Introduction. Down syndrome (DS) is one of the most common chromosomal abnormalities. Children with DS have an increased risk of developing acute lymphoblastic leukemia (ALL). Standard therapy is usually used to treat ALL in children with Down syndrome, but the outcome is worse than in the general population. The high toxicity of therapy is a particular problem.The purpose of the study – in this study we presents a comparative analysis of the results of therapy for children with DS and ALL (DS-ALL) who received therapy according to the ALL-MB 2008 and ALL-MB 2015 protocols.Materials and methods. The analysis included primary ALL patients, aged 1 to 18 years, who received therapy in Russian and Belarusian clinics participating in the Moscow–Berlin study from January 2008 to December 2020. To analyze the treatment results of DS-ALL patients, a “comparison group” was formed from all patients with ALL registered in the database, using the matched-pair method. Survival was calculated using the Kaplan–Meier method, toxicity analysis and clinical-genetic parameters were investigated using nonparametric statistical methods.Results. The results of therapy both among patients with DS-ALL who received therapy according to ALL-MB 2008 and ALL-MB 2015 in comparison with “sporadic” ALL (non-DS-ALL) are unsatisfactory. The event-free survival rate of patients with DS-ALL in the ALL-MB 2008 group was 61 ± 7 % versus 85 ± 4 % among non-DS-ALL (p = 0.001), in the ALL-MB 2015 group – 67 ± 7 % versus 84 ± 4 % respectively. Overall survival in the ALL-MB 2008 group was 70 ± 7 % in children with DS versus 88 ± 4 % in non-DS (p < 0.001), in the ALL-MB 2015 group – 78 ± 6 % versus 92 ± 3 % respectively (p < 0.001). The risk of therapy-related death was higher in patients with DS: 20.6 ± 6.1 % versus 4.6 ± 2.2 %; p < 0.001 in the ALL-MB 2008 group and 18 ± 4.1 % versus 3.3 ± 1.3 %; p < 0.001 in the ALL-MB 2015 group, without a significant increase in the risk of relapse. The effectiveness of induction therapy among patients with DS treated according to ALL-MB 2008 versus children with DS-ALL treated according to ALL-MB 2015 was 80 % versus 92 % respectively (p = 0.018). The probability of achieving continuous complete remission was also lower in the ALL-MB 2008 group compared to ALL-MB 2015 – 57 % versus 75 %; p < 0.001 respectively. Thus, the results of treatment of DS-ALL according to the ALL-MB 2015 protocol were better than those according to the ALL-MB 2008.Conclusion. The results of therapy for patients with DS-ALL are still unsatisfactory today, this circumstance dictates the need for new approaches to optimize therapy. The main problem for these patients remains the high toxicity of therapy and the associated lethality. Further progress in the treatment of DS-ALL may be associated with the development of new approaches to concomitant therapy, the use of molecular-targeted drugs and immunotherapy, as well as with the study of the molecular genetic characteristics of this subgroup of patients.

Проанализирована значимость прогностических факторов эффективности терапии у детей с острым лимфобластным лейкозом (ОЛЛ), получающих терапию по протоколу ALL-MB-2002, в зависимости от группы риска. В исследование были включены 1544 первичных больных ОЛЛ в возрасте от 1 года до 18 лет, получавших лечение в 36 клиниках России и Беларуси в период с 15 апреля 2002 г. до 1 января 2008 г. Из 1544 больных, включенных в анализ, пациенты группы стандартного риска (SRG) составили 69,2 %, промежуточного риска (ImRG) — 24,5 % и 6,3 % пациентов были отнесены к группе высокого риска. Анализ, проведенный у пациентов SRG, продемонстрировал резкие различия в выживаемости между отдельными подгруппами больных. Выявлены достоверные различия в показателях выживаемости пациентов в зависимости от возраста (старше и младше 10 лет), инициального лейкоцитоза (более и менее 30 × 10 9 /л), инициального пальпаторного увеличения селезенки (более и менее 4 см из-под края реберной дуги) и параметров раннего ответа на терапию (8-й и 15-й день). При ретроспективном определении больных, относящихся к SRG, с использованием новых критериев (инициальный лейкоцитоз <30 × 10 9 /л; селезенка < 4 см), прогностическая значимость раннего ответа на терапию нивелировалась. Среди пациентов ImRG не обнаружено никаких достоверных различий в показателях бессобытийной, общей и безрецидивной выживаемости и риске развития изолированных нейрорецидивов в зависимости от инициального иммунофенотипа бластных клеток (Т-ОЛЛ/не-Т-ОЛЛ). Шестилетний кумулятивный риск развития изолированных нейрорецидивов не различался у пациентов с Т- и не-Т-ОЛЛ, однако был выше у больных с инициальным лейкоцитозом ≥ 100 × 10 9 /л независимо от иммунофенотипа. Наихудшие показатели выживаемости отмечены у пациентов с не-Т-ОЛЛ и количеством лейкоцитов ≥ 100 × 10 9 /л — бессобытийная выживаемость в этой подгруппе составила всего 58 ± 7 %. При проведении многофакторного анализа выявлено, что для пациентов с Т-ОЛЛ независимое прогностическое влияние на выживаемость оказывает только величина инициального лейкоцитоза (р = 0,0333), тогда как для больных не-Т-ОЛЛ независимое значение имеют возраст (р = 0,0063), инициальный лейкоцитоз (р = 0,0066) и наличие поражения центральной нервной системы (р = 0,0112).Перенести в английский вариант Prognostic significance of different risk factors in children with acute lymphoblastic leukemia (ALL) treating according to ALL-MB 2002 protocol depending on risk group is analyzed. 1544 primary patients aged from 1 to 18 years, treating in 36 clinics of Russia and Belarus from April, 15 th , 2002 to January, 1th, 2008, was included in the study. From 1544 patients included, 69.2% were standard risk group (SRG), 24.5 % — intermediate risk group (ImRG) and 6.3% — high risk group. The expressed differences in survival rate between certain patient’s subgroups were revealed. Significant survival differences according to age (older and younger 10 years), initial leukocyte count (more and less than 30 × 10 9 /l), spleen size (more and less 4 cm below a costal arch at a palpation) and early therapy response (8th and 15th days of induction) are revealed. At retrospective definition of SRG patients with use of new criteria (initial leukocytosis < 30 × 10 9 /l and spleen size <4 cm), prognostic significance of therapy response was leveled in this subgroup of patients. Among ImRG patients any significant differences in EFS, OS, RFS and cumulative risk of isolated CNS (CIR IN ) relapse according to blast cells immunophenotype (T-ALL/non-T-ALL) were not shown. 6-years CIRIN was not different between patients with T-ALL and non-T-ALL, however was high in patients with initial leukocyte count ≥ 100 × 10 9 /l irrespective to immunophenotype. The worst survival appeared in patients with non-T-ALL and leukocyte count ≥100 × 10 9 /l — EFS in this subgroup was only 58±7%. Only initial leukocytosis had prognostic significance for patients with T-ALL (р=0.0333), whereas age (р = 0.0063), initial leukocytosis (р = 0.0066) and CNS involvement (р = 0.0112) as independent prognostic factors for patients with non-T-ALL in multifactorial analysis was revealed.

MLL-negative (mixed lineage leukemia – MLL) acute lymphoblastic leukemia (ALL) diagnosed in the first year of life is rare. Although infant ALL is often assumed to be fatal, no studies have been published on outcome of MLL-negative infant ALL. The present study reports the clinical characteristics and outcome of 60 patients with MLL-negative infant ALL treated with the series of Moscow-Berlin (MB) protocols, a regimen with reduced chemotherapy. MLL-negative ALL by infants with age < 6 months at the diagnosis was characterized by a higher white blood cell count, splenomegaly and prevalence of girls compared with older infants. Induction failure rate was 3.4 % for the whole group of patients and was not significantly different between infants with less or more 6 month old. EFS and OS for the whole group of patients were 62 ± 7 % and 59 ± 7 % with relapse rate of 28.7 %. But relapse rate was significantly higher in MLL-negative infant ALL patients with age < 6 month compared of that of pts with age  6 month (cumulative incidence was 60.7 ± 16.5 % vs 19.1 ± 6.7 %, p < 0.005). EFS and OS of MLL-negative infant ALL patients were significantly worse compared of that for the old infants (10 ± 9% vs 79 ± 7 % for EFS). The treatment according new MB regimens significantly improve the outcomes for the whole group and also for children with < 6 months age at the diagnosis.

One of the main risk-factors of acute lymphoblastic leukemia (ALL) is age. The most favorable age group is children from 2 to 9 years old, and the adolescents and young adults have the worst prognosis. Treatment of ALL at adolescents and young adults is a unique problem of modern hematology now. This work presents the analysis of 368 cases of patients with primary ALL 15–18 years old, which were registered in the database of Russian-Belarussian group from April 2002 to November 2014. The aim of the analysis was the estimation of effectiveness of different generations of protocol for adolescents and prognostic significance of different factors to reveal the ways of future therapy optimizing in this age group. Event-free survival of adolescents 15–18 years old according our study was 56 ± 5 % in ALL-MB-2002 study and 57 ± 6 % in ALL-MB-2008 study. We did not received any differences in survival based on immunophenotype of blast cells. But the risk group analysis showed the worst results at patients with ALL from pre-B-precursor cells of high risk. No difference was revealed according the gender. One of the general problems remains high toxicity of therapy at patients of this age group. Treatment related mortality (TRM) was 13.2 and 12 % at ALL-MB-2002 and ALL-MB-2008 accordingly. Main cause of deaths remains infection.

AIMTo determine predictors for decision-making on a differential approach to choosing glucocorticosteroids (GCS) for children and adolescents with acute lymphoblastic leukemia (ALL).SUBJECTS AND METHODSThe analysis covered 1064 primary patients aged to 1 to 18 years with ALL who had been registered at the clinics of Russia and Belorussia in April 2002 to November 2006. Before induction therapy, the patients were randomized into a dexamethasone (DEXA) 6 mg/m2 group (n=539) and a methylprednisolone (MePRED) 60 mg/m2 one (n=525).RESULTSThe entire group showed no statistically significant differences in survival rates between the patients receiving DEXA or MePRED. However, an analysis of age groups revealed the benefits of DEXA in children younger than 14 years (the event-free survival (EFS) was 76±2 and 71±2%, respectively (p=0.048); the overall survival (OS) was 81±2 and 77±2%, respectively (p=0.046); therapy-induced mortality was 6.4% (DEXA) andl 1.1% (MePRED) (p=0.01 4); the rate of isolated extramedullary relapses was 1.5% (DEXA) and 4.4% (MePRED) (p=0.009). At the same time, EFS and OS in 14-to-18-year-old adolescents were statistically significantly higher than in those who used MePRED (EFS, 65±6 and 52±6%, respectively (p=0.087); OS, 72±6 and 61±6%, respectively; (p=0.l 7).CONCLUSIONThe findings suggest that it is possible that the choice of a GCS for ALL therapy must be also based on a patient's age. There is a need for further studies of this matter in prospective randomized multicenter trials in children and adolescents.

T-cell acute lymphoblastic leukemia (T-ALL) is a tumor developing as a result of malignant transformation of precursor T-cells. Despite the fact that T-ALL is responsible for about 10-15% of all ALL cases in children, it is essential to separate T-ALL in a special subgroup, as a nosological entity by the tumor biology, poor clinical outcome and resistance to therapy. We analyze the results of treatment of 644 patients with T-ALL, registered in the data base of the Russian-Byelorussian Research Group over 24 years of its work. The initial characteristics of the patients, responses to therapy, prognostic factors, and efficacy of various therapeutic options are analyzed.

AIMTo evaluate the efficiency of the original ALL-MB-2002 protocol within the multicenter study of treatment of acute lymphoblastic leukemia (ALL) in children.SUBJECTS AND METHODSA total of 1873 primary patients with ALL aged 1 to 18 years, of whom 1544 patients were enrolled in this study, were notified at 36 clinics of Russia and Belarus from April 15, 2002, to January 1, 2008.RESULTSWith the median observation of 4.12 years, 7-year event-free survival (EFS) was 73 +/- 13%; overall survival (OS) 78 +/- 2%; relapse-free survival 82 +/- 1%. The rates of EFS and OS were equal and amounted to 76 +/- 2 and 80 +/- 2% in the standard-risk group (SRG) and intermediate-risk group (ImRG), respectively. In the high-risk group (HRG) patients, EFS and OS were as high as 30 +/- 6 and 37 +/- 6%, respectively. The frequency of relapses with central nervous system lesion was as much as 4.7% in all the patients, 6-year cumulative risk for isolated neurorecurrences being 2.5% in the SRG patients. Adolescents, patients with the baseline leukocytosis (more than 100 x 10(9)/l), and those with a splenic size of over 4 cm or more from the costal arch margin had substantially worse survival rates. A poor early response to therapy (on induction days 8 and 15) was also associated with its lower efficiency.CONCLUSIONDespite a considerable rise in the number of centers and a slight increase in the intensity of therapy, the results of the new ALL-MB-2002 protocol are as minimum equivalents obtained in the use of the previous ALL-MB-91 protocol. A significant improvement in the overall results of therapy and a reduction in the cumulative risk for isolated neurorecurrences were noted in the ImRG patients.

The aim of this study was to analyze response to therapy in patients receiving additionally PEG-asparaginase at the beginning of the cytoreductive phase and the probability of this induction by the level of attained remission. The analyzed group included 128 hematological patients from hospitals of Moscow and the Moscow region with first-diagnosed acute lymphoblastic leukemia, receiving therapy by ALL-MB-2002 protocol within the framework of randomized multi-center study from April 2005 to December 2006; PEG-asparaginase in a dose of 100 U/m(2) was injected on day 3 of the cytoreductive phase of therapy. Patients of the standard risk group received rubomicin only if they had at least 10% blast cells in the bone marrow on day 15 of therapy. Response to therapy was evaluated by the count of blast cells in the bone marrow on days 15 and 36. The retrospective control group consisted of 258 patients who received treatment by the standard ALL-MB-2002 protocol in the same hospitals from April 2002 to April 2005. On day 15 of therapy at least 5% blast cells were present in 15.6% patients injected with PEG-asparaginase during the induction phase and in 35.3% controls (p < 0.0001). On day 15 at least 10% blast cells were present in the myelograms of 11.7% patients from the pilot group and in 21.7% controls (p = 0.0177). Remissions on day 36 were attained in 98.4% patients in the pilot group and 98.1% controls (p = 1.0000). Hence, the level of remissions attained by two variants of induction therapy was virtually the same in the two groups, but early response to therapy, one of prognostic signs, was significantly better in patients who received PEG-asparaginase during the cytoreductive phase of induction therapy.