ALBERT

Description: Autoimmune lymphoproliferative syndrome type Ia (ALPS Ia) is caused by mutations in the CD95/APO1/FAS (TN-FRSF6) gene, which lead to a defective CD95 ligand (CD95L)–induced apoptosis. Soluble CD95 (sCD95) has been suggested to play an important role in the pathogenesis of diverse autoimmune and malignant diseases by antagonizing CD95L. Here we evaluate a family with 4 of its 5 members harboring an ex-6–3C→G mutation that affects the splice cis regulatory region (cctacag/ex-6→cctagag/ex-6) of the CD95 gene. The mutation causes skipping of exon-6, which encodes the transmembrane region of CD95, and thereby leads to an excessive production of sCD95 in all 4 affected individuals. The mutation is associated with a low penetrance of disease phenotype and caused mild and transient ALPS in one male patient whereas all other family members are completely healthy. In all family members with the mutation we found that the cell surface expression of CD95 was low and the activated T cells were resistant to CD95-induced apoptosis. Unexpectedly, excessive production or addition of sCD95 had no effect on the CD95-induced apoptosis in diverse cells. In contrast, increasing the surface expression of CD95 was able to correct the defect in apoptosis. Thus we conclude that the ALPS in the one male patient was caused by haploinsufficiency of membrane CD95 expression. Our data challenge the hypothesis that sCD95 causes autoimmunity.

Description: Abstract 4397 OBJECTIVES Thrombotic events have been reported as a major cause of morbidity after the Fontan procedure. There is no consensus about the type and duration of postoperative anticoagulation prophylaxis, due to the high risk of bleeding complications, the difficulties in monitoring and the questionable therapeutic compliance in children. In spite of the lack of long term prospective studies in this situation, the ACCP has recommended in their guidelines OAT following Fontan or Glenn operation for at least 6 months. This has also been our practice in our institution during the period of study. AIM OF THE STUDY To analyze the efficacy and complications of OAT in our pediatric patients after undergoing the Fontan operation. METHODS Retrospective chart review of all the children treated with OAT in our institution between 1995 and 2009. All patients were treated initially with acenocumarol 0,2 mg/kg, except the Fontan patients, who received 0,1 mg/kg. Target INR was 2–3 for all patients. The Mann-Whitney test was used to compare the rate of complications, and the percentage of visits out of target INR between the Fontan patients and the rest of the cohort. RESULTS There were 61 children (26 female/35 males) aged between 1 month and 17 years, who received OAT with a range of follow up between 4 months and 14 years: 27 after Fontan operation (Group A), an 34 for other reasons (Group B: n=13 non prothetic valve cardiopathy, n=21 treatment of thromboembolic disease). The average follow-up was similar in both groups (median of 6.5 months in group A vs.7.5 months in group B). There were few complications: 1 mild epistaxis and 1 thrombotic event in group B, and none in group A. There were no differences in the proportion of controls in normal range between both groups; there was a moderate proportion of controls outside the target range of INR, with higher distribution below the range than above the range. The median dose used to achieve the target INR was 0.3 mg/kg/d in Group A and 0.4 mg/kg/d in Group B. CONCLUSIONS Oral Anticoagulant therapy is safe and effective in pediatric patients,with very low rates of thrombotic or hemorragic complications including those undergoing the Fontan surgery. There were not any differences between both groups in any of the analizyed parameters. Disclosures: No relevant conflicts of interest to declare.

Description: Background: Despite a variety of treatment options, indolent non-Hodgkin's lymphoma (iNHL) remains a largely incurable disease with patients experiencing multiple relapses. Both rituximab (RTX) and bendamustine (Benda) are used as single agents for the treatment of relapsed/refractory iNHL. When given in combination to patients with relapsed iNHL, high response rates were observed (Rummel, 2016). Ofatumumab (OFA) is a human, anti-CD20 type-I antibody that binds a distinct epitope from RTX. A phase I/II study showed that OFA has activity in patients with follicular lymphoma (FL) who relapsed after RTX-containing therapy (Hagenbeek, 2008). Based on these experiences, COMPLEMENT A+B evaluated if OFA+Benda would improve progression-free survival (PFS) compared to Benda alone in unresponsive or progressive iNHL after RTX or RTX-containing regimen. Methods: This phase III, open-label, randomized, global, multi-center study enrolled adult patients (≥18 years) with CD20+ small lymphocytic, marginal zone, lymphophasmacytic and Grades 1-3A FL who had either stable disease after or disease progression during or within 6 months of RTX or RTX-containing regimen. Patients were randomized (1:1) to receive either OFA+Benda or Benda. Benda (90 mg/m2 in OFA+Benda arm and 120 mg/m2 in Bendaarm) was given on Days 1 and 2 every 21 days for up to 8 cycles. OFA (1000 mg) was given on Day 1 of Benda cycles and then every 28 days for a total of 12 doses. The primary endpoint was PFS as assessed by an independent review committee (IRC). Key secondary endpoints included PFS in patients with FL, overall response rates (ORR) and overall survival (OS) in all patients and in patients with FL which were tested hierarchically if the prior endpoint was statistically significant. Results: Overall, 346 patients were enrolled (173 in each arm) in 85 centers across 15 countries. Baseline characteristics were similar between the 2 arms. Median (range) age was 62 (21-87) years, majority were males (59%) and 69% had FL. Ann Arbor Stage IVA was common (OFA+Benda: 43%; Benda: 42%). Median duration of follow up was 61.1 months. Median treatment duration was longer in the OFA+Benda arm (OFA+Benda: 260 days; Benda: 135 days). Median (range) number of prior RTX therapy was 1 (1-8). In the OFA+Benda arm, 58% and 65% completed treatment with OFA and Benda, respectively, whereas in the Benda arm, 43% completed treatment. The main reason for premature discontinuation of OFA treatment in OFA+Benda arm was adverse events (AEs), 14%. The main reason for premature treatment discontinuation of Benda was AEs (OFA+Benda: 17%; Benda: 27%). Primary analysis was performed after 217 IRC-assessed PFS events occurred. In the OFA+Benda and Benda arms, 61% and 65% of patients, respectively, had PFS events (Figure 1). Median IRC-assessed PFS was 16.7 months in the OFA+Benda arm and 13.8 months in the Benda arm (hazard ratio [HR]=0.82, 95% confidence interval [CI] [0.62, 1.07]; p=0.1390). Similar results were seen in patients with FL where the median IRC-assessed PFS was similar in FL patients - 16.6 months in the OFA+Benda arm and 12.1 months in the Benda arm (HR=0.76, 95% CI [0.55,1.06]; p=0.1076) (Figure 2). IRC-assessed ORR was similar in both arms (OFA+Benda: 73%; Benda: 75%; difference in ORR [95% C]: -1.2% [-10.4%, 8.1]; p=0.8003). Median OS was 58.2 months and 51.8 months in the OFA+Benda and Benda arms, respectively (HR=0.89, 95% CI [0.63, 1.25]; p=0.4968). Frequencies of deaths (OFA+Benda: 38%; Benda: 41%) and on-treatment deaths (OFA+Benda: 7%; Benda: 9%) were similar in both arms. The main cause of death during the study was disease under study (OFA+Benda: 20%; Benda: 15%). Overall, 73% of patients in the OFA+Benda arm and 80% in the Benda arm experienced a ≥ Grade 3 AE. The most common ≥ Grade 3 AEs were neutropenia, thrombocytopenia, anemia, and leukopenia (Table 1). Conclusions: No significant improvement in PFS was seen with OFA+Benda as compared with Benda alone for patients with RTX-refractory iNHL. The safety profile for OFA was consistent with prior experience. The difference in outcomes compared to those in the GADOLIN trial (Sehn, 2016) could be due to the differences in drug exposure as patients in the GADOLIN study received maintenance anti-CD 20 therapy for up to 2 years; in the patient population as approximately 80% had FL in GADOLIN versus 69% in COMPLEMENT A+B; and in the mechanism of action of type-1 versus type-2 monoclonal antibody. Disclosures Rummel: Mundipharma: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Symbio: Honoraria; Celgene: Honoraria; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Astellas: Honoraria; Eisai: Honoraria. Janssens:Sanofi-Genzyme: Speakers Bureau; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Ad board, Speakers Bureau; Janssen: Consultancy, Speakers Bureau; Roche: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Ad board, Speakers Bureau; Amgen: Consultancy, Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees. MacDonald:Roche Canada: Honoraria; Abbvie: Honoraria; Janssen: Honoraria; Merck: Honoraria. Keating:Bayer: Honoraria, Membership on an entity's Board of Directors or advisory committees. Davis:Novartis: Employment. Lasher:Novartis: Employment. Lobe:Novartis: Employment. Izquierdo:Novartis: Employment, Equity Ownership. Friedberg:Bayer: Honoraria.

Description: The tumor microenvironment is characterized by multiple interactions of transformed malignant cells with non-transformed stroma or immune cells. Particularly macrophages play a pivotal role in this network determining disease progression and therapeutic response. In previous work we could show that macrophages are an essential mediator of therapeutic response in the synergistic response to the administration of the chemoimmunotherapy. The combination treatment strongly increases tumor clearance by repolarization of tumor-associated macrophages from a suppressive to an activated phenotypic state. Here, se analyzed the functional implications of the DNA damage response pathway for the generation of the ASAP and synergy in chemoimmunotherapy. We attempted to disrupt DNA damage response pathway in lymphoma cells generated from the hMB humanized Double-Hit-Lymphoma model by knock-down of key elements like ATM, DNA-PK or p53. We could prevent the formation of the stimulatory cytokine release effect on macrophage phagocytic capacity. Here, p53 status displays a key regulatory role on macrophage mediated malignant cell depletion. TP53 activation via Nutlin-3A treatment of lymphoma cell enhances ADCP in in p53 wild-type cells, while not displaying enhancement in p53-deficient lymphoma cells. Addressing the treatment in vivo using the hMB model for modeling of Double-Hit Lymphoma bearing mice we could demonstrate diminished ASAP and ADCP for p53-deficient lymphoma treated with cyclophosphamide in vivo. Using primary human CLL patient cells comparing both wild-type and p53-deficient status, the p53-deficient CLL cells failed to induce the stimulatory, cytokine-mediated effect on macrophage phagocytosis in response to combination treatment as seen with the p53 proficient CLL cells. Using a CLL mouse model by treating Eµ-TCL1/p53wt/wt as well as Eµ-TCL1p53-/- mice we could show that low-dose cyclophosphamide treated Eµ-TCL1p53-/- mice failed to induce an antibody mediated stimulatory effect on macrophage phagocytosis capacity as seen with Eµ-TCL1/p53wt/wt mice. A similar effect was seen for primary multiple myeloma cells in response to daratumumab displaying significantly less ADCP of p53-deficient multiple myeloma cells. As for the mechanism of p53-defined interaction within the tumor microenvironment we subjected p53-wild-type and p53-deficient lymphoma cells for proteomic analysis. Here we could identify a significantly deregulated protein expression profile for exosome release in p53 deficient lymphoma cells. Verifying this finding by assessing size and frequency exosomes released by respective cell populations we reveal profound changes induced by p53 loss. Furthermore we could identify up-regulation of PD-L1 in p53-deficient cells. Blocking this checkpoint in the ADCP assay could significantly restore phagocytic capacity of macrophages and overall therapeutic response. In this work, we indicate that p53 functional status determines phagocytic function and therapeutic response to monoclonal antibodies. We can verify this finding in independent models in vitro and in vivo as in primary CLL and myeloma patient cells. We furthermore identify altered exosome profiles and checkpoint inhibitor expression in lymphoma cells as underlying mechanism of macrophage modulation. Finally our ongoing research offers possibility to reveal and tailor new combinatorial treatment approaches for chemo-refractory patients. Disclosures Wendtner: Genetech: Consultancy, Honoraria, Other: travel support, Research Funding; GlaxoSmithKline: Consultancy, Honoraria, Other: travel support, Research Funding; Gilead: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Other: travel support, Research Funding; Pharmacyclics: Consultancy, Honoraria, Other: travel support, Research Funding; Abbvie: Consultancy, Honoraria, Other: travel support, Research Funding; MorphoSys: Consultancy, Honoraria, Other: travel support, Research Funding; Gilead: Consultancy, Honoraria, Other: travel support, Research Funding; Roche: Consultancy, Honoraria, Other: travel support, Research Funding; Mundipharma: Consultancy, Honoraria, Research Funding. Hallek:Janssen: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Mundipharma: Honoraria, Research Funding; Pharmacyclics: Honoraria, Research Funding; Roche: Honoraria, Research Funding; Gilead: Honoraria, Research Funding; Abbvie: Honoraria, Research Funding. Pallasch:Gilead: Research Funding.

Description: Platelets engage cues of pending vascular injury through coordinated adhesion, secretion and aggregation responses. These rapid, progressive changes in platelet form and function are orchestrated downstream of specific receptors on the platelet cell surface, and through intracellular signaling mechanisms that remain systematically undefined. This study brings together cell physiological and phosphoproteomics methods incorporating peptide tandem mass tag (TMT) labeling, sample multiplexing, synchronous precursor selection (SPS) and triple stage tandem mass spectrometry (MS3) to profile signaling mechanisms downstream of the immunotyrosine activation motif (ITAM) platelet collagen receptor GPVI. Altogether, 〉3,000 significant (FDR1,300 proteins were detected in initial and progressing conditions of GPVI-mediated platelet activation. With literature-guided causal inference tools, 〉300 site-specific signaling relations were mapped from phosphoproteomics data among key and emerging GPVI effectors (i.e., FcRg, Syk, PLCg2, PKCd, DAPP1). Through signaling validation studies and functional screening, other less-characterized targets were also considered within the context of GPVI/ITAM pathways, including Ras/MAPK axis proteins (i.e., KSR1, SOS1, STAT1, Hsp27). Networks highly regulated in GPVI/ITAM signaling out of context of curated knowledge were also illuminated, including a system of 〉40 Rab GTPases and associated regulatory proteins - where TAK1-mediated Rab7 S72 phosphorylation associated with endolysosomal maturation and GPVI-mediated platelet function. In addition to serving as a model for generating and testing hypotheses from omics datasets, this study puts forth a means to identify hemostatic effectors, biomarkers and therapeutic targets relevant to thrombosis, vascular inflammation and other platelet-associated disease states.

Description: This study was undertaken to assess the significance of lung-resistance related protein (LRP) expression in plasma cells from untreated multiple myeloma (MM) patients and to determine whether LRP was associated with a poor response and survival in patients treated with different dose regimens of melphalan. Seventy untreated patients received conventional oral dose melphalan (0.25 mg/kg, day 1 to 4) combined with prednisone (MP) or intravenous intermediate-IDM; 70 mg/m2) or high- (140 mg/m2) dose Melphalan (HDM). LRP expression was assessed with immunocytochemistry using the LRP-56 monoclonal antibody. LRP expression was found in 47% of patients. In the MP treated patients, LRP expression was a significant prognostic factor regarding response induction (P 

Description: Background: Chromosome 14q32 rearrangements involving the immunoglobulin heavy chain gene (IGH) affect less than 5% of chronic lymphocytic leukemia (CLL) patients. Their clinical course is aggressive and the outcome, worse than other CLL subtypes (Cavazzini et al, 2008; Gerrie et al, 2012). However, the biology of CLL showing IGH rearrangements (CLL-IGHR) is not completely defined. The identification of novel recurrent mutations in CLL by next generation-sequencing (NGS) has offered a more comprehensive view into the genomic landscape of the disease and improved the prognostication of CLL. Thus, mutational analysis might be especially useful in those patients with uncertain prognosis, such as those carrying IGH rearrangements. Aim: To analyze the mutational profile of CLL-IGHR patients by targeted NGS in order to improve our understanding of the genetic underpinnings of this subgroup. Methods: The study was based on 899 CLL patients, well characterized at cytogenetic, biological and clinical level, forty-two of them (4.7%) showing IGH rearrangements. Targeted NGS was performed in 231 CLL samples: 117 with 13q deletion, 27 with 11q deletion, 26 trisomy 12, 42 showing IGH rearrangements and the remaining 19 without any cytogenetic alteration. CD19+ B cells were isolated and DNA extracted. SureSelectQXT targeted enrichment technology and a custom-designed panel (MiSeq, Illumina), including 54 CLL-related and recurrent mutated genes, was carried out. The panel yielded 100x or greater coverage on 97% of the genomic regions of interest and the mean coverage obtained was 600x. Mutations were detected down to 3% allele frequency. Results: The mutational analysis of CLL-IGHR patients identified a total of 72 mutations in 32 genes. Seventy-one percent of patients (30/42) harbored at least one mutation. The most frequently mutated genes in this cohort were NOTCH1 (28.6%), POT1 (14.3%), TP53 (9.5%), SF3B1 (7%), BRAF (7%), EGR2 (7%), IGLL5 (7%) and MGA (7%), followed by BCL2, HIST1H1E and FBXW7 (4.8%), uncommonly mutated genes in CLL at these frequencies (Table 1). In fact, mutations in NOTCH1, BRAF, EGR2, BCL2, HIST1H1E and FBXW7 were significantly associated with CLL-IGHR patients (p=0.013, p=0.003, p=0.021, p=0.038, p=0.038 and p=0.021 respectively). In terms of time to the first therapy (TFT), CLL-IGHR had an intermediate-negative impact (median TFT=24 months) compared to the presence of cytogenetic alterations associated with good prognosis such as 13q deletions (median TFT〉120 months; p

Description: Background AFM13 is a bispecific, tetravalent NK cell-engaging antibody construct binding to CD30 on CD30+ tumor cells and CD16A on NK cells. By engaging CD16A-positive NK cells, AFM13 leads to NK cell-mediated killing of CD30-positive lymphoma cells (Reusch et al., 2014) making it an attractive agent to target classical Hodgkin lymphoma (HL). Pembrolizumab is a PD-1 blocking antibody which has shown high single-agent response rates in patients (pts) with relapsed/refractory HL (RRHL; Armand et al., 2016, Chen et al., 2017). AFM13 has shown clinical activity in RRHL as a single agent in a preceding Phase 1 study (Rothe et al., 2015). Preclinical in vivo data of the combination of AFM13 with PD-1 blockade showed synergistic activity and the potential for induction of cross-talk between innate and adaptive immunity (Zhao et al., 2016). We hypothesize that the combination of the two agents could improve outcomes in pts with RRHL. Methods This Phase 1b study is evaluating the safety and tolerability of the combination of AFM13 with pembrolizumab (Keytruda) as salvage therapy after failure of standard therapies including brentuximab vedotin (BV) in HL (NCT02665650). Pts receive escalating doses of AFM13 in combination with pembrolizumab at a dose of 200 mg flat administered every 3 weeks following a classical 3+3 design, followed by enrollment into an extension cohort at the maximum tolerated dose (MTD)/maximum administered dose (MAD). Response assessment is performed every 12 weeks by PET/CT according to the Lugano Classification (Cheson et al., 2014). The main objectives of the study is to ascertain the MTD/MAD along with the preliminary efficacy of the combination. Results As of June 29, 2018, 30 pts have been enrolled into the study. The median age is 34 years (range, 18-73), with a median of 4 (range 3-7) prior lines of therapy. All pts had relapsed or refractory disease (43% relapsed, 57% refractory) and had failed standard treatments including BV and 43% of pts (13/30) had BV as their latest therapy. Thirty seven percent (11/30) had undergone prior autologous stem cell transplantation. All 30 pts have completed the 6-week dose-limiting toxicity (DLT) observation period. Twelve pts were enrolled into the dose escalation cohorts (Cohorts 1 (n=3), 2 (n=3), and 3 (n=6)) and 18 into the Extension Cohort, with a total of 24 patients treated at the MAD (dose level 3). One DLT was observed in Cohort 3 (missing ≥25% of AFM13 during the DLT period) and another observed in the Extension Cohort (G4 infusion-related reaction; IRR). The most common related adverse events (AEs) were IRRs (80%), rash (30%), pyrexia (23%), nausea (23%), diarrhea (20%), fatigue (17%), headache (17%), increased aspartate aminotransferase (13%), and increased alanine aminotransferase (10%). Treatment related G3/4 AEs included IRRs (13%), elevated AST (3%), gastritis (3%), hypotension (3%), nausea (3%), neutropenia (3%), and vomiting (3%). The majority of IRRs were manageable with standard of care measures and did not lead to treatment discontinuations. Included in the efficacy analysis were the best response from 29 evaluable pts who had at least one post-baseline disease assessment as of the data cutoff on June 29, 2018. The overall response rate (ORR) and complete response (CR) rate for evaluable pts treated at the dose and schedule chosen for expansion (n=23; Cohort 3 and Extension Cohort) were 87% and 35% by the investigator-confirmed assessment, respectively. Independent assessment resulted in an ORR of 87% and CR rate of 39% for these pts. Updated data for all 30 patients will be presented at the meeting. Conclusions The combination of AFM13 and pembrolizumab is a well-tolerated salvage therapy in pts with RRHL. IRRs were the most frequently observed adverse events; however, most of these events were of mild or moderate severity and manageable. Both the ORR and CR rate compare favorably to monotherapy pembrolizumab in a similar RRHL population (Chen et al., 2017). The combination of AFM13 and pembrolizumab could be a potential new therapeutic option for HL patients. Disclosures Bartlett: Immune Design: Research Funding; Affimed: Research Funding; Bristol-Meyers Squibb: Research Funding; Merck & Co: Research Funding; Pharmacyclics: Research Funding; Celgene: Research Funding; Pharmacyclics: Research Funding; Genentech: Research Funding; Forty Seven: Research Funding; Novartis: Research Funding; Novartis: Research Funding; Millennium: Research Funding; ImaginAB: Research Funding; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Research Funding; KITE: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Seattle Genetics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Astra Zeneca: Research Funding; Acerta: Membership on an entity's Board of Directors or advisory committees. Chen:Affimed: Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Genentech Inc.: Consultancy; Seattle Genetics: Consultancy, Honoraria, Research Funding, Speakers Bureau; Merck & Co., Inc.: Consultancy, Research Funding, Speakers Bureau; Millennium Pharmaceuticals: Consultancy, Research Funding; Pharmacyclics: Consultancy, Research Funding. Domingo-Domenech:Affimed: Research Funding. Forero-Torres:Affimed: Research Funding. Garcia-Sanz:Affimed: Research Funding. Devata:Affimed: Research Funding. Rodriguez Izquierdo:Affimed: Research Funding. Lossos:Affimed: Research Funding. Reeder:Affimed: Research Funding. Sher:Affimed: Research Funding. Choe-Juliak:Affimed: Employment. Prier:Affimed: Research Funding. Schwarz:Affimed: Employment. Strassz:Affimed: Employment. Alland:Affimed: Employment. Ansell:Bristol-Myers Squibb: Research Funding; Celldex: Research Funding; LAM Therapeutics: Research Funding; Trillium: Research Funding; Pfizer: Research Funding; Regeneron: Research Funding; Seattle Genetics: Research Funding; Merck & Co: Research Funding; Affimed: Research Funding; Takeda: Research Funding.

Description: Background: Nivolumab, an immune checkpoint inhibitor, has been tested in patients with classical Hodgkin lymphoma (cHL) who failed standard treatment options and has demonstrated remarkable activity with acceptable safety profile in clinical trials. After the impressive results of nivolumab phase I study, a significant number of patients were granted early access to nivolumab through a Name Patient Program (NPP) or compassionate use in Spain. Demonstrating that results of nivolumab use in real-life are similar to those in clinical trials is of major clinical relevance. Objective: The aim of this retrospective study was to analyze the efficacy and safety profile of nivolumab for the treatment of relapsed/refractory (RR) cHL in a real-life context. Methods: We retrospectively collected data from 34 GELTAMO centers. Eligible patients included RR cHL patients treated with at least one cycle of nivolumab. The primary end-point was to describe the overall response rate (ORR). Secondary objectives were to assess the complete response rate (CR), safety of nivolumab, and clinical outcomes (overall survival [OS], and progression free survival [PFS]). Results: Between September 2015 and May 2018, 74 patients with RR cHL received nivolumab monotherapy dosed at 3mg/kg once every 2 weeks (97%). The median age was 38 years (range 17-78). Patients have received a median of 4 (1-15) prior therapy lines; all but 2 were previously treated with brentuximab vedotin (97%), and 38 (51%) of them underwent a hematopoietic stem cell transplantation (HSCT) (n=33 autologous, autoHSCT, and n=5 allogeneic, alloHCST). Median number of nivolumab cycles was 8 (1-65). Ten (14%) patients are still on treatment. Reasons for nivolumab discontinuation were disease progression in 23/64 (36%), referral to HSCT in 27/64 (42%), adverse events (AE) in 8/64 (13%), patient or physician's decision in 5/64 (8%), and unknown in 1/64 (1%). Treatment related AE were reported in 42/69 (61%). Half of them (21, 30%) were probably immune related AE: grade 1-2, 67% (cutaneous n=5, hepatitis n=3, hypothyroidism n=3, gastrointestinal n=3, suprarenal insufficiency n=1); grade 3-4, 24% (pneumonitis n=2, hepatitis n=1, encephalitis n=1, hypothyroidism n=1); grade 5, 3% (pneumonitis n=1, Stevens-Johnson syndrome + hepatitis + nephritis n=1). ORR was 58% (CR 21/72 patients, partial response [PR] 21/72). Stable disease (SD) was achieved in 9 patients (13%). After an initial response (4 PR and 3 SD), 7 patients developed lymphoma progression. A total of 40 (54%) patients finally underwent HSCT, 4 autoHSCT and 36 alloHCST. AlloHSCT was performed after a median of 63 days (41-115) and 8 patients received prior salvage therapy. Complications after alloHSCT consisted of non-infectious fever requiring steroid treatment in 13 (36%), acute graft-versus-host disease in 19 (53%) (2 of them grade 3-4, 1 death), hepatic venocclusive disease in 2 (6%, 1 death), and non-infectious pulmonary complications in 2 (6%). Five (14%) patients died due to transplant complications. At the last follow-up, all autoHSCT patients and 23/36 alloHSCT were in CR. The 2-year OS for the whole series (n=74) was 54% (median not reached). After a median follow-up of survivors patients of 12.5 months (1-31), 29 (39%) were alive in CR. Conclusions: Our real-life experience confirms the efficacy of nivolumab in very heavily pretreated cHL patients with an ORR of 58%. The safety profile of our cohort is comparable with that previously reported in clinical trials with manageable side effects and low treatment related mortality. In our study the percentage of patients who bridged to transplantation was significantly higher to that previously reported indicating this preference for Spanish physicians. AlloHSCT post-nivolumab showed encouraging results and toxicity seemed comparable to that previously described with other treatment regimens. Authors thank Bristol Myers Squibb for its support in this study. Disclosures Martinez: BMS: Research Funding; Takeda: Consultancy. García-Sanz:Janssen: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses; Takeda: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Honoraria; Hospira: Research Funding; Pharmacyclics: Research Funding; Spanish Government: Research Funding; Gilead: Research Funding; Amgen Inc.: Research Funding; Incyte: Consultancy.