Vol 18, No 1 (2019)

Despite remarksble improvements in the treatment of pediatric acute limphoblastic leukemia (ALL) over last decades, relapse still caries a poor prognosis with considerable morbidity and mortality. New strategies and approaches are extremely needed. According to the results of previous protocol ALL-REZ-2014 despite the implementation of bortezomib, as well as idarubicin and navelbine, which have not been used in first-line therapy, the new protocol had demonstrated no significant improvement in reaching a steady remission, especially for B-ALL relapses. The therapy results for the high risk group patients still far from optimal due to refractoriness to chemotherapy, death from infectious complications, as well as acute chemotherapy toxicity. This article demonstrates first results of pilot protocol All-REZ-2016 for high risk ALL relapses, which was approved by the Independent Ethics Committee of the Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology, and Immunology. Between 01.08.2016 and 01.12.2018 42 patients from our center were enrolled in ALL-REZ-2016 study. Patients aged 1-18 years with a first relapse of ALL without t(9;22) translocation were eligible , we included only high risk groups (S3, S4, S5) patients in this study. CD3+ apheresis was made before treatment for all patients with B-cell phenotype. To determine the efficiency and toxicity of fludarabine- and clofarabine-including chemotherapy regimens after the preliminary phase with prednisone 60mg/m², for patients with B-ALL randomization for blocks with fludarabine or clofarabine was performed. The next stage of the therapy was a course with blinatumomab (28 days) and weekly autologous lymphocyte infusions (x 4). ALL patients with T-ALL got 11 days of protocol N, and then studying the efficiency of clofarabine 52 mg/m² for TIII/TIV was planned, since nelarabine has been shown to be inefficient for this category. For the patients with TI/II ALL, nelarabine 650 mg/m2 therapy was given after protocol N. If remission was attained, a stem cell transplant was performed for all patients without delay. 42 patients were enrolled, the median age was 9.9 years (range 2.7-16.2), there was male predominance (63.8%), the majority had B-cell phenotype (61.7%). The estimated 2-year event-free survival (EFS) across all immunophenotypes was 47.7% (SE+/-8%) and a cumulative incidence of second relapse (CIR) was 27.1% (SE+/-7.6%). Patients with B-ALL had EFS 55% +/-10% and CIR 30.0% +/-9.9%, T-ALL had EFS 35% +/-13% and CIR 21.2+/-12%. We did not observe serious toxicity when using blinatumomab. The use of clofarabine and fludarabine was accompanied by deep immunosuppression and severe infectious episodes. Results for patients with B-cell relapses are much better then in previous protocol ALL-REZ-2014, using of autologous CD3+ lymphocytes infusion once a week during the continuous blinatumomab therapy is effective. For T-ALL relapses results remain unsatisfactory due to refractoriness, but number of patients is still small for final conclusions.

Methotrexate-induced subacute encephalopathy is one of the side effects of the aforementioned drug. The effect is characterized by certain neurological symptoms, presence of leukoencephalopathy on a magnetic resonance imaging (MRI) and slow-wave activity shown on an electroencephalogram (EEG). The aim of this work is to determine the clinical and electrophysiological characteristics of methotrexate-induced encephalopathy in paediatric patients with various types of cancer, as well as to compare the obtained data with researches and precedents presented in medical literature. The study was approved by the Independent Ethics Committee of the Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology, and Immunology. A retrospective analysis of treatment results was performed on 31 patients aged 1.5-17 who had subacute methotrexate-induced encephalopathy. Most patients (n = 26) have been diagnosed with acute lymphoblastic leukemia (ALL). According to the theurapeutic protocols, the patients received intravenous, intrathecal and intraventricular methotrexate treatment. The severity of methotrexate-induced encephalopathy was determined according to the NCI-CTCAE scale (version 4.0). All the patients underwent the EEG study. MRI was performed on 26 patients. Methotrexate-induced encephalopathy developed after 2-12 (on average 5.3 ± 3.1) days after methotrexate administration. Encephalopathy of grade I occurred in 35.45% of cases, of grade II - in 19.6%, of grade III and IV - in 25.8 and 19.4% of cases. 5 patients had symptoms recurred after therapy continuation. The most frequent neurological symptoms were: pathological level of sleepiness (50.1%), impaired consciousness (32.3%), cognitive impairment (25.8%), epileptic seizures (19.6%) and ataxia (19.6%). Regression of neurological symptoms occurred in 26 patients after 1-10 (on average 3.3 ± 2.2) days, 5 patients had persistent neurological deficit. The EEG pattern was represented by diffuse theta-wave activity (39%), theta-delta activity (42%), delta activity (6.5%), beta activity (3.0%), a decrease of alpha rhythm amplitude (6.5%), where no changes occurred for only 1 patient. Pathologic changes were seen on MRI in 84.6% of cases. The interdependence between the EEG changes, the time of debut and resolution of encephalopathy has been established. However, there has been no connection found between the severity of encephalopathy, the EEG pattern, the way of methotrexate administration, the age of the patients, the clearance of methotrexate and previous neurological disoders. The data obtained on the clinical picture and the time frame of methotrexate-induced encephalopathy initiation were similar to foreign ones. In different cases of patients with methotrexate-induced encephalopathy, EEG is not always represented as diffuse slow-wave theta-activity. The patients are recommended to undergo initial EEG in order for the electrophysiological studies on methotrexate encephalopathy to be assessed correctly. Further studies of the risk factors of methotrexate-induced encephalopathy are required.

The reduction of long-term survival and fertility is still a problem in management of Hodgkin lymphoma in children and adolescents. These problems are partly solved by reduction of radiotherapy and changing procarbazine on etoposide and dacarbazine. We analyzed medical data of patients with HL < 18 years that were treated by modified OEPA-COPDAC protocol since 1.01.2012 to 01.12.2017. The study was approved by the Independent Ethics Committee of the Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology, and Immunology. All patients despite gender didn't receive procarbazine. We analyzed data of 77 patients. Event-free survival (EFS) was 88% (95% CI 76.2-93.9%). EFS didn't differ between boys and girls 86.9% (95% CI 67.8-94.7%) and 88.7% (95% CI 67.3-96.1%) respectively (р = 0,9). EFS was significantly higher in patients without E-lesions compared with patients with E-lesions 90.8% (95% CI 77.8-96.2) and 72.7% (95% CI 28.4-89.6) respectively (p = 0.04). We analyzed toxicity of 40 cycles OEPA and 44 cycles COPDAC. Toxicity was acceptable. In our study we didn't detect significant difference in EFS in boys and girls. Procarbazine can be safely changed on etoposide in OPPA and dacarbazine in COPP in boys and girls with HL. E-lesions is a risk factor of inferior EFS.

Low grade gliomas (LGG) constitute 35-40% of all primary central nervous system (CNS) tumors in children, at least 10-12% of them affecting the optic pathway. The complexity of the localization and predominantly the diffuse type of growth of these tumors make the neurosurgical treatment not appropriate in most cases, which requires conservative treatment.

Objective: to analyze the results of carboplatin and vincristine chemotherapy (CT) regime in children with optic pathway gliomas (OPG). The study was approved by the Independent Ethics Committee of the Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology, and Immunology. In the study was included patients registered at the Burdenko Neurosurgery Institute from January 1, 2003 till December 31, 2015 with optic pathway glioma from 0 to 18 years old that were treated with combined carboplatin and vincristine chemotherapy. All patients were divided into 2 groups: the first group included patients who had newly diagnosed OPG (group 1), the second group included patients with OPG with radiological progression following observation times (group 2). Evaluation of the response to treatment was carried out on the 24th week and after completion of treatment by delineation of each slice of the MRI images in OsiriX MD software (© Pixmeo Sari, Switzerland) with subsequent automatic volume calculation.

Results: 104 patients were included in the analysis. 69 children were included to group 1, 35 patients in group 2. 60% of patients were boys, about a third of children were less than 18 months old, 17% of patients had Neurofibromatosis type I, 24% of patients had diencephalic cachexia. A biopsy of the tumor was performed in 76% of the patients, 54% of the patients had a piloid astrocytoma and 23% had a pilomixoid astrocytoma. The progression after the start of the chemotherapy was in 30 (28.9%) patients. 5-year event free survival (EFS) and overall survival (OS) were 58 ± 6% and 97 ± 2%, respectively. 5-year EFS was not statistically significantly different in patients of groups 1 and 2. According to our data, the age, histology of the tumor, the response to the 24th week of CT are independent prognostic factors.

Methotrexate is one of the most widely used chemotherapeutic agents against a number of malignancies in children. Clinical cases of acute and subacute neurotoxicity are described in literature, but it is necessary to underline a paucity of science information concerning pathogenesis, diagnostics and treatment options for this type of complication. The features of disease manifestation, diagnostic tools and principles of treatment have been presented in the article, using the clinical observation on 15 y.o. patient with osteosarcoma of right tibia, treated according EURAMOS 2007 protocol with high-dose methotrexate 12 g/m² as a 4-hour infusion. Parents gave their consent to use information about the child in the article. One cycle of therapy was complicated with reversible subacute neurotoxicity with alternating involvement of both cerebellar hemispheres. We discuss challenges of differential diagnosis of clinical presentation, underline value of diffusion-weighted magnetic resonance imaging, treatment options, possibilities of chemotherapy continuation with high-dose methotrexate.

B-cell lymphoma is unclassifiable, with signs intermediate between diffuse large-cell B-cell lymphoma and Hodgkin's lymphoma (LH), is a rare aggressive lymphoma with an uncertain prognosis that has specific morphological and immunophenotypic characteristics characteristic of both diffuse B-large-cell lymphoma and Hodgkin's lymphoma. In this article, the comparative characteristics of NIVCL and various variants of large cell B-cell lymphomas are presented, as well as a description of the clinical case of NVCL in a child of 3 years. Patient's parents agreed to use personal dats and photos in research and publications.

Primary immunodeficiencies (PID) are rare genetically determined disorders of immune system. PID are most often manifested by infectious and autoimmune complications. However, as the life expectancy of patients with PID has increased as a result of improved therapy, the increased risk of developing malignancies, primarily lymphomas, became more prominent. The incidence of malignancies in patients with PID ranges from 4 to 60%. The role of oncoviruses is important in the pathogenesis of lymphomas in PID, but there are also non-infectious causes. Lymphomas in severe combined immunodeficiency (SCID) are extremely rare, and are usually represented by post-transplant lymphoproliferative diseases (PTLD). The development of true lymphomas in SCID is an extremely rare event. We describe two clinical cases of lymphomas in children with X-linked SCID, with successful non-protocol therapy of lymphoma and subsequent transplantation of hematopoietic stem cells. Parents gave their consent to use information about the child in the article.

The purpose of this study is a comprehensive analysis of BCR-ABLl-like pediatric acute lymphoblastic leukemia (ALL) and to point out the difference between BCR-ABLl-like and Ph-like ALL in children. It was shown the genetic heterogeneity of BCR-ABLl-like ALL including cases with tyrosine kinase fusion genes, activating mutations in JAK-STAT, RAS. We also described various diagnostic options and prognostic role of BCR-ABL1-like ALL in children.

The main goal of the Federal Center (FC), not dependent on its profile, is to assist specialized, including high-technology medical care using new, unique and resource-intensive technologies. This statement is legally enforced by Russian Federal Law № 323. However following the other regulatory laws, such as State Program of guaranteed free medical care, acts that provide hospitalization and out-patient assistance as well as legislation in the field of procurement of medications and medical devices, in reality the FC are financially and legally equated to clinics of other levels (for example, polyclinics, regional and municipal hospitals) despite the complex patients' population and the requirements to their treatment results. The basic organization difficulties that face the federal centers are considered on the example of Dmitry Rogachev National Research Center of Pediatric Hematology, Oncology and Immunology.