This paper presents the results for the patients with acute lymphoblastic leukemia (ALL) from the high-risk group (HRG) treated according to the ALL-MB 2002 Protocol. The registration phase of the study was performed from 15.04.2002 to 01.01.2008. The study was approved by the Independent Ethics Committee and the Scientific Council of the Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology of Ministry of Healthcare of the Russian Federation. The study involved 36 departments (centers) of pediatric hematology/oncology in Russia and Belarus. One hundred and ten primary patients with ALL aged 1 to 18 years who met the criteria for high risk group, were analyzed: 29 patients with t(9;22), 11 patients with t(4;11), and 70 patients without stratifying genetic abnormalities who did not achieve remission by day 36 of induction therapy (16 patients from the standard risk group and 54 patients from the intermediate risk group, at initial). Median follow-up was 10.75 (8.6–13.8) years. First remission (CR1) was achieved in 80.9% of patients. 37.27% of patients relapsed, 51.22% of relapses were very early. The proportion of isolated bone marrow relapse was 73%, while isolated central nervous system relapses were observed in 4.55% of the cases. None of the patients developed a secondary tumor, 5.45% of patients were lost from follow-up. Only 15.7% of patients with CR1 received allogeneic hematopoietic stem cell transplantation. Only half of the patients with Ph-positive ALL received treatment with tyrosine kinase inhibitors. In total, 26.36% of patients remain in CR1. Overall and event-free survival were 32.9 ± 4.6% and 31.5 ± 4.5%, respectively. The cumulative risks of relapses and treatment-related mortality were 37.6 ± 4.3% and 20.9 ± 3.8%, respectively. There were no significant difference in the initial parameters and responses to therapy between the subgroups of patients. Overall and event-free survival were the highest in patients with ALL with t(4;11): 54.5 ± 15% and 45.5 ± 15%, respectively. The lowest overall and event-free survival were observed in the subgroup of patients without stratifying anomalies who did not achieve remission on day 36: 29.1 ± 5.6% and 27.1 ± 5.3%, respectively. The cumulative risk of relapse was the highest in patients who did not respond to induction therapy (42.9 ± 5.2%). The cumulative risk of treatment-related mortality was the highest in patients with Ph-positive ALL (31.0 ± 8.6%). The 5-year overall survival of patients with ALL relapse after high-risk therapy was extremely low – 7.7% (95% confidence interval 0–16.1), median overall survival after relapse in this group was only 187 days. This indicates that the options for second-line therapy of high-risk patients were severely limited at the time of ALL-MB 2002 study, because they included only chemotherapeutic strategies.

The paper presents the results of a multicenter randomized study of two-dose COLI-ASP regimens in therapy of consolidation of standard risk-group (SRG) children and adolescents with acute lymphoblastic leukemia (ALL) treated by the ALL-MB-2002 protocol. The principal aim of the study was to elucidate whether the dose of COLI-ASP might be reduced without losing the efficiency of therapy. The analysis covered primary ALL patients notified at 36 clinics of Russia and Belarus, enrolled for the study in the period of May 1, 2002, to October 10, 2006. Out of 819 patients to be examined, 414 received COLI-ASP in a dose of 10,000 U/m2 (a control group), and 405 children took it in a dose of 5,000 U/m2 (a study group). No statistically significant differences were found between the patients in gender, age, baseline leukocytosis, and spleen size. The study showed no statistically and clinically significant differences in event-free, overall, and relapse-free survival (EFS, OS, and RFS, respectively) and relapse rates with the use of two-dose COLI-ASP regimens. However, in the control group, the death rate in remission was twice greater than that in the study group (p = 0.02). Detailed analysis of the outcomes of therapy in some subgroups revealed no differences between the control and study groups. The Cox multiple regression analysis has indicated that the factors influencing EFS and RFS are the baseline sizes of the spleen, baseline leukocytosis, age, and a response to treatment in the period of induction, rather than the dose of E. coli asparaginase. The authors have also found that among the SRG patients, there is a subgroup of patients without risk factors, in whom the reduction in the COLI-ASP dose may substantially increase survival rates, by lowering toxicity and mortality in remission.

В статье представлен клинический случай лимфомы Беркитта у ребенка 5 лет с поражением небной миндалины, отражены особенности обследования, дифференциальной диагностики на этапе поликлинического звена.

Введение. Авторы описывают талассемию как группу генетически детерминированных болезней крови и возможные сочетания ее с другими заболеваниями, приводят данные найденных ими литературных источников по обсуждаемой тематике.Клинический случай. У пациентки с 3 лет с была диагностирована наследственная гемолитическая анемия – малая форма β-тассемии, а в 6 лет ребенок госпитализирован с острым лимфобластным лейкозом. Течение острого лейкоза не потребовало дополнительной гемотрансфузионной нагрузки по сравнению с другими пациентами. Была получена полная клинико-гематологическая ремиссия.Заключение. В статье представлен редкий случай развития острого лейкоза у ребенка, которому ранее был установлен диагноз талассемии. Нетяжёлая форма наследственной гемолитической анемии позволяет успешно справляться с проявлениями цитопенического синдрома при проводимой противоопухолевой терапии. Вопрос о характере связи развития лейкоза у ребенка с талассемией обсуждается в литературе с различных позиций.

The results of two consecutive multicenter clinical trials enrolled 241 patient with childhood mature B-cells non-Hodgkin lymphomas/leukemia are presented. Patients received treatment according B-NHL 2004mab protocol (n = 83) and B-NHL 2010M (n = 158) with combined immunochemotherapy (ICT) in Russian and Belarus pediatric clinics from 2004 to 2015 years. Primary patients with different mature B-NHL (Burkitt lymphoma/leukemia, diffuse large B-cell lymphoma and primary mediastinal B-cell lymphoma (DLBCL and PMBCL)) aged from 2 to 18 years are included in the studies.Protocol B-NHL 2004mab for treatment of children and adolescents with B-NHL/B-AL, stage III and IV, includes a combination of chemotherapy (PCT) and rituximab – an antibody against the B-cells receptor CD20. PCT courses similar to those in the B-NHL BFM90 protocol (group III) with the exception of methotrexate dose in induction courses, reduced to 1 g/m2 /24 h in order to reduce toxicity. Rituximab (Mabthera, 375 mg/m2 /h) used for the first time in the treatment of children and adolescents with B-NHL. Of the 83 patients included, clinical remission was achieved in 77 (92.8 %). With a median follow time of 51.6 months, remission continued in 23 (85.2 %) patients with B-AL, in 32 (88.9 %) patients with LB and 19 (95.0 %) patients – with DLBCL. With median follow time of 65.2 months, event-free and overall survival was 84 ± 6 and 82 ± 8 %, respectively.Based on previous experience in order to further optimize B-NHL treatment, new protocol B-NHL 2010M with effect-adapted therapy and improvement of stratification risk group criteria was proposed. Overall survival in patients of 1st and 2nd risk groups with full implementation of diagnosis and treatment is approaching 100 %. In interim analysis of 3rd risk group patients, pOS was 88 ± 3 %. The incidence of induction death (infections, metabolic complications) remains within 2.7 % (n = 4); refractory cases (n = 2; 1.3 %) and relapses (n = 4; 2.7 %) developed after 2–4 months of remission, were observed only in patients with Burkitt lymphoma/leukemia. In this cases 2nd line therapy and auto-HSCT is not allowed to achieve remission. All PMBCL and DLBCL patients were achieved remission, but in 50 % of cases only after second line, radio- and cell therapy.The authors conclude that a combined immunochemotherapy of B-NHL in children and adolescents, including the target drug (rituximab) and 5-day courses of cytostatic therapy, highly effective, despite a reduce induction intensity. Therapy for the analyzed protocol requires qualitative dynamic efficacy monitoring and timely correction of therapy. In order to solve a refractory problem and further reduce the toxicity, necessary to continue research using fundamental discoveries in recent years.

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.

Long-term survival of patients with generalized stages (111 and IV) of Burkitt's lymphoma and mature B-cell leukemia (B-ALL) with involvement of the central nervous system (CNS) is no more than 70%; the probability of recovery remains extremely low in cases with primary resistance to therapy or with relapses. The absence of possibilities for adequate intensive cytostatic therapy and neglected standards of accompanying therapy result in development during treatment of severe complications, leading to death or disability. Target immunotherapy by monoclonal antibodies to tumor cell antigens reduces the therapy toxicity without deteriorating its efficiency. The B-NHL-2004m protocol, developed at Federal Research Center of Pediatric Hematology, Oncology, and Immunology (Moscow) for the treatment of primary B-NHL/B-ALL in children and adolescents aged under 18 years, includes therapy by short highly intense polychemotherapy (PCT) courses in combination with rituximab (mabtera; a preparation of chimerical anti-CD20 antibodies) with reduced methotrexate dose in the first two PCT blocks. A total of 47 patients aged 2-16 years with the diagnosis of B-NHL/B-ALL were registered from March 2004 to December 2006; in 43 of these patients analyses were carried out on the base of the data for January 1, 2007. The disease was diagnosed in accordance with the criteria of WHO Classification; B-ALL was diagnosed from the presence of more than 25% anaplastic blast cells in the bone marrow. Results of analysis in 14 patients with first diagnosed B-ALL, who received therapy from June 2004 to January 2007 and have been followed up during 5 to 31 months (median period 13.9 months), are presented in this paper. The diagnosis was verified by morphological and immunocytochemical analysis of the tumor substrate. Three patients died during the induction phase of treatment, in the rest 11 patients remissions were attained. Sanitation of the bone marrow was attained after therapeutic course 1 in 6 (60%) patients and in 5 (40%) after course 2. In 2 cases without extramedullary involvement remissions have been attained after the 1 st course of therapy and last during 10 and 12 months. In cases with extramedullary tumors remissions were attained after course 2 in 4 patients, after courses 3 or 4 in 4 patients. All patients with delayed onset of the remission presented with initial nasopharyngeal involvement. The patients are in remission during 5-24 months. In one of these cases remission was confirmed by control second look operation. Satisfactory tolerance of the protocol was noted. Due to the use of mabtera, antitumor therapy could be realized in the majority of patients without reducing its effect, despite a lower dose and even canceling of one of the basic drugs (methotrexate) during therapeutic course 1. Due to this it became possible to fulfill the schedule of therapy (duration of intervals between the courses and of the entire protocol), which was fully completed during planned periods, including subsequent methotrexate therapy (5 g/m(2)) in all patients who survived the induction stage. Combined immuno- and cytostatic therapy led to remission in 78% children with B-ALL without complications necessitating discontinuation or violation of intense therapy. The study is planned to be continued, for making more definite conclusions.

The results of two consecutive multicenter clinical trials enrolled 241 patient with childhood mature B-cells non-Hodgkin lymphomas/leukemia are presented. Patients received treatment according B-NHL 2004mab protocol (n = 83) and B-NHL 2010M (n = 158) with combined immunochemotherapy (ICT) in Russian and Belarus pediatric clinics from 2004 to 2015 years. Primary patients with different mature B-NHL (Burkitt lymphoma/leukemia, diffuse large B-cell lymphoma and primary mediastinal B-cell lymphoma (DLBCL and PMBCL)) aged from 2 to 18 years are included in the studies. Protocol B-NHL 2004mab for treatment of children and adolescents with B-NHL/B-AL, stage III and IV, includes a combination of chemotherapy (PCT) and rituximab – an antibody against the B-cells receptor CD20. PCT courses similar to those in the B-NHL BFM90 protocol (group III) with the exception of methotrexate dose in induction courses, reduced to 1 g/m2 /24 h in order to reduce toxicity. Rituximab (Mabthera, 375 mg/m2 /h) used for the first time in the treatment of children and adolescents with B-NHL. Of the 83 patients included, clinical remission was achieved in 77 (92.8 %). With a median follow time of 51.6 months, remission continued in 23 (85.2 %) patients with B-AL, in 32 (88.9 %) patients with LB and 19 (95.0 %) patients – with DLBCL. With median follow time of 65.2 months, event-free and overall survival was 84 ± 6 and 82 ± 8 %, respectively. Based on previous experience in order to further optimize B-NHL treatment, new protocol B-NHL 2010M with effect-adapted therapy and improvement of stratification risk group criteria was proposed. Overall survival in patients of 1st and 2nd risk groups with full implementation of diagnosis and treatment is approaching 100 %. In interim analysis of 3rd risk group patients, pOS was 88 ± 3 %. The incidence of induction death (infections, metabolic complications) remains within 2.7 % (n = 4); refractory cases (n = 2; 1.3 %) and relapses (n = 4; 2.7 %) developed after 2–4 months of remission, were observed only in patients with Burkitt lymphoma/leukemia. In this cases 2nd line therapy and auto-HSCT is not allowed to achieve remission. All PMBCL and DLBCL patients were achieved remission, but in 50 % of cases only after second line, radio- and cell therapy. The authors conclude that a combined immunochemotherapy of B-NHL in children and adolescents, including the target drug (rituximab) and 5-day courses of cytostatic therapy, highly effective, despite a reduce induction intensity. Therapy for the analyzed protocol requires qualitative dynamic efficacy monitoring and timely correction of therapy. In order to solve a refractory problem and further reduce the toxicity, necessary to continue research using fundamental discoveries in recent years.