Vol 19, No 2 (2020)

Hematopoietic stem cell transplantation (HSCT) in children is a high-tech field of medicine that combines the latest achievements of pediatric hematology, oncology, immunology, transfusiology, molecular biology and cell therapy. The success of HSCT is largely owing to the unique experience of international and national cooperation between transplant centers. A regular joint analysis of transplantation activity, focused on identifying trends and problems that require theoretical and practical solutions, is one of the most important components of such cooperation. The present work summarizes the experience of HSCT in all major pediatric centers in Russia for the period 2015–2018.

Aсute myeloid leukemia (AML) in children aged 0–2 years and aсute lymphoid leukemia (ALL) up to 1 year (i.e., infants) frequently characterize high risk and poor prognosis. Аllogeneic hemopoietic stem cell transplantation (аllo-HCST) is a main curative but toxic option for these patients, and choice of allogeneic donor may be one of the important factor for long-term survival. Aim. To evaluate overall survival (OS), relapse free survival (RFS), transplant related mortality (TRM), "graft versus host" disease free/relapse free survival (GRFS) in infant with acute leukemia underwent allo-HCST from MUD vs haplodonor at 1st or 2nd remission. The study was approved by the Independent Ethics Committee and the Scientific Council of the I.P. Pavlov First Saint Petersburg State Medical University. 34 children with infant acute leukemia: 23 pts with AML (68%) and 11 – with ALL (32%) – underwent allo-HSCT from MUD vs haplo at 1st or 2nd remission between 2004–2018 were analyzed. Median age at allo-HCST – 22 months (6 months – 5 y.o.). HSCT was performed from MUD in 19 (56%) pts (group 1), haplo – 15 (44%) pts (group 2). Myeloablative conditioning received 29 (85%) pts. Reduced intensity conditioning received 5 (15%) pts. Posttransplant cyclophosphomyde (PtCy) was used in 10 (53%) pts in the group 1 and 14 (93%) pts. in the group 2 (p = 0.043). Engraftment was identified in 18 pts (95%) of group 1 and 12 pts (80%) of group 2 (p = 0.28). At the median follow up 3.5 years OS is 79% in the group 1 аnd 73% in the group 2 (p = 0.68). RFS is 79% in the group 1 аnd 67% in the group 2 (p = 0.41). GRFS is 39% in the group 1 аnd 47% in the group 2 (p = 0.5). TRM occurred in 2 pts (11%) of group 1 (due to infectious and toxicity) and no one of the group 2 (p = 0.2). Haplo-HSCT with PtCy is a good alternative to MUD with high efficacy and acceptable toxicity in children with infant acute leukemia at 1st or 2nd remission.

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a potentially curative therapy for patients with acute myeloid leukemia (AML). The conditioning regimen administered for this patient based on busulfan (Bu) combined with cyclophosphamide (Cy), fludarabine (Flu) or some other agents. Comparisons of myeloablative conditioning (MAC) versus reduced intensity conditioning (RIC) have demonstrated a various results between relapse and toxicity in a few reports. We suppose, that dose intensity of Bu across regimens may affect treatment outcomes. Aim of this retrospective study was to evaluate the impact dose of busulfan to overall survival (OS), transplant-related mortality (TRM), relapse-free survival (RFS), toxicity, the incidence of primary graft failure and acute "graft versus host" disease (GvHD) in transplantation in children and adolescents with AML. The study was approved by the Independent Ethics Committee and the Scientific Council of the I.P. Pavlov First Saint Petersburg State Medical University. We analyzed 110 AML pediatric patients with the median age 9 (range 1–19) y.o., who underwent first allo-HSCT with Bu based conditioning in R.M. Gorbacheva Memorial Institute from 2002 to 2018. Patients were divided into 3 groups: Bu1 – patients, who received Bu at the dose 8–10 mg/kg, n = 34 (31%), in Bu2 – dose of Bu was 12 mg/kg, n = 35 (32%), in Bu3 – dose of Bu was > 12 mg/kg, n = 41 (37%). In Bu1 Bu was combined with Flu in 31 (91%) pts and Cy in 3 (9%); in Bu2 – with Flu in 12 (34%), Cy in 7 (20%) and other agents in 16 (46%); in Bu3 – with Cy in 32 (78%), with Flu in 7 (17%) and other agents in 2 pts (5%) (p < 0.001). Patients in Bu2 received more Cy based GvHD prophylaxis regimens (69% vs 44% in Bu1, vs 29% in Bu3, p = 0.003) and more haplo grafts (51% vs 29% in Bu1, vs 15% in Bu3, p = 0.003). The complete remission at the HSCT was observed in 79 % in Bu1, 49% in Bu2, 61% in Bu3 (p = 0.02). Probabilities of OS, RFS, TRM were estimated by using the Kaplan–Meier method. Incidence of toxicity, acute GvHD and primary graft failure – by using Mann–Whitney U-test. Transplant engraftment was achieved in 95 (86%) of patients. Graft failure occurs in the 5 patients of Bu1 group (15%), in the 6 pts of Bu2 (17%) and in the 4 pts of Bu3 (10%) (p = 0.7). Median follow-up was 2 years for Bu1 and Bu3, 1 year for Bu2. Two-year OS was similar (Bu1 = 59% vs Bu2 = 60% vs Bu3 51%, p = 0.7). Two-year OS of pts with CR before HSCT was 70% in Bu1, 82% in Bu2, 60% in Bu3, p = 0,3 and 14%, 39%, 38% for pts with progression disease (PD), respectively (p = 0.5). Two-year RFS was 74% in Bu1, 82% in Bu2, 64% in Bu3 at CR (p = 0.4); 43%, 39% and 38% in pts with progression, respectively (p = 0.9). Median of RFS were also similar for the pts in PD (4 months in Bu1, 5 months in Bu2 and Bu3, p = 0.9) and not achieved for pts at CR. Drug related toxicity grade III–IV 4 experienced in 35% pts in Bu1, 29% in Bu2, in 54% in Bu3 (p = 0.04). Mucositis and toxic hepatitis were the most common adverse events. Sinusoidal obstruction syndrome (SOS) experienced in 8 pts from different group: 4 from Bu2 (11%), 3 from Bu3 (7%) and only pts from Bu1 (3%) with previously treated of inotuzumab (p = 0.4). The most pts with VOD (3/5) had PD at the HSCT. Cumulative incidence of acute GvHD grade 2 (15% vs 14% vs 10%, p = 0.8) were not different. Acute GvHD grade III–IV was observed a bit more often in Bu3 (34%), than in Bu1 (18%) and Bu2 (17%) (p = 0.09). TRM up to D+100 was also higher in Bu3 (15%), than in Bu2 (6%) and Bu1 (0%) (p = 0.05). The transplant results of children with similar disease status of AML, received MAC or RIC conditioning with various dose of Bu, were not associated with significant differences in overall outcomes. The higher dose Bu may increase incidence of toxicity grade III–IV (p = 0.04) and acute GvHD grade III–IV (p = 0.09) with increasing of early TRM (p = 0.05).

Allogeneic hematopoietic stem cell transplantation (HSCT) is a recognized method for treating children with a very high risk group for acute lymphoblastic leukemia (ALL) and a high risk group for acute myeloid leukemia (AML). The use of allogeneic HSCT for certain risk groups of acute leukemia significantly improves the survival of these patients compared to chemotherapeutic regimens. The aim of this study was to identify the causes of failure of HSC transplantation in children with acute leukemia in a homogeneous group of patients and the possibility of further improvement in survival rates. The study was approved by the Independent Ethics Committee and the Scientific Council of the Belarusian Research Center for Pediatric Oncology, Hematology and Immunology (Republic of Belarus). The study included 101 patients with ALL and 65 patients with AML who underwent the first HSCT, in accordance with the first-line treatment protocol or relapse for 2 consecutive time periods (1998–2008 and 2009–2018). For the entire group of patients, an increase in overall (by 13%) and event-free survival (by 7%) was revealed due to a decrease in post-transplant mortality not related to relapse by 16% (p = 0.077). Significant improvement in survival over time occurred in the group of patients with acute or chronic “graft versus host” disease. The data obtained indicate that all patients with acute leukemia who have indications for HSCT in the first line of treatment or relapse should be transplanted from any available donor, as this will significantly increase their chances of recovery.

Mucopolysaccharidosis type I (MPS IH; Hurler syndrome) is a hereditary storage disease caused by a deficiency of the lysosomal enzyme alpha-L-iduronidase. Enzyme replacement therapy may extend the lifespan of affected patients by 6–12 years but the only currently available radical treatment option is allogeneic hematopoietic stem cell transplantation (allo-HSCT). Objectives: We aim to evaluate the influence of conditioning regimens of various intensities and “graft versus host” disease (GvHD) prophylaxis with anti-thymocyte globulin and post-transplant Cyclophosphamide (PTCy) on overall (OS) and event-free (EFS) survival, the incidence of GvHD, the normalization of alpha-L-iduronidase and glycosaminoglycan (GAG) levels over time as well as cardiovascular and cognitive recovery following allo-HSCT. The study was approved by the Independent Ethics Committee and the Scientific Council of the I.P. Pavlov First Saint Petersburg State Medical University. We included 28 patients with MPS IH who had received allo-HSCT at the clinic at the R.М. Gorbacheva Memorial Institute of Children Oncology, Haematology and Transplantation. The five-year OS was 89%, the EFS – 57%. The use of myeloablative conditioning regimens and allo-HSCT within 12 months of diagnosis improve EFS in affected patients. The cumulative incidence of grade II–IV acute GvHD and grade III–IV acute GvHD was 43% and 18% respectively. The use of PTCy results in a significantly lower incidence of this complication (69% vs 33%, p = 0.013). After allo-HSCT, normal alpha-L-iduronidase levels and urinary GAG excretion were achieved in cases where graft function was normal. Allo-HSCT is an effective treatment for patients with MPS IH. Myeloablative conditioning regimens are the preferred treatment modality for this group of patients but in cases of comorbidities or poor physical status at the time of allo-HSCT, conditioning regimens with reduced intensity may be opted for instead. PTCy may be used for GVHD prevention in patients with MPS IH without increasing the risk of cardiac toxicity.

Conditioning for hematopoietic stem cells transplantation (HSCT) and long isolation period often results in movement disorders to patient undergoing HSCT. An increesing number of reaserch to showing of the importance physical therapy at different stages of HCST. Objective. Сomparative assessment muscles strength and vegetative support childhood at different stages of HSCT for the determine timing for the motor rehabilitation. 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. In the prospective comparative not randomized clinical trail were enrolled 27 patients aged 6–14 (11) years with acute lymphoblastic leukemia (ALL) (n = 8), acute myeloblastic leukemia (AML) (n = 8), sever aplastic anemia (n = 2) and primary immune deficiency (n = 9) at different stages of HSCT therapy. For all patients muscle strength and hemodynamic level in orthoclinistatic test were conducted before HSCT (-5 days of conditioning), after HSCT (+5 days after transplantation), and upon leaving hospital units (+30 days after HSCT). On the conditioning stage patient at ALL and AML diagnosis group had hyperchronotrope and hypostenic vegetative reaction type, while normostenic and normochronotrope vegetative reaction type at not malignant diseases diagnosis group. Muscle strength score at ALL and AML diagnosis group average was between 3–4 score, and 4–5 score at not malignant diseases diagnosis group. On the +5 days after HSCT in all researched diagnosis groups at 100% cases experienced hypostenic and hyper chronotrope vegetative type of reaction, and reduced muscle strength average 2 score. On the +30 days after HSCT at ALL diagnosis group experienced hypochronotrope and hypostenic type of vegetative reaction at 75% and 87.5% respectively, at AML diagnosis group experienced hypochronotrope and hypostenic type of vegetative reaction at 87.5% and 75% respectively, and at not malignant diagnosis group experienced hyperchronotrope and hyperstenic type of vegetative reaction at 81,8% cases. In the remaning cases at all diagnosis group experienced normostenic and normochronotrope type of vegetative reaction. Average muscle strength score at ALL and AML diagnosis group was 4 score. Average muscle strength score at not malignant diagnosis group was between 4–5 score. It’s important to get an early start physical therapist to childhood receiving of HSCT therapy.

The aim of this study was a retrospective analysis of the effectiveness of the domestic Factor VIII drug Octofactor for the prophylactic treatment of patients with hemophilia A living in the Amur Region. For the past 3 years, 10 hemophilia A patients over the age of 18 years have been receiving replacement therapy with this medication while other 10 hemophilia A patients of the same age have been receiving Factor VIII, a foreign drug. Each group included 6 patients with severe hemophilia A and 4 patients with moderate disease. This retrospective clinical study has been approved by the local Ethics Committee Amur State Medical Academy, Ministry of Healthcare of Russian Federation. All of the patients have signed voluntary informed consent for the use of their personal data in clinical studies and publications. Octofactor at a dose of 20–40 IU/kg body weight was administered every second or third day (2 to 3 times a week). Prevention has significantly reduced the need for hospitalization, improve performance. Patients with good adherence to treatment of spontaneous bleeding were not observed. Spontaneous bleeding of mild to moderate severity was diagnosed only in patients with low adherence to treatment, was stopped by administering the drug in therapeutic doses on an outpatient basis and did not require hospitalization. It was possible to achieve the desired indicators of clinical control – no more than 2 spontaneous hemarthrosis or other bleeding per year. Adverse reactions were not identified in patients treated with the drug Octofactor. With prophylactic treatment, it was possible to reduce the number of bleeding by 98%, both in patients using foreign commercial drugs of Factor VIII and in the treatment with Octofactor, compared with the period until 2005, when patients with hemophilia A received treatment on demand with cryoprecipitate and freshly frozen plasma. It is concluded that Octofactor preparation is not inferior to foreign Factor VIII concentrates in terms of efficiency and safety and can be effectively used for the prevention of bleeding in hemophilia A, including for individualized therapy

Wiskott–Aldrich syndrome (WAS) is a rare X-linked primary immunodeficiency characterized by microplatelet thrombocytopenia, eczema, frequent infections and an increased risk of autoimmune disorders and malignant neoplasms. Mutation detection in WAS gene is the gold standard for diagnosis of this disorder. This gene encodes a WASP protein, which works as regulator of cell cytoskeleton and is involved in the transmission of many intracellular signals. Nowadays there is no rapid and reliable method that allows to confirm WAS in a short period of time. Early detection of WAS in patients enables initiation of a donor search and preparation for the HSCT procedure. It also helps to avoid the development of severe and life-threatening conditions during waiting for genetic confirmation of the diagnosis by using pathogenetic therapy. Currently flow cytometry is one of the leading laboratory methods that permits to get the information about the expression of a protein in several hours. The study below describes rapid and reliable based on flow cytometry assay for WAS diagnosis. 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 46 patients with suspected WAS from 2 months to 17 years old. Patients were examined from January 2018 to January 2020. WAS gene defect was confirmed in 35 patients. It was calculated that normal threshold value for WASP expression is 7.07 with sensitivity and specificity 100% and 93.1% respectively. Besides negative correlation between WASP expression index and WAS clinical severity was shown (r = –0.63). This flow cytometry assay can be used for chimerism detection in WAS patients after HSCT. The flow cytometry assay for WASP protein evaluation is rapid, highly sensitive and highly specific. It allows to speed up diagnosis of this disorder.

We assessed the effectiveness of the registry of Kirov Research Institute of Hematology and Blood Transfusion, Federal Medical and Biological Agency of Russia, with a total of 35,117 hematopoietic stem cell donors recruited in 22 regions of the Russian Federation (as of 01 January 2019). It was established that a relatively small registry would be sufficient to find at least one fully matched donor for 43% of Russian patients. The sufficient representativeness of this hematopoietic stem cell donor registry is confirmed by the high concordance of established HLA haplotype profiles between the population of donors and the cohort of patients for whom a search of a matching donor was performed. This study was approved by the Independent Ethics Committee and Scientific Council of Kirov Research Institute of Hematology and Blood Transfusion, FMBA of Russia.

Pigmented epithelioid melanocytoma (PEM) is an uncommon, recently described melanocytic lesion. There is a high rate of regional metastases, but limited evidence of distant metastases, an indolent clinical course and favorable outcome. The article presents a clinical case of PEM with aggressive behavior and distant metastases in patient with Fanconi Anemia after hematopoietic stem cell transplantation. Parents gave their consent to use information about the child, including fotos, in the article.

Thalassemia is the most common form of hereditary anemia from the hemoglobinopathy group. The genetic disorder underlying thalassemia leads to impaired erythrocyte maturation, hemolysis, and the development of ineffective erythropoiesis with erythroid gland hyperplasia in the bone marrow and extramedullary. Regular blood transfusions and chelator therapy are standard therapy for patients with b-thalassemia. This method increases life expectancy, but does not improve its quality and does not cure the disease. Currently, allogeneic hematopoietic stem cell transplantation remains the only radical treatment for thalassemia. The paper discusses the historical aspects of the development of allogeneic hematopoietic stem cell transplantation in the context of transfusion-dependent form of b-thalassemia treatment.

The main function of the complement system is to provide humoral defence against foreign pathogens. It contributes to immune response and is a crucial component of innate immunity that provides immediate non-specific immune defence. Inherited or acquired deficiencies of the complement system associated with excessive activation or other impairments of complement activity have varied clinical manifestations. Paroxysmal nocturnal hemoglobinuria (PNH) is a rare acquired clonal blood disorder that clinically manifests with anemia, thrombosis, chest and abdominal pain, chronic kidney disease and bone marrow failure. The complement-mediated hemolysis due to the lack of membrane-bound complement-regulatory proteins CD55 and CD59 is a central underlying mechanism of the disease and mortality associated with PNH. The severity of clinical symptoms determines the type of treatment which may include allogeneic hematopoietic stem cell transplantation and pathogenetic treatment through the inhibition of the complement system. Eculizumab, a humanized monoclonal anti-C5 antibody, has become the first complement inhibitor to show effectiveness in treating any of complement-mediated hemolytic anemias and now serves as a standard of treatment for patients with PNH. Brisk development of biotechnological methods for the production of new drugs in Russia has enabled the initiation of drug discovery efforts and the creation of the world's first biosimilar of Eculizumab.