Vol 22, No 2 (2023)

   Currently, allogeneic hematopoietic stem cell transplantation (allo-HSCT) is an effective treatment option for relapsed / refractory (R / R) acute leukemia (AL) and high-risk AL. In this article, we present our own experience of allo-HSCT in children with R / R AL. The study was approved by the Independent Ethics Committee and the Scientific Council of the N. N. Blokhin National Medical Research Center of Oncology. Fifty-one patients with R / R AL were included in the study: 32 patients had acute lymphoblastic leukemia (ALL), 17 patients had acute myeloid leukemia (AML) and 2 patients had biphenotypic leukemia (BL). All patients underwent allo-HSCT from January 2021 to October 2022. The median age was 8.7 years (5 months – 17 years). At the time of allo-HSCT, 26 patients were in the second (and further) remission, the rest were in the first clinical and hematologic remission (high-risk AML and refractory ALL). Twenty-one (41.2 %) patients received allo-HSCT from a haploidentical donor, 19 (37.2 %) patients underwent allo-HSCT from an HLA-matched related donor and 11 (21.6 %) patients – from an HLA-matched unrelated donor. Pre-transplant conditioning in ALL: 27 patients received regimens based on total body irradiation at a dose of 12 Gy, 4 patients received busulfan-based conditioning regimens, and in 1 patient we used treosulfan. In AML and BL, we used conditioning regimens based on treosulfan/thiotepa (n = 10), treosulfan/melphalan (n = 8) or busulfan / melphalan (n = 1). Bone marrow (in 14 patients) and peripheral blood stem cells (in 37 patients) were used as a source of hematopoietic stem cells. In haploidentical allo-HSCTs in order to prevent graft-versus-host disease (GVHD) we performed TCRab/CD19 depletion followed by additional administration of abatacept / tocilizumab / rituximab on day –1 in 15 patients, 6 patients received post-transplant cyclophosphamide. In transplantations from HLA-matched related and unrelated donors, patients received combined immunosuppressive therapy with abatacept and rituximab on day –1, and calcineurin inhibitors were used as basic immunosuppressive therapy. All patients engrafted with a median time to engraftment of 13 (range, 9 to 24) days after allo-HSCT. Eight (15.7 %) patients developed a relapse of AL at different times after HSCT (five of them are alive). At the median follow-up of 9 (5–25) months, the overall and disease-free survival survival rates were 76.4 % and 68.8 %, respectively, for patients with AL. Acute GVHD was observed in 72.5 % of children, grade 3–4 GVHD was observed in 5.3 % of patients, and 13.7 % of children developed chronic GVHD. Most patients developed infectious complications in the early post-transplant period: febrile neutropenia (96.0 %), reactivation of viremia (47.3 %,) oropharyngeal mucositis (78.4 %), acute cystitis (12.3 %). The overall mortality rate was 17.6 %. Late mortality was associated with a relapse of AL.

   Acute myeloid leukemia (AML) is the second most common type of leukemia in children and accounts for up to 20 % of all leukemias. Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is an effective, and sometimes the only therapeutic option in high-risk patients with AML. Graft-versus-host disease (GVHD) is a major complication of allo-HSCT and the main cause of transplant-related mortality. GVHD prophylaxis in children includes calcineurin inhibitors, either alone or in combination with other immunosuppressants, which can lead to grade II–IV acute GVHD in 40–85 % of cases. Alternatively, GVHD can be prevented with high-dose cyclophosphamide (50 mg/kg/day) administered on days +3, +4 after allo-HSCT, either alone or in combination with other immunosuppressive drugs depending on HLA compatibility of the donor.

   The aim of this study was to evaluate outcomes after allo-HSCT from an unrelated donor with GVHD prophylaxis with post-transplant cyclophosphamide (PTC) in children in their first and second remission of AML in comparison with a historical control group.

   We retrospectively analyzed patient outcomes after 53 first-time allo-HSCTs from HLA-matched (n = 40) and partially-matched (8–9/10) (n = 13) unrelated donors performed in pediatric patients (aged 0 to 18 years) in their 1^st or 2^nd remission of AML at the R. M. Gorbacheva Research Institute for Pediatric Oncology, Hematology and Transplantation from 2008 to 2018. The study was approved by the Independent Ethics Committee and the Scientific Council of the I. P. Pavlov First Saint Petersburg State Medical University of Ministry of Healthcare of the Russian Federation. Our group of interest included 26 patients preventively treated for GVHD with 50 mg/kg of cyclophosphamide on days +3 and +4 in combination with calcineurin inhibitors (cyclosporin A – 2 (7.7 %) patients, tacrolimus – 24 (92.3 %) patients), the mTOR inhibitor sirolimus (5 (19.2 %) patients) or mycophenolate mofetil (21 (80.8 %) patients). The historical control group was made up of 27 patients whose GVHD prophylaxis was based on antithymocyte globulin used in combination with calcineurin inhibitors (tacrolimus – 5 (18.5 %) patients, cyclosporin A – 21 (77.8 %) patients) or the mTOR inhibitor sirolimus (1 (3.7 %) patients) or methotrexate (25 (92.6 %) patients), or mycophenolate mofetil (2 (7.4 %) patients). The groups were matched for diagnosis, age, disease status before allo-HSCT, the matched-to-partially-matched donor ratio, the source of hematopoietic stem cells and conditioning regimen intensity (myeloablative conditioning regimen (MAC) or reduced intensity conditioning regimen (RIC)). The median age at the time of allo-HSCT was 8.6 (0.97–18) years in the PTC group and 6.55 (1.42–17.76) years in the historical control group. In the PTC group, 21 (80.8 %) patients were diagnosed with primary AML and 5 (19.2 %) – with secondary AML, while the historical control group included 22 (81.5 %) and 5 (18.5 %) patients with primary and secondary AML respectively. Disease status at the time of allo-HSCT: 21 (80.8 %) patients treated with PTC were in the 1^st complete clinical and hematologic remission (CCHR) and 5 (19.2 %) – in the 2^nd CCHR; among the controls, there were 19 (70.4 %) cases of the 1^st CCHR and 8 (29.6 %) cases of the 2^nd CCHR. In the PTC group, 18 (69.2 %) patients underwent allo-HSCT from 10/10 fully HLA gene-matched donors and 8 (30.8 %) – from 9/10 HLA-matched donors. In the historical control group, 19 (70.4 %) patients had allo-HSCT from 10/10 fully HLA gene-matched donors, 4 (14.8 %) – from 9/10 matched donors, and 1 (3.7 %) – from an 8/10 matched donor. In the PTC group, MAC was used in 14 (53.8 %) patients, RIC – in 12 (46.2 %) patients. In the control group, MAC and RIC were used in 14 (51.9 %) and 13 (48.1 %) patients respectively. In the group treated with PTC, hematopoietic stem cells were derived from the bone marrow in 14 (53.8 %) patients, from the peripheral blood – in 12 (46.2 %) patients. In the historical group, bone marrow was used in 13 (48.1 %) patients and peripheral blood - in 14 patients (51.9 %). The median graft cellularity (CD34+ × 10⁶/kg) in the PTC group was 4.60 (1.7–10.9) × 10⁶/kg, in the historical group – 6.60 (1.0–13.2) × 10⁶/kg. The overall and relapse-free 5-year survival rates were higher in the PTC group than in the historical control group: 83.3 % (95 % confidence interval (CI) 60.9–93.5) vs 59.3 % (95 % CI 38.6–75.0), p = 0.0327 and 76.9 % (95 % CI 55.7–88.9) vs 48.1 % (95 % CI 28.7–65.2), respectively, p = 0.0198. The cumulative incidence of grade II–IV acute GVHD and grade III–IV acute GVHD by day +125 and of moderate and severe chronic GVHD, and the 2-year transplant-related mortality were significantly lower in the PTC group compared to the controls: 15.4 % (95 % CI 4.8–31.5) vs 51.8 % (95 % CI 31,9–68.5), p = 0.004; 7.7 % (95 % CI 1.3–21.7) vs 33.3 (95 % CI 16.8–50.9), p = 0.026; 23.4 % (95 % CI 9.5-41.0) vs 58.6 % (95 % CI 33.8–76.8), p = 0.022; 3.8 % (95 % CI 0.3–16.4) vs 25.9 % (95 % CI 11.5–43.1), p = 0.0232, respectively. GVHD-related mortality was higher in the historical control group than in the PTC group (3.8 % vs 18.5 %, p = 0.192). Thus, PTC-based GVHD prophylaxis was shown to be more effective in managing acute and chronic GVHD compared to antithymocyte globulin, with better overall, relapse-free and GVHD-free relapse-free survival rates and low transplant-related mortality.

   Literature data suggest that vitamin D (VD) deficiency may adversely affect many systems of the body, not only skeletal system, as believed earlier, but also central nervous system, cardiovascular system, urinary system, and immune system, which is particularly important for patients undergoing allogeneic hematopoietic stem cell transplantation (HSCT). Two consecutive studies of VD deficiency after allogeneic HSCT in pediatric patients showed that VD deficiency was associated with decreased overall survival. The correction of VD deficiency was also reported to be a challenge, and in some cases higher doses of VD were needed (200 IU/kg/day or more), but even with this more aggressive approach VD deficiency could persist. In this article, we present a literature review on this topic as well as our data on the management of VD deficiency and monitoring of serum 25-hydroxycholecalciferol (25-HVD) levels in 18 children undergoing allogeneic HSCT at our hospital. This study was approved by the Independent Ethics Committee of the Regional Children's Clinical Hospital (Yekaterinburg). Unfortunately, because of the small size of the patient group we were not able to obtain reliable scientific data. However, here we present our approach to the clinical management of VD deficiency, personalized dosing of VD, and safe therapeutic ranges of VD metabolites in blood. The majority of HSCT recipients in our study achieved therapeutic levels of 25-hydroxycholecalciferol. Treatment of VD deficiency in children undergoing allogeneic HSCT is a promising way to improve overall survival, but further studies are needed to develop optimal clinical strategies.

   Treatment of patients with high-risk neuroblastoma (NB) is a complex challenge, and it is based on response to certain elements of therapy. The development and introduction of new treatment approaches, such as GD2-targeted immunotherapy (IT), leads to improved survival in this cohort of patients.

   The aim of the study was to retrospectively assess the effectiveness of therapy in patients with high-risk NB before the introduction of IT into clinical practice.

   We retrospectively analyzed the data of 151 NB patients stratified into a high-risk group who had received treatment in accordance with the modified NB2004 protocol of the German Society for Pediatric Oncology and Hematology (GPOH) at the Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology from 01.2012 to 12.2017. This study was approved by the Independent Ethics Committee and the Academic Council of the Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology. All the study subjects (or their legal representatives) signed a voluntary informed consent form indicating their agreement to treatment and use of their data for research purposes. Overall survival (OS), event-free survival (EFS), and risk factors were analyzed in the patients with high-risk NB including those who had completed multimodal therapy with autologous hematopoietic stem cell transplantation and post-consolidation therapy with isotretinoin and had achieved a satisfactory response to induction therapy (complete response (CR), very good partial response (VGPR), partial response (PR)) (population of special interest). The main unfavorable prognostic clinical and molecular genetic factors affecting survival in the high-risk NB patients were older age, MYCN gene amplification, and stage 4 of the disease. The use of the modified GPOH NB2004 protocol resulted in a satisfactory response (CR/VGPR/PR) to the induction therapy in most patients: 124/151 (82.1 %). Surgery (other than primary tumor biopsy) led to improved survival, with no statistical difference between macroscopic radical surgery and macroscopic residual tumor. At the same time, radiation therapy (RT), as the second element of local control, had a significant impact on EFS in the group of the patients with stage 4 disease: the 3-year EFS was 39.4 % (95 % confidence interval (CI) 23.1–55.4) in the patients with RT versus 25.7 % (95 % CI 17.5–34.7) in the patients without RT (p = 0.0295). The introduction of a new high-dose TreoMel chemotherapy regimen did not result in worse survival rates but led to a decrease in transplant-related toxicity. The 5-year OS and 5-year EFS were 49.4 % (95 % CI 40.9–57.3 %) and 33.3 % (95 % CI 25.9–40.9) respectively for all the study subjects, and 81.6 % (95 % CI 70.3–88.9) and 55.1 % (95 % CI 43.1–65.5) respectively for the patients from the population of special interest. The analysis of the results of therapy in the high-risk NB patients who had received treatment at the Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology, yielded results comparable to those of the original GPOH NB2004 protocol. The patients with CR/VGPR/PR to the induction therapy who had completed the protocol treatment with autologous hematopoietic stem cell transplantation and isotretinoin post-consolidation therapy demonstrated higher 5-year EFS rates. However, there remains a need to develop more effective treatment regimens for high-risk NB.

Pure red cell aplasia (PRCA) is a rare complication of AB0-incompatible allogeneic hematopoietic stem cell transplantation, which manifests as a partial or complete absence of erythroid lineage in recipients with normal function of other hematopoietic lineages. There is a hypothesis, that lysis of erythroid precursors occurs because of antibody formation by population of residual B-lymphocytes and/or long-lived recipient’s plasma cells, which are capable for proliferation and active expression of the CD38 marker. That is why the invention of the IgG1 monoclonal antibody to CD38 presented as a new potentially effective targeted therapeutic option for patients with refractory PPCA. The article summarize clinical data on daratumumab for the therapy of PRCA in pediatric allogeneic hematopoietic stem cell transplantation recipients. The patients' parents gave their consent to the use of their children's data, including photographs, for research purposes and in publications.

   The problem of extramedullary (EM) involvement in acute myeloid leukemia (AML) in children is of considerable relevance since its pathogenesis remains understudied and the impact on prognosis is still unclear. The variability of tissue and organ involvement depends on immunophenotypic, cytogenetic, and molecular features of myeloid cells and can cause difficulties in diagnosis, thus making it necessary to combine imaging and laboratory tools for timely and accurate diagnosis of EM disease. The prognostic significance of EM involvement has not been established unequivocally, thus the need for intensification of chemotherapy, as well as for allogeneic hematopoietic stem cell transplantation in first remission, remain debatable. The results of target therapy in EM AML are encouraging and may reduce the risk of AML relapse. This article describes the clinical features of EM AML in children and reviews the diagnostic approaches as well as the advantages and limitations of existing laboratory and imaging methods. The molecular features of EM AML, current treatment options and prognosis have also been analyzed. The patients' parents gave their consent to the use of their children's data, including photographs, for research purposes and in publications.

   Studying diseases associated with viruses belonging to the family of Herpesviridae is an important challenge for medical researchers and clinicians because of the specific tropism of herpesviruses for immune cells, life-long persistence in human target cells, the ability to reactivate and the potential to cause a wide variety of clinical manifestations. Unlike other members of Herpesviridae, Epstein–Barr virus (EBV), also known as human herpes 4, displays tropism for B cells and mucosal epithelial cells, has the capacity to cause not only productive infection (infectious mononucleosis), but also establish various types of latency in cells, causes benign and malignant transformation of immune system cells (hemoblastoses) and mucosal epithelial cells (oral cavity cancer and gastric cancer). EBV causes 200 000 deaths worldwide every year, the majority of which are attributable to cancers associated with EBV persistence. Moreover, EBV is associated with a group of autoimmune disorders, such as multiple sclerosis, and secondary immunodeficiencies occurring in patients with infection of immune system cells. Mechanisms of the interaction between EBV and human cells implicated in cancer induction should be a focus of further research in fundamental virology, oncology and medicine as a whole. The interactions between EBV and target cells in mother-fetus-child system appear to be the most complicated. The inevitability of facing the virus and associated long-term consequences is determined by the time and mode of mother-to-child transmission of EBV, the presence of innate immune defense factors, genetics and molecular mechanisms of EBV latency. Recent scientific insights allow us to establish control over the evolution of EBV interactions with its host and to identify promising approaches to the prevention and treatment of previously incurable diseases associated with EBV.