The bispecific monoclonal antibody blinatumomab (CD19/CD3) is widely and successfully used to treat children with relapsed/refractory B-cell precursor acute lymphoblastic leukemia (BCP-ALL). Advances have also led to the use of immunotherapy in children with primary BCP-ALL. This paper presents the effectiveness of a single blinatumomab course instead of consolidation chemotherapy and with short maintenance therapy in primary BCP-ALL patients. 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. Between February 2020 and November 2022, 165 children with non-high-risk BCP-ALL (according to clinical stratification criteria defined in the study) were enrolled in the ALL-MB 2019 pilot study (NCT04723342). Patients received conventional risk-adapted induction therapy according to the ALL-MB 2015 protocol. Those who achieved complete morphological remission at the end of induction received 15 µg/m2/day of blinatumomab immediately after induction for 4 weeks, followed by 12 months of maintenance therapy. Minimal residual disease (MRD) was measured using multicolor flow cytometryat the end of induction, then immediately after blinatumomab course, and then four times during maintenance therapy at threemonth intervals. All 165 patients successfully completed induction therapy and achieved complete hematological remission. All had their MRD measured at the end of induction. One hundred thirty-six (82.2%) patients were MRD-negative, and the remaining 29 patients showed various levels of MRD positivity. MRD was assessed in all 164 patients who completed the blinatumomab course. One patient had blinatumomab discontinued due to acute neurotoxicity and was subsequently treated according to the intermediate-risk ALL-MB 2015 protocol. All but one patient achieved MRD negativity after blinatumomab course, regardless of MRD value at the end of induction. One adolescent girl with a high MRD level after induction remained MRD positive after blinatumomab course and further received high-risk therapy with allogeneic hematopoietic stem cell transplantation. At the time of analysis, 162 children had completed all therapy, including 12 months of maintenance. MRD was examined in 151 of them, and all were MRD negative. Over a 4-year study period with a median follow-up of 2.5 years, 10 relapses were registered: 4 in the standard-risk group and 6 in the intermediate-risk group. The 4-year event-free survival was 89.1 ± 3.7 % for all patients, 92.0 ± 4.2 % and 82.8 ± 8.1 % for the standard and intermediate risk groups, respectively. At the time of analysis, all patients were alive; no deaths were registered. Although the presented results are preliminary and more time is needed for definitive conclusions, a 4-week 15 µg/m2/day blinatumomab course immediately after induction followed by 12 months of maintenance therapy is effective in achieving and maintaining MRD negativity in children with non-high risk BCP-ALL. This study showed the fundamental possibility of treating ALL by combining immunotherapy with the bispecific monoclonal antibody blinatumomab with a significant chemotherapy reduction.

Children with acute lymphoblastic leukemia (ALL) and slow clearance of minimal residual disease (MRD) demonstrate a significantly worse outcome as compared to those with fast response to chemotherapy. Bispecific monoclonal antibody blinatumomab is the key drug for CD19-directed immunotherapy which opens wide opportunities for the elimination of MRD in patients with B-cell precursor ALL (BCP-ALL). Aim of the study – to evaluate the effectiveness of blinatumomab for MRD elimination in children with BCP-ALL and slow MRD clearance treated by the “ALL-MB 2015” protocol. 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. Patients from the “ALL-MB 2015” trial who demonstrated slow MRD clearance at the end of induction were included in the current study. MRD monitoring was performed by multicolor flow cytometry modified with respect to possible CD19 loss during targeted treatment. Threshold of 0.001% was used for MRD positivity definition. Between February 2020 and August 2023, 228 children with de novo Ph-negative KMT2A-negative BCP-ALL were defined as slow MRD responders according to the criteria of the “Moscow-Berlin” group. Fifty of them were treated with blinatumomab because of slow MRD clearance. Blinatumomab course was given immediately after induction in 23 children, after Consolidation I – in 14 patients, after Consolidation II – in 11 patients, while two children received immunotherapy prior to maintenance. After completion of blinatumomab course, 23 patients continued protocol treatment, 21 received maintenance only, two were treated with high-risk blocks and four received hematopoietic stem cell transplantation. Only 2 of 50 (4.0 %) patients remained MRD-positive after completion of blinatumomab course. By the end of December 2023, only two adverse events were registered: one relapse and one remission death. Two-year event-free survival was 94.7 % (standard error 3.6 %), while cumulative incidence of relapse was 2.6 % (standard error 2.7 %). Outcome in these 50 patients was much better in comparison with 178 children with a slow MRD response who did not receive blinatumomab. The use of blinatumomab in children with de novo Ph-negative BCP-ALL with slow MRD clearance allows achieving MRD-negative remission in nearly all cases. Although a longer follow-up is necessary for the reliable conclusion of CD19-directed therapy effectiveness, the promising results are obtained in the current study in this unfavorable patient group.

The achievement of remission at the end of induction (EOI) chemotherapy in patients with acute lymphoblastic leukemia (ALL) is the key parameter of treatment effectiveness evaluation. The aim of the study – defining complete remission by multicolor flow cytometry (MFC) and bone marrow (BM) cytomorphology (CM) at the EOI chemotherapy in children with B-lineage ALL. 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. The study included patients of “ALL-MB 2008” and “ALL-MB 2015” trials for whom minimal residual disease (MRD) was evaluated by MFC at the EOI simultaneously with CM BM investigation. Less than 5% blasts in BM and MRD < 1% were established as the remission achievement criteria for CM and MFC respectively. The study group included 1498 children aged from 1 to 18 years (median age was 4 years and 11 months) with B-cell precursor ALL. The overall concordance of MFC and CM was found to be 96.1% (1440 of 1498 patients). In 36 (2.4%) children with MRD ≥ 1%, M1 BM status was observed. In contrast, in 22 (1.5%) patients with M2/M3 BM status by CM, MRD value was below 1%. Treatment outcome was analyzed in 522 patients of “ALL-MB 2008” trial. Children with M2/M3 BM, as well as with MRD ≥ 1% demonstrated dramatically inferior outcome, in comparison to those who achieved remission. The presence of at least one of the mentioned criteria (M2/M3 status by CM or MRD ≥ 1% by MFC) defined a group of 23 (4.4%) patients with very low event-free survival (34.9%, standard error 11.0%) and very high cumulative incidence of relapse (56.4%, standard error 12.0%). For the evaluation of remission achievement, MFC and CM should be applied simultaneously at the EOI. High leukemic burden found by any of these methods is the clear definition of induction failure. MRD detection at the EOI should be implemented in any modern treatment protocol as an obligatory stage of treatment response monitoring and final risk group stratification. Considering the crucial importance of the MRD detection results, this study must be performed only in the reference laboratories of the study groups.

In present article comparative efficacy analysis of two conceptually various acute lymphoblastic leukemia (ALL) chemotherapy programs from 18. 04. 2002 till 01. 01. 2007 aimed at definition of optimum ALL chemotherapy strategy in children is presented. To obtain an ultimate correct analysis patients data bases from Moscow and St.-Petersburg oncohematology departments have been united to the subsequent carrying out of meta-analysis. 292 primary patients are included in this analysis from ALL-MB-2002 group and 126 patients from COALL-St.Petersburg-92 group aged from 4 months to 18 years. Analysis of treatment results dynamics in ALL patients received COALL-St.Petersburg-92 protocol for 2 periods: from 01. 01. 1999 till 18. 04. 2002 and from 18. 04. 2002 till 01. 01. 2007 is also presented. Detailed comparison of two chemotherapy programs efficacy has not found any statistically significant differences concerning such factors, as complete remission rate, early death rate and relapse rate, and as number of children who are in continuous complete remission. Event-free survival (EFS) in both groups was 78 ± 3 and 78 ± 4 %, respectively (р = 0.85). The overall survival (OS) was 80 ± 5 % for patients treated according to ALL-MB-2002 protocol, and 83 ± 4 % for patients receiving COALL-St.Petersburg-92 protocol (р = 0.65). Though comparison of ALL-MB-2002 and COALL-St.Petersburg-92 protocols has shown, that efficacy of both chemotherapy regimens is identical, however such advantages of ALL-MB-2002 protocol as reduced toxicity and greater simplicity in implementation could be crucial for the choice of optimal chemotherapy strategy for childhood ALL in Russia.

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.

Comparative retrospective analysis of treatment results of three different chemotherapy protocols - ALL BFM 90m, ALL MB 91 and PECO 92 — in primary ALL patients aged before 18 years, registered in Moscow and St-Petersburg clinics from 01.01.1993 to 01.01.1999 is presented. It has been shown, that treatment results of PECO 92 protocol have appeared much worse, thus, any differences in treatment results for children with ALL between ALL BFM 90m and ALL MB 91 protocols were not revealed. Event-free survival (pEFS) of St-Petersburg' patients, received PECO 92 protocol (60±3%), was significantly worse, in comparison with patients treated according to ALL BFM 90m protocol (74±4%; р=0,0056) and ALL MB 91 protocol (73±4%; р=0,0239). The high incidence of relapses became a main cause of efficacy decreasing. Differences of induction and remission death incidences between three chemotherapy protocols were not revealed. Significant and most expressive EFS differences between PECO-92 and two other protocols were obtained in boys, in a 1—10 age group, and in patients with leukocytes count > 100 000/mm3, in patients with non-T-ALL and in patients with spleen size >4 cm.

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.

The purpose of this work was evaluation of prognostic significance of 11q23/KMT2A rearrangements in infants (aged under 365 days) with B-cell precursor acute lymphoblastic leukemia (ALL) enrolled in Russian-Belarus multicenter trial MLLBaby. This study is supported by the Independent Ethics Committee and approved by the Academic Council of the Research Institute of Medical Cell Technologies (Ekaterinburg). Various 11q23/KMT2A rearrangements were revealed in 100 (72%) of 139 patients. Event-free survival (EFS) in the intermediate risk group of MLL-Baby trial was 35.1% (standard error (SE) 6.9%), in the high risk group – 38.3% (SE 7.1%) (p = 0.941). The most unfavorable prognosis had infants with translocation t(9;11)/KMT2A-MLLT3: EFS 18.8% (SE 9.8%), cumulative incidence of relapse (CIR) 75.0% (SE 9.7%). Intermediate results were obtained in patients with translocations t(4;11)/KMT2A-AFF1 and t(11;19)/KMT2A-MLLT1: EFS 36.9% (SE 7,2%) and 32,7% (SE 10.4%), respectively; CIR 46.3% (SE 7.8%) and 50.9% (SE 12.3%). The most favorable treatment outcome was achieved in infants carrying translocation t(10;11)(p12;q23)/KMT2A-MLLT10: EFS 83.3% (SE 15.2%), CIR 0,0%. In the multivariate analysis unfavorable outcome of KMT2A-rearranged infant ALL was associated with initial CNS involvement (p = 0.020), initial white blood cell count higher than 300 × 109 /L (p = 0.028), more than 5% blast cells on day 15 in bone marrow (p = 0.012) and presence of translocation t(11;19)/KMT2A-MLLT1 (p = 0.012).

Respiratory papillomatosis is a complex, unresolved problem of modern otorhinolaryngology. At the moment, there is no consensus on the principles of therapy for this disease, both surgical approaches and anti-relapse conservative therapy. Ювенильный респираторный папилломатоз представляет собой сложную, до настоящего времени неразрешенную проблему современной оториноларингологии. На данный момент нет единого мнения как о хирургических подходах, так и о принципах терапии данного заболевания – противорецидивной консервативной терапии.

Down syndrome (DS) is one of the most common chromosomal abnormalities. Children with DS are more likely to develop acute lymphoblastic leukemia (ALL). Standard therapy is usually used to treat DS-ALL, but children with DS-ALL have an inferior outcome compared to non-DS patients, mainly due to increased therapy toxicity. The purpose of the study: in this study we aimed to analyze our experience of treating DS-ALL according to original protocol “Moscow–Berlin”. This study is supported by the Independent Ethics Committee and approved by the Academic Council of the Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology. 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 SD-ALL patients, a comparison group was formed from all patients with ALL registered in the database, using the matched-pair method. A total of 8296 ALL patients were registered in the database, of which 135 (1.63%) were patients with DS-ALL. The predominant age group of DS-ALL patients is 3–10 years. Among them there was no T-cell ALL patient, and both favorable and unfavorable genetic abnormalities were significantly less common. There were no differences in early response between DS-ALL and non-DS-ALL patients. The event-free (61 ± 6%) and overall survival (74 ± 4%) of DS-ALL patients was significantly lower than in the comparison group (84 ± 3% and 89 ± 3% respectively; p < 0.001). No differences were found in relapse rate, while the treatment-related mortality (TRM) was higher in DS-ALL group (19.3 ± 3.5% versus 3.9 ± 1.2%; p˂0.001) in all treatment phase. The treatment results for DS-ALL patients remain unsatisfactory; therefore, new approaches to optimizing therapy are needed. High toxicity and associated TRM are the main problem. Future strategies to improve outcome in DS-ALL should include improved supportive care, the use of targeted drugs and immunotherapy, as well as the identification of new molecular genetic features.

Melanotic neuroectodermal tumor of infancy is a rare neoplasm that predominantly involves cranial bones and tends to occur during the first year of life. About 500 cases have been described in the literature to date; 6% of them have been reported to be malignant. Treatment for these malignant tumors was not documented and often turned out to be ineffective.Here we report a case of a child aged 2 years and 4 months who presented with a rapidly growing mass in the maxillary region spreading through the orbit into the anterior cranial fossa. The patient’s parents gave consent to the use of their child’s data, including photographs, for research purposes and in publications. He was treated at the Russian Children’s Clinical Hospital from July 2018 to November 2019. The child underwent chemoradiation and staged surgical removal of the tumor. Treatment with ICE and radiation therapy led to a significant reduction of the tumor volume and enabled us to perform cytoreductive surgery with the removal of the mass in the maxilla. Further treatment according to the CWS 2009 guidance for high-risk patients with NRSTS (NonRhabdomyosarcoma Soft Tissue Sarcoma) and radiation therapy resulted in further regression of intraorbital and intracranial components of the tumor and we performed a radical resection of the residual tumor conglomerate. Investigations during the course of treatment revealed no signs of metastatic involvement. The behavior of malignant melanotic neuroectodermal tumors of infancy is unpredictable, that is why in case of the massive involvement of the facial bones when surgery is associated with a high risk of functional impairment or cosmetic deformity, one should consider preoperative chemotherapy to reduce tumor size and intraoperative blood loss. Moreover, chemotherapy in combination with resection makes it possible to minimize the risk of local relapse or metastasis.

High risk of life threatening complications is distinctive for surgery of tumors, which are in contact with large main vessels. Planning for the removal of the primary focus of neuroblastoma (NB), characterized by similar localization, includes determining the timing and method of the operation, the required resection volume, predicting complications, developing ways to prevent them and relieve them. The study was approved by the Independent Ethics Committee and Scientific Board of N.I. Pirogova of RussianNationalResearchMedicalUniversity. The results of complex treatment of 11 children with NB of thoracoabdominal localization, aged from 9 to 55 months, are present in the research. 7 (64%) of them were stratified into a high-risk group, 3 (27%) – intermediate, 1 (9%) – low, according to the criteria of the NB-2004 protocol. The results were analyzed depending on the features of the operation and the course of the early postoperative period. The number of variants of tumor syntropy which coincided image-defined risk factors, revealed by computed tomography with contrast enhancement, was in the range from 2 to 7 (median – 5). The median volume of the removed part of the tumor was 95% (range from 92 to 98%). Among intraoperative complications aortic wall (1 (9%) observation), superior mesenteric vein (1 (9%) observation), right renal vein (2 (18%) observations), left renal vein (2 (18%) observations), inferior vena cava (2 (18%) observations) injury should be noted, which were sutured without subsequently detected hemodynamic disturbances and organ function. Complications in the early postoperative period were: partial ileus (1 (9%) observation), renal artery thrombosis (1 (9%) observation), inferior vena cava thrombosis (1 (9%) observation), pancreatic necrosis (1 (9%) observation). They demanded reoperation in two children: nephrectomy in a child with renal artery thrombosis at the fourth posroparative day and performing of anastomosis between the pancreas and small intestine at the 74 posroparative day in a patient with pancreatic necrosis. Among patients in the intermediate and high-risk groups, the event-free two-year survival rate was 50%, the total two-year survival rate was 88%. The prognosis of the disease does not reliably correlate with the duration of the relief of postoperative complications (p = 0.53) and the resection volume (p = 0.46). Surgical intervention and postoperative observation in children with NB of thoracoabdominal localization should be carried out by a team that has experience of similar operations, owning vascular suture technique, with a preliminary assessment of the image-defined risk factors. The purpose of the operation should be a resection aimed at cytoreduction and elimination of the mass-effect, without striving to remove all areas of the tumor.

Aim. The analysis of experience of nelarabine use in refractory/relapsed T-cell acute lymphoblastic leukemia (T-ALL) depending on the immunophenotype and the line of therapy. Materials and methods. All the patients with relapsed or refractory T-ALL aged from 0 to 18 years who received treatment with nelarabine as a part of the therapeutic element R6 were included in the study. For all patients a detailed immunological analysis of leukemia cells with discrimination of immunological variants TI, TII, TIII or TIV was performed. Patients administered with nelarabine as a first therapeutic element were referred to the first-line therapy group, other patients were referred to the second-line therapy group. Nelarabine was administered as intravenous infusion at a dose of 650 mg/m2, on days 1-5. Allogeneic hematopoietic stem cells transplantation (allo-HSCT) was considered for all patients. Results. From 2009 to 2017, 54 patients with refractory/relapsed T-ALL were treated with nelarabine. Five-year event-free survival (EFS) and overall survival (OS) was 28% for all patients, cumulative risk of relapse (CIR) was 27%. EFS was significantly higher in nelarabine first-line therapy group in comparison with second-line therapy group (34±8% vs 8±8%, p=0,05). In patients after allo-HSCT EFS, OS and CIR were 51±10%, 50±10% and 39,1±9,5% accordingly. The best results were achieved in patients with TI immunophenotype. No toxicity-related mortality as well as severe neurologic complications or discontinuation of therapy associated with use of nelarabine were reported. Conclusion. The use of nelarabine is an effective strategy for the treatment of relapsed and refractory T-ALL. The best treatment outcomes were obtained in patients with TI immunophenotype and in the first-line therapy group. Optimal dosage regimens can be established during controlled clinical trials.

Introduction. Neuroblastomas arise in the case of intimate association of the tumor with large vessels and internal organs. The early detailed stratification of cancer risk, as well as forecasting possible complications of surgery based on visual diagnostic methods, contribute to the improving the results in this category of patients. Material and methods. The study analyzes the results of the diagnosis and treatment of neuroblastoma of thoracoabdominal localization in 9 children aged from 9 to 55 months. All of them received the treatment according to the NB-2004 protocol. Before surgical intervention, the factors of the surgical risk were estimated from computed tomography with contrast, the number of factors averaged of 5. Results. The inclusion of the left renal artery and aorta into the tumor was revealed intraoperatively in 8 children, the involvement of the left renal vein, the right renal artery, the superior mesenteric artery was found in 7 patients, the right renal vein, the celiac trunk - in 6 cases, and the other large vessels - in a smaller number of cases. Damages of the right renal vein in 2 patients, left renal vein - in 2 children, aorta - in 1 child, inferior vena cava - in 2 observations and celiac trunk in 1 patient was sutured without subsequent complications. After injury and suturing of the inferior vena cava in a 1 patient, there was revealed a parietal thrombus without clinically significant hemodynamic disturbances. In 1 observation, postoperative thrombosis of the left renal artery caused the deterioration of the blood flow requiring nephrectomy. Damage to the pancreas in 1 child was accompanied by a long drainage and the formation of pancreatojejunostomy. The volume of the resection of the tumor amounted on average of 93%. The total number of complications in the early postoperative period accounted for 44%, out of which repeated surgical interventions were required in case of bleeding against the therapy of renal artery thrombosis in 1 patient and focal pancreatic necrosis in the 1 patient. The duration of postoperative follow-up was of 18 months. Overall survival is 100%, the event-free survival rate is of 78%. The continued growth of the tumor was registered in 2 patients in the high-risk group. Discussion. Neoadjuvant chemotherapy contributed to the enhancement of the radicalization of the surgical treatment, leading to a decrease in the size of the primary focus, metastases, and involvement of large vessels and internal organs in the tumor. The radical removal of neuroblastoma is acceptable in the absence of the invasive growth in the walls of large vessels and internal organs, otherwise, the resection should be performed for the purpose of cytoreduction and prevention of organ failure due to tumor compression.

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.

The relapse of acute lymphoblastic leukemia (ALL) in children is still a difficult task. This is due both to the difficulties of achieving a second remission and to the problems of organizing allogeneic bone marrow transplantation (BMT) in those patients who need it. The standard approach is the use of second-line drugs in the regime of high-dosage chemotherapy blocks, but the response rate for this treatment in patients with early relapses remains low and the response time is short. Recently, new drugs with different mechanisms of action have appeared that can give an opportunity for a full remission. The organization of a multicentre study on anti-relapse therapy in the Russian Federation is an urgent task, the solution of which can help in studying new approaches to therapy and in the organization of BMT logistics. This article presents the results of a pilot multicentre study on the treatment of relapses of ALL in children in the Russian Federation. The effectiveness of standard therapy for a group with late relapses and the efficacy and toxicity of interventional blocks with the use of bortezomib, clofarabine, nelarabine are presented.

Lineage switch is a rare phenomenon in which a transition from lymphoid to myeloid was observed in relapse of acute leukemia, or vice versa. This paper presents the four clinical case reports of acute lymphoblastic leukemia with MLL gene rearrangement (KMT2A) with myeloid phenotype in relapse.

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.

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 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.