Актуальность. В арсенал стандартного и эффективного лечения волосатоклеточного лейкоза (ВКЛ) входят аналоги пурина, интерферон-α (ИФН-α) и спленэктомия. Особой клинической проблемой остаются первично-резистентное течение ВКЛ и ранние рецидивы (в течение 2–3 лет после достижения ремиссии). Миелотоксичность кладрибина, медленная реализация эффекта ИФН-α делают невозможным применение этих препаратов при глубокой нейтропении/агранулоцитозе (особенно при наличии инфекционных осложнений), а также у пациентов с аллергическими реакциями/непереносимостью ИФН-α. Цель. Представить собственный опыт применения ингибитора B-RAF-киназы вемурафениба при ВКЛ с мутацией BRAFV600E у пациентов с резистентным течением болезни и наличием противопоказаний к стандартной терапии. Материалы и методы. В исследование включено 39 больных ВКЛ в возрасте 24–78 лет (медиана 55 лет). Женщин было 13, мужчин — 26. ВКЛ устанавливали в соответствии с рекомендациями ВОЗ 2017 г. Вемурафениб применяли в дозе 240 мг 1–2 раза в сутки в течение 3 мес. Анализу подвергнуты три группы пациентов: с ранними рецидивами и резистентным течением ВКЛ (n = 7), с глубокой нейтропенией/агранулоцитозом (с наличием инфекционных осложнений и без таковых, n = 29), с непереносимостью ИФН-α (n = 3). Результаты. У 6 (86 %) из 7 пациентов 1-й группы (с ранними рецидивами и резистентным течением ВКЛ) проведен полный курс терапии, включавшей вемурафениб с последующей стандартной химиотерапией кладрибином и далее с введением ритуксимаба с целью консолидации. Полная ремиссия достигнута у 5 (71 %) пациентов, частичная — у 1 (14 %). У 7-го пациента эффекта не достигнуто. У 28 (97 %) из 29 пациентов 2-й группы с глубокой нейтропенией/агранулоцитозом получен эффект с восстановлением показателей гемограммы, что позволило в дальнейшем провести базовый курс лечения кладрибином. У 1 пациента вемурафениб оказался неэффективным. У 3 пациентов из 3-й группы с непереносимостью ИФН-α вемурафениб применялся в качестве предшествующего этапа перед проведением курса кладрибина. После терапии кладрибином у 2 (67 %) пациентов достигнута полная ремиссия, у 1 (33 %) — частичная. Заключение. При ВКЛ с мутацией BRAFV600E вемурафениб в малых дозах может быть эффективным у пациентов с рецидивами и резистентным течением болезни, а также в период глубокой нейтропении с угрожающими жизни инфекционными осложнениями. Кроме того, вемурафениб используется при непереносимости ИФН-α в качестве предшествующего этапа лечения ВКЛ с мутацией BRAFV600E перед проведением базового курса кладрибина.

Introduction . Thanks to scientific advances and discoveries in the study of tumor cell biology, new effective drugs for the treatment of chronic lymphocytic leukemia/ small lymphocytic lymphoma have emerged. Currently, there are drugs with different application points at the molecular level. One such drug is acalabrutinib, which is a selective second-generation inhibitors of Bruton tyrosine kinase and has a more favorable toxicity profile. Objective . To evaluate the efficacy of acalabrutinib in patients with chronic lymphocytic leukemia/small lymphocytic lymphoma. Materials and methods . Since February 2020 acalabrutinib (100 mg 2 p/day orally) has been administered to 7 patients with chronic lymphocytic leukemia/small lymphocytic lymphoma (mean age 64 years) at the Hematology Research Center. Six patients received acalabrutinib in 1st-line therapy and one patient received acalabrutinib in 2nd-line therapy. The mean comorbidity index (CIRS) of the patients was 10 points (range, 8 to 14). Most patients had at least one of the adverse prognostic factors - IGHV nonmutated gene status, TP53 gene aberration (del17p13 and/or TP53 gene mutation), complex karyotype disorders. Results . All patients achieved partial remission of the disease (overall response 100% in the form of regression of B-symptoms, lymphocytic leukocytosis, splenomegaly) at the control period of treatment with acalabrutinib +12 months. The most frequent adverse events when taking acalabrutinib were the occurrence of headache in the first month of taking the drug, spontaneous subcutaneous hematomas. No hematologic toxicity, infectious complications, or cardiac complications were noted. At a median follow-up of 34 months, no patient showed disease progression. Conclusions . The selective Bruton tyrosine kinase inhibitor acalabrutinib has demonstrated high efficacy in patients with adverse risk factors, good tolerability and minimal toxicity, including in comorbid patients.

Background. The standard and effective treatment of hairy cell leukemia (HCL) involves purine analogs, interferon-а (IFN-а) administration, and splenectomy. However, primary resistant HCL and early relapses (within 2-3 years after achieving remission) remain clinical challenges. Due to myelotoxicity of cladribine and slow effect of IFN-а, these drugs can be administered neither in deep neutropenia/agranulocytosis patients (especially in case of infectious complications) nor in patients with IFN-а allergy/intolerance. Aim. To report clinical experience with vemurafenib, a B-RAF inhibitor, in HCL with BRAFV600E mutation in treatment-resistant patients with contraindications to standard therapy. Materials & Methods. The study enrolled 39 HCL patients aged 24-78 years (median 55 years), 13 women and 26 men. HCL was diagnosed in accordance with the WHO 2017 criteria. Vemurafenib 240 mg was administered once or twice a day within 3 months. Three groups of patients were analyzed: those with early relapses and resistant HCL (n = 7), those with deep neutropenia/agranulocytosis (with and without infectious complications, n = 29), and those with IFN-а intolerance (n = 3). Results. In 6 (86 %) out of 7 patients from group 1 (with early relapses and resistant HCL) a complete course of treatment was carried out, which included vemurafenib with subsequent standard cladribine chemotherapy and further consolidation with rituximab. Complete remission was achieved in 5 (71 %) patients, and partial remission was achieved in 1 (14 %) patient. The 7th patient was a non- responder. In 28 (97 %) out of 29 patients from group 2 with deep neutropenia/agranulocytosis, hematologic recovery was reported which allowed for further basic treatment with cladribine. In 1 patient vemurafenib appeared to be ineffective. In 3 patients from group 3 with IFN-а intolerance, vemurafenib administration was used as a stage of treatment preceding cladribine therapy. Cladribine treatment resulted in complete remission in 2 (67 %) patients and partial remission in 1 (33 %) patient. Conclusion. In HCL with BRAFV600E mutation, low-dose vemurafenib can be effective in patients with relapsed/refrac- tory disease as well as deep neutropenia with life-threatening infectious complications. In addition to that, vemurafenib administration can be used in cases of IFN-а intolerance as a stage of treatment of HCL with BRAFV600E mutation which precedes the basic cladribine therapy.

Синдром Казабаха-Мерритт (СКМ) — редкое заболевание, для которого характерно сочетание наличия сосудистой опухоли (гемангиомы) и изменений в лабораторных анализах: глубокая тромбоцитопения, гипофибриногенемия, коагулопатия потребления и повышение уровня D-димера. Диагностика СКМ представляет определенные сложности и основывается не только на выявлении характерных клинико-лабораторных особенностей, но и на результатах гистологического исследования сосудистой опухоли. Нами описаны 2 редких клинических случая выявления симптомокомплекса Казабаха-Мерритт у взрослых пациентов и пути терапевтической стратегии. Анализ проведенного лечения показал, что хирургическое лечение сопряжено с высоким риском и не привело к улучшению лабораторных параметров крови, а применение лекарственной терапии эффективно и безопасно. Kasabach-Merritt syndrome (KMS) is a rare disease characterized by a combination of vascular tumor (hemangioma) and changes in laboratory tests — deep thrombocytopenia, hypofibrinogenemia, consumptive coagulopathy and increased D-dimer level. Diagnostics of KMS presents certain difficulties and based not only on the identification of characteristic clinical and laboratory features, but also on the results of histological examination of a vascular tumor. We report two rare clinical cases of KMS in adult patients and ways of therapeutic strategy. Treatment analysis showed that surgical therapy was highly riskily and did not result in improvement of the laboratory blood parameters, while the use of drug therapy was effective and safe.

Cytopenia commonly occurs in case of chronic lymphocytic leukemia. It can either precede the diagnosis of chronic lymphocytic leukemia or appear at any time during the disease. Autoimmune hemolytic anemia, immune thrombocytopenia, and partial red cell aplasia are most often found among cytopenias in chronic lymphocytic leukemia. At the same time, the development of cytopenia may be associated with the displacement of normal hematopoiesis cells by tumor lymphocytes. It is very important to accurately diagnose and identify the cause of cytopenia in chronic lymphocytic leukemia, since the prognosis and therapy differ significantly.

The aim of the study was to investigate the role of IKZF1 deletions in adult patients with Ph-negative (Ph–) and Ph-positive (Ph+) B-cell acute lymphoblastic leukemia (ALL) who participated in the Russian Acute Lymphoblastic Leukemia (RALL) multicenter study. Our study included 67 patients with newly diagnosed B-cell ALL (49 Ph– and 18 Ph+ cases). Patients with Ph– B-cell ALL were treated according to RALL-2009 and RALL-2016 protocols and were followed up for a median of 18.1 months (range 1.5–93.4 months). Patients with Ph+ B-cell ALL were treated according to RALL- 2009 and RALL-2012 protocols with addition of tyrosine kinase inhibitors and were followed up for a median of 21.2 months (range 3.53–91.77 months). Intragenic deletions of IKZF1 were detected using breakpoint-specific fluorescent multiplex polymerase chain reaction. They were more frequently found in patients with Ph+ ALL (n = 10, 56%) than in patients with Ph– ALL (n = 9, 18%; p = 0.0074). No statistically significant association between IKZF1 deletions and age, sex, initial WCC of over 30 × 109/L, LDH above 750 U/mL, splenomegaly or neuroleukemia was observed. Notably, an expression of both myeloid antigens (MyAg) CD13 and СD33 was detected in almost half (n = 4,44%) of the Ph– ALL patients with IKZF1 deletions compared to only 1 patient (2.5%) without IKZF1 deletions (p = 0.0027). The presence of IKZF1 mutations was associated with persistence of minimal residual disease at 2 and 4 months of treatment, with higher leukemic cell counts; however, there seemed to be no observable differences in the long-term results of therapy regardless of whether or not IKZF1 mutations were present. Thus IKZF1 mutations in our study did not seem to be prognostically valuable for either Ph+ B-cell ALL or Ph– B-cell ALL, although they were shown to be associated with a delayed tumor clearance in patients with Ph– B-cell ALL.

Objective. To evaluate occurrence, variety, structural peculiarities and prognostic meaning of cytogenetic abnormalities in adult patients with Ph-negative acute lymphoblastic leukemia (ALL) receiving therapy according to ALL-2009 protocol. Materials and methods. The study included 115 adult patients with firstly diagnosed Ph-negative ALL: 58 male and 57 female aged from 15 to 61 years (mean age 26.5 years), who underwent treatment from September 2009 to September 2015 in National Medical Research Center for Hematology MH RF (n=101) and in hematology departments of regional hospitals (n=14). All patients received therapy of ALL-2009 protocol (ClinicalTrials.gov, NCT01193933). The median follow-up was 24.5 months (0.2-94.4 months). As a part of the study results of a standard cytogenetic assay (SCA) were analyzed and fluorescence hybridization in situ (FISH) with the use of DNA-probes was performed on archived biological material for structural changes in gene locuses MLL/t(11q23), с-MYC/t(8q24), TP53/ deletion 17p13, CDKN2A/ deletion 9p21, translocation t(1;19)/E2A-PBX1 и t(12;21)/ETV6-RUNX1; iAMP21 identification. Results. Karyotype was defined using SCA in 86% of patients. Normal karyotype was found in 48.5% of them, chromosome aberrations in 51.5% (structural changes were found in 19.2%, hyperploidy in 27.2%, and hypoploidy in 5.1%). In 17.2% of patients complex karyotype abnormalities were found. With the use of FISH technique aberrations were found in 67% of patients: 9p21/CDKN2A deletion in 24.3%, MLL/t(11q23) gene abnormalities in 7.8%, 17p13/TP53 deletion in 5.2%, abnormalities of c-MYC/t(8q24) in 1.7%, t(1;19)/E2A-PBX1 in 0.8%, and iAMP21 in 0.8%, other abnormalities (additional signals/absence of signals from gene locuses) in 26.4%, t(12;21)/ETV6-RUNX1 was not found. FISH technique use in addition to SCA allows to increase aberrant karyotype location from 51.5 to 67%. A statistically significant correlation of 9p21/CDKN2A deletion with high serum lactate dehydrogenase activity (p=0.02); MLL/t(11q23) gene abnormalities - with leucocytosis and high blast cells level in blood (p=0.0016), hyperploidy - with normal leukocyte count (p=0.02) was shown. In groups with different cytogenetic abnormalities no statistically significant differences of treatment with ALL-2009 protocol were found (in terms of complete remission, early mortality and treatment resistance). When connection of cytogenetic abnormalities and their combinations with long-term results were analyzed according to ALL-2009 protocol, only two characteristics - MLL/t(11q23) and c MYC/t(8q24) gene abnormalities had a statistically significant influence on disease-free survival (HR - 176.9; p

The aim of the study was to investigate the role of IKZF1 deletions in adult patients with Ph-negative (Ph-) and Ph-positive (Ph+) B-cell acute lymphoblastic leukemia (ALL) who participated in the Russian Acute Lymphoblastic Leukemia (RALL) multicenter study. Our study included 67 patients with newly diagnosed B-cell ALL (49 Ph- and 18 Ph+ cases). Patients with Ph B-cell ALL were treated according to RALL-2009 and RALL-2016 protocols and were followed up for a median of 18.1 months (range 1.5-93.4 months). Patients with Ph+ B-cell ALL were treated according to RALL-2009 and RALL-2012 protocols with addition of tyrosine kinase inhibitors and were followed up for a median of 21.2 months (range 3.53-91.77 months). Intragenic deletions of IKZFI were detected using breakpoint-specific fluorescent multiplex polymerase chain reaction. They were more frequently found in patients with Ph+ ALL (n = 10, 56%) than in patients with Ph ALL (n = 9, 18%; p = 0.0074). No statistically significant association between IKZF 1 deletions and age, sex, initial WCC of over 30 x 10(9)/L, LDH above 750 U/mL, splenomegaly or neuroleukemia was observed. Notably, an expression of both myeloid antigens (MyAg) CD13 and CD33 was detected in almost half (n = 4,44%) of the Ph ALL patients with IKZFI deletions compared to only 1 patient (2.5%) without IKZF 7 deletions (p = 0.0027). The presence of IKZF1 mutations was associated with persistence of minimal residual disease at 2 and 4 months of treatment, with higher leukemic cell counts; however, there seemed to be no observable differences in the long-term results of therapy regardless of whether or not IKZF1 mutations were present. Thus IKZF1 mutations in our study did not seem to be prognostically valuable for either Ph+B-cell ALL or Ph B-cell ALL, although they were shown to be associated with a delayed tumor clearance in patients with Ph B-cell ALL.

Introduction. CDKN2A deletion is a frequent cytogenetic abnormality in acute lymphoblastic leukemia (ALL), ranging from 18 to 46 %, associating with Т-cell ALL, high WBC counts, splenomegaly, lymphadenopathy. In pediatric group of patient’s CDKN2A deletion was associated with poor event-free survival. The prognostic impact of CDKN2A deletion in adult ALL patients appear controversial.The aim of this study was to evaluate the prognostic impact of the CDKN2A deletion in adult patients with acute lymphoblastic leukemia, which were treated by RALL-2009.Materials and methods. We present the results of the CDKN2A deletion in 110 adult patients with newly diagnosed Ph-negative (Ph‒) ALL, which were treated by RALL-2009 (NCT01193933) since June 2009 till September 2016. Patients characteristics: the median age was 26 years (range 15–54), 65 (59 %) of the 110 patients had a B-precursor phenotype, 42 (38 %) had a T-cell phenotype, 3 (2.7 %) patients – biphenotypical ALL. Interphase fluorescence in situ hybridization (FISH) was performed for detection CDKN2A deletion, MLL, с-MYC rearrangement, TP53 deletion, t (1;19) (q23; p13.3)/TCF3-PBX1, t (12;21) (p13.2; q22.1)/ETV6-RUNX1 and iAMP21. The median follow-up was 31 months (0.5 to 80 months).Results. The prevalence of the CDKN2A deletion in all studied population was 24.3 % (27 cases). Our study demonstrated that CDKN2A deletion had no significant association with age, sex and blast cells immunophenotype. The analysis for T-ALL has detected that CDKN2A deletion was strongly associated with high WBC count (the median is 86 × 109/L; p = 0.006) and with high lactate dehydrogenase level (the median is 3062 IU; p = 0.0004). But in BCP-ALL cases similar correlation was not found. CDKN2A deletion didn’t have statistically significant impact on outcome of patients. OS for patients with BCP-ALL with and without deletion was 85 and 76 % (p = 0.35); DFS was 92 and 65 % (p = 0.07), respectively. OS for T-ALL patients with and without deletion was 90 and 80 % (p = 0.63); DFS was 100 and 82 % (p = 0.24), respectively.Conclusion: CDKN2A deletion is not adverse prognostic factor in adult ALL patients treated according to protocol RALL-2009.

Aim. To analyze the efficiency and reproducibility of the ALL-2009 protocol within the Russian prospective multicenter study based on different principles of cytostatic effects (non-intensive, but continuous cytotoxic treatment and a small number of allogeneic hematopoietic stem cells). Subjects and methods. The ALL-2009 (NCT01193933) study conducted in April 2009 to December 2016 included 194 patients (95 males and 99 females) aged 15 to 55 years (median age 28 years) with Ph-negative B-cell acute lymphoblastic leukemia (ALL). There was early pre-B-cell ALL in 54 patients, common ALL in 101, pre-B ALL in 39, initial leukocytosis in 9.4·109/l (0.4-899.0), lactate dehydrogenase in 901 IU (31-13 059), an initial central nervous system lesion in 17 (8.7%), mediastinal injury in 3 (1.5%), and splenomegaly in 111 (57.2%). The results of standard cytogenetic analysis are known in 113 (60.4%) patients. Normal karyotypes were detected in 49 (54.5%) out of the patients; t(4;11) in 9 (5.4%), t(1;19) in 2 (1.2%), and other karyotypic abnormalities in 53 (46.9%). Thirteen (7.8%) patients underwent allogeneic hematopoietic stem cell transplantation in first complete remission (CR); their proportion did not differ in the federal and regional centers. Results. The frequency of CR achievement was the same in the federal and regional centers and generally amounted to 87.5%. Early (8.8%) and CR (9.6%) mortality rates remained high despite the low aggressiveness of cytotoxic action, necessitating the improvement of auxiliary treatment. The five-year overall survival (OS) rates vary considerably in the federal and regional centers (72.6 and 43.8%), the relapse-free survival (RFS) (70.2 and 53.4%) and recurrence risk (23.1 and 36.5%) are comparable. This suggests that the non-intensive, but continuous exposure principle built in the ALL-2009 protocol makes it possible to reproduce the envisaged treatment program and to achieve satisfactory results. Conclusion. The ALL-2009 protocol allows both the federal and regional centers to obtain the long-term results comparable with those of current foreign studies: OS (54.2%), RFS (56.5%); and relapse risk (35.4%). Multivariate analysis has identified age (over 30 years), initial leukocytosis (30·109/l and more) and t(4;11) among the main clinical prognostic factors. Gene mutation detection evaluated in a small number of patients (8/36) is not a poor prognostic sign. There is a need for further investigations with centralized evaluation of the mutation status of leukemic cells and the clearance of minimal residual disease.