Проведение рандомизированных многоцентровых исследований в области трансплантации гемопоэтических стволовых клеток (ТГСК) представляет значительные трудности, поэтому доля таких исследований невелика. Большинство клинических рекомендаций основывается на данных популяционных многоцентровых исследований регистров или хорошо контролируемых проспективных одноцентровых нерандомизированных исследований. С целью определить критерии хорошо контролируемого одноцентрового исследования, результаты которого могут быть подтверждены в многоцентровом анализе, проанализировано 44 группы пациентов из 22 совместных с группой EBMT исследований. Проведено сравнение результатов этих исследований с одноцентровыми данными и спланированными исследованиями НИИ ДОГиТ им. Р.М. Горбачевой. Выявлено, что статистически значимые различия наблюдались в 43 % случаев, при этом вероятность расхождения результатов при повышении числа пациентов в одноцентровых группах не уменьшалась, а увеличивалась (отношение шансов 1,037; 95%-й доверительный интервал 1,001–1,074; p = 0,046), что свидетельствует о различиях в методологии одноцентровых и многоцентровых исследований. При анализе причин статистически значимых результатов сформулированы следующие необходимые критерии высококачественных одноцентровых исследований в области ТГСК: 1) режимы кондиционирования и профилактики реакции «трансплантат против хозяина» (если они не являются предметом исследования) должны соответствовать наиболее часто используемым в практике; 2) группы пациентов должны быть однородными по своему статусу; 3) в исследование не должны включаться пациенты, получавшие лечение более чем за 5 лет до анализа; 4) пациенты должны получать современную противоопухолевую терапию на до- и посттрансплантационном этапах; 5) каждая сравниваемая группа должна включать более 30–40 пациентов.

This article presents data demonstrating frequent BAALC hyperexpression, also in combination with WT1 hyperexpression, in children and adults with acute myeloid leukemia (AML). Treatment included allogeneic hematopoietic stem cell transplantation. The analysis of serial measurements of BAALC and WT1 expression level in 50 AML patients (37 adults and 13 children) showed that the increased BAALC expression is more common in patients with M1, M2, M4, and M5 FAB variants of AML with equal frequency in adults and children. Furthermore, the increased BAALC expression was rather common in combination with the increased WT1 expression, which predicted poorer prognosis. Since BAALC expression level in AML patients is closely related to AML-producing progenitor cells of leukemia hematopoiesis, a serial study of this phenomenon offers insights into the role of these cells in emergence and development of post-transplantation relapses, which is of both theoretical and practical importance.

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.

Background. Recent advances in the treatment of relapsed/refractory acute lymphoblastic leukemia (R/R ALL) are attributed to the implementation of immunotherapy methods which include blinatumomab, the bispecific engager of a patient's endogenous T-cells (Blincyto™, Amgen®) (BC). Aim. To assess BC efficacy and toxicity in the treatment of R/R ALL patients with persistence of minimal tumor clone before and after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Materials & Methods. The trial included 66 B-ALL patients with CD19+ aged 18 to 72 years, 23 (35 %) of them with measurable minimal residual disease (MRD+) and 43 (65 %) with R/R ALL. In 18 (27 %) patients BC was administered after prior allo-HSCT. Results. In the overall group 2-year overall survival (OS) and disease-free survival (DFS) in patients with response to BC treatment were 53 % and 38 % respectively. In the R/R ALL group complete remission (CR) was achieved in 29 (67 %) patients including 24 (83 %) patients with negative MRD. CR rate was higher in standard cytogenetic risk group (73 %) in comparison with high-risk group (59 %). In patients with more or less than 50 % blast cells in bone marrow CR rate was 85 % and 61 %, respectively. When BC was administered after prior allo-HSCT and without it CR rate was 80 % and 60 %, respectively. In R/R ALL patients with response to BC 2-year OS and DFS were 40 % and 26 %, respectively, in the MRD+ group of ALL patients they were 66 % and 51 %, respectively. Relapse rate was lower in the group with allo-HSCT than in the group without it, i.e. 21 % vs. 55 %. Adverse events of grade 3-4 were observed in 25 (38 %) patients. In 11 (16 %) patients BC therapy had to be discontinued, in 5 (7 %) patients it was terminated prior to the scheduled date. Conclusion. BC efficacy is higher in the MRD+ group and in R/R ALL patients with smaller tumor mass. BC treatment after allo-HSCT yields remissions in most patients and can be combined with immune-adoptive therapy.

Literature review provides the analysis of treatment results of implementing allogeneic hematopoietic stem cell transplantation (allo-HSCT) in patients with cytogenetically unfavorable acute myeloid and lymphoblastic leukemias including monosomal, complex, and hyperdiploid karyotypes, t(3;3)/inv(3), t(v;11)(v;q23), t(4;11)(q21;q23), t(9;22)(q34;q11) translocations, 17p abnormalities, and some other disorders. The major disadvantage of allo-HSCT seems to be linked to a strong chromosome-damaging effect of cytostatic drugs used in conditioning regimens which in turn is associated with additional chromosome abnormalities occurring in tumors, increasing genomic instability, and tumor progression. On the other hand, one of the advantages of allo-HSCT can consist in its specific “graft versus leukemia” (GVL) effect whose degree has not yet been adequately studied. To minimize the risks of allo-HSCT in above mentioned patients it appears appropriate to apply new treatment approaches based on de-escalation of chromosome- and whole-genome-damaging effects and also to introduce recent methods of active stimulation and qualitative assessment of GVL effect into clinical practice.

Aim. Using strict criteria, to assess incidence, pretransplant risk factors, and outcomes of severe "poor graft function" (sPGF), following allogeneic hematopoietic stem cell transplantation (allo-HSCT) in adults. Materials & Methods. The study included 710 adult patients (median age was 31 years, range 18-70 years; 55 % male and 45 % female patients) with different hematological diseases and documented transplant engraftment after allo-HSCT from matched sibling (20 %), unrelated (67 %) and haploidentical (13 %) donors in the period from 2008 to 2016. Myeloablative and reduced-intensity conditioning regimens were administered in 30 % and 70 % of patients, respectively. The analysis was based on the following sPGF criteria: 2 or more lines of cytopenia (platelets < 20 x 109/L, absolute neutrophil count < 0.5 x 109/L, and hemoglobin < 70 g/L at any time after documented engraftment), complete or stable mixed donor chimerism > 90 %, and absence of relapse signs, rejection, and severe acute graft-versus-host reaction. The following factors were analyzed: age, sex, diagnosis, presence/absence of remission in acute leukemias, ferritin level, type of donor, HLA-match, blood group and sex match, graft source, number of transplanted CD34+ cells, and conditioning regimen. Multivariate analysis included parameters of univariate analysis with p < 0.05. Results. After allo-HSCT sPGF was identified in 103 patients with 2-year cumulative incidence of 15 % (95% confidence interval [95% CI] 12-18 %). In most cases sPGF developed during the 1st year after allo-HSCT (median 50 days). Bi- and trilineage cytopenia was found in 59 % and 41 % of cases, respectively. In multivariate analysis sPGF risk was associated with myelodysplastic syndrome, myeloproliferative disorders (hazard ratio [HR] 3.403; 95% CI 1.972-5.606; p < 0.0001), and haploidentical donors (HR 3.830; 95% CI 1.545-8.828; p = 0.001). The absence of remission at the time of allo-HSCT in acute leukemias and blood group incompatibility were of borderline significance. In almost half of the cases, sPGF had a poor outcome, including death from cytopenia-related complications, further relapses, and graft rejection. Prognosis of bilineage sPGF was more favorable than that of trilineage sPGF. Conclusion. The present large cohort study yielded the incidence and analyzed the structure of sPGF in adult patients with oncohematological diseases. In addition, the key pretransplant sPGF risk factors were identified. The results of the trial can serve to optimize the choice of therapy after allo-HSCT.

Background. Among a multitude of molecular genetic changes underlying acute myeloid leukemia (AML) disordered epigenetic regulation is of special importance. It includes expression change in miR-3151 gene forming a part of BAALC gene on chromosome 8 in q22.3 locus. At present BAALC gene overexpression is observed in a half of AML patients. A considerable part of them shows a combination of it with an increased transcriptional activity of miR-3151 gene, which is associated with the poorest AML prognosis. Aim. To assess the prognostic value of miR-3151 overexpression in synergistic interaction with BAALC host gene in AML patients after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Materials & Methods. The trial included bone marrow samples taken from 10 healthy SCT donors and 29 AML patients after receiving allo-HSCT. Relative miR-3151 expression level and relative BAALC copy number were measured by quantitative real-time polymerase chain reaction. Results. The analysis yielded a poor correlation between miR-3151 expression level and blast cell count in bone marrow (r = 0.330; p = 0.005) as well as between the expression levels of miR-3151 and BAALC (r = 0.273; p = 0.020). In addition, a great prognostic value of miR-3151 overexpression in post-transplantation period was confirmed (p = 0.005). Patients with miR-3151 and BAALC co-expression in posttransplantation period have also the poorest prognosis than the control group with regard to both disease-free survival and relapse risks within 2 years after allo-HSCT. Conclusion. Monitoring expression level of miR-3151 and its host gene BAALC in AML patients after receiving allo-HSCT seems to be important not only in AML prognosis but also in therapy efficacy evaluation.

INTRODUCTION:Allogenic transplantation of hemopoetic stem cells (allo-THSC) is one of the most effective treatment methods for Hurler syndrome, aimed at maximal correction of complications related to the genetic disorder. Presence of infection in the recipient is an adverse risk factor, affecting the possibility of starting the conditioning regimen and THSC peforming in general.AIM:To assess the condition of the nasal cavity and paranasal sinuses in Hurler syndrome patients before the allo-THSC, dynamics of these changes after the transplantation taking into account the correction of alpha-L-iduronidase enzyme level with donor blood cells.MATERIAL AND METHODS:From February 2012 to December 2017, In the Raisa Gorbacheva Research Institute of Child Oncology, Hematology and Transplantology of the Pavlov First Saint Petersburg State Medical University, eighteen Hurler syndrome patients (10 girls and 8 boys) received an allo-THSC. Median age at the time of the procedure was 23,5 months (min - 3,4; max - 24,8). Each patient with the shadowing of paranasal sinuses, rhinitis or nasal breathing difficulty received a standard rhinosinusitis treatment before the transplantation, effect of which was insignificant. Symptoms of rhinitis, condition of pharyngeal tonsil and paranasal sinuses were assessed before and auto the allo-THSC.RESULTS:In the post-allo-THSC, with the correction of alpha-L-iduronidase level each evaluated parameter has improved reliably (p-value < 0,05). Comparative analysis of the condition of the nasal cavity and pharyngeal tonsil before and after THSC was conducted on 14 patients out of 18. Rhinitis symptoms decreased in 9 (64,2%) patients; in 11 patients (78,5%) adenoids size reduced. Comparative analysis of the condition of paranasal sinuses was possible in 12 patients out of 18. Sinuses aeration improved in eight (66,6%) if patients.CONCLUSION:Nasal cavity and paranasal sinuses changes in Hurler syndrome patients before and after allo-THSC is poorly studied. Our experience demonstrates the normalization of nasal cavity, pharyngeal tonsila and paranasal sinuses symptoms in the majority of the patients receiving allo-THSC. These symptoms are, it seems a consequence of the underlying disease.

Background & Aims. The present retrospective single-center study analysed the impact of high-dose chemotherapy with melphalan with subsequent autologous hematopoietic stem cell transplantation (auto-HSCT) on survival in multiple myeloma (MM) in the era of new induction regimens. Materials & Methods. The clinical trial included 133 MM patients aged from 31.2 to 78.2 years (the median age was 55.3 years). There were 66 female and 67 male patients. Bortezomib-based regimens as first-line treatment were administered in 133 MM patients, 74 of them received high-dose chemotherapy with melphalan and either single (n = 25), or double (n = 49) auto-HSCT as consolidation therapy in the period from 2006 to 2016. Results. The overall 5-year survival (OS) rates were 86.5 % for the auto-HSCT treated group vs. 72.9 % for the non-auto-HSCT treated group (p = 0.03); 5-year progression-free survival (PFS) rates were 64.9 vs. 39 % for the auto-HSCT and non-auto-HSCT treated groups, respectively (p = 0.0016). MM relapse/progression occurred more frequently in the non-auto-HSCT treated patients (52.5 vs. 28.4 %; p = 0.0016). In multivariate analysis the age above 60 was determined as prognostic factor of lower PFS and increase in relapse/progression rate (p = 0.004 and p = 0.04, respectively). The variant of monoclonal protein (Bence-Jones myeloma) was determined as prognostic factor of higher OS and decrease in relapse/progression rate (p = 0.02 and p = 0.04, respectively). Complete nonresponsiveness to induction therapy has proved to be an independent predictor of both poor OS and PFS (p = 0.04 and p = 0.041, respectively). 2-year bortezomib-based maintenance therapy following the auto-HSCT treatment resulted in a statistically significant improvement in 5-year PFS (67.4 vs. 60.7 %; p = 0.03) and a decrease in relapse/progression frequency (26.1 vs. 32.1 %; p = 0.05). Conclusion. High-dose chemotherapy with melphalan with subsequent auto-HSCT is an effective MM treatment strategy, and a subsequent long-term maintenance therapy results in a PFS improvement and a decrease in relapse/progression frequency.

Aim. To estimate the efficacy of chemotherapy in acute leukemia patients resistant to previous standard treatment according to the series measurement of WT1 expression. Materials & Methods. The series measurement of WT1 expression formed the basis of the efficacy estimation of induction chemotherapy in 31 patients (15 men and 16 women aged from 3 months to 68 years; the median age was 28 years) with prognostically unfavourable variants of acute myeloid (AML) and lymphoblastic leukemia (ALL) (23 AML and 8 ALL patients). The WT1 gene expression was measured at baseline and 2-3 weeks after the treatment by the quantitative real-time PCR. The threshold level for detection was 250 copies of WT1/104 copies of ABL. The cytogenetic profile of leukemia cells was assessed by standard cytogenetics and FISH. Results. The baseline expression level of WT1 varied from 305 to 58,569 copies/104 copies of ABL. The expected reduction of WT1 expression after the first induction chemotherapy treatment was reported in 22/23 (96 %) AML patients and in 6/8 (75 %) ALL patients. According to our results WT1 expression reached the threshold in 13/31 (42 %) patients, including 9 AML patients and 4 ALL patients. After 11/31 (35 %) patients received the second course of treatment, WT1 expression level became normal in 8 cases (5 ALL and 3 AML patients). Despite high dose chemotherapy, HSCT and such agents as blinatumomab and gemtuzumab, an unfavourable outcome was observed in 18/31 (58 %) patients including 6 patients with complex karyotype (CK+) and 2 patients with monosomal karyotype (MK+). Once the MK+ and CK+ combination was observed, in another case the MK+ was combined with the prognostically unfavourable inv(3)(q21q26) inversion. Conclusion. Our results show that the molecular monitoring should be included as part of treatment of the prognostically unfavourable acute leukemia. The WT1 gene was shown to be the most appropriate marker. WT1 expression was shown to correlate with the common fusion genes allowing to estimate the blast cell count at the molecular level.

Aim. To demonstrate diagnostic and prognostic significance of series measurement of WT1 expression in patients with acute myeloid leukemia (AML) after allogenic hematopoietic stem cell transplantation (allo-HSCT). Materials & Methods. The clinical trial included 88 AML patients (38 females (43 %) and 50 males (57 %) aged 2-68, median 30 years). All the patients received allo-HSCT. Bone marrow was aspirated before (D0) and after HSCT (D+30, D+60, and D+100). Results. The univariate analysis showed statistically significant differences in 2-year overall survival with respect to the following factors: with and without remission at the moment of HSCT (p < 0.001), with and without chronic graft vs. host disease (cGVHD) (p = 0.002), primary or secondary (MDS) AML (p = 0.028), WT1 gene expression < and > 250 copies before HSCT (p < 0.001) and at time points D+60 (p = 0.012), and D+100 (p < 0.001). Multivariate analysis revealed similar statistical significance of differences among patients transplanted in remission (p = 0.041) and with cGVHD (p = 0.03). In univariate analysis statistically significant differences in 2-year event-free survival (EFS) were found: a) in patients with allo-HSCT, either in remission or not (p < 0.001); b) using HSC, but not bone marrow, as transplant source (p < 0.026); c) with normal or high WT1 expression at the stage of HSCT (p < 0.001) and at time point D+100 (p < 0.001); d) using HSC from related or unrelated donor (p = 0.006); e) in patients with cGVHD (p = 0.05). In multivariate analysis independent positive effect on EFS was observed only in patients with normal WT1 expression at D+100 (p = 0.011) and with cGVHD (p = 0.038). Cumulative incidence of posttransplant relapse (PTR) in AML patients with normal or high WT1 expression at the stage of HSCT within the 2-year follow-up was significantly different (28.2 vs. 58.9 %; p = 0.002), also in measurements of this parameter at D+60 and D+100 (p = 0.015 and p < 0.001, respectively). In 1/4 of patients cytological relapses (cPTR) appeared considerably later than molecular relapses (mPTR), i.e. 13-489 days later (median 35 days), which is accounted for by early preventive therapy aimed at cPTR prophylaxis against the background of already recorded mPTR. According to our data, GVHD plays a crucial role in cPTR management. Conclusion. Phenomenon of WT1 expression normalization after allo-HSCT in AML patients proves to have a high diagnostic and prognostic significance. Introduction of this approach into clinical practice seems highly advisable for national oncohematological centers.