AH. The PD-1 pathway in tolerance and autoimmunity. Immunol Rev. 2010;236:219-242.
Yoshida T, Jiang F, Honjo T, Okazaki T. PD-1 deficiency reveals various tissue-specific autoimmunity by H-2b and dose-dependent requirement of H-2g7 for diabetes in NOD mice. Proc Natl Acad Sci USA. 2008;105(9):3533-3538.
Wherry EJ, Ha SJ, Kaech SM, Haining WN, Sarkar S, Kalia V, Subramaniam S, Blattman J, Barber DL, Ahmed R. Molecular signature of CD8+ T cell exhaustion during chronic viral infection. Immunity. 2007; 27(4):670-684.
Kabir TF, Chauhan A, Anthony L, Hildebrandt GC. Immune checkpoint inhibitors in pediatric solid tumors: status in 2018. Ochsner Journal.2018; 18(4):370-376.
Dong H, Zhu G, Tamada K, Chen L. B7-H1, a third member of the B7 family, co-stimulates T-cell proliferation and interleukin-10 secretion. Nat Med. 1999;5:1365-1369.
Suda T, Takahashi T, Golstein P, Nagata S. Molecular cloning and expression of the Fas ligand, a novel member of the tumor necrosis factor family. Cell. 1993;75:1169-1178.
Pittet CL, Newcombe J, Prat A, Arbour N. Human brain endothelial cells endeavor to immunoregulate CD8 T cells via PD-1 ligand expression in multiple sclerosis. J Neuroinflammation. 2011 Nov 8;8:155.
Meti N, Esfahani K, Johnson NA. The role of immune checkpoint inhibitors in classical Hodgkin lymphoma. Cancers (Basel). 2018;10(6):204. doi:10.3390/cancers10060204.
Lepik KV. Immune checkpoint inhibitors in the treatment of lymphomas. Clinical Oncohematology. 2018;11(4):303-312 (In Russian).
Ansell SM. Beyond checkpoint inhibitors for Hodgkin lymphoma. 2018 Pan Pacific Lymphoma Conference. Invited Lecture. Presented July 19, 2018.
Lepik KV, Kozlov AV, Borzenkova ES, Popova MO, Moiseev IS, Darskaya EI, Gevorgyan AG, Tsvetkova LA, Bondarenko SN, Alyanskiy AL, Kondakova EV, Mikhailova NB, Afanasyev BV. Safety and efficacy of nivolumab applied at different dosage in the patients with relapsing Hodgkin lymphoma after allogeneic hematopoietic stem cell transplantation. Cell Ther Transplant. 2018; 7(2): 28-35.
Cheson BD, Fisher RI, Barrington SF, Cavalli F, Schwartz LH, Zucca E, Lister TA et al. Recommendations for Initial evaluation, staging, and response assessment of Hodgkin and non-Hodgkin lymphoma: the Lugano classification. J Clin Oncol. 2014;32(27):3059-3068.
Cheson BD, Ansell S, Schwartz L, Gordon LI, Advani R, Jacene HA, Hoos A, Barrington SF, Armand P. Refinement of the Lugano Classification lymphoma response criteria in the era of immunomodulatory therapy. 2016;128(21):2489-2496.
Ferhanoglu B, Ozbalak M, Bekoz H et al. Nivolumab for relapsed or refractory Hodgkin lymphoma: long term results of multi-center experience in Turkey. EHA Library. Jun 15, 2019; 266862; PS1245.
Geoerger B, Kang HJ, Yalon-Oren M et al. KEYNOTE-051: An update on the phase 2 results of pembrolizumab (pembro) in pediatric patients (pts) with advanced melanoma or a PD-L1–positive advanced, relapsed or refractory solid tumor or lymphoma. J Clin Oncol. 2018; 36(15, Suppl):10525-10525.
Kelly KM, Daw S, Mauz‐Körholz C , Mascarin M, Michel G, Cooper S, Beishuizen A, Leger KJ, Garaventa A, Buffardi S, Brugières L, Harker‐Murray P, Cole PD. Response-adapted treatment with Nivolumab and brentuximab vedotin in young patients with relapsed/refractory classical Hodgkin lymphoma: CHECKMATE744 Subgroup analyses. Hematol Oncol. 2019;37: 56-57.
Chen R, Zinzani PL, Fanale MA, Armand P, Johnson NA, Brice P, Radford J, Ribrag V, Molin D, Vassilakopoulos TP, Tomita A, von Tresckow B, Shipp MA, Zhang Y, Ricart AD, Balakumaran A, Moskowitz CH et al. Phase II study of the efficacy and safety of pembrolizumab for relapsed/refractory classic Hodgkin lymphoma. J Clin Oncol 2017; 35(19):2125-2132.
Lepik KV, Mikhailova NB, Kondakova EV, Tsvetkova LA, Zalyalov YR, Borzenkova ES, Moiseev IS, Baykov VV, Afanasyev BA. Efficacy and safety of nivolumab in the treatment of relapsed/refractory classical Hodgkin’s lymphoma: Pavlov First Saint Petersburg State Medical University experience. Oncohematology. 2018;13(4):17-26. (In Russian).
Santoro A, D'alo' F, Zinzani PL et al. Real-world data of nivolumab in classical Hodgkin lymphoma: results from the Italian Expanded Access Programme. Blood. 2017; 130:5171.
Herrera AF, Moskowitz AJ, Bartlett NL, Vose JM, Ramchandren R, Feldman TA, LaCasce AS, Ansell SM, Moskowitz CH, Fenton K, Ogden CA, Taft D, Zhang Q, Kato K, Campbell M, Advani RH. Interim results of brentuximab vedotin in combination with nivolumab in patients with relapsed or refractory Hodgkin lymphoma. Blood. 2018;131(11):1183-1194.
Ansell S et al: A phase 1 study of nivolumab in combination with ipilimumab for relapsed or refractory hematologic malignancies (CheckMate 039). 2016 ASH Annual Meeting. Abstract 183. December 5, 2016.
Dwary AD, Master S, Patel A, Cole C, Mansour R, Mills G, Koshy N, Peddi P, Burton G, Hammoud D, Beedupalli K. Excellent response to chemotherapy post immunotherapy. Oncotarget. 2017;8(53):91795-91802. doi:10.18632/oncotarget.20030.
Manson G, Mear JB, Herbaux C, Schiano JM, Casasnovas O, Stamatoullas A, Deau B, Schmitt A, Garnier G, Regny C, Bouabdallah K, Moles-Moreau MP, Ghesquieres H, Tempescul A, Dulery R et al. Long-term efficacy of anti-PD1 therapy in Hodgkin lymphoma with and without allogenic stem cell transplantation. Eur J Cancer. 2019; 115 (1):47-56.

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Козлов, Илья В. Казанцев, Татьяна В. Юхта, Полина С. Толкунова, Дарья А. Звягинцева, Асмик Г. Геворгян, Антон В. Малородов, Кирилл В. Лепик, Юрий Р. Залялов, Александр Н. Швецов, Анна В. Ботина, Вадим В. Байков, Елена В. Морозова, Юрий А. Пунанов, Наталья Б. Михайлова, Людмила С. Зубаровская, Борис В. Афанасьев" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(568) "

Андрей В. Козлов, Илья В. Казанцев, Татьяна В. Юхта, Полина С. Толкунова, Дарья А. Звягинцева, Асмик Г. Геворгян, Антон В. Малородов, Кирилл В. Лепик, Юрий Р. Залялов, Александр Н. Швецов, Анна В. Ботина, Вадим В. Байков, Елена В. Морозова, Юрий А. Пунанов, Наталья Б. Михайлова, 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

Ингибиторы контрольных точек показали высокую эффективность в лечении классической лимфомы Ходжкина (кЛХ). Пембролизумаб одобрен для применения у детей. Назначение данного препарата приводит к высокой частоте ответа на терапию и является относительно безопасным. Роль ниволумаба у детей с кЛХ еще только предстоит определить. Целями представленной работы были оценка эффективности и оценка побочных эффектов у детей с рецидивирующим и рефрактерным течением кЛХ. Терапия на основе ниволумаба была проведена у 21-го предлеченного пациента (9-18 лет) с кЛХ. Общий ответ отмечался у 86 % (полный ответ – 57% и частичный ответ – 29%). Трехлетняя общая выживаемость и выживаемость без прогрессирования составили 95% и 29%, соответственно. Отмечалось только одно клинически значимое осложнение ниволумаба (аутоиммунный тиреоидит). Не было зарегистрировано тяжелых побочных явлений проводимой терапии.

Ключевые слова

Лимфома Ходжкина, рецидивирующая, рефрактерное течение, дети, ниволумаб.

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Andrey V. Kozlov, Ilya V. Kazantzev, Tatyana V. Iukhta, Polina S. Tolkunova, Darya A. Zvyagintseva, Asmik G. Gevorgian, Anton V. Malorodov, Kirill V. Lepik, Yury R. Zalyalov, Alexander N. Shvetsov, Anna V. Botina, Vadim V. Baykov, Elena V. Morozova, Yury A. Punanov, Natalya B. Mikhailova, 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

Immune checkpoint inhibitors (ICIs) are rather efficient in classical Hodgkin's lymphoma (cHL). Pembrolizumab (pembro) is approved in children and demonstrates high response rates with acceptable toxicity. The role of nivolumab (nivo) in pediatric cHL is only to be elucidated. The aim of the presented study was to assess safety and efficiency of nivo in this age group with relapsed or refractory (R-R) cHL. Twenty-one pediatric heavily pre-treated patients 9-18 years old received nivo-based therapy. Overall response was registered in 86% (complete response – 57% and partial response – 29%). Three-year overall survival (OS) and progression free survival (PFS) were 95% and 29%, respectively. Only 1 clinically significant adverse effect (AE) of nivo was registered in the study (autoimmune thyroiditis). We did not observe any unacceptable toxicity of nivo.

Keywords

Children, Hodgkin's lymphoma, relapsed, refractory, nivolumab.

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Kozlov, Ilya V. Kazantzev, Tatyana V. Iukhta, Polina S. Tolkunova, Darya A. Zvyagintseva, Asmik G. Gevorgian, Anton V. Malorodov, Kirill V. Lepik, Yury R. Zalyalov, Alexander N. Shvetsov, Anna V. Botina, Vadim V. Baykov, Elena V. Morozova, Yury A. Punanov, Natalya B. Mikhailova, Ludmila S. Zubarovskaya, Boris V. Afanasyev" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(340) "

Keywords

Children, Hodgkin's lymphoma, relapsed, refractory, nivolumab.

Keywords

Children, Hodgkin's lymphoma, relapsed, refractory, nivolumab.

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

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Ключевые слова

Лимфома Ходжкина, рецидивирующая, рефрактерное течение, дети, ниволумаб.

Ключевые слова

Лимфома Ходжкина, рецидивирующая, рефрактерное течение, дети, ниволумаб.

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Introduction

Normal microbiota colonizing mucosal surfaces is usually identified at clinical laboratories by means of aerobic cultures in standard agar cultures. It comprises, mostly, saprophytic and oppor-tunistic bacteria. In particular, the microflora of normal oral mucosa is well known, and the most common bacterial species are identified [1, 2]. Members of normal oral microbiota exist as com-mensal flora in a symbiotic state within host tissue, thus suppressing colonization with more path-ogenic bacterial species as presented in excellent review by Hull, Chow [1]. The most common aerobic species isolated in clinical cultures from oral cavity and oropharynx mucosa include Gram-positive Streptococci (e.c., S.viridans), Staphylococcus epidermidis, Corynebacterium spp., Neisseria spp., etc. Moreover, oral cavity, and, especially, ginvival mucosa contain multiple an-aerobic flora which is represented by hundreds species, most of which could be detected only by DNA-based diagnostic techniques [3].

Intensive chemotherapy of cancer and, especially, hematopoietic stem cell transplantation (HSCT) are followed by severe immunosuppression. I.e., pronounced neutro-and lymphopenia develops within 1-2 weeks after HSCT, accomplished by reactivation of endogenous viruses, as well as opportunistic bacteria and nosocomial pathogens which may colonize different mucosal surfaces and replace conventional microflora, thus leading to local dysbacteriosis [4]. Local infections are a common consequence of severe leukopenia. E.g., a previous study of 143 HSCT patients [5] has shown nosocomial bacterial infections in ca. 25% of cases, especially, septicemia (43%), and respiratory infections. Some pathogenetic links between infections and oral mucositis were suggested by Laheji et al. [6].

In most oncohematological clinics, the bacterial cultures from local biomaterials are performed by clinical indications, e.g., due to febrile neutropenia or local inflammatory loci. Surveillance microbial diagnostics is also sometimes implemented, however, without any clinical benefits [7]. Majority of these studies concern reactivation/reinfection with different viruses, in particular, herpesviruses, parvoviruses etc. Studies in bacterial infections mainly deal with isolation of aerobically cultivated pathogenic strains, their toxins and antibiotic resistance, mainly, Pseudomonas spp., Klebsiella pneumoniae, Clostridium difficile or enteropathogenic E.coli infections.

To our knowledge, there were only few studies of microbial landscape in oral mucosa at different periods after HSCT [7]. In most cases, these studies are epidemiologically oriented, and provide relative frequencies of local pathogenic microorganisms in HSCT patients, and their potential correlations with clinically significant infections [8].

Only few works concern time dynamics of the microbial landscape in the patients after HSCT, however, lacking sufficient data on possible relations between the shifts of oral microbiota and common HSCT complications, i.e., local infections, oral mucositis, or acute graft-versus-host disease (aGVHD).

The aim of the present study was to estimate the frequency of cultivable aerobic microflora obtained from oral mucosa smears taken before HSCT and during 4 months posttransplant. We have evaluated time course for the most common microorganisms, as well as probable interactions between the frequency of their detection rates and occurrence of characteristic complications after HSCT, including mucositis, febrile neutropenia, acute GVHD, and clinically significant infectious complications.

Patients and methods

In the present study, we have evaluated results of clinical bacterial cultures from 630 smears of the oropharynx and tongue taken from 202 patients at the age of 1 to 69 (108 males and 94 females) subjected to allogeneic HSCT at the R. Gorbacheva Memorial Institute of Children Oncology, Hematology and Transplantation from January 2016 to December 2017. Allogeneic HSCT was performed for acute myeloblastic leukemia (AML, n-63), chronic myeloid leukemia (CML, n=28), acute lymphoblastic leukemia (ALL, n=34), severe aplastic anemia (SAA, n=22), refractory anemia (RA, n=6), plasma cell dysplasia (7 cases), primary myelofibrosis (PMF, n=10). Inborn genetic disorders were treated in 9 children, Hodgkin lymphoma, in 6 patients, non-Hodgkin’s lymphomas, in 4 cases, juvenile myelomonocytic leukemia, in 3 patients; polycythemia vera, in 2 patients, essential thrombocytopenia, etc. Myeloablative conditioning regimens were performed in for 122 patients, and non-myeloablative protocols were applied in 80 cases. Bone marrow was used as a source of stem cells in 97 cases, and peripheral stem cells, in 105 patients. HSCT was carried out from related HLA-compatible donors (n=35), related haploidentical donors (33 patients), or unrelated HLA-matched donors (112 cases). Patients or their close relatives signed appropriate informed consent for their participation in the research program, and usage of their personal medical data for the scientific evaluation. The smears for bacteriological studies were taken from oropharynx or tongue. Subsequent sampling was made before HSCT and within 120 days (4 months posttransplant), according to clinical indications from the attained physicians. The biomaterials were conserved, stored and processed at the Department of Clinical Microbiology, being seeded on agar plates and cultured on the conventional nutrient media under aerobic conditions.

Statistical analysis included the patients with at least 1 result before HSCT, and 2 results within 4 months posttransplant. All the data on clinical characteristics of the patients, HSCT parameters, conditioning therapy, posttransplant complications, and bacterial cultures were taken from the hospital reports of R. Gorbacheva Memorial Institute, and laboratory database at the 1^st St. Petersburg State I. Pavlov Medical University. Statistical evaluation was performed by means of the STATISTIСA 5.0 software, by means of non-parametric single-factor analysis using Hi-square criterion and Pearson correlation quotients to evaluate significance of differences between the samples. In some series, parametric methods were used using Student t-test.

Results

Common bacteria detectable in oral cavity

Total sample included 630 cultures from oral smears, with positive results for 389 specimens (61.8%). One microbial species was detected in 250 cases; 2 species, в 117 cultures, and 3 microbial species, in 22 cultures. The most common microorganisms were as follows: S.viridans 245/630 (38.9%); K.pneumoniae 42/630 (6.7%); S.epidermidis 120/630 (19.1%); Neisseria spp., 66/630 (10.5%); Corynebacterium spp., 78/630 (12.4%). Other bacteria were detected in <1% of the cultures (S. saprophyticus., Pseudomonas spp., S.faecalis, S.faecium). For statistical reasons, only 5 most common bacterial species were included into further analysis, i.e., S.viridans , K.pneumoniae, S.epidermidis, Neisseria spp., Corynebacterum spp.

Age factor

Frequency of the five common bacterial species in the oral cavity smears is shown in Table 1. For the age groups of 0-5, 6-14, 15-21 y.o., and adult persons (>22 y.o.), some significant age dependencies were revealed. I.e., S.viridans detection was maximal in smaller children (0 to 5 years old), as compared to the groups of 6-14 and 15-21 (p<0.02), then showing an increase in adult patients. Similar tendency was seen for Klebsiella pneumoniae, with higher detection rates in small children and adult patients.

Table 1. Detection of the common bacterial species in the specimens from oral cavity in children and adults at the whole observation period (-60 to +120 days post-HSCT)

Time dependence of microbial detection

Frequency of positive cultures was time-dependent, and varied for different microorganisms (Table 2). However, a significant drop was evident for all the detectable microbial species during 1^st month posttransplant, most obviously, due to intensive antibacterial prophylaxis started before HSCT. The early suppression was most pronounced for S.viridans, and S.epidermidis, a normal component of oral microflora. Interestingly, an initial marginal decrease of K.pneumoniae detection was followed by its sharp increase at 2-4 months (Fig. 1).

Table 2. Time dependence for the detection frequency of common aerobic microorganisms cultured from the oral cavity of HSCT patients

Note: The difference levels (p values) were determined by the non-parametric Hi-square test. This time dynamics for 3 distinct bacterial species is also shown in Fig. 1.

Figure 1. Prevalence of S.viridans (A), S.epidermidis (B), and K.pneumoniae (C) in bacterial cultures within 1-4 months after HSCT

Abscissa, terms posttransplant (months). Ordinate, frequency of positive results. Points at the graph show M+m values.

HSCT parameters

As seen from Table 3, we have not found any significant associations between the frequency of positive cultures of common oral microbes, and source of stem cells (bone marrow vs peripheral stem cells), or type of HSCT (related vs unrelated vs haploidentical HSCT). Meanwhile, decreased detection rates of S.epidermidis proved to be significantly associated with more intensive (myeloablative) therapy, as compared to reduced-intensity regimens (Table 3). As expected, K.pneumoniae was associated with clinically significant infectious complications of either location.

Table 3. Detection rates for some common oral microorganisms in HSCT recipients over 120 days post-HSCT: dependence on transplant characteristics and posttransplant complications

Mucositis, febrile neutropenia and clinical infections

In more than 50% of patients, oral mucositis was observed within early terms after HSCT. Our data have confirmed higher frequency of oral mucositis after myeloablative conditioning treat-ment (181/330, 54.9%) against 33.1% (80/242) following reduced-intensity conditioning (р=2×10^-7). Moreover, higher occurrence of febrile neutropenia was found in the group of patients with mucositis (50.3%) against 30.7% in mucositis-free cases (р=4×10^-8), as seen from Table 3. Taking into account similar terms of mucositis and dysbacteriosis (1^st month posttransplant), one could suggest infectious component for the oral inflammation. However, we did not reveal any significant correlations between mucositis rates, and frequency of positive cultures of the common microorganisms from oral mucosa (Table 3), thus suggesting a minimal role of these bacteria in genesis of the posttransplant oral inflammation. In addition, we have not revealed any significant correlations between presence of the major species of oral microflora, and acute skin GVHD (Table 3). Absence of correlations between bacterial landscape and main clinical complications may be connected with active antibacterial therapy over the period of post-transplant leukopenia (1-2 months post-HSCT).

Further, we have performed some comparisons between the frequencies of bacterial associations, rates of febrile neutropenia and clinically significant infections posttransplant. This survey has shown that the more frequent associations of >3 microbial species tends to correlate with higher FUO prevalence (Table 4). Increased incidence of FUO was also found after myeloablative conditioning (р=0.001), as well as in the group with oral mucositis (p=4×10^-8), as well as in cases of skin aGvHD (p=0.002), thus reflecting evident inflammatory component in the both types of skin and mucosal damage, however, without any association with. Hence, early neutropenic fever is more likely associated with cytostatic chemotherapy and allogeneic HSCT, rather than with local clinically significant infections posttransplant.

Interestingly, the numbers of transplanted hematopoietic stem cells (CD34+ cells) have shown a distinct direct correlation with occurrence of early mucositis (r=0.20; p=8×10⁷) thus again suggesting a clear relation between oral mucositis and potential immune effects of allogeneic hematopoietic cells posttransplant.

Table 4. Frequency of FUO and microbial associations: effects of different HSCT parameters and posttransplant complications

Microbial resistance

Klebsiella is the mostly discussed bacterial pathogen with high prevalence of antibiotic-resistant strains. We have tested in vitro the resistance of K.pneumoniae isolates seeded from oral cavity of 11 HSCT patients in 2017 (Table 5). Majority of the isolates showed resistance for most antibiotics commonly used in septic HSCT patients. However, most of the K.pneumoniae isolates proved to be sensitive to amikacin, gentamycin and meropenem.

Table 5. Differential in vitro antibiotic sensitivity of K.pneumoniae isolates obtained from oral cavity after hematopoietic stem cell transplantation

Note: R, resistance; S, sensitivity of the microorganism; I, intermediate values

Of note, in the patient F.Z., the initial sensitive phenotype was 1 month later changed to polyresistance, except of amikacin and meropenem, thus, probably, reflecting its replacement by a resistant bacterial strain.

Bacterial pathogens at the sites of dental infections

In 10 cases, tooth extraction was performed during 1^st month after HSCT, due to acute pulpitis and local septic process. Bacterial isolates from the post-extraction wounds were obtained in 10 cases, and the following bacteria were detected: Pseudomonas aeruginosa in 3 samples, S.viridans in 2 cases, Neisseria spp., S.faecalis, S.epidermidis were found in other specimens. Of them, only P.aeruginosa is a well-known pathogenic agent to cause purulent local inflammation.

Discussion

Overall rates of positive microbial cultures from oral cavity were rather high (61.8%). Cytotoxic damage to oral epithelium due to previous chemotherapy, as well as deep leukopenia after conditioning treatment and HSCT are the key pre-requisites for oral bacterial colonization [9]. However, conventional culturing of oral samples taken at different terms post HSCT (D-60 to D+120) have shown a sufficient decrease in cultivable oral microflora within 1^st month posttransplant. Such suppression of microflora could be readily explained by anti-microbial treatment administered during intensive cytostatic therapy of cancer [10, 11]. In our study, a deep suppression was shown for S.viridans, S.epidermidis, and K. pneumoniae. The latter is the known Gram-negative pathogen causing infectious complications at later terms (2-4 months posttransplant), with a tendency for polyresistance for antibiotics, as confirmed in our study.

Microbial associations of 3 or more bacteria could be found in some samples. Of note, posttransplant clinically significant infections proved to be much more often in cases with >3 microorganisms found in the oral samples, thus suggesting the microbial associations to be a marker of suppressed antimicrobial immunity post-HSCT.

Like as other common posttransplant complications, clinical infectious conditions did not show any direct correlations with either positive oral bacterial cultures, or early post-transplant mucositis (Table 3 and 4). Rather, fever of unknown origin (FUO), an early inflammatory condition without clear infectious reason, had a distinct relationship with myeloablative treatment, oral mucositis, and skin GvHD. Oral mucositis may be, at least, in part, dependent on common herpesvirus activation post-HSCT [12].

Among common bacterial species found in oral cavity of the patients, Klebsiella pneumoniae is known to produce a number of polyresistant strains, as confirmed in our study (Table 5). This feature of K.pneumoniae is typical to nosocomial infections. Decreased rates of Klebsiella detection at early terms (1^st month) following HSCT could be explained by relative sensitivity of most endogenous bacterial populations to routine decontaminating therapy. At later terms (2^nd and 3^rd months) the sensitivity-adapted antibiotic treatment in the patients with prolonged infectious complications under the ICU conditions, may cause selection of Klebsiella strains with extended resistance spectrum as, it was revealed in our F.Z. patient at 5-6 months after HSCT.

Therefore, phenotypic and molecular monitoring of standard lactamase genes in clinical isolates before and after HSCT may further elucidate the mechanisms of resistance selection among Klebsiella and other Gram-negative bacteia, aiming for development of combined treatment schedules [13].

In this respect, the role of oral bacterial infection in development of mucositis and GvHD still remains unclear. Meanwhile, over last decades, a crucial role of gut microbiome and altered intestinal mucosa due to broad-spectrum antibacterial therapy becomes more clear and clinically confirmed, both for infectious complications and acute GvHD [14, 15, 16].

Conclusion

Cytotoxic damage of oral mucosa during intensive chemotherapy may create sufficient prerequisites for bacterial colonization. Moreover, antibacterial prophylaxis in HSCT patients causes deep suppression of oral microflora during 1^st month post-HSCT, despite severe leukopenia in the patients. Known antibacterial pathogens, e.g., K.pneumoniae, or P.aerugunosa are revealed in oral cavity within 1-3 months posttransplant.

The consequences of combined anticancer and antibacterial treatment in HSCT patients deserve further studies, in particular, its correlation with mucositis, acute GvHD which may be still underlied by mixed microbial and viral infections. Bacterial imbalance post-HSCT may be a pre-requisite for additional anti-infectious therapy in complex clinical conditions involving infectious/cytotoxic/autoaggressive pathogenetic components. Significant shifts in common bacterial landscape caused by immunotoxic treatment and antibacterial therapy enable growth of other bacterial and fungal pathogens that should be studied in details by means of NGS techniques which should reveal, e.g., anaerobic pathogenic bacteria in posttransplant conditions.

References

Hull MW, Chow AW. Indigenous microflora and innate immunity of the head and neck. Infect Dis Clin N Am 2007; 21: 265-282.
Hegde MC, Kumar A, Bhat G, Sreedharan S. Oral microflora: a comparative study in HIV and normal patients. Indian J Otolaryngol Head Neck Surg. 2014; 66(Suppl 1): S126-S132.
Aas JA, Paster BJ, Stokes LN, Olsen I, Dewhirst FE. Defining the normal bacterial flora of the oral cavity. J. Clin. Microbiol. 2005; 43(11): 5721-5732.
Chukhlovin AB, Pankratova OS. Opportunistic microflora at unusual sites: marker pathogens in severe posttransplant immune deficiency. Cell Ther Transplant. 2017; 6(4): 28-41.
Marena C, Zecca M, Carenini ML, Bruschi A, Bassi ML, Olivieri P, Azzaretti S, Locatelli F. Incidence of, and risk factors for, nosocomial infections among hematopoietic stem cell transplantation recipients, with impact on procedure-related mortality. Infect Control Hosp Epidemiol. 2001;22(8):510-517.
Lahei AMGA, de Soet JJ, von dem Borne PA, Kuijper EJ, Kraneveld EA, van Loveren C, Raber-Durlacher JE. Oral bacteria and yeasts in relationship to oral ulcerations in hematopoietic stem cell transplant recipients. Support Care Cancer. 2012; 20:3231-3240.
Czirók E, Prinz GY, Dénes R, Reményi P, Herendi A. Value of surveillance cultures in a bone marrow transplantation unit. J Med Microbiol. 1997;46(9):785-791.
Vavilov VN, Averianova MY, Bondarenko SN, Stancheva NV, Zubarovskaya LS, Afanasyev BV. Bacterial infections within early period after allogeneic bone marrow transplantation. Ter Arkhiv, 2015; 87(7): 88-93 (In Russian).
Grigoriants AP, Rabinowitch IM, Chukhlovin AB. Stomatological problems and infectious complications after hematopoietic stem cell transplantation. Cell Ther Transplant 2017; 7(2):10-19.
Bergmann OJ. Alterations in oral microflora and pathogenesis of acute oral infections during remission-induction therapy in patients with acute myeloid leukaemia. Scand J Infect Dis. 1991;23(3):355-66.
Jones LR, Toth BB, Keene HJ. Effects of total body irradiation on salivary gland function and caries-associated oral microflora in bone marrow transplant patients. Oral Surg Oral Med Oral Pathol. 1992;73(6):670-676.
Pankratova OS, Chukhlovin AB, Shiryaev SN, Eismont YA, Vavilov VN, Zubarovskaya LS, Afanasyev BV. Herpesviruses and oral ulcerations in hematopoietic SCT recipients. Bone Marrow Transplantation. 2013; 48:1364-1365.
Fritzenwanker M, Imirzalioglu C, Herold S, Wagenlehner FM, Zimmer KP, Chakraborty T. Treatment Options for Carbapenem- Resistant Gram-Negative Infections. Dtsch Arztebl Int. 2018 ;115(20-21):345-352.
Blijlevens NMA, Donnelly JP, De Pauw BE. Mucosal barrier injury: biology, pathology, clinical counterparts and consequences of intensive treatment for haematological malignancy: an overview. Bone Marrow Transplantation (2000) 25, 1269-1278.
Weber D, Jenq RR, Peled JU, Taur Y, Hiergeist A, Koestler J, Dettmer K, Weber M, Wolff D, Hahn J, Pamer EG, Herr W, Gessner A, Oefner PJ, van den Brink MRM, Holler E. Microbiota disruption induced by early use of broad-spectrum antibiotics is an independent risk factor of outcome after allogeneic stem cell transplantation. Biol Blood Marrow Transplant. 2017; 23(5):845-852.
Goloshchapov OV, Kucher MA, Chukhlovin AB. Gut microbiome in hematopoietic stem cell transplantation: patient- and treatment-related factors. Cell Ther Transplant. 2018; 7(4):16-28.

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Introduction

Patients and methods

Results

Common bacteria detectable in oral cavity

Age factor

Table 1. Detection of the common bacterial species in the specimens from oral cavity in children and adults at the whole observation period (-60 to +120 days post-HSCT)

Time dependence of microbial detection

Table 2. Time dependence for the detection frequency of common aerobic microorganisms cultured from the oral cavity of HSCT patients

Note: The difference levels (p values) were determined by the non-parametric Hi-square test. This time dynamics for 3 distinct bacterial species is also shown in Fig. 1.

Figure 1. Prevalence of S.viridans (A), S.epidermidis (B), and K.pneumoniae (C) in bacterial cultures within 1-4 months after HSCT

Abscissa, terms posttransplant (months). Ordinate, frequency of positive results. Points at the graph show M+m values.

HSCT parameters

Table 3. Detection rates for some common oral microorganisms in HSCT recipients over 120 days post-HSCT: dependence on transplant characteristics and posttransplant complications

Mucositis, febrile neutropenia and clinical infections

Table 4. Frequency of FUO and microbial associations: effects of different HSCT parameters and posttransplant complications

Microbial resistance

Table 5. Differential in vitro antibiotic sensitivity of K.pneumoniae isolates obtained from oral cavity after hematopoietic stem cell transplantation

Note: R, resistance; S, sensitivity of the microorganism; I, intermediate values

Bacterial pathogens at the sites of dental infections

Discussion

Conclusion

References

Hull MW, Chow AW. Indigenous microflora and innate immunity of the head and neck. Infect Dis Clin N Am 2007; 21: 265-282.
Hegde MC, Kumar A, Bhat G, Sreedharan S. Oral microflora: a comparative study in HIV and normal patients. Indian J Otolaryngol Head Neck Surg. 2014; 66(Suppl 1): S126-S132.
Aas JA, Paster BJ, Stokes LN, Olsen I, Dewhirst FE. Defining the normal bacterial flora of the oral cavity. J. Clin. Microbiol. 2005; 43(11): 5721-5732.
Chukhlovin AB, Pankratova OS. Opportunistic microflora at unusual sites: marker pathogens in severe posttransplant immune deficiency. Cell Ther Transplant. 2017; 6(4): 28-41.
Marena C, Zecca M, Carenini ML, Bruschi A, Bassi ML, Olivieri P, Azzaretti S, Locatelli F. Incidence of, and risk factors for, nosocomial infections among hematopoietic stem cell transplantation recipients, with impact on procedure-related mortality. Infect Control Hosp Epidemiol. 2001;22(8):510-517.
Lahei AMGA, de Soet JJ, von dem Borne PA, Kuijper EJ, Kraneveld EA, van Loveren C, Raber-Durlacher JE. Oral bacteria and yeasts in relationship to oral ulcerations in hematopoietic stem cell transplant recipients. Support Care Cancer. 2012; 20:3231-3240.
Czirók E, Prinz GY, Dénes R, Reményi P, Herendi A. Value of surveillance cultures in a bone marrow transplantation unit. J Med Microbiol. 1997;46(9):785-791.
Vavilov VN, Averianova MY, Bondarenko SN, Stancheva NV, Zubarovskaya LS, Afanasyev BV. Bacterial infections within early period after allogeneic bone marrow transplantation. Ter Arkhiv, 2015; 87(7): 88-93 (In Russian).
Grigoriants AP, Rabinowitch IM, Chukhlovin AB. Stomatological problems and infectious complications after hematopoietic stem cell transplantation. Cell Ther Transplant 2017; 7(2):10-19.
Bergmann OJ. Alterations in oral microflora and pathogenesis of acute oral infections during remission-induction therapy in patients with acute myeloid leukaemia. Scand J Infect Dis. 1991;23(3):355-66.
Jones LR, Toth BB, Keene HJ. Effects of total body irradiation on salivary gland function and caries-associated oral microflora in bone marrow transplant patients. Oral Surg Oral Med Oral Pathol. 1992;73(6):670-676.
Pankratova OS, Chukhlovin AB, Shiryaev SN, Eismont YA, Vavilov VN, Zubarovskaya LS, Afanasyev BV. Herpesviruses and oral ulcerations in hematopoietic SCT recipients. Bone Marrow Transplantation. 2013; 48:1364-1365.
Fritzenwanker M, Imirzalioglu C, Herold S, Wagenlehner FM, Zimmer KP, Chakraborty T. Treatment Options for Carbapenem- Resistant Gram-Negative Infections. Dtsch Arztebl Int. 2018 ;115(20-21):345-352.
Blijlevens NMA, Donnelly JP, De Pauw BE. Mucosal barrier injury: biology, pathology, clinical counterparts and consequences of intensive treatment for haematological malignancy: an overview. Bone Marrow Transplantation (2000) 25, 1269-1278.
Weber D, Jenq RR, Peled JU, Taur Y, Hiergeist A, Koestler J, Dettmer K, Weber M, Wolff D, Hahn J, Pamer EG, Herr W, Gessner A, Oefner PJ, van den Brink MRM, Holler E. Microbiota disruption induced by early use of broad-spectrum antibiotics is an independent risk factor of outcome after allogeneic stem cell transplantation. Biol Blood Marrow Transplant. 2017; 23(5):845-852.
Goloshchapov OV, Kucher MA, Chukhlovin AB. Gut microbiome in hematopoietic stem cell transplantation: patient- and treatment-related factors. Cell Ther Transplant. 2018; 7(4):16-28.

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Чухловин1, Анна А. Спиридонова2, Ирина Б. Баранова3, Артур П. Григорьянц3, Мария Д. Владовская1, Людмила С. Зубаровская1, Борис В. Афанасьев1" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(348) "

Алексей Б. Чухловин¹, Анна А. Спиридонова², Ирина Б. Баранова³, Артур П. Григорьянц³, Мария Д. Владовская¹, Людмила С. Зубаровская¹, Борис В. Афанасьев¹

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¹ НИИ детской онкологии, гематологии и трансплантологии им. Р. М. Горбачевой, Санкт-Петербург, Россия
² Отделение клинической микробиологии, Первый Санкт-Петербургский государственный медицинский университет им. акад. И. П. Павлова, Санкт-Петербург, Россия
³ Кафедра челюстно-лицевой хирургии, 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) "25085" ["VALUE"]=> array(2) { ["TEXT"]=> string(5325) "Нормальная аэробная и факультативно-анаэробная микробиота, колонизирующая слизистую оболочку рта, часто выявляется в клинических лабораториях. Ее состав может быть важным показателем иммунокомпромиссных состояний. Данные параметры мало изучены у пациентов после трансплантации гемопоэтических клеток (ТГСК). Целью настоящей работы была оценка выявляемости обычной аэробной и факультативно-анаэробной микробиоты, культивированной из биоматериала полости рта до ТГСК и, по клиническим показаниям, в течение 4 мес. после этого лечения. <h3>Пациенты и методы</h3> Мы оценили результаты посевов образцов, взятых из ротовой полости у 202 больных с онкогематологическими и врожденными заболеваниями в возрасте от 1 до 69 лет, которым была проведена аллогенная ТГСК. Анализ проводился для 3 возрастных групп: 1-5, 6-14, 15-21 и >22 лет. <h3>Результаты</h3> После 630 проведенных бактериологических исследований, позитивные результаты культивирования получены в 61.8% образцов. Наиболее частыми микроорганизмами были следующие: S.viridans 245/630 (38.9%); K.pneumoniae 42/630 (6.7%); S.epidermidis 120/630 (19.1%); Neisseria spp. 66/630 (10.5%); Corynebacterium spp. 78/630 (12.4%). Частота выявления микроорганизмов зависела от времени после ТГСК, а именно отмечено снижение высеваемости S.epidermidis, Corynebacterium spp. и Klebsiella spp. в течение 1-го месяца после ТГСК, что можно объяснить эффективной ранней антибактериальной деконтаминацией пациентов, начиная с момента кондиционирования. Нами показано, что частота высеваемости S.viridans и K.pneumoniae в этих образцах была различной для отдельных возрастных групп, будучи существенно повышенной у детей самого младшего возраста (до 5 лет) и у взрослых пациентов (>22 лет), по сравнению со старшими детьми и подростками. Высеваемость K.pneumoniae в образцах из полости рта оказалась существенно повышенной через 2-3 месяца после ТГСК, что сопровождалось тяжелыми инфекционными осложнениями и наличием резистентности клинических изолятов Klebsiella к большинству антибиотиков. По клиническим показаниям проведена экстракция зубов в 10 случаях в течение 1-го мес. после ТГСК. Посевы раневого отделяемого из десен показали наличие Pseudomonas aeruginosa в 3 образцах, S.viridans – в 2 случаях. <h3>Выводы</h3> Иммунотоксические эффекты цитостатической терапии и анализ микробиоты после ТГСК заслуживают дальнейших исследований, в том числе – анализ биологического разнообразия микробиоты полости рта посредством секвенирования гена 16S rRNA. Эти результаты могут стать основой для рациональной антибактериальной терапии при ТГСК. <h2>Ключевые слова</h2> Онкогематология, дети, химиотерапия, трансплантация гемопоэтических стволовых клеток, бактериальные культуры, факторы риска." ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(5005) "

Нормальная аэробная и факультативно-анаэробная микробиота, колонизирующая слизистую оболочку рта, часто выявляется в клинических лабораториях. Ее состав может быть важным показателем иммунокомпромиссных состояний. Данные параметры мало изучены у пациентов после трансплантации гемопоэтических клеток (ТГСК). Целью настоящей работы была оценка выявляемости обычной аэробной и факультативно-анаэробной микробиоты, культивированной из биоматериала полости рта до ТГСК и, по клиническим показаниям, в течение 4 мес. после этого лечения.

Пациенты и методы

Мы оценили результаты посевов образцов, взятых из ротовой полости у 202 больных с онкогематологическими и врожденными заболеваниями в возрасте от 1 до 69 лет, которым была проведена аллогенная ТГСК. Анализ проводился для 3 возрастных групп: 1-5, 6-14, 15-21 и >22 лет.

Результаты

После 630 проведенных бактериологических исследований, позитивные результаты культивирования получены в 61.8% образцов. Наиболее частыми микроорганизмами были следующие: S.viridans 245/630 (38.9%); K.pneumoniae 42/630 (6.7%); S.epidermidis 120/630 (19.1%); Neisseria spp. 66/630 (10.5%); Corynebacterium spp. 78/630 (12.4%). Частота выявления микроорганизмов зависела от времени после ТГСК, а именно отмечено снижение высеваемости S.epidermidis, Corynebacterium spp. и Klebsiella spp. в течение 1-го месяца после ТГСК, что можно объяснить эффективной ранней антибактериальной деконтаминацией пациентов, начиная с момента кондиционирования. Нами показано, что частота высеваемости S.viridans и K.pneumoniae в этих образцах была различной для отдельных возрастных групп, будучи существенно повышенной у детей самого младшего возраста (до 5 лет) и у взрослых пациентов (>22 лет), по сравнению со старшими детьми и подростками. Высеваемость K.pneumoniae в образцах из полости рта оказалась существенно повышенной через 2-3 месяца после ТГСК, что сопровождалось тяжелыми инфекционными осложнениями и наличием резистентности клинических изолятов Klebsiella к большинству антибиотиков. По клиническим показаниям проведена экстракция зубов в 10 случаях в течение 1-го мес. после ТГСК. Посевы раневого отделяемого из десен показали наличие Pseudomonas aeruginosa в 3 образцах, S.viridans – в 2 случаях.

Выводы

Иммунотоксические эффекты цитостатической терапии и анализ микробиоты после ТГСК заслуживают дальнейших исследований, в том числе – анализ биологического разнообразия микробиоты полости рта посредством секвенирования гена 16S rRNA. Эти результаты могут стать основой для рациональной антибактериальной терапии при ТГСК.

Ключевые слова

Онкогематология, дети, химиотерапия, трансплантация гемопоэтических стволовых клеток, бактериальные культуры, факторы риска.

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Alexei B. Chukhlovin¹, Anna A. Spiridonova², Irina B. Baranova³, Artur P. Grigoriants³, Maria D. Vladovskaya¹, Ludmila S. Zubarovskaya¹, Boris V. Afanasyev¹

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¹ Raisa Gorbacheva Memorial Research Institute of Pediatric Oncology, Hematology and Transplantation, St. Petersburg, Russia
² Department of Clinical Microbiology, Pavlov University, St. Petersburg, Russia
³ Department of Orofacial Surgery, Pavlov University, St. Petersburg, Russia

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Normal aerobic and facultative anaerobic microbiota colonizing oral mucosa is usually identified at clinical laboratories. Its composition may be important index of immunocompromised conditions. These parameters are scarcely studied in patients undergoing hematopoietic stem cell transplantation (HSCT). The aim of this work was to evaluate incidence of common aerobic and facultative anaerobic microbiota cultured from oral samples taken before HSCT and, by clinical indications, within 4 months after the treatment.

Patients and methods

We evaluated results of bacterial cultures from oral smears taken in 202 patients with oncohematological and inborn diseases at the age ranging from 1 to 69 years subjected to allogeneic HSCT. The analysis was performed for 3 age groups: 1-5, 6-14, 15-21, and >22 years old.

Results

In total observation group of 630 oral samples, the bacterial cultures proved to be positive in 61.8% of specimens. The most common microorganisms were as follows: S.viridans 245/630 (38.9%); K.pneumoniae 42/630 (6.7%); S.epidermidis 120/630 (19.1%); Neisseria spp. 66/630 (10.5%); Corynebacterium spp. 78/630 (12.4%). The incidence of microbial detection was time-dependent, with significant decrease in S.epidermidis, Corynebacterium spp. and Klebsiella spp. during 1st month posttransplant which could be explained by early effective antibacterial decontamination since the time of conditioning in early posttransplant period. We have shown that the frequency of positive tests for S.viridans and K.pneumoniae in these samples were different for distinct age groups, i.e., the positivity rates were significantly higher in youngest children (up to 5 years old) and in adult patients (>22 years old), as compared with elder children and adolesсents. Incidence of K.pneumoniae in oral samples was found to be sufficiently increased 2-3 months after HSCT, being associated with severe infectious complications, with broad antibiotic resistance in most culturable Klebsiella isolates from the patients. For clinical indications, teeth extraction was made in 10 cases during 1^st month after HSCT, with Pseudomonas aeruginosa in 3 samples, S.viridans in 2 cases isolated from the local gum wounds. In conclusion, the immunotoxic effects of cytostatic therapy and microbiota analysis post-HSCT deserve further studies, including biodiversity analysis of oral microbiota by means of 16S rRNA gene sequencing. These results may represent a basis for rational antibacterial therapy in HSCT.

Keywords

Oncohematology, children, chemotherapy, hematopoietic stem cell transplantation, bacterial cultures, risk factors.

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Chukhlovin1, Anna A. Spiridonova2, Irina B. Baranova3, Artur P. Grigoriants3, Maria D. Vladovskaya1, Ludmila S. Zubarovskaya1, Boris V. Afanasyev1" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(240) "

Alexei B. Chukhlovin¹, Anna A. Spiridonova², Irina B. Baranova³, Artur P. Grigoriants³, Maria D. Vladovskaya¹, Ludmila S. Zubarovskaya¹, Boris V. Afanasyev¹

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Patients and methods

Results

Keywords

Oncohematology, children, chemotherapy, hematopoietic stem cell transplantation, bacterial cultures, risk factors.

Patients and methods

Results

Keywords

Oncohematology, children, chemotherapy, hematopoietic stem cell transplantation, bacterial cultures, risk factors.

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Ее состав может быть важным показателем иммунокомпромиссных состояний. Данные параметры мало изучены у пациентов после трансплантации гемопоэтических клеток (ТГСК). Целью настоящей работы была оценка выявляемости обычной аэробной и факультативно-анаэробной микробиоты, культивированной из биоматериала полости рта до ТГСК и, по клиническим показаниям, в течение 4 мес. после этого лечения. <h3>Пациенты и методы</h3> Мы оценили результаты посевов образцов, взятых из ротовой полости у 202 больных с онкогематологическими и врожденными заболеваниями в возрасте от 1 до 69 лет, которым была проведена аллогенная ТГСК. Анализ проводился для 3 возрастных групп: 1-5, 6-14, 15-21 и >22 лет. <h3>Результаты</h3> После 630 проведенных бактериологических исследований, позитивные результаты культивирования получены в 61.8% образцов. Наиболее частыми микроорганизмами были следующие: S.viridans 245/630 (38.9%); K.pneumoniae 42/630 (6.7%); S.epidermidis 120/630 (19.1%); Neisseria spp. 66/630 (10.5%); Corynebacterium spp. 78/630 (12.4%). Частота выявления микроорганизмов зависела от времени после ТГСК, а именно отмечено снижение высеваемости S.epidermidis, Corynebacterium spp. и Klebsiella spp. в течение 1-го месяца после ТГСК, что можно объяснить эффективной ранней антибактериальной деконтаминацией пациентов, начиная с момента кондиционирования. Нами показано, что частота высеваемости S.viridans и K.pneumoniae в этих образцах была различной для отдельных возрастных групп, будучи существенно повышенной у детей самого младшего возраста (до 5 лет) и у взрослых пациентов (>22 лет), по сравнению со старшими детьми и подростками. Высеваемость K.pneumoniae в образцах из полости рта оказалась существенно повышенной через 2-3 месяца после ТГСК, что сопровождалось тяжелыми инфекционными осложнениями и наличием резистентности клинических изолятов Klebsiella к большинству антибиотиков. По клиническим показаниям проведена экстракция зубов в 10 случаях в течение 1-го мес. после ТГСК. Посевы раневого отделяемого из десен показали наличие Pseudomonas aeruginosa в 3 образцах, S.viridans – в 2 случаях. <h3>Выводы</h3> Иммунотоксические эффекты цитостатической терапии и анализ микробиоты после ТГСК заслуживают дальнейших исследований, в том числе – анализ биологического разнообразия микробиоты полости рта посредством секвенирования гена 16S rRNA. Эти результаты могут стать основой для рациональной антибактериальной терапии при ТГСК. <h2>Ключевые слова</h2> Онкогематология, дети, химиотерапия, трансплантация гемопоэтических стволовых клеток, бактериальные культуры, факторы риска." 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Пациенты и методы

Результаты

Выводы

Ключевые слова

Пациенты и методы

Результаты

Выводы

Ключевые слова

" } ["ORGANIZATION_RU"]=> array(37) { ["ID"]=> string(2) "26" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:01:20" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(22) "Организации" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(15) "ORGANIZATION_RU" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "26" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "25084" ["VALUE"]=> array(2) { ["TEXT"]=> string(856) "1 НИИ детской онкологии, гематологии и трансплантологии им. Р. М. Горбачевой, Санкт-Петербург, Россия 2 Отделение клинической микробиологии, Первый Санкт-Петербургский государственный медицинский университет им. акад. И. П. Павлова, Санкт-Петербург, Россия 3 Кафедра челюстно-лицевой хирургии, Первый Санкт-Петербургский государственный медицинский университет им. акад. И. П. Павлова, Санкт-Петербург, Россия" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(796) "

" } } } }