Vol 18, No 2 (2019)

Primary refractory and relapsed refractory acute myeloid leukemia remains an unresolved problem in pediatric oncology. Children with AML who fail to achieve complete remission on high-dose cytarabine and antracyclines have no chance for survival without allogeneic hematopoietic stem cell transplantation. We evaluated the outcome of αβ-T-cell-depleted haploidentical transplantation in a cohort of children with chemorefractory acute myeloid leukemia. Thirty-six patients with either primary refractory (n = 14) or relapsed refractory (n = 22) acute myeloid leukemia in active disease status received a transplantation from haploidentical donors. The preparative regimen included cytoreduction with fludarabine and cytarabine and subsequent treatment with treosulfan and either melphalan or thiophosphamide. Serotherapy consisted of antithymocyte globuline in 14 pts and targeted immunomodulation with tocilizumab +/- abatacept in 22 pts. Grafts were PBSCs engineered by TCR-αβ/CD19 depletion. Posttransplant preemptive therapy included modified donor lymphocyte infusions with or without hypomethylating agents. Complete remission was achieved in 30 (83%) рts. The cumulative incidence of acute GVHD grade II–IV was 25%, and the cumulative incidence of chronic GVHD was 18%. Transplant-related mortality was 6%, and relapse incidence was 48%. Event-free survival was 46%, and overall survival was 41% at 2 years. Good early recovery of NK cells was associated with significantly improved survival and decreased relapse incidence. Our data suggest that αβ-T-cell-depleted haploidentical HSCT provides a reasonable chance of cure in a cohort of children with chemorefractory acute myeloid leukemia and creates a solid basis for further improvement. The study was approved by the Independent Ethics Committee of the Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology, and Immunology.

Graft-versus-host diseases (GVHD) is one of most significant complication after allogeneic hematopoietic stem cells transplantation (HSCT). T-cell activation is a major stage in the GVHD pathogenesis. T-cells require 2 signals for activation: cognate antigen/MHC binding T-cell receptors and positive costimulatory signals from antigen-presenting cells (APC). The predominant positive costimulatory signal to human CD4 T0-cells comes through the CD28 receptor. This signal can be blocked by fusion proteins (such as CTLA4-Ig). Abatacept is a soluble fusion protein, which links the extracellular domain of human CTLA-4 to the modified Fc portion of human IgG1. We present results of single-center prospective randomized study to evaluate the efficacy of adding abatacept to the GVHD prophylaxis protocol after hemopoietic stem cell transplantation in patients with non-malignant diseases. Study was approved by Ethics Committee and Scientific Council of the Institute (protocol # 9/2013 from 01.10.2013). During 4 years we included 62 patients, 30 of them received abatacept as additional agent. Cumulative incidence of acute GVHD was significantly lower in this group in compare with control group (p = 0,018). When we stratified patients in dependents of graft processing technology, we did not see any advantages of abatacept in patients after transplantation with TCRαβ+/СD19+ graft depletion. However, after HSCT with non-manipulated graft the abatacept showed significant efficacy in aGVHD prophylaxis compared with control group (p = 0,024). Abatacept can be recommended as effective additional agent for GVHD prophylaxis after allogeneic HSCT in patients with non-malignant diseases.

Generalized osteopetrosis is a rare hereditary disease characterized by impairment of skeleton bones formation, bone marrow dysfunction, neurologic deficiency and blindness. The main treatment for osteopetrosis is an allogeneic hematopoietic stem cell transplantation (allo-HSCT). To review and analyze experience of Department of bone marrow transplantation of RDKB (BMT RDKB) of allo-HSCT for patients with autosomal recessive generalized osteopetrosis; to evaluate tolerability and efficacy of the conditioning regiment administered. Between 2010 to 2018 years, 7 patients (2-male, 5-female) with autosomal recessive generalized osteopetrosis underwent allo-HSCT in tDepartment of bone marrow transplantation of RDKB. Median age at the moment of HSCT was 5,5 years (1–11 years). Before the transplantation myeloablative conditioning regimen was used: treosulfan, fludarabine and melphalan for 5 patients, treosulfan, fludarabine and thiotepa for 1 patient and treosulfan with fludarabine for 1 patient. In case of unrelated allo-HSCT antithymocyte globulin was added to the conditioning regimen. Bone marrow from matched (HLA- 10/10) unrelated donor was used for 4 patients, peripheral blood stem cells from matched unrelated donor was used for 1 patient, two grafts of unrelated umbilical cord blood (HLA 8/10 and 9/10) for 1 patient and peripheral blood stem cells from matched (HLA 10/10) from related donor – for 1 patient. For “graft-versus-host” disease (GVHD) prophylaxis either cyclosporine A/tacrolimus and methotrexate/ mofetil mycophenolate was used. White blood cell recovery had been achieved for 6 from 7 patients on +13 to +22 day (median +17 day). Quick autoreconstitution of hemopoesis was observed for the recipient of umbilical cord blood who got one myeloablative drug. The following early post transplantation complications were registered: oropharyngeal mucositis up to II degree in 6 patients, neutropenic enterocolitis up to II degree in 4 patients, up to III degree in 3 patients, sepsis in 3 patients. The GVHD symptoms occurred in 2 cases: skin form of II degree in one patient and skin form of II degree and intestinal form of IV degree in another patient. One patient with neurodegenerative form of osteopetrosis died with increase of hypertensive-hydrocephalus syndrome, cerebral edema with downward cerebellar herniation. During 5-6 months after allo-HSCT the 5 successfully transplanted patients experienced poor graft function but then reduction of extramedullary hemopoesis occurred and full engraftment was achieved. Hypercalcemia was reported in 2–5 months after allo-HSCT and was treated by administration of bisphosphonates. Visual impairment persisted after allo-HSCT. After 4–6 months after transplantation axis skeleton growth occurred for all 5 successfully transplanted patients, skull deformation reduced and no new zones of nerve’s compression were observed. No patients had any developmental delays after the treatment. Allo-HSCT is an effective systemic treatment of autosomal recessive generalized osteopetrosis. However because serious neurodegenerative condition cannot be reversed by allo-HSCT, such treatment may not be recommended for patients with heavy CNS impairment. Myeloablative conditioning regimen with two alkylating agents provides allogeneic reconstitution of hemopoesis. In post transplantation period, measures for hypercalcemia control are necessary. Early diagnostic of autosomal recessive generalized osteopetrosis can help to evaluate feasibility of allo-HSCT and to start treatment on time thus provide chance for long-term rehabilitation and prevention of serious disability. The study was approved by the Independent Ethics Committee of Russian Children's Clinical Hospital.

Тhere is increasing experience of protein C concentrate administration in world practice, but despite that, information of this drug administration in patients with oncohematological diseases and primary immunodeficiency syndromes is lacking. Objective: to study the effectiveness of protein C concentrate administration in pediatric patients with acquired protein C deficiency during the treatment of oncological, hematological or immunological diseases. Medical charts of 12 patients who received inpatient treatment and protein C concentrate administration in the Dmitry Rogachev National Clinical Research Center from 01/01/2012–12/31/18 were analyzed. Depending on the presence or absence of thrombosis, the patients were divided into two groups. Single and daily doses, the number of injections per day, the duration of therapy and the percentage of activity of protein C activity were studied in both groups. Вoth groups included 6 patients, median of a single administrated dose of protein C was lower in the group of patients with thrombosis than in patients without them (20 and 71.4 IU/kg, p < 0.0001), while there were obtained no differences between treatment efficacy (p = 0.45). When comparing the administered dose of the drug in children with unresolved and resolved thrombosis, it was found that the median single dose in patients with ineffective treatment was lower than in those who had effective treatment (8.78 and 71.4 IU/kg, respectively, p < 0.0001); the median daily dose was also lower in the group with ineffective treatment (20 and 71.4 IU/kg, respectively, p < 0.005). Рrotein C administration in children with acquired deficiency for the purpose of antithrombotic prophylaxis can be potentially effective, especially in those patients who already have a thrombosis at the moment of administration. The effectiveness of such prophylaxis may depend on the dose of the injected concentrate. To determine the appropriate dose and mode of administration of the drug in children a prospective study is required. The study was approved by the Independent Ethics Committee of the Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology, and Immunology.

Anemia of prematurity is a common pathology in premature infants. The prevalence of anemia of prematurity is inversely proportional to the gestational age and body weight at birth. The pathogenetic importance of impaired erythropoietin (EPO) production in anemia of prematurity provides the rationale for therapy with erythropoiesis stimulating agents (ESAs) including recombinant EPO. A comparative analysis of the effectiveness of different regimens of recombinant human erythropoietin in extremely and very low birth weight infants (ELBW and VLBW) was studied. Research has been set as a prospective analysis of 133 VLBW and ELBW infants (in the period from December 2017 to February 2019). Gestational age (GA) of the children ranged from 26 to 33 weeks, of these, GA of 75 children (56%) was 30 weeks or less. Depending on the treatment of anemia of prematurity all infants were divided into 5 groups: group 1 (n = 26) – premature babies who were prescribed ESAs since 3 day of life 200 IU/kg 3 times per week subcutaneously; group 2 (n = 21) – premature babies who were prescribed ESAs since 3 day of life 400 IU/kg 3 times per week subcutaneously; group 3 (n = 37) – premature babies who were prescribed ESAs since 8 day of life 200 IU/kg 3 times per week subcutaneously; group 4 (n = 18) – premature babies who were prescribed ESAs since 8 day of life 400 IU/kg 3 times per week subcutaneously; group 5 (n = 31) premature infants who did not receive treatment with recombinant human erythropoietin (control group). Subgroups of children of gestational age ≤ 30 weeks were identified in each group. The groups and subgroups did not differ significantly in gestational age, weight, birth length, and Apgar score at 1 and 5 minutes of life, p > 0.05. Also, there were no statistically significant differences in the age of the 1st transfusion, the frequency and total volume of transfusions, the duration of respiratory therapy, the duration of hospitalization, including treatment in NICU, body weight and age at discharge. The frequency of retinopathy of prematurity stage ≥ 3, periventricular leukomalacia, bronchopulmonary dysplasia of moderate and severe severity, intraventricular hemorrhages of varying severity, necrotizing enterocolitis was not statistically significant in the study groups and subgroups. Statistically significant differences in the concentration of hemoglobin in the peripheral blood of premature infants were revealed at discharge. In the control group, children had a lower level of hemoglobin at discharge (94 g/l) compared with the groups with early appointment of ESAs (109 g/l and 107 g/l in groups 1 and 2, respectively, P0-1 = 0.048 and P0-2 = 0.047) due to newborn GA ≤ 30 weeks. It is preferable to use of the drug ESAs at a dose of 200 IU/kg 3 p/week p/, starting from the 3rd day of life. The effectiveness of erythropoietin therapy, the time of its start and various treatment regimens remain controversial issues that require further study. The study was approved by the Independent Ethics Committee of the National Medical Research Center for Obstetrics, Gynecology and Perinatology named after Academician V.I. Kulakov.

The thoracic air-leak syndrome (TALS) can be a presentation of late-onset noninfectious pulmonary complications in children with a chronic pulmonary graft-versus-host disease (cGVHD) after allogeneic hematopoietic stem cell transplantation. We determined the frequency of occurrence of TALS in patients of the Center after HSСT in the period from January 2012 to December 2017. We have described the main X-ray signs of the Thoracic air-leak syndrome and manifestations of late onset noninfectious pulmonary complications in children. The study was approved by the Independent Ethics Committee of the Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology, and Immunology. Parents patients agreed to use personal data in research and publications.

We present a clinical case of hematopoietic stem cell transplantation (HSCT) in a patient with Wiskott-Aldrich syndrome. In spite of donor different ABO-system, the own blood group was verified in 6 months after HSCT, which was initially regarded as a risk of myeloid rejection. During the diagnosis, the hypothesis of absorption of the recipient’s ABO-system proteins onto the donorderived red blood cells was confirmed. The study of the immunological profile allowed to exclude the risks of hemolytic reactions and to predict a favorable outcome in the patient. Parents gave their consent to use information about the child in the article.

This article describes clinical case of a child with proteasome-associated autoinflammatory syndrome-2 (PRAAS2). First two cases in unrelated boys were described in July, 2018 by M. Cecilia Poli, Frederic Ebstein. We describe another case of PRAAS2. Mutations of the POMP-gene underlie PRAAS2 pathogenesis, causing defects of the POMP protein which plays important role in proteasomes maturation and leads to the clinical symptoms observed in three described cases. We also provide a short PRAAS2 background description, as well as key pathogenesis components, clinical findings description and analysis of three known PRAAS2 cases. Parents gave their consent to use personal data, including photos for clinical research and publications.

Modern technologies of treatment of children with oncohaematological diseases allowed to noticebly increase the survival indexes in this group of patients, enhancing the value of maintenance of their life quality. More than half of those who received long-term steriod and radiation treatment develop cataract that causes decrease in vision. In this review we represent data concerning mechanisms of cataract formation in patients after steriod and radiation treatment, results of anatomical, physiological and biochemical studies of the lens as well as metabolic changes in aqueous humor leading to cataract formation.