Introduction. The long-term event-free survival of patients with high-risk neuroblastoma (NB) receiving intensive complex therapy according to current russian standard do not exceed 40 %. Also, there is no standard tactics in patients with primary resistant and relapsed disease, most of them die due to disease progression. While, anti-GD2 immunotherapy (IT) proved to be effective in patients with high-risk NB, in Russian Federation this method is not generally available. There are currently two pilot studies ongoing in Raisa Gorbacheva Memorial Institute aimed to evaluate the effectiveness of anti-GD2 antibodies in high-risk NB patients.Aim of the study – describing a single-center experience of anti-GD2 IT in primary high-risk NB patients and patients with primary resistant and relapsed disease.Materials and methods. A total of 20 patients received anti-GD2 antibodies, 16 of them were included into pilot trials. The median age at IT initiation was 5 (3–17) years. In 13 cases the therapy was initiated in patients with high-risk disease after auto-HSCT, in 3 cases – in patients with 1st systemic relapse of primary resistant disease after 2nd-line therapy and haplo-HSCT, in 1 case – in patient with 2nd chemosensitive relapse after haplo-HSCT. Also, 3 patients with progressive chemoresistant disease received anti-GD2 antibodies as monotherapy (n = 1) or in combination with chemotherapy (n = 2) as salvage regimen.Results. Patients receiving anti-GD2 antibodies after auto-HSCT retain response to therapy in 11 of 13 cases with a median follow-up period of 15 (6–27) months, in 2 cases there was disease progression during or immediately after IT cessation. Both patients with disease progression responded well to salvage therapy. Two of 3 haplo-HSCT recipients with prior good response to 2nd-line therapy are currently in remission 16 and 36 months past haplo-HSCT, one patient progressed 55 months after transplantation. A patient with 2nd late relapse after haplo-HSCT currently maintains remission on IT. Both patients with chemorefractory progressive disease did not respond to IT and died due to disease progression. IT was characterized by acceptable toxicity. In most cases it was complicated by Gr 1–2 fever, rash or neuropathic pain effectively controlled by supportive therapy. However, three patients had signs of neurotoxicity requiring therapy termination in one case.Conclusion. Dinutuximab beta IT is characterized by acceptable toxicity. With a median follow-up of 18 (6–59) months the majority (14 of 17) patients receiving anti-GD2 antibodies as maintenance therapy after auto- or allogeneic HSCT retain response. However, we did not observe any response in patients with progressive chemorefractory disease.

There is no doubt that autologous hematopoietic stem cell transplantation (auto-HSCT) with high-dose polychemotherapy (PCT) is a standard method for the second remission consolidation in case of relapse or for the fist remission consolidation in refractory disease in adult patients with non-Hodgkin lymphomas (NHL) (with the exception of lymphoblastic lymphoma in which allogeneic transplantation is preferable). Similar to patients older than 18 years of age, an identical algorithm is applied in pediatric patients, however in the absence of randomized clinical trials and due to a small number of patients, the evidence base in children is weaker compared to adults, which complicates the analysis. Due to a signifiant number of nonrandomized studies confiming the benefis of transplantation, it is impossible to plan and make a direct comparison of auto-HSCT and standard chemotherapy in pediatric patients within a randomized study primarily because of ethical reasons. Although transplantation is not able to fundamentally change the prognosis in all children with relapsed or refractory (R/R) NHL, a cure cannot be achieved without this method. Taking into account that most of the works devoted to auto-HSCT in children with R/R NHL were published more than 10 years ago, current data on this issue are of great interest due to the large-scale implementation of the effective methods of targeted and immunotherapy over the past decade. This study was approved by the Independent Ethics Committee and the Scientifi Council of the I.P. Pavlov First Saint-Petersburg State Medical University, Ministry of Healthcare of the Russian Federation. At the R.M. Gorbacheva Research Institute of Pediatric Oncology, Hematology and Transplantation, 31 children with R/R NHL underwent auto-HSCT from 2008 to 2020. The median age at the time of transplantation was 14 (2–18) years. At the onset of the disease, most patients were diagnosed with stage III or IV cancer (n = 30, 97%), the CNS involvement was registered in 4 patients (13%), the bone marrow involvement was registered in 2 patients (6%). The histological variants were as follows: primary mediastinal large B-cell lymphoma (n = 11, 35%), anaplastic large cell lymphoma (n = 6, 9%), Burkitt's lymphoma (n = 5, 16%), diffse large B-cell lymphoma (n = 5, 16%), peripheral T-cell lymphoma (n = 2, 7%), unspecifid B-NHL (n = 1, 3%) and lymphoblastic lymphoma (n = 1, 3%). The Karnofsky performance status prior to transplantation was ≥ 90% in all patients. The median time from diagnosis to auto-HSCT was 304 (122–3888) days. The median number of prior lines of therapy was 2 (1–4). In the majority of the patients (n = 27, 87%), a fist-line treatment was carried out according to the principles developed by the BFM group and in 4 older children (13%), we used regimens based on CHOP. As a second-line treatment, 18 (58%) patients received R-ICE (rituximab, ifosfamide, carboplatin, etoposide); the rest of the patients were treated with other regimens. NHL was relapsed (n = 14, 45%) or refractory (n = 17, 55%). A histological confimation of R/R NHL was carried out in 11 (35%) patients; in the rest of the cases, the diagnosis was made based on the imaging results and their correlation with the clinical presentation. Remission prior to auto-HSCT was achieved in 90% (n = 28) of cases: complete remission was observed in 39% (n = 8) of cases, and partial remission was observed in 51% (n = 16) of cases. In addition, transplantation was carried out in three patients (10%) who did not achieve remission. The graft sources were peripheral hematopoietic stem cells (n = 19, 61%) and bone marrow (n = 12, 39%). The median CD34+cells/kg was 3.85 (2–7.6). As conditioning regimens we used BEAM (n = 13, 42%) and BeEAM (n = 18, 58%). Both regimens consisted of etoposide 200 mg/m2/day from D5 to D2, cytarabine 400 mg/m2/day from D5 to D2, melphalan 140 mg/m2/day on D1. The regimens diffred in the following: we used carmustine 300 mg/m2/day on D6 in BEAM or bendamustine 160 mg/m2/day on D7 and D6 in BeEAM. Immunotherapy or targeted therapy prior to auto-HSCT was carried out in the majority of the patients (n = 25, 80%). The following medications were used: rituximab (n = 20, 65%), brentuximab vedotin (n = 6, 19%), nivolumab (n = 3, 10%), crizotinib (n = 2, 6%). Temporary three-lineage grade IV cytopenia was observed in all patients after auto-HSCT. Grade III–IV mucositis was registered in 10 (30%) patients, and 3 (10%) children developed grade III–IV infectious complications. Transplant-related mortality was not registered. During the follow-up period, six (19%) patients died due to the underlying disease progression. At the median follow-up of 888 (66–3375) days, the 5-year overall (OS) and event-free (EFS) survival rates were 70% (95% CI: 43–86) and 62% (95% CI: 41–80), respectively. The cumulative incidence of relapse was 38% (95% CI: 20–58). Based on the data obtained in our work, we can conclude that the use of targeted or immunotherapy provides a statistically signifiant improvement in overall survival (OS) (p = 0.013). This is associated with both factors: a more sustained remission prior to auto-HSCT and the availability of effctive treatment for some patients (mainly for the patients with anaplastic large cell lymphoma) in case of relapse after auto-HSCT. The achieved long-term survival rate is comparable or even slightly superior to the data previously obtained by other researchers. Almost one third of the patients suffred from primary mediastinal large B-cell lymphoma, and this is one of the possible reasons for higher long-term OS and EFS rates compared to the previously published results. Moreover, the presence of 6 patients with R/R anaplastic large cell lymphoma with a more favorable prognosis, and, probably, the absence of the morphological confimation of R/R NHL (“second look”) in some patients (n = 20, 65%) could have inflenced the survival rates, which does not exclude the possible inclusion of a number of cured patients in the work. The importance of our work lies in the fact that a signifiant part of the patients (n = 25, 80%) underwent targeted or immunotherapy. This allowed us to show the effctiveness of transplantation in different types of NHL in children in the so-called era of immunotherapy. Auto-HSCT is an effctive and relatively safe treatment strategy for children with R/R NHL which makes it possible to achieve a cure in a signifiant number of patients. The use of targeted and immunotherapy improves the prognosis in transplanted patients. A second biopsy is recommended to confim R/R NHL.

Lymphoblastic lymphoma (LBL) in children is curable in most cases, but there is still a significant proportion of patients in whom standard therapy is ineffective. Thus, patients develop a relapse or a primary refractory disease in about 10% of cases (R/R). In this case, the main treatment method is allogeneic hematopoietic stem cell transplantation (allo-HSCT). The choice in favor of transplantation is predominantly based on the experience in adult patients. A small number of pediatric patients accounts for the limited data in pediatrics. The prognosis of these patients is always extremely poor. It has been shown that the survival of patients after allo-HSCT is higher only if remission is achieved prior to the transplantation. In order to provide more evidence in support of allo-HSCT, randomized clinical trials are needed. However, such studies in the field of allo-HSCT are quite difficult to conduct, and this necessitates the search for alternative methods of evidence-based medicine in this area. Probably, the achievement of high survival rates could be considered a sufficient argument in favor of this method. This study was approved by the Independent Ethics Committee and the Scientific Council of the I.P. Pavlov First Saint-Petersburg State Medical University of the Ministry of Healthcare of Russia. In this work, we summarize the experience in allo-HSCT in children with R/R LBL obtained at the R.M. Gorbacheva Research Institute for Pediatric Oncology, Hematology and Transplantation, I.P. Pavlov First Saint-Petersburg State Medical University. This work is one of the few ones devoted exclusively to the role of alloHSCT in the treatment of pediatric R/R LBL. From 2006 to 2020, at the R.M. Gorbacheva Research Institute for Pediatric Oncology, Hematology and Transplantation, I.P. Pavlov First Saint-Petersburg State Medical University, allo-HSCT was performed in 13 children and adolescents with R/R LBL (2 patients underwent 2 transplantations). Repeated transplantations were performed due to progression and primary graft failure. The median number of prior lines of therapy was 2.5 (2–4). Remission prior to alloHSCT was observed in 7 cases. The graft sources were a fully HLA-matched related donor (n = 3), a fully HLA-matched unrelated donor (n = 4), and a haploidentical donor (n = 8). The following schedules were used as a conditioning regimen: fludarabine 150 mg/m2 + busulfan 8–14 mg/kg (n = 8), fludarabine 150 mg/m2 + melphalan 140 mg/m2 (n = 5), fludarabine 150 mg/m2 + treosulfan 30 mg/m2 (n = 2). In most cases, the prevention of “graft versus host” disease (GVHD) was based on post-transplant cyclophosphamide (n = 11). Cyclophosphamide alone was used in fully matched related transplantation (n = 2), in combination with tacrolimus and cellsept – in unrelated transplantation (n = 1), and in combination with sirolimus and tacrolimus – in haploidentical transplantation (n = 8). A combination of ATGAM, methotrexate and cyclosporin A was used three times in alloHSCT from an unrelated donor for the prevention of GVHD. In one allo-HSCT from a fully matched related donor, cyclosporin A alone was used for the prevention of GVHD. The graft sources were bone marrow (n = 9) and peripheral blood stem cells (n = 4). The median CD34+ cells/kg was 3.8 (1.1–10.0). At the median follow-up of 651 (106–3034) days, the 3-year event-free survival rate was 52% (95% CI: 25–74), the incidence of relapse/progression was 48% (95% CI: 26–76). Five out of thirteen patients died during the study period. The cause of death was the underlying disease in all cases. The cumulative incidence of acute and chronic GVHD was 28% (95% CI: 11–58%) and 24% (95% CI: 5–48), respectively. This work is one of the largest in terms of the number of transplanted children with R/R LBL. Our results are superior to those obtained in case of using only chemotherapy in comparison with the historical control and are comparable with the few previously published data on allo-HSCT in children. In this study, we included patients who underwent allo-HSCT. Among them, there were also children out of remission of LBL which implies that there was no selection of patients, and thus our study settings were close to the so-called real clinical settings. The drawbacks of this work include the following: the study was carried out at a single transplant center, there was no comparison group, the number of patients was low. Nevertheless, considering the complexity of conducting randomized trials in the field of allo-HSCT, the presented data serve as an important confirmation of the effectiveness of transplantation in R/R LBL.

Introduction. The long-term event-free survival of patients with high-risk neuroblastoma (NB) receiving intensive complex therapy according to current russian standard do not exceed 40 %. Also, there is no standard tactics in patients with primary resistant and relapsed disease, most of them die due to disease progression. While, anti-GD2 immunotherapy (IT) proved to be effective in patients with high-risk NB, in Russian Federation this method is not generally available. There are currently two pilot studies ongoing in Raisa Gorbacheva Memorial Institute aimed to evaluate the effectiveness of anti-GD2 antibodies in high-risk NB patients. Aim of the study – describing a single-center experience of anti-GD2 IT in primary high-risk NB patients and patients with primary resistant and relapsed disease. Materials and methods. A total of 20 patients received anti-GD2 antibodies, 16 of them were included into pilot trials. The median age at IT initiation was 5 (3–17) years. In 13 cases the therapy was initiated in patients with high-risk disease after auto-HSCT, in 3 cases – in patients with 1st systemic relapse of primary resistant disease after 2nd-line therapy and haplo-HSCT, in 1 case – in patient with 2nd chemosensitive relapse after haplo-HSCT. Also, 3 patients with progressive chemoresistant disease received anti-GD2 antibodies as monotherapy (n = 1) or in combination with chemotherapy (n = 2) as salvage regimen. Results. Patients receiving anti-GD2 antibodies after auto-HSCT retain response to therapy in 11 of 13 cases with a median follow-up period of 15 (6–27) months, in 2 cases there was disease progression during or immediately after IT cessation. Both patients with disease progression responded well to salvage therapy. Two of 3 haplo-HSCT recipients with prior good response to 2nd-line therapy are currently in remission 16 and 36 months past haplo-HSCT, one patient progressed 55 months after transplantation. A patient with 2nd late relapse after haplo-HSCT currently maintains remission on IT. Both patients with chemorefractory progressive disease did not respond to IT and died due to disease progression. IT was characterized by acceptable toxicity. In most cases it was complicated by Gr 1–2 fever, rash or neuropathic pain effectively controlled by supportive therapy. However, three patients had signs of neurotoxicity requiring therapy termination in one case. Conclusion. Dinutuximab beta IT is characterized by acceptable toxicity. With a median follow-up of 18 (6–59) months the majority (14 of 17) patients receiving anti-GD2 antibodies as maintenance therapy after auto- or allogeneic HSCT retain response. However, we did not observe any response in patients with progressive chemorefractory disease.

About 20% of initially high-risk patients with neuroblastoma (NB) develop primary resistant to chemotherapy and more than 50% of them subsequently have a relapse. There is currently no uniform approach to therapy in this group and long-term outcomes are dismal. The study was approved by the Independent Ethics Committee and the Scientific Council of the I.P. Pavlov First Saint Petersburg State Medical University. A total of 78 patients with a median age of 5 (1–20) years with primary resistant (n = 33) or (n = 45) relapsed NB receiving treatment in R.M. Gorbacheva Memorial Center were included in this study. In 20 cases the 2nd-line therapy including topotecan (n = 10) or irinotecan (n = 10) was used, 58 patients received combined chemo- and targeted therapy (RIST regimen: rapamycin, irinotecan, sirolimus, temozolomide). Nineteen patients with primary resistant disease (n = 4) or systemic relapse (n = 15) subsequently underwent an allogeneic hemopoietic stem cell transplantation from haploidentical donor (haplo-HSCT). In all cases fludarabin-based reduced intensity conditioning (RIC) regimens were used. Ten patents received modified graft (immunomagnetic selection or depletion), in 9 unmodified graft with subsequent post-transplant cyclophosphamide (PTCM) was used. Also, 16 of 19 haplo-HSCT recipients had post-transplant therapy. The clinical effect was seen in 79% of patients. The median event-free survival (EFS) in 2nd-line therapy and RIST recipients was 2.5 (1–11) and 8 (1–76) months, accordingly. The complete of good partial response in 2nd-line therapy or RIST recipients was seen in 5% and 15%, 14% and 31% of cases accordingly. The therapy toxicity was comparable in both groups. The median EFS for haplo-HSCT recipients was 15 months with 2-year OS and EFS in this group bring 44% and 21% accordingly. Seven of 19 (37%) patients are currently alive and 4 (21%) of 19 maintain response. All long-term responders have history of posttransplant therapy. There was no statistically significant difference based on graft-versus-host disease prophylaxis used (graft modification or PTCM) or KIR compatibility. Combined chemo- and targeted therapy (RIST) is characterized by acceptable toxicity and effective even in some previously resistant cases. In 20% of responders a long-term effect may be achieved by subsequent haplo-HSCT and post-transplant therapy.

Introduction. Neuroblastoma (NB) is the most common extracranial solid tumor in infants, but it is more rarely found in older children. Only 1–2 % of cases are registered in adolescents and young adults. The long-term prognosis in these patients is highly unfavorable due to indolent clinical course formed by peculiar biological characteristics of tumors. We publish a case study of 11 patients with NB older than 10 years at the time of diagnosis.Case series description. In 2008 to 2020 a total of 11 adolescent and young adults patients with median age of 14 (10–28) years were treated in Raisa Gorbacheva Memorial Research Institute of Children Oncology, Hematology and Transplantation, First Pavlov State Medical University of St. Petersburg. Seven of 11 patients had mediastinal neuroblastoma, in other cases the primary lesion was abdominal (n = 2), pelvic (n = 1), and in one case no primary lesion was defined. Ten of 11 patients had primary disseminated disease with lymph nodes (n = 5), bone (n = 5), bone marrow (n = 3), or hepatic (n = 1) metastases. Tumor morphology and cytogenetics were assessed in all patients, in 4 cases additional targeted sequencing of potentially pathogenic genes was performed. All patients received chemotherapy and local control measures according to high-risk NB guidelines, in 7 of 11 cases additional chemotherapy regimens were used. Seven of 11 patients also received dose-intensive consolidation with autologous hemopoietic stem cell transplantation (auto-HSCT). In case of primary resistance MIBG-therapy, targeted or immunotherapy were used. In 6 cases tumor morphology corresponded to undifferentiated neuroblastoma, in 5 cases to ganglioneuroblastoma. Although all cases were high-risk, they mostly lacked high-risk biological features seen in younger patients. None had MYCN amplification, the cytogenetic assay yielded the following aberrations: +2 (n = 2), del1p (n = 1), g17q (n = 1). All patients, in whom the targeted sequencing was performed had pathogenic mutations: ATRX (in two patients 19 and 28 years at diagnosis), TP53 and PIK3CA, FBXW7. Nine of 11 patients had primary resistant disease, in 7 cases response was obtained on second or subsequent therapy lines. Two patients responded two chemoand targeted therapy combination, in 3 cases monoor combined immunotherapy yielded prolonged (16–32 months) response. Six of 7 auto-HSCT recipients developed a relapse. 6 out of 11 patients are currently alive. In 2 cases, a complete response is maintained according to scintigraphy with 123I-MIBG, lasting 86 and 14 months after completion of therapy.Conclusions. NB is biologically different in adolescents and young adults. It is characterized by indolent clinical course with very high risk of late relapse. As most patients in this group are chemoresistant, the standard dose-intensive tactics may be less effective and perhaps more attention should be given to targeted and immunotherapy-based approaches.

The majority of children with NHL can be cured with first-line therapy but 10–25% of affected patients develop relapsed or refractory disease (R-R). The prognosis in these cases is unfavorable, no matter what form of modern treatment is adopted. New approaches to the treatment of this small, yet important, group of patients need to be introduced, including, first and foremost, targeted therapy and immunotherapy. As is known, PD-L1 is frequently expressed in non-Hodgkin lymphomas (NHL), which means that the use of checkpoint inhibitors (CPI) is theoretically justified. Objectives: to analyze the results of treatment with checkpoint inhibitors Nivolumab and Pembrolizumab in children with R-R NHL. The study was approved by the Independent Ethics Committee of the I.P. Pavlov First Saint-Petersburg State Medical University. We used CPIs in 8 children with R-R NHL undergoing treatment at the R.M. Gorbacheva Research Institute for Pediatric Oncology, Hematology and Transplantation. The median age was 12 (2–17) years. The distribution of the patients by diagnosis was as follows: primary mediastinal large B-cell lymphoma (PMBCL, n = 3), peripheral T-cell lymphoma (PTCL, n = 2), diffuse large B-cell lymphoma (n = 1), lymphoblastic lymphoma (n = 2). The median number of prior lines of therapy was 3 (1–5), and all patients had received at least 1 line of standard treatment. Refractory NHL was observed in 5 cases, and 3 patients had had multiple relapses (≥ 3). All patients had progression of their primary disease at the time of prescription of the CPI therapy. Nivolumab was administered at a dose of either 1 mg/kg (n = 4) or 3 mg/kg (n = 3) every 2 weeks, Pembrolizumab - at a dose of 2 mg/kg once every 3 weeks (n = 1). The median number of CPI doses received by the patients was 5.5 (2–12). In 5 patients, CPIs were administered as monotherapy, in 3 – in combination with cytostatic agents: FLAG, Gemcitabine and intrathecal triples (n = 1), Brentuximab vedotin (n = 1) and Bendamustine (n = 1). The efficacy of the treatment was evaluated in accordance with the LYRIC criteria. Once remission was achieved, we used hematopoietic stem cell transplantation and/or radiotherapy for consolidation. Response to the CPI therapy was observed in 4 out of 8 patients (complete response – in 2 patients). Interestingly, only patients with PMBCL and PTCL responded to the treatment. At the median follow-up of 368 (36–879) days, 5 patients were alive, with three of them remaining in long-term remission. During the follow-up period, there was only 1 clinically significant complication (cytopenia) that resolved after treatment with glucocorticosteroids. Finally, we would like to point out that this paper is one of the first reports on the successful use of CPIs in children with R-R NHL. PMBCL and PTCL turned out to be responsive to the treatment. This therapy can be used to achieve remission or possibly even cure in children whose only option would be palliative care if they were treated with standard approaches.