Vol 20, No 1 (2021)

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. 

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). 

The aim of this study was to describe the immunophenotype of leukemic cells in acute myeloid leukemia (AML) with inv(16) (p13.1q22)/CBFb-MYH11 and t(16;16)(p13.1;q22)/CBFb-MYH11 in children. 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. We investigated bone marrow samples from 36 pediatric patients with initially diagnosed AML with inv(16)(p13.1q22)/t(16;16)(p13.1;q22)/CBFb-MYH11. Immunophenotypic profile of leukemic cells was very heterogeneous: cells expressed antigens of early stages of differentiation (CD34, CD117, CD123) as well as markers of mature monocytes (CD11c, CD14, CD64) and neutrophils (CD65, CD15). Moreover, in 55.6% of cases lymphoid coexpressions were noticed (CD2 – the most frequent one). Furthermore, in 83.3% of cases we detected the separation of leukemic cells population into two parts: more “immature” – myeloblastic, which expressed early markers of differentiation (CD34, CD117), and more “mature” part, expressing monocytic antigens (CD11b, CD14, CD33). There was no clear separation between these parts of population. Despite the immunophenotypic similarity between monocytic part of leukemic population and normal monocytes, in 87.5% of studied cases there were same lymphoid coexpressions on these cells as on leukemic myeloblasts. Moreover, we showed that levels of CBFb-MYH11 expression in leukemic monocytes and myeloblasts were comparable. Presence of these characteristics in monocytes allows to consider them as part of leukemic cells population and take into consideration during the total immunophenotype reporting. 

Despite modern possibilities of laboratory diagnosis of hemorrhagic syndrome, in some patients, the causes of bleeding remain unspecified. Among these reasons, mild defects in the platelet link of hemostasis can potentially be hidden. The aim of the work is to identify the features of the function of the platelet hemostasis in children with unspecified hemorrhagic syndrome. 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. We examined 50 patients aged 2 to 17 years with various manifestations of bleeding and lack of laboratory data proving coagulopathy and/or thrombocytopenia; platelet cytofluorometry with activation was performed. The morphological characteristics of platelets in terms of size/granularity (FSC/SSC), the density of the CD62p receptor as a marker of a-granule secretion, and d-granules of platelets were assessed by the fluorescence of loaded mepacrine. Platelet activation was performed with a CRP + TRAP mixture. Comparison was carried out with the results of examination of 50 healthy children (control group - CG) aged 2 to 17 years. The severity of hemorrhagic syndrome was assessed using the standardized ISTH BAT score. The severity of hemorrhagic manifestations according to BAT ISTH score ranged from 2 to 6 points. As a result of the study, two groups of patients differing in the calculated parameter of the FSC/SSC ratio for non-activated platelets were identified. In the CG, the median FSC/SSC was 1.235 (from 1.1 to 1.4), in group 1 (n = 19), the median was 0.97 (from 0.9 to 1.05), and in group 2 (n = 31), the median was 1.24 (from 1.11 to 1.43). The number of platelets of the CG and the groups of patients did not differ significantly. A significant correlation between a decrease in the number of platelets and an increase in their size and granularity, while maintaining a high correlation between size and granularity was observed in groups of patients. In group 1, the overall granularity was increased regardless of the size and number of platelets, the volume of dense granules and membrane CD62p was increased, but the granular CD62p was decreased. The degranulation mechanism was not impaired in both groups of patients. Our results indicate convincingly the contribution of the storage pool and platelet morphology disorders to the development of hemorrhagic manifestations in children with unspecified hemorrhagic syndrome. 

Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma in childhood, but is very rare in infants. RMS diagnosed during the first year of life is reported to have poor outcome. The aim of the study was to analyze the results of therapy of RMS in the first year of life treated in federal center in Russian Federation. 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. All prospectively registered patients with RMS in infants treated during the period 02.2012–05.2018 (75 month) were included. Diagnosis was confirmed by histology. All patients were examined and stratified according to the GPOH Cooperative Weichteilsarkom Study (CWS) Group guidance 2009. 13 prospectively registered patients with RMS in infants treated during the period were included. Median age at initial diagnosis was 6.7 (range 0.23–11.9) months. The tumor was detected prenatally at 32 and 33 weeks of gestation in 2 (15%) patients. The age of these patients was ≤ 1 month in 2 of 13 patients. Tumor size was ≤ 5 cm in 8 (61,5%) of 13 patients. Median volume tumor was 24 (range 0.001–150) ml. The primary site was head and neck (n = 4; 31.5%), pelvis (n = 3; 23%), extremities (n = 3; 23%), genitourinary system (n = 2; 15%), other (n = 1; 7.5%). IRS stage distribution was stage III in 12 (92.5%) patients, stage IV – 1 (7.5%). Regional nodal metastasis (N1) occurred in 1 (7.5%) patient with tumor of the head and neck nonparameningeal. Distant metastasis occurred in 1 (7.5%) patient and the site of spread was subcutaneous fat (blueberry muffin syndrome), pleura, roots of both lungs, pancreas, bone marrow. Histology of these infants was RMA (n = 6; 46%), RME (n = 6; 46%) and spindle-cell RMS (n = 1; 7.5%). The FOXO1-fusion positive status was found in 4/6 patients RMA by fluorescence in situ hybridization (FISH). 11/13 (85%) patients were categorized as high risk, 1/13 (7.5%) as very high risk, 1/13 (7.5%) – treatment for stage IV patients with metastatic disease. All patients (n = 13; 100%) received chemotherapy according to CWS guidance 2009 protocol. All patients were administered at a reduced dose according to body weight. The distribution of treatment regimens was as follows: 11/13 (85%) – IVA, 1/13 (7.5%) – IVADO, 1/13 (7.5%) – CEVAIE. 3/13 patients aged less than 1 month was administered chemotherapy according to VAC. Initial surgery included biopsy in 8/13, surgery – 5/13 (R2 – resection). Local control was provided in 11/13 (85%) patients: only surgery in 7/13 (54%) patients, only radiotherapy in 1/13 (7.5%), radiotherapy and surgery 1/13 (7.5%), only brachytherapy 1/13 (7.5%), brachytherapy and surgery in 1/13 (7.5%). 2/13 patients were not local control: one patient with favorable site (vagina) and one patient with stage IV that showed complete response after chemotherapy in both cases. Radiotherapy including brachytherapy was administered of the all patients at the over 1 year. Radiotherapy was used in 2 of 13 patients (dose range 50.4 Gy and 51.2 Gy), brachytherapy – 36 Gy. At the start of the radiotherapy the age was 21.1 and 13.37 months, brachytherapy – 12,4 and 14,5 months. Second-look surgery was performed in 9/13 (69%) patients: R0 (n = 7), R1 (n = 1), R2 (n = 1). 2/9 patients were performed mutilating surgery: orbital exenteration and cystectomy. Induction therapy was completed in 12 (92.5%) of 13 patients. Median follow-up time was 42.7 (range 3.7–90) months. 8 patients were alive, 5 died. 8/13 patients whom alive were observation: 6/8 patients no relapse/progressive, 2/8 patients – remission after local relapse and progression. 3-year overall survival was 68,4% (95% confidence interval 42,6–94,1. 3-year event-free survival was 46,2% (95% confidence interval 19,1–73,3). Patients aged less than 1 year are particularly problematic. The relatively low event-free survival rate in this age group is associated with the impossibility of carrying out the entire volume of multimodal therapy and required a tailored therapeutic approach. 

Infectious agents are well-known ecological factors inducing/accelerating human autoimmune diseases. Host infection by a pathogen can lead to autoimmunity via multiple mechanisms: molecular mimicry; epitope spreading and presentation of cryptic epitopes of self-antigen owing to lysis of self-tissue by persisting pathogen or immune cells; bystander activation, adjuvant effect of pathogens as a result of non-specific activation of immune system; polyclonal activation of B-cells by chronic infection; activation of T-cells by bacterial superantigens. Infectious agents and nonpathogenic microorganisms can also protect from autoimmune diseases via activation of regulatory T-cells and displacement of balance between two classes of T helper cells in favor of Th2. This study is supported by the Independent Ethics Committee and approved by the Academic Council of the Institute of Bioorganic Сhemistry, National Academy of Sciences of Belarus. 

Mercaptopurine (МР) is a key element of the maintenance therapy of acute leukemias. Different amounts of active and toxic metabolites can be synthesized in patients who are receiving the same doses of the drug due to pharmacokinetic differences. This contributes to the unequal drug tolerability and the need of dose adjustment. For a long time, the only tool for adjusting 6-MP dose was the level of leukocytes and granulocytes in the peripheral blood. With the understanding of genetic factors affecting the metabolism of 6-MP and development of next-generation sequencing technology, clinical guidelines for thiopurine dosing based on a pharmacogenetic approach have been emerged. In this article, we report two patients belonging to a small ethnic group in Russia with abnormal 6-MP toleration and substantiate the advantages of a personalized, pharmacogeneticallybased approach to 6-MP administration. The patient's parents agreed to use the information, including the child's photo, in scientific research and publications. 

Congenital hemangiomas are rare benign vascular tumors that develop in utero and are fully formed by the time of birth. Depending on the ability to involution, there are three subtypes: RICH (repidly involuting congenital hemangioma), NICH (non involuting congenital hemangioma), PICH (partially involuting congenital hemangioma). PICH may be accompanied by thrombocytopenia and consumption coagulopathy. Despite clearly defined clinical and histological characteristics, it can be difficult to make a differential diagnosis between congenital hemangiomas and other vascular tumors (infantile hemangioma, kaposiform hemangioendothelioma/“fascicular” angioma and others). The clinical case in the article of a vascular tumor in a newborn complicated by thrombocytopenia and consumption coagulopathy was regarded as Kazabach-Merritt syndrome, which is based on kaposiform hemangioendothelioma/“fascicular” angioma. Rapid regression of the tumor and recovery of hemogram and coagulogram parameters, as well as anamnesis of the disease and initial characteristics of the tumor forced to reconsider the diagnosis. Based on the histological picture, the diagnosis of congenital hemangioma, RICH, was confirmed. Verification of the diagnosis made it possible to change therapeutic tactics and avoid chemotherapy. A giant hemangioma, accompanied by thrombocytopenia and consumption coagulopathy, may have a very favorable outcome – a complete resolution of the pathological process inherent in its natural course. The patient's parents agreed to use the information, including the child's photo, in scientific research and publications. 

Nodular lymphocyte predominant Hodgkin lymphoma (NLHLP) – B-cell lymphoma, which has been historically added to the group of Hodgkin's lymphomas, despite the peculiarities of the clinical course, treatment and prognosis, as well as morphological and immunophenotypical differences. In 75% of cases, the disease is detected at early stages (I–II according to Ann Arbor classification), has an indolent course and a favorable prognosis with 10-years an overall survival rate, more than 80%. Despite this, with long-term follow-up and the development of frequent relapses, transformation into diffuse large-cell B-cell lymphoma (DCBCL) or T-lymphocyte/histiocyte-rich DCBCL can occur, isolated cases in children. In the world literature, there are isolated cases of the development of NLHLP after treatment of DCBKL in adults, while among the pediatric population, cases have not been described. This article presents a clinical case of DCBKL in a 10-year-old child who, 5 years after the end of treatment, developed nodular Hodgkin's lymphoma with lymphocytic predominance. The patient's parents agreed to use the information, including the child's photo, in scientific research and publications. 

18 ноября 2020 г. Совет экспертов обсудил ряд вопросов, касающихся применения новых препаратов фактора свертывания крови VIII с пролонгированным периодом полувыведения. В частности, были рассмотрены результаты клинических исследований эффективности и безопасности применения препарата руриоктоког альфа пэгол у пациентов с гемофилией А.

Autoimmune lymphoproliferative syndrome is a primary immunodeficiency caused by defective FAS-mediated apoptosis and usually accompanied by hypergammaglobulinemia. Yet some exceptions take place in the cohort of patients that complicated timely diagnosis, in particular, some symptoms may resemble common variable immune deficiency. In this article, we describe the patient with rare case of agammaglobulinemia and genetically confirmed autoimmune lymphoproliferative syndrome. The patient's parents agreed to use the information, including the child's photo, in scientific research and publications. 

The last few decades survival rates of children with hematologic malignancies have improved significantly, due to a potentially curative chemotherapy protocols, the expansion of biological knowledge and innovative methods of therapy. However oncohematological pediatric patients are at high risk for rapid clinical deterioration due to numerous factors such as the severity of the underlying condition, interventions toxicity and associated immunosuppression. Using aggressive tactics of therapy with oncohematological diseases in children is also associated with complications and life-threatening events that lead to admission to the pediatric intensive care unit. Historically, these children have been considered as poor candidates for intensive care. Discussions around the transfer of children with hematological malignancies to intensive care units and also the expected prognosis raised complicate and delicate questions, especially from an ethical point of view. Despite the general tendency of improved survival rate, mortality in the intensive care unit on hematological malignancies children, unfortunately, is still high and, in comparison to adults, has remained relatively invariable over the past decades. These findings highlight the necessity for research in this group of patients. 

Infantile hemangioma (IH) it is the most common benign vascular tumor in children of the first year, which is based on abnormal proliferation of endothelial cells under the influence of the main pro-angiogenic factors VEGF and FGF. It develops in the first weeks after birth, forming over 3–9 months with regression in the next 3–7 years. Three-quarters of infantile hemangiomas are nodular and are not accompanied by malformations. At the same time, segmental IH is most often associated with syndromic forms. Despite spontaneous regression (in 90% of cases), some forms and localization of IH can lead to the development of complications, local and endangering vital functions. In most cases, the diagnosis is based on anamnesis, characteristic features of the tumor, and clinical course. Additional studies (ultrasound DG, MRI/CT) are necessary in complicated forms and in doubtful clinical cases. The patient's parents agreed to use the information, including the child's photo, in scientific research and publications. 

The review presents a description of the health status of children conceived using assisted reproductive technologies, identifies possible causes and risk factors for the development of pathology.