Withdrawal of radiotherapy in patients with brain tumors under four years decreases chance for cure. AutoHSCT in a series of pilot studies demonstrated a potential to improve outcomes in these patients. The study included 50 patients with median age of 39 months (7–53). Medulloblastoma (n = 28, 56%), ETMR (n = 9, 18%) and other histological types (n = 13, 26%) were most commonly diagnosed. Forty two patients (84%) received tandem autoHSCT by HIT-MED protocol, and single autoHSCT was performed in eight children (16%). Adjuvant radiotherapy was administered in 25 (50%) children and treatment of relapse included radiotherapy in 6 (12%). Median follow-up was 39.6 months (6–121). Long-term CIR was 37%, and TRM – 6%. Five-year OS was 71% in medulloblastoma, 37% in ETMR and in other tumors – 51% (p = 0.07). Irradiation-free OS at 5 years for children with medulloblastoma was 24%. For the whole cohort of CNS tumors, independently of histology, OS and PFS at five years were 60% and 46%, respectively Young children with medulloblastoma, following tandem autoHSCT, demonstrate OS comparable to older children. Patients with other histological types demonstrate suboptimal long-term survival rates after autoHSCT and one should assess whether these patients benefit from autoHSCT.

The majority of patients with Hodgkin lymphoma (HL) are cured, which represents one of the best cure rates in oncology. However, the prognosis is not as favorable in case of relapsed or refractory (RR) disease. Autologous hematopoietic stem cell transplantation (auto-HSCT) is an effective way to consolidate remission in patients with RR HL. Despite the many years of experience and the availability of results of randomized trials confirming the efficacy of high-dose chemotherapy in adults, the role of auto-HSCT in children with HL has not been studied as extensively, and there are only a limited number of publications on the subject. As is the case with the majority of other pediatric tumors, RR HL is a rare entity, which is why it is so difficult to study it. Here we share the experience of the R. M. Gorbacheva Research Institute for Pediatric Oncology, Hematology and Transplantation in auto-HSCT in children and adolescents with HL. The study was approved by an Independent Ethics Committee and the Scientific Council of the I.P. Pavlov First Saint-Petersburg State Medical University. We included 54 patients with RR HL who had undergone auto-HSCT during the period from 2007 to 2021. Refractory disease (n = 29; 54 %) was diagnosed in case of HL progression either during first-line therapy or in the first 3 months after the completion of the treatment. Relapsed disease was diagnosed in 25 (46 %) children. Early HL relapse (< 12 months since the start of therapy) was evident in 18 (72 %) patients, while late HL relapse (≥ 12 months since the start of therapy) occurred in 7 (28 %) children. The median number of lines of therapy before auto-HSCT was 3 (1–6). The first line of treatment was chemotherapy in accordance with the GPOH-HD (n = 27; 50 %), BEACOPP (n = 19; 35 %), or other protocols (n = 8; 15 %); the second line involved the use of IEP/ABVD (n = 14; 27 %), DHAP (n = 12; 23%), ICE (n = 13; 25 %), or other combinations (n = 13; 25%); and third-line treatment consisted of DHAP (n = 9; 29 %), a combination of brentuximab vedotin and bendamustine (n = 8; 26%), immune checkpoint inhibitors (ICIs) (n = 7; 22.5 %) or other regimens (n = 7; 22.5 %). ICIs were used for remission induction prior to auto-HSCT in 14 (26 %) patients. Response was assessed using the Lugano classification. Status before transplantation: complete remission (CR) – 21 (39 %) patients, partial remission (PR) – 30 (56 %), disease stabilization – 2 (3.5 %), disease progression – 1 (1.5 %). The BEAM conditioning regimen was used in 17 (31 %) patients, and the BeEAM regimen – in 32 (59 %) patients. The 3-, 5- and 10-year overall survival (OS) was 88% (95 % confidence interval (CI) 74–95), 80% (95 % CI 62–90) and 63% (95 % CI 34–81) respectively. The 10-year progression-free survival (PFS) was 46% (95 % CI 24–65). The median follow-up was 3.3 (0.1–12.3) years. The long-term PFS in children with CR and PR was 72% (95 % CI 41–89) and 33 % (95 % CI 8–61) respectively (p = 0.067). A total of 9 (16.7 %) patients died during follow-up. The main cause of death was progressive HL (n = 6), while some patients died in the early post-transplant period due to infections (n = 3; 5.6 %). The median time to relapse or progression after auto-HSCT was 6 (1–77) months. Out of 17 (31 %) patients with relapsed or progressive HL after auto-HSCT, 9 (53 %) children are alive at a median follow-up of 2.3 (0.7–9) years. Considering that our study included patients who had been more extensively pre-treated (the median number of lines of therapy – 3) than patients in the majority of other studies (the median number of lines of therapy – 2), it can be assumed that our results are superior to historical data. The improvement of transplantation outcomes observed over time can be attributed to better supportive treatment and probably, to the use of immunotherapy. According to the Center for International Blood and Marrow Transplant Research (CIBMTR), it is crucially important that long-term survival in children with RR HL be monitored closely since it can be drastically different from results obtained during the first years of follow-up - due to late relapses and complications of the received treatment. The 10-year survival rates show that the RR HL problem is yet to be resolved. With the help of auto-HSCT, approximately half of children and adolescents with RR HL can be cured. One of the most important favorable prognostic factors in these patients is the achievement of CR before transplantation. The use of immunotherapy for remission induction before auto-HSCT is also promising.

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.

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.

High-dose chemotherapy (HDCT) with autologous hemopoietic stem cell transplantation (auto-HSCT) is currently an integral part of a standard of care for younger medulloblastoma (MB) patients and MB patients with relapse. As HDCT regimens are characterized by neurotoxicity, it may add to the one of radiation therapy. Therefore, some patients may develop post-irradiation clinical symptoms and MRI changes characteristic for disease progression, pseudoprogression. We report on a case of a 16-year old patient with relapsed MB treated by standard chemotherapy with consequent HDCT and craniospinal irradiation with a boost to cranial fossa posterior. One month after the radiation therapy was finished she developed focal neurological symptoms. The MRI and PET scan have shown cerebellar changes characteristic for disease progression. However, the therаpy with corticosteroids and bevacizumab was able to resolve most clinical symptoms. The MRI scan have also shown evident positive dynamics. Therefore, the clinical course and imaging dynamics corresponded to pseudoprogression. The probability of pseudoprogression may be higher in patients with MB relapse receiving second irradiation and HDCT with auto-HSCT. As we often do not have a morphological proof of relapse, we have to distinguish between progressive disease and pseudoprogression by a complex of clinical course and imaging data.

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.

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.

Presence of bacteriuria and urinary microbiota composition is an important index of immunocompromised conditions. These parameters are scarcely studied in patients undergoing hematopoietic stem cell transplantation (HSCT). The aim of this work was to evaluate detection rates of cultured aerobic microbiota from urine samples taken by clinical indications before HSCT and within 4 months after the treatment. 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 evaluated results of bacterial cultures from 734 urine specimens taken in 50 patients with oncohematological and inborn diseases at the age ranging from 1 to 21 years who were subjected to allogeneic HSCT. The analysis was performed for 3 age groups: 1–5, 6–14, and 15–21 years old. The bacterial cultures proved to be positive with 37.6% of urine samples. The following microbes were revealed at highest rates: K. pneumoniae, 95/734 (12.9%); E. faecalis, 90/734 (12.3%); E. coli, 65/734 (8.9%); E. faecium, 50/734 (6.8%). The bacteriuria rates have shown distinct time dependence, with significantly decreased K. pneumoniae and E. coli detection at earliest terms (1st month) after myeloablative conditioning, which could be explained by effective antibacterial prophylaxis over the time of conditioning and in early posttransplant period. We have shown that the frequency of positive tests for K. pneumoniae и E. coli in these samples were different for distinct age groups, i.e., the positivity rates were significantly higher in youngest children (up to 5 years old) as compared with older age groups, being sufficiently increased 2–3 months after HSCT which may be an index of antibiotic resistance as well as a risk factor for infectious complications of other organs. We have also shown a highly significant increase in K. pneumoniae и E. coli positivity rates when using myeloablative conditioning regimen before HSCT. The immunotoxic effects of cytostatic therapy in HSCT deserve further studies, including biodiversity analysis of urinary microbiota by means of new-generation DNA sequencing. These results may serve as a basis for rational antibacterial therapy in HSCT.

Background. Ewing sarcoma (EWS) is a second most common pediatric bone tumor. About one quarter of all patients belong to a high-risk group characterized by a poor prognosis. In spite of high-dose chemotherapy (HDCT) with autologous hemopoietic stem cell transplantation (auto-HSCT) being traditionally viewed as a possible option for high-risk patients, there is stills no consensus on indications for this method in EWS patients.Study objective: to evaluate the HDCT effectiveness and most important prognostic factors in a prospective cohort of high-risk EWS patients. Materials and methods. A total of 73 EWS patients receiving treatment in R.M. Gorbacheva Memorial Institute were included in the study. All patients were characterized by one or several high-risk features: local (primary tumor volume >200 ml, axial localization, poor response to chemotherapy; n = 55; 76 %), primary disseminated disease (n = 58; 80 %), first chemoresponsive relapse (n = 7; 9 %). All patients received a myeloablative consolidation regimen consisting of busulfan 16mg/kg and melphalan 140mg/m2. In patients with primary disseminated disease an additional evaluation according to risk scale by R. Ladenstein et al. was performed. Based on risk points all patients were stratified as standard (n = 20), high (n = 26), and ultrahigh risk (n = 12).Results. The 5-year overall and event-free survivalfor a whole studied cohort were 40 and 37 %, accordingly. In patients with high-risk localized disease the 5-year overall and event-free survival were 48 and 45 %, accordingly. The HDCT regimen was characterized by acceptable toxicity. The main non-hematologic toxicities were infectious complications (n = 61) and gastrointestinal tract mucositis (n = 31). One patient of 76 died due to treatment-related complications. The multivariate analysis revealed the following risk factors: therapy response (hazard ratio (HR) 2.2; p <0.01), bone marrow involvement (HR 5.0; p = 0.01), primary tumor volume (HR 1.9; p = 0.01), and number of bone metastases (HR 2.2; p = 0.05). The risk group determined by R. Ladenstein score was also a good predictor for outcome with only 8 % of ultrahigh risk patients surviving 5 years past auto-HSCT.Conclusion. HDCT with auto-HSCT may potentially improve treatment results in some high-risk patient subgroups. While risk scale may help to determine patients most likely to benefit from this approach, the outcome in ultrahigh risk patients are still dismal.

Introduction.Neuroblastoma (NB) is the most common extracranial pediatric solid tumor. The high-risk group patients are characterized by adverse prognosis and require intensive complex therapy including high-dose chemotherapy (HDCT) with hematopoietic stem cell transplantation (auto-HSCT). The current study presents a single center experience of HSCT with auto-HSCT for high-risk NB performed in Raisa Gorbacheva Memorial Research Institute of Children Oncology, Hematology and Transplantation, First Pavlov State Medical University of St. Petersburg, Ministry of Health of Russia.Patients and methods.A cohort of 72 consecutive high-risk NB patients was included in the study. Among them 69 patients received Bu-Mel conditioning regimen (busulfan 16 mg/kg, melphalan 140 mg/m2 ), in 3 patients the 5D/5D regimen was used (carboplatin 1000 mg/m2 , irinotecan 150 mg/m2 , temozolomide 750 mg/m2 , etoposide 400 mg/m2 , cyclophosphamide 140 mg/kg). In most cases the autologous hematopoietic stem cells source was bone marrow (BM) (n = 59; 82 %), peripheral blood stem cells (PBSC) (n = 11; 15 %), or BM and PBSC (n = 2; 3 %). In 52/66 (79 %) patients with initial bone marrow involvement the potential transplant contamination was assessed by flow cytometry.Results.The 2-year and 5-year overall (OS) and event-free (EFS) survival was 61 % and 48 %, 41 % and 35 % accordingly. The main adverse factors for OS and EFS were age of more than 18 months at diagnosis, combined bone marrow and bones involvement, MYCN amplification, initial neuron-specific enolase level of more than 100 ng/ml, primary resistance or relapse, and metaiodobenzylguanidinepositive lesions persistence prior to or after HSCT with auto-HSCT.Conclusions.The results achieved are comparable to those described for similar cohorts. Some patient subgroups are unlikely to achieve response after HSCT with auto-HSCT. Therefore, additional stratification methods and treatment modalities are needed.Conflict of interest. The authors declare no conflict of interest.Funding. The study was performed without external funding.

Background:There is no standard therapy for B‐cell lymphoma, unclassifiable, with features intermediate between diffuse large B‐cell lymphoma and Hodgkin lymphoma (intermediate DLBCL/HL) because of its recent identification as a distinct entity by WHO and rarity of described cases. At the same time, patients with relapsed and refractory disease represent the group with dismal prognosis. Recent studies revealed that intermediate DLBCL/HL has frequent chromosome 9p24.1 alterations and hence the use of PD‐1 blockade might be effective treatment option. To our knowledge, only 3 cases with this approach were published and had positive results (Melani C. et al, N Engl J Med, 2017).Aims:We aimed to evaluate safety and efficacy of PD‐1‐inhibitor nivolumab in relapsed and refractory intermediate DLBCL/HL.Methods:We analyzed data of 5 patients with relapsed or refractory intermediate DLBCL/HL. The diagnosis was confirmed by immunohistochemical (IHC) staining of the biopsy specimens according to the morphological features of intermediate DLBCL/HL. Response was evaluated by PET‐CT and was defined according to LYRIC criteria. PDL‐1 expression was evaluated in three patients. In these patients high PD‐L1 level (100%, 100% and 90%) on the tumor cells was confirmed.Results:This analysis includes 3 men and 2 women. The median age at the time of diagnosis was 33 years old (range, 22‐87). Four patients received Hodgkin's lymphoma regimen as the first line therapy and 1 patient received non‐Hodgkin's lymphoma regimen. The median number of prior therapy lines was 4 lines (range, 2‐6 lines). High dose chemotherapy and autologous stem cell transplantation (SCT) was performed in 2 patients with no durable response. Immunotherapy was started at disease progression in all cases with the stages of disease 3‐4. Nivolumab was administered in the following regimens: as monotherapy in two patients, in combination with rituximab in one patient, in combination with brentuximab vedotin (BV) plus R‐EPOCH therapy in one patient and as monotherapy, nivolumab/bendamustine combination and nivolumab/BV combination in one patient. The median number of nivolumab infusions was 7 (range, 6‐24). An objective response was reached in 4 (80%) patients including 2 (40%) complete responses and 2 (40%) partial responses. One (20%) patient had an intermediate response according to LYRIC criteria. At a median follow‐up of 7 months (range, 5‐16) 4 (80%) patients are alive without signs of relapse/progression of disease and 1 patient died due to disease progression. Adverse events of nivolumab‐containing treatment included severe neutropenia and mild infusion reaction in one patient. As consolidation, haploidentical hematopoetic stem cell transplantation was perfomed in one patient, and allo‐SCT is currently scheduled in 2 patients.Summary/Conclusion:According to the data nivolumab‐containing treatment can induce objective response with acceptable safety profile and may represent possible salvage treatment option in heavily pretreated patients with intermediate DLBCL/HL. This and other observations serve as the rationale for assessment of nivolumab‐containing regimen for the treatment of intermediate DLBCL/HL in the prospective trials.