Abstract: Introduction: Allogeneic hematopoietic stem cells transplantation (allo-HSCT) is a potentially curative option for patients with relapsed and refractory Hodgkin lymphoma (rrHL). However, there is a question of applicability of allo-HSCT for patients previously treated with immune checkpoint inhibitors (ICIs). Initial reports indicate that allo-HSCT in this setting may be associated with increased risk of early transplant-related toxicity, graft versus host disease (GVHD), immune-related adverse events. But subsequently some studies demonstrated acceptable rates of both acute GVHD (aGVHD) and chronic GVHD (cGVHD) after prophylaxis with posttransplantation cyclophosphamide (PTCy). The aim of this study was to define safety and toxicity of allo-HSCT after ICIs for patients with rrHL. Patients and methods: We conducted a retrospective analysis of allo-HSCT results in 23 adult patients with rrHL performed between 2017 and 2019 in RM Gorbacheva Research Institute, Pavlov University. All patients were treated with ICIs before the transplantation (single-agent nivolumab, n=13; nivolumab and brentuximab vedotin, n=5; nivolumab and chemotherapy, n=5). The median time from the last dose of ICIs to allo-HSCT was 83 days (range, 50-350 days) and the median number of cycles was 20 (range, 6-32). Objective response to PD-1 therapy before allo-HSCT was documented in 15 patients (65%) including CR (n=9, 39%) and PR (n=6, 26%). Five patients (22%) had stable disease/disease progression and 3 patients (13%) were transplanted in indeterminate response according to LYRIC criteria. Three (13%) patients had matched HLA-related siblings, 12 patients (52%) had unrelated donors and 8 patients (35%) had haploidentical donors. All patients received reduced-intensity conditioning regimen (fludarabine 30 mg/m2, bendamustine 130 mg /m2 per day for 3 days (FluBe)) and PTCy-based GvHD prophylaxis. Bone marrow and peripheral blood stem cells was the graft source in 14 (61%) and 9 patients (39%), respectively. All analyses were performed using R 3.6.1 software. Results: At the time of analysis, median follow-up was 14 months (range, 1-26). Engraftment rate was 87%. Two patients had primary graft failure and there was 1 early death due to severe cytokine release syndrome after haploidentical HSCT. The 1-year OS and EFS were 83% (95% CI, 58-93) and 74% (95% CI, 49-87) respectively, whereas the 1-year cumulative incidences of relapse and NRM were 13% (95% CI, 5-39) and 13% (95% CI, 5-38) respectively.Out of the 20 patients with engraftment 15 patients developed acute GVHD including severe (grade III-IV) in 9 patients. All patients had skin aGVHD (stages 1, 2, and 3), 3 patients had gastrointestinal GVHD (stages 2, 3, and 4) and 2 patients had liver GVHD (stages 1 and 2). Four patients with steroid-refractory aGVHD received single-agent ruxolitinib (n=2) or combination of ruxolitinib with extracorporeal photopheresis (ECP) and steroids (n=2). All patients achieved complete response. Ten patients had chronic GVHD including 6 patients with moderate or severe disease. Most commonly skin (90%), mucosa (60%), gastrointestinal tract (30%), liver (20%), lung (10%) and eyes (20%) were involved. Four patients with steroid-refractory cGVHD achieved CR receiving combined immunosuppressive therapy (ruxolitinib and steroids, n=2; combination of steroids, cyclosporine A and ECP, n=2). One patient with severe skin cGVHD (score 3) achieved PR on combination of steroids and ECP, another patient with a severe refractory cGVHD (skin score 3, mucosa score 2 and lungs score 1) achieved stabilization only with third line of therapy (combination of ruxolitinib and imatinib). No cases of GVHD-related mortality were observed. There were no other immune-related adverse events. Conclusions: Our study showed the trend to higher incidence of aGVHD and cGHVD including steroid refractory form after ICIs, however this did not lead to GVHD-related mortality. Introduction of target agents for srGVHD might ameliorate GVHD-related mortality and morbidity in rrHL patients after ICIs. The optimal timing of allo-HSCT and regimen of GVHD prophylaxis are likely to be important in the successful outcome of the transplantation. Disclosures No relevant conflicts of interest to declare.

Abstract: We report on 318 patients with acute leukemia, receiving donor lymphocyte infusion (DLI) in complete hematologic remission (CHR) after allogeneic stem cell transplantation (alloSCT). DLI were applied preemptively (preDLI) for minimal residual disease (MRD, n  = 23) or mixed chimerism (MC, n  = 169), or as prophylaxis in high-risk patients with complete chimerism and molecular remission (proDLI, n  = 126). Median interval from alloSCT to DLI1 was 176 days, median follow-up was 7.0 years. Five-year cumulative relapse incidence (CRI), non-relapse mortality (NRM), leukemia-free and overall survival (LFS/OS) of the entire cohort were 29.1%, 12.7%, 58.2%, and 64.3%. Cumulative incidences of acute graft-versus-host disease (aGvHD) grade II–IV°/chronic GvHD were 11.9%/31%. Nineteen patients (6%) died from DLI-induced GvHD. Age ≥60 years ( p  = 0.046), advanced stage at transplantation ( p  = 0.003), shorter interval from transplantation ( p  = 0.018), and prior aGvHD ≥II° ( p  = 0.036) were risk factors for DLI-induced GvHD. GvHD did not influence CRI, but was associated with NRM and lower LFS/OS. Efficacy of preDLI was demonstrated by decreasing MRD/increasing blood counts in 71%, and increasing chimerism in 70%. Five-year OS after preDLI for MRD/MC was 51%/68% among responders, and 37% among non-responders. The study describes response and outcome of DLI in CHR and helps to identify candidates without increased risk of severe GvHD.

Abstract: Background Currently, the recommended dose of nivolumab for patients with relapsed or refractory classical Hodgkin lymphoma (r/r сHL) is 3 mg/kg. Nevertheless, published clinical cases indicate the possible efficacy of lower doses of nivolumab. Moreover, experimental studies provided the rationale for possible reduction of nivolumab dose in patients with solid tumors (Agrawal et al. 2016). The presented data creates prerequisites for studying the lower nivolumab doses efficacy and safety in the r/r cHL therapy. Patients and Methods This study included 42 patients (14 male/28 female) with r/r cHL who were treated with nivolumab 40 mg every 2 weeks. The median age of patients was 36 (22-53) years. The median number of prior therapy lines was 4 (2-7). Prior treatment contained high dose chemotherapy with ASCT in 9 pts (21%), brentuximab vedotin in 14 pts (33%) and allo-HSCT in 1 pt (2%). Four pts (9,5%) had the partial response (PR) and the remaining 38 pts (90,5%) had the disease progression (PD) at the moment of nivolumab initiation. B-symptoms were present in 23 pts (55%), ECOG status was grade 0-I in 25 pts (59,5%), grade II in 12 pts (29%), grade III in 4 pts (9,5%) and grade IV in 1 pt (2%). The primary endpoint was the overall response rate (ORR) determined by positron-emission tomography/computed tomography (PET/CT) using LYRIC criteria every 3 months. Key secondary endpoints included progression-free survival (PFS) and overall survival (OS). Adverse events (AE) were evaluated according to CTCAE 4.03. The patient group characteristics were evaluated using descriptive statistics methods, the survival analysis was performed using Kaplan-Meyer method (SPSS Statistics v.17). Results The median number of nivolumab cycles was 24 (2-38). The response was evaluated in 41 out of 42 pts. The ORR was 66%. The best response included complete response (CR) in 39%, PR in 27%, stable disease in 5%, PD in 2%, indeterminate response (IR) in 27% of pts. With a median follow-up of 27,5 mo (11,3-34,5) 41 pts (97,6%) were alive, the median OS was not reached. The 2-year PFS was 44,5% (95% CI, 28,2-59,6) The nivolumab therapy was discontinued in 39 pts (93%) due to scheduled discontinuation in 14 pts (33%), PD in 13 pts (31%), grade 3-4 AE in 2 pts (5%), change of therapy because of insufficient response in 6 pts (14%) and other reasons in 4 pts (10%). The progression of disease during nivolumab therapy was present in 14 (33%) pts and after nivolumab discontinuation in 6 (14%) pts. After disease progression 30 pts (71%) were retreated with nivolumab monotherapy or in combination with chemotherapy. The median time to additional therapy was 14,5 mo (4,2 -32,9). The adverse events of any severity were observed in 30 pts (71%). Grade 3 or higher AE were present in 4 pts (9,5%), including grade 3 arthralgia, grade 3 anemia, grade 4 pneumonia and pneumonitis, grade 4 increased level of alanine aminotransferase and grade 5 MDS in 1 pt. A significant reduction of PD1+CD3+ cell population of peripheral blood lymphocytes was observed after first nivolumab cycle (median 0.7% (0-1.7) versus 33% (15.7-80.1) before therapy initiation, p = 0.02, Wilcoxon signed-rank test). Conclusion Our study demonstrated the efficacy and safety of nivolumab 40 mg therapy. The presented results are comparable to previously published data of nivolumab 3 mg/kg therapy in patients with r/r cHL. Thus, this creates a basis for further direct comparative study of nivolumab efficacy in different doses Disclosures No relevant conflicts of interest to declare.

Abstract: Introduction Young patients with idiopathic aplastic anemia (AA) respond better to immunosuppressive therapy (IST) but the long-term outcome is suboptimal with non-response in 30% of patients as well as significant risks of relapse, ciclosporine (CSA) dependence and clonal evolution. Excellent results of up-front unrelated donor (UD) hematopoietic stem cell transplantation (HSCT) have been reported in a cohort of 29 children with idiopathic AA using an Alemtuzumab-based regimen, with low Graft versus Host Disease (GvHD) rates and only 1 death (Dufour C, BJH 2015). We took advantage of the SAAWP registry of the European Blood and Marrow Transplantation (EBMT) to analyze the outcomes of 65 young patients who received up-front UD HSCT in Europe. Methods : Patients who had received an UD HSCT for AA, between 2010 and 2018, registered in the SAAWP registry were included. Patients who had received IST (CSA or anti-thymocyte globulin (ATG)) before HSCT, cord blood, haplo-identical transplant were excluded as well as patients suffering from congenital bone marrow disorders. The primary endpoint was overall survival (OS) at 2 years. Secondary endpoints were GVHD-free/relapse-free survival (GRFS) - defined at 2 years as being alive, engrafted without acute GVHD grade III-IV, and extensive chronic GVHD during follow-up. Results : Sixty-five patients were included between 2010 and 2018; median age was 16 years old (9-26). Time to HSCT was 6.5 months (IQR 3.6-11.7). Thirty-nine patients were transplanted from a matched unrelated donor (at least 8/8 HLA matched), 11 patients had mismatched UD (HLA data missing for 14 patients). The two-year overall survival rate was 92% (95% CI, 85-99%) (figure 1,A) with a median follow-up of 32 months (25-43). Main cause of death was infection (2 out of 5 deaths). Failure occurred in 8% (1-15%) of the patients. Acute GVHD grade II-IV was observed in 13% (5-22%) of the patients and Grade III and IV happened for two patients (3%). Chronic GVHD at 2 years occurred for 12% (4-21%) of the patients, with no extensive case. GRFS was 87% (77-96%) at 2-years (Figure 1, B). In our cohort, 57 patients received in vivo T cell depletion using either ATG (n=33, 60%) or anti-lymphocyte globulin (n=4, 7%) or alemtuzumab (n=20, 30%). Due to low rate of events happening during outcome, no risk factor analysis could be driven. Conclusion: In this retrospective cohort of 65 patients with idiopathic aplastic anemia, up-front UD transplantation leads to promising results, confirming previous studies on a smaller cohort of patients. Moreover, we did not find any difference according to in vivo T-cell depletion type, suggesting excellent results are not exclusively related to alemtuzumab-based regimen. Because of obvious limitation related to retrospective studies, unreported events and information bias cannot be excluded. Prospective trials are on their way in the United States and in Europe to formally confirm upfront UD transplantation as standard of care for pediatric patients with idiopathic aplastic anemia. Disclosures Rambaldi: Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company). Research grant from Amgen Inc.; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company). Advisory board and speaker fees from Pfizer.; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support from Gilead.; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Support of parent study and funding of editorial support. Received travel support., Research Funding; University of Milan: Current Employment; BMS/Celgene: Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Astellas: Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Sanofi: Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Omeros: Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company). Griškevičius:Novartis: Research Funding. Dalle:Sanofi-Genzyme: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Orchard: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Medac: Consultancy, Honoraria; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: Honoraria; Bellicum: Consultancy, Honoraria; Incyte: Consultancy, Membership on an entity's Board of Directors or advisory committees; AbbVie Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; bluebird bio: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Risitano:Pfizer: Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Alnylam: Research Funding; Alexion: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Amyndas: Consultancy; Samsung: Membership on an entity's Board of Directors or advisory committees; RA pharma: Research Funding; Biocryst: Membership on an entity's Board of Directors or advisory committees; Apellis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Achillion: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees; Jazz: Speakers Bureau. Peffault De Latour:Apellis: Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Amgen: Research Funding; Alexion Pharmaceuticals Inc.: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau.