Anaplastic large cell lymphoma (ALCL) expressing the anaplastic lymphoma kinase (ALK) (ALK+ ALCL) is a rare type of lymphoma which comprises 10-15% of all non-Hodgkin lymphomas in children and 2–3% in young adults. Relapsed/refractory disease occurs even more rarely (25–40% of all cases). There is as yet no standard treatment for relapsed/refractory ALK+ ALCL. Patients with ALK+ ALCL usually present at advanced stages of the disease with extranodal involvement (skin, soft tissues, bones, lungs, liver, spleen and bone marrow) and B symptoms. ALK-positive ALCL affects males more often than females. There are two morphological variants: the common type (65% of cases) and the non-common type which is associated with a poorer prognosis. ALK+ ALCLs are often associated with t(2;5) and t(1;2), resulting in the formation of the NPM-ALK and the TPM3-ALK fusion proteins, respectively. Data about the treatment of relapsed/refractory ALK+ ALCL are limited. Earlier, targeted therapies (brentuximab vedotin (BV), ALK inhibitors) and risk-adapted chemotherapy followed by hematopoietic stem cell transplantation (HSCT) for remission consolidation were shown to be highly effective. A total of 15 patients with relapsed/refractory ALK+ ALCL were treated at the R.M. Gorbacheva Research Institute starting from 2002. Fourteen (93%) patients had ALK-positive ALCL of common morphology and one (7%) patient had the non-common variant (histiocytic). The study was approved by the Independent Ethics Committee and the Scientific Council of the Pavlov University. The expression of CD3 on tumor cells was assessed (CD3 positive: n = 4 (27%), CD3 negative: n = 8 (53%), no data: n = 3 (20%). The median age at the diagnosis was 26 years (11 months– 37 years). The median follow-up from the diagnosis was 9 years (1–19 years). Nine (60%) patients were aged > 18 years and six (40%) patients were aged < 18 years. There were 10 (67%) males and 5 (33%) females. At onset, 2 (13%) patients were diagnosed with early-stage disease (stage II), while the others were diagnosed with advanced-stage disease: 2 (13%) patients had stage III disease and 11 (74%) had stage IV disease. Staging was performed according to the St. Jude staging system (in children) and the Ann Arbour staging classification (in adults). Thirteen (86%) patients had extranodal involvement. Four (27%) patients had refractory disease (progression within the first three months or the absence of complete remission after the first-line treatment) and the rest 11 (73%) patients had recurrent ALK-positive ALCL. Six patients developed early relapse (< 12 months after remission was achieved); 5 patients had late relapse (after > 12 months of remission); local (1 site) and systemic relapses were diagnosed in 7 and 4 patients, respectively. Our patients received from 2 to 7 lines of treatment (the median is 4). In the first line of therapy, the patients were treated according to NHL-BFM based regimens (n = 9; 60%), the CHOP (n = 5; 33%), and the HyperCVAD (n = 1; 7%) protocols. In the second line of therapy, 8 (53%) patients were treated according to NHL-BFM based regimens; 2 (13%) patients were treated with GDP; 1 (7%) patient received DHAP chemotherapy; 1 (7%) patient received a combination of methotrexate and vinblastine (MTX + V); 1 (7%) patient received bendamustine as a single agent. Two (13%) patients were treated with chemotherapy in combination with targeted drugs (GDP + BV, n = 1; NHL-BFM + crizotinib, n = 1). As a third or subsequent line of treatment, the patients received a variety of chemotherapy regimens (n = 5; 33%) and chemotherapy in combination with targeted drugs (n = 10; 67%). Five (33%) patients underwent ALK-inhibitor therapy (crizotinib (n = 4) and ceritinib (n = 1)). Seven (46%) patients were treated with BV (BV as a single agent (n = 4) and BV + chemotherapy (n = 3)). The median number of treatment lines before autologous HSCT (auto-HSCT) and allogeneic HSCT (allo-HSCT) was 2 (2–3) and 3 (3–4), respectively. Auto-HSCT was carried out in 11 (73%) cases. Nine (60%) patients underwent allo-HSCT (from a matched unrelated donor (n = 6), from a matched related donor (n = 2), and from a haploidentical donor (n = 1)). One patient received NK cells from a haploidentical donor as maintenance. In 5 (33%) cases, alloHSCT was carried out following auto-HSCT. The conditioning regimens (CR) used for auto-HSCT included BEAM (carmustine – 300 mg/m2, etoposide – 800 mg/m2, Cytosar – 1600 mg/m2, melphalan – 140 mg/m2) – in 5 (45%) patients; BeEAM (bendamustine – 320 mg/m2, etoposide – 800 mg/m2, Cytosar – 1600 mg/m2, melphalan – 140 mg/m2) – in 5 (45%) patients; and BuCy (Cyclophosphan – 100 mg/kg, busulfan – 14 mg/kg) – in 1 (10%) case. Seven (78%) patients undergoing allo-HSCT received the FluBenda conditioning regimen (fludarabine – 90–150 mg/m2, bendamustine – 390 mg/m2) and post-transplant Cyclophosphan and calcineurin inhibitors for the prevention of graft-versus-host disease (GVHD) (n = 7; 78%); one (11%) patient received the FluMel regimen (fludarabine – 150 mg/m2, melphalan – 140 mg/m2) and CsA/MTX (Cyclosporin А, methotrexate) for GVHD prevention; and in 1 case (11%) data on the RC and GVHD prophylaxis were missing. Overall response to the second line of treatment was achieved in 10 (67%) patients, with complete response observed in 7 (47%) cases, and partial response –in 3 (20%) cases. Five out of the 7 patients treated with BV during different lines of therapy managed to achieve complete response. Four out of the 5 patients who had undergone treatment with ALK inhibitors, demonstrated complete response. The 10-year overall survival (OS) rate of the study patients reached 90% (95% confidence interval (CI) 47–99). The 10-year progression-free survival (PFS) rate after the second line of treatment was 39% (95% CI 13–64). The 10-year OS and PFS rates after auto-HSCT were 100% and 35% (95% CI 8–64) respectively. The 5-year OS following allo-HSCT was 85% (95% CI 33–98), while PFS was 60% (95% CI 19–85). Four out of the 11 patients who had undergone auto-HSCT relapsed, and 2 patients progressed. Median time to relapse/progression was 8 (6–27) months. Three out of the 9 patients who had been treated with allo-HSCT ended up relapsing (median time: 8 (6–17) months). Two patients achieved repeated remission (in one case, it was the result of treatment with ceritinib, while in the other case it became possible after the resection of the lesion, radiotherapy and prescription of crizotinib), and 1 study patient died as a result of disease progression 17 months after allo-HSCT. The 6 patients who had achieved complete remission before undergoing allo-HSCT, are still in CR. Five out of the 9 patients developed grade I–II acute GVHD with skin involvement but did not show any signs of chronic GVHD. The observed complications of chemotherapy and auto-HSCT were standard and manageable and were not the focus of attention in this study. Taking into account the high probability of developing resistance to ALK inhibitors and the high risk of relapse after treatment with BV, targeted therapy should be used to prepare patients for HSCT. The use of ALK inhibitors and BV in our study led to repeated remission in 80% and 71% patients respectively. It was demonstrated that in the majority of cases even heavily pretreated patients with ALK+ ALCL can be cured (which is not the case with other non-Hodgkin lymphomas), especially if allogenic HSCT (allo-HSCT) is carried out. Still, we think that auto-HSCT can also be considered for remission consolidation since OS rates following auto-HSCT and allo-HSCT are comparable (100% and 85%). Moreover, auto-HSCT can also be a valid option in the absence of a fully matched donor, i.e. when only an alternative (haploidentical or partially matched) donor is available, since the use of haploidentical HSCT in ALCL patients has not been studied well enough yet. Further research on the matter is warranted. It was demonstrated that a non-myeloablative conditioning regimen before allo-HSCT (FluBenda) could be opted for in patients with relapsed/refractory ALK+ ALCL and that it was similarly effective as myeloablative RC when compared with a historical control group. Disease status before HSCT was proven to have a statistically significant influence on PFS (the best prognosis was associated with complete remission). At the same time, other factors did not impact the prognosis. This may be explained by the relatively small number of patients included in the study. Relapsed/refractory ALK+ ALCL is a disease with a relatively good prognosis even in heavily pretreated patients. Targeted therapy is a very important and effective step in preparation for HSCT. Allo-HSCT is more effective than auto-HSCT but the latter can also be considered a valid therapeutic option.

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.

Hematopoietic stem cell transplantation (HSCT) in children is a high-tech field of medicine that combines the latest achievements of pediatric hematology, oncology, immunology, transfusiology, molecular biology and cell therapy. The success of HSCT is largely owing to the unique experience of international and national cooperation between transplant centers. A regular joint analysis of transplantation activity, focused on identifying trends and problems that require theoretical and practical solutions, is one of the most important components of such cooperation. The present work summarizes the experience of HSCT in all major pediatric centers in Russia for the period 2015–2018.

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/m 2 . 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.

Children and adolescents with refractory or relapsed Hodgkin's lymphoma (R-R HL) have unfavorable prognosis if ≥ 3 lines of therapies have to be used. New strategies based on innovative approaches are crucial for this group of patients. Nowadays immunotherapy for oncological diseases is the most promising and actively developing area. Brentuximab vedotin (BV) is efficient in adults with HL. Data in children are limited to pilot studies that are focused on response to treatment without analysis of survival. The present study demonstrates experience of Raisa Gorbacheva Memorial Institute of Children Oncology, Hematology and Transplantation (First Pavlov State Medical University of Saint-Petersburg) in the management of heavily pretreated (median number of prior lines – 4) children and adolescents with R-R HL. The study was approved by the Independent Ethics Committee of the Raisa Gorbacheva Memorial Research Institute of Children's Oncology, Hematology and Transplantation. Brentuximab vedotin was administered to 34 patients. Overall response was achieved in 71% (complete response – 29%, partial response – 42%). Long-term progression free and overall survival were 24 and 54%, respectively.