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ABVD (Adriamycin, bleomycin, vinblastine, dacarbazine) with or without radiation has been the standard treatment for limited-stage Hodgkin lymphoma (HL) but carries risks of bleomycin lung injury and radiation toxicity. Brentuximab vedotin (BV) is approved with AVD for stage III-IV HL, but carries increased risks of peripheral neuropathy (PN) and neutropenic fever, likely due to overlapping toxicity between BV and vinblastine. We therefore evaluated BV in combination with AD for 4 or 6 cycles based on interim positron emission tomography response. Thirty-four patients with nonbulky stage I-II HL were enrolled. Risk was early favorable in 53% and unfavorable in 47%. The overall and complete response rates (CRRs) were 100% and 97%, respectively, with a 5-year progression-free survival (PFS) of 91%. No differences in outcome were observed based on stage (I vs II) or risk status (early favorable vs unfavorable). The most common adverse events were nausea (85%), peripheral sensory neuropathy (59%), and fatigue (56%). There were no cases of grade-4 neutropenia or neutropenic fever, and no patient received granulocyte-colony stimulating factor. Most cases of PN were grade 1, and no patient experienced grade ≥3 PN. BV-AD produced a high CRR and durable PFS with most patients requiring 4 cycles of therapy. Compared with BV-AVD, the toxicity profile appeared improved, with predominantly grade 1 reversible PN and no case of grade 4 neutropenia or neutropenic fever. This regimen warrants further study in HL and may serve as a backbone for the addition of novel agents. This trial is registered on clinicaltrials.gov (NCT02505269).

Purpose Intolerance is the most common reason for kinase inhibitor (KI) discontinuation in CLL. Umbralisib a novel, highly selective PI3Kδ/CK1e inhibitor, is active and well tolerated in CLL patients. This phase 2 trial evaluated umbralisib in CLL patients who are intolerant to prior BTK or PI3K inhibitor therapy. Patients and methods In this phase 2 trial (NCT02742090), umbralisib was initiated at 800 mg oral daily in CLL patients requiring therapy per investigator discretion who were intolerant to prior BTK or PI3K inhibitor therapy, until progression or toxicity. Primary endpoint was progression-free survival (PFS). Secondary endpoints included time to treatment failure and umbralisib safety profile. DNA isolated from buccal swabs was genotyped for polymorphisms in CYP3A4, CYP3A5 and CYP2D6. Results Fifty-one patients were enrolled (44 BTKi and 7 PI3Kδi intolerant). Median age was 70 years (range 48-96), median of 2 prior lines of therapy (1-7), 24% had del17p and/or TP53 mutation, and 65% were IGHV unmutated. Most common AEs leading to prior KI discontinuation were rash (27%), arthralgia (18%), and atrial fibrillation (16%). Median progression free survival (PFS) was 23.5 months (95% CI 13.1-not estimable). 58% of patients were on umbralisib for a longer duration than prior KI. Most common (≥5%) grade ≥3 AEs on umbralisib (all causality) were neutropenia (18%), leukocytosis (14%), thrombocytopenia (12%), pneumonia (12%), and diarrhea (8%). Six patients (12%) discontinued umbralisib due to an AE. Eight patients (16%) had dose reductions and were successfully re-challenged. Conclusions Umbralisib is safe and effective in this BTK and alternate PI3K inhibitor intolerant CLL population. These are the first prospective data to confirm that switching from a BTK or alternate PI3K inhibitor to umbralisib can result in durable, well tolerated responses.

Prophylaxis is commonly used to prevent central nervous sy stem (CNS) relapse in diffuse large B-cell lymphoma (DLBCL), with no clear standard of care. We retrospectively evaluated 1162 adult patients across 21 US academic centers with DLBCL or similar histologies who received single-route CNS prophylaxis as part of frontline therapy between 2013 and 2019. Prophylaxis was administered intrathecally(IT) in 894 (77%) and using systemic high-dose methotrexate (HD-MTX) in 236 (20%); 32 patients (3%) switched route due to toxicity and were assessed separately. By CNS-International Prognostic Index (IPI), 18% were considered low-risk, 51% moderate, and 30% high. Double-hit lymphoma (DHL) was confirmed in 243 of 866 evaluable patients (21%). Sixty-four patients (5.7%) had CNS relapse after median 7.1 months from diagnosis, including 15 of 64 (23%) within the first 6 months. There was no significant difference in CNS relapse between IT and HD-MTX recipients (5.4% vs 6.8%, P = .4), including after propensity score matching to account for differences between respective recipient groups. Weighting by CNS-IPI, expected vs observed CNS relapse rates were nearly identical (5.8% vs 5.7%). Testicular involvement was associated with high risk of CNS relapse (11.3%) despite most having lower CNS-IPI scores. DHL did not significantly predict for CNS relapse after single-route prophylaxis, including with adjustment for treatment regimen and other factors. This large study of CNS prophylaxis recipients with DLBCL found no significant difference in CNS relapse rates between routes of administration. Relapse rates among high-risk subgroups remain elevated, and reconsideration of prophylaxis strategies in DLBCL is of critical need.

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.

There is a paucity of data regarding outcomes and response to standard therapy in patients with limited-stage (LS) agressive B-cell lymphoma (LS-ABCL) who harbor MYC rearrangement (MYC-R) with or without BCL2 and/or BCL6 rearrangements. We conducted a multicenter retrospective study of MYC-R LS-ABCL patients who received either rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP), or more intensive immunochemotherapy (IIC) plus or minus consolidative involved-field radiation therapy (IFRT). One hundred four patients from 15 academic centers were included. Forty four patients (42%) received R-CHOP, of whom 52% had IFRT. Sixty patients (58%) received IIC, of whom 40% had IFRT. Overall response rate was 91% (84% complete response [CR]; 7% partial response). Patients with double-hit lymphoma (DHL; n = 40) had a lower CR rate compared with patients with MYC-R only (75% vs 98%; P = .003). CR rate was higher in the IFRT vs no-IFRT group (98% vs 72%; P < .001). Median follow-up was 3.2 years; 2-year progression-free survival (PFS) and overal survival (OS) were 78% and 86% for the entire cohort, and 74% and 81% for the DHL patients, respectively. PFS and OS were similar across treatment groups (IFRT vs no IFRT, R-CHOP vs IIC) in the entire cohort and in DHL patients. Our data provide a historical benchmark for MYC-R LS-ABCL and LS-DHL patients and show that outcomes for this population may be better than previously recognized. There was no benefit of using IIC over R-CHOP in patients with MYC-R LS-ABCL and LS-DHL.

Background: Patients with relapsed indolent NHL (iNHL) have limited standard treatment options. Lenalidomide combined with rituximab (R 2) has shown complimentary clinical activity and is a tolerable regimen in both untreated and relapsed or refractory (R/R) patients with iNHL (RELEVANCE : N Engl J Med 2018;379:934 and AUGMENT: J Clin Oncol. 2019;37:1188). Methods: MAGNIFY is a multicenter, phase 3b trial in patients with R/R follicular lymphoma (FL) grades 1-3b, transformed FL (tFL), marginal zone lymphoma (MZL), or mantle cell lymphoma (MCL; NCT01996865) exploring optimal lenalidomide duration. In the induction phase, lenalidomide 20 mg PO on days 1-21 of a 28-day cycle + rituximab IV at 375 mg/m 2/week cycle 1 and then every 8 weeks starting with cycle 3 (R 2) are administered for 12 cycles. Patients with stable disease, partial response, or complete response/complete response unconfirmed (CR/CRu) were randomized 1:1 to R 2 vs rituximab maintenance for 18 months. Data presented here are the complete analysis from the induction phase in efficacy-evaluable patients with FL grades 1-3a or MZL (FL grade 3b, tFL, and MCL not included). The focus of this interim analysis was overall response rate (ORR) by 1999 IWG criteria in the induction intention-to-treat population. Results: As of March 5, 2021, 394 patients (318 [81%] FL gr1-3a; 76 [19%] MZL) were enrolled. The median follow-up was 40.6 mo (range, 0.6-79.6). Median age was 66 y (range, 35-91), 328 (83%) had stage III/IV disease, with a median of 2 prior therapies (94% prior rituximab-containing). ORR was 71% (n = 279) with 42% (n = 164) CR/CRu (Table). All patients have completed R 2 induction (n = 232, 59%) or discontinued study treatment (n = 162, 41%). 141 patients (36%) prematurely discontinued both lenalidomide and rituximab, primarily due to adverse events (AEs) (n = 54, 14%) or progressive disease (n = 42, 11%). The majority of patients who have completed induction have been randomized and entered maintenance (n = 217). Median duration of response in the induction period was not reached (95% CI, 43.9 mo-NR), and median progression-free survival in the induction safety population (n = 393) was 50.5 mo (95% CI, 39.5-NR). Efficacy results are reported in the table by histology subgroups (FL vs MZL), and rituximab-refractory, double-refractory, and early relapse statuses. Most common all-grade AEs were 47% fatigue, 43% neutropenia, 37% diarrhea, 30% nausea, and 30% constipation. Grade 3/4 AEs occurring in ≥ 5% of patients included 37% neutropenia (10 patients [3%] had febrile neutropenia), 8% leukopenia, 6% thrombocytopenia, 5% anemia, and 5% fatigue. Conclusions: These data represent complete analysis of all patients in the induction phase of MAGNIFY which continue to support that R 2 is active with a tolerable safety profile in patients with R/R FL grade 1-3a and MZL, including rituximab-refractory, double-refractory, and early relapse patients. Figure 1 Figure 1. Disclosures Lansigan: Celgene/BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees. Andorsky: Abbvie: Consultancy, Research Funding; Celgene/BMS: Consultancy, Research Funding; Epizyme: Research Funding. Coleman: 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; Abbvie: Research Funding; Bristol Myers: Research Funding; Celgene: Research Funding; Genentech: Research Funding; Gilead: Research Funding; BeiGene: Research Funding; Innocare: Research Funding; Merck: Research Funding; Pfizer: Research Funding; Roche: Research Funding. Yacoub: Dynavex: Current equity holder in publicly-traded company; Cara: Current equity holder in publicly-traded company; Ardelyx: Current equity holder in publicly-traded company; Agios: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; ACCELERON PHARMA: Membership on an entity's Board of Directors or advisory committees; CTI Biopharma: Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Incyte: Consultancy, Honoraria, Speakers Bureau; Seattle Genetics: Honoraria, Speakers Bureau; Hylapharm: Current equity holder in publicly-traded company. Melear: TG Therapeutics: Speakers Bureau; Astrazeneca: Speakers Bureau; Janssen: Speakers Bureau. Fanning: Sanofi: Speakers Bureau; Genmab: Membership on an entity's Board of Directors or advisory committees; TG Pharma: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Genentech: Membership on an entity's Board of Directors or advisory committees; Takeda: Speakers Bureau; ADC Therapeutics: Membership on an entity's Board of Directors or advisory committees; BMS: Speakers Bureau. Kolibaba: TG Therapeutics: Current Employment, Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company; Atara Biotechm: Consultancy; McKesson Specialty Health: Consultancy; Sunitomo Dainippon Pharma: Consultancy; Tolero Pharma: Consultancy, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company). Nowakowski: Incyte: Consultancy; Kymera Therapeutics: Consultancy; TG Therapeutics: Consultancy; Blueprint Medicines: Consultancy; Nanostrings: Research Funding; Curis: Consultancy; Selvita: Consultancy; Zai Labolatory: Consultancy; Daiichi Sankyo: Consultancy; Bantham Pharmaceutical: Consultancy; Karyopharm Therapeutics: Consultancy; Ryvu Therapeutics: Consultancy; Genentech: Consultancy, Research Funding; Kyte Pharma: Consultancy; Roche: Consultancy, Research Funding; Celgene/Bristol Myers Squibb: Consultancy, Research Funding; MorphoSys: Consultancy. Gharibo: BMS: Current Employment, 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. Ahn: Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company; ADC therapeutics: Current equity holder in publicly-traded company. Li: BMS: Current Employment, 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, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding. Sharman: BeiGene: Consultancy; TG Therapeutics: Consultancy; Lilly: Consultancy; Centessa: Current holder of stock options in a privately-held company, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics LLC, an AbbVie Company: Consultancy; AstraZeneca: Consultancy; BMS: Consultancy; AbbVie: Consultancy.

Introduction: While an association between AI diseases and the development of lymphoma (LYM) is known, the impact of AI diseases on patient (pt) outcome across varying LYM subtypes, including the role of immunosuppressive medications (ISM), is not well understood. Methods: We conducted a large, multicenter, RWE retrospective analysis of adult pts with a diagnosis (dx) of lymphoma (LYM) between 1/2000 and 12/2020 and a pre-existing AI disease (see full list AI in Table 1). We examined baseline clinical features at LYM diagnosis, underlying AI disease characteristics, type/duration of ISM, LYM therapy received and survival outcomes. Multinomial regression models adjusted for age and sex identified associations between LYM subtypes, AI diseases, and ISM exposure, and were reported as relative risk ratio (RRR). Survival rates were estimated by Kaplan-Meier. Univariate associations of baseline factors with survival in cases with non-missing data were examined by Cox model and stratified by International Prognostic Index (IPI). Results: In total, 785 pts were identified across 14 North American institutions, of which 694 pts with complete data were included in the final analysis. Rheumatoid arthritis was the most common AI disease (30%) (Table 1). Diffuse large B-cell lymphoma (DLBCL) was the most common histologic subtype (n=303, 44%), and it was the most prevalent histology for nearly every AI disease. The median duration between AI disease and LYM diagnosis was 108 months (mo) (1-816 mo). Several associations were found between specific AI diseases and LYM subtypes, including: Hashimoto's thyroiditis with marginal zone lymphoma (MZL, RRR 2.78 (95% CI 1.14-6.78, P=0.024), Waldenstrom's macroglobulinemia (RRR 7.12 (95% CI 1.07-47.3, P=0.031), and follicular lymphoma (RRR, 2.71, 95% CI 1.01-7.24, P=0.047); Polymyalgia rheumatica with CLL/SLL (RRR 21.27 (95% CI 4.57-98.96), P=0.0001) and MZL (RRR 6.62 (95% CI 1.38-31.80), P=0.018); Psoriasis with peripheral T-cell lymphoma (PTCL, RRR 3.85 (95% CI 1.21-12.22), P=0.022); and Inflammatory bowel disease with CLL/SLL (HR 4.60 (95% CI 1.72-12.34), P=0.002). Overall, 402 (58%) pts had ISM exposure prior to LYM dx, with 279 (40%) pts on active ISM at time of LYM dx. The most commonly used ISM agent was methotrexate (26%); the median duration of ISM prior to LYM diagnosis was 60 mo (1-480). Compared with DLBCL pts, those diagnosed with PTCLs were more likely to have had exposure to TNF-α inhibitors (RR 1.89, 95% CI 1.23-2.89, P=0.004) or apremilast, a phosphodiesterase-4 inhibitor (RR 19.2, 95% CI 2.6-149.9, P=0.005). Rituximab +/- chemotherapy was used as frontline therapy in the majority of B-cell LYM pts, including 90% of DLBCL. Of LYM pts on ISM at initial dx, 41% had a reduction in immunosuppression (RIS), of whom 81% stopped ISM completely (Table 1). Only 10% of pts who underwent RIS were reported to have a flare of AI disease during initial therapy, compared with 7% of pts who had a flare despite no RIS (P=NS). Survival by histology is depicted in Figure A/B. For DLBCL pts (n=303), survival appeared overall comparable to historically reported outcomes in the general DLBCL population. Neither antecedent use of ISM nor duration of ISM were associated with pt outcomes (data not shown). However, a survival advantage was identified among DLBCL pts whose ISM was stopped completely during frontline therapy compared with pts who were not on ISM at diagnosis (Figure C/D). In addition, 10 DLBCL pts underwent 100% RIS +/- rituximab with therapeutic intent and did not receive cytotoxic chemotherapy as part of frontline therapy. Among these, 4 pts (mean age 62 years (26-84); ISM: n=2 MTX, and 1 each azathioprine and etanercept/MTX; EBV+ 2/4) achieved complete remission and remain disease-free at time of last follow-up at 5, 74, 105, and 221 months post-DLBCL dx. Conclusions: Altogether, we identified several novel histologic associations of AI diseases with LYM histologic subtypes. Furthermore, prior receipt of TNF-α inhibitor or a phosphoediesterase 4 inhibitor were associated with a diagnosis of PTCL. For DLBCL pts with antecedent AI disease, complete cessation of ISM during frontline LYM therapy appeared to be associated with improved survival. Finally, there were a small number of select DLBCL pts who garnered long-term disease-free survival using RIS +/- rituximab as frontline therapy, similar to the treatment paradigm in post-transplant lymphoproliferative disorders. Figure 1 Figure 1. Disclosures Olszewski: TG Therapeutics: Research Funding; PrecisionBio: Research Funding; Celldex Therapeutics: Research Funding; Acrotech Pharma: Research Funding; Genentech, Inc.: Research Funding; Genmab: Research Funding. Feldman: Alexion, AstraZeneca Rare Disease: Honoraria, Other: Study investigator. Karmali: Karyopharm: Consultancy; Epizyme: Consultancy; Morphosys: Consultancy, Speakers Bureau; Kite, a Gilead Company: Consultancy, Research Funding, Speakers Bureau; Genentech: Consultancy; AstraZeneca: Speakers Bureau; BeiGene: Consultancy, Speakers Bureau; BMS/Celgene/Juno: Consultancy, Research Funding; EUSA: Consultancy; Janssen/Pharmacyclics: Consultancy; Roche: Consultancy; Takeda: Research Funding. Lunning: TG Therapeutics: Consultancy; Janssen: Consultancy; Verastem: Consultancy; Spectrum: Consultancy; Myeloid Therapeutics: Consultancy; AstraZeneca: Consultancy; Morphosys: Consultancy; ADC Therapeutics: Consultancy; Beigene: Consultancy; Daiichi-Sankyo: Consultancy; Kyowa Kirin: Consultancy; Celgene, a Bristol Myers Squibb Co.: Consultancy; Legend: Consultancy; Acrotech: Consultancy; Novartis: Consultancy; Kite, a Gilead Company: Consultancy; Karyopharm: Consultancy; AbbVie: Consultancy. Palmisiano: Genentech: Research Funding; AbbVie: Consultancy, Research Funding; Takeda: Consultancy; Foundation One: Consultancy. Danilov: Bristol-Meyers-Squibb: Honoraria, Research Funding; Gilead Sciences: Research Funding; Pharmacyclics: Consultancy, Honoraria; Beigene: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; TG Therapeutics: Consultancy, Research Funding; Takeda Oncology: Research Funding; Genentech: Consultancy, Honoraria, Research Funding; Bayer Oncology: Consultancy, Honoraria, Research Funding; Astra Zeneca: Consultancy, Honoraria, Research Funding; SecuraBio: Research Funding; Rigel Pharm: Honoraria. Barta: Kyowa Kirin: Honoraria; Acrotech: Honoraria; Daiichi Sankyo: Honoraria; Seagen: Honoraria. Lansigan: Celgene/BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees. Savage: Astra-Zeneca: Consultancy, Honoraria; Takeda: Other: Institutional clinical trial funding; Roche: Research Funding; Merck: Consultancy, Honoraria, Other: Institutional clinical trial funding; BMS: Consultancy, Honoraria, Other: Institutional clinical trial funding; Seattle Genetics: Consultancy, Honoraria; Servier: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria; Beigene: Other: Institutional clinical trial funding; Genentech: Research Funding.

Background: Relapse is expected when treating patients with follicular lymphoma (FL) and marginal zone lymphoma (MZL), with a shortened response associated with each relapse. Lenalidomide combined with rituximab (R2) has shown enhanced activity, with a recently reported median progression free-survival (PFS) of 39.4 months in patients with relapsed/refractory (R/R) indolent non-Hodgkin lymphoma, including those with FL and MZL (AUGMENT; J Clin Oncol. 2019;37:1188). Methods: MAGNIFY is a multicenter, phase IIIb trial in patients with R/R FL grades 1-3b, transformed FL (tFL), MZL, or mantle cell lymphoma (MCL; NCT01996865) in which optimal lenalidomide duration is being explored. Patients received 12 cycles of R2 (lenalidomide 20 mg/d, d1-21/28 + rituximab 375 mg/m2 weekly in cycle 1 and then on day 1 of cycles 3, 5, 7, 9, and 11) followed by 1:1 randomization in patients with stable disease, partial response, or complete response/complete response unconfirmed (CR/CRu) to R2 versus rituximab maintenance for 18 months. Data presented here focus on induction R2 in efficacy-evaluable MZL patients compared with the overall population of FL grades 1-3a+MZL (not including FL grade 3b, tFL, or MCL) receiving ≥ 1 treatment with baseline/post-baseline assessments. The primary end point is progression-free survival (PFS) by 1999 International Working Group criteria. Results: As of November 30, 2019, 393 patients with FL grades 1-3a and MZL enrolled; 76 (19%) had MZL. The median age of MZL patients was 68 years (range, 46-90), 68 (89%) had stage III/IV disease, and 72 (95%) had prior rituximab-containing therapy. Overall response rate was 68% with 39% CR/CRu, and median duration of response was 38.6 months (95% CI, 29.4-not reached [NR]). The median PFS was 41.2 months (95% CI, 38.4-NR). Efficacy results for MZL subtypes and the overall population (FL grades 1-3a + MZL) are shown in the table. Forty-two patients (55%) have completed 12 cycles of R2, and 41 (54%) have been randomized and entered maintenance. Twenty-eight patients (37%) prematurely discontinued both lenalidomide and rituximab, primarily due to adverse events (AEs; n = 11; 14%) and progressive disease (n = 6; 8%). The most common (≥ 20%) all-grade AEs were neutropenia (49%), diarrhea (37%), anemia (25%), thrombocytopenia (24%), and constipation (24%). Most common (≥ 10%) grade 3/4 AEs were neutropenia (41%; 1 patient [1%] had febrile neutropenia), thrombocytopenia (13%), and leukopenia (11%). Conclusions: R2 is active with a tolerable safety profile in patients with R/R MZL. The efficacy and safety profile of R2 in MZL patients were similar to results observed in the overall MAGNIFY population. Disclosures Coleman: Seattle Genetics: Research Funding; EMD Serono Research and Development Institute Inc.: Research Funding; Innocare: Research Funding; ARCUS Biosciences: Research Funding; AstraZeneca Pharmaceuticals, LP (Acerta Pharma BV Trials): Research Funding; AstraZeneca Pharmaceuticals, LP: Research Funding; BMS (Celgene Corporation): Research Funding; Eli Lilly and Company: Research Funding; Genetech (F. Hoffman-LaRoche Ltd): Research Funding; Hutchinson MediPharma, LTD: Research Funding; Ipsen Group: Research Funding; Karyopharma Therapeutics, Inc.: Research Funding; Klus Pharma, Inc.: Research Funding; MeiPharma, Inc.: Research Funding; Merck Sharp & Dohme Corp.: Research Funding; Novartis Pharmaceuticals: Research Funding; Incyte Corporation: Research Funding; Boston BIoMedical, Inc.: Research Funding; BeiGene: Research Funding; Acerta: Research Funding. Andorsky:CTI: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; AstraZeneca: Research Funding. Yacoub:Roche: Other: Support of parent study and funding of editorial support; Dynavax: Current equity holder in publicly-traded company; Ardelyx: Current equity holder in publicly-traded company; Incyte: Speakers Bureau; Hylapharm: Current equity holder in private company; Cara Therapeutics: Current equity holder in publicly-traded company; Agios: Honoraria, Speakers Bureau; Novartis: Speakers Bureau. Melear:Janssen: Speakers Bureau; AstraZeneca: Speakers Bureau. Fanning:Takeda: Consultancy, Speakers Bureau; Bristol Myers Squibb: Consultancy, Speakers Bureau; TG Therapeautics: Consultancy; Abbvie: Consultancy; Prisma Health: Current Employment; Sanofi Aventis: Speakers Bureau. Kolibaba:Atara Biotech: Consultancy; Compass Oncology: Ended employment in the past 24 months; Verastem: Honoraria; Seattle Genetics: Research Funding; Pharmacyclics: Research Funding; Novartix: Research Funding; Janssen: Research Funding; Gilead: Research Funding; Genentech: Research Funding; Celgene: Research Funding; Acerta: Research Funding; AbbVie: Research Funding; Sumitomo Dainippon Pharma Oncology: Consultancy, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company; TG Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Lansigan:BMS: Consultancy; Seattle Genetics: Consultancy; BMS Steering Committee for MAGNIFY Program: Membership on an entity's Board of Directors or advisory committees; Spectrum Pharma: Consultancy, Research Funding. Reynolds:IHA Hematology/Oncology Consultants: Current Employment. Nowakowski:Kymera: Consultancy; Ryvu: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other; Curis: Consultancy; Kite: Consultancy; MorphoSys: Consultancy, Research Funding; Denovo: Consultancy; Seattle Genetics: Consultancy; Nanostrings: Research Funding; Celgene/BMS: Consultancy, Research Funding; Roche: Consultancy, Research Funding. Gharibo:Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company; Bayer: Ended employment in the past 24 months. Ahn:BMS: Current Employment, Current equity holder in publicly-traded company. Li:BMS: Current Employment, Current equity holder in publicly-traded company. Rummel:Roche: Honoraria; Amgen GmbH: Honoraria; Celgene: Consultancy, Honoraria; Janssen: Honoraria; Novartis Pharma GmbH: Honoraria. Sharman:BeiGene: Research Funding; Bristol Meyers Squibb: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Pharmacyclics: Consultancy, Research Funding; AstraZeneca: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; AbbVie: Consultancy, Research Funding; TG Therapeutics: Consultancy, Research Funding; Acerta: Consultancy, Research Funding; Roche: Consultancy, Research Funding; Celgene: Consultancy, Research Funding.

Background: Lenalidomide combined with rituximab (R2) has shown complimentary clinical activity and is a tolerable regimen in both untreated and relapsed or refractory (R/R) patients with indolent non-Hodgkin lymphoma. Patients with advanced age at diagnosis are considered to be high risk, supporting post-hoc subgroup analyses by age, with a focus on patients aged ≥ 70 years from the MAGNIFY study. Methods: MAGNIFY is a multicenter, phase IIIb trial in patients with R/R follicular lymphoma (FL) grades 1-3b, transformed FL (tFL), marginal zone lymphoma (MZL), or mantle cell lymphoma (MCL; NCT01996865) exploring optimal lenalidomide duration. Lenalidomide 20 mg on days 1-21 of a 28-day cycle + rituximab 375 mg/m2/week cycle 1 and then every 8 weeks starting with cycle 3 (R2) are administered for 12 cycles followed by 1:1 randomization in patients with stable disease, partial response, or complete response/complete response unconfirmed (CR/CRu) to R2 vs rituximab maintenance for 18 months. Data presented here focus on induction R2 in efficacy-evaluable FL grade 1-3a and MZL patients (FL grade 3b, tFL, and MCL not included) receiving ≥ 1 treatment with baseline/postbaseline assessments. The primary end point is progression-free survival (PFS) by 1999 International Working Group criteria. Post-hoc analyses were performed by analyzing data from patients aged ≥ 70 years at time of study entry. Results: As of November 30, 2019, 393 patients have enrolled and 152 (39%) were aged ≥ 70 years. Baseline characteristics including histology, disease status, and prior treatments of patients ≥ 70 and the overall population are shown in the table. Median PFS in the ≥ 70 subgroup was 36.0 months (95% CI, 28.3-NR). Overall response rate and CR/CRu were 75% and 38%, with a median duration of response that was not reached (95% CI, 27.1-NR). Efficacy results for the overall population are shown in the table. In patients ≥ 70 the most common (≥ 20%) any-grade treatment emergent adverse events (TEAEs) were fatigue (44%), neutropenia (41%), diarrhea (34%), constipation (34%), and nausea (27%). Neutropenia (35%) was the only grade 3/4 TEAE occurring in > 10% of patients (febrile neutropenia occurred in 3 patients [2%]). TEAEs led to lenalidomide dose reduction in 69 patients (46%) and discontinuation in 40 patients (26%). Seventy-eight patients ≥ 70 (51%) completed all 12 cycles of induction treatment, and 72 (47%) have entered the maintenance phase. Sixty-one patients ≥ 70 (40%), compared to 35% of patients in overall population, prematurely discontinued both lenalidomide and rituximab, due to TEAEs (n = 26; 17%), progressive disease (n = 15; 10%), patient withdrawal (n = 12; 8%), death (n = 5; 3%), and other reasons (n = 3; 2%). Neutropenia was the only TEAE leading to discontinuation of lenalidomide in more than 2 patients (n = 10; 7%). Conclusions: Similar to findings in the overall population, R2 treatment in advanced-age patients with R/R FL and MZL resulted in encouraging efficacy, and with close attention to dose reduction there is a tolerable safety profile. Table Disclosures Lansigan: BMS Steering Committee for MAGNIFY Program: Membership on an entity's Board of Directors or advisory committees; Spectrum Pharma: Consultancy, Research Funding; BMS: Consultancy; Seattle Genetics: Consultancy. Andorsky:AstraZeneca: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; CTI: Research Funding. Coleman:Novartis Pharmaceuticals: Research Funding; Merck Sharp & Dohme Corp.: Research Funding; Boston BIoMedical, Inc.: Research Funding; BeiGene: Research Funding; Acerta: Research Funding; Innocare: Research Funding; ARCUS Biosciences: Research Funding; AstraZeneca Pharmaceuticals, LP (Acerta Pharma BV Trials): Research Funding; AstraZeneca Pharmaceuticals, LP: Research Funding; BMS (Celgene Corporation): Research Funding; Eli Lilly and Company: Research Funding; EMD Serono Research and Development Institute Inc.: Research Funding; Genetech (F. Hoffman-LaRoche Ltd): Research Funding; Hutchinson MediPharma, LTD: Research Funding; Incyte Corporation: Research Funding; Ipsen Group: Research Funding; Karyopharma Therapeutics, Inc.: Research Funding; Klus Pharma, Inc.: Research Funding; MeiPharma, Inc.: Research Funding; Seattle Genetics: Research Funding. Yacoub:Novartis: Honoraria, Speakers Bureau; Agios: Speakers Bureau; Incyte: Speakers Bureau; Hylapharm: Current equity holder in private company; Cara therapeutics: Current equity holder in publicly-traded company; Ardelyx: Current equity holder in publicly-traded company; Dynavax: Current equity holder in publicly-traded company. Melear:AstraZeneca: Speakers Bureau; Janssen: Speakers Bureau. Fanning:Prisma Health: Current Employment; Abbvie: Consultancy; TG Therapeautics: Consultancy; Bristol Myers Squibb: Consultancy, Speakers Bureau; Takeda: Consultancy, Speakers Bureau; Sanofi Aventis: Speakers Bureau. Kolibaba:Compass Oncology: Ended employment in the past 24 months; Atara Biotech: Consultancy; TG Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Sumitomo Dainippon Pharma Oncology: Consultancy, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company; AbbVie: Research Funding; Acerta: Research Funding; Celgene: Research Funding; Genentech: Research Funding; Gilead: Research Funding; Pharmacyclics: Research Funding; Seattle Genetics: Research Funding; Verastem: Honoraria; Janssen: Research Funding; Novartix: Research Funding. Reynolds:IHA Hematology/Oncology Consultants: Current Employment. Nowakowski:Ryvu: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other; Nanostrings: Research Funding; Seattle Genetics: Consultancy; Curis: Consultancy; MorphoSys: Consultancy, Research Funding; Roche: Consultancy, Research Funding; Kymera: Consultancy; Denovo: Consultancy; Kite: Consultancy; Celgene/BMS: Consultancy, Research Funding. Gharibo:Bayer: Ended employment in the past 24 months; Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Ahn:BMS: Current Employment, Current equity holder in publicly-traded company. Li:BMS: Current Employment, Current equity holder in publicly-traded company. Rummel:Celgene: Consultancy, Honoraria; Janssen: Honoraria; Amgen GmbH: Honoraria; Roche: Honoraria; Novartis Pharma GmbH: Honoraria. Sharman:Bristol Meyers Squibb: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Roche: Consultancy, Research Funding; Acerta: Consultancy, Research Funding; TG Therapeutics: Consultancy, Research Funding; BeiGene: Research Funding; Genentech: Consultancy, Research Funding; AbbVie: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Pharmacyclics: Consultancy, Research Funding; AstraZeneca: Consultancy, Research Funding.

Venetoclax (VEN) is approved for relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL) as monotherapy (VENmono) or in combination with rituximab. Whether VEN plus anti-CD20 (VENcombo) is superior to VENmono is unknown. We conducted a multicenter, retrospective cohort analysis comparing 321 CLL patients treated with VENmono vs VENcombo across the United States and the United Kingdom. We examined demographics, baseline characteristics, dosing, adverse events, response rates, and outcomes. The primary endpoints were progression-free survival (PFS) and overall survival (OS), estimated by Kaplan-Meier method, in patients treated with VENmono vs VENcombo. Univariate and bivariate analyses were performed with COX regression. Three hundred twenty-one CLL patients were included (3 median prior treatments, 78% prior ibrutinib). The overall response rates (ORRs) were similar (VENmono, 81% ORR, 34% complete remission [CR] vs VENcombo, 84% ORR, 32% CR). With a median follow-up of 13.4 months, no differences in PFS and OS were observed between the groups. In unadjusted analyses, the hazard ratios (HRs) for PFS and OS for VENmono vs VENcombo were HR 1.0 (95% confidence interval [CI], 0.6-1.8; P = .7) and HR 1.2 (95% CI, 0.6-2.3; P = .5), respectively. When adjusting for differences between the cohorts, the addition of an anti-CD20 antibody in combination with VEN did not impact PFS (HR, 1.0; 95% CI, 0.5-2.0; P = .9) or OS (HR, 1.1; 95% CI, 0.4-2.6; P = .8). We demonstrate comparable efficacy between VENmono and VENcombo in a heavily pretreated, high-risk, retrospective cohort, in terms of both response data and survival outcomes. Prospective studies are needed to validate these findings.

Introduction: FASN catalyzes de novo fatty acid (FA) biosynthesis, which is an oncogenic function observed in many cancers, including NHL. HIF1a inducible FASN activity is responsible for overcoming negative hypoxic influence and upregulation of glucose metabolism as observed during premalignant transformation. FASN catalytic activity is also dependent on precursors derived from glucose metabolism. However, implications of FASN targeted therapies on these interdependent metabolic interactions and the overall impact on cancer cell proliferation remains unknown. Methods: FASN small molecule inhibitors cerulenin, orlistat, TVB3657 and TVB3166 were evaluated using a diverse panel of B cell NHL lines and primary NHL cells for the impact on FASN inhibition signaling & induction of cell death (MTT, caspases & AnnexinV/PI). Global transcriptomics were done with Affymetrix Human 2.0 ST Genechip with Gene Set Enrichment and Ingenuity Pathway Analysis (GSEA & IPA). Metabolomic profiling was performed using mass spectrometry. TXNRD1, GSR, NQO1 expression and activity were evaluated by western blot and using enzyme assay kits. Global DNA & RNA synthesis were evaluated using ClickIt Edu and EU assay kits. RNAseq data available from 775 NHL patients were utilized for metabolic transcriptome mapping. Results: Treatment with all FASN inhibitors resulted in dose- and time-dependent reduction (>90%) in cell viability and cell death in all NHL cell lines. GSEA and IPA identified cell cycle & RNA metabolism as downregulated biological processes with carbohydrate and oxidative stress as upregulated biological processes observed. "Key gene" analysis predicted TNF signaling as a prominent response to FASN inhibition, validated as increased TNF secretion by ELISA with cell fractionation and western blot analysis revealing activation of TNF-PI3K signaling. Activation of PI3K with FASN inhibition also corresponded with increased expression of PI3K-dependent metabolic genes associated with glucose and lipid metabolism. Furthermore, metabolomic profiling in SUDHL10 cells revealed accumulation of the FASN precursor acetyl-CoA with FASN inhibition that was accompanied by increased ketogenic glycolytic and citric acid cycle activity. In addition, NADPH accumulation (FASN substrate) occurred with FASN inhibition, which was accompanied with reduction in ribose-phosphate and nucleotide pools as these processes are relevant to NADPH-generating PPP function. G6PD, TXNRD1, GSR & NQO1 were identified as "key genes" responsive to FASN inhibition. Interestingly, this cluster of "key genes" represented the entire enzymatic activity related to the first rate-limiting step in PPP. Subsequently, we determined that increased NADP(H) pools were responsible for impaired NADPH regenerating functions of TXNRD1 and GSR antioxidant enzymes, with PI3K-dependent activation of NQO1 and uptake of glucose facilitating de novo glutathione synthesis, which substituted for the loss of antioxidant functions in SUDHL10, SUDHL4 and Raji cells. All responses were sensitive to inhibition by PI3K inhibition (e.g., BKM120) with co-targeting via FASN & PI3K inhibition resulting in markedly increased oxidative stress, loss of mitochondrial membrane potential & synergistic cell death in NHL cell lines and primary NHL cells. Finally, FASN inhibition was associated with reduction in ribo/deoxy-ribonucleotide pools that decreased global transcriptional activity (de novo RNA synthesis, by EU labeling) and replication (by EdU incorporation in DNA) (Fig 1). Analysis of RNAseq data and mapping of metabolic transcriptome from 772 NHL patients showed consistently elevated expression of genes related to glycolysis, citric acid cycle, fatty acid and nucleotide metabolism in patients with mutations in p53, MYC, BCL2, mTOR, MYD88, PIM2 & CREBP genes, suggesting that these onco-metabolic interactions may be important for lymphomagenesis. Conclusions: Taken together, FASN oncogenic activity appears to extend beyond de novo fatty acid biosynthesis, serving as a central onco-metabolic regulator of malignant cell proliferation vis-à-vis integrating glucose, nucleotides, and antioxidant metabolic functions in NHL. In addition, co-targeting FASN and PI3K induced synergistic cell death. Altogether, blocking FASN and the dependent onco-metabolic functions represent highly novel targets for therapeutic strategies in NHL. Disclosures Chen: Oncomics, LLC: Consultancy, Patents & Royalties. Dave:Data Driven Bioscience: Equity Ownership. Evens:Seattle Genetics: Consultancy, Honoraria, Research Funding; Pharmacyclics: Consultancy, Honoraria; Epizyme: Consultancy, Honoraria; Tesaro: Research Funding; Verastem: Consultancy, Honoraria.

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: Ibrutinib, an orally and continuously administered Bruton tyrosine kinase inhibitor, allows for targeted, non-chemotherapy based treatment for chronic lymphocytic leukemia (CLL). While the initial US marketing approval for ibrutinib in CLL was for relapsed disease (February 2014), several trials have since shown favorable efficacy in the first-line setting. Ibrutinib was well tolerated in these pivotal studies, with discontinuation occurring in less than 9% at 12 months (O'Brien et al., Am J Hemato. 2019). Most early ibrutinib discontinuations in the first-line setting are due to adverse events (Tedeschi et al., EHA 2019), and optimal strategies to manage ibrutinib-related toxicities are not well defined. We hypothesized that ibrutinib is increasingly utilized for first-line treatment of CLL during routine management in the US, but that ibrutinib discontinuation rates for the real-world population are greater than those reported in clinical trials. Further, we expected to find greater odds of discontinuation in older adults and those with poor performance status, two groups underrepresented in clinical trials. Methods: We conducted a retrospective cohort study of CLL patients treated at community oncology practices using the nationwide Flatiron Health database. The Flatiron Health database is a longitudinal, demographically and geographically diverse database derived from de-identified electronic health record data from over 280 cancer clinics in the US. All patients initiated CLL therapy in the first-line setting between March 1, 2014 and February 28, 2019. We first assessed trends in the use of first-line ibrutinib (i.e., ibrutinib with/without an anti-CD20 antibody). We then focused on patients who received ibrutinib and had at least 180 days of available follow up or had died within this period. We used multivariable logistic regression to assess the association of patient characteristics with early discontinuation (defined as stopping within 180 days of initiation). Covariates included in our model were patient age, sex, race, insurance type, ECOG performance status, year of treatment, time from CLL diagnosis to ibrutinib initiation, chromosome 17p status, and geographical region. Results: We identified 5,634 individuals initiating first-line treatment for CLL, of whom 1,639 (29.1%) received an ibrutinib-based regimen. Use of ibrutinib in the first-line setting increased over time (Cochrane-Armitage test for trend, p Conclusion: While ibrutinib was increasingly utilized in the first-line setting for CLL within our large representative US community patient cohort, early discontinuation was more common than reported in pivotal trials. Given the complexity of the rapidly changing CLL treatment landscape, clinical decision support tools and other modern cancer care delivery approaches should be explored to improve administration of novel CLL therapies in the real-world setting. Disclosures Huntington: Genentech: Consultancy; Bayer: Consultancy, Honoraria; AbbVie: Consultancy; Celgene: Consultancy, Research Funding; DTRM Biopharm: Research Funding; Pharmacyclics: Honoraria. Barr:Merck: Consultancy; Janssen: Consultancy; AbbVie: Consultancy; Pharmacyclics LLC, an AbbVie company: Consultancy, Research Funding; TG Therapeutics: Consultancy, Research Funding; Seattle Genetics: Consultancy; Celgene: Consultancy; Genentech: Consultancy; Verastem: Consultancy; Gilead: Consultancy; Astra Zeneca: Consultancy, Research Funding. Jacobs:Genentech: Speakers Bureau; AstraZeneca: Speakers Bureau; Pharmacyclics LLC, an AbbVie Company: Research Funding, Speakers Bureau; TG Therapeutics: Honoraria, Research Funding; AbbVie: Consultancy, Speakers Bureau; JUNO: Consultancy; Gilead: Consultancy. Davidoff:PhRMA: Research Funding; Celgene: Research Funding. Gross:Johnson and Johnson: Research Funding; 21st Century Cancer: Research Funding; Pfizer: Research Funding.

Introduction: The majority of patients with classical Hodgkin lymphoma (cHL) will be cured with anthracycline-containing chemotherapy regimens. However, 10-20% of patients with early-stage disease and 30-40% of patients with advanced-stage cHL will relapse. The standard treatment for patients with relapsed cHL is salvage chemoimmunotherapy followed by high-dose chemotherapy (HDT) and autologous hematopoietic cell transplantation (auto-HCT) in chemotherapy-sensitive patients. Patients with primary treatment failure (PTF), i.e. patients who have progressive disease while on therapy or who fail to achieve complete remission (CR) at the end of initial therapy, or experience early relapse after CR1 are expected to have a worse prognosis than patients with late relapse. Since 2011 newer treatments, namely Brentuximab vedotin and PD1/PDL1 blockers have been introduced for the treatment of relapsed and refractory cHL. It is unknown whether changes in disease monitoring and management, including the availability of new agents, impacted survival of patients with cHL and PTF. Methods: Fifteen US academic medical centers contributed cases to the ECLIPSE study (Evaluation of Classical Hodgkin Lymphoma patients wIth Primary treatment failure and analySis of outcomEs). ECLIPSE retrospectively captured patient, disease and treatment characteristics and treatment response as assessed by treating physicians. Eligible patients were ≥ 15 years diagnosed with cHL on or after 2005, who received treatment with curative intent with anthracycline-containing chemotherapy regimens, and developed one of the 3 patterns of PTF: detection of progressive disease during or within 6 weeks of completion of chemotherapy (PP cohort, primary progression), partial response (PR) or stable disease (SD) by functional imaging at completion of chemotherapy (PR/SD cohort), or disease progression detected within 12 months of completion of chemotherapy after prior documentation of CR (ER cohort, early relapse). Patients were divided into two "eras" based on year of diagnosis, 2005-2010 (era1) and 2011-2018 (era2), with the latter expected to reflect changes in salvage therapy for cHL. Results: Patient characteristics for the 553 cases are summarized in Table. Median follow up of survivors was 58.7 and 31.2 months for patients diagnosed in era1 and era2, respectively. ABVD was the upfront treatment for 97.6% of cases. Nearly all patients (98.5%) received salvage therapy after PTF and 60.9% underwent auto-HCT. Patients who relapsed or progressed post auto-HCT received a median of 1 (range 0 to 3) salvage regimens. Five-year overall survival (OS) from time of PTF was 70.3% (95% CI=63.4-77.2%) for patients diagnosed in era1, and 77.6% (95% CI=70.3-84.8%, p = 0.018) for patients diagnosed in era2 (Figure A). While there was no difference in OS among the PP, PR/SD and ER cohorts in the era1 (Figure B), the PR/SD and ER cohorts had better OS than PP cohort in era2 (Figure C). On comparing the OS for each of the 3 cohorts between era1 and era2, there was an improvement in OS in the PR/SD (Figure E) and ER cohorts (Figure F) but no improvement among the PP cohort (D). Multivariable analysis of patients in era 2 identified only age (HR 1.05, 95% CI=1.03-1.07, P Conclusions: Though there has been an improvement in survival among cHL cases with PTF treated in the most recent years, the outcome of patients with PP did not change significantly across eras. Patients with PP disease should be prioritized for clinical trials incorporating newer agents and innovative cellular therapy to current available effective treatments. Disclosures Epperla: Pharmacyclics: Honoraria; Verastem Oncology: Speakers Bureau. Costa:Abbvie: Consultancy; Karyopharm: Consultancy; Fujimoto Pharmaceutical Corporation Japan: Other: Advisor; Sanofi: Consultancy, Honoraria, Speakers Bureau; GSK: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Janssen: Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria, Research Funding. Cashen:Novartis: Other: Speaker's Bureau; Seattle Genetics: Other: Speaker's Bureau; Celgene: Other: Speaker's Bureau. Hamadani:Otsuka: Research Funding; Takeda: Research Funding; Pharmacyclics: Consultancy; ADC Therapeutics: Consultancy, Research Funding; Merck: Research Funding; Sanofi Genzyme: Research Funding, Speakers Bureau; Celgene: Consultancy; Janssen: Consultancy; Medimmune: Consultancy, Research Funding. Barta:Mundipharma: Honoraria; Celgene: Research Funding; Takeda: Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Honoraria, Research Funding; Bayer: Consultancy, Research Funding; Mundipharma: Honoraria; Merck: Research Funding; Celgene: Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees. Reddy:Celgene: Consultancy; BMS: Consultancy, Research Funding; Genentech: Research Funding; Abbvie: Consultancy; KITE Pharma: Consultancy. Karmali:Gilead/Kite; Juno/Celgene: Consultancy, Speakers Bureau; Takeda, BMS: Other: Research Funding to Institution; Astrazeneca: Speakers Bureau. Bello:Celgene: Speakers Bureau. Chavez:Novartis: Membership on an entity's Board of Directors or advisory committees; Kite: 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; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Genentech: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Svoboda:AstraZeneca: Consultancy; Celgene: Research Funding; Incyte: Research Funding; Pharmacyclics: Consultancy, Research Funding; Kyowa: Consultancy; Merck: Research Funding; BMS: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding. Glenn:BMS: Research Funding; Merck: Research Funding; Genentech: Research Funding. Cohen:Lymphoma Research Foundation: Research Funding; Seattle Genetics, Inc.: Consultancy, Research Funding; ASH: Research Funding; Takeda Pharmaceuticals North America, Inc.: Research Funding; Gilead/Kite: Consultancy; Bristol-Meyers Squibb Company: Research Funding; Genentech, Inc.: Consultancy, Research Funding; Janssen Pharmaceuticals: Consultancy; LAM Therapeutics: Research Funding; UNUM: Research Funding; Hutchison: Research Funding; Astra Zeneca: Research Funding.

Introduction: Patients (pts) with limited stage (LS) aggressive large B-cell lymphoma (ALBCL) comprise 30-40% of ALBCLs and are usually treated with R-CHOP with or without consolidative involved field radiation therapy (IFRT). In pts with ALBCL, cytogenetic studies have identified a subset with high-risk disease who harbor MYC rearrangement (MYC-R) with or without BCL2 (BCL2-R) and/or BCL6 (BCL6-R) rearrangements. This has led to the adoption of intensive induction strategies in this population; however, it is unclear if such an approach is necessary in limited stage disease. Methods: We conducted a multi-center (15 US academic centers) retrospective study of MYC-R LS-ALBCL pts with diffuse large B-cell lymphoma (DLBCL) and high-grade B-cell lymphoma (HGBL) morphology. LS was defined by stage I and II confined to a single radiation field as determined by the treating center. Pts diagnosed between 1/1/2005 and 3/1/2017 were included. All pts received either R-CHOP or more intensive immuno-chemotherapy (IIC) (i.e. R-DA-EPOCH, R-hyperCVAD/MA, or R-CODOX-M/IVAC) with or without IFRT. Baseline demographic, clinical, laboratory, pathology and outcomes data was collected by retrospective chart review. Stage-modified IPI (sm-IPI) score was calculated [stage II (vs 1), age >60, elevated LDH, and ECOG performance status ≥ 2]. Differences in overall response rate (ORR), complete remission (CR) rate, 2-year progression-free survival (PFS) and overall survival (OS) were compared in pts treated with R-CHOP vs IIC and in pts treated with IFRT vs no IFRT. Results: A total of 142 pts with MYC-R LS-ALBCL were identified, of which 105 fulfilled the inclusion criteria. Baseline characteristics included: median age 65 yrs (range 21-85), 66% male; 14% stage I, 32% stage IE, 28% stage II, 26% stage IIE disease; 17% bulky, 58% extra-nodal, 15% transformed disease, 40% elevated LDH. The majority of pts (70%) had germinal center B-cell phenotype. Eighty-two pts had data on BCL2-R and BCL6-R, of which 41 (50%) had double-hit lymphoma (DHL), including 4 pts with triple-hit lymphoma. Forty-five pts (43%) received R-CHOP, of which 56% had IFRT. Sixty pts (57%) received IIC, of which 42% had IFRT. R-DA-EPOCH was the most common IIC regimen used (85%), followed by R-hyperCVAD/MA (12%). Age (p=0.38), stage (p=0.32), extra-nodal disease (p=0.84), LDH (p=0.09), sm-IPI (p=0.24), morphology (p=0.44) and double-hit status (p=1.00) were similar between pts receiving R-CHOP and IIC. Median no. of cycles (NOC) (6 vs 6) and proportion of pts who received IFRT (56% vs 42%, p=0.17) did not differ in the 2 groups. Median NOC were lower in IFRT vs no IFRT group (4 vs 6; p=0.02). Pts receiving IIC (vs. R-CHOP) were more likely to undergo CNS prophylaxis (CNS-P) (75% vs 29%, p ORR was 90% (83% CR, 7% PR). Pts with DHL were less likely to achieve a CR compared to pts with MYC-R only (73% vs 98%; p=0.011). CR rate was higher in the IFRT vs no-IFRT group (92% vs. 75%, p=0.028). In the 27 pts who had relapsed/refractory disease, distant relapses were more common in the IFRT vs no-IFRT group (87% vs 33%, p=0.007). Median follow-up was 3.2 yrs; 35 (33%) pts progressed or died. Of the 23 deaths, 15 were due to progressive lymphoma, 1 due to treatment-related toxicity and 7 due to unrelated causes. 2-year PFS and OS were 78% and 86% for the entire cohort and 72% and 82% respectively for DHL pts. Sm-IPI ≥ 2 (HR: 2.81, p=0.02) and age ≥ 70 (HR: 4.07, P Conclusions: Outcomes of MYC-R LS-ALBCL pts are excellent with 2-year PFS and OS of 78% and 86% respectively. There was no benefit of choosing IIC over R-CHOP or using CNS prophylaxis in pts with MYC-R LS-ALBCL and LS-DHL in our study. While IFRT was effective in inducing CRs and preventing local relapses, distant relapses limited its benefit. Pts with LS-DHL had lower CR rates with similar PFS and OS when compared to those with MYC-R as the sole cytogenetic abnormality. Longer follow up is needed to assess the impact of upfront treatment strategies on late relapses. Disclosures Landsburg: Takeda: Consultancy; Curis: Consultancy, Research Funding. Maddocks:Teva: Honoraria; AstraZeneca: Honoraria; Pharmacyclics/Janssen: Honoraria; Novartis: Research Funding; Pharmacyclics: Research Funding; Merck: Research Funding; BMS: Research Funding. Advani:Bayer Healthcare Pharmaceuticals: Other: Consultancy/Advisory Role; Cell Medica: Other: Consultancy/Advisory Role; Janssen Pharmaceutical: Other: Institutional Research Support; Regeneron Pharmaceuticals, Inc.: Other: Institutional Research Support; Merck: Other: Institutional Research Support; Kyowa: Other: Consulting/Advisory Role; Celgene: Other: Institutional Research Support; Roche/Genentech: Other: Consultancy/Advisory Role, Institutional Research Support; Takeda: Other: Consultancy/Advisory Role; Gilead/Kite: Other: Consultancy/Advisory Role; Autolus: Other: Consultancy/Advisory Role; AstraZeneca: Other: Consultancy/Advisory Role; Seattle Genetics: Other: Consultancy/Advisory role, Institutional Research Support; Bristol Myers Squibb: Other: Consultancy/Advisory role and Institutional Research Support; Forty Seven, Inc: Other: Institutional Research Support; Pharmacyclics: Other: Institutional Research Support; Agensys: Other: Institutional Research Support; Kura: Other: Institutional Research Support; Infinity: Other: Institutional Research Support; Millenium: Other: Institutional Research Support. Barta:Janssen: Membership on an entity's Board of Directors or advisory committees; Merck, Takeda, Celgene, Seattle Genetics, Bayer: Research Funding. Vose:Seattle Genetics, Inc.: Research Funding; Merck Sharp & Dohme Corp.: Research Funding; Novartis: Honoraria, Research Funding; Abbvie: Honoraria; Roche: Honoraria; Epizyme: Honoraria; Kite Pharma: Research Funding; Celgene: Research Funding; Incyte Corp.: Research Funding; Bristol Myers Squibb: Research Funding; Acerta Pharma: Research Funding; Legend Pharmaceuticals: Honoraria. Cohen:Takeda: Research Funding; Seattle Genetics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Millennium: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Research Funding; Pharmacyclics: Consultancy, Membership on an entity's Board of Directors or advisory committees; BioInvent: Consultancy; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Research Funding; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Infinity Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees. Karmali:AstraZeneca: Speakers Bureau; Gilead: Speakers Bureau. Mehta:Seattle Genetics: Research Funding; Kite: Consultancy, Speakers Bureau; Bristol-Myers Squibb: Consultancy, Research Funding; AstraZeneca: Consultancy, Speakers Bureau; Merck: Research Funding; Spectrum: Consultancy; Epizyme: Research Funding; F. Hoffmann-La Roche Ltd: Research Funding; Incyte: Research Funding; Gilead: Consultancy, Speakers Bureau; Celgene: Consultancy; Carevive: Other: Patient engagement; Medpage: Other: Medical website. Olszewski:Spectrum Pharmaceuticals: Consultancy, Research Funding; TG Therapeutics: Research Funding; Genentech: Research Funding. Hill:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: 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; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Genentech: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: 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; Amgen: Research Funding; Seattle Genetics: Honoraria, Membership on an entity's Board of Directors or advisory committees.

Background: Relapsed or refractory (R/R) Hodgkin lymphoma (HL) remains a significant clinical problem. Recently checkpoint blockade therapy (CBT) has shown striking activity in this setting, but the complete response (CR) rate is modest. Patients who relapse after CBT have limited therapeutic options. A prior, retrospective study showed that after anti-PD-1 therapy the objective response rate to chemotherapy alone was 61% (Rossi et al 2017). We investigated the effect of treatment subsequent to CBT in a large international multicenter retrospective analysis. Methods: Seventeen centers across the US and Canada are participating in this study to date. Medical records of each institution were queried to identify HL patients who received CBT and were subsequently treated with an additional line of therapy. The primary aim of this analysis was to determine the best response to post-CBT treatment in patients who discontinued CBT due to progression of disease (PD), preparation for stem cell transplant (SCT), or toxicity. Patients who discontinued CBT due to CR, and patients whose best response could not be determined due to death from another cause were excluded from analysis. Responses were assessed using Lugano criteria. Survival status was analyzed for the entire study population and stratified by post-CBT treatment regimen and disease subgroups using the Kaplan-Meier method. Progression free survival (PFS) was calculated for patients with at least stable disease (SD) to post-CBT treatment. Log rank tests were performed to test for statistical significance. Two-sided P Results: To date, out of 121 total lymphoma patients, a total of 77 HL patients received a subsequent line of therapy after CBT. Their median age was 37 (range 23-74); there were 38 men and 39 women. Fifty of these patients met inclusion criteria. Of the included patients, 15 were stages 1-2 and 35 were stages 3-4. These patients were heavily pre-treated with a median of 4 prior therapies before CBT (range 1-10). Thirty-one patients received prior brentuximab vedotin (BV) and 28 patients had undergone allogeneic (3) or autologous (25) SCT. The median duration of response (DOR) to the line of therapy prior to CBT was 3.5 months; 18 (36%) patients had relapsed disease, and the remaining 32 (64%) had refractory disease prior to CBT. The best response to CBT included: 2 (4%) CR, 21 (42%) partial response (PR), 13 (26%) SD, 14 (28%) PD. Patients discontinued CBT due to PD (72%), preparation for transplant (16%), toxicity (8%), CR after the addition of chemotherapy (2%), and an infectious complication (2%). Post-CBT treatment regimens included standard chemotherapy (46%), targeted therapy (22%), conditioning regimens for SCT (16%), other immunotherapy (4%), or clinical trial drugs (12%). The objective response rate (ORR) for all patients to post-CBT treatment was 52%: 17 (34%) CR and 9 (18%) PR. Eight (16%) patients achieved SD, while 16 (32%) patients progressed. Overall response rate to post-CBT treatment correlated with response to CBT itself. Among patients with a CR or PR to CBT, their ORR to post-CBT treatment was 70%, whereas for non-responders to CBT the ORR to post-CBT treatment was 37%. At a median time of follow-up of 14 months, the median PFS for patients who achieved a CR, PR, or SD to post-CBT treatment (n=34) is 10.7 months (Figure 1). Twenty (58.8%) of these patients have not yet progressed, and the OS has not been reached (Figure 2), as 85% of patients remain alive. Currently there is no statistical difference in survival based upon post-CBT treatment received (Figure 3, Table 1). However, of note 21 patients received SCT subsequent to their post-CBT treatment: 8 allo and 13 auto. All of these patients remain alive, however, 9 of 12 (75%) have progressed post SCT. Conclusions: In a heavily pretreated R/R HL population, treatment with CBT may sensitize patients to subsequent therapy, even after they progress on CBT. A response to CBT appears to correlate with response to post-CBT treatment, but PD to CBT did not preclude a response to subsequent therapy. Patient survival does not appear to be dependent upon the subsequent treatment regimen, although the majority of patients with at least stable disease went on to SCT. The long PFS in these patients is encouraging and may warrant further investigation. We plan to expand this analysis with additional patients prior to the December meeting. Disclosures Advani: Celgene: Research Funding; Roche/Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Participated in an advisory board, Research Funding; Kyowa: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Participated in an advisory board; Celgene: Research Funding; Astra Zeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Participated in an advisory board; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Autolus: Membership on an entity's Board of Directors or advisory committees, Other: Participated in an advisory board; Millenium: Research Funding; Janssen: Research Funding; Regeneron: Research Funding; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Other: Participated in an advisory board, Research Funding; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Kura: Research Funding; Agensys: Research Funding; Infinity: Research Funding; Cell Medica: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Participated in an advisory board; Merck: Research Funding; Bayer: Membership on an entity's Board of Directors or advisory committees, Other: Participated in an advisory board; Forty Seven Inc.: Research Funding; Gilead/Kite: Membership on an entity's Board of Directors or advisory committees, Other: Participated in an advisory board; Seattle Genetics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Participated in an advisory board, Research Funding. Herrera:AstraZeneca: Research Funding; Seattle Genetics: Research Funding; Pharmacyclics: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Merck, Inc.: Consultancy, Research Funding; Gilead Sciences: Research Funding; Genentech: Consultancy, Research Funding; Immune Design: Research Funding; KiTE Pharma: Consultancy, Research Funding. Chen:Millennium Pharmaceuticals: Consultancy, Research Funding; Genentech Inc.: Consultancy; Pharmacyclics: Consultancy, Research Funding; Affimed: Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding, Speakers Bureau; Bristol-Myers Squibb: Consultancy, Research Funding; Merck & Co., Inc.: Consultancy, Research Funding, Speakers Bureau. Ramchandren:Janssen: Consultancy, Research Funding; Pharmacyclics LLC an AbbVie Company: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy; Merck: Research Funding. Assouline:BMS: Honoraria, Research Funding, Speakers Bureau; Pfizer: Honoraria, Research Funding, Speakers Bureau; Roche: Honoraria, Research Funding, Speakers Bureau; Novartis: Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Wagner-Johnston:Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Merck: Research Funding; Celgene: Research Funding; ADC Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees; JUNO: Honoraria, Membership on an entity's Board of Directors or advisory committees; ASTEX: Research Funding; Novartis: Research Funding. Svoboda:Bristol-Myers Squibb: Consultancy, Research Funding; Pharmacyclics: Consultancy, Research Funding; KITE: Consultancy; Seattle Genetics: Consultancy, Research Funding; Kyowa: Consultancy; Regeneron: Research Funding; TG Therapeutics: Research Funding; Merck: Research Funding. Barta:Janssen: Membership on an entity's Board of Directors or advisory committees; Merck, Takeda, Celgene, Seattle Genetics, Bayer: Research Funding. Karmali:Gilead: Speakers Bureau; AstraZeneca: Speakers Bureau. Persky:Morphosys (IDMC): Consultancy; Spectrum: Research Funding; Genentech: Honoraria; Merck: Research Funding. Smith:Portola: Honoraria; BMS: Consultancy. Diefenbach:Trillium: Research Funding; Denovo: Research Funding; Millenium/Takeda: Research Funding; Acerta: Research Funding; Incyte: Research Funding; Seattle Genetics: Consultancy, Research Funding; Merck: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Genentech: Consultancy.

BACKGROUND: ABVD with or without radiation is standard therapy for limited stage HL, but carries risks of bleomycin-lung injury and radiation toxicity. Brentuximab vedotin (BV) is an anti-CD30 antibody drug conjugate which is highly active in relapsed classical HL. We previously combined BV with AVD in limited stage non-bulky classical HL which resulted in a high CR rate, but at the cost of increased neutropenia, neutropenic fever, and neuropathy, likely related to the overlapping toxicity profile with vinblastine. Similar toxicity findings were also observed with BV-AVD in advanced stage classical Hodgkin lymphoma. We therefore evaluated BV plus AD (BV-AD) without radiation therapy for non-bulky stage I-II classical HL with the goal of reducing toxicity and maintaining high rates of inducing CR. METHODS: This is a multicenter single arm open label phase 2 study. Patients received BV 1.2 mg/kg plus standard dose adriamycin and dacarbazine on days 1 and 15 of each 28 day cycle. GCSF prophylaxis was not included. Patients received 4 or 6 cycles of BV-AD based on the results of an interim PETCT scan performed following cycle 2. PET negativity was defined as Deauville scores 1-3. Patients in CR on interim PETCT received 4 total cycles of therapy; patients in PR completed 6 cycles. The primary endpoint is complete response rate (CRR) at end of treatment. A sample size of 34 was required to detect an end of treatment CRR of 95% with 91% power and alpha error of 0.09. RESULTS: 34 patients were enrolled. Median age is 36 (range 18-63). Stage is IA (3), IB (1), IIA (29) and IIB (1). Risk is classified per the GHSG criteria as early unfavorable in 47%, and favorable in 53%. The interim CR rate is 94%. Accordingly, 32 interim PET negative patients (94%) received 4 total cycles of therapy, and 2 interim PET positive patients (6%) received 6 total cycles of therapy. No patients received consolidative radiation therapy, per protocol. The primary endpoint of end of treatment CR rate is 100%. At a median follow-up of 15 months, the FFS, PFS and OS are all 100%. The most common adverse events of any grade are nausea (79%), peripheral sensory neuropathy (56%), fatigue (50%), constipation (38%), alopecia (35%) and neutropenia (24%). Most toxicities were low grade, with only 15% of subjects experiencing any grade 3 toxicity, and there were no grade 4 or 5 toxicities. Specifically, 2 patients had grade 3 neutropenia, and 1 patient each had grade 3 nausea/vomiting, pneumonia and thromboembolic event. Peripheral sensory neuropathy was grade 1 in 17 patients, and grade 2 in 2 patients. There were no cases of neutropenic fever. CONCLUSIONS: BV-AD for 4-6 cycles induces high interim and end of treatment CR rates of 94% and 100%, respectively, allowing 4 total cycles of therapy in most patients. The PFS, FFS and OS are all 100% at last follow up. Toxicity appears mild and notable for a low incidence of neutropenia, alopecia, and moderate peripheral neuropathy. This promising regimen avoids bleomycin, vinblastine, radiation and primary GCSF prophylaxis with resultant low toxicity and preserved high efficacy rates in patients with early favorable and early unfavorable non-bulky limited stage classical Hodgkin lymphoma. Follow up for this trial is ongoing. Figure. Figure. Disclosures Abramson: Merck: Consultancy; Seattle Genetics: Consultancy; Karyopharm: Consultancy; Verastem: Consultancy; Amgen: Consultancy; Humanigen: Consultancy; Juno Therapeutics: Consultancy; Gilead: Consultancy; Novartis: Consultancy; Bayer: Consultancy; Celgene: Consultancy. Sokol:Mallinckrodt Pharmaceuticals: Consultancy; Seattle Genetics: Consultancy; Spectrum Pharmaceuticals: Consultancy. Jacobsen:Merck: Consultancy; Seattle Genetics: Consultancy. LaCasce:Seattle Genetics: Consultancy, Honoraria; Research to Practice: Speakers Bureau; Humanigen: Consultancy, Honoraria; Bristol-Myers Squibb: Other: Data safety and monitoring board.

Background: Sickle cell disease (SCD) is a hemoglobinopathy that characteristically gives rise to a number of complications triggered by hemolytic anemia and vaso-occlusion. The prevalence of the disease is highest in sub-Saharan Africa, with the highest being in Nigeria where it affects over 6 million people.In spite of its overwhelming burden in Nigeria and the serious complications that result as a consequence, there is little in terms of epidemiological data specific to Nigeria regarding morbidity and management of the disease. Treatment of SCD and its complications includes early screening, patient education, genetic counseling, prophylaxis in the form of penicillin, vaccinations, folate supplementation, and the appropriate use of hydroxyurea (HU). While the efficacies of these treatments have been well documented in the West, morbidity and mortality due to SCD is still a significant public health problem in Nigeria. Particularly, HU has proved to be an effective disease-modifying treatment in the West. Many believe HU to be under-prescribed in Nigeria,but there is conflicting evidence. This study sought to assess the use of disease-modifying and preventive treatments, as well as barriers to treatment of sickle cell disease patients in Ibadan, Nigeria. Methods: We surveyed 50 outpatients at the University College Hospital of Ibadan (UCH) about their past and current treatment of SCD. Patients above age 12 with a primary diagnosis of SCD of any genotype were included. IRB approval was obtained through the UCH Ethics Committee and the Dartmouth College Committee for Protection of Human Subjects. All surveys were done on paper, and were administered to participants non-literate in English through a trained interpreter. Responses were input into SurveyMonkey and Excel for descriptive statistical analysis. Results: Of the people that submitted survey responses, 54% were male and 45% were female. The majority of respondents (84%) indicated that they had the SS genotype, while 14% were of SC genotype and 2% were uncertain of their genotype. The majority of respondents were between the ages of 19-45, and the majority had completed a university degree or higher education. When asked about prevention of SCD crises, 73% of respondents indicated they plan to seek genetic counseling prior to having children. Eighty-two percent of respondents indicated that they have taken prophylactic anti-malarials, while fewer people indicated that they use mosquito nets regularly for prevention of malaria (62%). Complication rates arising from SCD are listed in Table 1. When asked about pharmacotherapy options for treatment of SCD, 96% of respondents had been prescribed folate, compared to the 14% and 46% of respondents who had been prescribed oral penicillin and HU therapies, respectively. Compliance of the above drugs was relatively high as well, as the percentage of people who indicated they have taken folate (90%), penicillin (14%), and HU (42%) correlated similarly with those who had been prescribed. While the rate of those who had taken HU seem relatively high, the majority of those who had taken HU were doing so through the clinical trials of the drug being held at UCH (69%), rather than through an outside prescriber (31%). Of the 22 respondents not taking HU, 5 (23%) indicated that they would like to be taking it but are not able to, compared to the 7% of people not on penicillin who would like to be taking it. The largest potential barriers to treatment were inability to get to a hospital or clinic when necessary (16%) and lack of information about treatment options (32%). Conclusions: The most common treatment for SCD was folate therapy, followed by HU. Many patients receiving HU were formerly or currently enrolled in the clinical trials being run at UCH, which may suggest that it is not commonly prescribed by their regular providers. Most patients had faced at least one complication from SCD, and feel that their biggest deficits in treatment of SCD stem from their inability to get to a clinic or hospital in the event of a complication, and lack of information of the breadth of options that exist for management. More investigation remains to be done about the reasons for decreased usage of HU therapy among providers in Nigeria, and the efficacy of this treatment among adult patients. Given the low utilization of HU in this region, more follow up studies should be done about barriers such as cost, compliance, and access. Disclosures No relevant conflicts of interest to declare.

Introduction: Venetoclax (Ven), an oral BCL2 inhibitor, is approved for the treatment (tx) of relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL). Ven is generally well tolerated, and side effects observed in clinical trials have been consistent with other CLL tx. Clinical trials using the approved dose escalation schedule report negligible rates of clinical tumor lysis syndrome (TLS). We aimed to understand rates of select adverse events (AEs) including cytopenias, infections, and TLS in CLL patients (pts) treated with Ven in community and academic settings. To do so, we examined 297 pts with CLL who received Ven, either alone or paired, in this multicenter, international study. Methods: We conducted a retrospective cohort study of Ven treated pts with CLL across at 15 academic (n=169) and 51 community (n=128) centers outside of the clinical trial setting. This study represents a collaboration between US centers, CLL Collaborative Study of Real World Evidence (CORE), and UK CLL Forum. Demographics, baseline disease characteristics, Ven dosing, TLS risk (per FDA Ven label) and prophylaxis, and AEs were collected. Lab vs. clinical TLS was defined by Howard criteria. PFS was estimated by Kaplan Meier methodology. All comparisons were descriptive. Results: Of the 297 pts examined, median age at Ven initiation was 67 (range 37-91). The group was 69% male, 96% had R/R CLL, and 45% had del17p. Baseline characteristics stratified by practice setting are included in Table 1. 80% received Ven as monotherapy while 20% received it paired with another agent (anti-CD20 mAb (75%), ibrutinib (8.5%), other (16.5%)). All pts were treated outside of clinical trials. During dose escalation, 81% achieved a 400 mg dose and 65% maintained 400 mg following escalation (cyp3A4 use unknown). TLS risk was low in 40%, intermediate (int) in 32%, and high risk in 28%. CT scan prior to Ven initiation was performed in 62%. At least one hospitalization occurred for 56% of low, 80% of int, and 88% of high risk pts (63% of the total cohort). Table 1 describes the distribution of TLS risk and frequency of hospitalizations in academic, community centers. TLS prophylactic measures were available for a subset of pts. Allopurinol was used for 91% (n=68/75) of low, 93% (n=52/56) of int, and 94% (n=29/31) of pts at high risk for TLS. Rasburicase was used for 27% (n=28/102) of low, 42% (n=34/81) of int, and 72% (n=57/79) of high risk pts. Normal saline was used in 85% (n=62/73) of low, 88% (n=49/56) of int, and 97% (n=30/31) of high risk pts. TLS occurred in 8.4% of pts (n=25/297). Three lab and 2 clinical events occurred in low risk pts, 7 lab and 3 clinical events in int risk pts, and 7 lab and 3 clinical events in high risk pts. Of pts with TLS, 1 has discontinued Ven. Of pts with clinical TLS, all were hospitalized, received allopurinol and normal saline, and 28% received rasburicase. 72% with TLS had creatinine clearance Select AEs were neutropenia (ANC7 stools/day) 6.9%. For the subset who received Ven paired, AEs were not increased: 35% neutropenia, 29% thrombocytopenia, 22% infection, 6.3% neutropenic fever, and 6.4% diarrhea. TLS was observed in 3.4% of pts who received Ven paired vs. 9.3% who received Ven monotherapy. 29% pts required ≥1 dose reduction and 32% had ≥1 dose interruption. Median length of dose interruption was 7 days (range 1 - 132). 22 pts (7.4%) discontinued Ven due to an AE. PFS was similar in pts with ≥1 dose interruption vs. 0, pts who required dose interruption ≥8 days vs. Conclusions: Ven was well tolerated in this cohort; AE rates were similar to those reported in clinical trials. Both academic and community sites employed TLS prophylaxis consistent with FDA/EMA recommendations resulting in a small proportion of clinical TLS events ( Disclosures Fox: Sunesis: Consultancy; Celgene: Consultancy, Other: Travel support, Speakers Bureau; Roche: Consultancy, Other: Travel support, Research Funding, Speakers Bureau; Gilead: Consultancy, Other: Travel support, Research Funding, Speakers Bureau; AbbVie: Consultancy, Other: Travel support, Research Funding, Speakers Bureau; Janssen: Consultancy, Other: Personal fees and non-financial support, Speakers Bureau. Eyre:Gilead: Consultancy, Other: travel support; Abbvie: Consultancy, Other: travel support; Roche: Consultancy; Janssen: Consultancy, Other: travel support; Celgene: Other: travel support. Allan:Verastem: Membership on an entity's Board of Directors or advisory committees; AbbVie: Membership on an entity's Board of Directors or advisory committees; Acerta: Consultancy; Genentech: Membership on an entity's Board of Directors or advisory committees; Sunesis: Membership on an entity's Board of Directors or advisory committees. Schuster:OncLive: Honoraria; Physician's Education Source, LLC: Honoraria; Dava Oncology: Consultancy, Honoraria; Genentech: Honoraria, Research Funding; Pfizer: Membership on an entity's Board of Directors or advisory committees; Merck: Consultancy, Honoraria, Research Funding; Gilead: Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis Pharmaceuticals Corporation: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Nordic Nanovector: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Nabhan:Cardinal Health: Employment, Equity Ownership. Hill:Amgen: Research Funding; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: 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; Seattle Genetics: 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; Genentech: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Seattle Genetics: 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; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees. Shah:Lentigen Technology: Research Funding; Miltenyi: Other: Travel funding, Research Funding; Juno Pharmaceuticals: Honoraria; Exelexis: Equity Ownership; Oncosec: Equity Ownership; Geron: Equity Ownership. Lamanna:Jannsen: 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, Research Funding; Verastem: Research Funding; AstraZeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; TG Therapeutics: Research Funding; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics: Consultancy, Membership on an entity's Board of Directors or advisory committees; Acerta: Research Funding; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees. Cheson:AbbVie, Roche/Genentech, Pharmacyclics, Acerta, TG Therapeutics: Consultancy. Coombs:AROG: Other: Travel fees; H3 Biomedicine: Honoraria; Abbvie: Consultancy; DAVA Oncology: Honoraria; Incyte: Other: Travel fees. Barr:AbbVie, Gilead: Consultancy. Skarbnik:Gilead Sciences: Honoraria, Speakers Bureau; Pharmacyclics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Genentech: Honoraria, Speakers Bureau; Seattle Genetics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Honoraria, Speakers Bureau; Jazz Pharmaceuticals: Honoraria, Speakers Bureau; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Shadman:Pharmacyclics: Research Funding; Acerta Pharma: Research Funding; AstraZeneca: Consultancy; Genentech: Consultancy; Celgene: Research Funding; Verastem: Consultancy; Gilead Sciences: Research Funding; TG Therapeutics: Research Funding; AbbVie: Consultancy; Genentech: Research Funding; Mustang Biopharma: Research Funding; Beigene: Research Funding; Qilu Puget Sound Biotherapeutics: Consultancy. Ujjani:AbbVie: Consultancy, Speakers Bureau. Pagel:Pharmacyclics, an AbbVie Company: Consultancy; Gilead: Consultancy. Jacobs:Genentech: Honoraria. Schuh:Giles, Roche, Janssen, AbbVie: Honoraria. Brander:Genentech: Consultancy, Honoraria, Other: Institutional research funding for non investigator initiated clinical trial, Research Funding; Novartis: Consultancy, Other: DSMB; BeiGene: Other: Institutional research funding for non investigator initiated clinical trial, Research Funding; DTRM: Other: Institutional research funding for non investigator initiated clinical trial, Research Funding; TG Therapeutics: Consultancy, Honoraria, Other: Institutional research funding for non investigator initiated clinical trial, Research Funding; Acerta: Other: Institutional research funding for non investigator initiated clinical trial, Research Funding; AbbVie: Consultancy, Honoraria, Other: Institutional research funding for non investigator initiated clinical trial, Research Funding; Pharmacyclics, an AbbVie Company: Consultancy, Honoraria, Research Funding; Teva: Consultancy, Honoraria. Mato:Pharmacyclics: Consultancy, Honoraria, Research Funding; TG Therapeutics: Research Funding; Regeneron: Research Funding; Sunesis: Honoraria, Research Funding; Janssen: Consultancy, Honoraria; Acerta: Research Funding; Abbvie: Consultancy; AstraZeneca: Consultancy; Celgene: Consultancy; Prime Oncology: Speakers Bureau.

Background: Outcomes to salvage therapy for patients with relapsed/refractory (R/R) non-Hodgkin lymphoma (NHL) are suboptimal. Checkpoint blockade therapy (CBT) has been explored in the relapsed/refractory (R/R) NHL population, but response rates to single agent CBT therapy are modest. To date, there is no literature on whether treatment with CBT may sensitize NHL patients to subsequent therapy. We investigated the outcome of subsequent treatment in patients with R/R NHL who had received CBT in a large multicenter international retrospective analysis. Methods: Seventeen centers across the US and Canada are participating in this study to date. Medical records of each institution were queried to identify lymphoma patients who received CBT and were subsequently treated with an additional line of therapy. The primary aim of the current analysis was to determine the best response to post-CBT treatment in patients who discontinued CBT due to progression of disease (PD) or toxicity. Patients who discontinued CBT due to a complete response (CR), or patients whose best response to post-CBT therapy could not be determined due to death from another cause, were excluded from analysis. Responses were assessed using Lugano criteria. Survival status to date was analyzed for the entire study population and stratified by post-CBT treatment regimen categories and disease subgroups using the Kaplan-Meier method. Progression free survival (PFS) and overall survival (OS) were calculated for patients with at least stable disease (SD) to post-CBT treatment. Log rank tests were performed to test for statistical significance. Two-sided P Results: To date, out of 121 total lymphoma patients, we identified 42 NHL patients whom received therapy subsequent to CBT. The median age was 62 (range 27-85); 26 patients were men and 16 women. Twelve patients were stage 1-2, and 30 were stage 3-4. Forty patients, with 10 histologic subtypes (Table 1) were included in analysis. At least 24 patients (60%) had aggressive NHL; 12 (30%) had indolent histologies, and 4 (10%) were not otherwise specified (NOS). Seven patients had stem cell transplant (SCT) prior to CBT: 6 autologous (auto) and 1 allogeneic (allo). SCT occurred between 142 days and 8.3 years prior to treatment with CBT. The median number of treatments prior to CBT was 3 (range 1-9), and the median duration of response (DOR) to the treatment immediately prior to CBT was 2 months. The best response to CBT for these patients included: 4 partial response (PR), 11 SD, and 25 PD. Patients discontinued CBT due to PD (90%) and toxicity (10%). Post-CBT treatment regimens included standard chemotherapy (55%), targeted therapy (22.5%), and clinical trial drugs (22.5%). The overall response rate (ORR) to post-CBT treatment was 52.50% with 12 (30%) CR and 9 (22.5%) PR. Five patients (12.5%) had SD as their best response, and 14 (35.0%) PD. Of the patients with CR to post-CBT treatment, their best responses to CBT were PD for 6, SD for 4, and PR for 2. Currently, 13 patients have died: 12 from disease progression and 1 from AML, thus median overall survival (OS) has not been reached (Figure 1). Nine patients have not progressed on their subsequent therapy. For patients with CR, PR, or SD to post-CBT therapy, the median PFS is 12.5 months (Figure 2). The post-CBT treatment regimen used did not impact the survival outcome, and there is no significant evidence that post CBT treatment response and post CBT regimens are associated (Figure 3, Table 2). Fourteen patients had consolidative SCT after their post-CBT treatment: 11 allo and 3 auto. All of these patients remain alive and half have progressed. Conclusions: These data suggest that in a R/R NHL population, treatment with CBT may sensitize some patients to subsequent therapy even if they progress or do not respond to CBT. Patient survival and best response to post-CBT treatment were independent of the treatment regimen, but many of these treatments bridged patients to SCT. In many patients the post-CBT treatment responses with or without SCT were of a significantly greater duration than their pre-CBT DOR (2 months vs 1 year). For this population, especially if they are ineligible for SCT or CAR-T cell therapy, this may be a novel treatment approach. We plan to expand this analysis with additional patients prior to the December meeting. Disclosures Advani: Kura: Research Funding; Infinity: Research Funding; Kyowa: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Participated in an advisory board; Agensys: Research Funding; Janssen: Research Funding; Celgene: Research Funding; Bayer: Membership on an entity's Board of Directors or advisory committees, Other: Participated in an advisory board; Forty Seven Inc.: Research Funding; Roche/Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Participated in an advisory board, Research Funding; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Research Funding; Merck: Research Funding; Regeneron: Research Funding; Gilead/Kite: Membership on an entity's Board of Directors or advisory committees, Other: Participated in an advisory board; Cell Medica: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Participated in an advisory board; Autolus: Membership on an entity's Board of Directors or advisory committees, Other: Participated in an advisory board; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Other: Participated in an advisory board, Research Funding; Astra Zeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Participated in an advisory board; Seattle Genetics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Participated in an advisory board, Research Funding; Millenium: Research Funding; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Herrera:Immune Design: Research Funding; AstraZeneca: Research Funding; Merck, Inc.: Consultancy, Research Funding; Pharmacyclics: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Seattle Genetics: Research Funding; Gilead Sciences: Research Funding; KiTE Pharma: Consultancy, Research Funding; Genentech: Consultancy, Research Funding. Chen:Affimed: Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Pharmacyclics: Consultancy, Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding, Speakers Bureau; Millennium Pharmaceuticals: Consultancy, Research Funding; Genentech Inc.: Consultancy; Merck & Co., Inc.: Consultancy, Research Funding, Speakers Bureau. Ramchandren:Bristol-Myers Squibb: Consultancy; Seattle Genetics: Consultancy, Research Funding; Pharmacyclics LLC an AbbVie Company: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Merck: Research Funding. Assouline:Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Honoraria, Research Funding, Speakers Bureau; Pfizer: Honoraria, Research Funding, Speakers Bureau; Roche: Honoraria, Research Funding, Speakers Bureau; Novartis: Research Funding. Wagner-Johnston:Celgene: Research Funding; Merck: Research Funding; Novartis: Research Funding; JUNO: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; ADC Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees; ASTEX: Research Funding. Svoboda:Bristol-Myers Squibb: Consultancy, Research Funding; Regeneron: Research Funding; Merck: Research Funding; KITE: Consultancy; TG Therapeutics: Research Funding; Pharmacyclics: Consultancy, Research Funding; Kyowa: Consultancy; Seattle Genetics: Consultancy, Research Funding. Barta:Janssen: Membership on an entity's Board of Directors or advisory committees; Merck, Takeda, Celgene, Seattle Genetics, Bayer: Research Funding. Karmali:Gilead: Speakers Bureau; AstraZeneca: Speakers Bureau. Persky:Genentech: Honoraria; Morphosys (IDMC): Consultancy; Spectrum: Research Funding; Merck: Research Funding. Smith:BMS: Consultancy; Portola: Honoraria. Chavez:Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Speakers Bureau; Merck: Research Funding; Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Kite: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Humanigen: Consultancy. Diefenbach:Merck: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding; Incyte: Research Funding; Acerta: Research Funding; Millenium/Takeda: Research Funding; Denovo: Research Funding; Trillium: Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Genentech: Consultancy.

Introduction: Patients with aggressive peripheral T-cell lymphoma (PTCL) often undergo induction with anthracycline-based chemotherapy followed by autologous stem cell transplantation in fit patients. Up to 40% of patients have primary refractory disease, and even for those who respond to induction, 5-year overall survival (OS) is 32% with the exception of ALCL. This results in a significant number of patients who need treatment in the relapsed and refractory (R/R) setting. While there is no standard approach for this group, multiagent chemotherapy regimens are often used, particularly in those who may be transplant candidates. Several novel single agents have shown activity in R/R PTCL and can often be given in a more continuous fashion than combination chemotherapy. In order to explore the potential benefits of single agents in comparison to combination chemotherapy in R/R PTCL, we examined treatment outcomes in a prospectively enrolled cohort of PTCL patients. Methods: Patients were enrolled in the Comprehensive Oncology Measures for Peripheral T-cell Lymphoma Treatment (COMPLETE), a multinational prospective cohort of 500 newly diagnosed PTCL patients. Demographics, treatments, and outcomes were recorded until death or for at least 5 years. Analysis was restricted to 6 subtypes of PTCL: PTCL-NOS, AITL, ALCL, EATL, NKT, HSTCL. Primary refractory was defined as lack of a complete response (CR) to initial treatment. Relapsed was defined as a CR to initial treatment with progression at a later date. Patients in whom initial treatment was ≤4 days, unreported, or began >30 days before or after informed consent were excluded. Single agents were pralatrexate, romidepsin, brentuximab vedotin (BV), bendamustine, alisertib, denileukin diftitox, and lenalidomide. Combinations were any multiagent chemotherapy regimen excluding the above agents. Results: Of 462 patients with locked records, 57 met the above eligibility criteria and had treatment and followup data available for analysis. As first treatment in R/R disease, 26 patients received combination therapy (by subtype: PTCL-NOS [10], AITL [6], ALCL [3], EATL [1], NKT [5], HSTCL [1]) and 31 received single agents (by subtype: PTCL-NOS [13], AITL [5], ALCL [7], EATL [2], NKT [2], HSTCL [2]). The most common combination regimens had an ifosfamide-, gemcitabine-, or platinum-based backbone. Single agents used were: BV (12), romidepsin (8), pralatrexate (5), alisertib (3), bendamustine (1), denileukin diftitox (1), and lenalidomide (1). The objective response rate (ORR) for single agents was higher than for combination therapy (59% [17/29] vs. 46% [12/26], P=0.36), as was the CR rate (41% [12/29] vs. 19% [5/26], P=0.02). In those with R/R ALCL who received BV, ORR was 83% (5/6) and CR was 67% (4/6). Given these expected high response rates of BV in R/R ALCL, a subtype analysis excluding ALCL patients who received BV (ALCL-BV) was conducted and showed similar ORR between single and combination therapy (52% [12/23] vs. 46% [12/26], P=0.26), though CR still favored single agents (35% [8/23] vs. 19% [5/26], P=0.07). Excluding the ALCL-BV group, CRs were observed with BV (3/6), romidepsin (2/8), pralatrexate (1/5), bendamustine (1/1), and alisertib (1/3). Median progression-free survival (PFS) favored single over combination therapy (11.2 vs. 6.7 months, P=0.02). PFS in the ALCL-BV group was comparable at 11 months. Stem-cell transplantation occurred more frequently after single agent use than combination therapy (25% [8/31] vs. 7% [2/26]). Conclusion: Our analysis confirms the unmet need for better therapies in R/R PTCL. This data shows a trend towards increased CR and PFS with single agents in comparison to combination therapy, while maintaining the potential to bridge to transplantation. It is unclear whether the differences were driven by reduced toxicity and longer treatment duration with single agents, increased efficacy from BV in CD30-expressing cancers, or patient factors that led to therapy selection. However, despite the small size and exploratory nature of this analysis, single agents do not appear inferior to combination therapy with respect to disease control or ability to bridge to transplant with intent to cure. Our data can serve as a foundation for larger datasets or randomized trials which are needed to identify the truly superior strategy. In the meantime, the optimal approach for R/R PTCL remains unclear. Disclosures Schwartz: MS Biostatistics, LLC: Employment. Acosta:Spectrum: Employment. Pro:Seattle Genetics: Consultancy, Other: Travel expenses, Research Funding; kiowa: Honoraria; portola: Honoraria; Takeda Pharmaceuticals: Honoraria, Other: Travel expenses. Shustov:Seattle Genetics: Research Funding. Horwitz:Aileron Therapeutics: Consultancy, Research Funding; Millennium/Takeda: Consultancy, Research Funding; Mundipharma: Consultancy; ADC Therapeutics: Consultancy, Research Funding; Spectrum: Research Funding; Trillium: Consultancy; Corvus: Consultancy; Forty Seven: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Innate Pharma: Consultancy; Infinity/Verastem: Consultancy, Research Funding; Portola: Consultancy; Kyowa-Hakka-Kirin: Consultancy, Research Funding. Foss:Seattle genetics: Consultancy; Miragen: Consultancy, Speakers Bureau; Mallinkrodt: Consultancy; Spectrum: Consultancy.

Introduction: Venetoclax (Ven) is approved for relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL) as monotherapy (Ven mono) or in combination (Ven paired) with rituximab based on clinical trials with selected patients (pts) and limited ibrutinib exposure. Whether Ven paired is superior to Ven mono, patterns of care, and outcomes following Ven discontinuation are unknown. Further, better delineation of adverse events (AEs) when Ven is used outside of clinical trials is needed. To address these gaps, we conducted a multicenter, international study in partnership with CLL Collaborative Study of Real World Evidence (CORE) and UK CLL Study Forum examining the clinical experience of 348 Ven treated CLL pts, representing the largest series of Ven treated pts reported to date. Methods: We conducted a retrospective cohort analysis of CLL pts treated with Ven across 24 US and 42 UK academic and community centers. We examined demographics, baseline disease characteristics, dosing, AEs, TLS risk and outcomes, response rates, outcomes (overall survival (OS) and progression free survival (PFS)), and tx sequencing. TLS events were defined by Howard criteria. PFS and OS were estimated by the Kaplan Meier method. Comparisons of outcomes used the Log Rank test. Univariate and multivariate analyses were performed with COX regression. All other comparisons were descriptive. Results: Of these 348 CLL pts, 94% were R/R, median age 67 years (range:37-91), 69% male, 85% white, and 73% Rai stage ≥2. 19% received Ven on clinical trial. 79% had Ven mono; Ven was paired most commonly with anti-CD20 (n=51) and ibrutinib (n=10). Pts received a median of 3 tx (range 0-15) before Ven; 78% received ibrutinib, 29% received PI3Ki, 20% had ≥2 prior kinase inhibitors, and 68% had chemoimmunotherapy. Median time from most recent tx to Ven start was 1.1 months (range 0-62). Pre-Ven prognostic markers included 43% del17p, 34% TP53 mutated, 24% del11q, 38% complex karyotype (≥ 3 abnormalities), and 84% IGHV unmutated (Table 1). TLS risk was low in 38%, intermediate in 34% and high in 28%. During ramp up, TLS was observed in 10% (22 lab, 9 clinical TLS events, 3 missing data). Following dose escalation, 70% achieved a stable Ven dose of 400 mg, 33% required ≥ 1 dose interruption and 27% required ≥ 1 dose reduction. AEs included grade 3 neutropenia 39%, grade 3 thrombocytopenia 29%, infections 25%, grade ≥ 2 diarrhea 7.8%, and neutropenic fever 7.7%. AEs were similar whether treated on or off clinical trial. The ORR to Ven mono, Ven paired was 81% (34% CR), 86% (29% CR). With a median follow-up of 14.2 months, median PFS and OS were not reached (12 month PFS 74%, OS 82%). Figure 1 depicts PFS stratified by Ven mono vs. paired, clinical trial vs. clinical practice, del17p status, and complex karyotype. Pts who discontinued Ven due to AEs had better OS compared with those who discontinued due to progression or Richter Transformation (RT) (Median OS 47 vs. 15.1 vs. 8.6 months, respectively). In multivariate analyses, complex karyotype was the only independent predictor of PFS (HR 2.8, p Conclusions: In this heavily pretreated, poor risk group, Ven showed favorable outcomes with comparable toxicity and efficacy on or off clinical trial. Similar outcomes were observed for Ven mono and Ven paired; longer follow up is needed from studies of Ven paired to understand depth and durability of response. Complex karyotype independently predicted inferior PFS and OS. Without complex karyotype, del(17p), multiple lines of prior tx, and prior ibrutinib tx were independent predictors of inferior outcomes. Outcomes of retreatment with KI in Ven-failure previously treated with KI were poor. Data on sequencing cellular therapies post Ven is forthcoming. Disclosures Mato: AbbVie: Consultancy, Research Funding; Pharmacyclics, an AbbVie Company: Consultancy, Research Funding; Regeneron: Research Funding; AstraZeneca: Consultancy; Medscape: Honoraria; TG Therapeutics: Consultancy, Research Funding; Acerta: Research Funding; Prime Oncology: Honoraria; Portola: Research Funding; Celgene: Consultancy; Johnson & Johnson: Consultancy. Eyre:Abbvie: Consultancy, Other: travel support; Janssen: Consultancy, Other: travel support; Roche: Consultancy; Gilead: Consultancy, Other: travel support; Celgene: Other: travel support. Nabhan:Cardinal Health: Employment, Equity Ownership. Lamanna:Acerta: Research Funding; TG Therapeutics: Research Funding; Jannsen: 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, Research Funding; Verastem: Research Funding; 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; AstraZeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Hill:Pharmacyclics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: 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; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Genentech: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Research Funding; Seattle Genetics: 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; Pharmacyclics: 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; Seattle Genetics: 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. Brander:Pharmacyclics, an AbbVie Company: Consultancy, Honoraria, Research Funding; Acerta: Other: Institutional research funding for non investigator initiated clinical trial, Research Funding; Novartis: Consultancy, Other: DSMB; TG Therapeutics: Consultancy, Honoraria, Other: Institutional research funding for non investigator initiated clinical trial, Research Funding; Teva: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria, Other: Institutional research funding for non investigator initiated clinical trial, Research Funding; Genentech: Consultancy, Honoraria, Other: Institutional research funding for non investigator initiated clinical trial, Research Funding; DTRM: Other: Institutional research funding for non investigator initiated clinical trial, Research Funding; BeiGene: Other: Institutional research funding for non investigator initiated clinical trial, Research Funding. Barr:AbbVie, Gilead: Consultancy. Cheson:AbbVie, Roche/Genentech, Pharmacyclics, Acerta, TG Therapeutics: Consultancy. Shah:Geron: Equity Ownership; Lentigen Technology: Research Funding; Exelexis: Equity Ownership; Oncosec: Equity Ownership; Miltenyi: Other: Travel funding, Research Funding; Juno Pharmaceuticals: Honoraria. Allan:AbbVie: Membership on an entity's Board of Directors or advisory committees; Verastem: Membership on an entity's Board of Directors or advisory committees; Acerta: Consultancy; Sunesis: Membership on an entity's Board of Directors or advisory committees; Genentech: Membership on an entity's Board of Directors or advisory committees. Kennard:AbbVie, Gilead, Verastem: Consultancy. Schuster:Gilead: Membership on an entity's Board of Directors or advisory committees; Nordic Nanovector: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech: Honoraria, Research Funding; Physician's Education Source, LLC: Honoraria; Pfizer: Membership on an entity's Board of Directors or advisory committees; Merck: Consultancy, Honoraria, Research Funding; Dava Oncology: Consultancy, Honoraria; OncLive: Honoraria; Novartis Pharmaceuticals Corporation: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Skarbnik:Seattle Genetics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pharmacyclics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Honoraria, Speakers Bureau; Jazz Pharmaceuticals: Honoraria, Speakers Bureau; Genentech: Honoraria, Speakers Bureau; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead Sciences: Honoraria, Speakers Bureau. Coombs:AROG: Other: Travel fees; Abbvie: Consultancy; Incyte: Other: Travel fees; DAVA Oncology: Honoraria; H3 Biomedicine: Honoraria. Ujjani:AbbVie: Consultancy, Speakers Bureau. Jacobs:Genentech: Honoraria. Pagel:Pharmacyclics, an AbbVie Company: Consultancy; Gilead: Consultancy. Schuh:Giles, Roche, Janssen, AbbVie: Honoraria. Shadman:Celgene: Research Funding; Gilead Sciences: Research Funding; Mustang Biopharma: Research Funding; TG Therapeutics: Research Funding; AstraZeneca: Consultancy; Pharmacyclics: Research Funding; Genentech: Research Funding; Genentech: Consultancy; Acerta Pharma: Research Funding; Beigene: Research Funding; Verastem: Consultancy; Qilu Puget Sound Biotherapeutics: Consultancy; AbbVie: Consultancy. Fox:Abbvie: Consultancy, Other: travel support, Research Funding, Speakers Bureau; Janssen: Consultancy, Other: travel support, Speakers Bureau; Gilead: Consultancy, Other: travel support, Research Funding, Speakers Bureau; Roche: Consultancy, Other: travel support, Research Funding, Speakers Bureau; Celgene: Consultancy, Other: travel support, Speakers Bureau; Sunesis: Consultancy.

Introduction: Outcomes for patients with aggressive T cell lymphomas who are not cured by frontline therapies are poor. A Canadian retrospective analysis showed median overall survival (OS) to be 6.5 months combined for peripheral T-cell lymphoma (PTCL) patients in first relapse (Rel) and patients with primary refractory (Ref) disease (Mak, et al. JCO 2013). There have been no prospective studies that have examined the differences between Rel and Ref patients. In this analysis, we examined clinical features and outcomes for 285 patients prospectively enrolled in the COMPLETE Registry who completed frontline therapy and identified 119 patients with either Rel or Ref disease. We describe differences in clinical features, treatment, and outcomes between Rel and Ref patients. Methods: Patients with all subtypes of PTCL from 72 sites in the US were prospectively enrolled in the COMPLETE registry at initial diagnosis. Clinical and histopathologic features, treatment regimens, goals of therapy, toxicities, and outcomes were recorded. For this analysis, Ref disease was defined as no response to initial treatment or progression during or within 1 month of completing frontline therapy. Rel disease was defined as progression at least 1 month from completion of frontline therapy in patients who achieved a complete response (CR) or partial response (PR). Results: Of 285 patients in COMPLETE who had locked treatment and follow-up records required for this analysis, 50 met the criteria for Rel and 69 for Ref PTCL. Demographics (age, gender, race) and key clinical characteristics at initial diagnosis (histology [Table 1], bone marrow involvement, LDH, ECOG performance status) did not significantly differ between Rel and Ref patients. According to the treating physician, the primary goal of second-line therapy was cure in over half of both groups (52% for Rel, 60% for Ref); the remainder were managed with palliative intent. Rel patients received novel therapies (see Table 2 for definition) more frequently than Ref patients (58% vs. 28%) (P = 0.005) and were less likely to receive multi-agent regimens (24% vs. 45%; P = 0.04) [Table 2]. In the 55 Rel and Ref patients who received single-agent therapy, the most common agents were brentuximab vedotin (20%), romidepsin (15%), pralatrexate (9%) and gemcitabine (7%). In the 30 patients who received multi-agent therapy, the most common regimens were ICE (ifosfamide, carboplatin and etoposide) (17%), GemOx (gemcitabine and oxaliplatin) (17%), and CHOP or CHOP-like plus etoposide (13%). Despite similar frontline therapy with combination chemotherapy regimens, more Rel patients underwent high dose therapy and transplant compared to the Ref group (30% vs. 4%; P = 0.0005). Although single agent versus combination therapy showed similar objective response rates (ORR= CR+PR), the ORR of novel vs. traditional chemotherapy showed a trend favoring novel agents for the entire cohort (57% vs. 38%; P = 0.07). The ORR to second-line therapy was higher in Rel patients (63% vs. 38%; P = 0.02) as was the proportion achieving a CR (38% vs. 15%; P = 0.02). Further, Rel patients had longer OS compared Ref patients, with a median OS of 31 months (95% CI: 22.1 months to not reached) versus 10.2 months (95% CI: 6.5 - 15.9 months) from first diagnosis (Figure 1a) and 14.6 months versus 6.1 months (P = 0.048) from the time of relapse or progression (Figure 1b). For both Rel and Ref patients, there was no difference in survival by PTCL subtype. In both the Rel group and Ref groups, survival was significantly longer in patients treated with curative vs. palliative (as determined by the treating physician) intent (P = 0.01). Conclusions: Our analysis of real world outcomes in patients with aggressive T cell lymphomas demonstrates that outcomes are significantly worse for patients with Ref compared to those with Rel disease. Interestingly, novel single agent therapies were used most often as second-line therapy in Rel patients while multi-agent chemotherapy was used more frequently in Ref patients, despite the demonstration of activity of novel single agents in the Ref setting in other studies. The high proportion of patients with Rel or Ref disease in COMPLETE, and the demonstrated activity of novel agents in the Rel and Ref settings, supports initiatives to incorporate novel agents into frontline therapy for PTCL. Download : Download high-res image (122KB) Download : Download full-size image Download : Download high-res image (156KB) Download : Download full-size image Download : Download high-res image (109KB) Download : Download full-size image Disclosures Lansigan: Spectrum: Consultancy, Research Funding; Pharmacyclics: Consultancy; Teva: Research Funding; Celgene: Consultancy. Horwitz: Huya: Consultancy; Celgene: Consultancy; Takeda: Consultancy, Research Funding; Infinity: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy; Kyowa Hakka Kirin: Consultancy, Research Funding; Spectrum: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding; ADCT Therapeutics: Research Funding. Pinter-Brown: Celgene: Consultancy; Spectrum Pharmaceuticals: Consultancy; Seattle Genetics: Consultancy. Carson: American Cancer Society: Research Funding. Pro: Seattle Genetics: Honoraria; Takeda: Honoraria; Celegene: Honoraria. Hsi: Onyx Pharmaceuticals: Honoraria; Seattle Genetics: Honoraria; Eli Lilly: Research Funding; Cellerant: Honoraria, Research Funding; Abbvie: Honoraria, Research Funding; HTG Molecular Diagnostics: Consultancy. Federico: MedNet Solutions: Consultancy. Gisselbrecht: Roche/Genentech: Research Funding, Speakers Bureau. Schwartz: MedNet Solutions: Employment. Bellm: Merck: Equity Ownership; Johnson & Johnson: Equity Ownership; BMS: Equity Ownership; MedNet Solutions: Consultancy, Other: Reimbursement of travel-related expenses. Acosta: Spectrum Pharmaceuticals: Employment, Equity Ownership. Foss: Celgene: Consultancy, Research Funding, Speakers Bureau; Seattle Genetics: Consultancy, Speakers Bureau; Spectrum Pharmaceuticals: Consultancy; Eisai: Consultancy.

Background: In follicular lymphoma (FL) patients treated with first-line R-CHOP, early progression of disease (POD) within 2 years after diagnosis is associated with high risk for death (hazard ratio 6.4) and a 50% 5-year overall survival (Casulo et al. JCO 2015). Whether these observations hold for patients treated without chemotherapy is unknown. The Alliance for Clinical Trials in Oncology conducted three frontline rituximab-based non-chemotherapy-containing biologic immunotherapy doublet clinical trials: R-Galiximab (Anti-CD80, CALGB 50402), R-Epratuzumab (Anti-CD22, CALGB 50701) and R-Lenalidomide (CALGB 50803). We performed a retrospective analysis of 174 patients to determine outcomes of early progressors after initial biologic, non-cytotoxic treatment and risk factors for early POD. Methods: CALGB 50402 (n=60), CALGB 50701 (n=57), and CALGB 50803 (n=57) had similar eligibility criteria: previously untreated follicular lymphoma, grade 1, 2 or 3a with stage III, IV or bulky (single mass >7 cm) stage II disease, and ECOG PS 0 to 2. Early POD was defined as progression within 24 months from study entry. Univariate and multivariate logistic regression modeling using forward selection was performed to identify predictors of early POD. Kaplan-Meier (KM) method was used to estimate 2-year and 5-year overall survival probability. Hazard ratios (HR) and 95% CI were calculated using a univariate and multivariate Cox regression model adjusting for FLIPI. Results: Twenty-seven percent (48/174) of patients had early POD. Median survival follow-up time from study entry was 5.5 years (2.1 to 10.1 years) and median time from diagnosis to enrollment was 2 months (0.2 to 115 months). Median age was 54 (range: 22-90), 49% were male and 24% had low-, 52% intermediate- and 24% high-risk FLIPI (Table 1). Early POD from study entry conferred a worse OS [HR=4.86 (95% CI 1.90-12.4), p < 0.001]. After adjusting for FLIPI, patients with early POD from study entry had a worse OS compared with patients who did not progress within 2 years [HR=4.77 (95% CI 1.70-13.4), p=0.003]. For early POD, the 2-year survival probability was 89% (76-95%) vs. 100% for non-early POD, and the 5-year survival was 76% (60-86%) vs. 99% (95-99%), respectively (Figure 1). When the 2-year early POD interval was taken from time of diagnosis, similar findings were noted (n=171, HR for OS 5.27 (95% CI 1.98-14.0), p 0.0009) [Table 2]. Univariate analysis revealed age >60 (p=0.019), male sex (p=0.002), higher FLIPI (p4 (p=0.010), elevated LDH (p=0.004), nodal size >7 cm (p=0.002), albumin Conclusions: Early relapse within 2 years after diagnosis in patients receiving front-line rituximab-based biologic non-cytotoxic therapy is associated with an increased risk of death. These data are similar to previous findings in patients treated with R-CHOP from the National LymphoCare study, suggesting that the adverse survival of patients with early POD may be independent of systemic treatment modality. Novel clinicopathological approaches are needed at diagnosis to identify patients who are likely to have unfavorable outcomes, and for whom biologic doublets are efficacious. Support: U10CA180821, U10CA180882.ClinicalTrials.gov Identifier: NCT00117975 (CALGB 50402), NCT00553501 (CALGB 50701), and NCT01145495 (CALGB 50803) Disclosures Lansigan: Pharmacyclics: Consultancy; Teva: Research Funding; Celgene: Consultancy; Spectrum: Consultancy, Research Funding. Cheson:Gilead: Research Funding; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Acerta: Membership on an entity's Board of Directors or advisory committees, Research Funding. Czuczman:Celgene: Employment. Martin:Celgene: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Other: travel, accommodations, expenses; Teva: Research Funding; Acerta: Consultancy; Novartis: Consultancy; Gilead: Consultancy, Other: travel, accommodations, expenses. Hsi:Eli Lilly: Consultancy; Abbvie: Consultancy; Cellerant Therapeutics: Consultancy; Seattle Genetics: Honoraria; HTG molecular diagnostics: Honoraria. Bartlett:Gilead: Consultancy.

Background: DI-Leu16-IL2 is a recombinant fusion immunocytokine composed of interleukin-2 and a CD20-targeting monoclonal antibody that maintains the activities of both antibody and cytokine components but is also involved in tumor targeting, engagement of the immune system, and induction of an anti-cancer vaccine effect. Methods: In this multicenter open label, dose escalation trial to determine the maximum tolerated dose (MTD), optimal biological dose (OBD), and recommended phase 2 dose (RP2D), we evaluated the safety, tolerability, and efficacy of subcutaneously (SC) administered DI-Leu16-IL2 in patients (pts) with relapsed or refractory CD20+ B-cell lymphoma (NCT01874288). Following peripheral B-cell depletion with low-dose rituximab (50mg/m2), DI-Leu16-IL2 was administered SC for 3 consecutive days every 21 days for 6 cycles. A 3+3 dose escalation trial design began at 0.5 mg/m2. Responses were evaluated by PET in pts who had received at least 2 cycles of therapy. Immunologic correlates were done including peripheral blood flow cytometry and serum cytokine levels. Responding (complete or partial response, CR or PR) and stable disease (SD) pts were permitted to continue treatment for an additional year. Results: Twenty-two pts in 5 dose cohorts have been enrolled, 3 at 0.5 and 1mg/m2, 7 at 2mg/m2 and 4mg/m2, and 2 at 6mg/m2. The median age is 64 years (40-84), median prior therapies is 4 (range 1-21), with 100% having received prior rituximab and chemotherapy, and 41% with prior autologous stem cell transplant. Dose limiting toxicities (DLT) occurred in 2 pts at 6 mg/m2, both with delayed (8-10 days) grade 3 cytokine release syndrome (CRS), suggesting effector cell expansion as the cause. None of the CRS required treatment with tocilizumab, however one required dose reduction, and the other discontinued therapy. The Gr 3-4 drug-related adverse events (AEs) that required dose reduction were: QTC prolongation (Gr 3) in one patient at 4 mg/m2, tumor lysis syndrome (Gr 3) at 4mg/m2, and diarrhea (Gr 3) at 1mg/m2. Hematologic AEs were eosinophilia (Gr 1-2 = 22.7%), anemia (Gr 1-2 = 45%, Gr 3-4 = 9%), thrombocytopenia (Gr 1-2 = 36%, Gr 3-4 = 4.5%), neutropenia (Gr 1-2 = 14%, Gr 3-4 = 14%) in the 22 pts evaluable for toxicity. Other AEs were local injection site reactions (Gr 1-2 = 82%), pruritus (Gr 1-2 = 82%), edema (Gr 1-2 = 23% Gr 3-4 = 5%), fever (Gr 1-2 = 41%, Gr 3-4 = 5%), and chills (Gr 1-2 = 59%). Six pts have been enrolled at 4mg/m2 and no DLTs have been encountered. The MTD was determined to be 4mg/m2. Patients with CR or PR had higher pre-treatment absolute lymphocyte counts (>700/mcL) than pts with progressive disease (P < 0.05). Repetitive SC dosing elicited lymphocyte expansion at all dose levels. Although T-regulatory cell expansion was observed in the blood, it was not associated with a worse response. Pts achieving CR showed a trend towards lower % of granulocyte-like myeloid derived suppressor cells. Pts showed reproducible increases in cytokine levels of IL-10, MCP-1, IFNgamma, and TNFalpha. Pharmacokinetic data showed consistent drug levels between cycle 1 and 2.Therefore, the OBD and RP2D was determined to be 2mg/m2 which produced 3 CR and 3 SD. Durable tumor regression or stabilization was noted in 14 of 16 (88%) evaluable pts. There were 4 CR: 1 diffuse large B-cell lymphoma (DLBCL), 2 follicular lymphoma and 1 marginal zone lymphoma; 1 PR (DLBCL) and 9 SD, and objective response rate of 31% [Figure 1]. The median duration of disease stabilization was 8 months (4-14). Of the responders, the median duration of response was 13 months (10-15). One CR continues 11 months after stopping therapy at cycle 6. Conclusions: Promising clinical efficacy of DI-Leu16-IL2 has been observed with long-term responses in relapsed/refractory B-cell NHL pts. SC administration has permitted higher doses than could be achieved with IV treatment, however, at the higher dose range, CRS was observed. Even though the MTD was 4mg/m2, given the responses, AEs, and biologic activity in the Phase I study, the RP2D was determined to be 2mg/m2. Responses were associated with a higher starting ALC, and lymphocyte expansion was dose dependent, with reproducible serum cytokine profiles. The protocol continues to enroll pts in the expansion cohorts of this phase I/II study. DI-Leu16-IL2 given subcutaneously is safe and effective, and induces durable responses even after discontinuation of therapy, suggesting an anti-tumor vaccination effect. Disclosures Lansigan: Celgene: Consultancy; Teva: Research Funding; Pharmacyclics: Consultancy; Spectrum: Consultancy, Research Funding. Vlock:Alopexx Oncology, LLC: Employment. Gillies:Provenance Bioparmaceuticals Corp: Employment.

Background: Y90-Ibritumomab tiuxetan (90YIT) is approved for use for follicular lymphoma (FL) patients who have achieved a complete or partial response to frontline chemotherapy; however, its use after bendamustine and rituximab (BR) has not been reported. BR has proven to be a superior frontline therapy over R-CHOP in the treatment of FL and is a widely used initial treatment strategy. This analysis focuses on the long-term outcomes and safety of untreated follicular lymphoma patients treated with a short induction course of BR for 4 cycles followed by consolidation with 90YIT. Methods: Patients greater than 18 years with chemotherapy-naïve FL (grade 1-2 and 3a) requiring treatment were eligible. All patients had Stage II-IV disease and had adequate hematologic, liver, and renal function. Treatment consisted of an initial dose of rituximab 375 mg/m2. One week later, bendamustine 90 mg/m2 was administered on days 1 and 2, and rituximab 375 mg/m2 was given on day 1. BR was given for 4 cycles every 28 days. Patients were restaged 4-6 weeks after the last dose of BR. Patients were eligible for consolidation with 90YIT if they obtained at least a partial response after induction, had a platelet count greater than 100,000/mm3, a granulocyte count greater than 1,500/mm3, and bone marrow infiltration less than 25%. 90YIT was given 6-12 weeks after completion of the last cycle of BR. The primary endpoint is complete and unconfirmed complete response (CR/CRu) rate after sequential therapy with BR followed by 90YIT. Secondary endpoints are overall response rate after 4 cycles of BR, conversion rate from partial response (PR) after BR to CR/CRu after 90YIT, progression-free survival, and safety. The 1999 NHL Working Group Criteria was used to assess response. Results: From October 2010 to May 2014, forty-four patients were enrolled in this study (NCT01234766). 39 patients initiated treatment, and 5 were screen failures. Median age was 57 years [range 31-75]. The study enrolled FLIPI low (18%), intermediate (44%), and high (38%) risk patients; 33 of 39 (85%) were Grade 1-2 and 6 (15%) were Grade 3a. Twenty-two of 39 patients achieved CR/CRu (56%) and 16 of 39 patients had a PR (41%) for an overall response rate (ORR) of 97%. One patient had stable disease (SD). Four patients were not randomized to receive 90YIT: one in CR and one in PR were unable to receive 90YIT due to thrombocytopenia, one only achieved SD after BR, and one declined treatment. Thirty of 35 evaluable patients were in CR/CRu (86%), 4 remained in PR (11%) after 90YIT and one progressed during 90YIT, for an ORR of 97%. The number of patients in PR after BR who reached CR/CRu immediately after 90YIT were 10 of 16 (63%). Three (19%) additional patients converted to CR/CRu during follow-up, the latest occurring 16 months after 90YIT. After a median follow up of 30 months, 25 patients (71%) remain in CR/CRu, 10 patients (29%) have progressed/relapsed with a 24-month PFS of 80% (95% CI 63-90) [Figure]. The median PFS was not reached. Grade 3-4 hematologic toxicities during the 90YIT period included: neutropenia (34%), leukopenia (37%), thrombocytopenia (40%), lymphopenia (15%), and anemia (6%). There were no incidences of febrile neutropenia. One patient developed JC Virus/Progressive Multifocal Leukoencephalopathy, 13 months after receiving the last dose of rituximab and 90YIT on study. One patient developed chronic myeloid leukemia 11 months after, one patient developed acute myeloid leukemia 15 months after, and one patient developed uterine cancer 52 months after all study treatment. One patient died to progression of the lymphoma, 35 months after treatment. There have been no reported cases of myelodysplasia. Conclusions: In this 2.5 year report of patients that received BR followed by 90YIT, the CR/CRu rate of patients completing all study therapy is 71% and the 24-month PFS is 80%. There is a high rate of conversion in partial responders to CR/CRu (81%), some occurring more than one year after treatment with 90YIT. The durable PFS is comparable to what is reported in the FIT trial (Morschhauser et al. JCO 2013) and the phase II Spanish intergroup study (Canales et al. ASH 2013). BR followed by 90YIT is a well-tolerated regimen for follicular lymphoma with high response rates that is a safe and highly effective as first-line therapy. Long-term safety reflects the natural history of patients with indolent lymphomas. Figure Figure. Disclosures Lansigan: Pharmacyclics: Consultancy; Teva: Research Funding; Celgene: Consultancy; Spectrum: Consultancy, Research Funding.

Introduction: Most patients (pts) with diffuse large B cell lymphomas (DLBCL) are cured with first line chemoimmunotherapy including an anthracycline and rituximab. Pts who obtain complete remission (CR) but latter relapse often can be cured with salvage therapy and autologous hematopoietic cell transplantation (auto-HCT). This management paradigm often is applied to pts with primary treatment failure (PTF). However, this group is heterogeneous and detailed data on outcomes in current era is needed to identify the DLBCL pts for whom novel therapeutic strategies should be designed. Methods: Fifteen US academic medical centers contributed pts to the REgistry of diFfuse large B cell lymphoma with prImary treatmeNt failurE (REFINE) collaboration. REFINE retrospectively captured patient, disease and treatment characteristics and treatment response as assessed by treating physician. Eligible pts were ≥ 18 years diagnosed with DLBCL during 2008-2015, who received upfront cheomoimmunotherapy including anthracycline and CD20-directed antibody and developed one of 3 patterns of PTF: relapse < 6 months following CR (early relapse- ER); only partial remission (PR) or stable disease (SD) with upfront therapy (residual disease-RD); progressive disease (PD) while receiving upfront therapy (primary progression-PP). Pts with HIV infection, primary CNS lymphoma or lymphoma transforming from a more indolent histology were excluded. Results: Patient characteristics for the 331 cases are summarized in Table 1. Median follow up of survivors was 18.9 months. R-CHOP was the upfront treatment for 87.6% of pts. Nearly all pts (94.6%) received salvage therapy after PTF and prior to any HCT, with a median of 1 and range 0 to 5 regimens. Response to first salvage regimen was CR in 19.9%, PR in 21.8%, SD in 9.0% and PD in 40.8%. Only 15.1% of pts were enrolled in clinical trials. One hundred and thirty-two pts (39.9%) underwent auto-HCT and 33 (10.0%) allogeneic-HCT (8 after failure of auto-HCT). Two-year overall survival (OS) from time of PTF was 45.5% (95% C.I. 34.5-56.5%) for ER, 30.6% (95% C.I. 20.0-41.2%) for RD and 18.5% (95% C.I. 11.4-25.6%) for PP (P Conclusions: Pts with DLBCL experiencing PTF have poor prognosis but low clinical trial participation even when treated in academic centers. Pts with PP disease, intermediate-high/high NCCN-IPI at time of PTF or with c-myc(+) tumors constitute a UHR category with dismal outcomes on existing therapies. REFINE provides benchmarking for future experimental agents targeting this population. UHR pts represent an unmet medical need and should receive high priority for development of new drugs and cellular therapies. Table 1. Table 1. Figure 1. Figure 1. Disclosures Chavez: Janssen: Speakers Bureau. Reddy:INFINITY: Membership on an entity's Board of Directors or advisory committees; celgene: Membership on an entity's Board of Directors or advisory committees; KITE: Membership on an entity's Board of Directors or advisory committees; GILEAD: Membership on an entity's Board of Directors or advisory committees. Karmali:Celgene: Speakers Bureau. Calzada:Seattle Genetics: Research Funding. Barta:Janssen: Honoraria, Speakers Bureau; Celgene, Merck, Seattle Genetics: Research Funding. Lansigan:Spectrum: Consultancy, Research Funding; Pharmacyclics: Consultancy; Celgene: Consultancy; Teva: Research Funding. Flowers:Roche: Consultancy, Research Funding; Acerta: Research Funding; TG Therapeutics: Research Funding; NIH: Research Funding; Pharmacyclics, LLC, an AbbVie Company: Research Funding; Infinity: Research Funding; Gilead: Consultancy, Research Funding; Millenium/Takeda: Research Funding; ECOG: Research Funding; AbbVie: Research Funding; Mayo Clinic: Research Funding; Genentech: Consultancy, Research Funding. Fenske:Seatle Genetics: Honoraria; Millennium/Takeda: Research Funding; Celgene: Honoraria; Pharmacyclics: Honoraria. Cohen:Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Infinity: 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; Millennium/Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol-Myers Squibb: Research Funding; Seattle Genetics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Hamadani:Takeda: Research Funding. Costa:Sanofi: Honoraria, Research Funding.

Introduction: Modern chemoimmunotherapy cures the majority of patients (pts) with newly diagnosed diffuse large B cell lymphomas (DLBCL). The paradigm for pts who relapse has been salvage chemotherapy followed by autologous hematopoietic cell transplantation (auto-HCT) when chemosensitive disease. This approach is often also applied to pts with primary treatment failure (PTF), although this group is heterogeneous and outcomes of HCT in this population have not been well described. Methods: Fifteen US academic medical centers contributed pts to the REgistry of diFfuse large B cell lymphoma with prImary treatmeNt failurE (REFINE) collaboration. REFINE retrospectively captured patient, disease and treatment characteristics and response as assessed by treating center. Eligible pts were ≥ 18 years diagnosed with DLBCL during 2008-2015, who received upfront therapy including anthracycline and CD20-directed antibody and developed one of 3 patterns of PTF: relapse < 6 months following CR (early relapse- ER); only partial remission (PR) or stable disease (SD) with upfront therapy (residual disease-RD); progressive disease (PD) while receiving upfront therapy (primary progression-PP). Pts with HIV infection, primary CNS lymphoma or lymphoma transforming from a more indolent histology were excluded. Results: Among 331 cases included in REFINE, patterns of PTF were ER in 95 (28.7%), RD in 92 (27.8%) and PP in 144 (43.5%) pts. Salvage therapy was administered to 94.6% of pts. We analyzed the 157 (47.4%) PTF pts who subsequently underwent HCT, 132 auto-HCT and 33 allo-HCT (8 after failure of auto-HCT) (Table). Nearly half of pts were in CR at transplant, after 1-2 lines of salvage therapy. Among all pts receiving auto-HCT, 2-year progression-free survival (PFS) from time of transplant was 38.4% (95% C.I. 29.6-47.2%) and overall survival (OS) 54.9% (95% C.I. 44.9-64.9%). Two-year OS from auto-HCT was affected by pattern of PTF: 71.3% for ER, 55.0% for RD and 41.7% for PP (P=0.05). OS at 2-years was 23.7% for auto-HCT pts with germinal center B (GCB)type,c-myc(+) (by FISH) tumors vs. 66.7% for GCB, c-myc (-), vs. 67.8% for non-germinal center (NGC) (P=0.01). Auto-HCT pts with intermediate-high/high NCCN-IPI at time of PTF had 2-year OS of 28.6% vs. 66.0% for intermediate-low and 80.9% for low risk (P Conclusions: Pts with DLBCL experiencing PTF and 2 or more UHF features have dismal outcome after auto-HCT and should be targeted for experimental modalities of cellular therapy. Outcomes of allo-HCT in DLBCL with PTF are poor, due to rapid and fatal relapses. Table. Table. Figure. Figure. Disclosures Costa: Sanofi: Honoraria, Research Funding. Reddy:INFINITY: Membership on an entity's Board of Directors or advisory committees; KITE: Membership on an entity's Board of Directors or advisory committees; celgene: Membership on an entity's Board of Directors or advisory committees; GILEAD: Membership on an entity's Board of Directors or advisory committees. Karmali:Celgene: Speakers Bureau. Chavez:Janssen: Speakers Bureau. Calzada:Seattle Genetics: Research Funding. Barta:Janssen: Honoraria, Speakers Bureau; Celgene, Merck, Seattle Genetics: Research Funding. Flowers:Pharmacyclics, LLC, an AbbVie Company: Research Funding; Mayo Clinic: Research Funding; Acerta: Research Funding; Roche: Consultancy, Research Funding; TG Therapeutics: Research Funding; ECOG: Research Funding; Genentech: Consultancy, Research Funding; Gilead: Consultancy, Research Funding; NIH: Research Funding; Infinity: Research Funding; Millenium/Takeda: Research Funding; AbbVie: Research Funding. Fenske:Seatle Genetics: Honoraria; Pharmacyclics: Honoraria; Celgene: Honoraria; Millennium/Takeda: Research Funding. Cohen:Pharmacyclics: Consultancy, Membership on an entity's Board of Directors or advisory committees; Millennium/Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Infinity: 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, Research Funding; Seattle Genetics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol-Myers Squibb: Research Funding. Hamadani:Takeda: Research Funding.

Introduction: Fatty acid (FA) metabolism is altered in many solid tumor cancers in part through increased de novo synthesis of lipids via up-regulation of FASN as well as via increased utilization of lipids via β-oxidation. The dependence of DLBCL on FA metabolism, and potential associated oncogenic signaling pathways, are largely unknown. Methods: Cerulenin (FASN inhibitor), orlistat (combined FASN and lipoprotein lipase inhibitor), and BKM120 (PI3K inhibitor) small molecules were studied in OCI-LY3, OCI-LY19, SUDHL4, SUDHL6, and SUDHL10 DLBCL cell lines as well as in primary DLBCL cells for the impact on FA inhibition signaling and the induction of cell death (by MTT, cleaved caspases, and AnnexinV/PI by flow cytometric analysis). Synergy was assessed via Calcusyn software. All effects were compared by DLBCL cell of origin (COO). In addition, global transcriptome analyses of FASN inhibition were examined on Affymetrix Human 2.0 ST Genechip. Results: FASN protein was constitutively upregulated across all DLBCL cell lines, independent of COO. Treatment with pharmacological inhibitors of FASN (i.e., cerulenin or orlistat) resulted in dose- and time-dependent reduction in cell viability in all DLBCL cell lines. To further examine the dependence of DLBCL on fatty acids, OCI-LY3, SUDHL4, and SUDHL6 grown in presence of lipoprotein-depleted serum showed exquisite sensitivity to lipid deprivation resulting in near complete cytotoxicity (i.e., >98%) as determined by MTT, cleaved caspase 3 and PARP, and AnnexinV/PI. Moreover, these effects were completely rescued by Very Low Density Lipoprotein (VLDL) supplementation to growth medium. These effects were markedly more prominent in primary DLBCL cells compared with control non-malignant lymphocytes. Analysis of differentially expressed gene sets comparing germinal center (GC) and non-germinal center (non-GC) B-cell tumors with normal cells showed significant over expression of genes related to PI3K and lipid metabolism in GC B-cell tumors. Furthermore, global transcriptome analysis following cerulenin exposure revealed activation of carbohydrate and oxidative stress metabolism in GC-derived SUDHL6 and SUDHL10 cells. In the non-GC cell line, OCI-LY3, there was favorable biology induced with inhibition of progression when treated with cerulenin, with downregulated significant key genes representing growth promoting cytokines (Figure 1). Analysis of key significant genes in cerulenin-treated SUDHL10 cells resulted in induction of antioxidant genes (GSR, TXNRD1, NQO1, AIFM1) and oxidative stress responsive PHB, DHX9, HSP90 and PMPCA genes, which are upstream components of PI3K signaling. Western blot analysis with prohibitin (PHB) inhibitor rocoglamide in the presence of cerulenin inhibited phosphorylation of PI3K-p85 and also prominently downregulated FASN expression of GC-derived DLBCL, suggesting the role of PHB in PI3K response to cerulenin. In addition, inhibition of PI3K with BKM120 was shown to strongly down-regulate FASN expression in OCI-LY3, SUDHL6, and SUDHL10 DLBCL cells. Furthermore, treatment with BKM120 in combination with cerulenin was strongly synergistic (CI Conclusions: Multiple FA pathways are constitutively activated in DLBCL and cell survival appears strongly dependent on lipid metabolism, which appeared to occur independent of COO. Additionally, inhibition of FASN was regulated in part through PHB/PI3K-dependent pathways. Collectively, this work indicates that targeting FA metabolism may be considered as a valid therapeutic strategy for DLBCL. Further investigation is required to delineate the precise mechanisms through which PHB/PI3K regulates FASN and also to identify potential rational therapeutic combinations leveraging the addiction of DLBCL to FA signaling. Figure 1. Key significant gene analysis ofFASN inhibition inDLBCL cells. Cerulenin treatment in ABC OCI-LY3 shows (A) downregulation of growth promoting cytokines and growth factors and favorable tumor biology with predicted inhibition of tumor progression. In the GC derived SUDHL10 cells, (B) cerulenin resulted in activation of genes associated with oxidative stress response and PI3K associated mitochondrial genes with adverse tumor biology predicting tumor progression in GC DLBCL. Figure 1. Key significant gene analysis ofFASN inhibition inDLBCL cells. Cerulenin treatment in ABC OCI-LY3 shows (A) downregulation of growth promoting cytokines and growth factors and favorable tumor biology with predicted inhibition of tumor progression. In the GC derived SUDHL10 cells, (B) cerulenin resulted in activation of genes associated with oxidative stress response and PI3K associated mitochondrial genes with adverse tumor biology predicting tumor progression in GC DLBCL. Disclosures No relevant conflicts of interest to declare.

Introduction: Post-transplant lymphoproliferative disease (PTLD) encompasses a heterogeneous array of cases of lymphoma/lymphoma-like conditions arising in the setting of immunosuppression (IS) for prior organ or marrow transplant. Such pts face heightened risk of toxicity from exposure to cytotoxic chemotherapy, and may be best treated in the frontline with reduction of IS (RI) and anti-CD20 monoclonal antibody treatment (Trappe, 2012). Autoimmune (AI) disease has been associated with an increased risk of developing lymphoma; however, the relative impact of baseline clinical features, including prior IS, is unknown. Methods: We conducted a multicenter, retrospective analysis of adult pts with pre-existing AI conditions who were diagnosed with lymphoma since 1997. Baseline clinical features at diagnosis of lymphoid malignancy, including International Prognostic Index (IPI) risk factors; underlying AI disease; duration and type of IS; EBV status (by EBER in-situ hybridization); and primary therapy received (RI, rituximab [R] monotherapy, chemotherapy [+/- R]); were collected. Survival analyses were performed using Kaplan-Meier method. We then focused on those who had A) received IS other than corticosteroids (CS) alone; and B) those diagnosed with DLBCL. Those variables found to have significant correlation with OS by univariate analyses (UVA) were used to construct Cox proportional hazards model (multivariate analysis [MVA]) in order to determine which might have the strongest association with OS. Lastly, we sought to evaluate a potential role for RI and/or R as frontline therapy for those with DLBCL. Results: A total of 130 pts were included (Table 1). The most frequent AI disease was rheumatoid arthritis and for all cases, 76% had documented exposure to IS, for a median duration of 4.5 years (range 0.17-57 years) prior to diagnosis of lymphoma. The most common histologic subtype was DLBCL (52%). EBV status was reported for only 34% of pts, but was positive in 68% (25/37), all of whom had received prior exposure to IS beyond CS, and 80% of whom (20/25) were diagnosed with DLBCL. EBV status was infrequently tested in pts not previously exposed to IS (3/31). At a median follow-up of 61 months for the entire cohort, 2-year PFS and OS were 79% and 91%, respectively (Figure 1, Panel A). By UVA, age>60; PS>1; LDH> upper limit of normal (ULN); DLBCL (vs all other histologies); underlying rheumatoid arthritis (RA; vs all other AI diseases); and prior exposure to IS, each correlated with inferior OS (Table 1). By MVA, PS>1 and prior IS maintained significance (p1 (p 0.002) and prior IS (p 0.010) maintain significance (data not shown). Among 67 pts with DLBCL, median age was 61 (range 26-90), 60% had advanced stage disease, and 32% had IPI of 4 or 5. At a median follow-up of 32 months, the 2-year PFS and OS were 82% and 84%, respectively. There were no differences in frequency of any IPI factors between patients exposed to prior IS (n=53) and those who were naïve to prior IS (n=14). For those not exposed to prior IS, the 2-year OS was 100%, compared to 80% in those who received prior IS (p 0.24); corresponding 2-year PFS were 92% and 79%, respectively (p 0.41). Age>60 and PS>1 were associated with an inferior OS but use of IS was not associated with outcome (Table 2). The 2 year OS for those treated with R plus CHOP(like) chemotherapy, CHOP(like) chemotherapy (without R), R alone (+/- RI), and with RI alone were 92%, 75%, 90%, and 67%, respectively (Figure 1, Panel B; log-rank p value 0.55). Patients who received CHOP-like therapy +/- R, as compared to R and/or RI were more likely to be naïve to IS therapy (15/46 vs 0/22, p = 0.003) and have 2 or more EN sites of disease (15/46 vs 2/22, =0.041). These differences notwithstanding, the 2-year PFS for the two groups were 86% and 74% (p 0.16), and 2-year OS for the two groups were 88% and 82%, respectively (Figure 1, Panel C; p 0.91). Conclusions: Pts with immunosuppression-related lymphoma have high rates of 2-year OS and in DLBCL, IS does not appear to be associated with an inferior outcome. Similar to evolving treatment paradigms in PTLD, rituximab monotherapy and other cytotoxic chemotherapy-free regimens as well as risk-adapted approaches may warrant further evaluation in IS-related DLBCL. Disclosures Petrich: Seattle Genetics: Consultancy, Honoraria, Research Funding. Barta:Seattle Genetics: Research Funding. Feldman:Celgene: Honoraria, Speakers Bureau; Pharmacyclics/JNJ: Honoraria, Speakers Bureau; Seattle Genetics: Honoraria, Speakers Bureau. Savage:Seattle Genetics: Honoraria, Speakers Bureau; BMS: Honoraria; Infinity: Honoraria; Roche: Other: Institutional research funding.

Background: Patients withacute myeloid leukemia (AML) are at increased risk for both hemorrhage and thrombosis, including in the central nervous system. There is limited data on the incidence, clinical association and mortality associated with cerebrovascular accident (CVA) in hospitalized patients with active AML. The aim of this study is to evaluate the epidemiology and mortality of hospitalized patients with AML who suffered concurrent stroke from a large national database. Methods: Using the 2012 National Inpatient Sample (NIS), admissions with an International Classification of Diseases, 9th Revision, Clinical Modification (ICD-9-CM) codes for AML without remission and AML in relapse (205.00 and 205.02, respectively) were extracted, and correlated with age, gender, length of stay and mortality. All CVA (ICD-9-CM 434.91) data were extracted as well for comparison of mortality, length of stay (LOS). Results: Of the 7,296,968 unweighted admissions in the 2012 NIS, 9384 involved AML patients who had not yet achieved remission, and 1600 involved relapsed AML (Prevalence of 0.12% and 0.021% respectively). Of the combined group of admitted patients with active AML (N=10,984), 65 patients (0.59%) had a concomitant CVA (either hemorrhagic or ischemic, of whom 56 (0.51%) had active disease and 9 (0.08%) had relapsed disease). Compared to all other active AML patients, those who developed stroke were older (Mean age 66 y/o vs 58 y/o P=0.003), had longer LOS (20 days vs 12 days P= 0.53), were predominantly female (55% vs 45%; p=0.078) and had significantly higher inpatient mortality rates (36.9% vs 10.5%; OR 3.5; 95%CI 2.2, 5.5; P96 hours (OR 4.92; CI95% 1.02, 23.6; P=0.047) and continuous positive airway pressure ventilation (OR 3.03; CI95% 1.11, 8.26; P=0.031). Disseminated intravascular coagulation (DIC) and leukocytosis were more prevalent in AML patients with CVA compare to all AML patients, but the difference did not reach statistical significance. Conclusions: CVA in patients with active AML was strongly associated with older age and higher mortality, and appeared to be a relatively rare event, occurring in only 0.59% of patients. There was no statistically significant difference in LOS or gender distribution between those who developed CVA and those who did not amont active AML patients. As compared to all CVA patients, active AML patients with CVA had 5-fold higher risk of mortality. Significant acute renal failure, hypernatremia and thrombocytopenia appear to portend a higher risk of stroke in patients with active AML. It is unclear if UTI, and the need for mechanical ventilation is a predictor of stroke, as much as they may be a ramification of it. While more common in AML patients with CVA vs AML patients without CVA, we did not find DIC or hyperleukocytosis to be significantly predictive. Disclosures No relevant conflicts of interest to declare.

DI-Leu16-IL2 immunocytokine is a recombinant fusion protein composed of interleukin 2 (IL2) and a CD20 targeting monoclonal antibody. Pre-clinical studies have shown it maintains the activities of both antibody and cytokine components but is also involved in tumor targeting, engagement of the immune system and induction of an anti-cancer vaccine effect. In a SCID mouse model,DI-Leu16-IL2 is more effective than the individual components (IL-2 and CD20) given either alone or in combination (Gillies SD; 2005). DI-Leu16-IL2 administered intravenously to 8 relapsed/refractory Non-Hodgkin's Lymphoma (NHL) patients at a maximum dose of dose of 0.5 mg/m2 resulted in 1 complete, 1 possible partial response and 4 patients with stable disease (Nakamura R; 2013). In this multicenter open label, dose escalation trial the safety, efficacy and tolerability of subcutaneously (SC) administered DI-Leu16-IL2 was evaluated as well as the maximum tolerated dose (MTD) and optimal biological dose in patients with relapsed or refractory B cell CD20 positive lymphoma (NCT01874288). DI-Leu16-IL2 was administered on three consecutive days every 21 days up to 6 cycles. Peripheral B cell depletion was achieved with low-dose rituximab (50mg/m2) on day 1 if needed to keep rituximab levels >10µg/mL. The starting dose was 0.5 mg/m2 and followed a modified accelerated titration until dose limited toxicity (DLT) occurred. To be evaluable for response patients had to receive at least 2 cycles of DI-Leu16-IL2 and were then evaluated by PET/CT imaging. To date, 13 patients in 3 cohorts have been enrolled. The median age is 63 years (range, 48-83 years). Ten patients had diffuse large B cell lymphoma, 2 follicular and 1 marginal zone NHL. All were previously treated with rituximab-containing chemotherapy - median of 3 (range 1-6) prior regimens, including radiation therapy (n=5) and autologous transplantation (n=3). All patients had relapsed or refractory disease with biopsy-confirmed tumor cells expressing CD20. DI-Leu16-IL2 dose levels were 0.5 mg/m2 (n=3), 1 mg/m2 (n=3), 2 mg/m2 (n=7). DI-Leu16-IL2 was detectable in the serum at the lowest dose level. Median number of cycles were 4 (range 1-11). No DLTs have been observed. The most common drug-related adverse events (AEs) were grade 1-2 transient skin reactions with erythema, painless induration of injection site, pruritus, edema and mild constitutional symptoms (grade 1-2 chills, low-grade fever, fatigue, low appetite) suggesting an immune stimulatory response. Lymphocyte margination occurred with nadir of 0.3x103 /mL for median 2.7 days (range 1-5). Two grade 3 non-DLT toxicities (diarrhea and QTc prolongation with pre-existing RBBB) resulted in DI-Leu16-IL2 dose reduction. Transiently prolonged QTc (grade 1-2) occurred in 3 additional patients. Routine laboratory monitoring revealed grade 1-2 transient eosinophilia, anemia and thrombocytopenia in most subjects, grade 1-2 neutropenia (n=3) without neutropenic fever, grade 1 elevation of alkaline phosphatase or bilirubin. All AEs resolved completely within one week. Twelve patients are evaluable for response. After 2 cycles, tumor regression or stabilization was noted in 10 of 12 patients with mean tumor reduction of 30% (range 0%-80%). Six had sustained disease control after 4 cycles. One patient with small tumor bulk marginal zone lymphoma achieved a complete response by PET criteria, 3 patients had a partial response (55%, 55% and 80% tumor size reduction) and continue on therapy. Stable disease (SD) response was observed in all dose cohorts; best responses occurred at the highest dose level (2mg/m2) administered thus far. Three patients have had SD for up to 1 year. In conclusion, we have observed promising clinical efficacy of the novel immunocytokine DI-Leu16-IL2 in relapsed/refractory B cell NHL. SC administration has permitted higher doses than could be achieved with IV treatment and the MTD has yet to be reached. DI-Leu16-IL2 is biologically active in doses up to 2mg/m2. Repetitive SC dosing elicits clinical immune activation associated with clinical activity. Further dose escalation of DI-Leu16-IL2 is in progress. Prior DI-Leu16-IL2 therapy After 2 cycles at dose 2mg/m2 Figure 1. 65 year old female with diffuse large B cell lymphoma treated at dose level 2mg/m2 received 2 cycles of DI-Leu16-IL2. Treatment resulted in partial regression of multiple lymph node sites. Figure 1. 65 year old female with diffuse large B cell lymphoma treated at dose level 2mg/m2 received 2 cycles of DI-Leu16-IL2. Treatment resulted in partial regression of multiple lymph node sites. Disclosures Bachanova: Seattle Genetics Inc.: Consultancy, Research Funding.

Background: Fatty acid (FA) metabolism is altered in several cancers through increased de novo synthesis of lipids via up-regulation fatty acid synthase (FASN) and increased utilization of lipids via β-oxidation. We investigated the dependence of DLBCL survival on FA metabolism. In addition, we examined novel FASN inhibitors TVB3567 and TVB3166 in comparison with cerulenin for the effects on cell survival and PI3K and MAPK-related biological pathways associated with tumor-related FA metabolism in DLBCL. Methods: FASN inhibitors, TVB3567 and TVB3166 (3V Biosciences, CA), cerulenin (FASN inhibitor), orlistat (anti-lipoprotein lipase (LPL) and FASN), PI3K/mTOR, and MEK small molecule inhibitors were studied in OCI-LY3, OCI-LY19, SUDHL4, SUDHL6, and SUDHL10 DLBCL cell lines for the effects of FA inhibition on lipid metabolism, cell signaling, and cell death. The effects of FASN inhibition on global gene expression profile (GEP) were also determined with Affymetrix Human 2.0 ST Genechip with Gene set enrichment analysis (GSEA). We also utilized short hairpin RNA interference (shRNA) to study interactions between FASN and PI3K/MAPK signaling. Finally, AutoDock Vina software (autodock.scripps.edu) was utilized to analyze drug target (FASN enzyme) binding affinity and assist in the design of FASN inhibitors with higher target binding affinity. Results: DLBCL cell lines OCI-LY3, SUDHL4, and SUDHL6 grown in the presence of lipoprotein-depleted serum showed exquisite sensitivity to lipid deprivation resulting in near complete cytotoxicity by MTT. Lipid deprivation-induced apoptotic cell death, detected as cleaved caspase 3 and PARP and Annexin-V/PI positivity, in these cells. Further, these effects were completely rescued by Very Low Density Lipoprotein (VLDL) supplementation to growth medium in SUDHL4 confirming the high lipid-dependency on cell survival in DLBCL. Treatment with pharmacological inhibitors of FASN (ie, TVB3567, TVB3166, cerulenin, or orlistat) resulted in a dose- and time-dependent reduction in cell viability in all DLBCL cell lines. Ingenuity Pathway Analysis (IPA) from GEP with cerulenin-treated OCI-LY3 showed prominent suppression of CD40, TNF, and NFκB dependent inflammatory responses as well as activation of apoptosis as predominant biological activities including significant down-regulation of genes involved in Krebs cycle and p38 MAPK pathways. Interestingly, upstream regulation by IPA predicted activation of MEK/ERK and MYC-dependent functions; and in OCI-LY3 with shRNA knock down of FASN, we observed constitutive activation of ERK as detected with increased phosphorylation by western blot. Activation of MEK/ERK and MYC is expected in part owing to metabolic stress induced by FASN inhibition. Considering the impact of MEK/ERK pathways on lipid metabolism, we next investigated the impact of MEK/ERK on FA metabolism. FASN was significantly decreased following MEK or ERK shRNA in OCILY-3 and SUDHL10 cells. Similarly, pharmacological inhibition of MEK or PI3K/mTOR (using novel small molecule agents AZD6244 (selumetinib) or BEZ235, respectively) resulted in marked down-regulation of FASN expression. Based on these results, FASN inhibition appears to a promising therapeutic target for the treatment of DLBCL, however attaining clinical efficacy with existing compounds require the effective drug concentration to be within the nanomolar range. Thus, we utilized AutoDock to determine drug docking enzyme inhibition constant (ki). We identified high ki values of 33μM and 180μM for Cerulenin and Orilstat, respectively. Therefore, we have developed/constructed modified novel and potent anti-FA compounds with ki Conclusions: Collectively, we demonstrated that DLBCL cell survival is highly dependent on FA metabolism and that targeting lipid metabolism may be harnessed as a potential therapeutic strategy. We also showed that MEK/ERK-dependent mechanisms are intimately involved in promoting lipid addiction in DLBCL cells. Further investigation is warranted to delineate the mechanisms through which MEK/ERK regulate FASN expression and to determine in vivo implications of FASN inhibition on DLBCL tumor growth. In addition, continued development, design, and enhancement are needed to construct the most optimal anti-FA therapeutic agents. Disclosures Lansigan: Teva Pharmaceuticals: Research Funding; Spectrum Pharmaceuticals: Research Funding.

Background: Y90 Ibritumumab tiuxetan (90YIT) is approved for use for follicular lymphoma (FL) patients (pts) who have achieved a complete or partial response to frontline chemotherapy; however, its use after bendamustine and rituximab (BR) has never been studied. BR has proven to be a superior frontline therapy over R-CHOP in the treatment of FL and is a widely used initial treatment strategy. In this prospective, single-arm, open-label, multicenter phase II trial, we assessed the response rate and safety of a short induction course of BR for 4 cycles followed by consolidation with 90YIT for chemotherapy-naïve pts with FL. Methods: Consenting pts greater than 18 years with chemotherapy naïve FL (grade 1-2 and 3a) requiring treatment were eligible for this study. All pts had Stage II-IV disease and had adequate hematologic, liver, and renal function. Treatment consisted of an initial dose of rituximab 375mg/m2. One week later, bendamustine 90mg/m2 was administered on days 1 and 2, and rituximab 375mg/m2 was given on day 1. BR was given for 4 cycles every 28 days. Pts were restaged 4-6 weeks after the last dose of BR. Pts were considered eligible for consolidation with 90YIT if they obtained at least a partial response after induction, had a platelet count greater than 100,000/mm3, a granulocyte count greater than 1,500/mm3, and bone marrow infiltration less than 25%. 90YIT was give 6-12 weeks after completion of the last cycle of BR. The primary endpoint of this study is complete and unconfirmed complete response (CR/CRu) rate after sequential therapy with BR followed by 90YIT. Secondary endpoints are overall response rate after 4 cycles of BR, conversion rate from partial response (PR) after BR to CR/CRu after 90YIT, progression-free survival, and safety. The 1999 NHL Working Group Criteria was used to assess response. Results: Forty-two pts were enrolled in this study: 38 pts initiated study treatment, and 4 were screen failures. Median age was 58 years [range 31-74]. The study enrolled FLIPI low (18%), intermediate (47%), high (34%) risk pts; 32 of 38 (84%) were Grade 1-2 and 6 (16%) were Grade 3a. Response rates after 4 cycles of BR: Thirty-eight pts have completed 4 cycles of BR and 38 are evaluable for response. Twenty-two of 38 evaluable pts achieved a CR/CRu (58%) and 15 of 38 pts had a PR (39%) for an overall response rate (ORR) of 97%. One pt had stable disease (SD). Response rates after BR followed by 90YIT: Thirty of 38 BR-treated pts have received 90YIT and are evaluable for the primary endpoint of CR/CRu. Of the 38 BR treated pts, two in CR were unable to receive 90YIT due low platelets, one was not eligible to receive 90YIT due to achievement of SD only, one declined treatment, and four are not yet evaluable for response. Twenty-five of 30 evaluable pts are in CR/CRu (83%), 4 remain in PR (13%) after 90YIT and one progressed during 90YIT, for an ORR of 96%. Of the 14 pts who had a PR after BR, 7 (50%) converted to a CR/CRu immediately after 90YIT, with three (21%) additional conversions to CR/CRu in follow-up, the latest occurring 16 months after 90YIT. Grade 3-4 hematologic toxicities during BR included: lymphopenia (36%), neutropenia (8%), thrombocytopenia (3%), leukopenia (3%). Non-hematologic toxicities included grade 2 phlebitis (14%) and grade 3 hyperglycemia (8%), hyponatremia (3%), diarrhea (3%), infusion-related reaction (3%), headache (3%), rectal hemorrhage (3%). Grade 3-4 hematologic toxicities after 90YIT included: neutropenia (33%), leukopenia (36%), thrombocytopenia (36%), lymphopenia (14%), anemia (3%). Non-hematologic toxicities included skin infection (3%). Median neutrophil recovery was 8 weeks [range 8 to 12] and median platelet recovery was 9 weeks [range 5 to 36] after Y90IT. There have been no incidences of neutropenic fever. One pt developed chronic myelogenous leukemia, occurring 11 months after treatment with BR followed by Y90-IT. There have been no cases of myelodysplasia or acute myelogenous leukemia. Conclusions: In this nearly final analysis, the CR/CRu rate of pts completing all study therapy (BR followed by 90YIT) is 83%, the ORR is 96%, and the conversion rate from PR to CR/CRu is 71%. We conclude that sequential treatment with BR followed by Y90IT is highly effective and safe, and should be considered as a frontline treatment option for FL. Disclosures Lansigan: Teva Pharmaceuticals: Research Funding; Spectrum Pharmaceuticals: Research Funding.

Introduction Based on the activity of ofatumumab in patients with indolent B-cell non-Hodgkin lymphoma (NHL) and the potential synergistic effect of bortezomib in combination with anti-CD20 antibody therapy, a phase II study to investigate the effect of the combination of ofatumumab and bortezomib in patients with relapsed indolent B-cell NHL who relapsed >6 months after receiving a rituximab-containing regimen was initiated. Methods Patients 18 years or older with a pathologically confirmed low-grade B-cell NHL who relapsed >6 months after a rituximab-containing regimen were included in our study. Other inclusion criteria were ECOG performance status 0.75, and platelets >50,000/uL). Exclusion criteria included HBV+, HIV+, transformed lymphoma, primary cutaneous lymphoma, central nervous system involvement, Results We present data on 10 patients enrolled between October 2010 and April 2013. Median age was 66 years (range 55-93 years); eight patients (80%) were 60 years or older. There were 7 (70%) men and 3 (30%) women. LDH was elevated in 8 patients (80%). ECOG performance status was 0 in 9 (90%) and 1 in 1 patient (10%). Six patients (60%) had a histological diagnosis of follicular lymphoma, 1 (10%) mantle cell lymphoma, 1 (10%) small lymphocytic lymphoma, 1 (10%) marginal zone lymphoma, and 1 (10%) low-grade B-cell lymphoma, not otherwise specified. Stage III/IV was seen in 5 patients (50%). Eight patients (80%) had a high-risk FLIPI score. Median time from initial diagnosis to current therapy was 65 months (range 20-204 months). Median time from last rituximab-containing regimen was 24 months (range 11-48 months). Median number of previous therapies was 2 (range 1-4). Three patients (30%) had previously received radiotherapy. One patient (10%) had previously undergone autologous stem cell transplantation. Response rates after induction therapy were: 1 (10%) complete response (CR), 3 (30%) partial response (PR), 3 (30%) stable disease, 1 (10%) progressive disease, and 2 (20%) not evaluable for response. With exception of 1 patient who continues on therapy, the patients who achieved a response or had stable disease after induction therapy showed progression of disease during maintenance. Median duration of response in patients who responded was 4 months (range 1-9 months). At the time of this report, 7 patients (70%) are alive with disease, 2 (20%) are alive without evidence of disease, and 1 (10%) has expired. Five grade 3 or 4 adverse events (AEs) occurred; grade 4: diarrhea (n=1) and hyperglycemia (n=1); grade 3: infusion reaction (n=1), nausea (n=1) and rash (n=1). No grade 3 or 4 peripheral neuropathy or hematological AEs were observed. The most common grade 1 or 2 AEs were: infusion reactions (n=6), anemia (n=5), thrombocytopenia (n=5), fatigue (n=4), diarrhea (n=4), hyperglycemia (n=4) and lymphopenia (n=4). No deaths have occurred while on therapy. Conclusions The combination of ofatumumab and bortezomib given weekly for 4 weeks induced a response in 40% and stable disease in 30% of the patients. However, most of the patients experienced progression of disease during the maintenance phase of the study. Furthermore, there were five grade 3 or 4 AEs associated with therapy. Based on this interim analysis, it was decided to stop enrollment. The combination of ofatumumab and bortezomib, however, appears potentially active and deserves further study. Different schemas of therapy with longer induction or different maintenance schedule could prove to be safer and more effective. Disclosures: No relevant conflicts of interest to declare.

Background DHL are high-grade B-cell lymphomas (BCL) characterized by dual gene rearrangements (RA) of MYC and either BCL2 or BCL6. Outcomes are typically dismal, particularly when treated with R-CHOP, as compared to those observed in patients (pts) with similar histologies without dual RA. Few reports have evaluated the use of intensive induction regimens, with or without consolidative stem cell transplantation (SCT). We sought to evaluate the role of intensive induction as well as SCT, and to investigate predictors of outcome in DHL. Methods This study was an IRB-approved retrospective analysis across 15 centers. Cases were diagnosed between 2000-2012 as aggressive BCL harboring RA, by FISH, of MYC along with RA of BCL2 and/or BCL6. Pts were treated with either R-CHOP, or one of the following intensified regimens: R-HyperCVAD, R-EPOCH, R-CODOX-M/IVAC, R-ICE. Survival was estimated using Kaplan Meier method, and comparisons made with log rank test. Multivariable analysis (MVA) was performed using the Cox proportional hazard regression. Results One hundred six pts were analyzed. Median age at diagnosis was 60; 59% were male. The majority had DHL characterized by RA of MYC and BCL2 (77%); the remainder showed RA of MYC and BCL6 (10%), or all three (12%). History of indolent lymphoma was present in 29 pts (27%). The most common histology was DLBCL in 56 pts (53%), followed by BCL unclassifiable (BCLU) in 45 (42%), and Burkitt-like in 5 (5%). Thirty six pts (33%) received R-CHOP, 33 (31%) R-EPOCH, and 28 (36%) R-Hyper-CVAD or CODOX-M/IVAC. Fourteen pts (13%) were consolidated with SCT (n=1 allo and n=13 auto SCT); all were treated with intensive induction. Three additional pts underwent SCT in partial remission or progressive disease following R-CHOP induction. The median PFS and OS for the entire cohort were 8.8 mo and 12 mo, respectively (Table 1); of the 24 pts (23%) alive and without progression, median follow-up was 19 mo. R-EPOCH was superior in achieving complete response (CR) compared with R-CHOP (P 0.01), and trended towards significance compared with pts receiving other intensive induction (P 0.07). Additionally, primary refractory disease, observed in 37 pts (34.5%), occurred less frequently in pts receiving R-EPOCH compared to R-CHOP (P .005) or other intensive regimens (P 0.03); induction regimen did not impact OS in patients not receiving SCT (P 0.7; Fig 1). SCT in first remission was associated with improved OS (P 0.02), and PFS (P 0.006) compared with induction alone. However, among pts achieving CR, SCT was not associated with improved OS compared with observation (P 0.22; Fig 2). Pts with prior history of indolent NHL did not fare worse than those with de novo DHL (P 0.5). No difference in OS was observed based on histology (P 0.2). The following factors were evaluated in MVA: prior indolent lymphoma, histological subtype, IPI>/=3, primary refractory disease, type of induction (R-CHOP vs intensified), and consolidative SCT. Only primary refractory disease (P Conclusions In this analysis of DHL, primary refractory disease was the primary predictor of OS. Pts achieving CR did not appear to benefit from consolidative SCT, though our analysis was limited by the fact that pts receiving SCT are often highly selected (for chemosensitivity, age, comorbidities) and in this study, by the low number of pts receiving SCT. R-EPOCH was associated with a decreased rate of primary refractory disease compared to other regimens, and increased rate of CR compared to R-CHOP, but the lack of clear survival benefit suggests that relapsed disease offsets early benefit. Our analysis confirms the generally poor outcomes for pts with DHL, though a subset with chemosensitive disease has an improved prognosis, likely due to favorable disease biology. Further investigation on the role of SCT and of novel agents is needed for this high-risk population. ^Three patients untreated, one received multiple regimens Disclosures: Off Label Use: Brentuximab Vedotin is approved for relapsed, refractory Hodgkin Lymphoma in patients who have already had a transplant or are ineligible for one, or for patients with relapsed, refractory anaplastic large cell lymphoma. Patients treated on clinical trials or off label will be included in this presentation. Petrich:Genetech: Consultancy, Honoraria. Fenske:Seattle Genetics : Consultancy, Honoraria. Smith:Seattle Genetics, Inc.: Research Funding; Spectrum: Consultancy; Cephalon: Consultancy, Speakers Bureau; Celgene: Consultancy, Speakers Bureau; GlaxoSmith Kline: Speakers Bureau. Evens:Seattle Genetics: Consultancy, Honoraria; Millennium: Consultancy, Honoraria, Research Funding; Ziopharm, Inc: Research Funding; Celgene: Consultancy, Honoraria.

Background Fatty acid metabolism is altered in several cancers, which includes de novo synthesis by fatty acid synthase (FASN) and increased utilization of fatty acids via β-oxidation to meet cellular energy requirements. PI3K and MEK/ERK signal transduction are primary biological pathways that activate tumor-related fatty acid metabolism. Notably, these concepts have emerged primarily from solid tumor studies; there is a comparative paucity of data in lymphoma. We examined the functional roles of fatty acid metabolism in DLBCL cells and their interaction with oncogenic signal transduction pathways including PI3K, MEK/ERK and hypoxia inducible factor-1 alpha (HIF-1a). We also investigated potential therapeutic implications of targeting fatty acid metabolism for the treatment of DLBCL. Methods DLBCL cell lines OCI-LY3, OCI-LY19, SUDHL4, and SUDHL10 were examined in this study. Cerulenin (FASN inhibitor), Orlistat (FASN and LPL inhibitor), BEZ-235 (Dual PI3K/mTOR inhibitor), AZD6244 (MEK inhibitor) were used to study the effects of enzyme inhibition on lipid metabolism, cell signaling and cell death. We assessed cell viability with the MTT assay and apoptosis by flow cytometric analysis of Annexin-V/propidium iodide (PI). FASN or LPL mRNAs were quantified in DLBCL cell lines by quantitative RT-PCR as well as through gene expression profiling (GEP) analysis (by cell of origin) using the CaBIG dataset. Further, FASN and associated signaling pathways (MEK, ERK, and HIF-1a) were analyzed by Western blot. Finally, for investigation of potential interactions between FASN and HIF-1a or MAPK signaling, we utilized short hairpin RNA interference (shRNA) to knock out (KO) desired pathways. Results GEP analysis showed that genes related to fatty acid synthesis and mTOR were more prominently expressed in germinal center (GC) DLBCL (p=0.0006 vs GC control and p=0.0001 vs non-GC DLBCL), whereas genes involved in utilization of fatty acid for energy, PI3K and MAPK were preferentially expressed in non-GC DLBCL (p Conclusions Altogether, we demonstrated that fatty acid metabolism is highly upregulated in DLBCL and that there was preferential gene expression in DLBCL cells in part according to cell of origin. Further, PI3K/mTOR, MAPK and HIF-1a constitutively activated oncogenic pathways in DLBCL appeared here to directly regulate fatty acid metabolism. In addition, we showed that targeting fatty acid metabolism may be harnessed as a potential therapeutic strategy. Continued investigation is warranted to delineate the mechanisms through which MAPK and HIF-1a regulate FASN expression and to determine the in vivo implications of FASN inhibition on DLBCL tumor growth. Disclosures: No relevant conflicts of interest to declare.

Background T-cell lymphomas comprise 10-15% of newly diagnosed lymphomas. While a number of therapies are available for patients (pts) with relapsed and refractory disease, there is still an unmet need for novel agents and approaches. Sorafenib is a multi-kinase inhibitor that is approved for clinical use in renal cell and hepatocellular carcinoma. Molecular targets of sorafenib include B-raf, PDGFR, and VEGF. Recent studies have demonstrated overexpression of PDGFR and VEGF in Peripheral T-cell Lymphoma (PTCL) and Cutaneous T-cell Lymphoma (CTCL).1 We report results of a pilot study of sorafenib in patients with relapsed T-cell lymphomas. Methods Twelve patients with refractory T-cell lymphomas including 2 PTCL (one pt relapsed after allogeneic transplant and one after autologous transplant), 1AITL, and 9 CTCL ( stages IB=1, IIB=3, III-2, IV=3) were treated with sorafenib at a starting dose of 400 mg twice daily. Median age was 69 (range: 38-85). Seventy-five percent were female; 25% presented with B symptoms. The clinical activity of the drug was assessed by determining response rate, progression free survival, and duration of response or stable disease. Results Four patients (33%) had a CR (skin and/or nodes), including one with PTCL and one with AITL, 3 (25%) had a CR in the skin, including one Stage III CTCL and two with PTCL with skin involvement. In addition, 2 (17%) had a mixed response, including one Stage IIB and one Stage III CTCL. Two patients had SD, including one with Stage IIB and one with Stage IB CTCL. Dose reduction from the starting dose of 400 mg twice daily occurred in 66% (8) patients: dose reduced to 300 mg daily in 2 pts and 200 mg daily in 6 pts. Three patients discontinued the trial due to progressive disease (25%). Of the remaining pts, all but one had to discontinue the drug due to adverse effects. Skin toxicity from sorafenib occurred in 5 pts, including rash in 3 pts and fissuring and exfoliation of the palms and soles in 2 pts. The one pt with angioimmunoblastic T cell lymphoma had a clinical CR and was able to undergo an allogeneic stem cell transplant. Nine (69%) pts are still alive. Conclusions In this pilot study, Sorafenib demonstrated activity in pts with refractory T-cell lymphomas but dose modifications for skin toxicity occurred frequently, suggesting that a lower dose would be more tolerable. We plan to conduct a follow up study exploring lower doses of sorafenib and correlating clinical activity with tissue expression of ERK, PDGFR, and VEDGF. 1. Piccaluga PP, Agostinelli C, Zinzani PL, Baccarani M, Dalla Favera R, Pileri SA. Expression of platelet-derived growth factor receptor alpha in peripheral T-cell lymphoma not otherwise specified. The lancet oncology. Jun 2005;6(6):440. Disclosures: Off Label Use: sorafenib in t cell nhl. Foss:celgene: Honoraria, Research Funding; millenium: Honoraria, Membership on an entity’s Board of Directors or advisory committees; eisai: Membership on an entity’s Board of Directors or advisory committees; spectrum: Research Funding; merck: Research Funding; seattle genetics: Research Funding.

Abstract 2711 Background: Fatty acid synthase (FASN) is a key enzyme of fatty acid synthesis and is upregulated in many cancers. Increased FASN in cancer is associated with poor prognosis, while inhibition of FASN results in cancer cell death. The MEK/ERK signal transduction is one of the primary pathways that activate tumor-related FASN. Lipoprotein lipase (LPL) is also involved in fatty acid metablishm as it releases free fatty acid (FFA) from circulating lipoproteins, making them available for cellular uptake. Notably, these concepts have emerged primarily from solid tumor studies; there is a comparative paucity of data in lymphoma. We examined the functional roles of FASN and LPL in DLBCL cells and their interaction with oncogenic signal transduction pathways including MEK/ERK and an upstream target, hypoxia inducible factor-1 alpha (HIF-1a). We also investigated potential therapeutic implications of targeting fatty acid metabolism for the treatment of DLBCL. Methods: We used the DLBCL cell lines OCI-LY3, OCI-LY19, SUDHL4, and SUDHL10 in normoxic or hypoxic (0.2% O2) conditions. Cerulenin (FASN inhibitor) and Orlistat (FASN and LPL inhibitor) were utilized to examine the effect of fatty acid enzyme inhibition on cell signaling and cell death. We assessed cell viability with the MTT assay and apoptosis by flow cytometric analysis of Annexin-V/propidium iodide (PI). FASN and LPL mRNAs were quantified in DLBCL cell lines by RT-PCR as well as through gene expression profiling (GEP) analysis (by cell of origin) using the CaBIG dataset. Further, FASN and associated signaling pathways (MEK, ERK, and HIF-1a) were analyzed by Western blot. Finally, for investigation of potential interactions between FASN and HIF-1a, or MAPK signaling, we utilized short hairpin RNA interference (shRNA) to knock down (KD) pathways of interest. Results: FASN protein expression was readily detectable in all DLBCL cell lines in normoxia, while the expression of LPL was barely detectable in most cells, except in SUDHL10 and only in hypoxic conditions. RT-PCR showed that all DLBCL cell lines tested expressed high levels of FASN mRNA, while minimal levels of LPL could be detected; GEP showed that FASN was expressed more prominently in germinal center (GC) DLBCL (p=0.0006 vs GC control and p=0.0001 vs non-GC DLBCL), whereas LPL was preferentially expressed in non-GC DLBCL (p Conclusions: We demonstrated that FASN is constitutively activated in DLBCL with expression in part dependent on cell of origin, while LPL protein or message were mostly down-regulated. HIF-1a is a constitutively activated oncogenic pathway in DLBCL (Evens AM, et al. Br J Haematol 2008) and it appeared here to directly regulate FASN expression. In addition, we showed that targeting fatty acid metabolism may be harnessed as a potential therapeutic strategy. Further investigations are required to delineate the mechanisms through which MAPK and HIF-1a regulate FASN expression and to determine the in vivo implications of FASN inhibition on DLBCL tumor growth. Disclosures: No relevant conflicts of interest to declare.

Abstract 1581 Background It is well-recognized that de novo long chain fatty acid (FA) synthesis, driven by the key enzyme fatty acid synthase (FASN), is crucial for the growth and survival of many types of cancer cells. We and others have observed FASN protein expression in diffuse large B-cell lymphoma (DLBCL) tumors. Furthermore, we have shown that higher levels of FASN in DLBCL tumors strongly predicted inferior survival, which was independent from the international prognostic index. We also recently demonstrated that, in addition to FA synthesis, various cancer cells can acquire FA from circulating lipoproteins, using the secreted enzyme lipoprotein lipase (LPL), and that this promotes cell growth. DLBCL, however, has never been examined in this regard. In this study, we investigated the functional significance of both de novo FA synthesis via FASN and exogenous FA uptake via LPL in DLBCL. Methods Levels of FASN and LPL mRNAs in DLBCL cell lines (SUDHL4, SUDHL10, OCI-LY3, OCI-LY19) were studied using reverse transcriptase polymerase chain reaction. We determined FASN and LPL protein expression by flow cytometry using a novel anti-LPL antibody that we developed. DLBCL cell lines were cultured +/− Cerulenin (an inhibitor of FASN), Orlistat (an inhibitor of FASN and LPL), or in lipoprotein-depleted serum +/− supplementation with very low density lipoprotein (VLDL) particles. The MTT assay was used to assess cell proliferation. Results DLBCL cell lines exhibited >10-fold variation in levels of FASN mRNA. Cerulenin and Orlistat each caused dose-dependent inhibition of proliferation of each cell line. The cells were partially rescued by the addition of palmitic acid, the FA product of FASN. Surprisingly, flow cytometry revealed that SUDHL4 and OCI-LY3 cells, which did not secrete LPL or show detectable LPL activity, displayed the enzyme on the cell surface. Moreover, in stark contrast to several other cancer cell lines, DLBCL cells were exquisitely sensitive to withdrawal of lipoproteins from the culture media. Indeed, 75–95% of the cells underwent apoptosis after only 24 hours in lipoprotein-depleted serum. In complete serum, the provision of VLDL particles did not rescue DLBCL cells from FA synthesis inhibition using Cerulenin, suggesting that the serum contains sufficient lipoproteins to saturate the FA uptake system. This prediction was validated in experiments utilizing lipoprotein-depleted serum, in which add-back of VLDL particles completely rescued the cells from Cerulenin-induced demise in a dose-related manner, with full restoration at approximately 100–200mcg/ml of VLDL. Conclusions Our data demonstrate that DLBCL cells employ both de novo FA synthesis via FASN and exogenous FA uptake using LPL to satisfy their strict requirement for FA. Interference with either pathway, using FASN inhibitors or lipoprotein-depleted serum, is cytotoxic indicating that neither alone is sufficient to support proliferation. Further, DLBCL cells show a striking dependency on exogenous FA of dietary origin compared with all other cancer cells we have examined. The observation that the cell lines can be rescued by provision of VLDL particles strongly supports the functional significance of the exogenous FA uptake pathway for DLBCL. Our data thus demonstrate that the extracellular lipase LPL is critical for the growth and survival of DLBCL cells. Surprisingly, the cells deploy LPL to their surface, and we speculate that this promotes efficient FA acquisition from circulating lipoproteins. Recognition that DLBCL relies on both synthesis and uptake of FA will provide guidance for drug development and dietary modifications to effectively target the metabolic requirements of this tumor. Disclosures: No relevant conflicts of interest to declare.

Abstract 3657 Background: Bendamustine and rituximab is proving to be a superior first-line option in the treatment of follicular lymphoma. 90Y-ibritumomab tiuxetan is an effective consolidation strategy after chemotherapy induction in patients with follicular lymphoma, but has never been sequentially combined with bendamustine. In this prospective, single-arm, open-label, multicenter phase II trial (Fol-BRITE), we aim to assess the response rate and safety of a short induction course of bendamustine and rituximab (B-R) for 4 cycles followed by consolidation with 90Y-ibritumumab tiuxetan (90Y-IT) for chemotherapy-naïve patients with follicular lymphoma. Methods: Subjects greater than the age of 18 with chemotherapy-naïve follicular lymphoma (grade 1–2 and 3a) requiring treatment are eligible for this study. Treatment consists of an initial dose of rituximab 375mg/m2, and then one week later, bendamustine 90mg/m2 on days 1 and 2, and rituximab 375mg/m2 on day 1 of a 28-day cycle. B-R is given for a total of 4 cycles. Patients are eligible for consolidation with 90Y-IT if they obtain at least a partial response (PR) after induction, with a platelet count over 150,000/mm3, and granulocyte counts 1,500/mm3 and a bone marrow infiltration of Results: Nineteen patients have started treatment in this study to date, 13 have completed B-R and 7 have received 90Y-IT. Response rates after 4 cycles of B-R: Thirteen patients have completed 4 cycles of B-R and 13 are evaluable for response. Seven of 13 evaluable patients have had a CR (53.8%) and 5 of 13 patients have had a PR (38.5%) after 4 cycles of B-R for an OR rate of 92.3%. Response rates after B-R followed by 90Y-IT: Seven of 13 B-R-treated patients have received 90Y-IT and are evaluable for the primary endpoint of complete response. Of the 13 B-R treated patients, one patient in CR was unable to receive 90Y-IT due to thrombocytopenia, and one other patient was not eligible to receive 90Y-IT due to achievement of stable disease only. Six of the 7 evaluable patients are in CR (85.7%) and one patient remains in a PR (14.3%) after consolidation with 90Y-IT. Of the 3 subjects who attained a PR after B-R, 2 (66.7%) converted to a CR after 90Y-IT, with one late conversion 16 months after 90Y-IT. Hematologic toxicities after B-R included grade 4 neutropenia (1), grade 3–4 lymphopenia (3), and no grade 3–4 thrombocytopenia, out of 13 patients evaluable. Hematologic toxicities after 90Y-IT were acceptable, including grade 3–4 neutropenia (6), grade 3–4 lymphopenia (5), and grade 3–4 thrombocytopenia (4), out of 7 patients evaluable for toxicity. There have been no incidences of neutropenic fever. All patients have recovered their blood counts 7 to 12 weeks after Y90-IT. One out of 19 patients treated in this study has developed chronic myelogenous leukemia, occurring 11 months after treatment with Y90-IT. Conclusions: In this early pre-planned analysis of the first-stage of an optimal Simon two-stage design, we report this combination of therapy is both effective and safe. The CR rate of patients completing all study therapy is 85.7%, and well exceeds the limits required to continue this trial with an accrual goal of 39 subjects. Sequential treatment with B-R followed by Y90-IT is a promising option for the treatment of follicular lymphoma. Disclosures: Lansigan: Spectrum Pharmaceuticals: Advisory Board Other, Research Funding; Teva: Research Funding. Beaven:Celgene: Research Funding.

Abstract 2728 Background: TCLs are uncommon malignancies consisting of heterogeneous pathologic subtypes and outcomes. Despite development of prognostic models, there is little data of outcomes in large cohorts examining the impact of frontline therapy and the role of consolidative stem cell transplantation (SCT). Methods: We performed a multi-center retrospective analysis of a large cohort of newly diagnosed mature TCLs (non-cutaneous) from 2000–2010 across 9 U.S. academic centers. We examined detailed information regarding patient characteristics and treatment(s) received. Further, we determined prognostic factors for associations with survival in univariate analysis and multivariate Cox regression proportional models. Results: Among 402 cases of mature TCL, 341 had complete treatment and follow-up data. This included 107 cases of peripheral TCL (PTCL NOS), 89 anaplastic large cell lymphoma (ALCL), 77 angioimmunoblastic TCL (AITL), 23 NK/TCL, 20 acute t-cell leukemia/lymphoma (ATLL), 10 enteropathy-associated TCL (EATCL), 7 subcutaneous panniculitis-like TCL (SCPTCL), 5 hepatosplenic TCL (HSL), and 4 transformed CTCL (t-CTCL) cases. 60% of pts were men and the median age was 62 years (range 18–95). At initial diagnosis, performance status was 2–4 in 36%, B symptoms in 47%, elevated LDH in 55%, anemia in 64%, and hypoalbuminemia in 46% at baseline. 74% of pts had advanced-stage disease, 29% had bone marrow involvement, 52% had other (non-marrow) extranodal sites, and only 9% had bulky disease >7cm. Twenty-three pts received only palliative therapy all of whom survived Conclusions: In this large US cohort of TCL, response, PFS, and OS compared favorably with historical controls. Further, we documented that NK/TCL, AITL, and ALCL (ALK+ and negative) were all associated with improved OS vs PTCL NOS. On multivariable analysis, limited-stage disease was the predominant predictive factor for survival. Additionally, consolidative SCT was associated with improved PFS and OS, however this benefit appeared to be nullified after controlling for initial response. Disclosures: No relevant conflicts of interest to declare.

Abstract 2816 Background: Vorinostat is a histone deacetylase inhibitor with activity in lymphoma and leukemia. Vorinostat has been reported to act synergistically with topoisomeraseII inhibitors such as anthracyclines (Ac) by facilitating an open chromatin configuration thus enhancing double-strand DNA breaks and apoptosis. We conducted a phase 1 study of escalating doses of vorinostat with pegylated liposomal doxorubicin (V+PLD) in patients with relapsed or refractory lymphoma. The primary objective was to determine the maximum tolerated dose (MTD). Other endpoints included safety, tolerability, and activity of V+PLD. Methods: Patients age ≥18 years with relapsed or refractory lymphoma were enrolled sequentially into 1 of 3 dosing levels using a standard 3+3 design for up to 8 cycles. The study was conducted in accordance with the Declaration of Helsinki, good clinical practice and regulatory guidelines. Vorinostat 200 (dose level 1), 300 (dose level 2), or 400mg (dose level 3) twice daily on days 1–7 and PLD 30mg/m2 on day 3 of a 21-day cycle were administered to eligible and consenting patients. CTCAE v.3.0 was used to determine toxicities, and the revised criteria for malignant lymphoma were used to determine response. Results: 14 patients have been enrolled; 2 men and 12 women; median age 69 years [range 27–88]; median prior therapies (4) [1-11]; prior Ac (13); median prior Ac dose (300mg/m2) [108-440mg/m2]; prior HDACi (1); Dose level 1 (7); Dose level 2 (4); Dose level 3 (3). Lymphoma subtypes included: Hodgkin's lymphoma (HL)(4), peripheral T-cell lymphoma (3), diffuse large B-cell lymphoma (DLBCL)(5), grey zone lymphoma (1), lymphoplasmacytic lymphoma (1). Median number of study cycles was two [1-8](2). Grade 3–4 hematologic toxicities included: neutropenia (3) and thrombocytopenia (1). Grade 3–4 non-hematologic toxicities included: fatigue (2), nausea (1), anorexia (1), dehydration (1), AST/ALT elevation (1), amylase/lipase elevation (1). No cardiac toxicities were observed. There was one death attributed to disease progression. Partial responses (PR) were documented in two HL patients, stable disease (SD) in one HL and one DLBCL patient. Three patients continued therapy beyond 2 cycles. One HL patient with a PR tolerated 8 cycles despite a prior anthracycline dose of 350mg/m2 and 9 prior systemic treatments including ABVD, ICE, GND, DICEP, BEAM and autologous stem cell transplant, Gem and C-MOPP. Another HL patient with a PR after 2 cycles is currently on cycle 3 at dose level 3 and had 5 prior treatments including autologous transplant. One other HL patient with SD discontinued therapy after 2 cycles to proceed with alternative chemotherapy including allogeneic stem cell transplant. One patient with cutaneous DLBCL obtained a skin response but had overall stable disease and completed 6 cycles before disease progression; prior treatment included R-CHOP, R-ICE, CEPP, and GemOx. In addition, one patient with lymphoplasmacytic lymphoma had a clinical response after 1 cycle but therapy was discontinued because of neutropenia and her disease progressed. Conclusions: The combination of V+PLD is well tolerated even among older and heavily pretreated patients. There were no cardiac toxicities even in patients heavily pretreated with anthracyclines. The MTD has not been reached and enrollment to dose level 3 is ongoing. Disease control was achieved in 4 of 14 patients (2 PR and 2 SD). Of interest, 3 of 4 patients with HL achieved disease control (2 PR and one SD), and treatment with vorinostat in combination with anthracycline-based therapy warrants further investigation in HL. Disclosures: Lansigan: Merck: Speakers Bureau. Off Label Use: Vorinostat in combination with pegylated doxorubicin is considered experimental in lymphoma. Foss:Merck: Speakers Bureau.

Peripheral T-cell Lymphomas (PTCL) are a heterogenous group of malignanices that represent 10–15% of non-Hodgkin lymphoma (NHL). This group has a worse prognosis with conventional chemotherapy compared to B-cell lymphomas. Both autologous (AutoSCT) and allogeneic stem cell transplantation (AlloSCT) have been used as consolidation in first remission and at relapse, but the role of transplantation has not been clearly defined. We report a retrospective analysis of 42 patients with PTCL who underwent AutoSCT (24) or AlloSCT (18) between 8/1997 and 12/2007. The AlloSCT group consisted of 4 PTCL unspecified (PTCLu), 3 angioimmunoblastic T-cell lymphomas (AITL), 2 panniculitic T-cell lymphomas, 2 cutaneous T-cell lymphomas (CTCL) with large cell transformation, 2 NK-cell lymphomas, 2 anaplastic large cell lymphomas (ALCL, 1 Alk+, 1 Alk unknown), 1 hepatosplenic T-cell lymphoma, 1 enteropathic T-cell lymphoma, and 1 refractory CTCL. The AutoSCT group consisted of 6 PTCLu, 12 ALCL (5 Alk+, 5 Alk−, 2 Alk unknown), 4 AITL, 1 CTCL with transformation, and 1 T-lymphoblastic lymphoma. The median age of the AlloSCT and AutoSCT groups was 51 (range 29–72) and 52 years (range 19–67), respectively. The median number of prior treatments of the AlloSCT and AutoSCT groups were 3 (range 1 to 5) and 1 (range 1 to 5), respectively. Within the AlloSCT group there were 14 matched-related donor transplants, and 4 matched-unrelated donor transplants; 7 were ablative and 11 were reduced-intensity transplants; the AlloSCT conditioning regimens varied. The AutoSCT group predominantly received BEAM as their conditioning regimen. Median time from diagnosis to AlloSCT or AutoSCT was 18.4 (range 6.9 to 109) and 7.5 (range 3.9 to 25) months, respectively. Median follow-up times for the AlloSCT and AutoSCT groups were 28.6 and 23.5 months, respectively. The day 100 transplant-related mortality rates in the AlloSCT and AutoSCT groups were 11% and 0%, respectively. Within the AlloSCT group the relapse and non-relapse mortalities were 11% and 33%, respectively. In the AutoSCT group, the relapse mortality was 33%. The 1- and 2-year overall survival (OS) rates were similar within the AlloSCT and AutoSCT groups (78% vs 74%, and 67% vs 60%, respectively). The 1- and 2-year progression-free survival (PFS) rates for the AlloSCT vs AutoSCT groups were 68% vs 52%, and 53% vs 45%, respectively (p = 0.28). Within the AutoSCT group, 14 patients (58%) were transplanted in first complete remission (CR1), and 10 (42%) in second complete remission (CR2), beyond CR2, or partial remission (PR). Patients in CR1 had significantly better PFS (57 vs 17 months, p=0.007) and OS (76 vs 29 months, p=0.004) than those in CR2, PR2, or beyond. Within the AlloSCT group, there was a trend toward poorer OS in 6 patients (33%) who had prior AutoSCT (32 vs 60 months, p=0.15). One patient (6%) was transplanted in CR1, and is still alive. We conclude that outcomes for AutoSCT are best in CR1. For patients with resistant or relapsed disease, AlloSCT should be strongly considered rather than AutoSCT. Prior AutoSCT may affect the outcome of AlloSCT. These results suggest that a prospective randomized trial comparing AutoSCT and AlloSCT for aggressive PTCL in first remission is warranted.