Search

PTCL with T-follicular helper phenotype (PTCL-TFH) has recurrent mutations affecting epigenetic regulators, which may contribute to aberrant DNA methylation and chemoresistance. This phase 2 study evaluated oral azacitidine (CC-486), a DNA methyltransferase inhibitor, plus CHOP as initial treatment for PTCL (ClinicalTrials.gov - NCT03542266). CC-486 at 300 mg daily was administered for 7 days prior to C1 of CHOP, and for 14 days before CHOP C2-6. The primary endpoint was end-of-treatment CR. Secondary endpoints included ORR, safety and survival. Correlative studies assessed mutations, gene expression and methylation in tumor samples. Grade 3-4 hematologic toxicities were mostly neutropenia (71%), with febrile neutropenia uncommon (14%). Non-hematologic toxicities included fatigue (14%) and GI symptoms (5%). In 20 evaluable patients, CR was 75%, including 88.2% for PTCL-TFH (n=17). At a median follow-up of 21 months, 2-yr PFS was 65.8% for all and 69.2% for PTCL-TFH, while 2-yr OS was 68.4% for all and 76.1% for PTCL-TFH. The frequencies of the TET2, RHOA, DNMT3A, and IDH2 mutations were 76.5%, 41.1%, 23.5% and 23.5%, respectively, with TET2 mutations significantly associated with CR (p=0.007), favorable PFS (p=0.004) and OS (p=0.015), and DNMT3A mutations associated with adverse PFS (p=0.016). CC-486 priming contributed to the reprograming of the tumor microenvironment by upregulation of genes related to apoptosis (p

Signaling through JAK1 and/or JAK2 is common among tumor and nontumor cells within peripheral T-cell lymphoma (PTCL). No oral therapies are approved for PTCL, and better treatments for relapsed/refractory disease are urgently needed. We conducted a phase 2 study of the JAK1/2 inhibitor ruxolitinib for patients with relapsed/refractory PTCL (n = 45) or mycosis fungoides (MF) (n = 7). Patients enrolled onto 1 of 3 biomarker-defined cohorts: (1) activating JAK and/or STAT mutations, (2) ≥30% pSTAT3 expression among tumor cells by immunohistochemistry, or (3) neither or insufficient tissue to assess. Patients received ruxolitinib 20 mg PO twice daily until progression and were assessed for response after cycles 2 and 5 and every 3 cycles thereafter. The primary endpoint was clinical benefit rate (CBR), defined as the combination of complete response, partial response (PR), and stable disease lasting at least 6 months. Only 1 of 7 patients with MF had CBR (ongoing PR > 18 months). CBR among the PTCL cases (n = 45) in cohorts 1, 2, and 3 were 53%, 45%, and 13% (cohorts 1 & 2 vs 3, P = .02), respectively. Eight patients had CBR > 12 months (5 ongoing), including 4 of 5 patients with T-cell large granular lymphocytic leukemia. In an exploratory analysis using multiplex immunofluorescence, expression of phosphorylated S6, a marker of PI3 kinase or mitogen-activated protein kinase activation, in

Background T-cell/histiocyte-rich large B-cell lymphoma (THRLBCL) is an uncommon variant of diffuse large B cell lymphoma (DLBCL), characterized by low content of lymphoma cells in a background of extensive infiltrate of T-cells and histiocytes. Historically, THRLBCL was considered an aggressive variant of DLBCL with poorer outcomes and a 3-year OS We aimed to describe the clinical characteristics, prognostic factors, response to treatment, and outcome among pts diagnosed with THRLBCL at Memorial Sloan Kettering Cancer Center (MSKCC) in the rituximab era. Patients and Methods We retrospectively reviewed all cases of THRLBCL who were diagnosed in our center from January 2000 to October 2019. We collected data for demographic and clinical characteristics, pathology results, disease stage and sites of involvement, treatment regimen, and outcome. Fisher's exact test was used to assess associations between patient characteristics and treatment regimen. Fisher's exact test and Wilcoxon test were used to assess associations between categorical or continuous characteristics and response to treatment, respectively. The likelihood ratio test was used to assess significance of Cox regression univariate models. Overall survival (OS) was measured from date of diagnosis until last follow up or death. Event-free survival (EFS) was measured from end of treatment to last follow up or pathology proven relapse or disease progression. Survival curves were estimated using the Kaplan Meier method. Results A total of 100 pts were diagnosed with THRLBCL at our center during the study period. We excluded 33 pts who had missing data regarding stage, frontline treatment, or response. A total of 67 pts were included for analysis in our cohort. Median follow up duration among survivors was 3.4 years (range 0.4-10.8 years). Baseline characteristics are summarized in table 1. Forty-eight were males (72%). Median age at diagnosis was 41 years (range 19-86). Fifty-three (72%) pts were diagnosed at stage IV. Thirty-five (52%) pts had involvement of more than 1 extra-nodal site. The most common extranodal site was bone (60%). Fourteen pts had a positive bone marrow biopsy (26% of those evaluated). Univariate analysis was performed for age, gender, ethnicity, stage, extra-nodal sites, presence of B symptoms, performance status, elevated LDH, IPI score>=3, and history of NLPHL. None of these factors were found significantly associated with response rate, EFS, or OS. Frontline treatment is shown in table 2 and included R-CHOP or R-CHOP based treatment in 48% (n=32), R-EPOCH in 12% (n=8), R-CHOP/R-ICE (4 cycles of R-CHOP-14 followed by 3 cycles of R-ICE, Moskowitz CH, et al. JCO 2010) in 33% (n=22) and other regimens in 7.5% (n=5). CNS prophylactic treatment was given in 19 pts. One pt had an autologous stem cell transplant and 1 pt had an allogeneic stem cell transplant as part of frontline treatment. Fifty-one (76%) pts had a complete response (CR) to frontline treatment. Among these pts, 6 relapsed. Sixteen (24%) pts had refractory disease. Among pts with relapsed or refractory disease, 18 received additional therapy. In the whole cohort, 3-year EFS was 68% and 3-year OS was 85%. In a sub-group analysis of pts who received R-CHOP/R-ICE compared to pts who were treated with R-CHOP or R-EPOCH, CR rates were 95% and 70% respectively (p=0.014). The R-CHOP/R-ICE regimen was also associated with higher 3-year EFS of 86% compared to 62% (p=0.049) and a better 3-year OS of 100% compared with 79% (p=0.016). See figures 1-2. The 2 treatment groups were not significantly different with regards to baseline characteristics. Conclusions Our study demonstrates better outcomes among pts with THRLBCL compared to available historical data from the pre-rituximab era. In addition, with the limitation of a retrospective, single-center study, our data suggests that for newly diagnosed THRLBCL, treatment with a higher intensity regimen, such as R-CHOP/R-ICE, may be associated with favorable outcome. Disclosures Batlevi: Life Sci, GLG, Juno/Celgene, Seattle Genetics, Kite: Consultancy; Janssen, Novartis, Epizyme, Xynomics, Bayer, Autolus, Roche/Genentech: Research Funding. Falchi:Roche: Research Funding; Genmab: Research Funding. Hamlin:Molecular Templates: Research Funding; Portola Pharmaceutics: Consultancy; J&J Pharmaceuticals: Research Funding; Incyte: Research Funding; Celgene: Consultancy; Juno Therapeutics: Consultancy; Karyopharm: Consultancy; Portola: Research Funding. Horwitz:Forty Seven: Consultancy, Research Funding; ADCT Therapeutics: Consultancy, Research Funding; ASTEX: Consultancy; Beigene: Consultancy; Portola: Consultancy, Research Funding; Mundipharma: Consultancy; Innate Pharma: Consultancy; Corvus: Consultancy; Trillium: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding; Millenium/Takeda: Consultancy, Research Funding; Verastem: Consultancy, Research Funding; GlaxoSmithKline: Consultancy; Infinity/Verastem: Research Funding; Kyowa Hakka Kirin: Consultancy, Research Funding; Aileron: Consultancy, Research Funding; Vividion Therapeutics: Consultancy; Affirmed: Consultancy; Janssen: Consultancy; Kura Oncology: Consultancy; Miragen: Consultancy; Myeloid Therapeutics: Consultancy; Celgene: Consultancy, Research Funding; C4 Therapeutics: Consultancy; Daiichi Sankyo: Research Funding. Joffe:AstraZeneca: Membership on an entity's Board of Directors or advisory committees; Epizyme: Membership on an entity's Board of Directors or advisory committees. Kumar:AbbVie: Research Funding; Astra Zeneca: Honoraria, Other: Honoraria for Advisory Board; Celgene: Honoraria, Other: Honoraria for Advisory Board; Seattle Genetics: Research Funding; Pharmacyclics: Research Funding; Celgene: Research Funding; Adaptive Biotechnologies,: Research Funding; Kite Pharmaceuticals: Honoraria, Other: Honoraria for Advisory Board. Matasar:Pharmacyclics: Honoraria, Research Funding; Immunovaccine Technologies: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; IGM Biosciences: Research Funding; GlaxoSmithKline: Honoraria, Research Funding; Takeda: Consultancy, Honoraria; Daiichi Sankyo: Consultancy; Seattle Genetics: Consultancy, Honoraria, Research Funding; Rocket Medical: Consultancy, Research Funding; Teva: Consultancy; F. Hoffmann-La Roche Ltd: Consultancy, Honoraria, Research Funding; Juno Therapeutics: Consultancy; Genentech, Inc.: Consultancy, Honoraria, Research Funding; Merck: Consultancy; Bayer: Consultancy, Honoraria, Research Funding. Noy:Pharmacyclics: Research Funding; Medscape: Consultancy; NIH: Research Funding; Rafael Pharma: Research Funding; Janssen: Consultancy; Pharmacyclics: Consultancy; Morphosys: Consultancy; Targeted Oncology: Consultancy. Palomba:Genentech: Research Funding; Juno: Research Funding; Regeneron: Research Funding; Novartis: Honoraria; Merck: Honoraria; Celgene: Honoraria; Juno: Honoraria; Pharmacyclics: Honoraria. Straus:Karyopharm Therapeutics: Membership on an entity's Board of Directors or advisory committees; Targeted Oncology: Consultancy, Speakers Bureau; NY Lymphoma Rounds: Consultancy; Takeda Pharmaceuticals: Research Funding, Speakers Bureau; OncLive: Speakers Bureau; Elsevier: Membership on an entity's Board of Directors or advisory committees, Other: CME writer; ASH: Other: Conference in December 2019 on HL to other physicians during ASH; Seattle Genetics: Consultancy, Membership on an entity's Board of Directors or advisory committees; Imedex, Inc.: Speakers Bureau. Vardhana:Other: Other: SAV has received honoraria from Agios Pharmaceuticals and Rheos Pharmaceuticals, is an advisor for Immunai and has consulted for ADC Therapeutics. von Keudell:Bayer: Research Funding; Genentech: Research Funding; Pharmacyclics: Research Funding. Zelenetz:Celgene: Consultancy; Gilead: Consultancy; Genentech/Roche: Consultancy; Gilead: Research Funding; Adaptive Biotechnology: Consultancy; Sandoz: Research Funding; MorphoSys: Research Funding; Celgene: Research Funding; MEI Pharma: Research Funding; Roche: Research Funding; BeiGene: Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy; Novartis: Consultancy; Amgen: Consultancy. Moskowitz:Incyte: Research Funding; Merck: Consultancy; Seattle Genetics: Consultancy; Miragen Therapeutics: Consultancy; Imbrium Therapeutics, L.P.: Consultancy; Merck: Research Funding; Bristol-Myers Squibb: Research Funding; Seattle Genetics: Research Funding.

BACKGROUND: Treatment of chronic lymphocytic leukemia (CLL) with a fixed-duration venetoclax (Ven)-based regimen is now a standard of care (SOC) option for both frontline and relapsed refractory (R/R) disease based on results of the CLL14 and MURANO trials (Fischer et al NEJM 2019, Seymour et al NEJM 2018). As fixed-duration Ven regimens are now a SOC, it is expected that an increasing number of patients (pts) will ultimately progress after Ven exposure and require additional CLL-directed therapy. While many discuss re-treatment with Ven as a subsequent treatment option, the current literature contains response data on an extremely limited number of evaluable pts (11 pts MURANO, overall response rate (ORR) 55%; 3 pts VEN 365, ORR 100%). Whether re-treatment with Ven is an acceptable option remains an important unanswered clinical question. METHODS: We conducted a multicenter, retrospective study of CLL pts treated with a Ven-based regimen (Ven1) and then re-treated with a second Ven-based regimen (Ven2) in a later line of therapy (LOT). Data were collected from 13 centers and the CLL Collaborative Study of Real-World Evidence database. CLL pts were eligible for inclusion if they were treated with a Ven-based regimen in any LOT and then re-treated with a Ven-based regimen as a later LOT. Collected data included demographics, prognostic disease characteristics, tumor lysis syndrome (TLS) risk and incidence, clinical response and reasons for treatment discontinuation (dc). The primary study endpoint was investigator-assessed ORR (CR: complete response, PR: partial response, SD: stable disease, PD: progression of disease, iwCLL 2018). Kaplan-Meier method was used to estimate progression free survival (PFS). All other analyses were descriptive. RESULTS: We identified 25 pts who were re-treated with Ven. Pt characteristics prior to treatment with Ven1 are summarized in Table 1. In 24% of pts (n=6), Ven1 was administered as part of a clinical trial. Median prior LOT was 2 (range 0-10) with 12.0% treatment naïve and 60% with prior BTKi exposure. The majority of pts had ≥1 high-risk prognostic marker: del17p (39%), TP53 mut (27%), complex karyotype ≥5 abnormalities (30%) and unmutated IGHV (84%). For Ven1, treatment regimens, TLS risk, and dose are summarized in Table 2. With a median duration of exposure of 15 months (mos) (64% pts > 12 mos) for Ven1, the ORR was 88% (CR: 48%, PR: 40%, Figure 1A). Ten pts had minimal residual disease (MRD) assessments by flow cytometry; 8 pts (80%) achieved undetectable MRD (10^-4). Most common reasons for Ven1 dc included: toxicity (28%), completion of planned therapy (24%), MD/pt preference (24%), other (12%), alloHSCT (4%) and cost (4%). There was a median of 8.7 mos (36% > 12 mos) between Ven1 and the initiation of Ven2, and 88% did not receive another LOT between Ven1 and Ven2. Reasons for Ven2 initiation were either CLL progression (87.5%) or MRD-positive relapse (12.5%). For Ven2, TLS risk, TLS incidence and dose information are outlined in Table 2. TLS was a rare event during Ven re-treatment (4.5%, lab only). For Ven2, Ven monotherapy was the most common regimen (52%). Standard Ven dose-escalation was used for re-initiation in 17 of 19 pts with available data, however 1 pt started Ven2 at 400 mg daily (no TLS) and another underwent a prolonged ramp-up period. At the time of this analysis, 18 pts had available response assessments for Ven2: ORR is 72.2% (CR: 4, PR: 9, SD: 4 and PD: 1, Figure 1B). Median time from Ven2 to progression or last follow up is 8 mos (0.2-29 mos). Median PFS has not been reached. Estimated 12-month PFS is 69.1%. For pts with a CR to Ven2, median follow up time is 14.5 mos vs 7 mos for pts with PR or SD. Of 25 pts re-treated with Ven, 68% remain on Ven2 presently and 32% have discontinued Ven2, including due to CLL progression (n=4), completion of planned therapy (n=1), unrelated death (n=1), MD/pt preference (n=1). CONCLUSIONS: To our knowledge, this is the largest reported cohort of CLL pts re-treated with Ven after a prior Ven-based regimen. The high ORR in this pt population (median 2 prior therapies) suggests that re-treatment is a promising strategy and should be considered in treatment sequencing algorithms. Notably, pts with a CR to Ven2 had a longer median follow up than those with a PR or SD, suggesting a likelihood of deeper responses with time. Given the promising ORR, further research to prospectively validate Ven re-treatment is warranted. Updated data will be presented. Disclosures Allan: Celgene, Genentech, Janssen, TG Therapeutics: Research Funding; Abbvie, Janssen, AstraZeneca, Pharmacyclics: Honoraria; Acerta, Genentech, Abbvie, Sunesis, Ascentage, Pharmacyclics, Janssen, AstraZeneca, BeiGene: Consultancy. Sail:AbbVie Inc.: Current Employment, Current equity holder in publicly-traded company. Manzoor:Abbvie: Current Employment, Other: may hold stock or stock options. Pu:Takeda Pharmaceuticals: Consultancy. Barr:Gilead: Consultancy; Janssen: Consultancy; AstraZeneca: Consultancy, Research Funding; Abbvie/Pharmacyclics: Consultancy, Research Funding; Verastem: Consultancy; Morphosys: Consultancy; TG therapeutics: Consultancy, Research Funding; Seattle Genetics: Consultancy; Celgene: Consultancy; Merck: Consultancy; Genentech: Consultancy. Coombs:LOXO Oncology: Honoraria; MEI Pharma: Honoraria; Abbvie: Consultancy, Honoraria; Genentech: Honoraria; AstraZeneca: Honoraria; Octapharma: Honoraria; Novartis: Honoraria. Schuster:AlloGene, AstraZeneca, BeiGene, Genentech, Inc./ F. Hoffmann-La Roche, Juno/Celgene, Loxo Oncology, Nordic Nanovector, Novartis, Tessa Therapeutics: Consultancy, Honoraria; Novartis, Genentech, Inc./ F. Hoffmann-La Roche: Research Funding. Skarbnik:Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Alexion: Consultancy; Beigene: Speakers Bureau; Verastem: Speakers Bureau; Novartis: Speakers Bureau; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; CLL Society: Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Kite Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Rhodes:Verastem: Consultancy; Abbvie/Genentech: Consultancy; Pharmacyclics: Consultancy; AstraZeneca: Consultancy. Barrientos:Janssen: Honoraria; Sandoz: Consultancy; Oncternal Therapeutics: Research Funding; Bayer: Consultancy; Genentech: Consultancy; Gilead: Consultancy; AstraZeneca: Consultancy. Roeker:American Society of Hematology: Research Funding; Abbott Laboratories: Other: spouse with minority ownership interest ; AbbVie: Other: spouse with minority ownership interest . Leslie:Celgene: Speakers Bureau; Seattle Genetics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Speakers Bureau; KitePharma: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BeiGene: Honoraria, Speakers Bureau; Pharmacyclics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; AstraZeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Epizyme: Honoraria, Speakers Bureau; Karyopharm: Honoraria, Speakers Bureau; Bayer: Consultancy, Membership on an entity's Board of Directors or advisory committees; ADC therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; TG Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees. Kamdar:Roche: Research Funding. Choi:Pharmacyclics/Abbvie: Research Funding; Genentech: Consultancy. Simkovic:Abbvie: Consultancy, Other: travel expenses. Lansigan:Seattle Genetics: Consultancy; BMS: Consultancy; BMS Steering Committee for MAGNIFY Program: Membership on an entity's Board of Directors or advisory committees; Spectrum Pharma: Consultancy, Research Funding. Zelenetz:Novartis: Consultancy; Gilead: Research Funding; Janssen: Consultancy; Celgene: Consultancy; Gilead: Consultancy; Genentech/Roche: Consultancy; Roche: Research Funding; BeiGene: Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnology: Consultancy; MorphoSys: Research Funding; Amgen: Consultancy; Sandoz: Research Funding; Celgene: Research Funding; MEI Pharma: Research Funding. Moskowitz:Merck: Research Funding; Seattle Genetics: Research Funding; Bristol-Myers Squibb: Research Funding; Miragen Therapeutics: Consultancy; Incyte: Research Funding; Merck: Consultancy; Imbrium Therapeutics, L.P.: Consultancy; Seattle Genetics: Consultancy. Goy:Morphosys: Research Funding; AbbVie: Research Funding; MD Anderson: Research Funding; Regional Cancer Care Associates/OMI: Current Employment; Infinity Verastem: Research Funding; Infinity: Research Funding; Karyopharm: Research Funding; Genentech/Roche: Research Funding; CALBG: Research Funding; Constellation: Research Funding; Bayer: Research Funding; PracticeUpdate Oncology: Consultancy; RCCA/OMI: Current Employment; Acerta: Consultancy, Honoraria, Other: leadership role, Research Funding; AstraZeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: leadership role, Research Funding; Celgene: Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Other: leadership role, Research Funding; COTA: Consultancy, Current equity holder in publicly-traded company, Other: leadership role; Kite, a Gilead Company: Consultancy, Current equity holder in publicly-traded company, Honoraria, Other: leadership role, Research Funding; Xcenda: Consultancy; Hackensack UMC and University of Nebraska: Research Funding. Feldman:Pfizer: Research Funding; Kyowa Kirin: Consultancy, Research Funding; Eisai: Research Funding; Cell Medica: Research Funding; Amgen: Research Funding; Pharmacyclics: Honoraria, Other, Speakers Bureau; Abbvie: Honoraria; Bayer: Consultancy, Honoraria; Trillium: Research Funding; Portola: Research Funding; Janssen: Speakers Bureau; AstraZeneca: Consultancy; Viracta: Research Funding; Rhizen: Research Funding; Corvus: Research Funding; BMS: Consultancy, Honoraria, Research Funding; Kite: Honoraria, Other: Travel expenses, Speakers Bureau; Celgene: Honoraria, Research Funding; Takeda: Honoraria, Other: Travel expenses; Seattle Genetics, Inc.: Consultancy, Honoraria, Other: Travel expenses, Research Funding, Speakers Bureau. Furman:Verastem: Consultancy; Genentech: Consultancy; Beigene: Consultancy; AstraZeneca: Consultancy, Research Funding; Acerta: Consultancy; Abbvie: Consultancy; TG Therapeutics: Consultancy, Research Funding; Sunesis: Consultancy; Pharmacyclics: Consultancy; Oncotarget: Consultancy; Loxo Oncology: Consultancy; Janssen: Consultancy, Speakers Bureau; Incyte: Consultancy. Mato:Genentech: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; BeiGene: Consultancy; LOXO: Consultancy, Research Funding; AstraZeneca: Consultancy, Research Funding; TG Therapeutics: Consultancy, Other: DSMB, Research Funding; Adaptive: Consultancy, Research Funding; Pharmacyclics LLC, an AbbVie Company: Consultancy, Research Funding; AbbVie: Consultancy, Research Funding.

This phase 1-2 study evaluated brentuximab vedotin (BV) combined with nivolumab (Nivo) as first salvage therapy in patients with relapsed/refractory (r/r) classical Hodgkin lymphoma (cHL). In parts 1 and 2, patients received staggered dosing of BV and Nivo in cycle 1, followed by same-day dosing in cycles 2 to 4. In part 3, both study drugs were dosed, same day, for all 4 cycles. At end of study treatment, patients could undergo autologous stem cell transplantation (ASCT) per investigator discretion. The objective response rate (ORR; N = 91) was 85%, with 67% achieving a complete response (CR). At a median follow-up of 34.3 months, the estimated progression-free survival (PFS) rate at 3 years was 77% (95% confidence interval [CI], 65% to 86%) and 91% (95% CI, 79% to 96%) for patients undergoing ASCT directly after study treatment. Overall survival at 3 years was 93% (95% CI, 85% to 97%). The most common adverse events (AEs) prior to ASCT were nausea (52%) and infusion-related reactions (43%), all grade 1 or 2. A total of 16 patients (18%) had immune-related AEs that required systemic corticosteroid treatment. Peripheral blood immune signatures were consistent with an activated T-cell response. Median gene expression of CD30 in tumors was higher in patients who responded compared with those who did not. Longer-term follow-up of BV and Nivo as a first salvage regimen shows durable efficacy and impressive PFS, especially in patients who proceeded directly to transplant, without additional toxicity concerns. This trial was registered at www.clinicaltrials.gov as #NCT02572167.

This retrospective study aimed to better define the characteristics and outcomes of extranodal stage I diffuse large B-cell lymphoma (DLBCL) in the rituximab era. Patients diagnosed with stage I DLBCL from 2001 to 2015 treated with rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone (R-CHOP) or R-CHOP–like regimens with or without radiation (RT) were included. We identified 1955 patients with newly diagnosed DLBCL, of whom 341 had stage I and were eligible for this analysis. Extranodal presentation was observed in 224 (66%) patients, whereas 117 (34%) had nodal involvement. The most common extranodal sites were as follows: bone, 21%; stomach, 19%; testis, 9%; intestine, 8%; breast, 8%. Overall, 69% extranodal patients and 68% nodal patients received RT. Median follow-up was 5.5 years (interquartile range, 4.3-8.2). Ten-year overall survival (OS) and disease-free survival were 77% (95% confidence interval [CI], 67%-83%) and 77% (95% CI, 68%-85%). In the multivariable analyses, extranodal involvement was associated with worse OS (hazard ratio [HR], 3.44; 95% CI, 1.05-11.30) and progression-free survival (PFS; HR, 3.25; 95% CI, 1.08-9.72) compared with nodal involvement. Consolidation RT was associated with better OS (HR, 0.26; 95% CI, 0.12-0.49) and PFS (HR, 0.35; 95% CI, 0.18-0.69) in the extranodal population; however, the benefit was no longer observed in patients that were positron emission tomography (PET) negative at the end of immunochemotherapy. Relapses occurred usually late (median, 37 months), and the most common sites were the lymph nodes (31%) and the central nervous system (27%). Extranodal stage I DLBCL had a worse outcome than nodal stage 1 DLBCL. End of immunochemotherapy PET results may help select extranodal patients for consolidation RT.

INTRODUCTION: Nodal PTCL with T-follicular helper phenotype (PTCL-TFH), which includes angioimmunoblastic T-cell lymphoma, is characterized by recurrent mutations affecting epigenetic regulators. Azacitidine, a DNA demethylating agent, has shown clinical activity as a single agent and in combination in R/R PTCL. We report the mature findings, including survival outcome and biomarker analysis, of the first study of oral azacitidine (CC-486) plus CHOP as initial treatment for PTCL (ClinicalTrials.gov - NCT03542266). METHODS: This phase 2 study prioritized enrollment of PTCL-TFH. Subjects received CHOP on day 1 of each cycle for 6 cycles. Oral azacitidine (aza) priming at 300 mg daily was administered for 7 days prior to C1 of CHOP, and for 14 days before CHOP C2-6. The primary endpoint was CR per 2014 IWG criteria. Secondary endpoints included ORR, safety and survival. Correlative biomarker studies assessed mutation profile by whole exome NGS with germline control, genome-wide DNA methylation sequencing by RRBS, and gene expression by RNA-sequencing of paired tumor samples before and after aza priming prior to C1D1 chemotherapy. Survivals were estimated by Kaplan-Meier analysis, and log-rank tests were performed to correlate biomarkers to survival outcomes. RESULTS: A total of 21 subjects with previously untreated PTCL, including 17 with PTCL-TFH (81%), 3 with PTCL-NOS (14%), were enrolled and received treatment at 4 centers. The median age was 66 years (range 22-77), 19 (90%) had stage III/IV disease, 10 (48%) had elevated LDH, 7 (35%) had bone marrow involvement, and 9 (43%) had IPI 3-5. Treatment-emergent grade 3-4 hematologic toxicities included neutropenia (71%), thrombocytopenia (10%) and anemia (14%), with febrile neutropenia uncommon (14%). Grade 3-4 non-hematologic toxicities included fatigue (14%), hyponatremia (14%), diarrhea (5%), anorexia (5%), vomiting (5%), rash (5%), and elevated ALT (4.8%). There was no treatment-related mortality on study. As of July 2021 at a median follow-up of 21 months (range 16-30 months), 20 subjects were evaluable for primary endpoint, with one withdrawal after cycle 1. The end-of-treatment responses were all CRs, including CR at 75% (90%CI of 54.4 - 89.6%) for all evaluable patients (n=20) and 88.2% for PTCL-TFH (n=17). The 2-yr PFS was 65.8% (95%CI of 43.4-88.1%) for all patients, and 69.2% (95%CI of 46.7-91.7%) for PTCL-TFH. The 2-yr OS was 68% (95%CI of 46.7-89.2%) for all patients, and 75.6% (95%CI of 54.8-96.5%) for PTCL-TFH. The median PFS was estimated at 36 months (95%CI: 8 months - not reached). Consolidative stem cell transplant was performed in 10 subjects (9 auto and 1 allo), which did not impact PFS or OS. Mutational status was determined in 17 patients. The frequencies of the TET2, RHOA, DNMT3A, and IDH2 mutations were 76.5%, 41.1%, 23.5% and 23.5%, respectively, with RHOA and IDH2 mutations occurring in the hotspot positions (RHOA G17V, IDH2 R172G/T). For all patients, TET2 mutations were significantly associated with CR (p=0.007), favorable PFS (p=0.004) and OS (p=0.015), while DNMT3A mutations were associated with adverse PFS (p=0.016). Within the PTCL-TFH subgroup, TET2 mutations were associated with favorable PFS (p=0.014). RNAseq and RRBS assays were performed in 5 paired tumor samples before and after aza priming. Differentially upregulated genes revealed enrichment of gene sets related to apoptosis (p CONCLUSIONS: This study demonstrates that priming with oral azacitidine (CC486) in combination with CHOP as initial therapy is safe, effective, and produces sustained remission in PTCL-TFH subtype. Epigenetic priming with azacitidine appears to inhibit the proliferation of TFH lymphoma cells, providing potential synergistic mechanism of action with chemotherapy. This active combination will be further evaluated in the upcoming ALLIANCE/ US Intergroup randomized study A051902, comparing oral azacitidine-CHO(E)P vs duvelisib-CHO(E)P against CHO(E)P in CD30 negative PTCL. Figure 1 Figure 1. Disclosures Ruan: Pharmacyclics: Research Funding; Seagen: Consultancy; Kite Pharma: Consultancy; AstraZeneca: Research Funding; Daiichi Sankyo: Consultancy, Research Funding; BMS: Consultancy, Research Funding. Moskowitz: Janpix Ltd.: Consultancy; Merck: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding; ADC Therapeutics: Research Funding; Miragen: Research Funding; Bristol-Myers Squibb: Research Funding; Beigene: Research Funding; Imbrium Therapeutics L.P./Purdue: Consultancy; Takeda: Consultancy; Incyte: Research Funding. Mehta-Shah: C4 Therapeutics: Consultancy; Celgene: Research Funding; Innate Pharmaceuticals: Research Funding; Roche/Genentech: Research Funding; Corvus Pharmaceuticals: Research Funding; Karyopharm: Consultancy; Ono Pharmaceuticals: Consultancy; Secura Bio: Consultancy, Research Funding; Daiichi Sankyo: Consultancy, Research Funding; Bristol Myers Squibb: Research Funding; AstraZeneca: Research Funding; Kiowa Hakko Kirin: Consultancy; Verastem: Research Funding. Sokol: Dren Bio: Membership on an entity's Board of Directors or advisory committees; Kyowa-Kirin: Membership on an entity's Board of Directors or advisory committees. Kotlov: BostonGene Corp: Current Employment, Current holder of stock options in a privately-held company, Patents & Royalties. Horwitz: ADC Therapeutics, Affimed, Aileron, Celgene, Daiichi Sankyo, Forty Seven, Inc., Kyowa Hakko Kirin, Millennium /Takeda, Seattle Genetics, Trillium Therapeutics, and Verastem/SecuraBio.: Consultancy, Research Funding; Affimed: Research Funding; Aileron: Research Funding; Acrotech Biopharma, Affimed, ADC Therapeutics, Astex, Merck, Portola Pharma, C4 Therapeutics, Celgene, Janssen, Kura Oncology, Kyowa Hakko Kirin, Myeloid Therapeutics, ONO Pharmaceuticals, Seattle Genetics, Shoreline Biosciences, Inc, Takeda, Trillium Th: Consultancy; Celgene: Research Funding; C4 Therapeutics: Consultancy; Crispr Therapeutics: Research Funding; Daiichi Sankyo: Research Funding; Forty Seven, Inc.: Research Funding; Kura Oncology: Consultancy; Kyowa Hakko Kirin: Consultancy, Research Funding; Millennium/Takeda: Research Funding; Myeloid Therapeutics: Consultancy; ONO Pharmaceuticals: Consultancy; Seattle Genetics: Consultancy, Research Funding; Secura Bio: Consultancy; Shoreline Biosciences, Inc.: Consultancy; Takeda: Consultancy; Trillium Therapeutics: Consultancy, Research Funding; Tubulis: Consultancy; Verastem/Securabio: Research Funding. Coleman: Merck: Research Funding; Innocare: Research Funding; BeiGene: Research Funding; Gilead: Research Funding; Genentech: Research Funding; Celgene: Research Funding; Bristol Myers: Research Funding; Abbvie: Research Funding; immunomedics: Current equity holder in publicly-traded company, Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company; Pfizer: Research Funding; Roche: Research Funding. Melnick: Constellation: Consultancy; Epizyme: Consultancy; Daiichi Sankyo: Research Funding; Sanofi: Research Funding; Janssen Pharmaceuticals: Research Funding; KDAC Pharma: Membership on an entity's Board of Directors or advisory committees. Elemento: AstraZeneca: Research Funding; Eli Lilly: Research Funding; One Three Biotech: Consultancy, Other: Current equity holder; Freenome: Consultancy, Other: Current equity holder in a privately-held company; Champions Oncology: Consultancy; Volastra Therapeutics: Consultancy, Other: Current equity holder, Research Funding; Johnson and Johnson: Research Funding; Janssen: Research Funding; Owkin: Consultancy, Other: Current equity holder. Leonard: ADC Therapeutics, AstraZeneca, Bayer, BMS/Celgene, Epizyme, Inc., Genmab, Gilead/Kite, Karyopharm, BMS/Celgene, Regeneron, MEI Pharma, Miltenyi, Roche/Genentech, Sutro: Consultancy; Roche/Genentech: Consultancy. Martin: ADCT: Consultancy. Cerchietti: Celgene: Research Funding; Bristol Myers Squibb: Research Funding. OffLabel Disclosure: Oral azacitidine for treatment of peripheral T-cell lymphoma

Introduction: Peripheral T-cell lymphomas (PTCL) are a rare subset of non-Hodgkin lymphomas in which approximately 80% patients will have an overall response to CHOP based therapy but 5-year survival ranges between 20-40%. (Ellin et al Blood 2014) While response by PET/CTs have been helpful in risk stratifying patients (Mehta-Shah Blood Advances 2019), the high rate of relapse after complete response (CR) suggests that more sensitive determinants of minimal residual disease (MRD) could have prognostic and even therapeutic importance. T-cell receptor gene rearrangement sequencing (TCR) is standardly performed by next generation sequencing and is able to detect a known TCR clonotype at 10 -5. (Shah et al AMP 2017) Therefore, in a prospective multi-institutional study, we sought to evaluate the utility of TCR by next generation sequencing in quantifying MRD in PTCL. (NCT03297697). Here we report the results of the TCR evaluation at the end of CHOP-based therapy. Methods: Subjects with previously untreated PTCL (PTCL-NOS: peripheral T-cell lymphoma, NOS; angioimmunoblastic T-cell lymphoma: AITL; anaplastic large cell lymphoma: ALCL; T-follicular helper phenotype peripheral T-cell lymphoma: PTCL-TFH, monomorphic epitheliotropic intestinal T-cell lymphoma: MEITL) who were being treated with anthracycline based therapy for curative intent were eligible for the study. TCR (TRG or TRB) clonotype was established from baseline formalin fixed paraffin embedded tumor tissue or peripheral blood when tissue samples are not available. TCR clonality was identified using the LymphoTrack® TRG/TRB Assays - MiSeq® (Invivoscribe, San Diego, CA) when top %reads is ≥2.5% and is at least 2x compared to the background. Results: 43 subjects were enrolled in the study and 41 were evaluable (15 PTCL-NOS, 10 AITL, 7 ALK- ALCL, 5 ALK+ ALCL, 3 PTCL-NOS with TFH phenotype, 1 MEITL). One subject was enrolled with PTCL-NOS and later found to have T-ALL and was withdrawn from the study. One subject with ALK- ALCL withdrew consent prior to sample collection. Subjects initiated treatment with CHOEP (n=16), BV-CHP (n=11), CHOP (n=5), CEOP (n=1) CHOP+azacitidine (n=6), CHOEP+lenalidomide (n=1), EPOCH (n=1). The median age was 65 (range: 22-80). Sixteen underwent a consolidative autologous transplant. Among the 41 evaluable subjects, 73% (30/41) had tissue samples and 27% (11/41) had only PB samples for TCR clonotype assessment. TCR clonotype was identified in 78% (32/41) tissue samples and not in 23% (9/40: 1 Nodal TFH, 2 AITL, 1 ALK- ALCL, 5 ALK+ ALCL) samples. Of the 32 subjects with baseline clonotype, 2 patients (1 AITL, 1 PTCL) did not have end of treatment (EOT) samples for TCR MRD evaluation. For EOT MRD evaluation, 80% (24/30) were had detectable MRD by TCR (MRD positive) and 20% (6/30) had undetectable TCR (TCR MRD negative). For the EOT evaluation by PET/CT, 63% (19/30) had CR, 10% (3/30) had partial remission (PR) and 27% (8/30) had progressive disease (PD). Among the 6 TCR MRD negative subjects, PET/CT responses were 67% (4/6) for CR and 33% (2/6) for PR, respectively. Among the 24 TCR MRD positive subjects, PET/CT responses were 63% (15/24) for CR, 33% (1/24) for PR and 33% (8/24) for PD. Of those with positive MRD 13/24 (54%) have relapsed/progressed including 8 with primary refractory disease. At the end of CHOP-based therapy, 79% (15/19) subjects with PET CR were TCR MRD positive, and 21% (4/19) were TCR MRD negative. Among the 11 subjects with either PD or PR by PET/CT, 82% (9/11) were TCR MRD positive, and 18% (2/11) were TCR MRD negative. At a median follow up of 20.7 months, progression free survival and overall survival at 18 months did not differ between those who were TCR MRD positive or negative respectively at EOT (OS 64% vs 67% p=0.63; PFS 41% vs 50% p=0.40). We plan to present additional follow up for all patients on the study including MRD post autologous transplant at the time of the meeting. Conclusions: Measurement of peripheral blood TCR at the end of treatment is feasible in peripheral T-cell lymphomas using next generation sequencing with a known tumor clonotype. Detectable TCR at the end of treatment correlates with lack of CR but the majority of patients in complete remission by PET/CT have a detectable TCR clonotype at end of treatment. Longer follow up is required to determine if consolidative transplant alters TCR dynamics. This study was supported by the Lymphoma Research Foundation and T-cell Leukemia/Lymphoma Society. Figure 1 Figure 1. Disclosures Mehta-Shah: C4 Therapeutics: Consultancy; Ono Pharmaceuticals: Consultancy; Secura Bio: Consultancy, Research Funding; Daiichi Sankyo: Consultancy, Research Funding; AstraZeneca: Research Funding; Bristol Myers Squibb: Research Funding; Celgene: Research Funding; Innate Pharmaceuticals: Research Funding; Roche/Genentech: Research Funding; Corvus Pharmaceuticals: Research Funding; Karyopharm: Consultancy; Kiowa Hakko Kirin: Consultancy; Verastem: Research Funding. Jacobsen: Takeda: Consultancy; Syros: Consultancy; Janssen: Research Funding; Novartis: Research Funding; Pharmacyclics: Research Funding; Acerta: Research Funding. Fehniger: Wugen: Consultancy, Current equity holder in publicly-traded company, Patents & Royalties: related to memory like NK cells, Research Funding; Affimed: Research Funding; Compass Therapeutics: Research Funding; HCW Biologics: Research Funding; Kiadis: Other; ImmunityBio: Research Funding; OrcaBio: Other; Indapta: Other. Kahl: AbbVie, Acerta, ADCT, AstraZeneca, BeiGene, Genentech: Research Funding; AbbVie, Adaptive, ADCT, AstraZeneca, Bayer, BeiGene, Bristol-Myers Squibb, Celgene, Genentech, Incyte, Janssen, Karyopharm, Kite, MEI, Pharmacyclics, Roche, TG Therapeutics, and Teva: Consultancy. Bartlett: Celgene: Research Funding; Bristol Myers Squibb: Research Funding; Forty Seven: Research Funding; Genentech: Research Funding; Janssen: Research Funding; Kite, a Gilead Company: Research Funding; Merck: Research Funding; Millennium: Research Funding; Pharmacyclics: Research Funding; Autolus: Research Funding; Seagen: Consultancy, Research Funding; Roche/Genentech: Consultancy; ADC Therapeutics: Consultancy, Research Funding. Ghobadi: Amgen: Consultancy, Research Funding; Kite, a Gilead Company: Consultancy, Honoraria, Research Funding; Atara Biotherapeutics: Consultancy; Wugen: Consultancy; Celgene: Consultancy. Moskowitz: Seattle Genetics: Consultancy, Research Funding; Imbrium Therapeutics L.P./Purdue: Consultancy; Merck: Consultancy, Research Funding; ADC Therapeutics: Research Funding; Miragen: Research Funding; Beigene: Research Funding; Bristol-Myers Squibb: Research Funding; Takeda: Consultancy; Incyte: Research Funding; Janpix Ltd.: Consultancy. Jacobsen: Invivoscribe: Current Employment. Olson: Invivoscribe: Current Employment. Vigil: Invivoscribe: Current Employment. Hill: Invivoscribe: Current Employment. Elias: Invivoscribe: Current Employment. Huang: Invivoscribe: Current Employment. Horwitz: ADC Therapeutics, Affimed, Aileron, Celgene, Daiichi Sankyo, Forty Seven, Inc., Kyowa Hakko Kirin, Millennium /Takeda, Seattle Genetics, Trillium Therapeutics, and Verastem/SecuraBio.: Consultancy, Research Funding; Affimed: Research Funding; Celgene: Research Funding; Aileron: Research Funding; Acrotech Biopharma, Affimed, ADC Therapeutics, Astex, Merck, Portola Pharma, C4 Therapeutics, Celgene, Janssen, Kura Oncology, Kyowa Hakko Kirin, Myeloid Therapeutics, ONO Pharmaceuticals, Seattle Genetics, Shoreline Biosciences, Inc, Takeda, Trillium Th: Consultancy; C4 Therapeutics: Consultancy; Crispr Therapeutics: Research Funding; Daiichi Sankyo: Research Funding; Forty Seven, Inc.: Research Funding; Kura Oncology: Consultancy; Kyowa Hakko Kirin: Consultancy, Research Funding; Millennium/Takeda: Research Funding; Myeloid Therapeutics: Consultancy; ONO Pharmaceuticals: Consultancy; Seattle Genetics: Consultancy, Research Funding; Secura Bio: Consultancy; Shoreline Biosciences, Inc.: Consultancy; Takeda: Consultancy; Trillium Therapeutics: Consultancy, Research Funding; Tubulis: Consultancy; Verastem/Securabio: Research Funding.

Background Brentuximab vedotin (BV) has been investigated in several single arm phase II trials as a new therapeutic option for patients with a first relapse or primary refractory classical Hodgkin lymphoma (R/R cHL), but no randomized controlled trials have been done that compare the addition of BV to salvage chemotherapy in the R/R setting. The aim of this study was to investigate the effect of BV addition to salvage chemotherapy compared to chemotherapy alone on progression free survival (PFS), overall survival (OS) and complete metabolic response (CMR) rate prior to autologous stem-cell transplant (ASCT), and to identify prognostic factors for response and survival. Methods We collected individual patient data of 718 transplant eligible R/R cHL patients treated in prospective clinical trials, of which 391 patients were treated with BV and salvage chemotherapy (BV-cohort), and 327 with salvage chemotherapy alone (Chemo-cohort), followed by ASCT [Table 1]. For PFS and OS analysis, the BV- and Chemo-cohorts were matched by propensity scores on baseline characteristics (i.e. relapsed/refractory, bulky disease, extranodal disease, stage I-II/III-IV, B-symptoms and first-line treatment with BEACOPP). Primary refractory disease was defined as not having achieved a CMR on first-line treatment. A CMR was defined as Deauville score (DS)1-3. PET-scans in the Chemo-cohort were assessed using IWG criteria (Cheson 2007) at the time of the original study. Therefore, we re-evaluated PET-positive scans using DS. Results After matching by propensity scores, there were no statistically significant differences in baseline characteristics between the BV- and Chemo-cohorts [Table 2]. The 3-year PFS was 74% (95%CI: 68-80%) in the BV-cohort compared to 67% (61-74%) in the Chemo-cohort (p=0.13) [Fig1A]. The 3-year OS was 94% (90-97%) versus 80% (74-86%); p When corrected for baseline characteristics, there were no significant differences in PFS between studies within the BV-cohort that used a sequential approach, multiple chemotherapeutic agents (e.g. DHAP/ICE/ESHAP vs bendamustine/gemcitabine) or different cumulative BV doses. Patients treated with a sequential approach with BV-ICE or ICE-GVD who achieved a CMR pre-ASCT on BV or ICE alone showed no difference in PFS compared to patients who achieved a CMR after BV-ICE or ICE-GVD (p=0.97). Pre-ASCT PET response data were available for all patients in the BV-cohort and n=93 patients in the Chemo-cohort from the sequential ICE-GVD study. Patients with a CMR (n=349) had significant better PFS compared to patients with a partial response (n=67), with a 3-year PFS of 79% (75-84%) versus 58% (47-71%); p Conclusions The addition of BV to salvage chemotherapy followed by ASCT seems to increase PFS in relapsed, but not in primary refractory cHL patients. This suggests that in patients who are chemotherapy resistant other treatment modalities such as checkpoint inhibitors (CPI) should be considered. The observed increase in OS for the BV-cohort could be due to advances in treatment over time since novel therapies for patients who fail ASCT, such as CPI and BV, were not yet available at time of studies in the Chemo-cohort. Our study confirms the strong prognostic value of pre-ASCT CMR for PFS. B-symptoms, stage and primary refractory disease are prognostic factors for PFS and for achieving a pre-ASCT CMR. Figure 1 Figure 1. Disclosures Driessen: Takeda: Other: Travel support for ASH 2019. Herrera: Gilead Sciences: Research Funding; Merck: Consultancy, Research Funding; AstraZeneca: Consultancy, Research Funding; Seagen: Consultancy, Research Funding; Bristol Myers Squibb: Consultancy, Research Funding; ADC Therapeutics: Consultancy, Research Funding; Tubulis: Consultancy; Kite, a Gilead Company: Research Funding; Karyopharm: Consultancy; Genentech: Consultancy, Research Funding; Takeda: Consultancy. Zinzani: ImmuneDesign: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Bristol Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Portola: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen-Cilag: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sandoz: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Incyte: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; TG Therapeutics Inc: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Servier: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Kyowa Kirin: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Verastem: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BeiGene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Merck Sharp & Dohme: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; EUSA Pharma: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celltrion: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; ADC Therapeutics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Consultancy, Membership on an entity's Board of Directors or advisory committees. LaCasce: Bristol-Myers Squibb Company.: Other: Data Safetly and Monitoring. Moskowitz: Merck & Co., Inc.: Research Funding. Fuchs: MSD: Honoraria; Takeda: Consultancy, Honoraria; Lukon: Honoraria; BMS: Honoraria; Celgene: Honoraria. Borchmann: Gilead Sciences: Honoraria; BMS/Celgene: Honoraria; Janssen: Honoraria; Miltenyi Biotech: Honoraria; Novartis: Honoraria. Zijlstra: Takeda: Research Funding. Moskowitz: Incyte: Research Funding; Miragen: Research Funding; Takeda: Consultancy; Seattle Genetics: Consultancy, Research Funding; Janpix Ltd.: Consultancy; Imbrium Therapeutics L.P./Purdue: Consultancy; Bristol-Myers Squibb: Research Funding; Merck: Consultancy, Research Funding; Beigene: Research Funding; ADC Therapeutics: Research Funding. Kersten: BMS/Celgene: Consultancy; Kite/Gilead: Consultancy, Honoraria, Research Funding; Miltenyi Biotech: Consultancy; Takeda: Consultancy; Novartis: Consultancy, Honoraria; Roche: Honoraria.

Introduction Histone deacetylase (HDAC) inhibitors have single agent activity in various types of lymphoma. They restore antigen-specific immune recognition in B-cell lymphoma cells and modulate programmed cell death (PD)-1 expression on circulating T-lymphocytes. Pembrolizumab (PEM) is highly active in Hodgkin Lymphoma (HL) and demonstrates a 12-month PFS of 46% in patients with R/R HL. Preclinical studies have shown synergism of this combination in mouse models of various tumors. We present the interim efficacy analysis from the first stage of our phase II trial investigating the combination of the HDAC inhibitor Entinostat (ENT) and the PD-1-blocking antibody PEM in patients with R/R HL. Methods Patients with R/R HL received ENT 5-7 mg orally once weekly and PEM 200 mg intravenously once every three weeks. Prior use of anti-PD-1 or HDAC inhibitor was allowed if there had been clinical benefit. Tumor assessment was evaluated using the RECIL criteria. The primary endpoint is the 12-month progression-free survival (PFS). Using a Simon two-stage minimax design to power the study, 21 patients were to be enrolled in the first stage with a 12-month PFS rate of 40% considered undesirable and 60% desirable. Results At time of data censoring on 7/24/21, 22 patients with HL have been enrolled. The median number of prior therapies was 5 (2-17). 7 (32%) were refractory to the most recent therapy, 13 (59%) had received autologous stem cell transplant (ASCT), 12 (55%) prior anti-PD1 antibody therapy, and 3 (14%) prior HDAC inhibitor therapy. Out of 22 evaluable patients, the overall response rate (ORR) was 86% and the complete response (CR) rate was 45%. Responding patients included 9 with prior anti-PD-1 antibody and 3 with prior HDAC inhibitor therapy. With median duration of follow-up among survivors of 8.4 months (2-26), the 12-month PFS was 72% (44%-87%). Reasons for treatment discontinuation included: progression (n=6), toxicities (n=5) consolidation with transplant or radiation (n=3), withdrawal of consent (n=3), and completion of study protocol (n=2). Severe toxicities resulting in study discontinuation were pleural effusions, pericarditis, pneumonitis and peripheral neuropathy. Out of the 22 total patients with HL enrolled in this study, 50% of patients had grade ≥3 (41%) and thrombocytopenia (32%). 41% exhibited grade ≥3 non-hematologic AEs, which included pericardial or pleural effusions (n=2, 9%), as well as fatigue, musculoskeletal pain, abdominal pain, pneumonitis, elevated lipase, hyperglycemia, and peripheral neuropathy. AEs that were potentially immune-related included hypothyroidism (n=2, 9%), elevated transaminases (n=4, 18%), diarrhea (n=3, 14%) and pneumonitis (n=2, 8%). Conclusions Interim results following stage I of this phase 2 trial demonstrates a 12-month PFS rate of 74%, meeting the primary endpoint of the study and justifying continued investigation of the combination of PEM and ENT. In this heavily pretreated patient population, responses were seen in the majority of patients despite prior exposure to anti-PD-1 agents. Figure 1 Figure 1. Disclosures Vardhana: Immunai: Membership on an entity's Board of Directors or advisory committees. Moskowitz: Bristol-Myers Squibb: Research Funding; Seattle Genetics: Consultancy, Research Funding; ADC Therapeutics: Research Funding; Beigene: Research Funding; Miragen: Research Funding; Janpix Ltd.: Consultancy; Merck: Consultancy, Research Funding; Imbrium Therapeutics L.P./Purdue: Consultancy; Takeda: Consultancy; Incyte: Research Funding. Joffe: AstraZeneca. Epizyme: Consultancy. Khan: Seattle Genetics: Research Funding. Kumar: Seattle Genetics: Research Funding; Astra Zeneca: Honoraria, Other: Advisory Board, Research Funding; Kite Pharmaceuticals: Other: advisory board , Research Funding; Pharmacyclics: Research Funding; Abbvie Pharmaceuticals: Research Funding; Celgene: Honoraria, Other: advisory board, Research Funding; Adaptive Biotechnologies, Celgene, Abbvie Pharmaceticals, Pharmacyclics, Seattle Genetics: Research Funding. Zelenetz: Gilead: Honoraria; Genentech/Roche: Honoraria, Research Funding; AstraZeneca: Honoraria; MorphoSys: Honoraria; Novartis: Honoraria; Pharmacyclics: Honoraria; Verastem: Honoraria; SecuraBio: Honoraria; BMS/Celgene/JUNO: Honoraria, Other; MethylGene: Research Funding; Abbvie: Honoraria, Research Funding; Gilead: Honoraria, Research Funding; MEI Pharma: Honoraria, Research Funding; Janssen: Honoraria; Beigene: Honoraria, Other, Research Funding; Amgen: Honoraria; NCCN: Other; LFR: Other. Horwitz: Affimed: Research Funding; ADC Therapeutics, Affimed, Aileron, Celgene, Daiichi Sankyo, Forty Seven, Inc., Kyowa Hakko Kirin, Millennium /Takeda, Seattle Genetics, Trillium Therapeutics, and Verastem/SecuraBio.: Consultancy, Research Funding; Aileron: Research Funding; Acrotech Biopharma, Affimed, ADC Therapeutics, Astex, Merck, Portola Pharma, C4 Therapeutics, Celgene, Janssen, Kura Oncology, Kyowa Hakko Kirin, Myeloid Therapeutics, ONO Pharmaceuticals, Seattle Genetics, Shoreline Biosciences, Inc, Takeda, Trillium Th: Consultancy; Celgene: Research Funding; C4 Therapeutics: Consultancy; Crispr Therapeutics: Research Funding; Daiichi Sankyo: Research Funding; Forty Seven, Inc.: Research Funding; Kura Oncology: Consultancy; Kyowa Hakko Kirin: Consultancy, Research Funding; Millennium/Takeda: Research Funding; Myeloid Therapeutics: Consultancy; ONO Pharmaceuticals: Consultancy; Seattle Genetics: Consultancy, Research Funding; Secura Bio: Consultancy; Shoreline Biosciences, Inc.: Consultancy; Takeda: Consultancy; Trillium Therapeutics: Consultancy, Research Funding; Tubulis: Consultancy; Verastem/Securabio: Research Funding. Noy: Janssen: Consultancy, Honoraria; Epizyme: Consultancy; Morphosys: Consultancy; Rafael Parhma: Research Funding; Medscape: Consultancy; Targeted Oncology: Consultancy; Pharmacyclics: Consultancy, Research Funding. Batlevi: Memorial Sloan Kettering Cancer Center: Current Employment; Moderna: Current holder of individual stocks in a privately-held company; Viatris: Current holder of individual stocks in a privately-held company; BMS: Current holder of individual stocks in a privately-held company; Autolus: Research Funding; Pfizer: Current holder of individual stocks in a privately-held company; Dava Oncology: Honoraria; Bayer: Research Funding; Medscape: Honoraria; ADC Therapeutics: Consultancy; Regeneron: Current holder of individual stocks in a privately-held company; TouchIME: Honoraria; TG Therapeutics: Consultancy; Karyopharm: Consultancy; Seattle Genetics: Consultancy; Life Sciences: Consultancy; Kite Pharma: Consultancy; Juno/Celgene: Consultancy; GLG Pharma: Consultancy; Xynomic: Research Funding; Roche/Genentech: Research Funding; Novartis: Research Funding; Janssen: Research Funding; Epizyme: Research Funding. Matasar: Pharmacyclics: Honoraria, Research Funding; Juno Therapeutics: Consultancy; TG Therapeutics: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Rocket Medical: Consultancy, Research Funding; Genentech, Inc.: Consultancy, Honoraria, Research Funding; Merck: Consultancy; Merck Sharp & Dohme: Current holder of individual stocks in a privately-held company; GlaxoSmithKline: Honoraria, Research Funding; ImmunoVaccine Technologies: Consultancy, Honoraria, Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Memorial Sloan Kettering Cancer Center: Current Employment; IGM Biosciences: Research Funding; Bayer: Consultancy, Honoraria, Research Funding; Teva: Consultancy; Janssen: Honoraria, Research Funding; F. Hoffmann-La Roche Ltd: Consultancy, Honoraria, Research Funding; Daiichi Sankyo: Consultancy. Palomba: Nektar: Honoraria; Notch: Honoraria, Other: Stock; PCYC: Consultancy; Kite: Consultancy; Ceramedix: Honoraria; Novartis: Consultancy; Priothera: Honoraria; Juno: Patents & Royalties; Wolters Kluwer: Patents & Royalties; Lygenesis: Honoraria; Pluto: Honoraria; Rheos: Honoraria; BeiGene: Consultancy; Seres: Honoraria, Other: Stock, Patents & Royalties, Research Funding; WindMIL: Honoraria; Magenta: Honoraria. Lee: Intellisphere, LLC: Consultancy. Dogan: EUSA Pharma: Consultancy; Takeda: Consultancy, Research Funding; Roche: Consultancy, Research Funding; Peer View: Honoraria; Seattle Genetics: Consultancy; Physicians' Education Resource: Honoraria. Salles: Abbvie: Consultancy, Honoraria; BMS/Celgene: Consultancy; Kite/Gilead: Consultancy; Ipsen: Consultancy; Janssen: Consultancy; Genmab: Consultancy; Takeda: Consultancy; Morphosys: Consultancy, Honoraria; Rapt: Consultancy; Genentech/Roche: Consultancy; Epizyme: Consultancy, Honoraria; Beigene: Consultancy; Debiopharm: Consultancy; Regeneron: Consultancy, Honoraria; Loxo: Consultancy; Miltneiy: Consultancy; Novartis: Consultancy; Incyte: Consultancy; Bayer: Honoraria; Velosbio: Consultancy; Allogene: Consultancy. Younes: AZ: Current Employment, Other: Senior Vice President, Global Head of Haematology (Early and Late Stage) Oncology R&D at AstraZeneca. von Keudell: Pharmacyclics: Consultancy, Honoraria; AbbVie: Research Funding; Janssen: Research Funding; Merck: Consultancy, Honoraria; Merck: Research Funding; Incyte: Consultancy, Honoraria; BMS: Research Funding.

Introduction: Primary cutaneous diffuse large B-cell lymphoma, leg type (PCDLBCL,LT) is a rare subtype of lymphoma that has been reported to have aggressive clinical behavior and carry a poor prognosis. However, due to the extreme scarcity of data, optimal management of this entity remains poorly defined, particularly with respect to optimal induction therapy and the role for central nervous system (CNS) prophylaxis. We therefore reviewed our institutional experience with patients with PCDLBCL,LT to better delineate their clinical course and risk of CNS relapse. Methods: We searched our electronic database and individual electronic medical records for cases of skin-only PCDLBCL,LT and analyzed the presenting characteristics, treatment approaches, use of CNS prophylaxis, and clinical outcomes, including skin, systemic, and CNS relapse. Primary cutaneous follicle center lymphoma, primary cutaneous marginal zone lymphoma, and skin-only DLBCL arising in patients with a concurrent or antecedent indolent B-cell lymphoma were excluded. Additionally, cases with DLBCL involving both skin and nodal and/or extranodal sites at diagnosis were excluded. All patients underwent staging with positron emission tomography-computerized tomography (PET-CT). Diagnostic specimens were independently reviewed by hematopathologists with expertise in cutaneous lymphoma. Results: We identified 38 patients with PCDLBCL,LT followed at Memorial Sloan Kettering Cancer Center between July 2002 and October 2020. Fifteen (39%) were female and the median age was 76 years (range, 40-96). The disease was localized to the lower extremity in 15 cases (39%) and consisted of multiple lesions in 11 cases (29%). All but one patient had IPI 0-2. By Hans algorithm 79% of the samples had a non-GCB phenotype, 79% expressed MUM-1, 3% expressed CD10, and 82% exhibited Bcl2 expression. The median Ki-67 was 85% (range, 20%-100%). According to the CNS-IPI score, 25 out of 36 evaluable patients (69%) had low-risk disease and 11 (31%) intermediate-risk disease; no patient had high-risk disease. Induction therapy consisted of R-CHOP immunochemotherapy in 13 patients (33%), R-CHOP followed by radiation therapy (RT), at doses of 30-40 Gy, in 12 (31%), and RT alone, at doses of 30-45 Gy, in 10 (26%). One patient underwent excision alone, one received rituximab after excisional biopsy, and one best supportive care. Three patients (2 treated with chemotherapy + RT and one with chemotherapy only) received CNS prophylaxis with intrathecal methotrexate. Among 35 patients evaluable for response, the objective response rate was 86%, all of which were complete responses. One patient treated with rituximab had stable disease and 4 (2 treated with chemotherapy only, one RT, and one best supportive care) progressed. At a median follow-up of 8.9 years [range, 2.9-14.7], the 5-year progression-free survival for the cohort is 42% (Figure panel A). CNS relapse occurred in 5 patients (13%) involving leptomeninges in 1 case, parenchyma in 2, and both in 2. None of these patients received CNS prophylaxis. Of note, none of the three who did receive prophylaxis experienced CNS relapse. The 2-year and 5-year cumulative risk of CNS relapse are 7% and 19%, respectively (Figure panel B). At the time of this analysis, the 5-year overall survival rate is 66% (Figure Panel A), and in all, 16 patients (42%) have died. Among the 7 patients with known cause of death, 5 succumbed to progressive disease (including 3 with CNS disease), one to sepsis, and one to secondary acute myelogenous leukemia. Conclusions: To the best of our knowledge, this is the largest study analyzing the risk of CNS relapse in PCLBCL,LT patients treated with rituximab-containing immunochemotherapy. Our findings indicate that PCLBCL,LT is a highly aggressive disease associated with poor prognosis and high risk of CNS relapse. The 13% rate of CNS relapse in a population of patients with limited-stage disease, none of whom had high-risk CNS-IPI, suggests that alternate models of risk prediction are needed for patients with PCLBCL,LT and that clinical trials aimed at improving rates of cure and reducing the risk of CNS relapse for patients with PCLBCL,LT are needed. Figure 1 Figure 1. Disclosures Falchi: Abbvie: Consultancy, Research Funding; Genmab: Consultancy, Research Funding; Roche: Research Funding; Genetech: Research Funding. Ewalt: Loxo Oncology at Lilly: Membership on an entity's Board of Directors or advisory committees; Acceleron Pharma: Membership on an entity's Board of Directors or advisory committees. Batlevi: Memorial Sloan Kettering Cancer Center: Current Employment; Pfizer: Current holder of individual stocks in a privately-held company; Viatris: Current holder of individual stocks in a privately-held company; Life Sciences: Consultancy; Bayer: Research Funding; BMS: Current holder of individual stocks in a privately-held company; Seattle Genetics: Consultancy; Kite Pharma: Consultancy; Karyopharm: Consultancy; ADC Therapeutics: Consultancy; Dava Oncology: Honoraria; TouchIME: Honoraria; Moderna: Current holder of individual stocks in a privately-held company; TG Therapeutics: Consultancy; Medscape: Honoraria; Regeneron: Current holder of individual stocks in a privately-held company; Juno/Celgene: Consultancy; GLG Pharma: Consultancy; Xynomic: Research Funding; Roche/Genentech: Research Funding; Novartis: Research Funding; Epizyme: Research Funding; Janssen: Research Funding; Autolus: Research Funding. Caron: Astra-Zeneca: Current holder of individual stocks in a privately-held company; bristol myers: Current holder of individual stocks in a privately-held company; GlaxoSmithKlein: Current holder of individual stocks in a privately-held company; Johnson and Johnson: Current holder of individual stocks in a privately-held company; Novartis: Current holder of individual stocks in a privately-held company; pfizer: Current holder of individual stocks in a privately-held company; Teva: Current holder of individual stocks in a privately-held company. Hamlin: Alexion, AstraZeneca Rare Disease (formerly Portola Pharmaceuticals): Other: Study investigator, Research Funding; Incyte, Janssen, Molecular Templates: Research Funding; Kite, Karyopharm, Celgene: Membership on an entity's Board of Directors or advisory committees. Horwitz: ADC Therapeutics: Consultancy, Research Funding; Kyowa Hakko Kirin: Consultancy, Research Funding; Myeloid Therapeutics: Consultancy; Affimed: Research Funding; Vividion Therapeutics: Consultancy; Aileron: Research Funding; Verastem: Research Funding; C4 Therapeutics: Consultancy; Janssen: Consultancy; Seattle Genetics: Consultancy, Research Funding; Millennium /Takeda: Consultancy, Research Funding; Daiichi Sankyo: Research Funding; Forty Seven, Inc.: Research Funding; Trillium Therapeutics: Consultancy, Research Funding; Acrotech Biopharma: Consultancy; ONO Pharmaceuticals: Consultancy; Shoreline Biosciences, Inc.: Consultancy; Celgene: Research Funding; Tubulis: Consultancy; SecuraBio: Consultancy, Research Funding; Kura Oncology: Consultancy. Joffe: Epizyme: Consultancy; AstraZeneca: Consultancy. Khan: Seattle Genetics: Research Funding. Kumar: Seattle Genetics: Research Funding; Kite Pharmaceuticals: Other: advisory board , Research Funding; Pharmacyclics: Research Funding; Astra Zeneca: Honoraria, Other: Advisory Board, Research Funding; Celgene: Honoraria, Other: advisory board, Research Funding; Adaptive Biotechnologies, Celgene, Abbvie Pharmaceticals, Pharmacyclics, Seattle Genetics: Research Funding; Abbvie Pharmaceuticals: Research Funding. Moskowitz: Merck: Consultancy, Research Funding; Miragen: Research Funding; Janpix Ltd.: Consultancy; Bristol-Myers Squibb: Research Funding; Incyte: Research Funding; Beigene: Research Funding; ADC Therapeutics: Research Funding; Imbrium Therapeutics L.P./Purdue: Consultancy; Takeda: Consultancy; Seattle Genetics: Consultancy, Research Funding. Noy: Pharmacyclics: Consultancy, Research Funding; Medscape: Consultancy; Targeted Oncology: Consultancy; Morphosys: Consultancy; Rafael Parhma: Research Funding; Epizyme: Consultancy; Janssen: Consultancy, Honoraria. Palomba: Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; Kite Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees. von Keudell: Pharmacyclics: Consultancy, Honoraria; Merck: Consultancy, Honoraria; Incyte: Consultancy, Honoraria; AbbVie: Research Funding; Merck: Research Funding; BMS: Research Funding; Janssen: Research Funding. Zelenetz: MEI Pharma: Honoraria, Research Funding; Pharmacyclics: Honoraria; BMS/Celgene/JUNO: Honoraria, Other; Gilead: Honoraria, Research Funding; Gilead: Honoraria; Novartis: Honoraria; Verastem: Honoraria; AstraZeneca: Honoraria; MethylGene: Research Funding; MorphoSys: Honoraria; Genentech/Roche: Honoraria, Research Funding; NCCN: Other; SecuraBio: Honoraria; Amgen: Honoraria; Janssen: Honoraria; Beigene: Honoraria, Other, Research Funding; Abbvie: Honoraria, Research Funding; LFR: Other. Dogan: Takeda: Consultancy, Research Funding; Peer View: Honoraria; Physicians' Education Resource: Honoraria; Seattle Genetics: Consultancy; Roche: Consultancy, Research Funding; EUSA Pharma: Consultancy. Salles: Allogene: Consultancy; Miltneiy: Consultancy; Loxo: Consultancy; Velosbio: Consultancy; Takeda: Consultancy; Novartis: Consultancy; Rapt: Consultancy; Regeneron: Consultancy, Honoraria; Epizyme: Consultancy, Honoraria; Morphosys: Consultancy, Honoraria; Genmab: Consultancy; Incyte: Consultancy; Genentech/Roche: Consultancy; Ipsen: Consultancy; Janssen: Consultancy; Kite/Gilead: Consultancy; Debiopharm: Consultancy; BMS/Celgene: Consultancy; Beigene: Consultancy; Abbvie: Consultancy, Honoraria; Bayer: Honoraria. Matasar: Janssen: Honoraria, Research Funding; TG Therapeutics: Consultancy, Honoraria; Teva: Consultancy; Daiichi Sankyo: Consultancy; Merck Sharp & Dohme: Current holder of individual stocks in a privately-held company; Genentech, Inc.: Consultancy, Honoraria, Research Funding; F. Hoffmann-La Roche Ltd: Consultancy, Honoraria, Research Funding; GlaxoSmithKline: Honoraria, Research Funding; Bayer: Consultancy, Honoraria, Research Funding; IGM Biosciences: Research Funding; Rocket Medical: Consultancy, Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; ImmunoVaccine Technologies: Consultancy, Honoraria, Research Funding; Juno Therapeutics: Consultancy; Memorial Sloan Kettering Cancer Center: Current Employment; Pharmacyclics: Honoraria, Research Funding; Takeda: Consultancy, Honoraria; Merck: Consultancy.

Introduction Diffuse large B-cell lymphoma of the ocular adnexa (OA-DLBCL) is extremely rare and historically was associated with poor prognosis and higher risk of central nervous system (CNS) relapse. In the rituximab era its prognosis may be more favorable, particularly in individuals with limited-stage disease. However, published series of patients with extranodal limited-stage DLBCL, including a study from our group (Bobillo et al. Blood 2021), rarely included OA-DLBCL. Studies specifically looking at OA-DLBCL reported diverse treatment approaches, including some that are no longer current, such as chemotherapy without rituximab or radiation alone. Thus, the optimal management of limited-stage OA-DLBCL remains poorly defined. To address this knowledge gap, we reviewed treatments and outcomes of OA-DLBCL patients treated at Memorial Sloan Kettering Cancer Center (MKSCC). Methods We retrospectively reviewed electronic medical records of consecutive patients with DLBCL managed at MSKCC who had ocular adnexal involvement and stage IE or IIE disease, and complete clinical information. Patients with stage III-IV disease, or evidence of intraocular or CNS involvement were excluded. Results Between 2000 and 2020 we identified 17 patients with limited-stage OA-DLBCL. The median age at diagnosis was 66 years [range: 24-84], all had ECOG PS 0-1, 94% had IPI 0-1 and 94% CNS-IPI 0-1. Primary sites of ocular adnexal involvement included: extraconal orbit (9), intraconal orbit (2), lacrimal gland (4), and eyelid (2). Median greatest diameter of lesions was 3.0 cm [range: 0-4.8 cm]. Among 11 evaluable patients, the cell of origin by Hans algorithm was GCB in 64%, non-GCB in 36% (Table). Staging procedures included brain and/or orbit imaging in 100% (MRI in 88%, CT in 12%), PET-CT in 94%, bone marrow evaluation in 69% (negative in all cases), and CSF evaluation in 47% (negative in all cases). Sixteen patients were treated with R-CHOP and one with CHOP. Eleven patients received short-course chemotherapy (3 cycles in 7 patients, 4 cycles in 4), and 6 received full-course therapy (i.e., 6 cycles). Thirteen patients (76%) received radiation therapy (RT) to the ocular adnexa, including 9/11 patients treated with short-course treatment and 3/6 receiving 6 cycles. One patient with stage IIE disease received RT to the left neck after 3 cycles R-CHOP, but did not receive RT to ocular adnexum. Six patients received CNS prophylaxis, all with intrathecal methotrexate (Table). First-line systemic therapy resulted in complete response (CR) in all patients. At a median follow-up of 64 months [range: 11-147], the 2- and 5-year PFS are 93% (95% CI 79-100%), and 84% (95% CI 64-100%), respectively, and 2- and 5-year OS are 100% and 91.7% (95% CI 76-100%), respectively (Figure). One of 17 patients had systemic relapse 18 months after first-line therapy and underwent salvage therapy followed by high-dose therapy and autologous stem cell transplantation, and remains in CR. There were no CNS relapses. Due to the paucity of events, we found no statistically significant associations between the number of chemotherapy cycles or the use of RT and PFS or OS. At the time of this analysis, four patients have died, none from lymphoma; one of the four died from acute myeloid leukemia 3 years after treatment. Discussion Our study demonstrates high response rates and highly favorable long-term outcomes in patients with limited stage OA-DLBCL treated with R-CHOP and RT. Our results are in line with those reported by Bobillo et al. in patients with stage 1 DLBCL involving other extranodal sites. With the limitation of a small sample size, short course R-CHOP was not associated with significantly worse response rates or increased risk of recurrence. Whether consolidation radiation therapy improves the results of chemotherapy alone remains to be determined in larger studies. Figure 1 Figure 1. Disclosures Batlevi: Dava Oncology: Honoraria; TG Therapeutics: Consultancy; Seattle Genetics: Consultancy; Epizyme: Research Funding; Novartis: Research Funding; Medscape: Honoraria; Viatris: Current holder of individual stocks in a privately-held company; Roche/Genentech: Research Funding; Regeneron: Current holder of individual stocks in a privately-held company; Pfizer: Current holder of individual stocks in a privately-held company; Memorial Sloan Kettering Cancer Center: Current Employment; Bayer: Research Funding; Kite Pharma: Consultancy; Karyopharm: Consultancy; ADC Therapeutics: Consultancy; TouchIME: Honoraria; Life Sciences: Consultancy; BMS: Current holder of individual stocks in a privately-held company; Janssen: Research Funding; Autolus: Research Funding; Moderna: Current holder of individual stocks in a privately-held company; Xynomic: Research Funding; GLG Pharma: Consultancy; Juno/Celgene: Consultancy. Caron: Astra-Zeneca: Current holder of individual stocks in a privately-held company; bristol myers: Current holder of individual stocks in a privately-held company; GlaxoSmithKlein: Current holder of individual stocks in a privately-held company; Johnson and Johnson: Current holder of individual stocks in a privately-held company; Novartis: Current holder of individual stocks in a privately-held company; pfizer: Current holder of individual stocks in a privately-held company; Teva: Current holder of individual stocks in a privately-held company. Hamlin: Kite, Karyopharm, Celgene: Membership on an entity's Board of Directors or advisory committees; Incyte, Janssen, Molecular Templates: Research Funding; Alexion, AstraZeneca Rare Disease (formerly Portola Pharmaceuticals): Other: Study investigator, Research Funding. Horwitz: Tubulis: Consultancy; Affimed: Research Funding; ONO Pharmaceuticals: Consultancy; Trillium Therapeutics: Consultancy, Research Funding; Acrotech Biopharma: Consultancy; Aileron: Research Funding; Shoreline Biosciences, Inc.: Consultancy; Celgene: Research Funding; Forty Seven, Inc.: Research Funding; Kyowa Hakko Kirin: Consultancy, Research Funding; SecuraBio: Consultancy, Research Funding; Verastem: Research Funding; C4 Therapeutics: Consultancy; Janssen: Consultancy; Kura Oncology: Consultancy; Millennium /Takeda: Consultancy, Research Funding; Myeloid Therapeutics: Consultancy; Daiichi Sankyo: Research Funding; Seattle Genetics: Consultancy, Research Funding; Vividion Therapeutics: Consultancy; ADC Therapeutics: Consultancy, Research Funding. Joffe: AstraZeneca. Epizyme: Consultancy. Khan: Seattle Genetics: Research Funding. Kumar: Celgene: Honoraria, Other: advisory board, Research Funding; Kite Pharmaceuticals: Other: advisory board , Research Funding; Astra Zeneca: Honoraria, Other: Advisory Board, Research Funding; Abbvie Pharmaceuticals: Research Funding; Seattle Genetics: Research Funding; Adaptive Biotechnologies, Celgene, Abbvie Pharmaceticals, Pharmacyclics, Seattle Genetics: Research Funding; Pharmacyclics: Research Funding. Matasar: Janssen: Honoraria, Research Funding; Teva: Consultancy; Juno Therapeutics: Consultancy; Merck: Consultancy; IGM Biosciences: Research Funding; Genentech, Inc.: Consultancy, Honoraria, Research Funding; Merck Sharp & Dohme: Current holder of individual stocks in a privately-held company; TG Therapeutics: Consultancy, Honoraria; F. Hoffmann-La Roche Ltd: Consultancy, Honoraria, Research Funding; Bayer: Consultancy, Honoraria, Research Funding; Memorial Sloan Kettering Cancer Center: Current Employment; Rocket Medical: Consultancy, Research Funding; Pharmacyclics: Honoraria, Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Daiichi Sankyo: Consultancy; Takeda: Consultancy, Honoraria; ImmunoVaccine Technologies: Consultancy, Honoraria, Research Funding; GlaxoSmithKline: Honoraria, Research Funding. Moskowitz: Miragen: Research Funding; Merck: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding; Janpix Ltd.: Consultancy; Imbrium Therapeutics L.P./Purdue: Consultancy; Bristol-Myers Squibb: Research Funding; Takeda: Consultancy; Incyte: Research Funding; Beigene: Research Funding; ADC Therapeutics: Research Funding. Noy: Medscape: Consultancy; Targeted Oncology: Consultancy; Morphosys: Consultancy; Rafael Parhma: Research Funding; Pharmacyclics: Consultancy, Research Funding; Janssen: Consultancy, Honoraria; Epizyme: Consultancy. Palomba: Wolters Kluwer: Patents & Royalties; BeiGene: Consultancy; Rheos: Honoraria; PCYC: Consultancy; Juno: Patents & Royalties; Kite: Consultancy; Pluto: Honoraria; Novartis: Consultancy; Notch: Honoraria, Other: Stock; Seres: Honoraria, Other: Stock, Patents & Royalties, Research Funding; Magenta: Honoraria; WindMIL: Honoraria; Lygenesis: Honoraria; Nektar: Honoraria; Ceramedix: Honoraria; Priothera: Honoraria. von Keudell: Merck: Consultancy, Honoraria; AbbVie: Research Funding; Pharmacyclics: Consultancy, Honoraria; BMS: Research Funding; Merck: Research Funding; Incyte: Consultancy, Honoraria; Janssen: Research Funding. Zelenetz: SecuraBio: Honoraria; Pharmacyclics: Honoraria; AstraZeneca: Honoraria; MEI Pharma: Honoraria, Research Funding; Verastem: Honoraria; NCCN: Other; Janssen: Honoraria; BMS/Celgene/JUNO: Honoraria, Other; Amgen: Honoraria; Gilead: Honoraria; Gilead: Honoraria, Research Funding; Genentech/Roche: Honoraria, Research Funding; MethylGene: Research Funding; MorphoSys: Honoraria; Abbvie: Honoraria, Research Funding; LFR: Other; Beigene: Honoraria, Other, Research Funding; Novartis: Honoraria. Dogan: Roche: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Peer View: Honoraria; EUSA Pharma: Consultancy; Seattle Genetics: Consultancy; Physicians' Education Resource: Honoraria. Salles: Debiopharm: Consultancy; Takeda: Consultancy; Allogene: Consultancy; Velosbio: Consultancy; Genmab: Consultancy; Loxo: Consultancy; Miltneiy: Consultancy; Ipsen: Consultancy; Janssen: Consultancy; Kite/Gilead: Consultancy; Incyte: Consultancy; Morphosys: Consultancy, Honoraria; Novartis: Consultancy; Rapt: Consultancy; Regeneron: Consultancy, Honoraria; Genentech/Roche: Consultancy; Epizyme: Consultancy, Honoraria; BMS/Celgene: Consultancy; Beigene: Consultancy; Abbvie: Consultancy, Honoraria; Bayer: Honoraria.

Introduction Mutational profiling in peripheral T-cell lymphoma (PTCL) is increasingly used to aid in diagnosis (Wang. Blood 2015), predicting response (Ghione. Blood Adv 2020), and prognosis (Watatani. Leukemia 2019). However, many analyses lack details of upfront treatment and survival outcomes. The Memorial Sloan Kettering Integrated Mutation Profiling of Actionable Cancer Targets (MSK-IMPACT) is a custom hybridization capture-based assay encompassing the protein-coding exons of >400 targeted genes (Cheng. J Molec Diag 2015). Using the MSK-IMPACT data generated from a large TCL patient (pt) population (N=396), we sought alterations which may predict resistance to or high rates of relapse after CHOP-based chemotherapy. Methods PTCL pts with MSK-IMPACT were detected in the CBioPortal online platform. We included histologies treated with curative intent CHOP-based induction +/- autologous stem cell transplant (ASCT). This included PTCL-not otherwise specified (PTCL-NOS), angioimmunoblastic T-cell lymphoma (AITL), PTCL with a T-follicular helper phenotype (FH-TCL), ALK+ and ALK- anaplastic large cell lymphoma (ALCL), and monomorphic epitheliotropic intestinal T-cell lymphoma (MEITL). Univariate analysis (UVA) for PFS and OS based on the presence of recurring genetic alterations was done using Cox proportional hazard regression analysis. Mutations (mut) assessed included TET2, DNMT3A, RHOA, IDH2, TP53, FAT1, STAT3, STAT5B, JAK1, SETD2, and copy number alterations (CNA) in TP53 and CDKN2A. Comparisons of survival curves were performed by log-rank test. As many pts were sequenced at relapse, to minimize bias, relevant findings were confirmed in the smaller set of pts sequenced at diagnosis and/or before relapse (prospective cohort). Results In total, 131 pts met inclusion criteria and had >1 MSK-IMPACT. One pt with a 49-gene panel was also included (N=132). The prospective cohort had 73 (55%) pts. Histologies were PTCL-NOS (N=36, 27%), AITL (N=62, 47%), FH-TCL (N=9, 7%), ALK-ALCL (N=15, 11%), ALK+ALCL (N=6, 5%), and MEITL (N=4, 3%). Regimens were CHOP + etoposide (N=59, 45%), CHOP (N=40, 30%), brentuximab + CHP (N=15, 11%), other CHOP-based (N=18, 14%). The most frequent mut were TET2 (N=69, 52%), RHOA (N=40, 30%), DNMT3A (N=25, 19%), TP53 (N=21, 16%), and IDH2 (N=15, 11%), and for CNA were losses of TP53 (N=9, 7%) and CDKN2A (N=9, 7%). TET2 mut were most frequent in AITL (N=51, 82%), FH-TCL (N=6, 67%), and PTCL-NOS (N=10, 28%). RHOA mut were found in 2 cases of PTCL-NOS (6%) with the rest in AITL (N=33, 53%) and FH-TCL (N=5, 56%). DNMT3A mut were most frequent in AITL (N=19, 31%) and FH-TCL (N=4, 44%). IDH2 mut were exclusive to AITL (N=14, 23%) and FH-TCL (N=1, 11%). TP53 mut were found in all histologies: ALK-ALCL (N=5, 33%), PTCL-NOS (N=10, 28%), FH-TCL (N=2, 22%), AITL (N=2, 3%), and in one case each of ALK+ALCL (17%) and MEITL (25%). The 24-month PFS was 28% for the entire cohort, and 42% for the prospective cohort. On UVA for genetic alterations, only TP53 mut (P=0.0011) and TP53 deletions (P=0.009) associated with inferior PFS. On MVA, only TP53 mut remained significant (HR 2.0 [95% CI 1.1-3.5] P=0.02). No alteration associated with inferior OS. For the entire cohort, median PFS was 4.5 mos for TP53 mut (N=21) vs. 10.5 mos for TP53 wild-type (WT) (N=111) (log-rank P=0.0008). This was similar in the prospective cohort with a median PFS of 4.1 vs. 19.7 mos (log-rank P=0.02) (Figure 1). Compared to TP53 WT, TP53 mut were more likely to have PTCL-NOS (P=0.03), concurrent deletions of TP53 (P=0.0005), and a higher median number of alterations (P=0.01). There were no differences in age, stage, marrow disease, or IPI/PIT scores between TP53 mut and TP53 WT pts. There was a trend towards fewer CR (P=0.054) in TP53 mut. There were no differences in ITT with ASCT between the groups (P=0.5). This was similar in the prospective cohort (P=0.4). Six total (29%) TP53 mut received ASCT, and PFS was similar to ASCT in TP53 WT (median 18.2 vs. 19.7 mos, P=0.5), but 5/6 (83%) ultimately relapsed. Conclusions TP53 mut correlated with lower rates of CR, higher rates of relapse, and shorter PFS in this dataset of PTCL treated with CHOP-based chemotherapy. OS was not different compared to TP53 WT tumors. The confounding impact of histology and other prognostic factors as well as the lack of uniform prospective mutational profiling in this retrospective series precludes definitive conclusions and requires prospective confirmation. Figure 1 Figure 1. Disclosures Sauter: Juno Therapeutics: Consultancy, Research Funding; Sanofi-Genzyme: Consultancy, Research Funding; Spectrum Pharmaceuticals: Consultancy; Novartis: Consultancy; Genmab: Consultancy; Precision Biosciences: Consultancy; Kite/Gilead: Consultancy; Celgene: Consultancy, Research Funding; Gamida Cell: Consultancy; GSK: Consultancy; Bristol-Myers Squibb: Research Funding. Khan: Seattle Genetics: Research Funding. Moskowitz: ADC Therapeutics: Research Funding; Beigene: Research Funding; Seattle Genetics: Consultancy, Research Funding; Miragen: Research Funding; Bristol-Myers Squibb: Research Funding; Merck: Consultancy, Research Funding; Janpix Ltd.: Consultancy; Imbrium Therapeutics L.P./Purdue: Consultancy; Takeda: Consultancy; Incyte: Research Funding. Dogan: Seattle Genetics: Consultancy; Roche: Consultancy, Research Funding; Peer View: Honoraria; EUSA Pharma: Consultancy; Takeda: Consultancy, Research Funding; Physicians' Education Resource: Honoraria. Horwitz: ADC Therapeutics: Consultancy, Research Funding; Acrotech Biopharma: Consultancy; Affimed: Research Funding; Aileron: Research Funding; Celgene: Research Funding; C4 Therapeutics: Consultancy; Daiichi Sankyo: Research Funding; Forty Seven, Inc.: Research Funding; Kyowa Hakko Kirin: Consultancy, Research Funding; Janssen: Consultancy; Kura Oncology: Consultancy; Millennium /Takeda: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding; Trillium Therapeutics: Consultancy, Research Funding; SecuraBio: Consultancy, Research Funding; Myeloid Therapeutics: Consultancy; ONO Pharmaceuticals: Consultancy; Shoreline Biosciences, Inc.: Consultancy; Tubulis: Consultancy; Vividion Therapeutics: Consultancy; Verastem: Research Funding.

Background: In untreated Hodgkin lymphoma (HL), metabolic tumor volume (MTV) significantly declined following pembrolizumab monotherapy, regardless of baseline MTV, and may serve as a better measure of treatment response to PD-1 blockade than the Lugano Classification (Allen, et al. Blood 2021). Furthermore, standard PET evaluation can fail to differentiate between malignancy, pseudoprogression and physiological background in patients (pts) receiving PD-1 blockade. The predictive power and prognostic significance of MTV in patients with relapsed or refractory (RR) HL receiving PD-1 blockade is unknown. We sought to examine the role of MTV in HL pts treated with PD-1 blockade. Methods: We identified 30 pts who received pembrolizumab or nivolumab-based therapy off-study for RR HL between July 2015 and May 2021. In the PET/CT analysis, all lesions were visually identified, and all measurable lesions were selected for the analysis. Responses were assessed by Lugano Classification. Indeterminant response (IR) was defined as evidence of progression on PET without clinical deterioration as per the Lyric Criteria. MTV was obtained by summing the metabolic volumes of all measurable lesions, using the 41% SUVmax threshold to measure each lesion MTV using Beth Israel plugin. MTV was evaluated at baseline (MTV0) and at first reassessment (MTV1) after initiation of PD-1 blockade. Δ (delta) MTV was calculated as % change in MTV from MTV0 to MTV1. Receiver operating characteristic (ROC) curve was performed for ΔMTV and best overall response rate (BOR) to determine the optimal cut-off value. Overall survival (OS) was measured from PD-1 blockade initiation to death or last follow-up. We examined the association between MTV and clinical factors, PET-1 response, and overall survival using Cox proportional hazards model and Fisher exact test, respectively. Results: 25 patients had complete clinical data and PET/CT analysis (Table 1). The median age at first relapse was 39 years (range: 18-81); 64% were male. 6 pts previously received PD-1 blockade on clinical trials and discontinued treatment due to study completion or toxicity. The median time between PET0 and PET1 was 3.4 months (range 2.0-7.3). Median MTV0 and MTV1 values were 39.8 ml and 17.1 ml, respectively. With a median follow up from initiation of PD-1 blockade among survivors of 38.7 months, 5 pts (19%) died. The median OS of the entire cohort was not reached (95%CI: 76.4-NR) (Figure 1). The best response to PD-1 blockade included 15 (60%) with complete metabolic response (CMR), 5 (20%) with partial metabolic response (PMR), and 5 (20%) with progression of disease (POD). Median ΔMTV was -70% (range -100 to +909%). MTV0 was not predictive of OS, PET1 response, or BOR. However, ΔMTV predicted for PET1 response (p=0.004) and BOR (p=0.004). 18 (72%) pts had a reduction in ΔMTV (range: -100, -22), while 7 (28%) pts had an increase in ΔMTV (range: 33-909). The optimal ΔMTV threshold for prediction of BOR was 120% (Figure 1). ΔMTV Among pts with IR on PET-1, ΔMTV Conclusions: Quantitative change in MTV from baseline to first reassessment may aid in predicting treatment response and long-term outcomes in patients with RR HL receiving PD-1 blockade, particularly those initially characterized as achieving indeterminate response. Further prospective clinical trials are needed to validate the role of ΔMTV in predicting response and long-term outcomes for RR HL pts receiving PD-1 blockade. Figure 1 Figure 1. Disclosures Moskowitz: Merck & Co., Inc.: Research Funding. Matasar: Seattle Genetics: Consultancy, Honoraria, Research Funding; TG Therapeutics: Consultancy, Honoraria; Bayer: Consultancy, Honoraria, Research Funding; Genentech, Inc.: Consultancy, Honoraria, Research Funding; Memorial Sloan Kettering Cancer Center: Current Employment; Juno Therapeutics: Consultancy; Merck: Consultancy; Pharmacyclics: Honoraria, Research Funding; Rocket Medical: Consultancy, Research Funding; Daiichi Sankyo: Consultancy; GlaxoSmithKline: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; ImmunoVaccine Technologies: Consultancy, Honoraria, Research Funding; Merck Sharp & Dohme: Current holder of individual stocks in a privately-held company; Teva: Consultancy; F. Hoffmann-La Roche Ltd: Consultancy, Honoraria, Research Funding; IGM Biosciences: Research Funding; Takeda: Consultancy, Honoraria. Zelenetz: Amgen: Honoraria; MorphoSys: Honoraria; Novartis: Honoraria; MEI Pharma: Honoraria, Research Funding; Beigene: Honoraria, Other, Research Funding; Gilead: Honoraria, Research Funding; Pharmacyclics: Honoraria; SecuraBio: Honoraria; Genentech/Roche: Honoraria, Research Funding; Abbvie: Honoraria, Research Funding; Verastem: Honoraria; BMS/Celgene/JUNO: Honoraria, Other; MethylGene: Research Funding; AstraZeneca: Honoraria; Janssen: Honoraria; NCCN: Other; LFR: Other; Gilead: Honoraria. Joffe: AstraZeneca. Epizyme: Consultancy. von Keudell: Merck: Research Funding; Janssen: Research Funding; BMS: Research Funding; Incyte: Consultancy, Honoraria; AbbVie: Research Funding; Merck: Consultancy, Honoraria; Pharmacyclics: Consultancy, Honoraria. Batlevi: Medscape: Honoraria; Memorial Sloan Kettering Cancer Center: Current Employment; Moderna: Current holder of individual stocks in a privately-held company; Pfizer: Current holder of individual stocks in a privately-held company; ADC Therapeutics: Consultancy; Regeneron: Current holder of individual stocks in a privately-held company; TG Therapeutics: Consultancy; Kite Pharma: Consultancy; Seattle Genetics: Consultancy; TouchIME: Honoraria; BMS: Current holder of individual stocks in a privately-held company; Bayer: Research Funding; Viatris: Current holder of individual stocks in a privately-held company; Karyopharm: Consultancy; Juno/Celgene: Consultancy; Life Sciences: Consultancy; Dava Oncology: Honoraria; GLG Pharma: Consultancy; Xynomic: Research Funding; Roche/Genentech: Research Funding; Novartis: Research Funding; Epizyme: Research Funding; Janssen: Research Funding; Autolus: Research Funding. Caron: Astra-Zeneca: Current holder of individual stocks in a privately-held company; bristol myers: Current holder of individual stocks in a privately-held company; GlaxoSmithKlein: Current holder of individual stocks in a privately-held company; Johnson and Johnson: Current holder of individual stocks in a privately-held company; Novartis: Current holder of individual stocks in a privately-held company; pfizer: Current holder of individual stocks in a privately-held company; Teva: Current holder of individual stocks in a privately-held company. Noy: Rafael Parhma: Research Funding; Morphosys: Consultancy; Medscape: Consultancy; Pharmacyclics: Consultancy, Research Funding; Targeted Oncology: Consultancy; Epizyme: Consultancy; Janssen: Consultancy, Honoraria. Salles: Velosbio: Consultancy; Morphosys: Consultancy, Honoraria; Regeneron: Consultancy, Honoraria; Novartis: Consultancy; Epizyme: Consultancy, Honoraria; Allogene: Consultancy; Rapt: Consultancy; Genentech/Roche: Consultancy; Takeda: Consultancy; Miltneiy: Consultancy; Loxo: Consultancy; Kite/Gilead: Consultancy; Genmab: Consultancy; Incyte: Consultancy; Ipsen: Consultancy; Janssen: Consultancy; Debiopharm: Consultancy; BMS/Celgene: Consultancy; Beigene: Consultancy; Abbvie: Consultancy, Honoraria; Bayer: Honoraria. Moskowitz: ADC Therapeutics: Research Funding; Takeda: Consultancy; Incyte: Research Funding; Merck: Consultancy, Research Funding; Beigene: Research Funding; Seattle Genetics: Consultancy, Research Funding; Bristol-Myers Squibb: Research Funding; Miragen: Research Funding; Janpix Ltd.: Consultancy; Imbrium Therapeutics L.P./Purdue: Consultancy.

Introduction Marginal Zone Lymphoma (MZL) includes three subtypes of indolent lymphoma: splenic MZL, extranodal MZL of mucosa-associated lymphoid tissue (MALT) and nodal MZL. The diagnosis of MZL is often made by exclusion of other lymphoma subtypes based on phenotype. One of the markers that are often involved in this discernment is CD5. The CD5 is not expressed in most of the cases of MZL, probably independently of the subtype, while it is usually expressed in different diseases such as Mantle Cell Lymphoma and Small Lymphocytic Lymphoma/Chronic Lymphocytic Leukemia. A subgroup of MZL, however, unequivocally expresses CD5, and very little is known about the characteristics and outcomes of these patients compared to their CD5 negative counterparts. Methods From our pathology database, we collected all the reports of indolent lymphoma containing the words "marginal zone" and/or "MALT" diagnosed or reviewed at MSKCC. We reviewed the text of the selected pathology reports to identify all cases that were unequivocally MZL and reported positivity or negativity of the CD5 marker in the lymphoma cells. From the electronic medical records, we collected all the relevant clinical information for all CD5+ MZL cases, and for a subset of CD5- MZL cases with a 1:2 match for age at diagnosis and sex. The survival and baseline characteristics analyses only included patients that were followed by our lymphoma group. We report differences between groups with the chi-squared test. Overall survival (OS) was estimated using the cumulative incidence method, and time to treatment (TTT) was estimated using the subdistribution function to adjust for semi-competing risk of death on treatment initiation. A modified proportional hazards model was used to compare the subdistribution hazard between groups, and a standard Cox proportional hazards model was used to compare the hazard of death between groups. Results From 03/1998 to 09/2019, 64 patients were diagnosed with CD5+ MZL and followed by the Lymphoma Service at MSKCC. The control group of CD5- MZL included 137 patients that matched the CD5+ positive patients for age at diagnosis and sex. 20.3% of the CD5+ vs 14.6% of the CD5- MZL were nodal (p=0.30); Extra-nodal (EN) localizations included: GI tract - other than stomach (5.9% CD5+, 9.4% CD5-), stomach (17.7% CD5+, 17.1% CD5-), skin (7.8% CD5+, 12.0% CD5-), lung (9.8% CD5+, 12.0% CD5-), eye (9.8% CD5+, 7.7% CD5-), spleen (25.5% CD5+, 18% CD5-), multiple sites (13.7% CD5+, 10.3% CD5-), other single EN sites (9.8% CD5+, 13.7% CD5-). IPI score was low in 52% CD5+ vs 61% CD5-; low intermediate in 28% CD5+ vs 19% CD5-; high intermediate in 21% CD5+ vs 13% CD5-; no CD5+ had high IPI, while 7% of CD5- did (chi-square p=0.04). Transformation to DLBCL was similar in the 2 groups with 7% events in CD5+ and 4% in CD5- (p=0.42). Bone marrow involvement seemed to be more prevalent in the CD5+ MZL (67.5% vs 47.2% of the CD5-; p=0.04). IGHV was mutated in 80% of the CD5+ and 64% of the CD5- (p=0.24). OS analysis was performed first considering death by any cause: median OS was not reached for CD5+ MZL (95% C.I. 8.8 years - NE) and it was 27 years for CD5- (95% C.I. 14.3 years - NE). No difference was observed between CD5+ vs CD5- (p=0.9, Figure 1A). We also calculated MZL related survival, including deaths related to transformation to high grade lymphoma. No difference was observed between CD5+ vs CD5-, (p=0.3, Figure 1B). Median time to 1st treatment (including topical treatment and radiation therapy) was 1.4 years (95% C.I. 0.4 - 2.3) for CD5+ and 0.4 years (95% C.I. 0.3 - 0.9). No difference was observed between CD5+ vs CD5- (p=0.2, Figure 1C). Median time to first systemic treatment was 4.3 years (95% C.I. 1.6 - 12.9) for CD5+ and 7 years (95% C.I. 3.1 - 15.4) for CD5- MZL. No difference was observed between CD5+ vs CD5- (p=0.6, Figure 1D). Conclusions In this retrospective case-control analysis assessing the differences between CD5+ and CD5- MZL in terms of clinical presentation, survival, transformation occurrence and time to first topical or systemic treatment, we demonstrate that the two subgroups might have some differences in terms of bone marrow involvement but probably no difference in terms of outcome. Our sample size is small, and larger studies on a population with more events might clarify, with multivariate analysis, if these differences are real. Figure Disclosures Joffe: Epizyme: Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Membership on an entity's Board of Directors or advisory committees. Palomba:Pharmacyclics: Honoraria; Celgene: Honoraria; Merck: Honoraria; Novartis: Honoraria; Regeneron: Research Funding; Juno Therapeutics, a Bristol-Meyers Squibb Company: Honoraria, Research Funding; Genentech: Research Funding. Noy:Rafael Pharma: Research Funding; Janssen: Consultancy; Pharmacyclics: Consultancy; Medscape: Consultancy; Targeted Oncology: Consultancy; Morphosys: Consultancy; Pharmacyclics: Research Funding; NIH: Research Funding. Matasar:Daiichi Sankyo: Consultancy; Immunovaccine Technologies: Honoraria, Research Funding; Pharmacyclics: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; IGM Biosciences: Research Funding; GlaxoSmithKline: Honoraria, Research Funding; Rocket Medical: Consultancy, Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Genentech, Inc.: Consultancy, Honoraria, Research Funding; Merck: Consultancy; Bayer: Consultancy, Honoraria, Research Funding; Teva: Consultancy; F. Hoffmann-La Roche Ltd: Consultancy, Honoraria, Research Funding; Juno Therapeutics: Consultancy; Takeda: Consultancy, Honoraria. Hamlin:J&J Pharmaceuticals: Research Funding; Portola Pharmaceutics: Consultancy; Portola: Research Funding; Molecular Templates: Research Funding; Incyte: Research Funding; Celgene: Consultancy; Karyopharm: Consultancy; Juno Therapeutics: Consultancy. Kumar:Kite Pharmaceuticals: Honoraria, Other: Honoraria for Advisory Board; Astra Zeneca: Honoraria, Other: Honoraria for Advisory Board; Celgene: Honoraria, Other: Honoraria for Advisory Board; Seattle Genetics: Research Funding; Pharmacyclics: Research Funding; Celgene: Research Funding; Adaptive Biotechnologies,: Research Funding; AbbVie: Research Funding. Moskowitz:Seattle Genetics: Consultancy; Miragen Therapeutics: Consultancy; Imbrium Therapeutics, L.P.: Consultancy; Merck: Research Funding; Bristol-Myers Squibb: Research Funding; Incyte: Research Funding; Seattle Genetics: Research Funding; Merck: Consultancy. Falchi:Genmab: Research Funding; Roche: Research Funding. von Keudell:Merck: Consultancy, Honoraria. Straus:Targeted Oncology: Consultancy, Speakers Bureau; Seattle Genetics: Consultancy, Membership on an entity's Board of Directors or advisory committees; ASH: Other: Conference in December 2019 on HL to other physicians during ASH; Elsevier: Membership on an entity's Board of Directors or advisory committees, Other: CME writer; OncLive: Speakers Bureau; Takeda Pharmaceuticals: Research Funding, Speakers Bureau; NY Lymphoma Rounds: Consultancy; Imedex, Inc.: Speakers Bureau; Karyopharm Therapeutics: Membership on an entity's Board of Directors or advisory committees. Horwitz:Aileron: Consultancy, Research Funding; ADCT Therapeutics: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Forty Seven: Consultancy, Research Funding; Infinity/Verastem: Research Funding; Kyowa Hakka Kirin: Consultancy, Research Funding; Millenium/Takeda: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding; Trillium: Consultancy, Research Funding; Corvus: Consultancy; Innate Pharma: Consultancy; Mundipharma: Consultancy; Portola: Consultancy, Research Funding; Beigene: Consultancy; C4 Therapeutics: Consultancy; Daiichi Sankyo: Research Funding; GlaxoSmithKline: Consultancy; Janssen: Consultancy; Kura Oncology: Consultancy; Miragen: Consultancy; Myeloid Therapeutics: Consultancy; Verastem: Consultancy, Research Funding; Vividion Therapeutics: Consultancy; Affirmed: Consultancy; ASTEX: Consultancy. Dogan:Takeda: Consultancy; Roche: Consultancy, Research Funding; Physicians Education Resource: Consultancy; Corvus Pharmaceuticals: Consultancy; Seattle Genetics: Consultancy; EUSA Pharma: Consultancy; AbbVie: Consultancy; National Cancer Institute: Research Funding. Zelenetz:BeiGene: Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnology: Consultancy; Novartis: Consultancy; Amgen: Consultancy; Janssen: Consultancy; Celgene: Consultancy; Gilead: Consultancy; Genentech/Roche: Consultancy; Gilead: Research Funding; Roche: Research Funding; Celgene: Research Funding; Sandoz: Research Funding; MorphoSys: Research Funding; MEI Pharma: Research Funding.

Introduction: Peripheral T-cell lymphomas (PTCL) are a rare subset of non-Hodgkin lymphomas with an overall response rate to CHOP-based therapy of 80% but 5-year survival ranges between 20-40%. (Ellin et al Blood 2014) While response by PET/CT is prognostic (Mehta-Shah Blood Advances 2019), the high rate of relapse after complete response suggests that more sensitive determinants of minimal residual disease may have prognostic and even therapeutic importance. T-cell receptor gene rearrangement (TCR) by next generation sequencing is able to detect a known TCR clonotype at 10-5. (Shah et al AMP 2017) Therefore, in a prospective multi-institutional study, we sought to evaluate the utility of peripheral blood TCR by next generation sequencing in quantifying minimal residual disease in peripheral T-cell lymphoma. (NCT03297697) Here we report the results of TCR evaluation at the end of CHOP-based therapy. Methods: Patients with previously untreated PTCL (PTCL-NOS: peripheral T-cell lymphoma, NOS; angioimmunoblastic T-cell lymphoma: AITL; anaplastic large cell lymphoma: ALCL;, monomorphic epitheliotropic intestinal T-cell lymphoma: MEITL) treated with anthracycline based therapy for curative intent were eligible for the study. TCR (TCR gamma, TRG, or TCR beta, TRB) clonotype was established from baseline diagnostic tumor tissue. Peripheral blood (10cc) was collected in Streck tubes for TCR clonotype at each cycle of therapy, after completion of CHOP-based therapy, every 6 months for two years, at progression and in the stem cell product (if collected). TCR clonality was assessed and tracked using the LymphoTrack® TRG/TRB Assays-MiSeq® (Invivoscribe, San Diego, CA). Results: 39 patients were enrolled in the study (16 PTCL-NOS, 10 AITL, 7 ALK- ALCL, 5 ALK+ ALCL, 1 MEITL). One patient was enrolled with PTCL-NOS but was withdrawn after confirming a diagnosis of T-ALL. One patient with ALK- ALCL withdrew consent prior to sample collection. 19 patients have completed frontline therapy and have end of treatment TCR analysis available. The remaining 18 patients either have not yet completed treatment or did not have samples analyzed at the time of submission. Patients received CHOEP (n=10), BV-CHP (n=4), CHOP (n=32), CEOP (n=1) and CHOP+azacitidine (n=1). Median age was 61 (range: 22-80). Sixteen completed 6 cycles of therapy and of these, 7 underwent consolidation with an autologous transplant. One stopped due to intolerance after 5 cycles and remains in complete remission. 2 had progression of disease prior to completion of 6 cycles of therapy. At end of treatment evaluation by PET/CT, 13/19 (68%) had complete remission, 1/19 (5%) had partial remission and 5/19 (26%) had progressive disease. Of the 19 patients, 15 (78.9%), including 1 with leukemic disease, had TCR clonotype identifiable in the baseline diagnostic tissue, and 4 (21.1%) did not have a TCR clonotype identified (3 PTCL NOS, 1 ALK+ ALCL) in tumor tissues at baseline. Two of 15 patients had undetectable TCR clonotype in the blood at end of treatment and neither of them has relapsed. Thirteen of the 15 patients had detectable TCR clonotype at end of treatment. Of the 10 patients in complete remission by PET/CT at the end of treatment with known clonotype, 8 had a detectable TCR clonotype and 2 had undetectable TCR at the end of CHOP-based therapy. Five of 6 patients with PD or PR at end of treatment had detectable TCR clonotype in the blood and 1 lacked clonotype in baseline samples. At a median follow up of 13.1 months, only one patient has relapsed and this patient had positive peripheral blood TCR at end of treatment despite PET CR. We will present the end of treatment evaluation for all patients on the study at the time of the meeting. Conclusions: Measurement of peripheral blood TCR at the end of treatment is feasible in PTCL using next generation sequencing with a known tumor clonotype. Lack of radiographic CR was highly correlated with detectable TCR, but detectable TCR was also frequently seen in complete remission by PET/CT. Longer follow up, including analysis of TCR following autologous transplant, is required to determine if TCR clonotype at the end of CHOP-based therapy predicts likelihood of relapse and to evaluate the dynamics of TCR clonotype during and after completion of treatment. This study was supported by the Lymphoma Research Foundation and T-cell Leukemia/Lymphoma Society. Disclosures Mehta-Shah: Bristol Myers-Squibb: Research Funding; Celgene: Research Funding; Kyowa Hakko Kirin: Consultancy; C4 Therapeutics: Consultancy; Verastem: Research Funding; Karyopharm Therapeutics: Consultancy; Corvus: Research Funding; Innate Pharmaceuticals: Research Funding; Genetech/Roche: Research Funding. Fehniger:Indapta: Consultancy; Nkarta: Consultancy; Kiadis: Consultancy; HCW Biologics: Research Funding; Compass Therapeutics: Research Funding; ImmunityBio: Research Funding; Orca Biosystems: Consultancy; Wugen: Consultancy. Jacobsen:Takeda: Honoraria; Acerta: Consultancy; Astra-Zeneca: Consultancy; Merck: Consultancy; F. Hoffmann-LaRoche: Research Funding; Novartis: Research Funding; Pharmacyclics: Research Funding. Kahl:AbbVie: Consultancy; BeiGene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene Corporation: Consultancy; AstraZeneca Pharmaceuticals LP: Consultancy, Membership on an entity's Board of Directors or advisory committees; Roche Laboratories Inc: Consultancy; Genentech: Consultancy; Pharmacyclics LLC: Consultancy; Acerta: Consultancy, Research Funding; ADC Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Bartlett:Seattle Genetics: Consultancy, Research Funding; Millennium: Research Funding; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck: Research Funding; Acerta: Consultancy; Affimed Therapeutics: Research Funding; BTG: Consultancy; Janssen: Research Funding; BMS/Celgene: Research Funding; Immune Design: Research Funding; Kite, a Gilead Company: Research Funding; Forty Seven: Research Funding; ADC Therapeutics: Consultancy; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics: Research Funding; Roche/Genentech: Consultancy, Research Funding; Autolus: Research Funding. Ghobadi:Amgen: Consultancy, Research Funding; WuGen: Consultancy; EUSA: Consultancy; Bristol Myers Squibb: Consultancy; Kite: Consultancy, Research Funding. Moskowitz:Merck: Research Funding; Seattle Genetics: Consultancy; Imbrium Therapeutics, L.P.: Consultancy; Miragen Therapeutics: Consultancy; Incyte: Research Funding; Seattle Genetics: Research Funding; Bristol-Myers Squibb: Research Funding; Merck: Consultancy. Huang:Invivoscribe: Current Employment. Hutt:Invivoscribe: Current Employment. Vigil:Invivoscribe: Current Employment. Olson:Invivoscribe: Current Employment. Jacobsen:Invivoscribe: Current Employment. Horwitz:GlaxoSmithKline: Consultancy; Daiichi Sankyo: Research Funding; Myeloid Therapeutics: Consultancy; Innate Pharma: Consultancy; Mundipharma: Consultancy; Beigene: Consultancy; Portola: Consultancy, Research Funding; Corvus: Consultancy; Trillium: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding; Millenium/Takeda: Consultancy, Research Funding; Kyowa Hakka Kirin: Consultancy, Research Funding; Infinity/Verastem: Research Funding; Forty Seven: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Aileron: Consultancy, Research Funding; ADCT Therapeutics: Consultancy, Research Funding; ASTEX: Consultancy; Affirmed: Consultancy; Miragen: Consultancy; Kura Oncology: Consultancy; Janssen: Consultancy; Vividion Therapeutics: Consultancy; Verastem: Consultancy, Research Funding; C4 Therapeutics: Consultancy.

Introduction: Mediastinal gray zone lymphoma (MGZL) is an extremely rare form of non-Hodgkin lymphoma with a predominance in young men and with features that are intermediate between nodular sclerosis classical Hodgkin lymphoma (cHL) and primary mediastinal B-cell lymphoma (PMBL). Shared features of these tumor types include tumor CD30 expression and the presence of 9p24.1 chromosomal alterations with expression of programmed death 1 (PD-1) ligand. Compared with PMBL, patients (pts) with MGZL have inferior survival outcomes when treated with conventional chemotherapy (Wilson et al. Blood 2014). Nivolumab is a fully human immunoglobulin G4 anti-PD-1 immune checkpoint inhibitor monoclonal antibody; brentuximab vedotin (BV) is an anti-CD30 antibody-drug conjugate. In the CheckMate 436 study, the combination of nivolumab and BV demonstrated a high objective response rate (ORR; 73%) and complete response (CR) rate (37%) in pts with relapsed/refractory (R/R) PMBL (Zinzani et al. J Clin Oncol 2019). A separate study in R/R cHL also showed impressive efficacy (ORR: 82%; CR: 61%), suggesting some complementary action between the two agents (Herrara et al. Blood 2018). A case series highlighted the clinical activity of PD-1 inhibitor monotherapy in R/R MGZL (Melani et al. N Engl J Med 2017). Given the overlapping features of MGZL with PMBL and cHL, we evaluated the efficacy and safety of nivolumab + BV in a separate MGZL cohort in CheckMate 436. Methods: The expansion cohort of the open-label, phase 1/2 CheckMate 436 (NCT02581631) study enrolled pts ≥ 18 years old with ECOG performance status of 0 or 1, and with confirmed R/R MGZL after autologous hematopoietic cell transplantation (auto-HCT) or, if ineligible for auto-HCT, after ≥ 2 multi-agent chemotherapy regimens. Pts received 240 mg nivolumab (on Day 8 of Cycle 1, then Day 1 of following cycles) and 1.8 mg/kg BV (on Day 1 of each cycle) every 3 weeks until disease progression or unacceptable toxicity. Primary endpoints were investigator-assessed ORR per the Lugano 2014 criteria and safety. Key secondary endpoints included CR rate, overall survival (OS), duration of response (DOR), and progression-free survival (PFS). Results: A total of 10 pts were treated and evaluable. Median age (range) was 35 (25-72) years, with only 1 pt aged > 65 years (72 years). Six pts (60%) were male; all pts had a mediastinal mass. Pts had a median of 2 prior lines of systemic cancer therapy, and none had received prior auto-HCT. At database lock, 8 months after the last pt received the first treatment, all pts had discontinued treatment (5 due to disease progression, 3 due to maximum clinical benefit, 1 due to allogenic [allo]-HCT, and 1 due to auto-HCT). Pts received a median of 7 doses of nivolumab and 7 doses of BV. ORR per investigator was 70% (80% CI, 45-88), with 5 pts (50%) achieving CR (Table). The time to CR was 1.2-1.3 months and the duration of CR was 1.5-3.2 months before pts were censored for subsequent therapy. The 5 pts who achieved CR were bridged to hematopoietic cell transplantation (4 allo- and 1 auto-HCT) and censored (all were alive at database lock). Eight pts (89%) who were evaluable for response had tumor reduction of > 25% (Figure). At a median follow-up of 12.4 (range, 0.1-25.5) months, the 6-month OS rate was 80.0% (95% CI, 40.9-94.6). DOR and PFS could not be estimated due to earlier censoring of pts who received subsequent therapies. Nine pts (90%) experienced any grade treatment-related adverse events (TRAEs); the most common any grade TRAEs were neutropenia (n = 3; 1 grade 1, 1 grade 2, 1 experienced 4 grade 1/2 events and 1 grade 3 event) and paresthesia (n = 3; all grade 1). Three pts (30%) had grade 3-4 TRAEs. Infusion-related reaction occurred in 1 pt (grade 1). One pt had an immune-mediated AE (grade 2 maculo-papular rash, which resolved without systemic steroids). A serious drug-related AE occurred in 1 elderly pt (grade 3 febrile neutropenia). There were 3 deaths, all caused by disease progression. Conclusions: Nivolumab + BV demonstrated a high investigator-assessed ORR of 70%, with a 50% CR rate and a tolerable safety profile in pts with R/R MGZL, similar to findings in PMBL. The regimen represents a potential option for bridging to hematopoietic cell transplantation based on the brisk and frequent responses and a safety profile that compares favorably with historic data using standard chemotherapy regimens. Study support: BMS. Writing support: Jane Cheung, Caudex, funded by BMS. Figure 1 Disclosures Santoro: Takeda, Roche, Abbvie, Amgen, Celgene, AstraZeneca, ArQule, Lilly, Sandoz, Novartis, Bristol-Myers Squibb, Servier, Gilead Sciences, Pfizer, Eisai, Bayer, MSD: Speakers Bureau; Arqule, Sanofi: Consultancy; Bristol Myers Squibb, Servier, Gilead, Pfizer, Eisai, Bayer, MSD: Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb, SERVIER, Gilead Sciences, Pfizer, Eisai, Bayer, MSD, Sanofi, ArQule: Consultancy; Takeda, Roche, Abbvie, Amgen, Celgene, AstraZeneca, ArQule, Lilly, Sandoz, Novartis, Bristol-Myers Squibb, Servier, Gilead Sciences, Pfizer, Eisai, Bayer, MSD: Speakers Bureau; Bristol-Myers Squibb, SERVIER, Gilead Sciences, Pfizer, Eisai, Bayer, MSD, Sanofi, ArQule: Consultancy; Bristol-Myers Squibb, SERVIER, Gilead Sciences, Pfizer, Eisai, Bayer, MSD, Sanofi, ArQule: Consultancy, Speakers Bureau. Moskowitz:Merck: Consultancy; Imbrium Therapeutics, L.P.: Consultancy; Miragen Therapeutics: Consultancy; Incyte: Research Funding; Merck: Research Funding; Bristol-Myers Squibb: Research Funding; Seattle Genetics: Research Funding; Seattle Genetics: Consultancy. Carlo-Stella:Servier, Novartis, Genenta Science srl, ADC Therapeutics, F. Hoffmann-La Roche, Karyopharm, Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb, Merck Sharp & Dohme, Janssen Oncology, AstraZeneca: Honoraria; Boehringer Ingelheim and Sanofi: Consultancy; ADC Therapeutics and Rhizen Pharmaceuticals: Research Funding. Fanale:Seattle Genetics: Current Employment, Current equity holder in publicly-traded company. Francis:Bristol-Myers Squibb Company: Current Employment, Current equity holder in publicly-traded company. Sacchi:Bristol-Myers Squibb Company: Current Employment. Savage:Roche (institutional): Research Funding; Merck, BMS, Seattle Genetics, Gilead, AstraZeneca, AbbVie, Servier: Consultancy; BeiGene: Other: Steering Committee; Merck, BMS, Seattle Genetics, Gilead, AstraZeneca, AbbVie: Honoraria. OffLabel Disclosure: Nivolumab was used in combination with brentuximab vedotin (BV) for evaluation of its efficacy and safety in patients with relapsed/refractory mediastinal gray zone lymphoma.

Background: Fit patients (pts) with mantle cell lymphoma (MCL) are commonly treated with immunochemotherapy and consolidative high-dose therapy + stem cell rescue (cHDT/SCR), yet this approach has not demonstrated an overall survival (OS) benefit in a randomized trial. Outcomes for pts with high-risk MCL (TP53 aberrancy, high proliferation index, blastic histology) after cHDT/SCR are poor, and not all pts with MCL are eligible for this approach. Methods: We conducted a phase II study of sequential immunochemotherapy incorporating lenalidomide enriching for pts with high-risk disease features (defined as blastoid/pleomorphic histology and/or Ki67 >=30%). The three phases of tx were: 1) lenalidomide (15 mg daily, days 1-14) plus R-CHOP for four 21-day cycles; 2) R-HiDAC for 2 cycles (initially age-based cytarabine 1-3 g/m2; 3 g/m2 dose removed after 16 pts due to hematologic toxicity); and 3) rituximab monthly plus lenalidomide (15 mg daily) for 6 months (mos). Eligibility requirements were untreated stage II-IV MCL, KPS ≥70%, and adequate organ function; we sought ≥2/3 high-risk pts. We performed MRD testing on peripheral blood (cellular DNA) using the clonoSEQ Assay (Adaptive Biotechnologies). We obtained PET/CT and MRD testing after each phase of treatment and also MRD evaluation at 6 mos post-rituximab + lenalidomide maintenance. The primary endpoint was the rate of 3-yr progression-free survival (PFS), (acceptable PFS ≥75%, unacceptable ≤60%, based on desired proportion of high-risk pts). Results: Among 49 pts enrolled, 47 were evaluable for PFS (1 had progressive disease (PD) and 1 had toxicity during len-R-CHOP). Characteristics for 47 evaluable pts are shown in Table 1: 64% were high-risk and 18% had TP53 mutation. 45 completed maintenance (1 had PD during R-HiDAC and 1 withdrew to pursue cHDT/SCR) and 43 achieved complete response (CR), 1 stable disease, and 1 PD at end of treatment (EoT), yielding overall response rate of 91%, all CR (Figure 1). With a median follow-up of 2.8 yrs among survivors, the 3-yr PFS was 64% (95 CI 50, 82) and OS 85% (95 CI 74, 99). Three-yr PFS differed by TP53 status (14% mut vs. 85% wt, P < 0.0001, Table 2). Of 4 pts with PD, 3 had TP53 mutation and 1 had an unknown mutation status. Among TP53 wt pts, there was no significant difference in outcomes by risk (Table 2). MRD results were not obtained in 4 pts. Among 45 pts with MRD results, tumor clonal characterization for MRD evaluation was successful in 87% (39/45). MRD results are shown in Figure 2. Examining the initial phase of treatment (len-R-CHOP and R-HiDAC), among 37 pts with results at 1x10-5 sensitivity (1E5) following len-RCHOP, a substantial proportion (32%, 12/37 pts) remained MRD+ and 11 of 12 MRD+ pts post len-RCHOP converted to MRD- following R-HiDAC. At 1x10-6 sensitivity (1E6) following R-HiDAC, 5/20 pts were MRD+, and among responding pts, shorter median PFS was observed in MRD+ versus MRD- pts (23.1 mos vs. NR, P = 0.03). Examining the final phase of treatment (rituximab + lenalidomide maintenance) and observation period, among 37 pts with MRD results at 1E5 at EoT, 4 were MRD+, 2 of which were simultaneous (within 2 weeks of testing) with relapse; the remaining two MRD+ pts had median PFS 4.9 mos versus 37.4 mos for the 32 non-relapsed MRD- pts (P < 0.001). At 1E6, 6 pts who were MRD- at EoT converted to MRD+ after 6 mos of observation. MRD status at 1E6 at 6-mos post-EOT correlated with PFS: among 20 non-relapsed pts (6 MRD+, 14 MRD-), median PFS was 30.8 mos for MRD- versus 13.2 mos for MRD+ (P = 0.02). Conclusions: In a novel approach of sequential immunochemotherapy plus lenalidomide enrolling majority high-risk pts, outcomes for TP53-mutant pts were poor and we did not reach our primary endpoint of 3-yr PFS ≥75%. Among TP53-wt pts, this treatment program was highly effective even among pts with elevated Ki-67 (>=30%) and was associated with a high response rate, a 3-yr rate of PFS of 85%, and a high rate of MRD- at EoT. A substantial proportion of pts converted to MRD- after receipt of R-HiDAC, highlighting the efficacy of cytarabine in MCL. There was a high rate of MRD- after induction chemoimmunotherapy (Len-R-CHOP + R-HiDAC) at 1E5 (97%) and at 1E6 (80%), and the latter predicted remission duration. Several pts converted from MRD- to MRD+ at 6-mos post-EOT and eventually relapsed, suggesting that a more prolonged period of maintenance may be beneficial. Finally, MRD at 1E6 at 6 mos following EoT predicted response duration. Disclosures Batlevi: Life Sci, GLG, Juno/Celgene, Seattle Genetics, Kite: Consultancy; Janssen, Novartis, Epizyme, Xynomics, Bayer, Autolus, Roche/Genentech: Research Funding. Dogan:National Cancer Institute: Research Funding; EUSA Pharma: Consultancy; Takeda: Consultancy; Seattle Genetics: Consultancy; Corvus Pharmaceuticals: Consultancy; Physicians Education Resource: Consultancy; Roche: Consultancy, Research Funding; AbbVie: Consultancy. Drullinsky:Novartis: Research Funding; Roche: Research Funding. Gerecitano:Janssen: Current Employment. Hamlin:Portola Pharmaceutics: Consultancy; J&J Pharmaceuticals: Research Funding; Juno Therapeutics: Consultancy; Celgene: Consultancy; Incyte: Research Funding; Molecular Templates: Research Funding; Portola: Research Funding; Karyopharm: Consultancy. Ho:Invivoscribe, Inc.: Honoraria. Jacob:Adaptive Biotechnologies: Current Employment, Current equity holder in publicly-traded company. Matasar:Rocket Medical: Consultancy, Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Daiichi Sankyo: Consultancy; Takeda: Consultancy, Honoraria; GlaxoSmithKline: Honoraria, Research Funding; IGM Biosciences: Research Funding; Janssen: Honoraria, Research Funding; Pharmacyclics: Honoraria, Research Funding; Immunovaccine Technologies: Honoraria, Research Funding; Merck: Consultancy; Bayer: Consultancy, Honoraria, Research Funding; Juno Therapeutics: Consultancy; F. Hoffmann-La Roche Ltd: Consultancy, Honoraria, Research Funding; Teva: Consultancy; Genentech, Inc.: Consultancy, Honoraria, Research Funding. Moskowitz:Incyte: Research Funding; Imbrium Therapeutics, L.P.: Consultancy; Seattle Genetics: Consultancy; Miragen Therapeutics: Consultancy; Merck: Consultancy; Seattle Genetics: Research Funding; Bristol-Myers Squibb: Research Funding; Merck: Research Funding. Mullins:Adaptive Biotechnologies: Current Employment, Other: shareholder. Straus:Elsevier: Membership on an entity's Board of Directors or advisory committees, Other: CME writer; NY Lymphoma Rounds: Consultancy; Imedex, Inc.: Speakers Bureau; Karyopharm Therapeutics: Membership on an entity's Board of Directors or advisory committees; Targeted Oncology: Consultancy, Speakers Bureau; ASH: Other: Conference in December 2019 on HL to other physicians during ASH; Seattle Genetics: Consultancy, Membership on an entity's Board of Directors or advisory committees; OncLive: Speakers Bureau; Takeda Pharmaceuticals: Research Funding, Speakers Bureau. Younes:BioPath: Consultancy; Daiichi Sankyo: Consultancy; Takeda: Consultancy; Novartis: Consultancy; AstraZeneca: Current Employment; BMS: Consultancy; Curis: Consultancy; Epizyme: Consultancy; HCM: Consultancy; Janssen: Consultancy. Zelenetz:Amgen: Consultancy; Celgene: Research Funding; Genentech/Roche: Consultancy; Sandoz: Research Funding; Novartis: Consultancy; Janssen: Consultancy; Adaptive Biotechnology: Consultancy; Celgene: Consultancy; Gilead: Consultancy; BeiGene: Membership on an entity's Board of Directors or advisory committees; Gilead: Research Funding; MorphoSys: Research Funding; MEI Pharma: Research Funding; Roche: Research Funding. Kumar:Celgene: Honoraria, Other: Honoraria for Advisory Board; Astra Zeneca: Honoraria, Other: Honoraria for Advisory Board; Celgene: Research Funding; Pharmacyclics: Research Funding; Adaptive Biotechnologies,: Research Funding; AbbVie: Research Funding; Seattle Genetics: Research Funding; Kite Pharmaceuticals: Honoraria, Other: Honoraria for Advisory Board.

Background: Allogeneic hematopoietic transplantation (HCT) is frequently considered for patients (pts) with relapsed T-cell lymphoma (TCL) and less often as consolidation of initial therapy. Outcomes from prior registry data show that only 31% of pts remain disease free 3 years after HCT (Smith et al. JCO 2013). However, several single institution studies have superior outcomes. We previously presented an analysis of allogeneic transplant in T-cell lymphoma but have expanded this effort to 12 academic centers with longer follow up (Mehta-Shah ASH 2017). Methods: We analyzed the patient characteristics at time of diagnosis and transplant, treatment history, overall (OS) and progression-free survival (PFS) in consecutive TCL pts who had an HCT from 1/1/2000-12/31/2019 at 12 academic institutions. Results: Patient characteristics are shown in Table 1. 508 pts were identified with median age 51 years (16 - 72). 452 (86.5%) had known remission status at the time of HCT: 245 (54.4%) complete remission (CR), 168 (37.2%) partial remission (PR), 23 (5.0%) stable disease (SD), 16 (3.2%) progressive disease (PD). Seventy-eight (15.5%) had a prior autologous HCT. Thirty-six (7%) pts underwent HCT in CR1, 352 (69%) for relapsed/refractory TCL, and was not specified in 120 pts (24%). The median HCT comorbidity index (HCT-CI) score was 1 (0-11). Conditioning regimens were myeloablative (n=180), reduced intensity/non-myeloablative (n=323), unknown (n=3). Donor type was known for 471 pts: 192 matched related (MRD), 183 matched unrelated (MUD), 53 mismatched (MMD), 18 haploidentical donors, 25 umbilical cord blood. In this series, the 2 year OS and PFS rate following HCT were 59.1% (95%CI: 54.6-63.3%) and 45.8% (95%CI: 41.3-50.2%) respectively. 5 year OS and PFS rate were 50.8% (95%CI: 46.1-55.3%) and 39.4% (95%CI: 34.9-43.9%) (Fig 1) For disease specific 2-year and 5-year PFS, see Table 1. At a median follow-up of 29.7 mo (0.1-263 mo), 163 pts had relapsed and 261 pts had died. The median time from relapse post HCT to death was 10.2 mo (0-158.4 mo). Of 261 deaths: 81 were due to transplant related mortality (TRM), 69 were confirmed to be from TCL, and 111 were from non-relapse mortality/unknown. There was not a significant difference in PFS for pts with AITL, PTCL-NOS, ALK positive ALCL or ALK negative ALCL, with median PFS of 23.2 mo (95%CI:15.3-64.2). However, when AITL was compared specifically to PTCL-NOS or ALCL, those with AITL had a trend towards improved median PFS (51.4 mo vs. 18.4 mo, p=0.14) and improved median OS (not reached vs. 73.1 mo, p=0.26). At 5 years, PFS was worse for CTCL (18.6%, 95% CI: 9.7%-30.0%) compared to PTCL subtypes (43.8%; 95% CI: 37.3%-50.0%)(p Disease status at the time of HCT was associated with PFS (p Conclusions: We present the largest series of HCT in TCL. In this dataset, HCT provided durable disease control for a significant portion of pts with relapsed or refractory or otherwise high risk TCL. Depth of response to therapy immediate prior to HCT was associated with PFS. Patients with AITL appeared to have a trend towards improved outcome with HCT compared to other common PTCL histologies. Patients with CTCL had a higher rate of relapse compared to PTCL subtypes, but OS was similar. MRD HCTs were associated with lower TRM. This data supports the curative potential of HCT in a patient group with otherwise poor survival and limited treatment options. Disclosures Mehta-Shah: Corvus: Research Funding; Genetech/Roche: Research Funding; Verastem: Research Funding; Karyopharm Therapeutics: Consultancy; Bristol Myers-Squibb: Research Funding; Celgene: Research Funding; C4 Therapeutics: Consultancy; Kyowa Hakko Kirin: Consultancy; Innate Pharmaceuticals: Research Funding. Dahi:Kite: Consultancy. Sauter:Sanofi-Genzyme: Consultancy, Research Funding; Kite - a Gilead Company: Consultancy; Spectrum Pharamaceuticals: Consultancy; Gamida Cell: Consultancy; GSK: Consultancy; Bristol-Myers Squibb: Research Funding; Celgene: Consultancy, Research Funding; Novartis: Consultancy; Genmab: Consultancy; Precision Biosciences: Consultancy, Research Funding; Juno Therapeutics: Consultancy, Research Funding. Moskowitz:Merck: Research Funding; Imbrium Therapeutics, L.P.: Consultancy; Bristol-Myers Squibb: Research Funding; Miragen Therapeutics: Consultancy; Merck: Consultancy; Seattle Genetics: Consultancy; Incyte: Research Funding; Seattle Genetics: Research Funding. Jacobsen:Novartis: Research Funding; Takeda: Honoraria; Pharmacyclics: Research Funding; F. Hoffmann-LaRoche: Research Funding; Astra-Zeneca: Consultancy; Acerta: Consultancy; Merck: Consultancy. William:Celgene: Consultancy, Honoraria; Guidepoint Global: Consultancy; Seattle Genetics: Research Funding; Dova: Research Funding; Incyte: Research Funding; Merck: Research Funding; Kyowa Kirin: Consultancy, Honoraria. Barta:Monsanto: Consultancy; Pfizer: Honoraria; Janssen: Honoraria; Seattle Genetics: Honoraria, Research Funding; Atara: Honoraria. Allen:Clinical Care Options: Speakers Bureau; Curio Sciences: Honoraria; Research to Practice: Speakers Bureau; Imbrium: Consultancy, Other; Bayer: Consultancy, Other. Song:Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen, Celgene,Takeda: Consultancy, Honoraria; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees; GlaxoSmithKline: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene/BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Research Funding; Otsuka: Honoraria. Ruan:Celgene: Consultancy, Research Funding; Seattle Genetics: Research Funding; Kite Pharma: Consultancy; Juno: Consultancy; BMS: Consultancy, Research Funding; Pharmacyclics: Research Funding; AstraZeneca: Consultancy, Research Funding. McKinney:Kite/Gilead: Honoraria, Speakers Bureau; Kite/Gilead, Seattle Genetics, Molecular Templates, BTG, Pharmacyclics, Verastem, Genentech, Inc., Celgene: Consultancy; UNUM, Molecular Templates, Incyte, Beigene, Denovo Biopharma, Pharmacyclics, Nordic Nanovector, BMS, Genentech, Inc., Celgene: Research Funding. Beaven:Tessa Therapeutics: Research Funding; Roche: Research Funding; Seattle Genetics: Research Funding; MorphoSysAb: Research Funding; LoxoOncology: Research Funding; Celgene: Research Funding. Haverkos:Viracta THerapeutics: Consultancy. Alpdogan:Seattle Genetics: Consultancy; Kiowa Kirin: Consultancy. Porcu:Kiowa Kirin: Research Funding; Kura Oncology: Research Funding; Innate Pharma: Membership on an entity's Board of Directors or advisory committees, Research Funding; Galderma: Research Funding; Daiichi: Consultancy, Honoraria; Celgene: Research Funding; Cell Medica: Research Funding; Miragen: Research Funding; Verastem: Consultancy; Viracta Therapeutics: Membership on an entity's Board of Directors or advisory committees. Horwitz:Daiichi Sankyo: Research Funding; GlaxoSmithKline: Consultancy; Janssen: Consultancy; Kura Oncology: Consultancy; Myeloid Therapeutics: Consultancy; Miragen: Consultancy; ADCT Therapeutics: Consultancy, Research Funding; Aileron: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Forty Seven: Consultancy, Research Funding; Infinity/Verastem: Research Funding; Kyowa Hakka Kirin: Consultancy, Research Funding; Millenium/Takeda: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding; Trillium: Consultancy, Research Funding; Corvus: Consultancy; Innate Pharma: Consultancy; Mundipharma: Consultancy; Portola: Consultancy, Research Funding; Beigene: Consultancy; C4 Therapeutics: Consultancy; Verastem: Consultancy, Research Funding; Vividion Therapeutics: Consultancy; Affirmed: Consultancy; ASTEX: Consultancy.

Introduction: The standard approach for relapsed or refractory (RR) classical Hodgkin lymphoma (cHL) following front-line treatment failure is second line therapy (SLT) aimed to achieve complete response (CR), followed by consolidation with high dose therapy and autologous hematopoietic cell transplantation (HDT/AHCT). No one standard SLT exists and options include regimens containing platinum, gemcitabine, and more recently brentuximab vedotin (BV). Complete response rates associated with these regimens range from 50-70%. Due to the increasing use of BV in the front-line setting, development of SLT regimens that are both highly effective and BV-sparing are needed. Programmed death-1 (PD-1) inhibitors are highly active in RR cHL and have the potential to enhance the efficacy of standard chemotherapy. Here we report the results of our phase II study evaluating a novel anti-PD-1-based regimen, pembrolizumab plus gemcitabine, vinorelbine, and liposomal doxorubicin (pembrolizumab-GVD), as SLT for RR cHL. Methods: Transplant eligible patients (pts) with RR cHL following failure of 1-line of therapy were eligible. Treatment consisted of 2 to 4 cycles of pembrolizumab (200mg IV, day 1), gemcitabine (1000mg/m2 IV, days 1 and 8), vinorelbine (20mg/m2 IV, days 1 and 8) and liposomal doxorubicin (15mg/m2, days 1 and 8), given on 21-day cycles. Pts who achieved CR by PET (Deauville ≤3) after 2 or 4 cycles proceeded to HDT/AHCT. HDT/AHCT was carried out according to institutional standards and BV maintenance was allowed following HDT/AHCT. The primary endpoint was CR rate after 2 or 4 cycles of pembrolizumab-GVD. Enrollment occurred according to a Simon 2-stage design with sample size based upon a projected CR rate of 70%. In stage 1, 23 pts enrolled and 12 or more CRs were required to proceed to stage II; in stage II, an additional 16 pts enrolled. Out of a total of 39 pts, 24 CRs were required to declare this regimen promising. Results: Among 39 patients enrolled, 37 are evaluable for toxicity (2 pts have not yet started treatment) and 34 are evaluable for response (4 pts too early, 1 pt found to have composite lymphoma after enrollment). Of 37 treated pts, median age is 36 (range 21-71), 43% are male, 23 (62%) had advanced stage disease, and 15 (41%) had primary refractory disease. With regard to RR cHL risk factors (B-symptoms, extranodal disease, and relapse/refractory disease within 1 year of initial treatment), 4(11%) had no risk factors (RFs), 21 (57%) had 1 RF, 9 (24%) had 2 RFs, and 3 (8%) had all 3 RFs. Treatment was well tolerated with most adverse events being grade 1 or 2 (see figure 1). Grade 3 AEs included rash (n=1), elevated AST/ALT (n=3), oral mucositis (n=2), and neutropenia (n=3). Figure 2 shows the outcome for all 37 treated pts. Among 34 evaluable pts, 31 (91%) achieved CR after 2 cycles and 3 achieved partial response. An additional 1 pt achieved CR after 4 cycles of pembrolizumab-GVD, therefore in total, 32 of 34 (94%) achieved CR following pembrolizumab-GVD. 4 pts with CR after 2 cycles received an additional 2 cycles of pembrolizumab-GVD in order to delay HDT/AHCT during the height of the COVID-19 pandemic (n=3) or due to refusing HDT/ASCT (n=1). To date, 32 have undergone HDT/AHCT following 2 (n=27) or 4 (n=5) cycles of treatment. 1 pt is awaiting HDT/AHCT; 1 pt refused HDT/ASCT and received pembrolizumab maintenance instead. 2 pts received involved site radiation therapy to initial area of relapsed disease prior to planned HDT/AHCT and 10 pts received post-HDT/ASCT maintenance with BV. Median follow-up post-HDT/AHCT is 9 mos (range 0.03-20.9 mos) and all pts remain in remission to date. Conclusion: Second-line therapy with pembrolizumab-GVD is a highly effective and well-tolerated regimen that can efficiently bridge pts with RR cHL to HDT/AHCT. Updated results including all 39 enrolled pts will be presented at the meeting. Given the high CR rate observed with pembrolizumab-GVD, an expansion cohort evaluating 8 cycles of pembrolizumab maintenance (instead of HDT/AHCT) for patients who achieve CR after 4 cycles of pembrolizumab-GVD is planned. Disclosures Moskowitz: Merck: Consultancy; Incyte: Research Funding; Miragen Therapeutics: Consultancy; Seattle Genetics: Consultancy; Imbrium Therapeutics, L.P.: Consultancy; Merck: Research Funding; Seattle Genetics: Research Funding; Bristol-Myers Squibb: Research Funding. Shah:Amgen Inc.: Research Funding; Janssen: Research Funding. Kumar:AbbVie: Research Funding; Celgene: Honoraria, Other: Honoraria for Advisory Board; Seattle Genetics: Research Funding; Astra Zeneca: Honoraria, Other: Honoraria for Advisory Board; Celgene: Research Funding; Kite Pharmaceuticals: Honoraria, Other: Honoraria for Advisory Board; Adaptive Biotechnologies,: Research Funding; Pharmacyclics: Research Funding. Lahoud:MorphoSys: Other: Advisory Board. Batlevi:Life Sci, GLG, Juno/Celgene, Seattle Genetics, Kite: Consultancy; Janssen, Novartis, Epizyme, Xynomics, Bayer, Autolus, Roche/Genentech: Research Funding. Hamlin:J&J Pharmaceuticals: Research Funding; Portola: Research Funding; Incyte: Research Funding; Portola Pharmaceutics: Consultancy; Juno Therapeutics: Consultancy; Karyopharm: Consultancy; Celgene: Consultancy; Molecular Templates: Research Funding. Straus:Karyopharm Therapeutics: Membership on an entity's Board of Directors or advisory committees; Imedex, Inc.: Speakers Bureau; Targeted Oncology: Consultancy, Speakers Bureau; NY Lymphoma Rounds: Consultancy; Takeda Pharmaceuticals: Research Funding, Speakers Bureau; OncLive: Speakers Bureau; Elsevier: Membership on an entity's Board of Directors or advisory committees, Other: CME writer; ASH: Other: Conference in December 2019 on HL to other physicians during ASH; Seattle Genetics: Consultancy, Membership on an entity's Board of Directors or advisory committees. Horwitz:ASTEX: Consultancy; Verastem: Consultancy, Research Funding; Myeloid Therapeutics: Consultancy; Miragen: Consultancy; Kura Oncology: Consultancy; Janssen: Consultancy; GlaxoSmithKline: Consultancy; Daiichi Sankyo: Research Funding; C4 Therapeutics: Consultancy; Affirmed: Consultancy; Vividion Therapeutics: Consultancy; Beigene: Consultancy; Portola: Consultancy, Research Funding; Mundipharma: Consultancy; Innate Pharma: Consultancy; Corvus: Consultancy; Trillium: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding; Millenium/Takeda: Consultancy, Research Funding; Kyowa Hakka Kirin: Consultancy, Research Funding; Infinity/Verastem: Research Funding; Forty Seven: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Aileron: Consultancy, Research Funding; ADCT Therapeutics: Consultancy, Research Funding. Falchi:Genmab: Research Funding; Roche: Research Funding. Joffe:Epizyme: Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Membership on an entity's Board of Directors or advisory committees. Noy:Pharmacyclics: Research Funding; Pharmacyclics: Consultancy; Janssen: Consultancy; Rafael Pharma: Research Funding; NIH: Research Funding; Morphosys: Consultancy; Medscape: Consultancy; Targeted Oncology: Consultancy. Matasar:Teva: Consultancy; Genentech, Inc.: Consultancy, Honoraria, Research Funding; Merck: Consultancy; Bayer: Consultancy, Honoraria, Research Funding; Juno Therapeutics: Consultancy; F. Hoffmann-La Roche Ltd: Consultancy, Honoraria, Research Funding; GlaxoSmithKline: Honoraria, Research Funding; IGM Biosciences: Research Funding; Janssen: Honoraria, Research Funding; Pharmacyclics: Honoraria, Research Funding; Immunovaccine Technologies: Honoraria, Research Funding; Rocket Medical: Consultancy, Research Funding; Takeda: Consultancy, Honoraria; Daiichi Sankyo: Consultancy; Seattle Genetics: Consultancy, Honoraria, Research Funding. Vardhana:Other: Other: SAV has received honoraria from Agios Pharmaceuticals and Rheos Pharmaceuticals, is an advisor for Immunai and has consulted for ADC Therapeutics. von Keudell:Genentech: Research Funding; Bayer: Research Funding; Pharmacyclics: Research Funding. Zelenetz:Novartis: Consultancy; Janssen: Consultancy; Celgene: Consultancy; Amgen: Consultancy; Adaptive Biotechnology: Consultancy; BeiGene: Membership on an entity's Board of Directors or advisory committees; Roche: Research Funding; Gilead: Research Funding; Genentech/Roche: Consultancy; Gilead: Consultancy; Sandoz: Research Funding; Celgene: Research Funding; MEI Pharma: Research Funding; MorphoSys: Research Funding. OffLabel Disclosure: Pembrolizumab as second-line therapy for Hodgkin lymphoma

Introduction Breast Implant Associated Anaplastic Large Cell Lymphoma (BIA-ALCL) is a rare subtype of ALCL that arises as a seroma or a mass in the space surrounding textured breast implants. In July 2019 the FDA had reported 573 cases worldwide and 33 deaths connected to the lymphoma. However, collections of cases usually come from large groups of institutions or countries, with different approaches regarding surgery and treatment. Here we describe a cohort of 18 cases undergoing implant removal and capsulectomy and followed at Memorial Sloan Kettering Cancer Center (MSKCC) Methods We retrospectively analyzed all the cases of women with breast implants undergoing implant removal and capsulectomy for BIA-ALCL at MSKCC from January 2011 to June 2020. Results are expressed in absolute numbers and percentages, survival is calculated with the Kaplan Maier method. Results Of 27 total BIA-ALCL cases seen at MSKCC, 18 women had their primary surgery for implant removal and capsulectomy by our surgery division, analyzed in our central pathology and treated and/or expectantly monitored in our T cell lymphoma clinic. Sixteen patients (89%) had implants as reconstruction after breast cancer (of which 12/16, 75% had received adjuvant/neoadjuvant chemotherapy (CT), 3, 19% radiotherapy (RT). Two subjects (11%) had implants for cosmetic reasons). Four patients (25%) had undergone implants exchange after initial reconstruction. BRCA mutational status was known in 9 patients (56%), with 3/9 women (33%) having BRCA mutations (2 BRCA2, 1 BRCA1) and one additional woman initially thought to have a mutation of BRCA2, subsequently re-classified as polymorphism. After a median exposure of 11 years (STDEV 6 y), 10 years from last implant change, median age at BIA-ALCL diagnosis was 57 years (STDEV 10 y). Implant characteristics were as follows: 18/18 (100%) silicone surface, 17/18 (94%) had a biocell textured surface, 1/18 (6%) unknown surface, 9/18 (50%) silicone filled, and 9/18 (50%) saline filled. BIA-ALCL presented as effusion in 14/18 (78%) of cases, mass in 3/18 (17%) of cases, and PET+ intramammary lymphadenopathy in 1/18 (6%). Pre-surgery, cases were assessed with PET/CT in 15/18 (83%), US in 15/18 (83%) and MR in 7/18 (39%). Initial treatment was implant removal and capsulectomy for all women, with removal of all the implants in place. One early case received implant removal and replacement with a smooth textured implant with partial capsulectomy prior to confirmed diagnosis. Three of 18 (16%) who presented with higher stage disease received additional treatment: one received chemotherapy (Brentuximab Vedotin - cyclophosphamide - doxorubicin - prednisone, BV-CHP) followed by RT consolidation, and 2 received RT consolidation only. Patients were followed for a median of 26 months (STDEV 2.22 months) after diagnosis, with clinical exam every 3-6 months (100%), PET/CT in 16/18 (89%), and MR in 4/18 (22%). No patient died of lymphoma progression or recurrence. One patient died from progression of breast cancer. One woman (described above) recurred 2 years after receiving incomplete capsulectomy and smooth surface implant re-placement. She underwent repeat implant removal and bilateral capsulectomy and remains disease free at 6.5 years from the second surgery. Another patient was likely diagnosed at recurrence: she underwent unilateral implant removal and partial unilateral capsulectomy for recurrent delayed seroma (at the time of this implant removal BIA-ALCL could not be confirmed). 1.5 years later she developed a recurrent seroma on the contralateral side where a textured device remained. BIA-ALCL diagnosis was confirmed at this time. Overall survival (Figure 1), was 94% at 2 years and progression-free survival was 89% at 2 years. Conclusions Our data on this cohort of patietns with BIA-ALCL surgically treated and followed at a single institution, confirm the importance of adequate surgery (bilateral implant removal and complete capsulectomy) in patients presenting with seroma-confined disease. This dataset reinforces the high rates of progression free and overall survivalwhen diagnosis is identified and treatment performed in those with limited stage disease. Studies are ongoing to determine the role of somatic mutations like BRCA1-2. Figure: overall and progression-free survival of BIA-ALCL women operated and followed at MSKCC Figure 1 Disclosures Cordeiro: Inamed: Consultancy, Research Funding; Acelity: Consultancy; Allergan: Consultancy, Research Funding. Moskowitz:Bristol-Myers Squibb: Research Funding; Merck: Research Funding; Merck: Consultancy; Miragen Therapeutics: Consultancy; Seattle Genetics: Consultancy; Seattle Genetics: Research Funding; Incyte: Research Funding; Imbrium Therapeutics, L.P.: Consultancy. Dogan:Takeda: Consultancy; AbbVie: Consultancy; National Cancer Institute: Research Funding; Seattle Genetics: Consultancy; EUSA Pharma: Consultancy; Corvus Pharmaceuticals: Consultancy; Roche: Consultancy, Research Funding; Physicians Education Resource: Consultancy. Horwitz:Vividion Therapeutics: Consultancy; Affirmed: Consultancy; Daiichi Sankyo: Research Funding; GlaxoSmithKline: Consultancy; Janssen: Consultancy; Kura Oncology: Consultancy; ASTEX: Consultancy; C4 Therapeutics: Consultancy; Beigene: Consultancy; Portola: Consultancy, Research Funding; Mundipharma: Consultancy; Innate Pharma: Consultancy; Corvus: Consultancy; Trillium: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding; Millenium/Takeda: Consultancy, Research Funding; Kyowa Hakka Kirin: Consultancy, Research Funding; Infinity/Verastem: Research Funding; Forty Seven: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Aileron: Consultancy, Research Funding; ADCT Therapeutics: Consultancy, Research Funding; Verastem: Consultancy, Research Funding; Myeloid Therapeutics: Consultancy; Miragen: Consultancy.

Introduction: MAVORIC was an open-label, multicenter, randomized phase 3 study evaluating the safety and efficacy of mogamulizumab (moga) compared to vorinostat (vori) in patients with mycosis fungoides (MF) or Sézary syndrome (SS) who had failed at least one prior course of systemic therapy (NCT01728805). Primary results have been reported (Kim et al. Lancet Oncol 2018) and were based on a data cutoff date of December 31, 2016. The primary endpoint was progression-free survival (PFS); patients in the moga treatment arm experienced significantly longer PFS compared to patients in the vori treatment arm (median 7.7 months vs 3.1 months; p Methods: Patients were randomized 1:1 to moga 1.0 mg/kg administered intravenously on Days 1, 8, 15, and 22 of the first cycle and on Days 1 and 15 of subsequent cycles or vori 400 mg administered orally once daily. Patients randomized to vori were allowed to cross over to moga upon progression or intolerable toxicity. Safety was assessed by reported adverse events (AEs), changes in physical examinations, vital sign measurements, electrocardiograms, and laboratory analyses. Results: In total, 372 patients were randomized (moga, 186; vori, 186), of whom 370 received study drug and were included in the safety analysis (moga, 184; vori, 186). For the final safety analysis, median duration of follow-up was 34.5 months (range, 0.13-70.0) in the randomized part of the study. Median treatment exposure was 170 days (range, 1-1813) for moga and 84 days (4-1230) for vori, which represent the same median values but broader ranges compared to the primary analysis (primary analysis, 170 days [1-1379] for moga and 84 days [4-1058] for vori). The type and frequency of AEs in either the moga or vori treatment groups (Table) were consistent with those reported in the primary analysis. TEAEs, regardless of causality, that were reported at similar rates in the two treatment groups included constipation, peripheral edema, headache, and anemia. TEAEs (all causality) that occurred at higher frequency in the moga vs vori arm included infusion-related reaction (33.2% vs 0.5%) and drug eruption (25.0% vs 1.1%); the majority of these events were grade 1 or 2 (Table). The types and frequencies of AEs attributable to moga (per Investigator assessment) included infusion-related reaction (33.2% [61/184]), drug eruption (23.9% [44/184]), and fatigue (18.5% [34/184]), and for vori, diarrhea (55.4% [103/186]), nausea (38.2% [71/186]), and fatigue (33.3% [62/186]). In patients who crossed over from the vori to moga arm and received study drug (n=135), the most frequently reported AEs attributable to moga were infusion-related reaction (37.8% [51/135]), drug eruption (24.4% [33/135]), fatigue (7.4% [10/135]), increased alanine aminotransferase (7.4% [10/135]), and increased aspartate aminotransferase (7.4% [10/135]). Discontinuation rates due to AEs were similar between treatment arms and in crossover patients (moga, 21.7% [40/184]; vori, 23.7% [44/186]; crossover, 25.9% [35/135]). The most common AEs leading to discontinuation were drug eruption in the moga arm (7.1% [13/184]) and fatigue in the vori arm (4.3% [8/186]). Overall, the rates of drug-related serious TEAEs were similar between treatment arms and in crossover patients (moga, 19.6% [36/184]; vori, 16.7% [31/186]; crossover, 11.9% [16/135]). After the data cutoff for the primary analysis, 1 additional patient randomized to moga (decreased appetite, general physical health deterioration, hypoalbuminemia) and 1 crossover patient (cerebral hemorrhage) experienced TEAEs with an outcome of death, all considered unrelated to study treatment per Investigator. Conclusions: This final safety analysis from the MAVORIC study in patients with previously treated MF and SS demonstrates that moga was generally well tolerated. Longer follow-up and treatment exposure did not identify any new safety signals. The type and incidence of treatment-related AEs among patients receiving moga after crossover were similar to those observed for patients initially randomized to moga. Disclosures Kim: Merck: Research Funding; Portola Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Horizon: Research Funding; Corvus: Honoraria, Membership on an entity's Board of Directors or advisory committees; Galderma: Research Funding; Elorac: Research Funding; Soligenix: Research Funding; Kyowa Hakko Kirin: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Eisai: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Forty Seven Inc: Research Funding; Seattle Genetics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Medivir: Honoraria, Membership on an entity's Board of Directors or advisory committees; Innate Pharma: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Trillium: Research Funding; Neumedicine: Research Funding; miRagen: Research Funding. Bagot:Innate Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Zinzani:MSD: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Eusapharma: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sanofi: Consultancy; Celltrion: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen-Cilag: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Servier: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sandoz: Membership on an entity's Board of Directors or advisory committees; Immune Design: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Portola: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Roche: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Kyowa Kirin: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; TG Therapeutics: Honoraria, Speakers Bureau; Verastem: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Duvic:Seattle Genetics: Consultancy, Honoraria, Research Funding; Eisai: Research Funding; Shape: Research Funding; UT MD Anderson Cancer Center: Employment; USCLC Registry: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Secretary/treasurer of Item h; Spatz Foundation: Research Funding; Tetralogic: Research Funding; Millennium (formerly Takeda): Research Funding; Mallinckrodt Pharmaceuticals (formeraly Therakos, Inc): Research Funding; Kyowa Hakko Kirin Co., Ltd.: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Forty Seven Inc: Membership on an entity's Board of Directors or advisory committees; Cutaneous Lymphoma Foundation: Membership on an entity's Board of Directors or advisory committees; PleXus Communications: Speakers Bureau; Guidepoint Global: Consultancy; Evidera, Inc.: Consultancy; Cell Medica Inc.: Consultancy; Allos: Research Funding; Rhizen Pharma: Research Funding; Oncoceuticals: Research Funding; Soligenetics: Research Funding; Cell Medica Ltd.: Honoraria; Therakos: Speakers Bureau; Jonathan Wood & Assoc.: Speakers Bureau; Hawaiian Dermatology Society: Speakers Bureau; Hemedicus: Speakers Bureau; Janssen Pharmaceuticals (div of Johnson & Johnson): Speakers Bureau. Morris:Guys Hospital: Employment. Kim:Medimmune: Research Funding; Soligenix: Research Funding; Kyowa Kirin: Research Funding; Galderma: Consultancy, Research Funding; Actelion: Consultancy, Research Funding. Musiek:Menlo: Other: Investigator; Helsinn: Membership on an entity's Board of Directors or advisory committees; Soligenix: Other: Investigator; Pfizer: Other: Investigator; Elorac: Other: Investigator; Kyowa: Honoraria, Other: Above honoraria: for Ad Board; miRagen: Other: Investigator. Ortiz-Romero:Actelion: Consultancy, Membership on an entity's Board of Directors or advisory committees; Kyowa: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; PLCG1: Patents & Royalties; miRagen: Membership on an entity's Board of Directors or advisory committees; MEDA: Research Funding; Innate Pharma: Membership on an entity's Board of Directors or advisory committees; 4SC: Membership on an entity's Board of Directors or advisory committees. Eradat:Kyowa: Research Funding; Kite: Research Funding; Pharmacyclics: Consultancy, Honoraria, Research Funding, Speakers Bureau; Roche: Research Funding; Genentech: Consultancy, Honoraria, Research Funding, Speakers Bureau; AbbVie: Consultancy, Honoraria, Research Funding, Speakers Bureau; Gilead: Research Funding. Magnolo:University Hospital of Muenster, Center of Innovative Dermatology: Employment. Scarisbrick:Kyowa Kirin: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees; Recordat: Consultancy; 4SC: Consultancy, Membership on an entity's Board of Directors or advisory committees; Innate Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; Helsinn: Consultancy, Membership on an entity's Board of Directors or advisory committees. Dalle:Kyowa: Other: Principal Investigator in clinical trials promoted by Kyowa. Fisher:Kyowa Kirin: Consultancy. Poligone:Stemline Therapeutics: Consultancy, Speakers Bureau; Regeneron: Consultancy, Speakers Bureau; Actelion: Consultancy, Speakers Bureau; Astex Pharmaceuticals: Research Funding; Bioniz: Research Funding; Celgene: Consultancy; Helsinn: Research Funding, Speakers Bureau; Innate Pharma: Research Funding; Kyowa Hakko Kirin: Consultancy, Honoraria, Research Funding, Speakers Bureau; miRagen: Research Funding; Soligenix: Research Funding. Pro:Takeda: Consultancy, Honoraria, Other: Travel Expenses; Celgene: Consultancy, Honoraria; Kyowa Hakka Kirin: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria, Other: Travel Expenses, Research Funding. Quaglino:Actelion: Honoraria, Other: Advisory Board; Innate Pharma: Honoraria, Other: Advisory Board; Takeda: Honoraria, Other: Advisory Board; Kyowa Kirin: Honoraria, Other: Advisory Board; Helsinn: Honoraria, Other: Advisory Board; Therakos: Honoraria, Other: Advisory Board. Reddy:AbbVie: Honoraria; Janssen: Honoraria; KITE: Honoraria; Merck: Research Funding; Celgene: Honoraria, Speakers Bureau. Geskin:Merck: Other: Supported/Contracted Research; UpToDate: Patents & Royalties: Royalty, Receipt of Intellectual Property Rights / Patent Holder; Actelion: Other: Supported/Contracted Research; Helsinn: Consultancy, Honoraria, Other: Supported/Contracted Research; Stratpharma: Other: Supported/Contracted Research; Mallinckrodt: Consultancy, Honoraria, Other: Supported/Contracted Research; Medscape: Speakers Bureau; Medivir: Consultancy, Honoraria. Halwani:Amgen: Other: Investigator; Takeda: Other: PI; Seattle Genetics: Other: PI; Pharmacyclics: Other: Investigator; miRagen: Other: PI; Kyowa Hakko Kirin: Other: PI; Immune Design: Other: PI; Genentech, Inc.: Other: Investigator; Bristol-Myers Squibb: Other: PI; AbbVie: Other: PI. Khot:Peter MacCallum Cancer Centre: Employment; Amgen: Consultancy, Speakers Bureau; Celgene: Consultancy; Janssen: Consultancy; Kyowa Hakko Kirin: Consultancy. Korman:Genentech: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Dermira: Research Funding; Glaxo: Honoraria, Membership on an entity's Board of Directors or advisory committees; Immune Pharma: 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; Kyowa: Research Funding; Leo: Research Funding; Menlo: Research Funding; Merck: Research Funding; Novartis: Consultancy, Honoraria, Speakers Bureau; Pfizer: Research Funding; Principia: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Prothena: Research Funding; Regeneron: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Rhizen: Research Funding; Sun: Honoraria, Membership on an entity's Board of Directors or advisory committees; Syntimmune: Research Funding; UCB: Research Funding; Valeant: Honoraria, Membership on an entity's Board of Directors or advisory committees; Eli Lilly: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol-Myers Squibb: Research Funding; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Horwitz:Seattle Genetics: Consultancy, Research Funding; Affimed: Consultancy; Astex: Consultancy; Portola: Consultancy; ADCT Therapeutics: Research Funding; Kyowa Hakko Kirin: Consultancy; Infinity/Verastem: Consultancy, Research Funding; Miragen: Consultancy; Seattle Genetics: Consultancy, Research Funding; Forty-Seven: Research Funding; Celgene: Consultancy, Research Funding; Millennium/Takeda: Consultancy, Research Funding; Miragen: Consultancy; Innate Pharma: Consultancy; Kura: Consultancy; Corvus Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Miragen: Consultancy; Infinity/Verastem: Consultancy, Research Funding; Millennium/Takeda: Consultancy, Research Funding; Portola: Consultancy; Kura: Consultancy; Celgene: Consultancy, Research Funding; Kura: Consultancy; Kyowa Hakko Kirin: Consultancy; Infinity/Verastem: Consultancy, Research Funding; Forty-Seven: Research Funding; Trillium: Research Funding; Corvus Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Research Funding; Astex: Consultancy; Affimed: Consultancy; ADCT Therapeutics: Research Funding; Aileron: Research Funding; Corvus Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Kyowa Hakko Kirin: Consultancy; Trillium: Research Funding; Millennium/Takeda: Consultancy, Research Funding; Mundipharma: Consultancy; Millennium/Takeda: Consultancy, Research Funding; Kyowa Hakko Kirin: Consultancy; Portola: Consultancy; Aileron: Research Funding; Mundipharma: Consultancy; Celgene: Consultancy, Research Funding; Mundipharma: Consultancy; Seattle Genetics: Consultancy, Research Funding; ADCT Therapeutics: Research Funding; Portola: Consultancy; Kura: Consultancy; ADCT Therapeutics: Research Funding; Corvus Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Infinity/Verastem: Consultancy, Research Funding; Aileron: Research Funding; Affimed: Consultancy; Trillium: Research Funding; Innate Pharma: Consultancy; Affimed: Consultancy; Astex: Consultancy; Mundipharma: Consultancy; Aileron: Research Funding; Miragen: Consultancy; Trillium: Research Funding; Innate Pharma: Consultancy; Forty-Seven: Research Funding; Forty-Seven: Research Funding; Innate Pharma: Consultancy; Astex: Consultancy; Seattle Genetics: Consultancy, Research Funding. Lamar:Seattle Genetics: Consultancy; Kyowa: Consultancy, Membership on an entity's Board of Directors or advisory committees. Moskowitz:Cell Medica: Consultancy; ADC Therapeutics: Consultancy; Merck: Research Funding; Erytech Pharma: Consultancy; Takeda Pharmaceuticals: Consultancy; Erytech Pharma: Consultancy; Merck: Research Funding; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Erytech Pharma: Consultancy; Incyte: Research Funding; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Merck: Research Funding; Erytech Pharma: Consultancy; ADC Therapeutics: Consultancy; ADC Therapeutics: Consultancy; Bristol-Myers Squibb: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Erytech Pharma: Consultancy; Bristol-Myers Squibb: Consultancy, Research Funding; miRagen Therapeutics Inc: Consultancy, Research Funding; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Takeda Pharmaceuticals: Consultancy; Seattle Genetics: Consultancy, Honoraria, Research Funding; Cell Medica: Consultancy; Erytech Pharma: Consultancy; Seattle Genetics: Consultancy, Honoraria, Research Funding; Cell Medica: Consultancy; Merck: Research Funding; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; ADC Therapeutics: Consultancy; Merck: Research Funding; Cell Medica: Consultancy; Cell Medica: Consultancy; ADC Therapeutics: Consultancy; Incyte: Research Funding; Takeda Pharmaceuticals: Consultancy; Seattle Genetics: Consultancy, Honoraria, Research Funding; Cell Medica: Consultancy; Cell Medica: Consultancy; miRagen Therapeutics Inc: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; miRagen Therapeutics Inc: Consultancy, Research Funding; Erytech Pharma: Consultancy; miRagen Therapeutics Inc: Consultancy, Research Funding; Incyte: Research Funding; Incyte: Research Funding; miRagen Therapeutics Inc: Consultancy, Research Funding; miRagen Therapeutics Inc: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Merck: Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; ADC Therapeutics: Consultancy; Merck: Research Funding; ADC Therapeutics: Consultancy; Bristol-Myers Squibb: Consultancy, Research Funding; Merck: Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Cell Medica: Consultancy; Seattle Genetics: Consultancy, Honoraria, Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Incyte: Research Funding; Takeda Pharmaceuticals: Consultancy; Takeda Pharmaceuticals: Consultancy; Cell Medica: Consultancy; Cell Medica: Consultancy; Cell Medica: Consultancy; Incyte: Research Funding; Incyte: Research Funding; Erytech Pharma: Consultancy; ADC Therapeutics: Consultancy; Erytech Pharma: Consultancy; Erytech Pharma: Consultancy; Erytech Pharma: Consultancy; Bristol-Myers Squibb: Consultancy, Research Funding; Erytech Pharma: Consultancy; Erytech Pharma: Consultancy; Seattle Genetics: Consultancy, Honoraria, Research Funding; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Merck: Research Funding; Takeda Pharmaceuticals: Consultancy; Merck: Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Merck: Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; miRagen Therapeutics Inc: Consultancy, Research Funding; Incyte: Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Merck: Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; miRagen Therapeutics Inc: Consultancy, Research Funding; ADC Therapeutics: Consultancy; miRagen Therapeutics Inc: Consultancy, Research Funding; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Takeda Pharmaceuticals: Consultancy; Takeda Pharmaceuticals: Consultancy; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Takeda Pharmaceuticals: Consultancy; ADC Therapeutics: Consultancy; ADC Therapeutics: Consultancy; Incyte: Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; ADC Therapeutics: Consultancy; Incyte: Research Funding; Cell Medica: Consultancy; Incyte: Research Funding; Takeda Pharmaceuticals: Consultancy; Incyte: Research Funding; Takeda Pharmaceuticals: Consultancy; Takeda Pharmaceuticals: Consultancy; Takeda Pharmaceuticals: Consultancy; Cell Medica: Consultancy; Cell Medica: Consultancy; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Cell Medica: Consultancy; miRagen Therapeutics Inc: Consultancy, Research Funding; miRagen Therapeutics Inc: Consultancy, Research Funding; Takeda Pharmaceuticals: Consultancy; Incyte: Research Funding; miRagen Therapeutics Inc: Consultancy, Research Funding; Erytech Pharma: Consultancy; miRagen Therapeutics Inc: Consultancy, Research Funding; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Merck: Research Funding; miRagen Therapeutics Inc: Consultancy, Research Funding; Incyte: Research Funding; miRagen Therapeutics Inc: Consultancy, Research Funding; Incyte: Research Funding; Takeda Pharmaceuticals: Consultancy; ADC Therapeutics: Consultancy; ADC Therapeutics: Consultancy; ADC Therapeutics: Consultancy; Erytech Pharma: Consultancy; Seattle Genetics: Consultancy, Honoraria, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Merck: Research Funding; Merck: Research Funding; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding. Wells:Takeda Pharmaceuticals Australia Pty Limited: Membership on an entity's Board of Directors or advisory committees; MSD Australia: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Akilov:Trillium Therapeutics: Consultancy, Other: PI on the clinical trials, Research Funding; Pfizer: Research Funding. Cowan:Kyowa Kirin: Consultancy. Dummer:Merck Sharp & Dohme: Other: Intermittent, project focused consulting and/or advisory relationships; Novartis: Other: Intermittent, project focused consulting and/or advisory relationships; Bristol-Myers Squibb: Other: Intermittent, project focused consulting and/or advisory relationships; Roche: Other: Intermittent, project focused consulting and/or advisory relationships; Amgen: Other: Intermittent, project focused consulting and/or advisory relationships; Takeda: Other: Intermittent, project focused consulting and/or advisory relationships; Pierre Fabre: Other: Intermittent, project focused consulting and/or advisory relationships; Sun Pharma: Other: Intermittent, project focused consulting and/or advisory relationships; Sanofi: Other: Intermittent, project focused consulting and/or advisory relationships; Catalym: Other: Intermittent, project focused consulting and/or advisory relationships; Second Genome: Other: Intermittent, project focused consulting and/or advisory relationships. Lechowicz:Kyowa Kirin Inc: Consultancy; Spectrum: Consultancy. Foss:Eisai: Consultancy; Seattle Genetics: Consultancy, Other: fees for non-CME/CE services ; miRagen: Consultancy; Acrotech: Consultancy; Mallinckrodt: Consultancy; Spectrum: Other: fees for non-CME/CE services . Wilcox:University of Michigan: Employment. Porcu:Innate Pharma: Honoraria, Other: Scientific Board, Research Funding; Viracta: Honoraria, Other: Scientific Board, Research Funding; BeiGene: Other: Scientific Board, Research Funding; Incyte: Research Funding; Daiichi: Research Funding; Kyowa: Honoraria, Other: Scientific Board, Research Funding; ADCT: Research Funding; Spectrum: Consultancy. Vermeer:Kyowa: Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding. Abhyankar:Therakos: Other: Consulting, Speakers Bureau; Incyte: Speakers Bureau. Pacheco:University of Colorado: Employment. William:Techspert: Consultancy; Guidepoint Global: Consultancy; Defined Health: Consultancy; Celgene Corporation: Consultancy; Kyowa Kirin, Inc.: Consultancy. Fukuhara:Kyowa-Hakko Kirin: Honoraria; Bayer: Research Funding; Mundi: Honoraria; Janssen Pharma: Honoraria; Mochida: Honoraria; Ono Pharmaceutical Co., Ltd.: Honoraria; Takeda Pharmaceutical Co., Ltd.: Honoraria, Research Funding; Chugai Pharmaceutical Co., Ltd.: Honoraria; Eisai: Honoraria, Research Funding; Celgene Corporation: Honoraria, Research Funding; Nippon Shinkyaku: Honoraria; Zenyaku: Honoraria; AbbVie: Research Funding; Gilead: Research Funding; Solasia Pharma: Research Funding. Munoz:Pharmacyclics /Janssen: Consultancy, Research Funding, Speakers Bureau; Bayer: Consultancy, Speakers Bureau; Merck: Consultancy; Kyowa: Consultancy, Honoraria, Speakers Bureau; Seattle Genetics: Consultancy, Honoraria, Research Funding, Speakers Bureau; Celgene/Juno: Consultancy, Research Funding; Genentech: Consultancy, Research Funding, Speakers Bureau; Fosunkite: Speakers Bureau; AstraZeneca: Speakers Bureau; Portola: Research Funding; Incyte: Research Funding; Kite/Gilead: Consultancy, Research Funding, Speakers Bureau; Bristol-Myers Squibb: Consultancy; Alexion: Consultancy; Pfizer: Consultancy. Querfeld:Elorac: Other: Investigator, Research Funding; Trillium: Consultancy, Other: Investigator, Research Funding; Medivir: Consultancy; miRagen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Investigator; Helsinn: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Investigator; Soligenix: Other: Investigator; City of Hope Cancer Center and Beckman Research Institute: Employment; Celgene: Other: Investigator, Research Funding; Kyowa: Membership on an entity's Board of Directors or advisory committees, Other: Investigator; Eisai: Other: Investigator; Bioniz: Membership on an entity's Board of Directors or advisory committees, Other: Investigator. Uhara:Kyowa Kirin Co., Ltd: Honoraria, Research Funding. Huen:Innate Pharmaceuticals: Research Funding; Galderma Inc: Research Funding; Rhizen Pharmaceuticals: Research Funding; Glaxo Smith Kline Inc: Research Funding. Tobinai:Meiji Seika: Honoraria; Takeda Pharmaceutical: Consultancy, Honoraria, Research Funding; Daiichi Sankyo: Consultancy, Honoraria; Janssen Pharmaceutical: Honoraria, Research Funding; Kyowa Kirin: Honoraria, Research Funding; Ono Pharmaceutical: Consultancy, Honoraria, Research Funding; Zenyaku Kogyo: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Mundi Pharma: Consultancy, Honoraria, Research Funding; Eisai: Honoraria, Research Funding; HUYA Bioscience: Consultancy, Honoraria; Bristol-Myers Squibb: Honoraria; AbbVie: Research Funding; Verastem: Honoraria; Chugai Pharmaceutical: Honoraria, Research Funding; Yakult: Honoraria; Solasia: Honoraria. Tokura:Kyowa Kirin Pharmaceutical Development, Inc.: Honoraria. Boh:Actelion: Other: Principal Investigator; Tulane University School of Medicine: Employment; Celgene: Other: Principal Investigator, Speaker, Grants; Sun: Other: Speaker; Janssen: Other: Principal Investigator, Speaker, Grants; Novartis: Other: Principal Investigator, Speaker, Grants; Soligenix: Other: Principal Investigator; Incyte: Other: Principal Investigator; Regeneron: Other: Principal Investigator, Grants; Ortho Dermatologics: Other: Speaker, Grants; Pfizer: Other: Principal Investigator; UCB: Other: Speaker, Grants; Elorac: Other: Principal Investigator; Abbvie: Other: Principal Investigator. Nicolay:Teva Pharmaceutical Industries: Honoraria, Other: Conference participation fees; Novartis AG: Consultancy, Honoraria; Biogen GmbH: Consultancy, Honoraria; Almirall Hermal AG: Consultancy, Honoraria; Actelion Pharmaceuticals: Consultancy, Honoraria; Innate Pharma: Consultancy; Kyowa Hakko Kirin: Consultancy, Honoraria; Takeda Pharmaceuticals: Consultancy. Leoni:Kyowa Kirin Pharmaceutical Development, Inc.: Employment. Ito:Kyowa Kirin Pharmaceutical Development, Inc.: Employment. Herr:Kyowa Kirin, Inc.: Employment. Sokol:EUSA: Consultancy.

INTRODUCTION Despite major clinical advancements, mantle cell lymphoma (MCL) remains a therapeutic challenge with a considerable number of patients experiencing a dismal course. We sought to map the genomic landscape of MCL at diagnosis and at disease progression. We aimed to identify genomic drivers of aggressive phenotype, resistance and relapse and to characterize the genomic evolution of this disease. METHODS We evaluated the genetic landscape of 210 MCL patients, comparing patients sequenced pretreatment (pre-Tx) to those sequenced at disease progression (POD), including 23 patients with sequential samples. We used CLIA certified targeted sequencing platforms covering 151 genes recognized in lymphoma, including single nucleotide variants (SNV) and copy number alterations (CNA). We compared clinical characteristics, histologic features, IGHV mutational status and genomic profiles between pre-Tx and POD samples. We evaluated the association between genomic features and overall survival (OS) in pre-Tx cases. RESULTS Median age was 65 (range 31-92) with a male predominance (75%, n=172). Patients sequenced at POD were characterized by a higher rate of blastoid histology (31% n=20 vs. 10% n=16, p The most prevalent genomic abnormalities (mut) seen in the entire cohort were ATM (49%, n=111); TP53 (30%, n=69); KMT2D (22%, n=51); CCND1 (16%, n=37); WHSC1 (14%, n=33); and BIRC3 (14%, n=32). Compared to pre-Tx, POD cases had higher rates of TP53mut (49% n=33 vs. 22% n=36, p There were 110 cases with IGHV data (27% n=30 mutated and 73% n=80 unmutated). Mutated IGHV was associated with a higher rate of CCND1mut (37% n=11 vs. 8% n=6, p We evaluated pathological characteristics of the sequenced tumor biopsy. Blastoid histology (219 evaluable) observed in 16% (n=36) was associated with TP53mut (61% n=22 vs. 22% n=41, p=30% (171 evaluable) was associated with TP53mut (38% n=63 vs. 9% n=6, p=60% enriched for CCND1mut (28% n=11 vs. 15% n=10 30%>= Ki67 < 60% and 9% n=6 Ki67= Ki67 < 60% and no cases with Ki67 There were 23 patients with sequential biopsies with a median time difference of 37m (IQR 18-57) between samples. pre-Tx and POD sequential samples had strikingly similar genomic alterations (figure 2). Furthermore, the mutation landscape of these pre-Tx samples was highly similar to that seen in the overall POD samples. For example, TP53mut were observed in 48% of sequential pre-Tx samples, similar to 49% seen in overall POD samples and not to the 22% seen in overall pre-Tx samples. Genomic clustering identified four distinct clusters of patients with ATMmut (BIRC3mut; KMT2Dmut; NOTCH1/CCND1 and None) a cluster of WHSC1mut and a cluster of TP53mut associated with SMARCA4mut (figure 3). Survival analysis was limited to 151 pre-Tx patients and who had completed treatment or managed expectantly (20%, n=30). With a median follow-up of 49m, TP53mut was associated with shorter OS (HR 4.15; 1.9-9.0) corresponding to a 4yOS of 63% vs. 92% in TP53wt (figure 4). In 22 patients (15%) with BIRC3mut, no deaths were observed (p=0.03). Notably, however, the rate of BIRC3mut at POD was similar to pre-Tx and not associated with superior outcomes. CONCLUSIONS Our data suggests that the ultimate outcome of MCL is driven by clones present at diagnosis and in most cases is not the result of clonal evolution. As with former studies TP53mut is the strongest driver of poor outcome. Still a considerable subset of patients fares well. BIRC3mut seemed to confer a good prognosis, however this observation needs to be validated in a dedicated study as the rate of BIRC3mut was similar between pre-Tx and POD and not associated with a better prognosis in the latter. We identify several genomic clusters associated with targetable mutations. Figure Disclosures Kumar: Seattle Genetics: Research Funding. Straus:Hope Funds for Cancer Research: Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Consultancy, Honoraria; Elsevier (PracticeUpdate): Consultancy, Honoraria. Palomba:Hemedicus: Other: Immediate Family Member, Speakers Bureau ; Merck & Co Inc.: Other: Immediate Family Member, Consultancy (includes expert testimony); Seres Therapeutics: Other: Immediate Family Member, Equity Ownership and Membership on an entity's Board of Directors or advisory committees; STRAXIMM: Other: Immediate Family Member, Membership on an entity's Board of Directors or advisory committees; Kite Pharmaceuticals: Other: Immediate Family Member, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; Noble Insights: Consultancy; Evelo: Other: Immediate family member, Equity Ownership; MSK (IP for Juno and Seres): Other: Immediate Family Member, Patents & Royalties - describe: intellectual property rights . Noy:Janssen: Consultancy; Medscape: Honoraria; Prime Oncology: Honoraria; NIH: Research Funding; Pharamcyclics: Research Funding; Raphael Pharma: Research Funding. Horwitz:Forty-Seven: Research Funding; Kura: Consultancy; Corvus Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Infinity/Verastem: Consultancy, Research Funding; Astex: Consultancy; Innate Pharma: Consultancy; Celgene: Consultancy, Research Funding; Infinity/Verastem: Consultancy, Research Funding; Kyowa Hakko Kirin: Consultancy; Mundipharma: Consultancy; Aileron: Research Funding; Millennium/Takeda: Consultancy, Research Funding; Astex: Consultancy; Astex: Consultancy; Trillium: Research Funding; Trillium: Research Funding; Infinity/Verastem: Consultancy, Research Funding; Innate Pharma: Consultancy; Kura: Consultancy; Millennium/Takeda: Consultancy, Research Funding; Millennium/Takeda: Consultancy, Research Funding; Innate Pharma: Consultancy; Seattle Genetics: Consultancy, Research Funding; Mundipharma: Consultancy; Aileron: Research Funding; ADCT Therapeutics: Research Funding; Forty-Seven: Research Funding; Affimed: Consultancy; Miragen: Consultancy; Celgene: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding; Aileron: Research Funding; ADCT Therapeutics: Research Funding; ADCT Therapeutics: Research Funding; Kura: Consultancy; Celgene: Consultancy, Research Funding; Miragen: Consultancy; Seattle Genetics: Consultancy, Research Funding; Aileron: Research Funding; Infinity/Verastem: Consultancy, Research Funding; Mundipharma: Consultancy; Miragen: Consultancy; Affimed: Consultancy; Affimed: Consultancy; Corvus Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Astex: Consultancy; Kura: Consultancy; Kyowa Hakko Kirin: Consultancy; Kyowa Hakko Kirin: Consultancy; Miragen: Consultancy; Innate Pharma: Consultancy; Forty-Seven: Research Funding; ADCT Therapeutics: Research Funding; Corvus Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Mundipharma: Consultancy; Forty-Seven: Research Funding; Affimed: Consultancy; Trillium: Research Funding; Portola: Consultancy; Trillium: Research Funding; Portola: Consultancy; Kyowa Hakko Kirin: Consultancy; Millennium/Takeda: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Portola: Consultancy; Portola: Consultancy; Seattle Genetics: Consultancy, Research Funding; Corvus Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Moskowitz:miRagen Therapeutics Inc: Consultancy, Research Funding; miRagen Therapeutics Inc: Consultancy, Research Funding; Cell Medica: Consultancy; Merck: Research Funding; Cell Medica: Consultancy; ADC Therapeutics: Consultancy; Erytech Pharma: Consultancy; ADC Therapeutics: Consultancy; Erytech Pharma: Consultancy; ADC Therapeutics: Consultancy; Seattle Genetics: Consultancy, Honoraria, Research Funding; Takeda Pharmaceuticals: Consultancy; Takeda Pharmaceuticals: Consultancy; Seattle Genetics: Consultancy, Honoraria, Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Merck: Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Incyte: Research Funding; Cell Medica: Consultancy; Cell Medica: Consultancy; Cell Medica: Consultancy; Cell Medica: Consultancy; Cell Medica: Consultancy; Bristol-Myers Squibb: Consultancy, Research Funding; Takeda Pharmaceuticals: Consultancy; ADC Therapeutics: Consultancy; Erytech Pharma: Consultancy; Erytech Pharma: Consultancy; miRagen Therapeutics Inc: Consultancy, Research Funding; ADC Therapeutics: Consultancy; ADC Therapeutics: Consultancy; Bristol-Myers Squibb: Consultancy, Research Funding; miRagen Therapeutics Inc: Consultancy, Research Funding; Incyte: Research Funding; Takeda Pharmaceuticals: Consultancy; Takeda Pharmaceuticals: Consultancy; Takeda Pharmaceuticals: Consultancy; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Cell Medica: Consultancy; Seattle Genetics: Consultancy, Honoraria, Research Funding; Takeda Pharmaceuticals: Consultancy; miRagen Therapeutics Inc: Consultancy, Research Funding; Incyte: Research Funding; Merck: Research Funding; Takeda Pharmaceuticals: Consultancy; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Incyte: Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Takeda Pharmaceuticals: Consultancy; Bristol-Myers Squibb: Consultancy, Research Funding; miRagen Therapeutics Inc: Consultancy, Research Funding; ADC Therapeutics: Consultancy; ADC Therapeutics: Consultancy; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Incyte: Research Funding; ADC Therapeutics: Consultancy; ADC Therapeutics: Consultancy; Bristol-Myers Squibb: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; miRagen Therapeutics Inc: Consultancy, Research Funding; ADC Therapeutics: Consultancy; Takeda Pharmaceuticals: Consultancy; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Merck: Research Funding; Incyte: Research Funding; Cell Medica: Consultancy; ADC Therapeutics: Consultancy; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Cell Medica: Consultancy; Seattle Genetics: Consultancy, Honoraria, Research Funding; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Erytech Pharma: Consultancy; Erytech Pharma: Consultancy; Erytech Pharma: Consultancy; Erytech Pharma: Consultancy; Bristol-Myers Squibb: Consultancy, Research Funding; Incyte: Research Funding; Incyte: Research Funding; miRagen Therapeutics Inc: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Incyte: Research Funding; miRagen Therapeutics Inc: Consultancy, Research Funding; Incyte: Research Funding; Incyte: Research Funding; miRagen Therapeutics Inc: Consultancy, Research Funding; Cell Medica: Consultancy; Cell Medica: Consultancy; Cell Medica: Consultancy; Incyte: Research Funding; Incyte: Research Funding; Takeda Pharmaceuticals: Consultancy; miRagen Therapeutics Inc: Consultancy, Research Funding; Takeda Pharmaceuticals: Consultancy; Takeda Pharmaceuticals: Consultancy; Cell Medica: Consultancy; miRagen Therapeutics Inc: Consultancy, Research Funding; Erytech Pharma: Consultancy; Bristol-Myers Squibb: Consultancy, Research Funding; Incyte: Research Funding; miRagen Therapeutics Inc: Consultancy, Research Funding; miRagen Therapeutics Inc: Consultancy, Research Funding; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Merck: Research Funding; Merck: Research Funding; Merck: Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; miRagen Therapeutics Inc: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Merck: Research Funding; Merck: Research Funding; Merck: Research Funding; Erytech Pharma: Consultancy; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Merck: Research Funding; Merck: Research Funding; Merck: Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Merck: Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Erytech Pharma: Consultancy; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Erytech Pharma: Consultancy; Takeda Pharmaceuticals: Consultancy; Bristol-Myers Squibb: Consultancy, Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Incyte: Research Funding; Erytech Pharma: Consultancy; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; ADC Therapeutics: Consultancy; Erytech Pharma: Consultancy; Erytech Pharma: Consultancy; Merck: Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Cell Medica: Consultancy; ADC Therapeutics: Consultancy; ADC Therapeutics: Consultancy; Takeda Pharmaceuticals: Consultancy. Matasar:Bayer: Other: Travel, accommodation, expenses; Janssen: Honoraria, Research Funding; Pharmacyclics: Consultancy, Honoraria, Research Funding; GlaxoSmithKline: Honoraria, Research Funding; Daiichi Sankyo: Consultancy; Seattle Genetics: Consultancy, Honoraria, Other: Travel, accomodation, expenses, Research Funding; Rocket Medical: Consultancy, Research Funding; Teva: Consultancy; Merck: Consultancy, Equity Ownership; Juno Therapeutics: Consultancy; Roche: Consultancy, Honoraria, Other: Travel, accommodation, expenses , Research Funding; Bayer: Consultancy, Honoraria, Other; Genentech, Inc.: Consultancy, Honoraria, Other: Travel, accommodation, expenses , Research Funding. Batlevi:Juno Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees. von Keudell:Genentech: Consultancy; Bayer: Consultancy; Pharmacyclics: Consultancy; Pharmacyclics: Consultancy; Genentech: Consultancy; Bayer: Consultancy. Dogan:Takeda: Consultancy; Novartis: Consultancy; Celgene: Consultancy; Seattle Genetics: Consultancy; Corvus Pharmaceuticals: Consultancy; Roche: Consultancy, Research Funding. Younes:Janssen: Honoraria, Research Funding; Roche: Consultancy, Honoraria, Research Funding; Abbvie: Honoraria; Takeda: Honoraria; Pharmacyclics: Research Funding; AstraZeneca: Research Funding; Genentech: Research Funding; HCM: Consultancy; BMS: Research Funding; Syndax: Research Funding; Merck: Honoraria, Research Funding; Curis: Honoraria, Research Funding; Epizyme: Consultancy, Honoraria; Xynomics: Consultancy; Celgene: Consultancy, Honoraria; Biopath: Consultancy. Zelenetz:Genentech/Roche: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Karyopharm: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Karyopharm: Consultancy, Membership on an entity's Board of Directors or advisory committees; MEI Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; Morphosys: Consultancy, Membership on an entity's Board of Directors or advisory committees; Verastem: Consultancy, Membership on an entity's Board of Directors or advisory committees; DAVA Oncology: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics/AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Astra-Zeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics/AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Beigene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Morphosys: Consultancy, Membership on an entity's Board of Directors or advisory committees; Beigene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bayer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; MEI Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; Astra-Zeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; DAVA Oncology: Consultancy, Membership on an entity's Board of Directors or advisory committees; Genentech/Roche: Consultancy, Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bayer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Verastem: Consultancy, Membership on an entity's Board of Directors or advisory committees.

Bronchial-associated lymphoid tissue lymphoma (BALT) is a rare subtype of extranodal marginal zone lymphoma that is often diagnosed incidentally, without symptoms or compromise of pulmonary function. It usually progresses slowly . However, in contrast to other subtypes, oncologists may feel compelled to initiate treatment at the time of diagnosis, because of concern for progression resulting in irreversible lung damage. It is unclear, in many cases, whether the morbidity of treatment would be greater than that of the lymphoma itself. To address this issue, we compared patients with BALT initially managed expectantly to those receiving front-line treatment. A retrospective single institutional review of newly diagnosed primary BALT treated at Memorial Sloan Kettering Cancer Center between 1995 and 2017 was performed. Patients with evidence of extra-thoracic disease (except for isolated bone marrow involvement) and those with concurrent malignancy were excluded. Expectant management (active surveillance) was defined as a management plan of observation rather than treatment at diagnosis and at least 3 months of follow-up from completion of all diagnostic workup until initiation of subsequent therapy if necessary. Surgical Resection referred to complete resection of all disease lesions for diagnosis. Overall (OS) and event-free survival (EFS) were determined from diagnosis as time to treatment or death of any cause, among patients with surgical resection, active surveillance, and time-to-next treatment among those treated at diagnosis with systemic immuno/chemo-immunotherapy (systemic treatment). Medical records of 200 consecutive patients with MZL involving the lung were reviewed, and 127 met the criteria for primary BALT. Of the remaining 73 patients, 25 had concurrent malignancy and 48 had extra-thoracic disease. Nearly half (48%; n=61) had initial active surveillance, 40% (n=51) surgical resection, and 12% (n=15) systemic treatment at diagnosis. Median age was 65 years (IQR 54-74). Females predominated (64%, n=81). Rates of current or prior smoking (61%; n=78) and of autoimmune/connective tissue disease (20%; n=26) were high. Nearly half of the cases with concurrent cancers were primary carcinomas of the lung (n=11). Most patients presented with a single lesion (76%; n=96) with median size 2.5 cm (IQR 1.6-3.6) and without lobar predominance. A minority (5.5%; n=7) presented with thoracic nodal involvement, while 25% (n=32) presented with pleural involvement or effusion. Overall, few patients had bone marrow involvement, B symptoms, cytopenia or elevated LDH. With a median follow-up of over 60 months (IQR 25 - 107), estimated 6-year OS for the entire cohort was 92% (0.86, 0.98). Notably, high survival rates were found in all 3 groups (Figure 1). Estimated 6-year survivals were 88% (0.77,1.00) for patients with disease remaining after biopsy managed by active surveillance, 100% with initial complete diagnostic excision (surgical resection) and 78% (0.59, 1.00) for those with initial systemic treatment who likely had extensive initial disease and/or symptoms. Active surveillance patients had a shorter EFS than surgical resection patients but not than systemic treatment patients (6yEFS 63% vs. 74% vs. 57%, respectively; p=0.006). Estimated 6-year EFS (survival without treatment) of patients initially managed by active surveillance was 63% (95% CI 0.5-0.8), and 12% required only a single line of therapy (6yEFS2 85%; 95% CI 0.7-1.0). In conclusion, BALT is an indolent disease in most patients that can be managed expectantly and may not require therapy for many years. Slightly better survival in patients with fully resected disease could represent a selection bias of earlier detection or biologically less active disease. Initial observation of the pace of the disease in asymptomatic patients may clarify the minority who require treatment and avoid or delay its potential risks in the majority. Figure 1 Disclosures Rajeeve: ASH-HONORS Grant: Research Funding. Zelenetz:Verastem: Consultancy, Membership on an entity's Board of Directors or advisory committees; DAVA Oncology: Consultancy, Membership on an entity's Board of Directors or advisory committees; DAVA Oncology: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Morphosys: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics/AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Verastem: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bayer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Astra-Zeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bayer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Beigene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Beigene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees; Karyopharm: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Genentech/Roche: Consultancy, Membership on an entity's Board of Directors or advisory committees; Genentech/Roche: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics/AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; MEI Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; MEI Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Astra-Zeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees; Karyopharm: Consultancy, Membership on an entity's Board of Directors or advisory committees; Morphosys: Consultancy, Membership on an entity's Board of Directors or advisory committees. Palomba:STRAXIMM: Membership on an entity's Board of Directors or advisory committees; Evelo: Equity Ownership; Kite Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Seres Therapeutics: Equity Ownership; Noble Insights: Consultancy; Merck & Co Inc.: Consultancy; MSK (IP for Juno and Seres): Patents & Royalties; Hemedicus: Speakers Bureau; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees. Moskowitz:Pharmacyclics: Research Funding; Seattle Genetics, Inc.: Consultancy, Research Funding; Merck: Consultancy, Research Funding; ADC Therapeutics: Research Funding; Celgene: Consultancy; Genentech: Consultancy, Research Funding. Noy:Medscape: Honoraria; Prime Oncology: Honoraria; NIH: Research Funding; Janssen: Consultancy; Pharamcyclics: Research Funding; Raphael Pharma: Research Funding. Horwitz:Mundipharma: Consultancy; Celgene: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Innate Pharma: Consultancy; Portola: Consultancy; Celgene: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding; Affimed: Consultancy; Affimed: Consultancy; Kyowa Hakko Kirin: Consultancy; Millennium/Takeda: Consultancy, Research Funding; Millennium/Takeda: Consultancy, Research Funding; Infinity/Verastem: Consultancy, Research Funding; Kura: Consultancy; Forty-Seven: Research Funding; Trillium: Research Funding; Mundipharma: Consultancy; Affimed: Consultancy; Kyowa Hakko Kirin: Consultancy; ADCT Therapeutics: Research Funding; Miragen: Consultancy; Trillium: Research Funding; Forty-Seven: Research Funding; Infinity/Verastem: Consultancy, Research Funding; Astex: Consultancy; Portola: Consultancy; Mundipharma: Consultancy; Mundipharma: Consultancy; Corvus Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Corvus Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Astex: Consultancy; Kyowa Hakko Kirin: Consultancy; Seattle Genetics: Consultancy, Research Funding; ADCT Therapeutics: Research Funding; Millennium/Takeda: Consultancy, Research Funding; Astex: Consultancy; Portola: Consultancy; Kura: Consultancy; Innate Pharma: Consultancy; Kura: Consultancy; Miragen: Consultancy; Seattle Genetics: Consultancy, Research Funding; Aileron: Research Funding; ADCT Therapeutics: Research Funding; ADCT Therapeutics: Research Funding; Infinity/Verastem: Consultancy, Research Funding; Corvus Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Kyowa Hakko Kirin: Consultancy; Miragen: Consultancy; Portola: Consultancy; Trillium: Research Funding; Seattle Genetics: Consultancy, Research Funding; Aileron: Research Funding; Forty-Seven: Research Funding; Aileron: Research Funding; Kura: Consultancy; Aileron: Research Funding; Miragen: Consultancy; Corvus Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Affimed: Consultancy; Innate Pharma: Consultancy; Astex: Consultancy; Forty-Seven: Research Funding; Innate Pharma: Consultancy; Millennium/Takeda: Consultancy, Research Funding; Infinity/Verastem: Consultancy, Research Funding; Trillium: Research Funding. Moskowitz:Incyte: Research Funding; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Incyte: Research Funding; Merck: Research Funding; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Incyte: Research Funding; Incyte: Research Funding; Cell Medica: Consultancy; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Merck: Research Funding; Merck: Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Merck: Research Funding; miRagen Therapeutics Inc: Consultancy, Research Funding; miRagen Therapeutics Inc: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; miRagen Therapeutics Inc: Consultancy, Research Funding; miRagen Therapeutics Inc: Consultancy, Research Funding; miRagen Therapeutics Inc: Consultancy, Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Incyte: Research Funding; Cell Medica: Consultancy; Cell Medica: Consultancy; miRagen Therapeutics Inc: Consultancy, Research Funding; Erytech Pharma: Consultancy; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Cell Medica: Consultancy; Merck: Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Erytech Pharma: Consultancy; Merck: Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Takeda Pharmaceuticals: Consultancy; Merck: Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Merck: Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Merck: Research Funding; Merck: Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Merck: Research Funding; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Merck: Research Funding; Merck: Research Funding; Erytech Pharma: Consultancy; ADC Therapeutics: Consultancy; Seattle Genetics: Consultancy, Honoraria, Research Funding; miRagen Therapeutics Inc: Consultancy, Research Funding; Incyte: Research Funding; Takeda Pharmaceuticals: Consultancy; Incyte: Research Funding; Cell Medica: Consultancy; Incyte: Research Funding; Cell Medica: Consultancy; miRagen Therapeutics Inc: Consultancy, Research Funding; Incyte: Research Funding; Cell Medica: Consultancy; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Erytech Pharma: Consultancy; Incyte: Research Funding; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Erytech Pharma: Consultancy; Erytech Pharma: Consultancy; ADC Therapeutics: Consultancy; ADC Therapeutics: Consultancy; ADC Therapeutics: Consultancy; Bristol-Myers Squibb: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Cell Medica: Consultancy; ADC Therapeutics: Consultancy; ADC Therapeutics: Consultancy; Incyte: Research Funding; Incyte: Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; miRagen Therapeutics Inc: Consultancy, Research Funding; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Erytech Pharma: Consultancy; Bristol-Myers Squibb: Consultancy, Research Funding; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Incyte: Research Funding; ADC Therapeutics: Consultancy; ADC Therapeutics: Consultancy; Erytech Pharma: Consultancy; Erytech Pharma: Consultancy; Bristol-Myers Squibb: Consultancy, Research Funding; Erytech Pharma: Consultancy; Erytech Pharma: Consultancy; ADC Therapeutics: Consultancy; Cell Medica: Consultancy; miRagen Therapeutics Inc: Consultancy, Research Funding; Merck: Research Funding; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; ADC Therapeutics: Consultancy; Bristol-Myers Squibb: Consultancy, Research Funding; miRagen Therapeutics Inc: Consultancy, Research Funding; Erytech Pharma: Consultancy; ADC Therapeutics: Consultancy; miRagen Therapeutics Inc: Consultancy, Research Funding; Takeda Pharmaceuticals: Consultancy; Takeda Pharmaceuticals: Consultancy; Cell Medica: Consultancy; ADC Therapeutics: Consultancy; ADC Therapeutics: Consultancy; miRagen Therapeutics Inc: Consultancy, Research Funding; Incyte: Research Funding; miRagen Therapeutics Inc: Consultancy, Research Funding; Takeda Pharmaceuticals: Consultancy; Incyte: Research Funding; Takeda Pharmaceuticals: Consultancy; Cell Medica: Consultancy; Cell Medica: Consultancy; Takeda Pharmaceuticals: Consultancy; Takeda Pharmaceuticals: Consultancy; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Erytech Pharma: Consultancy; Takeda Pharmaceuticals: Consultancy; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Cell Medica: Consultancy; Cell Medica: Consultancy; Cell Medica: Consultancy; Takeda Pharmaceuticals: Consultancy; Seattle Genetics: Consultancy, Honoraria, Research Funding; ADC Therapeutics: Consultancy; ADC Therapeutics: Consultancy; Bristol-Myers Squibb: Consultancy, Research Funding; Takeda Pharmaceuticals: Consultancy; Takeda Pharmaceuticals: Consultancy; miRagen Therapeutics Inc: Consultancy, Research Funding; Takeda Pharmaceuticals: Consultancy; Takeda Pharmaceuticals: Consultancy; Bristol-Myers Squibb: Consultancy, Research Funding; Merck: Research Funding; Erytech Pharma: Consultancy; Erytech Pharma: Consultancy; Bristol-Myers Squibb: Consultancy, Research Funding; Takeda Pharmaceuticals: Consultancy; Bristol-Myers Squibb: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding. Matasar:GlaxoSmithKline: Honoraria, Research Funding; Teva: Consultancy; Juno Therapeutics: Consultancy; Merck: Consultancy, Equity Ownership; Roche: Consultancy, Honoraria, Other: Travel, accommodation, expenses , Research Funding; Genentech, Inc.: Consultancy, Honoraria, Other: Travel, accommodation, expenses , Research Funding; Bayer: Consultancy, Honoraria, Other; Daiichi Sankyo: Consultancy; Seattle Genetics: Consultancy, Honoraria, Other: Travel, accomodation, expenses, Research Funding; Rocket Medical: Consultancy, Research Funding; Bayer: Other: Travel, accommodation, expenses; Janssen: Honoraria, Research Funding; Pharmacyclics: Consultancy, Honoraria, Research Funding. Kumar:Seattle Genetics: Research Funding. von Keudell:Bayer: Consultancy; Bayer: Consultancy; Pharmacyclics: Consultancy; Pharmacyclics: Consultancy; Genentech: Consultancy; Genentech: Consultancy. Batlevi:Juno Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees. Younes:Syndax: Research Funding; BMS: Research Funding; Celgene: Consultancy, Honoraria; AstraZeneca: Research Funding; Pharmacyclics: Research Funding; Takeda: Honoraria; Abbvie: Honoraria; HCM: Consultancy; Biopath: Consultancy; Xynomics: Consultancy; Epizyme: Consultancy, Honoraria; Roche: Consultancy, Honoraria, Research Funding; Merck: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Curis: Honoraria, Research Funding; Genentech: Research Funding. Straus:Seattle Genetics: Consultancy, Honoraria; Elsevier (PracticeUpdate): Consultancy, Honoraria; Hope Funds for Cancer Research: Membership on an entity's Board of Directors or advisory committees.

Introduction: The standard therapy for early stage, unfavorable risk Hodgkin lymphoma (HL) with disease bulk is combined modality therapy, typically 4-6 cycles of ABVD followed by 30Gy involved-site radiotherapy (ISRT) (Eich JCO 2010). In this pilot study with four sequential cohorts, we studied whether consolidative radiotherapy could be reduced or eliminated in early stage, unfavorable risk HL patients treated with brentuximab vedotin (BV) and AVD chemotherapy. In the first cohort, we demonstrated that BV+AVD and 30Gy ISRT had an acceptable safety profile without significant pulmonary toxicity and promising efficacy (Kumar Blood 2016). In subsequent cohorts, we tested whether the ISRT dose could be reduced to 20Gy (cohort 2), the RT field could be reduced with consolidation volume radiation (CVRT; cohort 3), and whether radiation therapy could be eliminated (cohort 4). Methods: Patients received 4 cycles of BV 1.2 mg/kg with AVD chemotherapy every 2 weeks, followed by 30 Gy ISRT in cohort 1, 20Gy ISRT in cohort 2, 30 Gy CVRT in cohort 3, and no radiotherapy in cohort 4. CVRT targets PET-negative residual masses greater than 1.5cm on post-chemotherapy CT imaging. Eligible patients in cohorts 1-2 included untreated stage I/II, classical HL with any one of the following unfavorable risk factors: bulky disease (MSK criteria: maximal transverse or coronal diameter >7 cm on CT), elevated ESR, extranodal involvement, >2 lymph node sites, or infradiaphragmatic disease. In cohort 3-4, early stage patients with bulky disease by MSK criteria were eligible. PET/CT after 2 and 4 cycles and after ISRT were interpreted with the 5-point Deauville scale (negative=1-3). The primary endpoint of cohort 1 was to evaluate safety and tolerability of the treatment combination, with special attention to pulmonary toxicity; the primary endpoint of cohorts 2-4 was to evaluate preliminary efficacy with the rate of complete responses (CRs) at end of treatment (EOT). Results: In June 2019, the study was fully accrued with 117 patients enrolled across four cohorts. Patients had a median age of 32 (range 18-59), 98% stage II, 86% with MSK-defined disease bulk (>7cm in transverse or coronal dimension), 27% with traditionally defined bulk (>10cm in transverse dimension), 50% elevated ESR, 38% B-symptoms, 21% extranodal involvement, 56% >2 involved lymph node sites, and 3.4% infradiaphragmatic disease. 26 patients (22%) had advanced stage disease by German Hodgkin Study Group criteria: IIBX (n=16), IIBE (n=5), and IIBXE (n=6). Of the patients enrolled in cohorts 1-3 with interim PET imaging, 85% and 91% achieved a negative PET scan after 2 and 4 cycles of therapy, respectively, and 95% achieved a CR at EOT. In cohort 4, 24 of the 29 enrolled patients have completed 4 cycles of therapy. Thus far, 93% of patients achieved a negative PET-2 scan (25 of 27 patients), 77% of patients achieved a negative PET-4 scan (17 of 22 patients), and 91% achieved a CR at EOT (20 of 22 patients). The remaining two patients with equivocal PET-4 results will have repeat short-interval scans to clarify EOT response. The overall median follow-up of survivors is 29 months: 56 months for cohort 1, 38 months for cohort 2, 24 months for cohort 3, and 5 months for cohort 4. Seven events have occurred in the study thus far. In cohort 1, two patients had primary refractory disease after chemotherapy and were treated off study. In cohort 2, one patient in remission died in a motor vehicle accident and one late relapse occurred at 34 months. In cohort 3, two patients had primary refractory HL after CVRT and one relapse occurred at 9 months. Overall, the 2-year PFS is 94% (95% CI 0.90, 0.99), see Figure. Across all 4 cohorts, the BV+AVD treatment was well-tolerated; the most common toxicities were peripheral neuropathy, abdominal pain, and neutropenia that were generally mild-moderate in severity, reversible, and manageable. Conclusion: BV+AVD x 4 cycles is an active treatment program for early stage, unfavorable risk HL, including patients with bulky disease. The efficacy of BV+AVD in this setting has facilitated a safe reduction in radiation dose and field evidenced by excellent and similar outcomes across the first 3 cohorts. With substantial follow-up, 20Gy ISRT appears equivalent to 30Gy ISRT following BV+AVD. The preliminary outcomes from the final cohort with chemotherapy alone are also promising, however, follow-up is short. Updated response data will be presented at the meeting. Disclosures Kumar: Seattle Genetics: Research Funding. Casulo:Gilead: Honoraria, Other: Travel, accommodation, expenses; Roche: Other: Travel, accommodation, expenses; Celgene: Research Funding. Advani:Kyowa Kirin Pharmaceutical Developments, Inc.: Consultancy; Cell Medica, Ltd: Consultancy; Kura: Research Funding; Merck: Research Funding; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Stanford University: Employment, Equity Ownership; Seattle Genetics: Consultancy, Research Funding; Agensys: Research Funding; AstraZeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees; Autolus: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bayer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Research Funding; Infinity Pharma: Research Funding; Forty-Seven: Research Funding; Gilead Sciences, Inc./Kite Pharma, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees; Regeneron: Research Funding; Janssen: Research Funding; Millennium: Research Funding; Roche/Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celmed: Consultancy, Membership on an entity's Board of Directors or advisory committees. Budde:F. Hoffmann-La Roche Ltd: Consultancy. Barr:Janssen: Consultancy; Astra Zeneca: Consultancy, Research Funding; Verastem: Consultancy; Gilead: Consultancy; AbbVie: Consultancy; Pharmacyclics LLC, an AbbVie company: Consultancy, Research Funding; TG Therapeutics: Consultancy, Research Funding; Celgene: Consultancy; Merck: Consultancy; Seattle Genetics: Consultancy; Genentech: Consultancy. Batlevi:Juno Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees. Friedberg:Acerta: Other: Data & Safety Monitoring Committee; Bayer: Honoraria, Other: Data & Safety Monitoring Committee. Horwitz:Corvus Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Mundipharma: Consultancy; Mundipharma: Consultancy; Aileron: Research Funding; Infinity/Verastem: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding; Innate Pharma: Consultancy; Innate Pharma: Consultancy; Seattle Genetics: Consultancy, Research Funding; Millennium/Takeda: Consultancy, Research Funding; Astex: Consultancy; Infinity/Verastem: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding; Trillium: Research Funding; Celgene: Consultancy, Research Funding; Astex: Consultancy; Kyowa Hakko Kirin: Consultancy; Trillium: Research Funding; Affimed: Consultancy; Innate Pharma: Consultancy; Affimed: Consultancy; Corvus Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Miragen: Consultancy; Corvus Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Astex: Consultancy; Celgene: Consultancy, Research Funding; Infinity/Verastem: Consultancy, Research Funding; Infinity/Verastem: Consultancy, Research Funding; Innate Pharma: Consultancy; Kura: Consultancy; Kyowa Hakko Kirin: Consultancy; Kyowa Hakko Kirin: Consultancy; Millennium/Takeda: Consultancy, Research Funding; Millennium/Takeda: Consultancy, Research Funding; Affimed: Consultancy; Miragen: Consultancy; Miragen: Consultancy; Portola: Consultancy; Trillium: Research Funding; Mundipharma: Consultancy; Portola: Consultancy; Astex: Consultancy; Aileron: Research Funding; Aileron: Research Funding; Celgene: Consultancy, Research Funding; Forty-Seven: Research Funding; Trillium: Research Funding; Forty-Seven: Research Funding; Forty-Seven: Research Funding; Aileron: Research Funding; Portola: Consultancy; ADCT Therapeutics: Research Funding; Affimed: Consultancy; Mundipharma: Consultancy; ADCT Therapeutics: Research Funding; ADCT Therapeutics: Research Funding; ADCT Therapeutics: Research Funding; Portola: Consultancy; Forty-Seven: Research Funding; Miragen: Consultancy; Kura: Consultancy; Kura: Consultancy; Kura: Consultancy; Kyowa Hakko Kirin: Consultancy; Millennium/Takeda: Consultancy, Research Funding; Corvus Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding. Matasar:Genentech, Inc.: Consultancy, Honoraria, Other: Travel, accommodation, expenses , Research Funding; Bayer: Consultancy, Honoraria, Other; Roche: Consultancy, Honoraria, Other: Travel, accommodation, expenses , Research Funding; Merck: Consultancy, Equity Ownership; Juno Therapeutics: Consultancy; Teva: Consultancy; Rocket Medical: Consultancy, Research Funding; Bayer: Other: Travel, accommodation, expenses; Janssen: Honoraria, Research Funding; Pharmacyclics: Consultancy, Honoraria, Research Funding; GlaxoSmithKline: Honoraria, Research Funding; Daiichi Sankyo: Consultancy; Seattle Genetics: Consultancy, Honoraria, Other: Travel, accomodation, expenses, Research Funding. Moskowitz:Erytech Pharma: Consultancy; Erytech Pharma: Consultancy; Cell Medica: Consultancy; Cell Medica: Consultancy; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Takeda Pharmaceuticals: Consultancy; ADC Therapeutics: Consultancy; ADC Therapeutics: Consultancy; Merck: Research Funding; Takeda Pharmaceuticals: Consultancy; Erytech Pharma: Consultancy; ADC Therapeutics: Consultancy; Takeda Pharmaceuticals: Consultancy; Takeda Pharmaceuticals: Consultancy; Seattle Genetics: Consultancy, Honoraria, Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Merck: Research Funding; ADC Therapeutics: Consultancy; ADC Therapeutics: Consultancy; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Merck: Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Merck: Research Funding; Merck: Research Funding; Merck: Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Merck: Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Erytech Pharma: Consultancy; Bristol-Myers Squibb: Consultancy, Research Funding; Incyte: Research Funding; miRagen Therapeutics Inc: Consultancy, Research Funding; miRagen Therapeutics Inc: Consultancy, Research Funding; Incyte: Research Funding; miRagen Therapeutics Inc: Consultancy, Research Funding; Incyte: Research Funding; Incyte: Research Funding; Incyte: Research Funding; Incyte: Research Funding; Incyte: Research Funding; Incyte: Research Funding; miRagen Therapeutics Inc: Consultancy, Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Merck: Research Funding; Merck: Research Funding; Erytech Pharma: Consultancy; ADC Therapeutics: Consultancy; Seattle Genetics: Consultancy, Honoraria, Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Merck: Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; ADC Therapeutics: Consultancy; Takeda Pharmaceuticals: Consultancy; Seattle Genetics: Consultancy, Honoraria, Research Funding; Incyte: Research Funding; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; miRagen Therapeutics Inc: Consultancy, Research Funding; miRagen Therapeutics Inc: Consultancy, Research Funding; miRagen Therapeutics Inc: Consultancy, Research Funding; miRagen Therapeutics Inc: Consultancy, Research Funding; miRagen Therapeutics Inc: Consultancy, Research Funding; ADC Therapeutics: Consultancy; Takeda Pharmaceuticals: Consultancy; Takeda Pharmaceuticals: Consultancy; Takeda Pharmaceuticals: Consultancy; Takeda Pharmaceuticals: Consultancy; Takeda Pharmaceuticals: Consultancy; Takeda Pharmaceuticals: Consultancy; Takeda Pharmaceuticals: Consultancy; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Erytech Pharma: Consultancy; Bristol-Myers Squibb: Consultancy, Research Funding; Erytech Pharma: Consultancy; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Cell Medica: Consultancy; miRagen Therapeutics Inc: Consultancy, Research Funding; Cell Medica: Consultancy; Cell Medica: Consultancy; miRagen Therapeutics Inc: Consultancy, Research Funding; ADC Therapeutics: Consultancy; ADC Therapeutics: Consultancy; Cell Medica: Consultancy; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Takeda Pharmaceuticals: Consultancy; Cell Medica: Consultancy; Cell Medica: Consultancy; ADC Therapeutics: Consultancy; ADC Therapeutics: Consultancy; Merck: Research Funding; Erytech Pharma: Consultancy; Erytech Pharma: Consultancy; Erytech Pharma: Consultancy; Erytech Pharma: Consultancy; Cell Medica: Consultancy; Cell Medica: Consultancy; Cell Medica: Consultancy; Cell Medica: Consultancy; Cell Medica: Consultancy; Cell Medica: Consultancy; Incyte: Research Funding; Incyte: Research Funding; Incyte: Research Funding; Incyte: Research Funding; Takeda Pharmaceuticals: Consultancy; Cell Medica: Consultancy; Merck: Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Takeda Pharmaceuticals: Consultancy; Seattle Genetics: Consultancy, Honoraria, Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; miRagen Therapeutics Inc: Consultancy, Research Funding; miRagen Therapeutics Inc: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Merck: Research Funding; Erytech Pharma: Consultancy; Bristol-Myers Squibb: Consultancy, Research Funding; miRagen Therapeutics Inc: Consultancy, Research Funding; Incyte: Research Funding; Incyte: Research Funding; miRagen Therapeutics Inc: Consultancy, Research Funding; Erytech Pharma: Consultancy; ADC Therapeutics: Consultancy; Merck: Research Funding; Merck: Research Funding; Erytech Pharma: Consultancy; Erytech Pharma: Consultancy; ADC Therapeutics: Consultancy; Seattle Genetics: Consultancy, Honoraria, Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; ADC Therapeutics: Consultancy. Noy:Prime Oncology: Honoraria; NIH: Research Funding; Medscape: Honoraria; Janssen: Consultancy; Pharamcyclics: Research Funding; Raphael Pharma: Research Funding. Palomba:Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; STRAXIMM: Membership on an entity's Board of Directors or advisory committees; Kite Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Evelo: Equity Ownership; MSK (IP for Juno and Seres): Patents & Royalties; Noble Insights: Consultancy; Merck & Co Inc.: Consultancy; Seres Therapeutics: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Hemedicus: Speakers Bureau. Straus:Elsevier (PracticeUpdate): Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria; Hope Funds for Cancer Research: Membership on an entity's Board of Directors or advisory committees. Younes:Roche: Consultancy, Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Curis: Honoraria, Research Funding; Merck: Honoraria, Research Funding; Abbvie: Honoraria; Takeda: Honoraria; Pharmacyclics: Research Funding; AstraZeneca: Research Funding; Genentech: Research Funding; Biopath: Consultancy; Xynomics: Consultancy; Epizyme: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; HCM: Consultancy; BMS: Research Funding; Syndax: Research Funding. Zelenetz:Beigene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Genentech/Roche: Consultancy, Membership on an entity's Board of Directors or advisory committees; MEI Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics/AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Karyopharm: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Verastem: Consultancy, Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Morphosys: Consultancy, Membership on an entity's Board of Directors or advisory committees; Astra-Zeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees; Karyopharm: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics/AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Verastem: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Astra-Zeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees; DAVA Oncology: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bayer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Genentech/Roche: Consultancy, Membership on an entity's Board of Directors or advisory committees; Beigene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bayer: Consultancy, Membership on an entity's Board of Directors or advisory committees; MEI Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; Morphosys: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees; DAVA Oncology: Consultancy, Membership on an entity's Board of Directors or advisory committees. Moskowitz:ADC Therapeutics: Research Funding; Merck: Consultancy, Research Funding; Seattle Genetics, Inc.: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; Celgene: Consultancy; Pharmacyclics: Research Funding.

Introduction:Programmed death-1 (PD-1) inhibitors are highly active in relapsed and refractory (RR) classical Hodgkin lymphoma (cHL), however their role as part of second-line therapy (SLT) for cHL is largely unexplored. The standard approach following front-line treatment failure is SLT, aimed to achieve complete response (CR), followed by consolidation with high dose therapy and autologous stem cell transplant (HDT/ASCT). There is no one standard SLT and options include platinum-containing regimens, gemcitabine-containing regimens and more recently brentuximab vedotin (BV)-containing regimens. Due to the increasing use of BV in the front-line setting, development of SLT regimens that are both highly effective and BV-sparing are needed. In this phase II study, we aimed to establish the safety and efficacy of SLT with the PD-1 inhibitor, pembrolizumab, combined with the outpatient-administered salvage regimen, GVD (gemcitabine, vinorelbine, liposomal doxorubicin). Methods: Transplant eligible patients (pts) with RR cHL following failure of 1-line of therapy are eligible. Treatment consists of 2 to 4 cycles of pembrolizumab (200mg IV, day 1), gemcitabine (1000mg/m2 IV, days 1 and 8), vinorelbine (20mg/m2 IV, days 1 and 8) and liposomal doxorubicin (15mg/m2, days 1 and 8), given on 21-day cycles. Response is assessed by PET after 2 and 4 cycles. Pts who achieve CR by PET (Deauville ≤3) after 2 or 4 cycles proceed to HDT/ASCT. An initial safety assessment for the first 6 treated pts was completed before continuing further enrollment. We report here the results of the safety assessment and the first stage of a Simon 2-stage design. Results:To date, 18 out of a planned 39 pts enrolled; 14 completed the first 2 cycles of treatment and underwent the first response assessment. Characteristics for the 14 evaluable pts are shown in the table. In brief, median age is 36 (range 21-43), 4 (29%) have primary refractory disease and 9 (64%) relapsed within the first year of initial treatment. No dose limiting toxicities were observed during the safety assessment and no significant adverse events were observed to date. Of the 30 cycles administered, 5 (17%) cycles were delayed due to treatment related adverse events which included grade 3 rash (3%) and grade 3 liver function test abnormalities (13%). Among the 14 evaluable pts, 13 (93%) achieved CR after 2 cycles of treatment and 1 achieved partial response. To date, 3 pts are proceeding to HDT/ASCT and 11 pts completed HDT/ASCT following 2 (n=10) or 4 (n=1) cycles of treatment. Median follow-up post HDT/ASCT is 4 mos (range 0.3-8.8 mos) and all pts remain in remission to date. Conclusion:Early trial results suggest that pembrolizumab-GVD is a highly effective and well-tolerated regimen that can efficiently bridge pts with RR cHL to HDT/ASCT. Efficacy criteria for stage one of the Simon 2-stage design was met and enrollment continues to better characterize CR rate and tolerability. Disclosures Moskowitz: ADC Therapeutics: Consultancy; Seattle Genetics: Consultancy, Honoraria, Research Funding; Merck: Research Funding; Erytech Pharma: Consultancy; Takeda Pharmaceuticals: Consultancy; Takeda Pharmaceuticals: Consultancy; miRagen Therapeutics Inc: Consultancy, Research Funding; Incyte: Research Funding; miRagen Therapeutics Inc: Consultancy, Research Funding; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; miRagen Therapeutics Inc: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Cell Medica: Consultancy; miRagen Therapeutics Inc: Consultancy, Research Funding; Cell Medica: Consultancy; Bristol-Myers Squibb: Consultancy, Research Funding; miRagen Therapeutics Inc: Consultancy, Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; ADC Therapeutics: Consultancy; Bristol-Myers Squibb: Consultancy, Research Funding; Merck: Research Funding; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; ADC Therapeutics: Consultancy; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Merck: Research Funding; Cell Medica: Consultancy; Bristol-Myers Squibb: Consultancy, Research Funding; Merck: Research Funding; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Takeda Pharmaceuticals: Consultancy; ADC Therapeutics: Consultancy; Erytech Pharma: Consultancy; Seattle Genetics: Consultancy, Honoraria, Research Funding; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; miRagen Therapeutics Inc: Consultancy, Research Funding; Takeda Pharmaceuticals: Consultancy; Bristol-Myers Squibb: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Erytech Pharma: Consultancy; ADC Therapeutics: Consultancy; Bristol-Myers Squibb: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Erytech Pharma: Consultancy; Bristol-Myers Squibb: Consultancy, Research Funding; ADC Therapeutics: Consultancy; Bristol-Myers Squibb: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Erytech Pharma: Consultancy; Erytech Pharma: Consultancy; miRagen Therapeutics Inc: Consultancy, Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Takeda Pharmaceuticals: Consultancy; Cell Medica: Consultancy; Erytech Pharma: Consultancy; Cell Medica: Consultancy; Cell Medica: Consultancy; Incyte: Research Funding; miRagen Therapeutics Inc: Consultancy, Research Funding; Incyte: Research Funding; Incyte: Research Funding; Cell Medica: Consultancy; Incyte: Research Funding; miRagen Therapeutics Inc: Consultancy, Research Funding; Takeda Pharmaceuticals: Consultancy; Incyte: Research Funding; miRagen Therapeutics Inc: Consultancy, Research Funding; ADC Therapeutics: Consultancy; Takeda Pharmaceuticals: Consultancy; Merck: Research Funding; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Erytech Pharma: Consultancy; miRagen Therapeutics Inc: Consultancy, Research Funding; Erytech Pharma: Consultancy; miRagen Therapeutics Inc: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Incyte: Research Funding; Erytech Pharma: Consultancy; Seattle Genetics: Consultancy, Honoraria, Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; ADC Therapeutics: Consultancy; Cell Medica: Consultancy; Merck: Research Funding; Takeda Pharmaceuticals: Consultancy; Merck: Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Incyte: Research Funding; ADC Therapeutics: Consultancy; ADC Therapeutics: Consultancy; Erytech Pharma: Consultancy; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Merck: Research Funding; Merck: Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Erytech Pharma: Consultancy; Erytech Pharma: Consultancy; Incyte: Research Funding; Cell Medica: Consultancy; miRagen Therapeutics Inc: Consultancy, Research Funding; Cell Medica: Consultancy; Incyte: Research Funding; Cell Medica: Consultancy; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Takeda Pharmaceuticals: Consultancy; Cell Medica: Consultancy; Takeda Pharmaceuticals: Consultancy; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; ADC Therapeutics: Consultancy; Takeda Pharmaceuticals: Consultancy; Incyte: Research Funding; Takeda Pharmaceuticals: Consultancy; Takeda Pharmaceuticals: Consultancy; Cell Medica: Consultancy; Cell Medica: Consultancy; Cell Medica: Consultancy; Takeda Pharmaceuticals: Consultancy; Merck: Research Funding; miRagen Therapeutics Inc: Consultancy, Research Funding; Incyte: Research Funding; ADC Therapeutics: Consultancy; Incyte: Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Incyte: Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; miRagen Therapeutics Inc: Consultancy, Research Funding; Merck: Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; ADC Therapeutics: Consultancy; ADC Therapeutics: Consultancy; Seattle Genetics: Consultancy, Honoraria, Research Funding; Merck: Research Funding; Merck: Research Funding; Erytech Pharma: Consultancy; Incyte: Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Merck: Research Funding; Merck: Research Funding; Takeda Pharmaceuticals: Consultancy; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; ADC Therapeutics: Consultancy; Erytech Pharma: Consultancy. Shah:Amgen: Research Funding; Janssen: Research Funding. Kumar:Seattle Genetics: Research Funding. Batlevi:Juno Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees. Straus:Seattle Genetics: Consultancy, Honoraria; Elsevier (PracticeUpdate): Consultancy, Honoraria; Hope Funds for Cancer Research: Membership on an entity's Board of Directors or advisory committees. Rodriguez-Rivera:Memorial Sloan Kettering Cancer Center: Employment. Colbourn:ABBV: Other: Stock; CELG: Other: Stock; BIIB: Other: Stock; SGEN: Other: Stock; JNJ: Other: Stock; LLY: Other: Stock; GILD: Other: Stock; MRK: Other: Stock; SNY: Other: Stock. Horwitz:Corvus Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Corvus Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Kura: Consultancy; Celgene: Consultancy, Research Funding; Infinity/Verastem: Consultancy, Research Funding; Corvus Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Millennium/Takeda: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding; Affimed: Consultancy; Aileron: Research Funding; Trillium: Research Funding; ADCT Therapeutics: Research Funding; Affimed: Consultancy; Astex: Consultancy; Infinity/Verastem: Consultancy, Research Funding; Trillium: Research Funding; Astex: Consultancy; Aileron: Research Funding; Seattle Genetics: Consultancy, Research Funding; Millennium/Takeda: Consultancy, Research Funding; Kyowa Hakko Kirin: Consultancy; Infinity/Verastem: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Forty-Seven: Research Funding; Celgene: Consultancy, Research Funding; ADCT Therapeutics: Research Funding; Corvus Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Seattle Genetics: Consultancy, Research Funding; Portola: Consultancy; Forty-Seven: Research Funding; Aileron: Research Funding; Seattle Genetics: Consultancy, Research Funding; Aileron: Research Funding; Forty-Seven: Research Funding; Trillium: Research Funding; ADCT Therapeutics: Research Funding; Astex: Consultancy; Trillium: Research Funding; Forty-Seven: Research Funding; Affimed: Consultancy; ADCT Therapeutics: Research Funding; Affimed: Consultancy; Astex: Consultancy; Innate Pharma: Consultancy; Innate Pharma: Consultancy; Kyowa Hakko Kirin: Consultancy; Mundipharma: Consultancy; Innate Pharma: Consultancy; Infinity/Verastem: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Kura: Consultancy; Kyowa Hakko Kirin: Consultancy; Kura: Consultancy; Kyowa Hakko Kirin: Consultancy; Miragen: Consultancy; Millennium/Takeda: Consultancy, Research Funding; Millennium/Takeda: Consultancy, Research Funding; Mundipharma: Consultancy; Miragen: Consultancy; Miragen: Consultancy; Portola: Consultancy; Mundipharma: Consultancy; Miragen: Consultancy; Kura: Consultancy; Innate Pharma: Consultancy; Mundipharma: Consultancy; Portola: Consultancy; Portola: Consultancy. Palomba:Hemedicus: Other: Immediate Family Member, Speakers Bureau ; Merck & Co Inc.: Other: Immediate Family Member, Consultancy (includes expert testimony); Seres Therapeutics: Other: Immediate Family Member, Equity Ownership and Membership on an entity's Board of Directors or advisory committees; STRAXIMM: Other: Immediate Family Member, Membership on an entity's Board of Directors or advisory committees; Kite Pharmaceuticals: Other: Immediate Family Member, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; Noble Insights: Consultancy; Evelo: Other: Immediate family member, Equity Ownership; MSK (IP for Juno and Seres): Other: Immediate Family Member, Patents & Royalties - describe: intellectual property rights . Noy:Prime Oncology: Honoraria; NIH: Research Funding; Janssen: Consultancy; Medscape: Honoraria; Pharamcyclics: Research Funding; Raphael Pharma: Research Funding. Matasar:Genentech, Inc.: Consultancy, Honoraria, Other: Travel, accommodation, expenses , Research Funding; Daiichi Sankyo: Consultancy; Bayer: Consultancy, Honoraria, Other; Roche: Consultancy, Honoraria, Other: Travel, accommodation, expenses , Research Funding; Merck: Consultancy, Equity Ownership; Juno Therapeutics: Consultancy; Teva: Consultancy; Rocket Medical: Consultancy, Research Funding; Seattle Genetics: Consultancy, Honoraria, Other: Travel, accomodation, expenses, Research Funding; GlaxoSmithKline: Honoraria, Research Funding; Pharmacyclics: Consultancy, Honoraria, Research Funding; Bayer: Other: Travel, accommodation, expenses; Janssen: Honoraria, Research Funding. Vardhana:Rheos Pharmaceuticals: Honoraria; ADC Therapeutics: Consultancy; Agios Pharmaceuticals: Honoraria. von Keudell:Bayer: Consultancy; Pharmacyclics: Consultancy; Pharmacyclics: Consultancy; Genentech: Consultancy; Genentech: Consultancy; Bayer: Consultancy. Younes:Roche: Consultancy, Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Curis: Honoraria, Research Funding; Merck: Honoraria, Research Funding; Abbvie: Honoraria; Takeda: Honoraria; Pharmacyclics: Research Funding; AstraZeneca: Research Funding; Genentech: Research Funding; Biopath: Consultancy; Xynomics: Consultancy; Epizyme: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; HCM: Consultancy; BMS: Research Funding; Syndax: Research Funding. Zelenetz:Karyopharm: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Karyopharm: Consultancy, Membership on an entity's Board of Directors or advisory committees; MEI Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics/AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; DAVA Oncology: Consultancy, Membership on an entity's Board of Directors or advisory committees; Genentech/Roche: Consultancy, Membership on an entity's Board of Directors or advisory committees; Verastem: Consultancy, Membership on an entity's Board of Directors or advisory committees; Beigene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Verastem: Consultancy, Membership on an entity's Board of Directors or advisory committees; Beigene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Morphosys: Consultancy, Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees; Genentech/Roche: Consultancy, Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Morphosys: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bayer: Consultancy, Membership on an entity's Board of Directors or advisory committees; DAVA Oncology: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics/AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Astra-Zeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Astra-Zeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees; MEI Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bayer: Consultancy, Membership on an entity's Board of Directors or advisory committees. Moskowitz:Genentech: Consultancy, Research Funding; Seattle Genetics, Inc.: Consultancy, Research Funding; Celgene: Consultancy; Pharmacyclics: Research Funding; ADC Therapeutics: Research Funding; Merck: Consultancy, Research Funding. OffLabel Disclosure: Pembrolizumab is not approved for second-line use for classical Hodgkin lymphoma.

Introduction Brentuximab vedotin (BV) targets CD30, a receptor expressed on the Reed-Sternberg cells of classic Hodgkin lymphoma (cHL). Nivolumab (Nivo) restores antitumor immunity by blocking the PD-1 receptor on activated T-cells. In this phase 1/2 study, combination treatment (tx) with BV + Nivo demonstrated durable efficacy in patients (pts) with relapsed/refractory (R/R) cHL (Herrera, Blood 2018; NCT02572167). Biomarkers consistent with innate and adaptive immune activation were observed in the peripheral blood of pts treated with the combination regimen. Herein, we associate biomarkers in the peripheral blood with clinical response, and present follow-up results for pts who received BV + Nivo under staggered and concurrent dosing schedules. Methods Enrolled pts had cHL that relapsed or was refractory to frontline chemotherapy. In Parts 1 and 2 (staggered dosing), pts received up to 4 cycles of BV 1.8 mg/kg and Nivo 3.0 mg/kg given on Days 1 and 8 of Cycle 1, respectively, and together on Day 1 of Cycles 2-4. Pts in Part 3 (concurrent dosing) received the same dose of both agents on Day 1 of all 4 cycles. After investigators assessed response (Cheson 2014, with the incorporation of LYRIC [Cheson 2016] for pts in Part 3), pts could undergo ASCT. Results Demographics and baseline characteristics were similar across all treated pts (N=91) in the staggered and concurrent dosing cohorts; median age 34 years (yrs, range; 18-69), 42% with primary refractory disease, and 30% with relapse within 1 yr of frontline therapy. All 91 pts are off-tx and have been observed through the 100-day safety reporting period. A total of 86 pts (92%) completed all 4 cycles of BV + Nivo. Early tx discontinuations were due to; AE (peripheral neuropathy and increased GGT [1 pt each]), progressive disease (PD), investigator decision, and pt decision (1 pt each). Most common AEs prior to ASCT or additional salvage therapy were nausea (52%) and infusion-related reactions (IRRs, 43%). Excluding IRRs, 14% of pts had immune-related AEs requiring tx with systemic steroids, including rash (8%), pneumonitis (4%), and AST increased, diarrhea, and Guillain-Barre syndrome (1% each). The ORR for all-treated pts was 85%, with 67% complete response (CR). A total of 67 pts (74%) underwent ASCT after tx with BV + Nivo. There were 22 pts who received additional salvage therapy after BV + Nivo (7 PD, 6 partial response, 5 stable disease, and 4 CR at EOT), 17 of whom later underwent ASCT. At a median of 22.6 months (range; 1.2, 41.2) from the start of tx, the estimated 2-yr PFS rate in all treated pts was 78%, and for pts who underwent ASCT after tx with BV + Nivo was 91% (Figure 1). At 2 years, the estimated OS rate for all treated pts was 93%. Staggered and concurrent dosing of BV + Nivo resulted in increased levels of activated and dividing CD4+ T cells, activated and dividing CD8+ T cells (concurrent dosing-only), regulatory T cells (Tregs), and circulating plasmablasts in blood. We did not observe any associations between the magnitude of these changes and clinical response. Pts with CR exhibited trends for higher pre-tx blood levels of CD30+ Tregs and CD30+ Th subsets compared to pts without CR, suggesting BV depletion of these populations may have a role in the clinical mode of action of BV + Nivo. Although pre-tx levels of cytotoxic lymphocytes (CTLs) in blood did not differentiate pts with CR from other pts, pts in the lower quartile of pre-tx CTL levels showed significantly shorter PFS than other pts, suggesting a potential association between CTLs and disease control. Changes in blood cytokine and chemokine levels were observed after BV + Nivo, including increased levels of IL-18, IP-10, I-TAC, and sCD30, and decreased levels of TARC, IL-2Ra, and IL-6. Our analyses support strong correlations between pre-tx cytokine/chemokine levels and clinical benefit including trends linking lower pre-tx levels of IL-18, I-TAC, and IL-2RA to achieving CR and longer PFS. Conclusion BV + Nivo, both staggered and current dosing, showed tolerability and high CR rates with durable remissions among pts with R/R cHL. Analysis of blood biomarkers identified trends potentially linking baseline levels of CD30+ immune cells and the baseline pt inflammatory state with the activity of BV + Nivo. Together, these encouraging results support further investigation of BV + Nivo as initial salvage therapy in pts with R/R cHL. Figure 1 Disclosures Moskowitz: Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Erytech Pharma: Consultancy; Erytech Pharma: Consultancy; ADC Therapeutics: Consultancy; Merck: Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Merck: Research Funding; Merck: Research Funding; Cell Medica: Consultancy; Takeda Pharmaceuticals: Consultancy; Merck: Research Funding; ADC Therapeutics: Consultancy; Bristol-Myers Squibb: Consultancy, Research Funding; Erytech Pharma: Consultancy; Takeda Pharmaceuticals: Consultancy; Incyte: Research Funding; Merck: Research Funding; Merck: Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Cell Medica: Consultancy; Takeda Pharmaceuticals: Consultancy; Cell Medica: Consultancy; ADC Therapeutics: Consultancy; Incyte: Research Funding; Takeda Pharmaceuticals: Consultancy; Takeda Pharmaceuticals: Consultancy; Merck: Research Funding; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Cell Medica: Consultancy; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Takeda Pharmaceuticals: Consultancy; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Cell Medica: Consultancy; miRagen Therapeutics Inc: Consultancy, Research Funding; Incyte: Research Funding; Takeda Pharmaceuticals: Consultancy; Seattle Genetics: Consultancy, Honoraria, Research Funding; Takeda Pharmaceuticals: Consultancy; Cell Medica: Consultancy; ADC Therapeutics: Consultancy; Erytech Pharma: Consultancy; Erytech Pharma: Consultancy; Erytech Pharma: Consultancy; Bristol-Myers Squibb: Consultancy, Research Funding; Erytech Pharma: Consultancy; Bristol-Myers Squibb: Consultancy, Research Funding; miRagen Therapeutics Inc: Consultancy, Research Funding; Incyte: Research Funding; miRagen Therapeutics Inc: Consultancy, Research Funding; Incyte: Research Funding; Cell Medica: Consultancy; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Erytech Pharma: Consultancy; Takeda Pharmaceuticals: Consultancy; Takeda Pharmaceuticals: Consultancy; Merck: Research Funding; Takeda Pharmaceuticals: Consultancy; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Incyte: Research Funding; Cell Medica: Consultancy; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Incyte: Research Funding; ADC Therapeutics: Consultancy; Merck: Research Funding; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; ADC Therapeutics: Consultancy; Incyte: Research Funding; Incyte: Research Funding; Cell Medica: Consultancy; Incyte: Research Funding; ADC Therapeutics: Consultancy; Erytech Pharma: Consultancy; Bristol-Myers Squibb: Consultancy, Research Funding; Erytech Pharma: Consultancy; Takeda Pharmaceuticals: Consultancy; Takeda Pharmaceuticals: Consultancy; Cell Medica: Consultancy; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Takeda Pharmaceuticals: Consultancy; Cell Medica: Consultancy; Erytech Pharma: Consultancy; Seattle Genetics: Consultancy, Honoraria, Research Funding; Erytech Pharma: Consultancy; Seattle Genetics: Consultancy, Honoraria, Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; miRagen Therapeutics Inc: Consultancy, Research Funding; Merck: Research Funding; miRagen Therapeutics Inc: Consultancy, Research Funding; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; miRagen Therapeutics Inc: Consultancy, Research Funding; Merck: Research Funding; Cell Medica: Consultancy; Seattle Genetics: Consultancy, Honoraria, Research Funding; Incyte: Research Funding; miRagen Therapeutics Inc: Consultancy, Research Funding; Incyte: Research Funding; miRagen Therapeutics Inc: Consultancy, Research Funding; miRagen Therapeutics Inc: Consultancy, Research Funding; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; miRagen Therapeutics Inc: Consultancy, Research Funding; Incyte: Research Funding; ADC Therapeutics: Consultancy; Bristol-Myers Squibb: Consultancy, Research Funding; Erytech Pharma: Consultancy; Erytech Pharma: Consultancy; ADC Therapeutics: Consultancy; Incyte: Research Funding; ADC Therapeutics: Consultancy; miRagen Therapeutics Inc: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; ADC Therapeutics: Consultancy; ADC Therapeutics: Consultancy; ADC Therapeutics: Consultancy; Bristol-Myers Squibb: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; miRagen Therapeutics Inc: Consultancy, Research Funding; miRagen Therapeutics Inc: Consultancy, Research Funding; miRagen Therapeutics Inc: Consultancy, Research Funding; miRagen Therapeutics Inc: Consultancy, Research Funding; Cell Medica: Consultancy; Cell Medica: Consultancy; Seattle Genetics: Consultancy, Honoraria, Research Funding; Merck: Research Funding; Incyte: Research Funding; Merck: Research Funding; Merck: Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Erytech Pharma: Consultancy; Takeda Pharmaceuticals: Consultancy; ADC Therapeutics: Consultancy; Cell Medica: Consultancy; Seattle Genetics: Consultancy, Honoraria, Research Funding; Merck: Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; ADC Therapeutics: Consultancy; Seattle Genetics: Consultancy, Honoraria, Research Funding. Advani:Celmed: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Research Funding; Forty-Seven: Research Funding; Infinity Pharma: Research Funding; Pharmacyclics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead Sciences, Inc./Kite Pharma, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees; Regeneron: Research Funding; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees; Kyowa Kirin Pharmaceutical Developments, Inc.: Consultancy; Merck: Research Funding; Kura: Research Funding; Bayer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Research Funding; Autolus: Consultancy, Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees; Agensys: Research Funding; Cell Medica, Ltd: Consultancy; Stanford University: Employment, Equity Ownership; Seattle Genetics: Consultancy, Research Funding; Millennium: Research Funding; Janssen: Research Funding; Roche/Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Bartlett:Affimed Therapeutics: Research Funding; Bristol-Myers Squibb: Research Funding; Celgene: Research Funding; Dynavax: Research Funding; Forty-Seven: Research Funding; Genentech: Research Funding; Gilead: Research Funding; Immune Design: Research Funding; Janssen: Research Funding; Kite Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Medimmune: Research Funding; Merck: Research Funding; Millennium: Research Funding; Novartis: Research Funding; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics: Research Funding; Seattle Genetics, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Vose:Acerta Pharma: Honoraria, Other: Grants, Research Funding; Bristol-Meyers Squibb Company: Research Funding; Celgene Corporation: Research Funding; Incyte Corporation: Research Funding; Kite Pharma: Honoraria, Other: Grants, Research Funding; Novartis: Research Funding; Seattle Genetics: Research Funding; AbbVie: Consultancy, Honoraria; Epizyme: Consultancy, Honoraria; Legend Pharmaceuticals: Honoraria. Ramchandren:Genentech: Research Funding; Seattle Genetics, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol-Myers Squibb: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Research Funding; Pharmacyclics LLC, an Abbvie company: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck: Research Funding; Sandoz-Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees. Feldman:Takeda: Honoraria, Speakers Bureau; Celgene: Honoraria, Research Funding, Speakers Bureau; Seattle Genetics: Consultancy, Honoraria, Other: Travel expenses, Speakers Bureau; AbbVie: Honoraria, Other: Travel expenses, Speakers Bureau; Pharmacyclics: Honoraria, Other: Travel expenses, Speakers Bureau; Janssen: Honoraria, Speakers Bureau; Kite Pharma: Honoraria, Other: Travel expenses, Speakers Bureau; Bayer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Research Funding; Cell Medica: Research Funding; Roche: Research Funding; Corvus: Research Funding; Eisai: Research Funding; Kyowa Hakko Kirin: Research Funding; Pfizer: Research Funding; Portola Pharma: Research Funding; Roche: Research Funding; Trillium: Research Funding; Viracta: Research Funding. LaCasce:BMS: Consultancy; Research to Practice: Speakers Bureau; Humanigen: Consultancy; Seattle Genetics: Consultancy, Research Funding. Christian:Bristol-Myers Squibb: Research Funding; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech: Membership on an entity's Board of Directors or advisory committees, Research Funding; Cephalon: Research Funding; Janssen: Research Funding; Immunomedics: Research Funding; Celgene: Research Funding; Acerta: Research Funding; Triphase: Research Funding; Millennium Pharmaceuticals Inc: Research Funding; Merck: Research Funding. Ansell:Bristol-Myers Squibb: Research Funding; LAM Therapeutics: Research Funding; Seattle Genetics: Research Funding; Regeneron: Research Funding; Trillium: Research Funding; Seattle Genetics: Research Funding; Mayo Clinic Rochester: Employment; Affimed: Research Funding; Regeneron: Research Funding; Trillium: Research Funding; Mayo Clinic Rochester: Employment; Bristol-Myers Squibb: Research Funding; LAM Therapeutics: Research Funding; Affimed: Research Funding. Moskowitz:ADC Therapeutics: Research Funding; Merck: Consultancy, Research Funding; Seattle Genetics, Inc.: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; Celgene: Consultancy; Pharmacyclics: Research Funding. Brown:Seattle Genetics, Inc.: Employment, Equity Ownership. Taft:Seattle Genetics, Inc.: Employment, Equity Ownership. Ansari:Seattle Genetics, Inc.: Employment, Equity Ownership. Zak:Seattle Genetics, Inc.: Employment, Equity Ownership. Sacchi:Seattle Genetics, Inc.: Research Funding. Manley:Seattle Genetics: Employment, Equity Ownership. Herrera:Merck: Consultancy, Research Funding; AstraZeneca: Research Funding; Adaptive Biotechnologies: Consultancy; Pharmacyclics: Research Funding; Immune Design: Research Funding; Kite Pharma: Consultancy, Research Funding; Genentech, Inc.: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Gilead Sciences: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding.

Introduction: Central nervous system (CNS) relapse in patients with diffuse large B-cell lymphoma (DLBCL) is an uncommon yet often fatal complication with an overall survival (OS) of less than 6 months. According to the clinical risk model CNS-IPI, patients with 4-6 risk factors have a 2-year rate of CNS relapse of 10%. Involvement of certain extranodal sites such as testes or breast also confers increased risk, even with low-CNS-IPI. In high-risk patients, CNS prophylaxis is usually recommended, although the optimal regimen remains unclear. In this study, we examined the efficacy of different regimens on preventing CNS relapse in high-risk patients. Methods: We reviewed all newly diagnosed patients (pts) with DLBCL at Memorial Sloan Kettering Cancer Center from 2001 to 2017 treated with frontline rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone (RCHOP) or RCHOP-like regimens. Patients with primary mediastinal lymphoma, HIV-positive or known CNS disease at diagnosis were excluded. High risk for CNS (HR-CNS) relapse was defined by high-CNS IPI (4-6 risk factors) or low-CNS IPI with testicular, breast, kidney/adrenal and/or bone marrow (BM) involvement. CNS prophylaxis was administered per physician preference. Results: We identified 2002 pts treated with RCHOP or RCHOP-like regimens. Among them, 569 (28%) were classified as HR-CNS relapse and were included in the study. Median age was 68 years (range 21-91) and 290 (51%) were male. The high-risk extranodal sites were: BM, n=118 (20%); kidney/adrenal, n=106 (18%); testes, n=51 (9%) and breast, n=47 (8%). 158 pts (28%) had more than 2 extranodal sites. Cell or origin determined by Hans algorithm was non-germinal center (GCB) (non-GCB) in 40%, GCB in 39% and missing in 21%. 284 pts (50%) received CNS prophylaxis: intrathecal (IT) methotrexate (MTX) and/or IT cytarabine, n= 245 (86%); or high-dose intravenous MTX (HD-MTX), n=40 (14%). Pts's characteristics are shown in Table 1. After a median follow-up of 5.6 years, CNS relapse was observed in 36 out of 569 pts with HR-CNS relapse (5-year risk 6.4%), of whom 14 (39%) had received prophylaxis (IT, n=12; HD-MTX, n=2). The risk of CNS relapse at 5 years in pts who received IT prophylaxis was 5.6% compared with 5.2% in pts who received intravenous HD-MTX. Pts with HR-CNS relapse who did not receive prophylaxis had a 5-year risk for CNS relapse of 7.6% (p=0.34) (Figure 1). Pts with non-GCB phenotype had a higher risk of CNS relapse compared with patients with GCB subtype (5-year risk of 10% vs. 2%) (p=0.03). The median time to CNS relapse was 9 months (range 6-110 months). Pts who received prophylaxis, (either IT or HD-MTX), relapsed later than patients who did not receive prophylaxis, with a median time to relapse of 19 months (range 7-55) vs. 8 months (range 6 to 110), respectively. The risk of CNS relapse at 1 year was lower for pts who received prophylaxis (IT or HD-MTX) compared to pts who did not, 1% vs. 3.2%, risk ratio (RR) 0.30 (95% CI; 0.07,0.68). However, over time the risk of CNS relapse became similar between prophylaxis and non-prophylaxis groups, with a 5-year risk of 5.8% vs. 7.6% (RR 0.76, CI 95%; 0.37, 1.55), respectively (Figure 2). CNS relapses were confined to the CNS (n=26, 72%) or included systemic relapsed in addition to CNS (n=10, 28%). CNS sites of relapse are detailed in table 2. Overall survival (OS) in patients with CNS relapse was worse than in pts who relapsed outside the CNS, with a 2-year OS of 24% (95% CI, 12%-40%) vs. 40% (95% CI, 31%-48%), respectively (p=0.002). Conclusion: In the era of chemoimmunochemotherapy, CNS prophylaxis tended to delay relapse rather than effectively preventing it. Although we did not detect differences in the efficacy between intrathecal and intravenous HD-MTX, larger studies are needed to better compare the efficacy of these two preventive modalities. Disclosures Noy: Medscape: Honoraria; Janssen: Consultancy; Prime Oncology: Honoraria; NIH: Research Funding; Pharamcyclics: Research Funding; Raphael Pharma: Research Funding. Horwitz:Corvus Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Corvus Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Mundipharma: Consultancy; Affimed: Consultancy; ADCT Therapeutics: Research Funding; Astex: Consultancy; Innate Pharma: Consultancy; Seattle Genetics: Consultancy, Research Funding; Miragen: Consultancy; Miragen: Consultancy; Kura: Consultancy; Kura: Consultancy; Innate Pharma: Consultancy; Infinity/Verastem: Consultancy, Research Funding; Trillium: Research Funding; Celgene: Consultancy, Research Funding; Portola: Consultancy; Millennium/Takeda: Consultancy, Research Funding; Millennium/Takeda: Consultancy, Research Funding; Portola: Consultancy; Trillium: Research Funding; Celgene: Consultancy, Research Funding; Astex: Consultancy; Infinity/Verastem: Consultancy, Research Funding; Kura: Consultancy; Miragen: Consultancy; Affimed: Consultancy; Millennium/Takeda: Consultancy, Research Funding; Aileron: Research Funding; Seattle Genetics: Consultancy, Research Funding; Mundipharma: Consultancy; Celgene: Consultancy, Research Funding; Kyowa Hakko Kirin: Consultancy; Seattle Genetics: Consultancy, Research Funding; Innate Pharma: Consultancy; Trillium: Research Funding; Forty-Seven: Research Funding; Aileron: Research Funding; Aileron: Research Funding; Astex: Consultancy; Forty-Seven: Research Funding; Miragen: Consultancy; Infinity/Verastem: Consultancy, Research Funding; Forty-Seven: Research Funding; Infinity/Verastem: Consultancy, Research Funding; Kyowa Hakko Kirin: Consultancy; Mundipharma: Consultancy; Corvus Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Astex: Consultancy; Trillium: Research Funding; Celgene: Consultancy, Research Funding; ADCT Therapeutics: Research Funding; Kura: Consultancy; Millennium/Takeda: Consultancy, Research Funding; Affimed: Consultancy; Portola: Consultancy; Seattle Genetics: Consultancy, Research Funding; Aileron: Research Funding; Forty-Seven: Research Funding; Innate Pharma: Consultancy; Kyowa Hakko Kirin: Consultancy; Portola: Consultancy; Affimed: Consultancy; ADCT Therapeutics: Research Funding; Corvus Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; ADCT Therapeutics: Research Funding; Mundipharma: Consultancy; Kyowa Hakko Kirin: Consultancy. Palomba:Hemedicus: Other: Immediate Family Member, Speakers Bureau ; Merck & Co Inc.: Other: Immediate Family Member, Consultancy (includes expert testimony); Seres Therapeutics: Other: Immediate Family Member, Equity Ownership and Membership on an entity's Board of Directors or advisory committees; STRAXIMM: Other: Immediate Family Member, Membership on an entity's Board of Directors or advisory committees; Kite Pharmaceuticals: Other: Immediate Family Member, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; Noble Insights: Consultancy; Evelo: Other: Immediate family member, Equity Ownership; MSK (IP for Juno and Seres): Other: Immediate Family Member, Patents & Royalties - describe: intellectual property rights . Matasar:Juno Therapeutics: Consultancy; Merck: Consultancy, Equity Ownership; Genentech, Inc.: Consultancy, Honoraria, Other: Travel, accommodation, expenses , Research Funding; Bayer: Consultancy, Honoraria, Other; Roche: Consultancy, Honoraria, Other: Travel, accommodation, expenses , Research Funding; Bayer: Other: Travel, accommodation, expenses; Janssen: Honoraria, Research Funding; Pharmacyclics: Consultancy, Honoraria, Research Funding; Teva: Consultancy; Rocket Medical: Consultancy, Research Funding; Seattle Genetics: Consultancy, Honoraria, Other: Travel, accomodation, expenses, Research Funding; Daiichi Sankyo: Consultancy; GlaxoSmithKline: Honoraria, Research Funding. Straus:Hope Funds for Cancer Research: Membership on an entity's Board of Directors or advisory committees; Hope Funds for Cancer Research: Membership on an entity's Board of Directors or advisory committees; Elsevier (PracticeUpdate): Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria; Hope Funds for Cancer Research: Membership on an entity's Board of Directors or advisory committees. Batlevi:Juno Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees. Moskowitz:Incyte: Research Funding; miRagen Therapeutics Inc: Consultancy, Research Funding; ADC Therapeutics: Consultancy; Seattle Genetics: Consultancy, Honoraria, Research Funding; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Merck: Research Funding; Erytech Pharma: Consultancy; ADC Therapeutics: Consultancy; Erytech Pharma: Consultancy; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Merck: Research Funding; Incyte: Research Funding; Incyte: Research Funding; Erytech Pharma: Consultancy; miRagen Therapeutics Inc: Consultancy, Research Funding; Merck: Research Funding; Cell Medica: Consultancy; Erytech Pharma: Consultancy; Incyte: Research Funding; Takeda Pharmaceuticals: Consultancy; Cell Medica: Consultancy; Takeda Pharmaceuticals: Consultancy; Bristol-Myers Squibb: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Incyte: Research Funding; Cell Medica: Consultancy; Cell Medica: Consultancy; miRagen Therapeutics Inc: Consultancy, Research Funding; Cell Medica: Consultancy; Takeda Pharmaceuticals: Consultancy; Takeda Pharmaceuticals: Consultancy; Incyte: Research Funding; miRagen Therapeutics Inc: Consultancy, Research Funding; Takeda Pharmaceuticals: Consultancy; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Takeda Pharmaceuticals: Consultancy; miRagen Therapeutics Inc: Consultancy, Research Funding; Incyte: Research Funding; Takeda Pharmaceuticals: Consultancy; Incyte: Research Funding; ADC Therapeutics: Consultancy; ADC Therapeutics: Consultancy; ADC Therapeutics: Consultancy; Seattle Genetics: Consultancy, Honoraria, Research Funding; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Takeda Pharmaceuticals: Consultancy; Seattle Genetics: Consultancy, Honoraria, Research Funding; Cell Medica: Consultancy; Takeda Pharmaceuticals: Consultancy; Seattle Genetics: Consultancy, Honoraria, Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Merck: Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Merck: Research Funding; Merck: Research Funding; Merck: Research Funding; Merck: Research Funding; Erytech Pharma: Consultancy; Bristol-Myers Squibb: Consultancy, Research Funding; Merck: Research Funding; miRagen Therapeutics Inc: Consultancy, Research Funding; miRagen Therapeutics Inc: Consultancy, Research Funding; Cell Medica: Consultancy; miRagen Therapeutics Inc: Consultancy, Research Funding; ADC Therapeutics: Consultancy; Bristol-Myers Squibb: Consultancy, Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Merck: Research Funding; Merck: Research Funding; Cell Medica: Consultancy; Cell Medica: Consultancy; Cell Medica: Consultancy; Incyte: Research Funding; Incyte: Research Funding; ADC Therapeutics: Consultancy; Incyte: Research Funding; ADC Therapeutics: Consultancy; ADC Therapeutics: Consultancy; Bristol-Myers Squibb: Consultancy, Research Funding; Erytech Pharma: Consultancy; miRagen Therapeutics Inc: Consultancy, Research Funding; Erytech Pharma: Consultancy; Cell Medica: Consultancy; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; miRagen Therapeutics Inc: Consultancy, Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Takeda Pharmaceuticals: Consultancy; Erytech Pharma: Consultancy; Erytech Pharma: Consultancy; miRagen Therapeutics Inc: Consultancy, Research Funding; Erytech Pharma: Consultancy; ADC Therapeutics: Consultancy; Cell Medica: Consultancy; ADC Therapeutics: Consultancy; Erytech Pharma: Consultancy; miRagen Therapeutics Inc: Consultancy, Research Funding; miRagen Therapeutics Inc: Consultancy, Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; ADC Therapeutics: Consultancy; ADC Therapeutics: Consultancy; Bristol-Myers Squibb: Consultancy, Research Funding; ADC Therapeutics: Consultancy; Erytech Pharma: Consultancy; Bristol-Myers Squibb: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Erytech Pharma: Consultancy; Bristol-Myers Squibb: Consultancy, Research Funding; Incyte: Research Funding; miRagen Therapeutics Inc: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Merck: Research Funding; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Takeda Pharmaceuticals: Consultancy; Merck: Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Cell Medica: Consultancy; Bristol-Myers Squibb: Consultancy, Research Funding; Merck: Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; ADC Therapeutics: Consultancy; Erytech Pharma: Consultancy; Bristol-Myers Squibb: Consultancy, Research Funding; Incyte: Research Funding; miRagen Therapeutics Inc: Consultancy, Research Funding; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Erytech Pharma: Consultancy; Takeda Pharmaceuticals: Consultancy; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Incyte: Research Funding; Cell Medica: Consultancy; Takeda Pharmaceuticals: Consultancy; Takeda Pharmaceuticals: Consultancy; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Cell Medica: Consultancy; Takeda Pharmaceuticals: Consultancy; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Incyte: Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Merck: Research Funding. von Keudell:Bayer: Consultancy; Genentech: Consultancy; Pharmacyclics: Consultancy; Pharmacyclics: Consultancy; Genentech: Consultancy; Bayer: Consultancy. Dogan:Roche: Consultancy, Research Funding; Corvus Pharmaceuticals: Consultancy; Seattle Genetics: Consultancy; Celgene: Consultancy; Takeda: Consultancy; Novartis: Consultancy. Zelenetz:DAVA Oncology: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bayer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Karyopharm: Consultancy, Membership on an entity's Board of Directors or advisory committees; DAVA Oncology: Consultancy, Membership on an entity's Board of Directors or advisory committees; Karyopharm: Consultancy, Membership on an entity's Board of Directors or advisory committees; Verastem: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Morphosys: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics/AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics/AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bayer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees; DAVA Oncology: Consultancy, Membership on an entity's Board of Directors or advisory committees; Genentech/Roche: Consultancy, Membership on an entity's Board of Directors or advisory committees; Karyopharm: Consultancy, Membership on an entity's Board of Directors or advisory committees; Morphosys: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Morphosys: Consultancy, Membership on an entity's Board of Directors or advisory committees; MEI Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; Astra-Zeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees; MEI Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics/AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Beigene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Astra-Zeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees; Verastem: Consultancy, Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees; Morphosys: Consultancy, Membership on an entity's Board of Directors or advisory committees; Verastem: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Karyopharm: Consultancy, Membership on an entity's Board of Directors or advisory committees; Genentech/Roche: Consultancy, Membership on an entity's Board of Directors or advisory committees; Genentech/Roche: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Verastem: Consultancy, Membership on an entity's Board of Directors or advisory committees; Morphosys: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics/AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Karyopharm: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Verastem: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics/AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics/AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; DAVA Oncology: Consultancy, Membership on an entity's Board of Directors or advisory committees; Genentech/Roche: Consultancy, Membership on an entity's Board of Directors or advisory committees; Verastem: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Karyopharm: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Morphosys: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Beigene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Genentech/Roche: Consultancy, Membership on an entity's Board of Directors or advisory committees. Younes:BMS: Research Funding; AstraZeneca: Research Funding; Genentech: Research Funding; Roche: Consultancy, Honoraria, Research Funding; Xynomics: Consultancy; Syndax: Research Funding; Epizyme: Consultancy, Honoraria; HCM: Consultancy; Celgene: Consultancy, Honoraria; Takeda: Honoraria; Abbvie: Honoraria; Merck: Honoraria, Research Funding; Curis: Honoraria, Research Funding; Pharmacyclics: Research Funding; Janssen: Honoraria, Research Funding; Biopath: Consultancy.

Introduction: Peripheral T-cell lymphomas (PTCL) represent a heterogeneous group of aggressive non-Hodgkin lymphomas, with suboptimal outcomes with conventional chemotherapy. Autologous hematopoietic stem cell transplant (AHCT) is a therapeutic strategy for patients in first remission. However, progression-free survival (PFS) after AHCT is only 36-45% (d'Amore et al JCO 2012, Reimer et al JCO 2009), signifying an unmet therapeutic need for improving outcomes post-transplant. Maintenance therapy after AHCT may improve PFS. Romidepsin is a histone deacetylase (HDAC) inhibitor that is FDA approved for the treatment of relapsed/refractory T-cell lymphoma, and is a potential option for maintenance therapy. We present the results of the first multicenter study to evaluate the PFS of patients receiving maintenance therapy after upfront AHCT in PTCL patients. Methods: This was a phase 2, open-label, multicenter, investigator-initiated study in adult patients with PTCL (Table 1). 25 patients transplanted in first complete response or first partial response (CR1 or PR1) (Cohort 1) were evaluable for the primary endpoint of 2-year PFS. We enrolled another cohort (n=8) with high-risk histologies in CR/PR1 (n= 1), or transplanted in CR/PR2 or later (n=7) (Cohort 2). Patients underwent AHCT with carmustine, etoposide, cytarabine and melphalan (BEAM) conditioning. Maintenance romidepsin 14 mg/m2 was initiated between days 42-80 post AHCT, and administered every other week through 6 months, every 3 weeks through 1 year and every 4 weeks from 1 year through 2 years post AHCT. The Kaplan-Meier method was used to estimate PFS. Desired 2-year PFS was 70%. Results: Table 1 lists patient and disease characteristics. In Cohort 1, median follow up was 13.8 months (3.5 - 54.1 mon). Estimated 2-year PFS was 49% (30 - 80, 95% CI) (Figure 1). Median PFS was 20.0 months (12.0- NA, 95% CI). In Cohort 2, median follow up was 23.2 months (range, 9.1 - 35.7 months). Median PFS was 13.9 months (5.6 - NA, 95% CI). Estimated 2-year PFS was 47% (21 - 100, 95% CI). Angioimmunoblastic T-cell lymphoma (AITL) patients represented the largest subgroup within the study. 2-year PFS of these patients in Cohort 1 was 44% (20-96, 95% CI). In Cohort 1, 16 patients are off therapy (9 for disease progression, 2 for toxicity, 2 for patient choice and 3 completed therapy). Across cohorts, 5 patients required dose reduction. 6 patients experienced ≥ grade 3 toxicity (neutropenia=4, anemia=2, thrombocytopenia=2 and lymphopenia=2). 8 serious adverse events (SAEs) occurred in 6 patients after romidepsin treatment (epistaxis, fever, febrile neutropenia, hypotension, fatigue, myalgia, generalized muscle weakness, dyspnea, and CMV retinitis). Grade 2 toxicities included dysgeusia (5), neutropenia (3), anorexia (2), atrial fibrillation (1), hematuria (1), nausea (1), and fatigue (1). Grade 1 toxicities included dysgeusia (7), fatigue (4), nausea (4), anorexia (2), constipation (2), diarrhea (1), neutropenia (1), thrombocytopenia (1), and vomiting (1). Conclusions: Maintenance romidepsin was overall well-tolerated without significant additional grade 3-4 toxicity. At first assessment, the estimated median 2-year PFS in Cohort 1 of 49% does not indicate PFS improvement with romidepsin maintenance. Enrollment is complete and 9 patients in Cohort 1 are still on treatment. Final PFS will be updated. Disclosures Khan: ASCO/Conquer Cancer Foundation sponsored by Gilead Sciences: Research Funding; Back Bay Life Science Advisors: Honoraria. Shustov:Seattle Genetics, Inc.: Research Funding. Shadman:Sound Biologics: Consultancy; Sunesis: Research Funding; ADC Therapeutics: Consultancy; BeiGene: Research Funding; Pharmacyclics: Consultancy, Research Funding; Verastem: Consultancy; Celgene: Research Funding; TG Therapeutic: Research Funding; Gilead: Consultancy, Research Funding; AbbVie: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; Acerta Pharma: Research Funding; Astra Zeneca: Consultancy; Atara Biotherapeutics: Consultancy; Mustang Bio: Research Funding. Cassaday:Kite/Gilead: Research Funding; Amgen: Consultancy, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; Merck: Research Funding; Seattle Genetics: Research Funding; Seattle Genetics: Other: Spouse's disclosure: employment, stock and other ownership interests; Incyte: Research Funding. Ruan:AstraZeneca: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria; Pharmacyclics LLC, an AbbVie company: Research Funding; Juno: Consultancy; Kite: Consultancy. Moskowitz:Takeda Pharmaceuticals: Consultancy; Merck: Research Funding; ADC Therapeutics: Consultancy; Erytech Pharma: Consultancy; Incyte: Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Erytech Pharma: Consultancy; Incyte: Research Funding; ADC Therapeutics: Consultancy; Merck: Research Funding; miRagen Therapeutics Inc: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; miRagen Therapeutics Inc: Consultancy, Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Incyte: Research Funding; Takeda Pharmaceuticals: Consultancy; ADC Therapeutics: Consultancy; miRagen Therapeutics Inc: Consultancy, Research Funding; ADC Therapeutics: Consultancy; Incyte: Research Funding; ADC Therapeutics: Consultancy; Bristol-Myers Squibb: Consultancy, Research Funding; ADC Therapeutics: Consultancy; ADC Therapeutics: Consultancy; Bristol-Myers Squibb: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Cell Medica: Consultancy; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Erytech Pharma: Consultancy; Erytech Pharma: Consultancy; Bristol-Myers Squibb: Consultancy, Research Funding; Incyte: Research Funding; Merck: Research Funding; Merck: Research Funding; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Merck: Research Funding; Incyte: Research Funding; Incyte: Research Funding; miRagen Therapeutics Inc: Consultancy, Research Funding; miRagen Therapeutics Inc: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Merck: Research Funding; miRagen Therapeutics Inc: Consultancy, Research Funding; Cell Medica: Consultancy; Merck: Research Funding; miRagen Therapeutics Inc: Consultancy, Research Funding; Takeda Pharmaceuticals: Consultancy; ADC Therapeutics: Consultancy; Bristol-Myers Squibb: Consultancy, Research Funding; ADC Therapeutics: Consultancy; Erytech Pharma: Consultancy; Erytech Pharma: Consultancy; Incyte: Research Funding; ADC Therapeutics: Consultancy; ADC Therapeutics: Consultancy; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Takeda Pharmaceuticals: Consultancy; Takeda Pharmaceuticals: Consultancy; Seattle Genetics: Consultancy, Honoraria, Research Funding; Takeda Pharmaceuticals: Consultancy; Takeda Pharmaceuticals: Consultancy; Seattle Genetics: Consultancy, Honoraria, Research Funding; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Merck: Research Funding; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Merck: Research Funding; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Takeda Pharmaceuticals: Consultancy; Takeda Pharmaceuticals: Consultancy; miRagen Therapeutics Inc: Consultancy, Research Funding; Cell Medica: Consultancy; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Cell Medica: Consultancy; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Takeda Pharmaceuticals: Consultancy; ADC Therapeutics: Consultancy; Takeda Pharmaceuticals: Consultancy; Incyte: Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; miRagen Therapeutics Inc: Consultancy, Research Funding; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Merck: Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; miRagen Therapeutics Inc: Consultancy, Research Funding; Merck: Research Funding; Cell Medica: Consultancy; Merck: Research Funding; Merck: Research Funding; miRagen Therapeutics Inc: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Erytech Pharma: Consultancy; Merck: Research Funding; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Merck: Research Funding; ADC Therapeutics: Consultancy; Erytech Pharma: Consultancy; Erytech Pharma: Consultancy; Erytech Pharma: Consultancy; Bristol-Myers Squibb: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; miRagen Therapeutics Inc: Consultancy, Research Funding; Incyte: Research Funding; Takeda Pharmaceuticals: Consultancy; Erytech Pharma: Consultancy; Seattle Genetics: Consultancy, Honoraria, Research Funding; Incyte: Research Funding; Incyte: Research Funding; Incyte: Research Funding; miRagen Therapeutics Inc: Consultancy, Research Funding; miRagen Therapeutics Inc: Consultancy, Research Funding; Cell Medica: Consultancy; Cell Medica: Consultancy; Cell Medica: Consultancy; Cell Medica: Consultancy; Cell Medica: Consultancy; Cell Medica: Consultancy; Incyte: Research Funding; Takeda Pharmaceuticals: Consultancy; Takeda Pharmaceuticals: Consultancy; Incyte: Research Funding; Takeda Pharmaceuticals: Consultancy; ADC Therapeutics: Consultancy; ADC Therapeutics: Consultancy; Erytech Pharma: Consultancy; Cell Medica: Consultancy; Cell Medica: Consultancy; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Erytech Pharma: Consultancy; Cell Medica: Consultancy; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Cell Medica: Consultancy; Erytech Pharma: Consultancy; Erytech Pharma: Consultancy; miRagen Therapeutics Inc: Consultancy, Research Funding. Zelenetz:Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; DAVA Oncology: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Genentech/Roche: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bayer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Morphosys: Consultancy, Membership on an entity's Board of Directors or advisory committees; Beigene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Beigene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics/AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Karyopharm: Consultancy, Membership on an entity's Board of Directors or advisory committees; MEI Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Astra-Zeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Morphosys: Consultancy, Membership on an entity's Board of Directors or advisory committees; Verastem: Consultancy, Membership on an entity's Board of Directors or advisory committees; Karyopharm: Consultancy, Membership on an entity's Board of Directors or advisory committees; Astra-Zeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bayer: Consultancy, Membership on an entity's Board of Directors or advisory committees; MEI Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; DAVA Oncology: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics/AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Genentech/Roche: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Verastem: Consultancy, Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees. Noy:Medscape: Honoraria; Janssen: Consultancy; Prime Oncology: Honoraria; NIH: Research Funding; Pharamcyclics: Research Funding; Raphael Pharma: Research Funding. Straus:Hope Funds for Cancer Research: Membership on an entity's Board of Directors or advisory committees; Elsevier (PracticeUpdate): Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria. Kumar:Seattle Genetics: Research Funding. Sauter:Celgene: Consultancy; Novartis: Consultancy; Genmab: Consultancy; Precision Biosciences: Consultancy; Kite/Gilead: Consultancy; Juno Therapeutics: Consultancy, Research Funding; Sanofi-Genzyme: Consultancy, Research Funding; Spectrum Pharmaceuticals: Consultancy; GSK: Consultancy. Shah:Amgen: Research Funding; Janssen: Research Funding. Matasar:Genentech, Inc.: Consultancy, Honoraria, Other: Travel, accommodation, expenses , Research Funding; Bayer: Consultancy, Honoraria, Other; Roche: Consultancy, Honoraria, Other: Travel, accommodation, expenses , Research Funding; Merck: Consultancy, Equity Ownership; Juno Therapeutics: Consultancy; Teva: Consultancy; Rocket Medical: Consultancy, Research Funding; Seattle Genetics: Consultancy, Honoraria, Other: Travel, accomodation, expenses, Research Funding; Daiichi Sankyo: Consultancy; GlaxoSmithKline: Honoraria, Research Funding; Pharmacyclics: Consultancy, Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Bayer: Other: Travel, accommodation, expenses. Van Besien:Miltenyi Biotec: Research Funding. Giralt:Sanofi: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Takeda: Consultancy. Horwitz:Mundipharma: Consultancy; Astex: Consultancy; Trillium: Research Funding; Kyowa Hakko Kirin: Consultancy; Millennium/Takeda: Consultancy, Research Funding; Corvus Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Portola: Consultancy; Aileron: Research Funding; Miragen: Consultancy; Celgene: Consultancy, Research Funding; Kura: Consultancy; Millennium/Takeda: Consultancy, Research Funding; Portola: Consultancy; ADCT Therapeutics: Research Funding; Innate Pharma: Consultancy; Affimed: Consultancy; Aileron: Research Funding; Seattle Genetics: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding; Corvus Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Infinity/Verastem: Consultancy, Research Funding; ADCT Therapeutics: Research Funding; Corvus Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Astex: Consultancy; Innate Pharma: Consultancy; Kyowa Hakko Kirin: Consultancy; Seattle Genetics: Consultancy, Research Funding; Mundipharma: Consultancy; Affimed: Consultancy; Forty-Seven: Research Funding; Portola: Consultancy; Trillium: Research Funding; Affimed: Consultancy; Miragen: Consultancy; Astex: Consultancy; Millennium/Takeda: Consultancy, Research Funding; Miragen: Consultancy; Astex: Consultancy; Infinity/Verastem: Consultancy, Research Funding; Mundipharma: Consultancy; Celgene: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Kura: Consultancy; Corvus Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Forty-Seven: Research Funding; Portola: Consultancy; Mundipharma: Consultancy; Aileron: Research Funding; Kura: Consultancy; Celgene: Consultancy, Research Funding; Infinity/Verastem: Consultancy, Research Funding; Infinity/Verastem: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding; Kura: Consultancy; Innate Pharma: Consultancy; Aileron: Research Funding; Kyowa Hakko Kirin: Consultancy; Millennium/Takeda: Consultancy, Research Funding; Miragen: Consultancy; Affimed: Consultancy; ADCT Therapeutics: Research Funding; Trillium: Research Funding; Kyowa Hakko Kirin: Consultancy; Forty-Seven: Research Funding; Forty-Seven: Research Funding; Trillium: Research Funding; Innate Pharma: Consultancy; ADCT Therapeutics: Research Funding. OffLabel Disclosure: Romidepsin has been FDA approved for the treatment of relapsed/refractory cutaneous T-cell lymphoma and has accelerated approval for treatment of relapsed/refractory peripheral T cell lymphoma. We are studying its use as maintenance therapy after autologous stem cell transplant.

Introduction: Signaling through JAK1 and/or JAK2 is common among tumor and non-tumor cells within peripheral and cutaneous T cell lymphomas (PTCL and CTCL). We conducted a phase II study of the JAK1/2 inhibitor, ruxolitinib, in patients (pts) with PTCL and CTCL and assessed the predictive value of genetic, immunohistochemical (IHC) and multiparametric immunofluorescence (mIF) biomarkers of JAK/STAT pathway activation for ruxolitinib response. Methods: This is an investigator-initiated multi-center phase II study for pts with relapsed or refractory (RR) PTCL or CTCL following at least 1 systemic therapy. Biopsies from each patient were subjected to next-generation sequencing for JAK1, JAK2, STAT3, STAT5 and other relevant genes along with IHC assessment for phosphorylated STAT3 (pSTAT3). Pts enrolled into biomarker-defined cohorts: 1) activating JAK and/or STAT mutations (allele frequency of 0.1 or greater); 2) no JAK/STAT mutation but ≥ 30% pSTAT3 expression among tumor cells by IHC; or 3) neither. Pts received treatment with ruxolitinib 20 mg BID until progression and were assessed for response after cycles 2, 5 and every three cycles thereafter. Tissue samples collected at baseline, on-treatment, and at progression were collected and assessed by mIF (Vectra platform, HALO analysis) using markers specific for lymphoma subtype, macrophage activation, JAK/STAT and PI3 kinase signaling. Results: The study completed enrollment with 53 pts, including 18 in cohort 1, 14 in cohort 2, and 21 in cohort 3. Cohort 3 includes 10 pts for whom JAK/STAT characterization is pending. Disease histologies per cohort are detailed in table 1. Treatment-related serious adverse events included HSV-1 stomatitis (n=1), spontaneous bacterial peritonitis (n=1), febrile neutropenia (n=3), and herpes zoster (n=1). Additional grade 3 or 4 drug-related adverse events affecting >1 pt included neutropenia (n=13), anemia (n=8), thrombocytopenia (n=5), and lymphopenia (n=3). Among the 53 pts, 4 have not yet reached first response assessment and 1 withdrew consent following only 1 week of treatment; therefore 48 are evaluable for response. Among 48 pts, there were 3 (6%) complete responses, 8 (17%) partial responses, and 6 (12.5%) with cytopenia improvement and disease stabilization lasting more than 6 months (SD>6 mo). Overall response rate (ORR) was 23% and overall clinical benefit rate (CBR) (ORR plus SD>6 mo) was 35%. Median duration of response was 7.3 months (range 1.3-26.1 months). ORRs in cohorts 1, 2 and 3 were 28%, 31%, and 12% (cohorts 1&2 vs 3, p=0.28). CBRs in cohorts 1, 2 and 3 were 44%, 46%, and 18% (cohorts 1&2 vs. 3, p=0.07) (table 2). More frequent responses were observed in the following histologies: angioimmunoblastic T cell lymphoma, peripheral T cell lymphoma with T-follicular helper phenotype, T-cell prolymphocytic leukemia, and large granular lymphocyte leukemia (table 3). Nine pre-treatment biopsies were analyzed by mIF from 4 ruxolitinib responders and 5 non-responders. The most notable finding was that responders to ruxolitinib had markedly lower pS6 expression within tumor cells of pre-treatment biopsies (mean pS6 expression 9.03 +/- 4.8 vs 48.19 +/- 6.6 for nonresponders; p=0.0027). In a patient with prolonged CR on ruxolitinib, progression biopsy was characterized by a marked increase in tumor cell pS6 staining. Additional samples are being analyzed and updated results will be reported at the meeting. Conclusion: The JAK1/JAK2 inhibitor ruxolitinib is a well-tolerated and readily available therapy for pts with relapsed/refractory PTCL and CTCL. Among patients with IHC and/or genetic evidence of JAK/STAT activation, ruxolitinib has similar efficacy to approved agents for relapsed/refractory T-cell lymphoma. The association between pS6 expression and response to ruxolitinib suggests that active PI3K/mTOR signaling confers intrinsic and acquired resistance to ruxolitinib. Disclosures Moskowitz: ADC Therapeutics: Consultancy; Takeda Pharmaceuticals: Consultancy; Seattle Genetics: Consultancy, Honoraria, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Takeda Pharmaceuticals: Consultancy; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Takeda Pharmaceuticals: Consultancy; Takeda Pharmaceuticals: Consultancy; Bristol-Myers Squibb: Consultancy, Research Funding; miRagen Therapeutics Inc: Consultancy, Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Erytech Pharma: Consultancy; Seattle Genetics: Consultancy, Honoraria, Research Funding; Merck: Research Funding; Takeda Pharmaceuticals: Consultancy; Merck: Research Funding; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Incyte: Research Funding; Merck: Research Funding; Takeda Pharmaceuticals: Consultancy; ADC Therapeutics: Consultancy; Merck: Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; miRagen Therapeutics Inc: Consultancy, Research Funding; miRagen Therapeutics Inc: Consultancy, Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Merck: Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Merck: Research Funding; miRagen Therapeutics Inc: Consultancy, Research Funding; Erytech Pharma: Consultancy; Erytech Pharma: Consultancy; Incyte: Research Funding; Takeda Pharmaceuticals: Consultancy; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Takeda Pharmaceuticals: Consultancy; Seattle Genetics: Consultancy, Honoraria, Research Funding; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Merck: Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Merck: Research Funding; Merck: Research Funding; Cell Medica: Consultancy; Bristol-Myers Squibb: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; miRagen Therapeutics Inc: Consultancy, Research Funding; Incyte: Research Funding; miRagen Therapeutics Inc: Consultancy, Research Funding; ADC Therapeutics: Consultancy; miRagen Therapeutics Inc: Consultancy, Research Funding; Incyte: Research Funding; Cell Medica: Consultancy; Merck: Research Funding; ADC Therapeutics: Consultancy; Cell Medica: Consultancy; Incyte: Research Funding; miRagen Therapeutics Inc: Consultancy, Research Funding; Erytech Pharma: Consultancy; Cell Medica: Consultancy; Cell Medica: Consultancy; miRagen Therapeutics Inc: Consultancy, Research Funding; Incyte: Research Funding; Erytech Pharma: Consultancy; Cell Medica: Consultancy; Takeda Pharmaceuticals: Consultancy; Cell Medica: Consultancy; Cell Medica: Consultancy; Bristol-Myers Squibb: Consultancy, Research Funding; Incyte: Research Funding; Incyte: Research Funding; Takeda Pharmaceuticals: Consultancy; Cell Medica: Consultancy; Takeda Pharmaceuticals: Consultancy; Takeda Pharmaceuticals: Consultancy; Cell Medica: Consultancy; Cell Medica: Consultancy; miRagen Therapeutics Inc: Consultancy, Research Funding; Cell Medica: Consultancy; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; miRagen Therapeutics Inc: Consultancy, Research Funding; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Takeda Pharmaceuticals: Consultancy; Incyte: Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; miRagen Therapeutics Inc: Consultancy, Research Funding; Erytech Pharma: Consultancy; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Incyte: Research Funding; ADC Therapeutics: Consultancy; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Cell Medica: Consultancy; Merck: Research Funding; ADC Therapeutics: Consultancy; Erytech Pharma: Consultancy; Erytech Pharma: Consultancy; Erytech Pharma: Consultancy; ADC Therapeutics: Consultancy; Incyte: Research Funding; Incyte: Research Funding; miRagen Therapeutics Inc: Consultancy, Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; ADC Therapeutics: Consultancy; Bristol-Myers Squibb: Consultancy, Research Funding; ADC Therapeutics: Consultancy; ADC Therapeutics: Consultancy; miRagen Therapeutics Inc: Consultancy, Research Funding; Incyte: Research Funding; Merck: Research Funding; Takeda Pharmaceuticals: Consultancy; Cell Medica: Consultancy; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Merck: Research Funding; Incyte: Research Funding; Merck: Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Incyte: Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; ADC Therapeutics: Consultancy; ADC Therapeutics: Consultancy; ADC Therapeutics: Consultancy; ADC Therapeutics: Consultancy; ADC Therapeutics: Consultancy; Erytech Pharma: Consultancy; Erytech Pharma: Consultancy; Erytech Pharma: Consultancy; Erytech Pharma: Consultancy; Bristol-Myers Squibb: Consultancy, Research Funding; Erytech Pharma: Consultancy; Erytech Pharma: Consultancy; Bristol-Myers Squibb: Consultancy, Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Cell Medica: Consultancy; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Merck: Research Funding; Takeda Pharmaceuticals: Consultancy; miRagen Therapeutics Inc: Consultancy, Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding. Jacobsen:Acerta: Consultancy; Novartis: Research Funding; Astra-Zeneca: Consultancy; F. Hoffmann-LaRoche: Research Funding; Merck: Consultancy, Research Funding; Takeda: Honoraria; Pharmacyclics: Research Funding. Ruan:Janssen: Consultancy, Honoraria; Pharmacyclics LLC, an AbbVie company: Research Funding; Kite: Consultancy; Juno: Consultancy; Celgene: Consultancy, Honoraria, Research Funding; AstraZeneca: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria, Research Funding. Geyer:Amgen: Research Funding; Dava Oncology: Honoraria. Noy:Medscape: Honoraria; Janssen: Consultancy; Prime Oncology: Honoraria; NIH: Research Funding; Pharamcyclics: Research Funding; Raphael Pharma: Research Funding. Straus:Elsevier (PracticeUpdate): Consultancy, Honoraria; Hope Funds for Cancer Research: Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Consultancy, Honoraria. Dogan:Roche: Consultancy, Research Funding; Corvus Pharmaceuticals: Consultancy; Seattle Genetics: Consultancy; Celgene: Consultancy; Novartis: Consultancy; Takeda: Consultancy. Weinstock:Celgene: Research Funding. Horwitz:Aileron: Research Funding; Corvus Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding; Kura: Consultancy; Infinity/Verastem: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding; Aileron: Research Funding; Trillium: Research Funding; Kyowa Hakko Kirin: Consultancy; Corvus Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Astex: Consultancy; Miragen: Consultancy; Affimed: Consultancy; ADCT Therapeutics: Research Funding; Forty-Seven: Research Funding; Portola: Consultancy; Miragen: Consultancy; Mundipharma: Consultancy; Miragen: Consultancy; Seattle Genetics: Consultancy, Research Funding; Millennium/Takeda: Consultancy, Research Funding; Innate Pharma: Consultancy; Affimed: Consultancy; ADCT Therapeutics: Research Funding; Millennium/Takeda: Consultancy, Research Funding; Millennium/Takeda: Consultancy, Research Funding; Infinity/Verastem: Consultancy, Research Funding; Kyowa Hakko Kirin: Consultancy; Trillium: Research Funding; Astex: Consultancy; Astex: Consultancy; Celgene: Consultancy, Research Funding; Infinity/Verastem: Consultancy, Research Funding; Infinity/Verastem: Consultancy, Research Funding; Kura: Consultancy; Kura: Consultancy; Kyowa Hakko Kirin: Consultancy; Trillium: Research Funding; Celgene: Consultancy, Research Funding; ADCT Therapeutics: Research Funding; Corvus Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Astex: Consultancy; Aileron: Research Funding; Forty-Seven: Research Funding; Innate Pharma: Consultancy; Forty-Seven: Research Funding; Mundipharma: Consultancy; Celgene: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding; Portola: Consultancy; Kyowa Hakko Kirin: Consultancy; Millennium/Takeda: Consultancy, Research Funding; Trillium: Research Funding; Aileron: Research Funding; Kura: Consultancy; Miragen: Consultancy; Innate Pharma: Consultancy; Mundipharma: Consultancy; Mundipharma: Consultancy; ADCT Therapeutics: Research Funding; Corvus Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Portola: Consultancy; Portola: Consultancy; Forty-Seven: Research Funding; Innate Pharma: Consultancy; Affimed: Consultancy; Affimed: Consultancy. OffLabel Disclosure: Off-label use of ruxolitinib for T-cell lymphoma will be discussed

Background: The acute and lymphoma subtypes Human T-lymphotropic virus 1-associated adult T-cell leukemia/lymphoma (HTLV-1 ATLL) are frequently characterized by chemo-refractoriness, a generally aggressive clinical course, and poor outcomes. Despite progress in characterizing the disease biology and the development and implementation of newer agents such as mogamulizumab, survival remains poor, especially for patients with relapsed or refractory disease. Furthermore, besides these many challenges, there is a paucity of comprehensive published data in Western (i.e. non-Japanese) patients. Methods: In a retrospective analysis, we identified 109 patients with pathologically-confirmed ATLL evaluated at our institution since 2001. 11 were excluded due to lack of clinical follow-up. Patient, disease, and treatment information was extracted for analysis. The International Prognostic Index (IPI) and Prognostic Index for PTCL-U (PIT) were calculated at time of diagnosis. Response rate was calculated based on the best response (CR/PR) during induction, with response retrospectively assessed based on available data using Lugano criteria. Median survival was calculated using Kaplan-Meier analysis and follow-up using a reverse Kaplan-Meier method, with survival and follow-up as of July 2019 Results: Ninety eight patients were included in our cohort (Table 1); 46 patients (47%) received initial treatment at another institution. The most common ATLL subtypes were lymphoma (n=43, 44%) acute (n=39, 40%), and smoldering/chronic (n=16, 16%). The median age at diagnosis was 53 years (range 30-92) and the median duration of follow-up from diagnosis was 65 months (95% CI: 41 to 178). With a median follow-up in survivors of 41.2 months, 21 patients are alive. The most common cause of death was disease (69/77 patients, 90%). The median overall survival (OS) among all patients was 13.2 months (Figure 1; range 1.3-240). For acute/lymphoma subtype disease, most patients initially received EPOCH/CHOEP (54 patients), CHOP (18 patients), or BV-CHP (3 patients); practice patterns evolved since the late 2000's to include more etoposide and BV-CHP rather than CHOP. Among 76 patients with lymphoma/acute with reviewable restaging information, 30 (40%) achieved CR. For patients with active disease following induction, a variety of subsequent therapies were used, most commonly romidepsin and pralatrexate, each utilized in 15 patients. Of 68 patients considered for transplant (55 saw a transplant physician, 13 had HLA typing sent), 23 patients ultimately underwent transplant, including 5 autologous and 18 alloSCT. Among patients referred who did not undergo transplant (N = 30), the most common reason was disease-related (24 patients, 80%) followed by patient preference (4 patients, 13%). Since 2010, only two patients underwent autoSCT at our center: one experienced primary graft failure necessitating autologous reconstitution and another lacked suitable allograft donor. Most patients, 13/18 (72%), were in CR at time of alloSCT; 11 patients underwent transplant in first remission, 7 at subsequent timepoints. Donor and graft sources included matched related (n=6), one identical twin, matched unrelated (n=2), mismatched related (n=1), mismatched unrelated (n=2), cord blood (n=4) and haploidentical (n=2). Four patients relapsed after autoSCT, 6 patients following alloSCT, and 2 treatment-related deaths occurred post alloSCT. Progression-free and OS at median follow-up of 39.2 months among alloSCT recipients was 60.6% and 64.1%, respectively (Figure 2). Conclusions: We describe the treatment patterns and outcomes for a large series of non-Japanese patients at our center with ATLL. We confirm the poor outcomes with conventional therapy seen in other studies, with only 40% of lymphoma/leukemia subtype patients achieving CR with first-line therapy, and a median OS of 13.2 months among all patients. AlloSCT offers promise as an effective option that achieved durable long-term responses in many patients, yet its applicability is limited by chemorefractory disease. Larger studies are needed to confirm our findings and to identify effective salvage therapies to attain remission and bridge patients to alloSCT. For patients ineligible for alloSCT due to age/comorbidity, lack of suitable donor, or disease refractoriness, novel therapeutic approaches are urgently needed to improve outcomes. Disclosures Moskowitz: Bristol-Myers Squibb: Consultancy, Research Funding; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Erytech Pharma: Consultancy; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Takeda Pharmaceuticals: Consultancy; Merck: Research Funding; Takeda Pharmaceuticals: Consultancy; Seattle Genetics: Consultancy, Honoraria, Research Funding; Incyte: Research Funding; Incyte: Research Funding; Merck: Research Funding; Erytech Pharma: Consultancy; ADC Therapeutics: Consultancy; Erytech Pharma: Consultancy; Merck: Research Funding; ADC Therapeutics: Consultancy; miRagen Therapeutics Inc: Consultancy, Research Funding; miRagen Therapeutics Inc: Consultancy, Research Funding; Takeda Pharmaceuticals: Consultancy; ADC Therapeutics: Consultancy; Erytech Pharma: Consultancy; Erytech Pharma: Consultancy; Seattle Genetics: Consultancy, Honoraria, Research Funding; Erytech Pharma: Consultancy; Erytech Pharma: Consultancy; Bristol-Myers Squibb: Consultancy, Research Funding; miRagen Therapeutics Inc: Consultancy, Research Funding; miRagen Therapeutics Inc: Consultancy, Research Funding; Incyte: Research Funding; miRagen Therapeutics Inc: Consultancy, Research Funding; miRagen Therapeutics Inc: Consultancy, Research Funding; Cell Medica: Consultancy; Cell Medica: Consultancy; Cell Medica: Consultancy; Incyte: Research Funding; Takeda Pharmaceuticals: Consultancy; Cell Medica: Consultancy; Cell Medica: Consultancy; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Cell Medica: Consultancy; Incyte: Research Funding; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Takeda Pharmaceuticals: Consultancy; Merck: Research Funding; ADC Therapeutics: Consultancy; Merck: Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; ADC Therapeutics: Consultancy; Bristol-Myers Squibb: Consultancy, Research Funding; miRagen Therapeutics Inc: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Takeda Pharmaceuticals: Consultancy; Takeda Pharmaceuticals: Consultancy; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Cell Medica: Consultancy; Takeda Pharmaceuticals: Consultancy; Seattle Genetics: Consultancy, Honoraria, Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Merck: Research Funding; ADC Therapeutics: Consultancy; miRagen Therapeutics Inc: Consultancy, Research Funding; miRagen Therapeutics Inc: Consultancy, Research Funding; Incyte: Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Cell Medica: Consultancy; Incyte: Research Funding; miRagen Therapeutics Inc: Consultancy, Research Funding; Cell Medica: Consultancy; Cell Medica: Consultancy; Incyte: Research Funding; Takeda Pharmaceuticals: Consultancy; Incyte: Research Funding; Takeda Pharmaceuticals: Consultancy; Cell Medica: Consultancy; Cell Medica: Consultancy; Cell Medica: Consultancy; Seattle Genetics: Consultancy, Honoraria, Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Takeda Pharmaceuticals: Consultancy; Merck: Research Funding; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; ADC Therapeutics: Consultancy; Erytech Pharma: Consultancy; Bristol-Myers Squibb: Consultancy, Research Funding; miRagen Therapeutics Inc: Consultancy, Research Funding; Incyte: Research Funding; Incyte: Research Funding; Takeda Pharmaceuticals: Consultancy; Merck: Research Funding; ADC Therapeutics: Consultancy; Erytech Pharma: Consultancy; Bristol-Myers Squibb: Consultancy, Research Funding; Cell Medica: Consultancy; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Cell Medica: Consultancy; Seattle Genetics: Consultancy, Honoraria, Research Funding; miRagen Therapeutics Inc: Consultancy, Research Funding; Incyte: Research Funding; Incyte: Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; miRagen Therapeutics Inc: Consultancy, Research Funding; Incyte: Research Funding; Takeda Pharmaceuticals: Consultancy; Incyte: Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; miRagen Therapeutics Inc: Consultancy, Research Funding; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Merck: Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Takeda Pharmaceuticals: Consultancy; Merck: Research Funding; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; ADC Therapeutics: Consultancy; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Takeda Pharmaceuticals: Consultancy; Erytech Pharma: Consultancy; Erytech Pharma: Consultancy; Bristol-Myers Squibb: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Merck: Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; ADC Therapeutics: Consultancy; miRagen Therapeutics Inc: Consultancy, Research Funding; Erytech Pharma: Consultancy; Erytech Pharma: Consultancy; Merck: Research Funding; ADC Therapeutics: Consultancy; ADC Therapeutics: Consultancy; ADC Therapeutics: Consultancy; ADC Therapeutics: Consultancy; ADC Therapeutics: Consultancy; Erytech Pharma: Consultancy; Merck: Research Funding; Merck: Research Funding; Erytech Pharma: Consultancy; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Merck: Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding. Dogan:Roche: Consultancy, Research Funding; Corvus Pharmaceuticals: Consultancy; Seattle Genetics: Consultancy; Celgene: Consultancy; Takeda: Consultancy; Novartis: Consultancy. Kumar:Seattle Genetics: Research Funding. Matasar:Genentech, Inc.: Consultancy, Honoraria, Other: Travel, accommodation, expenses , Research Funding; Bayer: Consultancy, Honoraria, Other; Roche: Consultancy, Honoraria, Other: Travel, accommodation, expenses , Research Funding; Merck: Consultancy, Equity Ownership; Juno Therapeutics: Consultancy; Teva: Consultancy; Rocket Medical: Consultancy, Research Funding; Seattle Genetics: Consultancy, Honoraria, Other: Travel, accomodation, expenses, Research Funding; Daiichi Sankyo: Consultancy; GlaxoSmithKline: Honoraria, Research Funding; Pharmacyclics: Consultancy, Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Bayer: Other: Travel, accommodation, expenses. Noy:Medscape: Honoraria; Janssen: Consultancy; Prime Oncology: Honoraria; NIH: Research Funding; Pharamcyclics: Research Funding; Raphael Pharma: Research Funding. Perales:Nektar Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol-Meyers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bellicum: Honoraria, Membership on an entity's Board of Directors or advisory committees; NexImmune: Membership on an entity's Board of Directors or advisory committees; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees; MolMed: Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Omeros: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Merck: Consultancy, Honoraria; Medigene: Membership on an entity's Board of Directors or advisory committees; Servier: Membership on an entity's Board of Directors or advisory committees; Kyte/Gilead: Research Funding; Miltenyi: Research Funding. Straus:Elsevier (PracticeUpdate): Consultancy, Honoraria; Hope Funds for Cancer Research: Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Consultancy, Honoraria. Zelenetz:Genentech/Roche: Consultancy, Membership on an entity's Board of Directors or advisory committees; Morphosys: Consultancy, Membership on an entity's Board of Directors or advisory committees; MEI Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics/AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Astra-Zeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees; Astra-Zeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Beigene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics/AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Verastem: Consultancy, Membership on an entity's Board of Directors or advisory committees; Genentech/Roche: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Verastem: Consultancy, Membership on an entity's Board of Directors or advisory committees; MEI Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; DAVA Oncology: Consultancy, Membership on an entity's Board of Directors or advisory committees; Karyopharm: Consultancy, Membership on an entity's Board of Directors or advisory committees; Beigene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; DAVA Oncology: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bayer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bayer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Karyopharm: Consultancy, Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees; Morphosys: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees. Sauter:Juno Therapeutics: Consultancy, Research Funding; Sanofi-Genzyme: Consultancy, Research Funding; Spectrum Pharmaceuticals: Consultancy; Novartis: Consultancy; Genmab: Consultancy; Precision Biosciences: Consultancy; Kite/Gilead: Consultancy; Celgene: Consultancy; GSK: Consultancy. Horwitz:Millennium/Takeda: Consultancy, Research Funding; Affimed: Consultancy; Celgene: Consultancy, Research Funding; Kura: Consultancy; Trillium: Research Funding; Mundipharma: Consultancy; Celgene: Consultancy, Research Funding; Kyowa Hakko Kirin: Consultancy; Portola: Consultancy; Kura: Consultancy; Infinity/Verastem: Consultancy, Research Funding; ADCT Therapeutics: Research Funding; Portola: Consultancy; Celgene: Consultancy, Research Funding; Portola: Consultancy; Astex: Consultancy; Seattle Genetics: Consultancy, Research Funding; Miragen: Consultancy; Miragen: Consultancy; Seattle Genetics: Consultancy, Research Funding; Aileron: Research Funding; ADCT Therapeutics: Research Funding; Forty-Seven: Research Funding; Aileron: Research Funding; Infinity/Verastem: Consultancy, Research Funding; Forty-Seven: Research Funding; Trillium: Research Funding; Corvus Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Innate Pharma: Consultancy; Astex: Consultancy; Celgene: Consultancy, Research Funding; Infinity/Verastem: Consultancy, Research Funding; Kura: Consultancy; Kyowa Hakko Kirin: Consultancy; Forty-Seven: Research Funding; Astex: Consultancy; Mundipharma: Consultancy; Innate Pharma: Consultancy; Trillium: Research Funding; Astex: Consultancy; Kyowa Hakko Kirin: Consultancy; Millennium/Takeda: Consultancy, Research Funding; Millennium/Takeda: Consultancy, Research Funding; Affimed: Consultancy; Seattle Genetics: Consultancy, Research Funding; Aileron: Research Funding; Kyowa Hakko Kirin: Consultancy; Corvus Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Kura: Consultancy; Innate Pharma: Consultancy; Aileron: Research Funding; Innate Pharma: Consultancy; Mundipharma: Consultancy; Trillium: Research Funding; Affimed: Consultancy; Corvus Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; ADCT Therapeutics: Research Funding; ADCT Therapeutics: Research Funding; Corvus Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Millennium/Takeda: Consultancy, Research Funding; Miragen: Consultancy; Seattle Genetics: Consultancy, Research Funding; Mundipharma: Consultancy; Portola: Consultancy; Forty-Seven: Research Funding; Miragen: Consultancy; Infinity/Verastem: Consultancy, Research Funding; Affimed: Consultancy.

Background: Treatment strategies for patients (pts) with relapsed/refractory (RR) classical Hodgkin lymphoma (cHL) continue to evolve as brentuximab vedotin (BV) and immune checkpoint inhibitors are utilized in pre-transplant salvage regimens. These new approaches are based on promising results of non-randomized trials, but it is not clear how they perform outside of clinical studies. We aimed to investigate selection patterns, toxicities, and outcomes of salvage regimens prior stem cell transplant (SCT) used currently in the United States for pts with RR cHL in the non-trial setting. Methods: We conducted a multisite, retrospective study of pts with RR cHL who were treated with a first salvage regimen (salvage 1) with intent to proceed to SCT within the past 5 years. Only pts who were treated outside of a clinical trial with salvage 1 were included. Responses were based on treating physician assessment using Revised Response Criteria for Malignant Lymphoma (Cheson et al, JCO 2014). Kaplan Meier survival curves were generated using STATA 15.0 software. Results: We identified 160 pts with diagnosis of RR cHL from 6 U.S. centers who received salvage 1 in the non-trial setting between January 2013 and January 2018. The pts' characteristics are described in Table 1. Both primary refractory pts (41%) and those with relapsed disease (59%) were included. The most common salvage 1 regimen for RR cHL was ifosfamide, carboplatin, etoposide (ICE) in 68% followed by BV monotherapy (14%) and BV+bendamustine (9%). Only 1 pt (1%) received immune checkpoint inhibitor. There were no statistically significant factors that would increase likelihood of receiving BV-containing salvage 1 including primary refractory status, age, and advanced stage. In the cohort of 59 pts who required more than one line of salvage therapy, the most common second salvage regimen (salvage 2) was BV monotherapy (42%), followed by various BV-containing combinations (22%), and ICE (19%). Only 14% of pts received 3 or more lines of salvage therapy prior to SCT. Out of 107 pts who received ICE as salvage 1, 33% were administered second salvage while out of 35 pts who received BV-containing regimen as salvage 1, 53% required salvage 2 (X2=4.7, p=0.03). Of 148 pts who ultimately underwent SCT, 52% were exposed to BV and 12% to an immune checkpoint inhibitor as part of any salvage regimen at some point prior to SCT. Response assessment to salvage 1 were available for 154 pts; 47% pts achieved complete response (CR), 30% partial response (PR), and 19% had progressive disease (PD). The responses to specific salvage 1 regimens are summarized in Table 2. For those pts undergoing salvage 2, 48% achieved CR, 19% PR and 30% had PD. Radiation was administered to 11% of pts at any point of salvage treatment prior SCT. In terms of toxicities, there were no deaths attributed to complications from any of the salvage therapies. When compared to ICE, pts undergoing BV or BV+bendamustine as salvage 1 had lower risk of neutropenic fever (0% vs 7%) and GI toxicities (10% vs 18%), but had higher risk of experiencing peripheral neuropathy (5% vs 15%). Out of 148 pts who ultimately underwent SCT, the majority had autologous (96%) and 6 (4%) pts had allogeneic SCT. The majority (73%) of patients were in CR immediately prior SCT. Four pts (3%) died due to SCT-related toxicities. BV maintenance was used in 35% of pts. Exposure to BV during salvage 1 prior SCT did not affect the likelihood of receiving BV maintenance. While there was no statistically significant difference in progression free survival (PFS) between chemotherapy only and BV-containing salvage 1, there was a trend toward improved PFS with BV-containing salvage 1 as shown in Figure 1. The 2-year PFS for chemotherapy only salvage 1 was 71% (95% CI: 60-79%) vs. 80% (95% CI: 60-91%) for BV-containing salvage treatments. Conclusion: Growing number of salvage regimens are used in RR cHL. In the current practice outside of clinical trials, 23% of RR cHL pts received BV during salvage 1. In total, 37% received more than one salvage treatment and 52% received BV as part of salvage therapy prior SCT. It is unlikely that a prospective randomized trial will be conducted to compare various salvage treatment options. However, further analysis of sub-populations who may benefit from a particular regimen or optimal treatment sequences may lead to more effective and less toxic treatment strategies for pts with RR cHL. Disclosures Svoboda: Seattle Genetics: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Merck: Research Funding; Incyte: Research Funding; Pharmacyclics: Consultancy, Research Funding; AstraZeneca: Consultancy; Celgene: Research Funding; Kyowa: Consultancy; Kite: Consultancy. Andreadis:Genentech: Equity Ownership, Other: Spouse is Employee; Novartis: Honoraria, Research Funding; Amgen: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Gilead: Consultancy; Jazz Pharmaceuticals: Consultancy; Bayer: Consultancy. Feldman:Portola Pharma: Research Funding; Eisai: Research Funding; Kyowa Hakko Kirin: Research Funding; Janssen: Honoraria, Speakers Bureau; Pharmacyclics: Honoraria, Other: Travel expenses, Speakers Bureau; AbbVie: Honoraria, Other: Travel expenses, Speakers Bureau; Roche: Research Funding; Viracta: Research Funding; Trillium: Research Funding; Pfizer: Research Funding; Seattle Genetics: Consultancy, Honoraria, Other: Travel expenses, Speakers Bureau; Kite Pharma: Honoraria, Other: Travel expenses, Speakers Bureau; Bayer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Research Funding; Corvus: Research Funding; Roche: Research Funding; Cell Medica: Research Funding; Takeda: Honoraria, Speakers Bureau; Celgene: Honoraria, Research Funding, Speakers Bureau. Khan:Back Bay Life Science Advisors: Honoraria; ASCO/Conquer Cancer Foundation sponsored by Gilead Sciences: Research Funding. Moskowitz:ADC Therapeutics: Consultancy; Cell Medica: Consultancy; Merck: Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Takeda Pharmaceuticals: Consultancy; Seattle Genetics: Consultancy, Honoraria, Research Funding; Takeda Pharmaceuticals: Consultancy; miRagen Therapeutics Inc: Consultancy, Research Funding; ADC Therapeutics: Consultancy; Cell Medica: Consultancy; miRagen Therapeutics Inc: Consultancy, Research Funding; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Erytech Pharma: Consultancy; miRagen Therapeutics Inc: Consultancy, Research Funding; miRagen Therapeutics Inc: Consultancy, Research Funding; Incyte: Research Funding; Cell Medica: Consultancy; miRagen Therapeutics Inc: Consultancy, Research Funding; Merck: Research Funding; Merck: Research Funding; ADC Therapeutics: Consultancy; Seattle Genetics: Consultancy, Honoraria, Research Funding; Cell Medica: Consultancy; Seattle Genetics: Consultancy, Honoraria, Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; ADC Therapeutics: Consultancy; miRagen Therapeutics Inc: Consultancy, Research Funding; miRagen Therapeutics Inc: Consultancy, Research Funding; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Merck: Research Funding; Merck: Research Funding; Merck: Research Funding; Merck: Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; ADC Therapeutics: Consultancy; Incyte: Research Funding; Cell Medica: Consultancy; Takeda Pharmaceuticals: Consultancy; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; miRagen Therapeutics Inc: Consultancy, Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Incyte: Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; miRagen Therapeutics Inc: Consultancy, Research Funding; Cell Medica: Consultancy; miRagen Therapeutics Inc: Consultancy, Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Merck: Research Funding; miRagen Therapeutics Inc: Consultancy, Research Funding; Incyte: Research Funding; ADC Therapeutics: Consultancy; Erytech Pharma: Consultancy; ADC Therapeutics: Consultancy; Erytech Pharma: Consultancy; ADC Therapeutics: Consultancy; Erytech Pharma: Consultancy; ADC Therapeutics: Consultancy; Erytech Pharma: Consultancy; Incyte: Research Funding; Takeda Pharmaceuticals: Consultancy; Takeda Pharmaceuticals: Consultancy; Seattle Genetics: Consultancy, Honoraria, Research Funding; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; ADC Therapeutics: Consultancy; Erytech Pharma: Consultancy; Erytech Pharma: Consultancy; Bristol-Myers Squibb: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Erytech Pharma: Consultancy; Bristol-Myers Squibb: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Erytech Pharma: Consultancy; Bristol-Myers Squibb: Consultancy, Research Funding; miRagen Therapeutics Inc: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Erytech Pharma: Consultancy; Bristol-Myers Squibb: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Erytech Pharma: Consultancy; Erytech Pharma: Consultancy; Erytech Pharma: Consultancy; Merck: Research Funding; Incyte: Research Funding; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Incyte: Research Funding; Takeda Pharmaceuticals: Consultancy; Bristol-Myers Squibb: Consultancy, Research Funding; miRagen Therapeutics Inc: Consultancy, Research Funding; Cell Medica: Consultancy; Takeda Pharmaceuticals: Consultancy; Takeda Pharmaceuticals: Consultancy; Cell Medica: Consultancy; Incyte: Research Funding; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Takeda Pharmaceuticals: Consultancy; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Merck: Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Takeda Pharmaceuticals: Consultancy; Merck: Research Funding; Merck: Research Funding; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Erytech Pharma: Consultancy; Seattle Genetics: Consultancy, Honoraria, Research Funding; Merck: Research Funding; Merck: Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Incyte: Research Funding; Takeda Pharmaceuticals: Consultancy; Bristol-Myers Squibb: Consultancy, Research Funding; Cell Medica: Consultancy; Cell Medica: Consultancy; Cell Medica: Consultancy; Cell Medica: Consultancy; Erytech Pharma: Consultancy; Takeda Pharmaceuticals: Consultancy; Bristol-Myers Squibb: Consultancy, Research Funding; Takeda Pharmaceuticals: Consultancy; Cell Medica: Consultancy; Cell Medica: Consultancy; Incyte: Research Funding; Incyte: Research Funding; Cell Medica: Consultancy; ADC Therapeutics: Consultancy; Incyte: Research Funding; miRagen Therapeutics Inc: Consultancy, Research Funding; Merck: Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; miRagen Therapeutics Inc: Consultancy, Research Funding; Takeda Pharmaceuticals: Consultancy; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; ADC Therapeutics: Consultancy; ADC Therapeutics: Consultancy; ADC Therapeutics: Consultancy; ADC Therapeutics: Consultancy; Incyte: Research Funding; Takeda Pharmaceuticals: Consultancy; Incyte: Research Funding; Incyte: Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding. Portell:Roche/Genentech: Research Funding; Xencor: Research Funding; TG Therapeutics: Research Funding; Acerta/AstraZeneca: Research Funding; Kite: Consultancy, Research Funding; BeiGene: Consultancy, Research Funding; Bayer: Consultancy; Amgen: Consultancy; Genentech: Consultancy, Research Funding; Janssen: Consultancy; Pharmacyclics: Consultancy; AbbVie: Research Funding; Infinity: Research Funding. Dwivedy Nasta:Merck: Consultancy, Other: data safety monitorin; 47 (Forty Seven): Research Funding; Roche: Research Funding; Rafael: Research Funding; Debiopharm: Research Funding; Aileron: Research Funding; ATARA: Research Funding; Pharmacyclics: Research Funding; Celgene: Honoraria; Millenium/takeda: Research Funding. Landsburg:Takeda: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Curis, INC: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Curis, INC: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Seattle Genetics: Speakers Bureau; Seattle Genetics: Speakers Bureau; Takeda: Research Funding; Triphase: Research Funding; Triphase: Research Funding. Barta:Mundipharma: Honoraria; Seattle Genetics: Honoraria, Research Funding; Takeda: Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees; Celgene: Research Funding; Mundipharma: Honoraria; Bayer: Consultancy, Research Funding; Merck: Research Funding; Celgene: Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees. Chong:Tessa: Consultancy; Merck: Research Funding; Novartis: Consultancy. Schuster:Acerta: Consultancy, Honoraria, Research Funding; AstraZeneca: Consultancy, Honoraria; Nordic Nanovector: Consultancy, Honoraria; Genentech: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria, Research Funding; Merck: Consultancy, Honoraria, Research Funding; Gilead: Consultancy, Honoraria, Research Funding; Pharmacyclics: Consultancy, Honoraria, Research Funding; Loxo Oncology: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Novartis: Honoraria, Patents & Royalties: Combination CAR-T and PD-1 Inhibitors, Research Funding. OffLabel Disclosure: Brentaximab vedotin containing salvage in Hodgkin lymphoma

Background/methods: Identifying relapsed or refractory (RR) classical Hodgkin lymphoma (cHL) patients (pts) eligible for lower-intensity second-line therapy (SLT) will aid in improving short-term and long-term treatment-related toxicity. We conducted a phase II study evaluating PET-adapted SLT with single-agent brentuximab vedotin (BV) followed by augICE (augmented ifosfamide, carboplatin, etoposide) for BV-naïve patients with RR cHL (Lancet Oncology 2015). In this study, patients who failed 1 line of therapy for cHL were treated with 2 or 3 cycles of BV, 1.2mg/Kg, administered weekly, 3 weeks on and 1 week off. Those who achieved PET-normalization proceeded directly to consolidation with autologous stem cell transplantation (ASCT). Those with persistent abnormalities on PET received 2 cycles of augICE prior to consideration for ASCT. At 3-year follow-up, outcomes for patients who achieved PET-normalization following BV alone or BV followed by augICE were identical. Furthermore, baseline metabolic tumor volume (bMTV) predicted outcome and improved the prognostic significance of pre-ASCT PET (Blood 2017). We now report 6-year follow-up from this study evaluating PET-adapted SLT with BV and augICE. Results: 65 pts enrolled onto this protocol, of whom 18 achieved PET-normalization (Deauville ≤ 2) after single-agent BV. These 18 pts included 8 (44%) with primary refractory disease, 7 (39%) with advanced stage disease, and 8 (44%) with extranodal disease. 17 of the 18 pts proceeded directly to ASCT and 1 pt experienced delay resulting in disease progression. That individual achieved PET-normalization following additional salvage chemotherapy (gemcitabine/vinorelbine/liposomal doxorubicin) and proceeded to ASCT. Of the other 47 pts who remained PET-positive after single-agent BV, 35 achieved PET-normalization after augICE, 9 remained PET-positive after augICE, 2 received no additional treatment before proceeding to ASCT (1 pt with Deauville 3 response to BV, 1 with Deauville 4 response), and 1 pt withdrew consent and was lost to follow-up. 64 of 65 pts proceeded to transplant and median post-ASCT follow-up is 5.98 yrs (range 4.4-7.2 yrs). 6-yr overall survival is 86%, 6-yr progression free survival (PFS) is 73%, and 6-yr time to tumor progression (TTP) is 78%. Overall, there have been 8 deaths, which were due to disease progression (n=5), progressive multifocal leukencephalopathy (PML) (n=1), treatment-related respiratory failure (n=1), and myelodysplastic syndrome (MDS) (n=1). Pts who proceeded to ASCT following single-agent BV achieved durable remission with 6-year TTP of 80%. Outcomes for the BV-only group were similar to those who required BV and augICE to become PET-negative (6-yr TTP 82%) and were more favorable than for those who remained PET-positive after BV and augICE (6-yr TTP 56%, p=0.058) (Figure 1). With 6-yr follow-up, bMTV > 109.5 cm3remained prognostic for the entire group and aided in predicting which pts ultimately developed disease progression. In particular, among the pts who achieved PET-normalization with BV alone prior to ASCT, 6-yr TTP was 92% vs 40% for low and high bMTV respectively, p=0.017 (Figure 2). Similarly, for pts who achieved PET-normalization following BV and augICE, 6-yr TTP was 85% vs 33% for low and high bMTV respectively, p=0.002. Conclusions: For pts with RR cHL, long-term remission can be achieved following lower-intensity SLT with single-agent BV followed by ASCT, provided PET-normalization is achieved after single-agent BV. bMTV identifies which pts within this favorable group are likely to develop disease progression and therefore treatment strategies using bMTV to direct intensity of therapy should be explored. Disclosures Moskowitz: Erytech Pharma: Consultancy; Incyte: Research Funding; Cell Medica: Consultancy; Incyte: Research Funding; ADC Therapeutics: Consultancy; Cell Medica: Consultancy; Takeda Pharmaceuticals: Consultancy; miRagen Therapeutics Inc: Consultancy, Research Funding; ADC Therapeutics: Consultancy; Merck: Research Funding; Takeda Pharmaceuticals: Consultancy; Takeda Pharmaceuticals: Consultancy; Erytech Pharma: Consultancy; Merck: Research Funding; Cell Medica: Consultancy; Cell Medica: Consultancy; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; miRagen Therapeutics Inc: Consultancy, Research Funding; Takeda Pharmaceuticals: Consultancy; Merck: Research Funding; miRagen Therapeutics Inc: Consultancy, Research Funding; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Incyte: Research Funding; Takeda Pharmaceuticals: Consultancy; Takeda Pharmaceuticals: Consultancy; Merck: Research Funding; Takeda Pharmaceuticals: Consultancy; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Cell Medica: Consultancy; Seattle Genetics: Consultancy, Honoraria, Research Funding; Merck: Research Funding; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Cell Medica: Consultancy; Seattle Genetics: Consultancy, Honoraria, Research Funding; Incyte: Research Funding; Cell Medica: Consultancy; Seattle Genetics: Consultancy, Honoraria, Research Funding; Takeda Pharmaceuticals: Consultancy; Merck: Research Funding; Erytech Pharma: Consultancy; Incyte: Research Funding; Incyte: Research Funding; Incyte: Research Funding; miRagen Therapeutics Inc: Consultancy, Research Funding; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; miRagen Therapeutics Inc: Consultancy, Research Funding; miRagen Therapeutics Inc: Consultancy, Research Funding; Erytech Pharma: Consultancy; Bristol-Myers Squibb: Consultancy, Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; miRagen Therapeutics Inc: Consultancy, Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Takeda Pharmaceuticals: Consultancy; miRagen Therapeutics Inc: Consultancy, Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Incyte: Research Funding; Merck: Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; miRagen Therapeutics Inc: Consultancy, Research Funding; Erytech Pharma: Consultancy; Erytech Pharma: Consultancy; Incyte: Research Funding; Takeda Pharmaceuticals: Consultancy; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Incyte: Research Funding; Erytech Pharma: Consultancy; Merck: Research Funding; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Merck: Research Funding; ADC Therapeutics: Consultancy; Erytech Pharma: Consultancy; Cell Medica: Consultancy; Seattle Genetics: Consultancy, Honoraria, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; ADC Therapeutics: Consultancy; Merck: Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Merck: Research Funding; Cell Medica: Consultancy; Bristol-Myers Squibb: Consultancy, Research Funding; Cell Medica: Consultancy; Takeda Pharmaceuticals: Consultancy; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Takeda Pharmaceuticals: Consultancy; Merck: Research Funding; Merck: Research Funding; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Takeda Pharmaceuticals: Consultancy; Erytech Pharma: Consultancy; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Cell Medica: Consultancy; ADC Therapeutics: Consultancy; Erytech Pharma: Consultancy; Seattle Genetics: Consultancy, Honoraria, Research Funding; Erytech Pharma: Consultancy; Takeda Pharmaceuticals: Consultancy; Seattle Genetics: Consultancy, Honoraria, Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; ADC Therapeutics: Consultancy; ADC Therapeutics: Consultancy; ADC Therapeutics: Consultancy; miRagen Therapeutics Inc: Consultancy, Research Funding; ADC Therapeutics: Consultancy; Erytech Pharma: Consultancy; Bristol-Myers Squibb: Consultancy, Research Funding; ADC Therapeutics: Consultancy; Cell Medica: Consultancy; Erytech Pharma: Consultancy; miRagen Therapeutics Inc: Consultancy, Research Funding; miRagen Therapeutics Inc: Consultancy, Research Funding; Erytech Pharma: Consultancy; Incyte: Research Funding; Cell Medica: Consultancy; Incyte: Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; miRagen Therapeutics Inc: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; miRagen Therapeutics Inc: Consultancy, Research Funding; Incyte: Research Funding; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; ADC Therapeutics: Consultancy; ADC Therapeutics: Consultancy; ADC Therapeutics: Consultancy; Incyte: Research Funding; ADC Therapeutics: Consultancy; Takeda Pharmaceuticals: Consultancy; Erytech Pharma: Consultancy; Bristol-Myers Squibb: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Incyte: Research Funding; Cell Medica: Consultancy; Merck: Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Cell Medica: Consultancy; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Merck: Research Funding; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; miRagen Therapeutics Inc: Consultancy, Research Funding; ADC Therapeutics: Consultancy. Horwitz:Seattle Genetics: Consultancy, Research Funding; Forty-Seven: Research Funding; Trillium: Research Funding; Miragen: Consultancy; Portola: Consultancy; Infinity/Verastem: Consultancy, Research Funding; Affimed: Consultancy; Innate Pharma: Consultancy; Corvus Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Innate Pharma: Consultancy; Trillium: Research Funding; Portola: Consultancy; Aileron: Research Funding; Mundipharma: Consultancy; Seattle Genetics: Consultancy, Research Funding; Millennium/Takeda: Consultancy, Research Funding; Infinity/Verastem: Consultancy, Research Funding; Affimed: Consultancy; Mundipharma: Consultancy; Aileron: Research Funding; Forty-Seven: Research Funding; ADCT Therapeutics: Research Funding; Miragen: Consultancy; ADCT Therapeutics: Research Funding; Kyowa Hakko Kirin: Consultancy; ADCT Therapeutics: Research Funding; Astex: Consultancy; Corvus Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Kyowa Hakko Kirin: Consultancy; Astex: Consultancy; Affimed: Consultancy; Millennium/Takeda: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding; Miragen: Consultancy; Kyowa Hakko Kirin: Consultancy; Miragen: Consultancy; Mundipharma: Consultancy; Aileron: Research Funding; ADCT Therapeutics: Research Funding; Mundipharma: Consultancy; Millennium/Takeda: Consultancy, Research Funding; Astex: Consultancy; Corvus Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Corvus Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Innate Pharma: Consultancy; Celgene: Consultancy, Research Funding; Forty-Seven: Research Funding; Astex: Consultancy; Portola: Consultancy; Seattle Genetics: Consultancy, Research Funding; Kura: Consultancy; Aileron: Research Funding; Kyowa Hakko Kirin: Consultancy; Millennium/Takeda: Consultancy, Research Funding; Trillium: Research Funding; Innate Pharma: Consultancy; Trillium: Research Funding; Kura: Consultancy; Infinity/Verastem: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Forty-Seven: Research Funding; Portola: Consultancy; Kura: Consultancy; Affimed: Consultancy; Kura: Consultancy; Celgene: Consultancy, Research Funding; Infinity/Verastem: Consultancy, Research Funding. Kumar:Seattle Genetics: Research Funding. Matasar:Genentech, Inc.: Consultancy, Honoraria, Other: Travel, accommodation, expenses , Research Funding; Bayer: Consultancy, Honoraria, Other; Roche: Consultancy, Honoraria, Other: Travel, accommodation, expenses , Research Funding; Merck: Consultancy, Equity Ownership; Juno Therapeutics: Consultancy; Teva: Consultancy; Rocket Medical: Consultancy, Research Funding; Seattle Genetics: Consultancy, Honoraria, Other: Travel, accomodation, expenses, Research Funding; Daiichi Sankyo: Consultancy; GlaxoSmithKline: Honoraria, Research Funding; Pharmacyclics: Consultancy, Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Bayer: Other: Travel, accommodation, expenses. Noy:Medscape: Honoraria; Prime Oncology: Honoraria; NIH: Research Funding; Janssen: Consultancy; Pharamcyclics: Research Funding; Raphael Pharma: Research Funding. Palomba:Hemedicus: Other: Immediate Family Member, Speakers Bureau ; Merck & Co Inc.: Other: Immediate Family Member, Consultancy (includes expert testimony); Seres Therapeutics: Other: Immediate Family Member, Equity Ownership and Membership on an entity's Board of Directors or advisory committees; STRAXIMM: Other: Immediate Family Member, Membership on an entity's Board of Directors or advisory committees; Kite Pharmaceuticals: Other: Immediate Family Member, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; Noble Insights: Consultancy; Evelo: Other: Immediate family member, Equity Ownership; MSK (IP for Juno and Seres): Other: Immediate Family Member, Patents & Royalties - describe: intellectual property rights . Shah:Amgen: Research Funding; Janssen: Research Funding. Perales:Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol-Meyers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bellicum: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Omeros: Honoraria, Membership on an entity's Board of Directors or advisory committees; Nektar Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees; MolMed: Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Merck: Consultancy, Honoraria; Kyte/Gilead: Research Funding; Servier: Membership on an entity's Board of Directors or advisory committees; Medigene: Membership on an entity's Board of Directors or advisory committees; Miltenyi: Research Funding; NexImmune: Membership on an entity's Board of Directors or advisory committees; Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Sauter:Juno Therapeutics: Consultancy, Research Funding; Sanofi-Genzyme: Consultancy, Research Funding; Spectrum Pharmaceuticals: Consultancy; Novartis: Consultancy; Genmab: Consultancy; Precision Biosciences: Consultancy; Kite/Gilead: Consultancy; Celgene: Consultancy; GSK: Consultancy. Straus:Elsevier (PracticeUpdate): Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria; Hope Funds for Cancer Research: Membership on an entity's Board of Directors or advisory committees. Younes:BMS: Research Funding; Syndax: Research Funding; Genentech: Research Funding; Roche: Consultancy, Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Curis: Honoraria, Research Funding; Merck: Honoraria, Research Funding; Abbvie: Honoraria; Biopath: Consultancy; Xynomics: Consultancy; Epizyme: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; HCM: Consultancy; Takeda: Honoraria; Pharmacyclics: Research Funding; AstraZeneca: Research Funding. Zelenetz:MEI Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bayer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Genentech/Roche: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Morphosys: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bayer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics/AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Verastem: Consultancy, Membership on an entity's Board of Directors or advisory committees; Beigene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics/AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; MEI Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; DAVA Oncology: Consultancy, Membership on an entity's Board of Directors or advisory committees; Karyopharm: Consultancy, Membership on an entity's Board of Directors or advisory committees; Beigene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Verastem: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Astra-Zeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees; Morphosys: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; DAVA Oncology: Consultancy, Membership on an entity's Board of Directors or advisory committees; Genentech/Roche: Consultancy, Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Karyopharm: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Astra-Zeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees. Moskowitz:Merck: Consultancy, Research Funding; ADC Therapeutics: Research Funding; Seattle Genetics, Inc.: Consultancy, Research Funding; Celgene: Consultancy; Pharmacyclics: Research Funding; Genentech: Consultancy, Research Funding. OffLabel Disclosure: Brentuximab vedotin is not FDA approved for use in the second-line setting for Hodgkin lymphoma.

In this issue of Blood, Witzig et al report on the promising in vitro and in vivo activity of everolimus in T-cell lymphoma (TCL) and pave the way for future combination studies.

This multicenter pilot study assessed the safety and efficacy of brentuximab vedotin (BV) and AVD (adriamycin, vinblastine, and dacarbazine) followed by 30 Gy involved site radiation therapy (ISRT). Patients with newly diagnosed, early stage classical Hodgkin lymphoma (HL) with unfavorable-risk features were treated with 4 cycles of BV and AVD. Patients who achieved a negative positron emission tomography (PET) scan (Deauville score of 1-3) received 30 Gy ISRT. Thirty patients received treatment and were assessable for toxicity. Twenty-nine patients completed 4 cycles of BV + AVD, and 25 patients BV + AVD + 30 Gy ISRT. No clinically significant noninfectious pneumonitis was observed. Serious adverse events (≥grade 3) were reported in 4 patients, including febrile neutropenia, peripheral neuropathy, and hypertension. After 2 and 4 cycles of BV + AVD, 90% (26 of 29) and 93% (27 or 29) of patients achieved a negative PET scan, respectively. Two patients with biopsy-proven primary refractory HL were treated off-study. All 25 patients who completed BV + AVD + ISRT achieved a complete response. With a median follow-up of 18.8 months, by intent to treat, the 1-year progression-free survival is 93.3% (95% confidence interval, 84-102). Overall, the treatment was well-tolerated with no evidence of significant pulmonary toxicity. The majority of patients (≥90%) achieved negative interim PET scans after 2 and 4 cycles of BV + AVD. Excluding the 2 primary refractory patients, all patients are disease free, suggesting that this is a highly active treatment program even in patients with substantial disease bulk. This trial was registered at www.clinicaltrials.gov as #NCT01868451.

Background: Current treatment of advanced stage Mycosis fungoides (MF) and Sézary syndrome (SS) remains unsatisfactory. Complete responses (CR) are typically Methods: This single-arm, multicenter study by the Cancer Immunotherapy Trials Network (CITN) enrolled 24 patients with MF/SS stages IB-IV, with at least one prior systemic therapy. Pembrolizumab was administered at 2 mg/kg every 3 weeks for up to two years. The primary endpoint was overall response rate (ORR) using global response criteria according to the ISCL/EORTC consensus guidelines. Skin responses were measured by mSWAT. Secondary endpoints were safety/tolerability, time to response (TTR), duration of response (DOR) and progression-free survival (PFS). Correlative studies included immunohistochemistry (IHC), mass cytometry, whole exome sequencing, gene expression profiling, and serum cytokine analysis. Results: Patients had advanced stage disease (23/24 with stage IIB-IV MF/SS), and were heavily pretreated (median of 4 prior systemic therapies). The ORR was 38% with 2 CR and 7 PR. Of the 9 responding patients, 6 had ≥90% improvement in skin disease by mSWAT. The median TTR was 11 weeks. Responses were durable, with 8 of 9 responses ongoing at last follow up (median DOR 64 weeks, range 32-153 weeks). One responding patient progressed 2 months after discontinuing treatment due to an adverse event (AE). The median PFS was not reached. Overall, the toxicity profile was similar to prior studies of pembrolizumab. Four patients discontinued treatment due to treatment related serious AEs of duodenitis, pneumonitis, hepatitis, and corneal ulcer. Skin flare reactions were observed early in the treatment course in 40% of patients with SS, but none with MF. The skin flare reactions did not result in any treatment discontinuation, and did not correlate with subsequent response to treatment. There was no significant association between response and clinical characteristics including stage, disease type (MF vs. SS), or number of prior therapies. IHC assessment of PD-1, PD-L1, and PD-L2 did not predict response. Treatment resulted in an increase of PD-L1 expression by both IHC and nanoString analysis. A nanoString18 gene signature of tumor inflammation that is predictive of response to pembrolizumab in other tumor types was not predictive in this cohort. High dimensional mass cytometry enabled precise identification and phenotyping of malignant T cells. There was a positive correlation between PD-1 expression on the malignant T cells and development of the skin flare reaction. Whole exome sequencing revealed genomic disruptions of PD-1 signaling including copy loss of PD-1. No associations were found between outcomes and genomic events involving the PD1/PD-L1 axis, total mutation number, or neoantigen numbers. Conclusions: The 38% ORR rate in this heavily pretreated population was 38% with a highly encouraging DOR of 64 weeks. No predictive biomarkers have emerged thus far, but additional studies are ongoing. Additional combination studies with pembrolizumab are warranted to improve response rates. Figure. Figure. Disclosures Khodadoust: Innate Pharma: Research Funding. Porcu:Innate Pharma: Consultancy. Foss:Miragen: Consultancy, Speakers Bureau; Seattle genetics: Consultancy; Spectrum: Consultancy; Mallinkrodt: Consultancy. Moskowitz:Bristol Myers-Squibb: Consultancy, Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Incyte: Research Funding; Merck: Research Funding; Takeda: Honoraria; ADC Therapeutics: Research Funding. Shustov:Seattle Genetics: Research Funding. Sokol:Seattle Genetics: Consultancy; Mallinckrodt Pharmaceuticals: Consultancy; Spectrum Pharmaceuticals: Consultancy. Yearley:Merck: Employment. Horwitz:Mundipharma: Consultancy; Celgene: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding; ADC Therapeutics: Consultancy, Research Funding; Kyowa-Hakka-Kirin: Consultancy, Research Funding; Forty Seven: Consultancy, Research Funding; Millennium/Takeda: Consultancy, Research Funding; Infinity/Verastem: Consultancy, Research Funding; Aileron Therapeutics: Consultancy, Research Funding; Portola: Consultancy; Trillium: Consultancy; Innate Pharma: Consultancy; Spectrum: Research Funding; Corvus: Consultancy. Kim:miRagen: Research Funding; Horizon Pharma: Consultancy, Research Funding; Neumedicine: Consultancy, Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Galderma: Research Funding; Soligenix: Research Funding; Eisai: Membership on an entity's Board of Directors or advisory committees, Research Funding; Tetralogic: Research Funding; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees; Portola: Research Funding; Merck: Research Funding; Medivir: Membership on an entity's Board of Directors or advisory committees; Kyowa-Kirin-Pharma: Membership on an entity's Board of Directors or advisory committees, Research Funding; Innate Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Forty Seven Inc: Research Funding.

Introduction: Mycosis fungoides (MF) is an epidermotropic primary cutaneous T-cell lymphoma. Its leukemic variant is recognized as Sezary syndrome (SS), although a study suggests that MF and SS may be distinct entities arising from different T-cell subsets; effector memory T-cells and central memory T-cells, respectively (Campbell JJ et al. Blood. 2010;116(5):767-771). Recent studies show bright PD-1 (T follicular helper (TFH)-like), and CD25/FOXP3 (Treg-like) expression in a subset of MF/SS cases by immunohistochemistry, and these findings raise the possibility that the cell-of-origin of MF/SS may be heterogeneous (Cetinozman F et al. Arch Dermatol. 2012;148(12):1379-1385, Prince HM et al. J Am Acad Dermatol. 2012;67(5):867-875, Satou A et al. Histopathology. 2016;68(7):1099-1108). In order to address this question comprehensively, we evaluated the expression levels of PD-1 on lymphoma cells of MF/SS patients by flow cytometry in peripheral blood (PB), and the results were compared to other T-cell lymphomas including angioimmunoblastic T-cell lymphoma (AITL). We also performed extensive flow cytometric immunophenotyping to algorithmically assess cell-of-origin of MF/SS with a subset of patients (Maecker HT et al. Nat Rev Immunol. 2012;12(3):191-200). Methods: Patients who were diagnosed with T-cell lymphoma at Memorial Sloan Kettering Cancer Center between August 2015 and August 2018, and have circulating lymphoma cells in PB were selected for this study. Diagnosis of MF/SS was confirmed by skin biopsy along with the clinical presentation. PD-1 expression levels on lymphoma cells in PB were evaluated by 10-color flow cytometry including anti-CD279 (PD-1) antibody. Immunophenotyping to assess cell-of-origin of lymphoma cells (T-cell subset analysis) was performed with 3 tube/10-color flow cytometry, using the following antibodies: CD3, CD4, CD8, CD25, CD27, CD45RA, CD45RO, CD127, CD279, HLA-DR, CCR4, CCR6, CCR7, and CXCR3. Results: Our study group is composed of 82 patients, including 34 MF/SS, 22 AITL, 2 anaplastic large cell lymphoma, ALK-negative (ALCL, ALK-), 8 adult T-cell leukemia/ lymphoma (ATLL), 5 peripheral T-cell lymphoma, NOS (PTCL-NOS), 5 T-cell large granular lymphocytic leukemia (T-LGL), and 6 T-cell prolymphocytic leukemia (T-PLL). The expression levels of PD-1 of lymphoma cells of the patients with MF/SS were widely variable (mean fluorescence intensity (MFI); Mean 949.0; range 101.0 - 3188.6) (Fig 1). 32.4% (11/34) of MF/SS cases showed high PD-1 expression equivalent to that of AITL cases. T-cell subset analysis to assess cell-of-origin was performed in 14 patients, including 4 patients with MF and 10 patients with SS (Table 1). While routine flow cytometric analysis showed similar immunophenotype other than the variation of PD-1, by flow cytometric T-cell subset analysis, we identified 3 patients with lymphoma cells showing T follicular helper (TFH) immunophenotype with CCR4+/CXCR3-/CCR6- and bright CD279 expression (case 2, 6, 8) (Table 2). Lymphoma cells of 8 patients showed effector memory CD4+ T-cell immunophenotype defined as CCR7-/CD45RA- (case 1, 3, 4, 5, 9, 10, 12, 13). Among these 8 patients, 2 patients had a subset of lymphoma cells showing central memory CD4+ T-cell immunophenotype defined as CCR7+/CD45RA- (case 5 and 12), and 2 patients had a subset with effector CD4+ cell immunophenotype defined as CCR7-/CD45RA+ (case 9, 13). 2 patients (case 7, 14) showed central memory CD4+ T-cell immunophenotype only, and 1 patient showed effector CD4+ T-cell immunophenotype only (case 11) (Table 2, Fig 2, 3). No cases showed Treg immunophenotype. The small sample size limited any subset analysis but we did not see obvious association between cell-of-origin of lymphoma cells and clinical features including prognosis, nodal presentation, number of circulating tumor cells, and histological findings in this study with limited number of cases. Conclusions: Lymphoma cells in MF/SS show marked heterogeneity of expression of PD-1 including clear subset arising from TFH. This suggests MF/SS may represent multiple biological entities. Further studies will be necessary to investigate the clinical significance of cell-of-origin of MF/SS. Disclosures Yabe: Y-mAbs Therapeutics: Consultancy. Moskowitz:ADC Therapeutics: Research Funding; Incyte: Research Funding; Bristol Myers-Squibb: Consultancy, Research Funding; Takeda: Honoraria; Merck: Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding. Horwitz:Infinity/Verastem: Consultancy, Research Funding; Trillium: Consultancy; Innate Pharma: Consultancy; Portola: Consultancy; Kyowa-Hakka-Kirin: Consultancy, Research Funding; Aileron Therapeutics: Consultancy, Research Funding; ADC Therapeutics: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding; Mundipharma: Consultancy; Millennium/Takeda: Consultancy, Research Funding; Forty Seven: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Spectrum: Research Funding; Corvus: Consultancy.

Introduction: The JAK/STAT pathway is frequently activated in peripheral T-cell lymphomas (PTCLs) and cutaneous T cell lymphomas (CTCLs) however the utility of JAK inhibition as a therapeutic strategy in these diseases is not known. We hypothesize that JAK/STAT pathway alteration (defined by elevated phospho-STAT3 (pSTAT3) expression or presence of JAK or STAT mutations) will predict for sensitivity to JAK inhibition in PTCL and CTCL. We are conducting a phase II study of ruxolitinib, a JAK1/2 inhibitor, in which we assess its efficacy in a cohort of patients (pts) with PTCL and CTCL enriched for JAK/STAT pathway alterations. Methods: This is an investigator-initiated multi-center phase II study evaluating the efficacy of ruxolitinib 20mg twice daily in PTCL and CTCL. Pts with relapsed or refractory (rel/ref) PTCL or CTCL following at least 1 systemic therapy are eligible to enroll onto one of three of the following cohorts: Cohort 1: Disease determined to have JAK or STAT mutations. Cohort 2: Disease with functional evidence of JAK/STAT activation (defined as ≥ 30% pSTAT3 expression by immunohistochemistry). Cohort 3: Disease does not meet criteria for cohort 1 or 2. Pts initially enrolled onto cohort 3 and determined to have JAK/STAT mutations or functional JAK/STAT activation after enrollment are moved to cohorts 1 or 2. Cohorts 1, 2, and 3 are enrolling up to 17, 17 and 18 pts respectively by Simon 2-stage design. Pts receive treatment until progression and are assessed for response to therapy after cycles 2, 5 and every three cycles thereafter. Results: The first stage has been completed for cohorts 1 and 3 and 33 out of planned 52 pts enrolled to date. Details regarding histology, mutations, and treatment course appear in the table and figure. For Cohort 1, 10 out of planned 17 pts enrolled. Mutations involved JAK1 (1), JAK3 (3), STAT3 (4), and STAT5B (4). Out of 8 evaluable pts, overall response rate (ORR) was 38% with 3 partial responses (PR). In addition, 3 pts have ongoing stable disease (SD) lasting 8-18 months. Altogether, 75% achieved clinical benefit (objective response or SD >6 months). For Cohort 2, 5 out of planned 17 pts enrolled. Among the 5 evaluable pts, ORR was 40% with 1 complete response (CR) and 1 PR. For Cohort 3, 18 pts out of planned 18 pts enrolled. Out of 14 evaluable pts, ORR was 21% with 3 PRs. Grade 3 or higher drug-related adverse events (AEs) observed among the 33 pts enrolled included anemia (4), neutropenia (7), thrombocytopenia (2), and lymphopenia (7). Treatment related serious adverse events (SAEs) included 1 episode each of HSV-1 stomatitis, spontaneous bacterial peritonitis, febrile neutropenia, and herpes zoster. Conclusion: Responses observed across all three cohorts of pts with PTCL and CTCL with a trend towards higher rates and more durable responses among pts with JAK/STAT alterations. Efficacy of ruxolitinib in PTCL and CTCL provides proof of concept that JAK/STAT activation is a viable target in T-cell lymphomas. Enrollment onto cohorts 1 and 2 and assessment for JAK/STAT alternations among pts in cohort 3 continues. Figure. Figure. Disclosures Moskowitz: Incyte: Research Funding; ADC Therapeutics: Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Bristol Myers-Squibb: Consultancy, Research Funding; Merck: Research Funding; Takeda: Honoraria. Jacobsen:Merck: Consultancy; AstraZeneca: Consultancy; Seattle Genetics: Consultancy. Weinstock:Travera: Equity Ownership; Astra Zeneca, JAX, Samumed, Regeneron, Sun Pharma, Prescient: Patents & Royalties; Novartis, Dragonfly, Travera, DxTerity, Travera: Consultancy; Novartis, Astra Zeneca, Abbvie, Aileron, Surface Oncology, Daiichi Sankyo: Research Funding; Novartis: Consultancy, Research Funding; Genentech/Roche, Monsanto: Consultancy. Horwitz:Aileron Therapeutics: Consultancy, Research Funding; Portola: Consultancy; Celgene: Consultancy, Research Funding; ADC Therapeutics: Consultancy, Research Funding; Spectrum: Research Funding; Kyowa-Hakka-Kirin: Consultancy, Research Funding; Infinity/Verastem: Consultancy, Research Funding; Innate Pharma: Consultancy; Trillium: Consultancy; Forty Seven: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding; Mundipharma: Consultancy; Millennium/Takeda: Consultancy, Research Funding; Corvus: Consultancy.

Introduction: About 20% of patients (pts) with primary mediastinal B-cell lymphoma (PMBL) are not cured after first-line treatment; those with chemosensitive relapse may benefit from autologous hematopoietic cell transplantation (auto-HCT). However, outcomes remain poor for pts with chemorefractory disease and those who have relapsed after auto-HCT. In PMBL, there is increased expression of the programmed death-1 (PD-1) ligands and expression of CD30 on tumor cells. Evasion of host immune responses by tumor cells may lead to resistance to standard chemotherapy. Nivolumab is a fully human IgG4 monoclonal antibody that binds to immune checkpoint PD-1, abrogates tumor inhibitory signals, and augments host antitumor immune response. Brentuximab vedotin (BV) is an antibody-drug conjugate that binds to CD30-expressing cells and induces apoptosis and immunogenic cell death. Combination of nivolumab and BV may therefore have synergistic antitumor activity against relapsed/refractory PMBL (rrPMBL). This study evaluated the safety and efficacy of nivolumab + BV in this pt population. Methods: This expansion cohort of a phase 1/2 open-label, single-arm, international study (NCT02581631) enrolled pts with PMBL aged ≥15 years, an Eastern Cooperative Oncology Group (ECOG) performance status ≤1, confirmed CD30 expression in ≥1% of tumor cells, measurable disease per Lugano 2014 classification, and relapsed/refractory disease after either high-dose conditioning chemotherapy and auto-HCT, or ≥2 prior multi-agent chemotherapies if auto-HCT ineligible. Nivolumab (240 mg IV flat dose) and BV (1.8 mg/kg IV, prespecified dose modifications allowed) were received every 3 weeks until disease progression or unacceptable toxicity. Pts were evaluated for safety (primary objective) continuously during treatment and at scheduled intervals during follow-up. Descriptive statistics were used to present pt characteristics and adverse events (AEs). The primary efficacy endpoint was investigator-assessed objective response rate (ORR) according to Lugano 2014 classification. Results: At database lock, 30 pts were treated with nivolumab + BV and included in this interim analysis. At enrollment, median (range) age was 35.5 (19-83) years. Thirteen pts (43%) had stage III or IV disease at initial diagnosis. Pts had received a median of 2 prior systemic therapies before enrollment, and 4 (13%) received auto-HCT (Table). Treatment-related AEs (TRAEs) were reported in 25 pts (83%). The most frequently reported TRAEs were neutropenia (27%), peripheral neuropathy (20%), and hyperthyroidism (13%). Grade 3-4 TRAEs were reported in 10 pts (33%), including 8 pts (27%) with neutropenia, 2 pts (7%) each with thrombocytopenia or decreased neutrophil count, and 1 pt (3%) each with hypersensitivity, diarrhea, or maculopapular rash. Three pts (10%) had treatment-related serious AEs, including 1 pt with grade 3-4 diarrhea and maculopapular rash, and 1 pt with grade 5 acute kidney injury. At the time of the meeting, ORR and complete remission rate will be presented based on a planned interim analysis. Conclusions: These results demonstrate that in pts with CD30-expressing rrPMBL, the combination of nivolumab and BV has a manageable safety profile and may provide a potential treatment option for this patient population. Study support: BMS. Writing support: Janice Zhou, Caudex, funded by BMS. Table. Table. Disclosures Moskowitz: Bristol Myers-Squibb: Consultancy, Research Funding; Merck: Research Funding; Incyte: Research Funding; Takeda: Honoraria; ADC Therapeutics: Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding. Cunningham:Roche pharmaceuticals: Research Funding. Barr:AbbVie, Gilead: Consultancy. Kline:iTeos: Research Funding; Merck: Honoraria, Research Funding. Kuruvilla:Gilead: Consultancy, Honoraria; Lundbeck: Honoraria; Celgene: Honoraria; BMS: Consultancy, Honoraria; Abbvie: Consultancy; Roche: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Merck: Consultancy, Honoraria; Karyopharm: Honoraria; Princess Margaret Cancer Foundation: Research Funding; Amgen: Honoraria; Leukemia and Lymphoma Society Canada: Research Funding; Seattle Genetics: Consultancy, Honoraria. Johnson:Lundbeck: Consultancy, Honoraria, Other: travel, Research Funding; Seattle Genetics: Honoraria; Merck: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria; AbbVie Inc.: Consultancy, Honoraria, Research Funding; Roche: Consultancy, Honoraria, Other: travel, Research Funding. Mehta-Shah:Spectrum: Consultancy; Bristol-Myers Squibb: Research Funding; Verastem: Research Funding; Genetech: Research Funding; Celgene: Research Funding. Manley:Seattle Genetics: Employment, Equity Ownership. Sharma:Bristol-Myers Squibb: Employment. Francis:Bristol-Myers Squibb: Employment, Other: company stock options. Cohen:Bristol-Myers Squibb: Employment, Other: company stock ownership. Zinzani:BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; PFIZER: Honoraria, Membership on an entity's Board of Directors or advisory committees; PFIZER: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Speakers Bureau; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celltrion: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Bayer: Membership on an entity's Board of Directors or advisory committees; Astra Zeneca: Speakers Bureau; TG Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees; TG Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees; Merck: Honoraria, Membership on an entity's Board of Directors or advisory committees; SERVIER: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Verastem: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: Membership on an entity's Board of Directors or advisory committees; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; MSD: Honoraria, Speakers Bureau; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Bayer: Membership on an entity's Board of Directors or advisory committees; Merck: Honoraria, Membership on an entity's Board of Directors or advisory committees.