Abstract: 7533 Background: Peripheral T-cell lymphomas (PTCL) have suboptimal outcomes with conventional chemotherapy. Autologous hematopoietic stem cell transplant (AHCT) is a therapeutic strategy for patients in first complete or partial remission (CR1 or PR1), with median progression-free survival (PFS) after AHCT of 36-48% by intent to treat (d’Amore et al JCO 2012, Reimer et al JCO 2009). Romidepsin (romi) is a histone deacetylase inhibitor approved for treatment of relapsed/refractory T-cell lymphoma. We present updated data of the first multicenter study to evaluate PFS of patients (pts) receiving maintenance therapy with romi after AHCT. Methods: This was a phase 2, open-label, investigator-initiated study (expected PFS 45%, desired PFS 70%; success achieved if 15 or more pts out of 25 were progression-free at 2 years post-AHCT). 26 pts transplanted in CR1 or PR1 were evaluable for the primary endpoint of 2-year PFS (Cohort 1, Table). An exploratory cohort (Cohort 2, n=7) enrolled pts either transplanted ≥ CR/PR2 (n=5) or with high risk histologies (n=2). Pts underwent AHCT with carmustine, etoposide, cytarabine and melphalan (BEAM) conditioning. Maintenance romi 14 mg/m2 started days 42-80 post AHCT; every other week through 6 mon, every 3 weeks through 1 year and every 4 weeks through 2 years post AHCT. PFS was estimated by Kaplan-Meier. Results: 47 pts consented; 13 did not receive romi (no AHCT, n=2; relapse before romi, n=3; cardiac comorbidity, n=3, patient declined, n=5). 1 consented pt did not have PTCL. 15 out of the first 25 pts in Cohort 1 were progression free after 2 years; median follow up of 31 mon (21 - 36 mon). Estimated 2-year PFS was 62% (45-83%, 95% CI); median PFS 30 mon (12.0- NA, 95% CI). In Cohort 2, estimated 2-year PFS was 43% (18 – 100, 95% CI); median follow up of 30 mon (range, 24 – 37 mon); median PFS 14 mon (5 – NA, 95% CI). Across cohorts, 5 pts required dose reduction. The most common toxicities (≥10% of pts, all grades) were fatigue (n=24, 73%), decreased platelets (n=16, 48%) and anemia (n=16, 48%). Conclusions: While the study did not meet its desired primary efficacy endpoint, maintenance romi was well-tolerated with an estimated 2-year PFS of 62%, greater than historical data. A larger, randomized study would be needed to determine the superiority of this approach. Clinical trial information: NCT01908777. [Table: see text]

Abstract: To improve curability and limit long-term adverse effects for newly diagnosed early-stage (ES), unfavorable-risk Hodgkin lymphoma. METHODS In this multicenter study with four sequential cohorts, patients received four cycles of brentuximab vedotin (BV) and doxorubicin, vinblastine, and dacarbazine (AVD). If positron emission tomography (PET)-4–negative, patients received 30-Gy involved-site radiotherapy in cohort 1, 20-Gy involved-site radiotherapy in cohort 2, 30-Gy consolidation-volume radiotherapy in cohort 3, and no radiotherapy in cohort 4. Eligible patients had ES, unfavorable-risk disease. Bulk disease defined by Memorial Sloan Kettering criteria ( 〉 7 cm in maximal transverse or coronal diameter on computed tomography) was not required for cohorts 1 and 2 but was for cohorts 3 and 4. The primary end point was to evaluate safety for cohort 1 and to evaluate complete response rate by PET for cohorts 2-4. RESULTS Of the 117 patients enrolled, 116 completed chemotherapy, with the median age of 32 years: 50% men, 98% stage II, 86% Memorial Sloan Kettering–defined disease bulk, 27% traditional bulk ( 〉 10 cm), 52% elevated erythrocyte sedimentation rate, 21% extranodal involvement, and 56% 〉 2 involved lymph node sites. The complete response rate in cohorts 1-4 was 93%, 100%, 93%, and 97%, respectively. With median follow-up of 3.8 years (5.9, 4.5, 2.5, and 2.2 years for cohorts 1-4), the overall 2-year progression-free and overall survival were 94% and 99%, respectively. In cohorts 1-4, the 2-year progression-free survival was 93%, 97%, 90%, and 97%, respectively. Adverse events included neutropenia (44%), febrile neutropenia (8%), and peripheral neuropathy (54%), which was largely reversible. CONCLUSION BV + AVD × four cycles is a highly active and well-tolerated treatment program for ES, unfavorable-risk Hodgkin lymphoma, including bulky disease. The efficacy of BV + AVD supports the safe reduction or elimination of consolidative radiation among PET-4–negative patients.

Abstract: e20017 Background: FDG avidity above liver on interim PET (PET2) during frontline ABVD is considered a marker of impending treatment failure and an indication to switch to an intensified regimen. However, in clinical practice the utility of PET2 for treatment decisions is less clear. We describe outcomes of patients with positive PET2 who continued treatment with ABVD in the clinical setting. Methods: A retrospective study of all patients with newly diagnosed advanced-stage Hodgkin lymphoma treated with frontline ABVD at Memorial Sloan Kettering Cancer Center between 2008-2017. Eligibility criteria were set to correspond with the RATHL inclusion criteria (stage IIB - IV, or IIA bulky or ≥ 3 involved sites). We identified all PET2 reports indicating suspected residual uptake. All positive PET2 images were then reviewed by a single study radiologist. To increase reproducibility and avoid selection of borderline cases, we defined as PET2 positive only those cases with a lesion-to-liver (mean) SUV ratio ≥ 1.3. We also used a recently published stringent criterion of lesion-to-liver (max) ratio ≥ 1.4 (mPET2+). Progression-free and overall survival (PFS, OS) were calculated from the date of initial treatment until progression or death of any cause. Consolidative radiation was not considered a PFS event, and all progressions were verified by biopsy. Results: We identified 227 patients fitting RATHL inclusion criteria treated with ABVD. Median age was 34, with 25% (58) ≥ 45 years, 12% (26) had an IPS ≥ 4; 28% (64) stage II (5% II-X) and 38% (87) with extranodal involvement. 57 (25%) patients had a PET2 report indicating suspected residual lymphoma (PET2+), however, only 32 (14%) met the more stringent mPET2+ criterion. Most patients with PET2+ continued ABVD (84%, 48), and 9 switched to escBEACOPP (this subset of patients had substantially worse disease and are not the focus of this analysis). 21 (9%) patients received consolidative radiation. With a median follow-up of 47 months (42-54m), PET2+ patients who continued ABVD had a 3yPFS of 70% (58-85%, n = 48); mPET+ had a 3yPFS of 71% (55-92%, n = 24). Overall survival was excellent regardless of PET2 status (5yOS 97%). Conclusions: The outcome of PET2+ patients in this analysis was better than previously reported and the continuation of ABVD was appropriate for most patients. Use of a confirmatory biopsy is important for identifying true progressions. Patients with PET2+ had an excellent OS. Evaluation of the superiority of alternative regimens in PET2+ patients requires an ABVD comparator arm.

Abstract: Patients with follicular lymphoma (FL) frequently require multiple treatments during their disease course; however, survival based on lines of treatment remains poorly described in the post-rituximab era. Also, the Follicular Lymphoma International Prognostic Index (FLIPI) score was developed to predict survival at diagnosis, yet it remains unknown whether increase in FLIPI score following an initial observation period is associated with less-favorable outcomes. To address these knowledge gaps, we retrospectively studied 1088 patients with FL grade 1–3A managed between 1998 and 2009 at our institution. Median overall survival (OS) and progression-free survival (PFS) after first-line treatment were not reached and 4.73 years, respectively. Following successive lines of treatment, years of median OS and PFS were, respectively: after second-line, 11.7 and 1.5; third-line, 8.8 and 1.1; fourth-line, 5.3 and 0.9; fifth-line, 3.1 and 0.6; sixth-line, 1.9 and 0.5. In initially observed, subsequently treated patients, FLIPI score increase after observation was associated with inferior survival following first-line treatment. The reduced survival we observed after second-line and later therapy supports the development of new treatments for relapsed patients and benchmarks historical targets for clinical endpoints. This study also highlights the utility of changes in FLIPI score at diagnosis and after observation in identifying patients likely to have worse outcomes.

Abstract: 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 & lt;50% (Achten et al., J Clin Oncol, 2002). To date, most series evaluating outcomes for patients (pts) with THRLBCL were published in the pre-rituximab era. Recent analysis suggested that outcomes for this disease may be better for pts treated in the rituximab era (Ollila et el., Leukemia & Lymphoma, 2009). However, data regarding treatment patterns and outcomes for pts with THRLBCL in the rituximab era is limited. 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 & gt;=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.

Abstract: Background: Prognosis of follicular lymphoma (FL) has long been defined by the FLIPI score (Solal-Céligny et al., 2004) which is a 5 factor risk model consisting of age, stage, lactate dehydrogenase, hemoglobin and number of nodal areas. The FLIPI model has been validated at diagnosis in both the pre- and post-Rituximab eras. However, many patients are initially observed and have prolonged lead time from diagnosis to first treatment. In this study, we investigated whether FLIPI risk group at diagnosis changed by the time of initial treatment, and whether change of FLIPI risk group impacted treated outcome. Patients and Methods: All adult (≥18 yo) patients with de novo follicular lymphoma (FL) treated at our center between 1998 and 2007 were evaluated. Study excluded patients with ≤2 follow up visits, known divergent of composite histology at diagnosis, and active concurrent malignancies. FLIPI was scored at diagnosis and at initiation of first treatment. For patients with missing FLIPI data, FLIPI category was scored if the omission did not alter the FLIPI category. Stable FLIPI risk group was defined as FLIPI score being low or intermediate at diagnosis and at initiation of first treatment (Low-Low, Int-Int). Progressed FLIPI risk group was defined by the population which changed categories from low or intermediate at diagnosis to a higher category at initiation of treatment (Low-Int, Low-High, Int-High). FLIPI scores were available for 570 patients at both diagnosis and initial treatment. Overall survival (OS) and progression free survival (PFS) were evaluated by Kaplan-Meier method and compared by log-rank tests. Time of diagnosis was used as time origin for OS analyses. When OS analyses involved FLIPI score at the first treatment, time of the first treatment was used as the entry time to adjust the risk sets to account for the fact that FLIPI at first treatment is unknown before the onset of the first treatment. Chi-squared tests and Fisher's exact tests were used to compare categorical variables by FLIPI score change status. Progression free survival before and after 24 months (PFS24) of initial therapy were calculated. Results: For 898 FL patients, median follow up was 9.2 years (range 0.23 - 16.84), median OS not reached. Based on FLIPI at diagnosis, the 5 year OS is 97.2% for low risk, 93.0% for int risk, and 80.2% for high risk, 10 yr OS is 90.9% for low risk, 77.7% for int risk, and 67.6% for high risk. Of 570 patients with FLIPI at diagnosis and first treatment, median time to first treatment was 0.18 years (range 0-12.5) for patients with stable FLIPI (N=280) and 2.70 years (range 0.01-13.33) for patients with progressed FLIPI (N=83). For patients observed ≥ 6 and 12 months, the median time to first treatment was 1.21 years (N=47, range 0.51-12.5) and 2.49 years (N=29, range 1.0-12.5) for patients with stable FLIPI and 3.77 years (N=62, range 0.54-13.3) and 3.92 years (N=57, range 1.13-13.3) for patients with progressed FLIPI, respectively. Progressed FLIPI was observed in 14.6% (83/570) of patients. The incidence of progressed FLIPI was 51.4% (57/111) in patients observed ≥1 year before initiating therapy. Parameters contributing to progressed FLIPI compared to stable FLIPI were decreased hemoglobin (29% versus 6%), increased nodal areas affected (43% versus 2%) and higher LDH (37% versus 5%). Patients with stable FLIPI had longer PFS at 12 and 24 months, 88.6% versus 73.8% (P=0.006) and 79.3% versus 66.1% (P= 0.031) (Figure 1). Analysis of patients initially observed ≥ 6 or 12 months demonstrated that progressed FLIPI negatively affected OS and PFS (Figure 2, observed ≥ 12 month data not shown). Median PFS for patients observed ≥ 6 months was 8.36 years for stable FLIPI, 3.14 years for progressed FLIPI. At observation of ≥ 12 months, median PFS was 6.25 and 3.22 years for stable and progressed FLIPI, respectively. Increased FLIPI was associated with increased risk of transformation throughout the disease course (25% vs 16%, P=0.039). Conclusion: Progressed FLIPI between diagnosis and first line treatment is associated with a reduced PFS, and increased incidence of histologic transformation. In patients who are initially observed, a progressed FLIPI reduces OS and PFS. The effect on PFS may be related to treatment bias and ongoing analysis is underway. Progressed FLIPI potentially identifies a population with heightened risk of transformation. Disclosures Hamlin: Seattle Genetics: Research Funding; Gilead: Membership on an entity's Board of Directors or advisory committees; Portola: Research Funding; Novartis: Research Funding; Molecular Templates: Research Funding; Xencor: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees. Horwitz:Seattle Genetics: Consultancy, Research Funding; Celgene: Consultancy; Huya: Consultancy; Infinity: Consultancy, Research Funding; Kyowa Hakka Kirin: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; ADCT Therapeutics: Research Funding; Spectrum: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy. Kumar:Celgene: Honoraria, Other: Scientific Advisory Board; Pharmacyclics: Research Funding; Seattle Genetics: Research Funding; Adaptive Biotechnologies: Research Funding; Celgene: Research Funding. Moskowitz:Bristol Myers Squibb: Honoraria; Merck: Honoraria; Seattle Genetics: Honoraria, Research Funding. Moskowitz:Merck: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Research Funding; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees, Research Funding. Palomba:Pharmacyclics: Consultancy. Zelenetz:Gilead Sciences: Research Funding.

Abstract: BACKGROUND: Treatment may be safely deferred in asymptomatic patients with advanced stage, low tumor burden follicular lymphoma (FL) until onset of symptoms or organ failure without compromising overall survival (OS). A randomized trial comparing immediate rituximab vs. observation in this setting reported a Time to New Treatment benefit without a corresponding OS benefit (Ardeshna et al, Lancet Oncol 2014). This is a comparison of Time to 1st Treatment (TT1T, observation arm) vs. Time to 2nd Treatment (TT2T, rituximab arm) and thus biased to immediate intervention. TT2T might be a less biased primary endpoint for trials evaluating immediate intervention vs. observation. Time to Treatment n (TT(n)T) is a function of cumulative time spent from diagnosis in periods of observation, treatment, and remission, and TT(n)T approaches OS as n approaches the maximum number of therapies received, thus we also hypothesize that TT2T might be a surrogate for OS. We have therefore performed a comprehensive evaluation of standard endpoints (TT1T, OS, and EFS12), described TT2T as a novel endpoint for trials evaluating intervention vs. observation in asymptomatic patients with advanced stage, low tumor burden FL, and aimed to determine if TT2T is a reliable surrogate for OS. METHODS: We identified 246 consecutive patients at our institution, diagnosed from 1998 to 2007 with advanced stage, low tumor burden follicular lymphoma grade 1-3A, for whom physician intention at diagnosis was observation. Median time to event was calculated using the Kaplan-Meier method for each event: TT1T, TT2T, and OS. Modified Kendall's tau was used to assess the correlation between TT1T, TT2T, and OS, accounting for censoring in these quantities. Tests of modified Kendall's tau against 0 (i.e. no correlation) were performed. EFS12 was defined as non-death event within 12 months of initiation of first treatment, and median OS for EFS12 analysis was calculated from end of first treatment. Of 69 patients who received chemoimmunotherapy as first therapy following initial observation, the log-rank test was used to compare survival distributions by EFS12. RESULTS: Of 246 patients with advanced stage, follicular lymphoma grade 1-3A for whom physician intention at diagnosis was observation, there was a slight female predominance (1.16:1), 34.6% were above age 60 with a median age of 56.1 years (range 25-88), and 11.8% (29/246) developed histologic transformation prior to 1st/2nd therapy, including 7.7% (19/246) prior to 1st treatment. At a median follow-up of 10.9 years: median TT1T was 43.5 months (3.5-217.4+, 179 events), median TT2T was 151.8 months (range 5.2-219.6+, 101 events), and median OS was not reached (range 5.2-219.6+, 48 events). The modified Kendall's tau measuring correlation between TT1T and OS was 0.012 (p = 0.537), and was 0.078 (p 〈 0.001) between TT2T and OS, suggesting that TT2T is strongly correlated with OS while TT1T is not. Failure to achieve EFS12 was observed in 10.3% (7/68) and associated with inferior OS (p=0.001). Of 7 patients who failed to achieve EFS12, 3 had histologic transformation. CONCLUSIONS: TT2T is a preferred primary endpoint for clinical trials evaluating intervention vs. observation. In patients with advanced stage, low tumor burden FL who are initially observed, the median time from diagnosis to 2nd treatment is 12.7 years. Future trials evaluating the role of immediate therapy in low tumor burden FL might restrict eligibility to high risk patients expected to have inferior TT2T. Efforts are ongoing to develop biomarkers (e.g. m7-FLIPI) that identify a population enriched with high risk patients. Our data also suggest that TT2T might be a better surrogate for OS than TT1T, and analyses are ongoing to validate this finding. Figure 1 Figure 1. Disclosures Hamlin: Molecular Templates: Research Funding; Seattle Genetics: Research Funding; Portola: Research Funding; Gilead: Membership on an entity's Board of Directors or advisory committees; Novartis: Research Funding; Xencor: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees. Horwitz:Spectrum: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy; Huya: Consultancy; Infinity: Consultancy, Research Funding; Kyowa Hakka Kirin: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding; Celgene: Consultancy; ADCT Therapeutics: Research Funding. Palomba:Pharmacyclics: Consultancy. Moskowitz:Merck: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Research Funding; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees, Research Funding. Noy:Pharmacyclics, LLC, an AbbVie Company: Other: travel, accommodations, expenses, Research Funding. Kumar:Celgene: Research Funding; Pharmacyclics: Research Funding; Adaptive Biotechnologies: Research Funding; Seattle Genetics: Research Funding; Celgene: Honoraria, Other: Scientific Advisory Board. Zelenetz:Amgen: Consultancy; Takeda Pharma: Consultancy; Novartis: Consultancy; Nanostring Tech: Consultancy; Portola Pharmaceuticals: Consultancy; Adaptive Biotechnology: Consultancy; Bristol Myers: Research Funding; Boehringer Ingelheim: Other: DMC Membership; Janssen: Consultancy, Research Funding; Hospira: Consultancy; Celgene: Consultancy; Gilead: Consultancy, Research Funding; GSK: Consultancy, Research Funding; Genentech/Roche: Consultancy, Research Funding.

Abstract: 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