In children with acute lymphoblastic leukemia (ALL), relapse is still the leading cause of treatment failure occurring in 10–15% of cases. Overall survival after relapse plateaus at 50–60%, whereas event-free survival after second and third relapse is approximately 25% and 15%, respectively. The introduction of new immunotherapeutic agents such as blinatumomab (a bispecific T-cell engager), inotuzumab ozogamicin (InO; a CD22 + monoclonal antibody) and a chimeric antigen T-cell receptor targeted to CD19 + can significantly increase the effectiveness of treatment for relapsed ALL and help patients achieve remission faster and thus shorten the time to allogeneic hematopoietic stem cell transplantation (allo-HSCT). However, the toxicity of these novel agents and their impact on the results of allo-HSCT are still to be investigated. Our study included 55 patients with refractory B-cell ALL aged from 3 to 17 years (the median age was 10 years). The study was approved by the Independent Ethics Committee and the Scientific Council of the I.P. Pavlov First Saint Petersburg State Medical University. The patients were divided into two groups based on whether they received inotuzumab ozogamicin or not: InO+ group ( n = 24; 43.6%) and InO– group ( n = 31; 56.4%). The majority of the patients underwent haploidentical HSCT ( n = 53; 96.4%); 1 (1.8%) patient received HSCT from a matched related donor, and 1 (1.8%) from a matched unrelated donor. Conditioning regimens before allo-HSCT included: myeloablative conditioning ( n = 20; 36.4%), reduced toxicity myeloablative conditioning ( n = 5; 9.1%), and reduced intensity conditioning ( n = 30; 54.5%). Acute graft-versus-host disease prophylaxis with post-transplant cyclophosphamide was given to 49 (87.7%) recipients; 6 (12.3%) patients received seroprophylaxis. Basic combined immunosuppressive therapy consisting of a calcineurin inhibitor and an mTOR inhibitor was used in 35 (63.6%) cases, and single m-TOR inhibitor treatment was administered to 20 (36.4%) patients. In the InO+ group, 21 (87.5%) patients achieved complete remission with incomplete hematologic recovery before allo-HSCT: 5 (23.8%) patients had minimal residual disease (MRD), and 16 (76.2%) patients were MRD negative. In the InO– group, remission with incomplete hematologic recovery before allo-HSCT was achieved in 15 (48.4%) patients: 3 (9.7%) cases were MRD positive and 12 (38.7%) were MRD negative ( p = 0.003). All the patients underwent allo-HSCT, regardless of response to prior therapy. Engraftment was achieved in the InO+ group in 20 (83.3%) children in a median of 22 days (D+22) and in the InO– group in 25 (80.6%) children in a median of 19 days (D+19). Relapse was observed in 11 (55%) patients in the InO+ group and in 15 (60%) patients in the InO– group at a median of 164 days and 203 days post-transplant, respectively ( p = n. s.). In the InO+ group, 5 (31.25%) out of 16 patients in complete remission with incomplete hematologic recovery and negative MRD status relapsed after allo-HSCT within a median of 105 days (D+58 – D+169). In the InO–, 6 (50%) out of 12 patients in complete remission with incomplete hematologic recovery and negative MRD status relapsed within a median of 296 days (D+108 – D+929). Due to the small number of patients in the groups, a correlation and regression analysis showed a weak correlation between the use of InO before allo-HSCT and the occurrence of post-transplant relapse (Pearson's contingency coefficient was 0.178). Loss of the HLA haplotype at relapse was found in 1 (4.2%) patient from the InO+ group and in 2 (6.5%) patients from the InO– group ( p = n. s.). Transplant-associated thrombotic microangiopathy was diagnosed in 6 (25%) recipients in the InO+ group and in 3 (9.7%) recipients in the InO– group. Eight (32%) patients in the InO+ group and 3 (9.7%) patients in the InO– group had clinical manifestations of sinusoidal obstruction syndrome. Our study suggests the effectiveness of inotuzumab ozogamicin for the treatment of relapsed B-ALL in children before allo-HSCT. Patients with large tumor burden and high expression of CD22 + would benefit the most from therapy with InO. The application of reduced intensity conditioning regimen after CD22 + directed monoclonal antibody therapy significantly improves the overall survival rates by reducing early transplant-related mortality and makes it possible to use adoptive immunotherapy as a next line of treatment. Current allo-HSCT protocols and approaches to acute graft-versus-host disease prevention help control the development of severe complications in the early post-transplant period. Our study showed that adoptive immunotherapy via donor lymphocyte infusions can be applied in patients treated with InO who experience loss of the HLA haplotype at relapse after allo-HSCT.

Acute myeloid leukemia (AML) is the second most common type of leukemia in children and accounts for up to 20 % of all leukemias. Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is an effective, and sometimes the only therapeutic option in high-risk patients with AML. Graft-versus-host disease (GVHD) is a major complication of allo-HSCT and the main cause of transplant-related mortality. GVHD prophylaxis in children includes calcineurin inhibitors, either alone or in combination with other immunosuppressants, which can lead to grade II–IV acute GVHD in 40–85 % of cases. Alternatively, GVHD can be prevented with high-dose cyclophosphamide (50 mg/kg/day) administered on days +3, +4 after allo-HSCT, either alone or in combination with other immunosuppressive drugs depending on HLA compatibility of the donor. The aim of this study was to evaluate outcomes after allo-HSCT from an unrelated donor with GVHD prophylaxis with post-transplant cyclophosphamide (PTC) in children in their first and second remission of AML in comparison with a historical control group. We retrospectively analyzed patient outcomes after 53 first-time allo-HSCTs from HLA-matched (n = 40) and partially-matched (8–9/10) (n = 13) unrelated donors performed in pediatric patients (aged 0 to 18 years) in their 1 st or 2 nd remission of AML at the R. M. Gorbacheva Research Institute for Pediatric Oncology, Hematology and Transplantation from 2008 to 2018. The study was approved by the Independent Ethics Committee and the Scientific Council of the I. P. Pavlov First Saint Petersburg State Medical University of Ministry of Healthcare of the Russian Federation. Our group of interest included 26 patients preventively treated for GVHD with 50 mg/kg of cyclophosphamide on days +3 and +4 in combination with calcineurin inhibitors (cyclosporin A – 2 (7.7 %) patients, tacrolimus – 24 (92.3 %) patients), the mTOR inhibitor sirolimus (5 (19.2 %) patients) or mycophenolate mofetil (21 (80.8 %) patients). The historical control group was made up of 27 patients whose GVHD prophylaxis was based on antithymocyte globulin used in combination with calcineurin inhibitors (tacrolimus – 5 (18.5 %) patients, cyclosporin A – 21 (77.8 %) patients) or the mTOR inhibitor sirolimus (1 (3.7 %) patients) or methotrexate (25 (92.6 %) patients), or mycophenolate mofetil (2 (7.4 %) patients). The groups were matched for diagnosis, age, disease status before allo-HSCT, the matched-to-partially-matched donor ratio, the source of hematopoietic stem cells and conditioning regimen intensity (myeloablative conditioning regimen (MAC) or reduced intensity conditioning regimen (RIC)). The median age at the time of allo-HSCT was 8.6 (0.97–18) years in the PTC group and 6.55 (1.42–17.76) years in the historical control group. In the PTC group, 21 (80.8 %) patients were diagnosed with primary AML and 5 (19.2 %) – with secondary AML, while the historical control group included 22 (81.5 %) and 5 (18.5 %) patients with primary and secondary AML respectively. Disease status at the time of allo-HSCT: 21 (80.8 %) patients treated with PTC were in the 1 st complete clinical and hematologic remission (CCHR) and 5 (19.2 %) – in the 2 nd CCHR; among the controls, there were 19 (70.4 %) cases of the 1 st CCHR and 8 (29.6 %) cases of the 2 nd CCHR. In the PTC group, 18 (69.2 %) patients underwent allo-HSCT from 10/10 fully HLA gene-matched donors and 8 (30.8 %) – from 9/10 HLA-matched donors. In the historical control group, 19 (70.4 %) patients had allo-HSCT from 10/10 fully HLA gene-matched donors, 4 (14.8 %) – from 9/10 matched donors, and 1 (3.7 %) – from an 8/10 matched donor. In the PTC group, MAC was used in 14 (53.8 %) patients, RIC – in 12 (46.2 %) patients. In the control group, MAC and RIC were used in 14 (51.9 %) and 13 (48.1 %) patients respectively. In the group treated with PTC, hematopoietic stem cells were derived from the bone marrow in 14 (53.8 %) patients, from the peripheral blood – in 12 (46.2 %) patients. In the historical group, bone marrow was used in 13 (48.1 %) patients and peripheral blood - in 14 patients (51.9 %). The median graft cellularity (CD34+ × 10 6 /kg) in the PTC group was 4.60 (1.7–10.9) × 10 6 /kg, in the historical group – 6.60 (1.0–13.2) × 10 6 /kg. The overall and relapse-free 5-year survival rates were higher in the PTC group than in the historical control group: 83.3 % (95 % confidence interval (CI) 60.9–93.5) vs 59.3 % (95 % CI 38.6–75.0), p = 0.0327 and 76.9 % (95 % CI 55.7–88.9) vs 48.1 % (95 % CI 28.7–65.2), respectively, p = 0.0198. The cumulative incidence of grade II–IV acute GVHD and grade III–IV acute GVHD by day +125 and of moderate and severe chronic GVHD, and the 2-year transplant-related mortality were significantly lower in the PTC group compared to the controls: 15.4 % (95 % CI 4.8–31.5) vs 51.8 % (95 % CI 31,9–68.5), p = 0.004; 7.7 % (95 % CI 1.3–21.7) vs 33.3 (95 % CI 16.8–50.9), p = 0.026; 23.4 % (95 % CI 9.5-41.0) vs 58.6 % (95 % CI 33.8–76.8), p = 0.022; 3.8 % (95 % CI 0.3–16.4) vs 25.9 % (95 % CI 11.5–43.1), p = 0.0232, respectively. GVHD-related mortality was higher in the historical control group than in the PTC group (3.8 % vs 18.5 %, p = 0.192). Thus, PTC-based GVHD prophylaxis was shown to be more effective in managing acute and chronic GVHD compared to antithymocyte globulin, with better overall, relapse-free and GVHD-free relapse-free survival rates and low transplant-related mortality.

Relapse of acute myeloid leukemia (AML) after allogeneic hematopoietic stem cell transplantation (allo-HSCT) remains one of the main causes of reduced long-term survival. Modern methods for predicting the risk of AML relapse after allo-HSCT take into account the data on the pre-transplant level of minimal residual disease (MRD) determined by flow cytometry and molecular biological studies of recurrent genetic abnormalities, which are currently widespread in clinical practice. Recent studies of the expression of genes characteristic of leukemic stem cells (LSCs) have shown prognostic significance for children with AML in relation to treatment response and the risk of relapse. The study of LSC persistence in order to predict the risk of recurrence after allo-HSCT in children with AML in addition to standard MRD detection methods may be of great importance. The aim of the work was to evaluate the impact of MRD status, both using classic methods and taking into account the genes characteristic of LSC, on the results of allo-HSCT in children with AML. The study was approved by the Independent Ethics Committee and the Scientific Council of the I.P. Pavlov First Saint Petersburg State Medical University of Ministry of Healthcare of the Russian Federation. To assess MRD using standard diagnostic methods, we analyzed the data of 95 children with AML in their 1 st –2 nd remission (cohort 1). MRD status was negative in 67 (70.6 %) patients; in 28 (29.4 %) children, MRD status was positive according to molecular genetic studies and / or immunophenotyping results. For pre-transplant evaluation of the expression of genes characteristic of LSC, we investigated bone marrow samples of 50 patients (cohort 2) using real-time polymerase chain reaction. The DNMT3B , GPR56 , CD34 , SOCS2 , SPINK2 , FAM30A , and ABL genes were studied by real-time polymerase chain reaction, followed by calculation of the pLSC6 value using the formula: DNMT3b × 0.189 + GPR56 × 0.054 + CD34 × 0.0171 + SOCS2 × 0.141 + SPINK2 × 0.109 + FAM30A × 0.0516. At the time of allo-HSCT, 37 (74 %) children with AML were in their 1 st or 2 nd remission of the disease, 13 (26 %) were out of the 1 st –2 nd remission. With a median follow-up of 5 years in the group of patients with a positive MRD status, determined by standard methods (cohort 1), overall survival (OS) was 67.9 % vs 73.1 % for patients with a negative MRD status (p = 0.83). The cumulative incidence of relapse was 50 % and 22 %, respectively; p = 0.012. When assessing the level of expression of genes characteristic of LSC (cohort 2), a pLSC6 level was above the median in 18/37 (49 %) patients. The results of linear regression showed that the pre-transplant level of expression of genes characteristic of LSC was not associated with the number of blasts/MRD (odds ratio 1.002; 95 % confidence interval 0.979–1.025). One-year OS rates did not differ significantly in children in the 1st–2nd remission of AML, depending on pLSC6 level: 84.2% in patients with low pLSC6 and 72.2 % – with high pLSC6 (p = 0.4), event-free survival in the corresponding groups – 68.4 % and 61.1 %, respectively (p = 0.34). The cumulative incidence of early relapse after allo-HSCT in the group of AML patients with a high pLSC6 score was significantly higher than in children with a low pLSC6 score before allo-HSCT (22 % and 0 %, respectively; p = 0.03). MRD does not have a statistically significant effect on OS. However, MRD positivity before allo-HSCT increases cumulative incidence of relapse. The level of expression of genes characteristic of LSC, determined before allo-HSCT, showed a prognostic significance in relation to the development of early AML relapse after allo-HSCT.

Juvenile myelomonocytic leukemia (JMML) is a rare and aggressive myeloproliferative/myelodysplastic neoplasm of early childhood characterized by activation of the Ras signaling pathway. Allogeneic hematopoietic stem cell transplantation (alloHSCT) is the only proven curative treatment for JMML. However, the 5-year overall survival is about 52–64%. In this work, we analyzed 4 clinical cases of patients with relapses of JMML with loss of heterozygosity in HLA (LoH) after allo-HSCT. The patients' parents gave their consent to the use of their children's data, including photographs, for research purposes and in publications. Two patients received a second allo-HSCT from an alternative donor, two patients – from the same donor. A positive result in the form of a durable remission was observed in one patient who underwent a second allo-HSCT from an alternative donor and restored HLA genetic heterozygosity. At the same time, immunotherapy with infusions of donor lymphocytes led to the development of graft-versus-host disease without potentiating the antileukemic effect. Thus, a second allo-HSCT from an alternative donor for the treatment of relapsed JMML with HLA LoH is necessary to restore the “graft-versus-JMML” response. The study was approved by the Independent Ethics Committee and the Scientific Council of the I.P. Pavlov First Saint Petersburg State Medical University of Ministry of Healthcare of the Russian Federation.

The loss of a patient-specific HLA haplotype on the surface of the blast cell population is one of the ways a tumor can evade the immune surveillance of donor cells. This phenomenon is observed in approximately 30 % of relapses in patients with hematologic malignancies who underwent partially mismatched allogeneic hematopoietic stem cell transplantation (HSCT). In this study, for the first time, a large cohort of pediatric patients (n = 80) with relapsed acute myeloid (AML) or acute lymphoblastic (ALL) leukemia after allogeneic HSCT was analyzed with the help of the STR method (highlypolymorphic microsatellite marker analysis) using 6 HLA haplotype markers. The study was approved by the Independent Ethics Committee and the Scientific Council of the I. P. Pavlov First Saint Petersburg State Medical University of Ministry of Healthcare of the Russian Federation. Loss of heterozygosity (LOH) was observed in 18 / 80 (22 %) relapsed patients with various types of acute leukemia: out of these, 8 / 44 (18 %) patients had B-cell ALL, 4 / 10 (40 %) patients – T-cell ALL and 6 / 25 (24 %) patients – AML. All relapses with LOH were observed in patients who had undergone haploidentical HSCT, and were found to occur later than relapses without loss of the HLA haplotype (median time to relapse: 8.8 months vs 6.2 months, p = 0.043). In the patients treated with haploidentical HSCT (n = 61), we assessed factors increasing the risk of LOH at relapse. The number of previous therapy lines in the patients with AML (n = 17) and acute or chronic graft-versus-host disease in the patients with ALL (n = 44) were associated with an increasedrisk of genetic loss of the HLA haplotype (p = 0.008 and p = 0.015 respectively). A relapse following the second allogeneic HSCT was associated with LOH in 4 / 5 (80 %) patients, p = 0.008. The prognosis of the patients with LOH was extremely poor. At a median follow-up of 6 months, the overall survival from relapse was 22 % in the LOH group and 37 % in the non-LOH group. The median overall survival was 4.5 months (95 % confidence interval 3–NA) and 10.3 months (95 % confidence interval 5.7–16.1) respectively, p = 0.063. Among the patients with LOH, the best survival rates were observed in those who had undergone a repeat allogeneic HSCT from a different donor. Thus, the analysis of LOH is an important tool for determining the prognosis and further treatment in pediatric patients with acute leukemias. We strongly recommend that this diagnostic test should be included into standard testing of patients after partially-mismatched allogeneic HSCT.

Pleuropulmonary blastoma (PPB) is a very rare tumor of childhood that arises from the mesenchyme of the lung and is associated Infant acute lymphoblastic leukemia (ALL) is characterized by a high incidence of KMT2A gene rearrangements and poor outcome. Despite intensified therapy protocols, infant ALL remains a difficult-to-treat disease, with a high relapse rate. Allogeneic bone marrow transplantation is the only curative method aimed to curing the disease. Over the last decades, donor lymphocyte infusion (DLI) has been used as a salvage therapy after post-transplant relapses in B-ALL patients with a proven antileukemic effect. The combination of blinatumomab and DLI is a promising immunoadoptive therapy for resistant ALL based on the induction of “graft versus leukemia” effect by activating donor T-lymphocytes. We analyzed the results of combined immunoadoptive therapy with a bispecific T-cell activator blinatumomab and DLI in 3 infants with ALL, as well as the outcome of monotherapy with a bispecific T-cell activator in one infant. The study was approved by the Independent Ethics Committee and the Scientific Council of the I.P. Pavlov First Saint Petersburg State Medical University. All infants initially had the KMT2A gene rearrangement and were classified as high-risk. The indication for immunoadoptive therapy was an early combined relapse of the disease after haploidentical hematopoietic stem cell transplantation in one patient and minimal residual disease (MRD) in three patients. All patients achieved long term hematological remission of the disease, 3 (75%) patients – MRD negative remission. The median duration of bone marrow response was 24 (8–63) months. One patient developed a bone marrow relapse in 8 months after therapy, two patients developed isolated extramedullary relapse. We did not see toxic complications and induction of graft-versus-host disease during immunoadoptive therapy. At the time of the follow up, all patients are alive, three remains in lasting hematological remission.

Профилактические инфузии донорских лимфоцитов используют у пациентов с высоким риском развития рецидива заболевания после алло-ТГСК. Данные по безопасности раннего введения ИДЛ у детей крайне ограничены. В работе отражены частота клинически значимой реакции «трансплантат против хозяина» (РТПХ) и ее связь с общей и безрецидивной выживаемостью. Проанализированы 37 детей с острыми лейкозами и ЮММЛ, получивших профилактические ИДЛ в течение первых 6 месяцев после алло-ТГСК. Развитие острой/хронической РТПХ средней степени выявлено у 7 из 37 детей (19%), не отмечено тяжелых форм РТПХ. Наиболее часто диагностировали кожную форму хронической РТПХ в сочетании с поражением печени. Случаи летальности, связанные с осложнениями после ИДЛ, не были зарегистрированы. Напротив, индукция острой/хронической РТПХ улучшала показатели безрецидивной выживаемости и не влияла на общую выживаемость, p=0,04 и p=0,3 соответственно. Prophylactic donor lymphocytes infusion (DLI) is used in patients with a high risk of relapse after allo-HSCT. The data about safety of early start DLI in children are extremely limited. This study demonstrates the incidence of clinically significant graft versus host disease (GVHD) and correlation with overall and disease-free survival. We analyzed 37 children with acute leukemia and JMML, who had received prophylactic DLI within the first 6 months after HSCT. Moderate acute/chronic GVHD was diagnosed in 7/37 children (19%), nobody developed severe GVHD. The most children had chronic GVHD with involvement of skin and liver. There were no cases GVHD-related mortality. The induction of acute/chronic GVHD improved the relapse-free survival and did not influence on overall survival, p=0.04 and p=0.3, respectively.

Aim. To assess prognostic factors and to analyze the outcomes of nivolumab therapy in patients with relapsed/re-fractory classic Hodgkin's lymphoma (cHL) after autologous hematopoietic stem cell transplantation (auto-HSCT). Materials & Methods. The retrospective analysis included 42 patients treated with nivolumab 3 mg/kg after auto-HSCT in the period from 2016 to 2020. The response to nivolumab therapy was assessed every three months by whole-body PET/CT based on LYRIC criteria. Toxicity profile was assessed by establishing adverse events (AE) based on NCI CTCAE 4.03 criteria. Results. The study included 42 patients with relapsed/re-fractory cHL: 21 (50 %) men and 21 (50 %) women. The median age was 32.5 years (range 22-43 years). At diagnosis the following cHL stages were identified: stage II in 14 pts (33.3 %), stage III in 12 pts (28.6 %), and stage IV in 16 pts (38.1 %). Primary chemoresistance after the first-line therapy was observed in 26 pts (61.9 %) and early relapse in 4 pts (9.52 %). The median follow-up was 38 months, 3-year overall survival was 97 % (95% confidence interval, 95% CI, 83.2-99.6 %), 3-year progression-free survival (PFS) was 34.8 % (95% CI 20.3-49.9 %; median 12.9 months). Objective response was reported in 69 % of patients, complete response (CR) in 33.3 %, partial response in 35.7 %, stable disease in 7.1 %, indeterminate response in 14.3 %, and progression in 9.5 % of patients. The analysis of factors affecting PFS revealed significant differences in patients who reached CR after 6 nivolumab cycles: 3-year PFS 56.2 % (95% CI 24.4-79.1 %) vs. 25.2 % (95% CI 10.46-43.1 %) in patients who did not reach CR (p = 0.054). If extranodal lesions were identified at nivolumab therapy onset, PFS was 29 % (95% CI 7.8-37.5 %) vs. 68 % (95% CI 35.9-86.8 %) in their absence (p = 0.0079). The overall rate of AEs on nivolumab therapy was 92.9 %, severe AEs of grade 3-4 were observed in 19.1 % of patients. Conclusion. Nivolumab shows high efficacy in the treatment of patients with relapsed/refractory cHL after the failure of auto-HSCT and considerably improves prognosis compared with historical control. The efficacy of nivolumab is independent of brentuximab vedotin use and duration of prior therapy. Throughout the follow-up period the toxicity level of nivolumab was acceptable and controlled. Clinical factors that affect prognosis for patients on immunotherapy were identified.

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a potentially curative therapy for patients with acute myeloid leukemia (AML). The conditioning regimen administered for this patient based on busulfan (Bu) combined with cyclophosphamide (Cy), fludarabine (Flu) or some other agents. Comparisons of myeloablative conditioning (MAC) versus reduced intensity conditioning (RIC) have demonstrated a various results between relapse and toxicity in a few reports. We suppose, that dose intensity of Bu across regimens may affect treatment outcomes. Aim of this retrospective study was to evaluate the impact dose of busulfan to overall survival (OS), transplant-related mortality (TRM), relapse-free survival (RFS), toxicity, the incidence of primary graft failure and acute "graft versus host" disease (GvHD) in transplantation in children and adolescents with AML. The study was approved by the Independent Ethics Committee and the Scientific Council of the I.P. Pavlov First Saint Petersburg State Medical University. We analyzed 110 AML pediatric patients with the median age 9 (range 1–19) y.o., who underwent first allo-HSCT with Bu based conditioning in R.M. Gorbacheva Memorial Institute from 2002 to 2018. Patients were divided into 3 groups: Bu1 – patients, who received Bu at the dose 8–10 mg/kg, n = 34 (31%), in Bu2 – dose of Bu was 12 mg/kg, n = 35 (32%), in Bu3 – dose of Bu was > 12 mg/kg, n = 41 (37%). In Bu1 Bu was combined with Flu in 31 (91%) pts and Cy in 3 (9%); in Bu2 – with Flu in 12 (34%), Cy in 7 (20%) and other agents in 16 (46%); in Bu3 – with Cy in 32 (78%), with Flu in 7 (17%) and other agents in 2 pts (5%) (p < 0.001). Patients in Bu2 received more Cy based GvHD prophylaxis regimens (69% vs 44% in Bu1, vs 29% in Bu3, p = 0.003) and more haplo grafts (51% vs 29% in Bu1, vs 15% in Bu3, p = 0.003). The complete remission at the HSCT was observed in 79 % in Bu1, 49% in Bu2, 61% in Bu3 (p = 0.02). Probabilities of OS, RFS, TRM were estimated by using the Kaplan–Meier method. Incidence of toxicity, acute GvHD and primary graft failure – by using Mann–Whitney U-test. Transplant engraftment was achieved in 95 (86%) of patients. Graft failure occurs in the 5 patients of Bu1 group (15%), in the 6 pts of Bu2 (17%) and in the 4 pts of Bu3 (10%) (p = 0.7). Median follow-up was 2 years for Bu1 and Bu3, 1 year for Bu2. Two-year OS was similar (Bu1 = 59% vs Bu2 = 60% vs Bu3 51%, p = 0.7). Two-year OS of pts with CR before HSCT was 70% in Bu1, 82% in Bu2, 60% in Bu3, p = 0,3 and 14%, 39%, 38% for pts with progression disease (PD), respectively (p = 0.5). Two-year RFS was 74% in Bu1, 82% in Bu2, 64% in Bu3 at CR (p = 0.4); 43%, 39% and 38% in pts with progression, respectively (p = 0.9). Median of RFS were also similar for the pts in PD (4 months in Bu1, 5 months in Bu2 and Bu3, p = 0.9) and not achieved for pts at CR. Drug related toxicity grade III–IV 4 experienced in 35% pts in Bu1, 29% in Bu2, in 54% in Bu3 (p = 0.04). Mucositis and toxic hepatitis were the most common adverse events. Sinusoidal obstruction syndrome (SOS) experienced in 8 pts from different group: 4 from Bu2 (11%), 3 from Bu3 (7%) and only pts from Bu1 (3%) with previously treated of inotuzumab (p = 0.4). The most pts with VOD (3/5) had PD at the HSCT. Cumulative incidence of acute GvHD grade 2 (15% vs 14% vs 10%, p = 0.8) were not different. Acute GvHD grade III–IV was observed a bit more often in Bu3 (34%), than in Bu1 (18%) and Bu2 (17%) (p = 0.09). TRM up to D+100 was also higher in Bu3 (15%), than in Bu2 (6%) and Bu1 (0%) (p = 0.05). The transplant results of children with similar disease status of AML, received MAC or RIC conditioning with various dose of Bu, were not associated with significant differences in overall outcomes. The higher dose Bu may increase incidence of toxicity grade III–IV (p = 0.04) and acute GvHD grade III–IV (p = 0.09) with increasing of early TRM (p = 0.05).

Aсute myeloid leukemia (AML) in children aged 0–2 years and aсute lymphoid leukemia (ALL) up to 1 year (i.e., infants) frequently characterize high risk and poor prognosis. Аllogeneic hemopoietic stem cell transplantation (аllo-HCST) is a main curative but toxic option for these patients, and choice of allogeneic donor may be one of the important factor for long-term survival. Aim. To evaluate overall survival (OS), relapse free survival (RFS), transplant related mortality (TRM), "graft versus host" disease free/relapse free survival (GRFS) in infant with acute leukemia underwent allo-HCST from MUD vs haplodonor at 1st or 2nd remission. The study was approved by the Independent Ethics Committee and the Scientific Council of the I.P. Pavlov First Saint Petersburg State Medical University. 34 children with infant acute leukemia: 23 pts with AML (68%) and 11 – with ALL (32%) – underwent allo-HSCT from MUD vs haplo at 1st or 2nd remission between 2004–2018 were analyzed. Median age at allo-HCST – 22 months (6 months – 5 y.o.). HSCT was performed from MUD in 19 (56%) pts (group 1), haplo – 15 (44%) pts (group 2). Myeloablative conditioning received 29 (85%) pts. Reduced intensity conditioning received 5 (15%) pts. Posttransplant cyclophosphomyde (PtCy) was used in 10 (53%) pts in the group 1 and 14 (93%) pts. in the group 2 (p = 0.043). Engraftment was identified in 18 pts (95%) of group 1 and 12 pts (80%) of group 2 (p = 0.28). At the median follow up 3.5 years OS is 79% in the group 1 аnd 73% in the group 2 (p = 0.68). RFS is 79% in the group 1 аnd 67% in the group 2 (p = 0.41). GRFS is 39% in the group 1 аnd 47% in the group 2 (p = 0.5). TRM occurred in 2 pts (11%) of group 1 (due to infectious and toxicity) and no one of the group 2 (p = 0.2). Haplo-HSCT with PtCy is a good alternative to MUD with high efficacy and acceptable toxicity in children with infant acute leukemia at 1st or 2nd remission.

Цель. Оценка прогностических факторов и анализ результатов лечения при использовании ниволумаба у пациентов с рецидивами и рефрактерным течением классической лимфомы Ходжкина (кЛХ) после трансплантации аутологичных гемопоэтических стволовых клеток (аутоТГСК). Материалы и методы. Проведен ретроспективный анализ результатов лечения 42 пациентов, получавших ниволумаб в дозе 3 мг/кг после аутоТГСК в период с 2016 по 2020 г. Ответ на терапию ниволумабом оценивался каждые 3 мес. посредством ПЭТ/КТ всего тела согласно критериям LYRIC. Профиль токсичности оценивался путем регистрации нежелательных явлений (НЯ) согласно критериям NCI CTCAE 4.03. Результаты. В исследование включено 42 пациента с рецидивами и рефрактерным течением кЛХ: 21 (50 %) мужчина и 21 (50 %) женщина. Медиана возраста составила 32,5 года (диапазон 22–43 года). Стадия кЛХ на момент постановки диагноза: II — у 14 (33,3 %) пациентов, III — у 12 (28,6 %), IV — у 16 (38,1 %). Первичная химиорезистентность после первой линии терапии констатирована у 26 (61,9 %) пациентов, ранний рецидив — у 4 (9,52 %). Медиана наблюдения составила 38 мес., 3-летняя общая выживаемость — 97 % (95%-й доверительный интервал [95% ДИ] 83,2–99,6 %), 3-летняя выживаемость без прогрессирования (ВБП) — 34,8 % (95% ДИ 20,3–49,9 %; медиана 12,9 мес.). Объективный ответ констатирован у 69 % пациентов, полный ответ (ПО) — у 33,3 %, частичный — у 35,7 %, стабилизация заболевания — у 7,1 %, неопределенный ответ — у 14,3 %, прогрессирование — у 9,5 %. Анализ факторов, влияющих на ВБП, выявил статистически значимые различия у пациентов, достигших ПО после 6 введений ниволумаба: 3-летняя ВБП 56,2 (95% ДИ 24,4–79,1 %) vs 25,2 % (95% ДИ 10,46–43,1 %) у пациентов, не достигших ПО (p = 0,054). При наличии экстранодальных поражений на момент начала терапии ниволумабом ВБП составила 29 (95% ДИ 7,8–37,5 %) vs 68 % (95% ДИ 35,9–86,8 %) при их отсутствии (p = 0,0079). Общая частота НЯ на фоне терапии ниволумабом составила 92,9 %, тяжелые НЯ III–IV степени выявлены у 19,1 % пациентов. Заключение. Ниволумаб демонстрирует высокую эффективность в лечении пациентов с рецидивами и рефрактерным течением кЛХ после неудачи аутоТГСК и значительно улучшает прогноз по сравнению с историческим контролем. Эффективность ниволумаба не зависит от использования брентуксимаба ведотина или длительности предшествующей терапии. На протяжении всего периода наблюдения ниволумаб показал приемлемый и контролируемый уровень токсичности. Выявлены клинические факторы, влияющие на прогноз у пациентов на фоне иммунотерапии.