Introduction. Over the past 5 years, signifi cant progress has been achieved in the treatment of patients with Ph-negative acute lymphoblastic leukemia (ALL). Treatment results were compared between two protocols of the Russian multicenter studies «ALL-2009» and «ALL-2016», in which multicomponent high-dose consolidation was not used. The principle of continuity of treatment was observed with modifi cation of doses of cytostatic drugs depending on the depth of cytopenia.Aim – to compare the 5-year results of two studies and to determine the factors of unfavorable prognosis in the treatment of patients with ALL.Materials and methods. The studies were performed from April 2009 to April 2016 (ALL-2009) and from April 2016 to September 2021 (ALL-2016), and 596 patients were included: 330 in ALL-2009 and 266 in ALL-2016. The analysis was performed in March 2022. The median age of patients in ALL-2009 was 28 years (15–55), in ALL-2016 – 32.5 years (18–55). Cytogenetic studies were performed in 242 patients in ALL-2009 (73.3 %) and 236 patients in ALL-2016 (88.7 %). Patients in the ALL-2016 protocol underwent a centralized assessment of minimal residual disease (MRD) by fl ow cytometry on protocol +70 day (after completion of two induction phases), +133 and +190 days. Transplantation of allogeneic stem hematopoietic cells was performed in 7 % of patients in ALL-2009 and in 9 % in ALL-2016.Results. Overall, relapse-free survival (OS, RFS) and the probability of relapse for a period of 3 years from the moment of inclusion of patients in a particular study were 59 %, 63 % and 23 % for ALL-2009, and for ALL-2016 – 64 %, 59 % and 22 %, respectively. For patients with B-cell precursor ALL, two cytogenetic risk groups were formed, in which long-term survival rates differed signifi cantly: the standard group (hyperploid set of chromosomes and normal karyotype) – OS 63 %, RFS 70 %, and high cytogenetic risk (any abnormal karyotype, except for hyperploidy) – OS 49 %, RFS 52 % (р = 0.001, р = 0.0014). In T-ALL, cytogenetic markers had no prognostic value, but the immunophenotype of early T-cell precursor turned out to be an important predictor of poor prognosis (the probability of relapse was 52 % compared with 15 % for all other immunophenotypic variants). According to the results of centralized monitoring of MRD, it was determined that for B-cell precursor ALL, the signifi cant negative factors are the high cytogenetic risk group and positive MRD status at +70 day, and for T-cells, the early immunophenotype and positive MRD status at +133 day.

Background. 6-mercaptopurine (6-MP) is a drug that is included in the treatment protocols for children and adults with acute lymphoblastic leukemias/lymphomas (ALL/LBL). It is known that individual differences in 6-MP tolerance can be explained by the TPMT and NUDT15 polymorphisms.Aim. To determine 6-MP toxicity profile in adult patients with Ph-negative ALL/LBL treated by ALL-2016 protocol, depending on the TPMT and NUDT15 polymorphisms.Materials and methods. The study included 54 adult patients with Ph-negative ALL/LBL (40 male and 14 female). The median age was 31 (18-51) years. T-ALL/LBL was diagnosed in 29 patients, B-ALL/LBL - in 22, acute leukemia with a mixed immunophenotype - in 3. All patients received treatment according to the multicenter study ALL-2016 (ClinicalTrials.gov, NCT03462095). polymorphisms in NUDT15 (*2, *3) and TPMT (*2, *3A, *3B, *3C) genes were detected using the allele-specific real-time polymerase chain reaction. Genomic DNA was extracted from patients peripheral blood samples. On the induction and consolidation therapy by the protocol, the received and proper 6-MP doses were calculated for all the patients. Drug toxicity was evaluated based on clinical and laboratory data.Results. TPMT and NUDT15 polymorphisms were detected in 11 (20 %) patients, more often in B-ALL - 7 (32 %) of 22 (p <0.05). A lower dose of 6-MP was received by patients with TPMT, NUDT15 polymorphisms only at consolidation IV (p = 0.01). we didn't find a correlation between the 6-MP toxicity and the polymorphisms in our patients (p >0.05).Conclusion. There were no differences in the received dose of 6-MP and the incidence of toxicity in adult patients between Ph-negative ALL/LBL with or without TPMT and NUDT15 polymorphisms treated according to ALL-2016 protocol (p >0.05). further studies including evaluation of 6-MP metabolites concentrations are required for a more complete understanding of the metabolism of this drug.

За последнее десятилетие были достигнуты значимые успехи в лечении острых Т-лимфобластных лейкозов (Т-Олл) и Т-лимфобластных лимфом (Т-лБл), в том числе за счет выполнения трансплантации гемопоэтических стволовых клеток (ТГСК). На основании анализа полученных данных российского многоцентрового исследования Олл-2009 (ClinicalTrials.gov NCT01193933) было показано, что выполнение аутологичной ТГСК (ауто-ТГСК) у больных Т-Олл/лБл улучшает долгосрочные результаты лечения. Однако исследование было нерандомизированным и необходимость выполнения ауто-ТГСК в клинической практике требует дальнейшего изучения. Цель исследования -оценка значения ауто-ТГСК у больных Т-Олл / лБл в рамках многоцентрового проспективного рандомизированного исследования Олл-2016 (ClinicalTrials.gov NCT03462095). Материалы и методы. В исследование были включены 109 взрослых больных Т-Олл / лБл (соотношение мужчин и женщин 82:27). Медиана возраста составила 31 (18-52) год. Диагноз Т-Олл был установлен у 88 (81 %) больных, Т-лБл -у 21 (19 %). лечение всем больным проводили по протоколу Олл-2016. С помощью веб-платформы по завершению индукционной терапии (+70-й день) все больные Т-Олл / лБл, которые достигли клинико-гематологическую ремиссию заболевания, были рандомизированы на ветвь ауто-ТГСК или проведение только химиотерапии (хТ). Централизованный мониторинг минимальной остаточной болезни (МОБ) в образцах костного мозга выполняли методом многоцветной проточной цитометрии в контрольные точки исследования по протоколу Олл-2016. Статистический анализ проводили с использованием SAS 9.4. Результаты. Рандомизированы 87 больных Т-Олл / лБл: на ветвь ауто-ТГСК (n = 44) и ветвь хТ (n = 43). В дальнейший анализ были включены 25 больных, которым выполнена ауто-ТГСК, и 36 больных, получающих только хТ. Трехлетняя безрецидивная выживаемость при Т-Олл составила 62 % (ауто-ТГСК) против 81 % (хТ) (p = 0,3422), при Т-лБл -67 % (ауто-ТГСК) против 79 % (хТ) (p = 0,59). персистенция МОБ на +70-й день терапии по протоколу Олл-2016 была выявлена у 40 % (ауто-ТГСК) и у 67 % (хТ) больных (p = 0,057). при многофакторном анализе было определено, что Т-Олл из ранних Т-клеточных предшественников (ETp) и МОБ-положительный статус после окончания II фазы индукции являются основными факторами риска рецидива при лечении по протоколу Олл-2016.

Introduction. There are several forms of the L-asparaginase which are characterized by differences in the half-life, the spectrum of toxicity as well as other factors.Aim — to determine the incidence of different types of L-asparaginase toxicity in adult patients with Ph-negative acute lymphoblastic leukemia (ALL) treated according to the ALL-2016 protocol.Materials and methods. From December 2016 to February 2023 the multicenter prospective randomized study “ALL-2016” included 313 patients with newly diagnosed Ph-negative ALL. Information about the 256 patients who had toxicity of native L-asparaginase was entered into an electronic database. The ratio of men and women was 155:101. The median age was 32  (18–54) years. We analyzed 1253  courses of therapy that included the administration of L-asparaginase.Results. L-asparaginase toxicity and adverse reactions were diagnosed in 67 (26 %) of 256 patients. Of the 1253 courses, 102 (8 %) had complications associated with the administration of this drug. Grade 1–2 toxicity of L-asparaginase was diagnosed in 34 (51 %) patients: allergic reaction — in 6 (18 %), thrombosis of brachiocephalic veins associated with the installation of a central venous catheter — in 2 (6 %), increased pancreatic amylase in blood serum and diastase in urine, without clinical signs of pancreatitis — in 3 (9 %), lower protein-synthesis function of liver — in 23 (68 %), hepatotoxicity — in 15 (44 %). Grade 3–4 toxicity of L-asparaginase was diagnosed in 33 (49 %) patients, of which 22 (67 %) required discontinuation of the drug. The median of the development of complications of L-asparaginase was the third administration. None of the patients died as the result of the toxicity of native form of the drug. The 5-year overall survival (OS) and the probability of relapse (PR) in the group of patients in which L-asparaginase was discontinued at the stage of induction of remission and in the group of patients who continued L-asparaginase treatment at remission consolidation and maintenance therapy did not differ significantly: OS — 89 % vs 70 % (p = 0.0921), PR — 47 % vs 33 % (р = 0.8633).Conclusion. In adult patients, L-asparaginase withdrawal due to toxicity, in most cases, occurs at the stage of the remission induction. It is possible that the replacement of the native form the drug to the pegylated one in adult patients with ALL, in whom L-asparaginase is canceled at the stage of remission induction, improves long-term survival rates.