Nara G. Stepanyan

Background. Germ cell tumors (GCT) in children represent a group of chemosensitive malignant neoplasms. However, for a small subset of patients with refractory, relapsed, or disseminated GCT, the prognosis remains extremely poor, with overall survival rates potentially not exceeding 45%. High-dose chemotherapy (HDCT) followed by autologous hematopoietic stem cell transplantation (auto-HSCT) is considered a treatment strategy with the potential to improve outcomes in this patient population. Objective – to analyze the experience of HDCT with auto-HSCT in children with poor-prognosis GCT, with assessment of the efficacy and safety of this therapeutic approach. Materials and methods. This single-center retrospective study enrolled 20 children (9 boys and 11 girls) with relapsed (n = 9), refractory (n = 3), and disseminated (n = 8) forms of GCT who received HDCT followed by auto-HSCT. The median age is 2 (1–18) years. All patients had a graft of adequate cellularity collected prior to transplantation: the median CD34+ cell dose was 3.6 (range 2.0–8.1) ×106/kg body weight. A tandem HDCT regimen was administered to 14 patients (first course: carboplatin 1200 mg/m2, etoposide 1500 mg/m2, second course: etoposide 1500 mg/m2 and thiotepa 900 mg/m2). Six patients received a single-course HDCT regimen (etoposide 1500 mg/m2 and thiotepa 900 mg/m2). The median follow-up was 27 (range 1–61) months. Results. All patients achieved hematopoietic recovery following auto-HSCT. Febrile neutropenia developed in 11 patients (55.0%) during the early post-transplant period, with a mean duration of fever of 4 (range 0–6) days. Oropharyngeal mucositis and gastrointestinal mucositis were observed in all 20 patients (100.0%), and dermatological toxicity was noted in 16 patients (80.0%). In the majority of cases, the severity of toxic and infectious complications did not exceed grade 2. At a median follow-up of 2.7 years, overall survival was 84.0%, event-free survival was 78.0%, and relapse-free survival was 81.0%. Disease progression after auto-HSCT was documented in 3 patients, 2 of whom remain alive. Two patients died: one due to disease progression, and one due to an infectious episode at the place of residence 6 months after the completion of therapy. Conclusion. HDCT with auto-HSCT in children with poor-prognosis GCT may be considered an effective therapeutic approach with an acceptable toxicity profile.

Background. Tandem high-dose chemotherapy (HDCT) followed by autologous hematopoietic stem cell transplantation (auto-HSCT) is an intensification strategy for consolidation therapy in children with certain high-risk solid malignant neoplasms (SMN). Despite evidence supporting the efficacy of this approach, its tolerability, technical feasibility, and toxicity profile in the pediatric population remain subjects of ongoing investigation. Objective – to analyze the tolerability, toxicity, and technical feasibility of tandem HDCT with auto-HSCT in children with high-risk SMN, including a comparative assessment against single auto-HSCT. Materials and methods. A retrospective-prospective single-center study was conducted, enrolling 115 pediatric patients (median age 48 (range – 7–215) months) with high-risk SMN who underwent HDCT with auto-HSCT. The study group comprised 20 patients who received tandem HDCT with auto-HSCT: 14 with germ cell tumors, 4 with neuroblastoma, 1 with hepatoblastoma, and 1 with sialoblastoma. The historical control group (n = 95) included 74 patients with neuroblastoma, 16 with Ewing sarcoma, and 5 with germ cell tumors, all of whom received single auto-HSCT. A graft of satisfactory quality was successfully collected from all patients in the study group. All patients received a conditioning regimen according to the underlying disease protocol, performance status, and baseline characteristics. Therapy toxicity, outcomes, and transplant-related mortality (TRM) were evaluated. Results. Hematopoietic recovery was achieved in all patients in the study group after both transplantation stages, the median time to neutrophil engraftment was 10.5 and 11.5 days after auto-HSCT №1 and auto-HSCT №2, respectively. Grade III–IV toxic complications were recorded in 40.0% of patients after auto-HSCT №1 and in 90.0% after auto-HSCT №2 (p = 0.001), which was comparable to the historical control group (81.1%). TRM in the study group was 0%. At the time of last follow-up, 17 (85.0%) patients in the study group were alive, of whom 16 (80.0%) were in remission; in the historical control group, 74 (77.9%) patients were alive, of whom 70 (73.7%) were in remission. Conclusion. Tandem HDCT with auto-HSCT is a technically feasible consolidation strategy in children with high-risk SMN, with an acceptable tolerability and toxicity profile. The absence of TRM and a manageable toxicity profile comparable to single auto-HSCT support the expansion of indications for this approach. Further multicenter studies are needed to evaluate long-term outcomes and optimize patient selection criteria.

Introduction. Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is one of the most important curative and consolidating treatment options for hematologic malignancies, immunologic diseases, and solid tumors. Nevertheless, its use may be limited due to life-threatening post-transplant complications, such as acute graft-versus-host disease (aGVHD), chronic graft-versus-host disease (cGVHD), and poor graft function. The standard treatment for these complications includes the administration of immunosuppressive drugs. However, their side effects and limited effectiveness necessitate the continued search for additional treatments, among which the use of mesenchymal stem cells (MSCs) may prove highly effective. Materials and methods. In this retrospective/prospective study conducted from 2021 to 2025, we enrolled 25 patients aged from 10 months to 16 years (with a median age of 11 years) with refractory aGVHD, cGVHD, and/or poor graft function after allo-HSCT. MSCs isolated from the bone marrow of allogeneic donors and cultured to passages 2–3 were administered intraosseously/intravenously or through a nasojejunal tube every 1–2 weeks. The primary endpoint was clinical response to therapy. Results. The median cell product dose was 20 (4–69) × 106 cells/kg recipient body weight. A response to MSC therapy was achieved in 15 (60.0%) out of 25 patients: in 8/9 (88.9%) patients with isolated poor graft function, in 4/6 patients who had both poor graft function and GVHD, and in 3/10 patients with isolated aGVHD/cGVHD. No adverse events associated with MSC administration were observed in any patient. Conclusion. The use of allogeneic MSCs in pediatric patients with refractory complications of allo-HSCT is a safe and potentially effective method. Our results are consistent with published data and warrant prospective randomized studies with a structured design and more precise response criteria.

Relevance. Despite the overall decline in the use of auto-HSCT, there remains a need for treatment intensification in pediatric patients with highrisk solid tumors. Tandem auto-HSCT represents a promising approach to improve therapeutic efficacy, but its toxicity and impact on long-term outcomes require further investigation, particularly in the Russian patient population.The aim of study – to evaluate the feasibility, toxicity, and long-term outcomes of tandem autologous hematopoietic stem cell transplantation (auto-HSCT) in children with high-risk solid malignant neoplasms in the Russian Federation.Materials and methods. This retrospective multicenter study included 108 (100 %) pediatric patients (median age – 2 years) with solid malignant neoplasms who underwent tandem high-dose chemotherapy with auto-HSCT at 9 centers in the Russian Federation (2004–2024). Main diagnoses included brain tumors – n = 66 (61.1 %), germ cell tumors – n = 25 (23 %), and neuroblastoma – n = 12 (11.1 %). Toxicity was assessed using CTCAE v5.0 criteria, and survival analysis was performed using the Kaplan–Meyer method.Results. The most common complications were febrile neutropenia (88.9 %) and oropharyngeal mucositis (87.1 %), with severe toxicities (Grade 3–4) being rare. The 3-year overall survival was 72.2 %, and event-free survival was 62.7 %.Conclusion. The study demonstrated that tandem auto-HSCT is a feasible procedure with manageable toxicity. These findings suggest the potential of tandem auto-HSCT for children with high-risk solid tumors, though further prospective studies with long-term outcome assessments are needed to define optimal indications.

Germ cell tumors (GCTs) are a heterogeneous group of tumors that develop from pluripotent germ cells, diagnosed most often in infants, young children, adolescents and young adults, and are characterized by different localization, histological picture, clinical course and prognosis. Despite the fairly high efficiency of modern standard chemotherapy protocols for GCTs, the treatment of their relapses and refractory forms, which make up to 30–40 % of all GCTs and have an extremely unfavorable prognosis, is very difficult. Currently, there is no single strategy for the treatment of relapses and refractory forms of GCTs, however, the world and domestic literature presents data on the successful use of high-dose chemotherapy (HDCT) in such patients followed by autologous hematopoietic stem cell transplantation (auto-HSCT). To develop and optimize protocols for this therapy method, and therefore improve the treatment outcomes for patients with relapses and refractory forms of GCT, it is necessary to analyze a larger number of studies from various transplant centers working in this area. The article presents current literature data on the use of HDCT followed by auto-HSCT in patients with GCT, as well as a clinical case of successful 2 courses of HDCT with auto-HSCT in tandem mode in a child with a refractory form of GCT with subsequent maintenance of complete remission for 2 years.

Introduction. Autologous hematopoietic stem cell transplantation (auto-HSCT) is an effective method of treatment a number of malignant neoplasms and severe non-malignant diseases in addition to standard treatment protocols. Auto-HSCT requires previous successful collection of autologous hematopoietic stem cells (HSC) by apheresis with preliminary mobilization. Standard mobilization schemes include the use of granulocyte colony-stimulating factor (G-CSF), however, some patients have insufficient mobilization (IM) of HSC, which creates significant obstacles to the collection of HSC. Timely detection of predictors of IM can allow to adjust its protocol, as well as individualize the HSC apheresis regimen. Aim of the study – based on the results of the analysis of mobilization and apheresis modes of autologous HSC in patients with various malignant neoplasms to identify the most significant factors causing IM of HSC for the further development of methods for optimizing the mobilization and collection modes of HSC.Materials and methods. The study included 257 patients aged from 3 to 215 months (median age – 84 [36.0; 144.0] months) with various malignant neoplasms who received treatment at the Research Institute of Pediatric Oncology and Hematology named after Academician of the Russian Academy of Medical Sciences L.A. Durnov at N.N. Blokhin National Medical Research Center of Oncology, Ministry of Health of Russia from 2019 to 2023. According to the treatment protocol of malignant neoplasms, all patients received high-dose polychemotherapy followed by auto-HSCT as a consolidation phase of treatment. HSC mobilization was performed in advance in order to successfully perform apheresis of autologous HSCs. The main group (the group IM, n = 64) of patients included persons who did not achieve a CD34⁺ cells in peripheral blood of 20 cells/μl by the day of apheresis, despite full compliance with the established mobilization protocol. The comparison group (the “sufficient mobilization” (SM) group, n = 193) consisted of patients who achieved a CD34⁺ cells in peripheral blood of 20 cells/μl or more by the day of apheresis. Mobilization regimens included various chemotherapeutic agents (G-CSF, cyclophosphamide in the previous chemotherapy scheme, plerixafor and its combinations), the dose of which, the duration of the regimen, as well as the dose escalation depended on the initial characteristics of both the main treatment protocol and the somatic and infectious status of the patient. In the studied patient groups, the frequency of factors potentially capable of influencing the quality of mobilization before HSC apheresis was analyzed: the tumor type and stage, the number of previous courses of polychemotherapy, the presence and amount of myelotoxic agents in polychemotherapy, recovery of hematopoiesis before the start of mobilization, pretreatment, response to therapy, history of radiation therapy and surgery, the need for escalation of the G-CSF dose in the mobilization mode.Results. Significant differences (p < 0.05) between the comparison groups were obtained for such factors influencing the success of mobilization as the main diagnosis (the worst mobilization results were in patients with Ewingʼs sarcoma), tumor stage and response to previous treatment (mobilization was more successful in patients with disease stabilization). A significant negative impact on the efficiency of mobilization was also demonstrated by such factors as the lack of hematopoiesis recovery before mobilization, pretreatment (4 or more courses of chemotherapy preceding mobilization), the presence of radiation therapy, a combination of radiation and surgical treatment in the therapy protocol preceding mobilization, the presence of carboplatin and temozolomide in the chemotherapy course, as well as three myelotoxic agents simultaneously, and escalation of the G-CSF dose during mobilization. Despite the worse characteristics of the graft, as well as the technically more difficult procedure for collecting HSCs in the IM group of patients, the average number of CD34⁺ cells per kg was 1.5 × 10⁶ /kg [0.7–2.7], which demonstrates the possibility of achieving a suboptimal number of stem cells in one apheresis procedure even in patients with poor mobilization. However, in the group of IM, not only escalation of doses of stimulant agents, but also prolongation of the apheresis procedure itself with an increase a number of processed blood volume and the volume of the graft. This not only increases the resources spent on the procedure, but also increases the risks for patients and creates additional difficulties for specialists performing the procedure. To optimize the mobilization and collection modes of the HSC, it is necessary to take into account the presence of risk factors for poor mobilization and plan in advance for such patients an individual regimen of both escalation and monitoring of the mobilization, as well as preparation for a special regimen of HSC collection.Conclusion. According to the results of our study, significant predictors of IM are the characteristics of the main diagnosis, not an achievement of tumor regress, lack of hematopoiesis recovery before the start of mobilization, pretreatment, the presence of radiation therapy in the treatment protocol preceding mobilization, a combination of radiation and surgical treatment, the presence of carboplatin and temozolomide in the chemotherapy scheme, as well as three myelotoxic agents simultaneously, and escalation of the G-CSF dose in the mobilization mode. It is the patients who may require optimization of the mobilization and collection of HSCs.

High-dose chemotherapy (HDCT) followed by autologous hematopoietic stem cell transplantation (auto-HSCT) is a therapeutic option that allows potentiating the antitumor effect in patients with malignant neoplasms (MNs) belonging to the high-risk group. However, despite the effectiveness of this method, the risks of developing infectious and toxic complications in the early and late post-transplantation period are higher than the risks associated with treatment according to standard protocols and can significantly worsen the results of transplantation. We carried out a retrospective analysis of the results of auto-HSCT in a cohort of 156 patients with high-risk solid MNs treated at the L.A. Durnov Research Institute of Pediatric Oncology and Hematology, the N.N. Blokhin National Medical Research Center of Oncology of Ministry of Healthcare of the Russian Federation in 2020–2023. The study was approved by the Independent Ethics Committee and the Scientific Council of the N.N. Blokhin National Medical Research Center of Oncology. The study included 78 (50%) boys and 78 (50%) girls, the median age of the patients was 8 years 7 months (9 months – 17 years 8 months). Auto-HSCT was performed in 90 (57.7%) patients with neuroblastoma, 25 (16.0%) – with Ewing's sarcoma, 16 (10.3%) – with germ cell tumors, 13 (8.4%) – with nephroblastoma, 7 (4.5%) – with retinoblastoma, 3 (1.9%) – with medulloblastoma, 1 (0.6%) patient with pleuropulmonary blastoma and 1 (0.6%) patient with sialoblastoma. We used the following conditioning regimens: treosulfan + melphalan (n = 116), carboplatin + thiotepa + etoposide (n = 17), melphalan (n = 13), carboplatin + thiotepa + etoposide + cyclophosphamide (n = 10). Depending on the clinical indications and the treatment protocol used, 136 (87.2%) patients underwent one course of HDCT, and 20 (12.8%) patients underwent tandem HDCT. In most patients, the median recovery time for granulocytes and platelets was 11 (8–19) days and 14 (12–21) days, respectively. The most common infectious complications in patients after auto-HSCT were mucositis (89.1%), neutropenic enterocolitis (76.9%), febrile neutropenia (71.2%), less often: catheter-associated bloodstream infection (9%), pneumonia (14.1%), acute respiratory distress syndrome (0.6%). As regards toxic complications, all patients had emetic syndrome, 98 (62.8%) had dermatological toxicity, 9 (5.8%) had hemorrhagic cystitis, 116 (74.3%) had hepatic toxicity, 14 (9%) had neurotoxicity, 102 (65.4%) had moderate nutritional insufficiency. Episodes of hemorrhagic syndrome due to thrombocytopenia were observed in 44.2% of patients. After auto-HSCT, most patients develop chemotherapy-induced (including infectious) complications, which can not only significantly disrupt the patients’ well-being and quality of life, but also, depending on the severity, pose a threat to their life. The correct choice of conditioning regimen, effective collection of hematopoietic stem cells, complex accompanying therapy, timely diagnosis and treatment of complications can significantly improve the results of auto-HSCT in children with high-risk solid MNs.

Treatment of non-Hodgkin lymphomas (NHL) in children using risk-based chemotherapy protocols is currently effective in 80–95% of cases, even in advanced stages of the disease. However, relapsed/refractory forms of NHL (which are less common) have an extremely unfavorable course with low survival rates. The addition of autologous and allogeneic hematopoietic stem cell transplantation (HSCT) to a comprehensive treatment program for relapsed/refractory forms of NHL can improve treatment results due to the antitumor effect of chemotherapy drugs of the conditioning regimen and the graft-versus-tumor effect, which is, however, less significant than in leukemia. Moreover, post-transplant complications after allogeneic HSCT in some cases can offset its positive results in NHL; therefore, to reduce toxicity, especially in severe somatic status of the patient, preference is often given to reduced-intensity conditioning regimens. This article presents two clinical cases. In one case, autologous HSCT was carried out for the first relapse of Burkitt's lymphoma. However, the patient developed a second relapse and underwent allogeneic HSCT from a haploidentical donor. In the second case, HSCT from an unrelated HLA identical donor was carried out in a patient with relapsed anaplastic large cell lymphoma. Both patients received reduced-intensity conditioning regimens. This approach helped to avoid the development of severe post-transplant complications, ensuring successful engraftment and achievement of donor hematopoietic chimerism. Early after transplantation, the patient with relapsed Burkitt's lymphoma developed a second tumor – acute T-lymphoblastic leukemia, from which the patient died. Despite treatment with targeted drug crizotinib, the second patient showed lymphoma progression, which resulted in death. The patients' parents gave consent to the use of their children's data, including photographs, for research purposes and in publications.

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.