The treatment of relapsed/refractory gray zone lymphoma (r/r GZL) remains challenging. Genetic aberrations involving 9p24.1 and associated with programmed death ligand (PD-L1/L2) upregulation are important in GZL pathogenesis and immune evasion. Immune checkpoint inhibitor nivolumab (PD-1-blocking antibody) may be an attractive treatment strategy in GZL. We have retrospectively assessed efficacy and toxicity of nivolumab-based regimens in nine patients with r/r GZL. Most of the patients n=7 (78%) had primary chemoresistance and the median number of prior therapy lines was 3 (range, 2-5). At the start of nivolumab treatment disease stage III-IV was in n=6 (67%) patients and bulky disease was in n=3 (33%) patients. All nine patients had high-level of PD-L1 expression (80%-100%) on tumor cells. In this group n=4 (44%) patients received nivolumab as monotherapy, n=3 (33%) received nivolumab in combination with chemotherapy, n=1 (11%) received nivolumab in combination with BV and n=1 (11%) received nivolumab in combination with lenalidomide. The objective response rate among all treated patients was 89% with 6 cases (67%) of complete response and 2 (22%), with partial response. One patient (11%) had stabilization of the disease as best response.Median duration of response was 14 (range 5-26) months. Median follow-up time was 25 months (range, 6-30) from the start of nivolumab-based treatment. Overall survival and progression free survival rates were 83% and 38%, respectively. This case series demonstrated that nivolumab-based regimen may be an effective treatment option for patients with r/r GZL.

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.

Development of murine model of allogeneic bone marrow transplantation and graft versus host diseaseModeling of allogeneic bone marrow transplantation and graft versus host disease (GVHD) plays a crucial role in the improvement of transplantation procedures and testing novel immunosuppressive drugs. In this study we evaluated the feasi bility of busulfan and cyclophosphamide conditioning with post transplantation cyclophosphamide (150 mg/kg) in donor recipient pairs C57Bl/6 Balb/с and Balb/с C57Bl/6. We ob served that Balb/с mice as opposed to C57Bl/6 mice can't be the recipients because of the unacceptably high acute mortality from acute toxicity of chemotherapeutic drug. Histological studies in the C57Bl/6 recipients revealed acute GVHD in 93 % of animals. All animals had only grade I-II severity of GVHD. This model has the potential for future studies in the field of transplantology, nonetheless a decrease in the intensity of prophylaxis is required to augment the manifestations of GVHD.

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Randomized multicenter trials in the area of hematopoietic stem cell transplantation (HSCT) face considerable challenges, therefore, their amount is relatively small. Most clinical guidelines are based on the data of multicenter registry studies or well-controlled prospective single-center non-randomized studies. To determine the criteria of a well-controlled single-center trial the results of which can be confi rmed by a multicenter analysis, the total of 44 groups of patients from 22 cooperative studies in collaboration with EBMT were analyzed. The results of these studies were compared with single-center data and the results of the planned studies of RM Gorbacheva Scientifi c Research Institute of Pediatric Oncology, Hematology and Transplantation. In 43 % of cases signifi cant diff erences were observed. The probability of diff erences did not decrease with an increasing number of patients in the single-center groups, but became higher (odds ratio 1.037; 95% confi dence interval 1.001-1.074; p = 0.046), which highlights the diff erences in methods of single- and multicenter trials. While analyzing the reasons for signifi cant diff erences the following necessary criteria for high-quali ty single-center trials in the area of HSCT were formulated: 1) conditioning regimens and graft-versus-host disease prophylaxis (if they are not subject of the study) need to be consistent with the most frequently used practices; 2) groups of patients should be status-homogeneous; 3) the trial must not include patients treated more than 5 years before the analysis; 4) patients should receive current antitumor therapy at pre- and post-transplantation stages; 5) each compared group should include more than 30-40 patients