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Background: ZUMA-1 is the registrational Phase 1/2 study of axi-cel, an autologous anti-CD19 chimeric antigen receptor (CAR) T-cell therapy, in pts with refractory LBCL. In ZUMA-1 Cohorts 1+2 (C1+2; N=101), rates of Grade (Gr) ≥3 cytokine release syndrome (CRS) and neurologic events (NEs) were 13% and 28%, respectively, at the 6-mo primary analysis; the objective response rate (ORR) was 82% (54% complete response [CR]; Neelapu et al. NEJM. 2017). ZUMA-1 safety management C6 assessed whether prophylactic and earlier corticosteroids and/or tocilizumab could reduce incidence and severity of CRS and NEs. With a median follow-up of 8.9 mo (N=40) for C6, there were no Gr ≥3 CRS, a low rate of Gr ≥3 NEs (13%), and high response rates (Oluwole et al. BJH. 2021). Here, we present a 1-yr updated analysis of C6 supported by propensity score matching (PSM) analysis to compare outcomes for pts in C6 vs C1+2. Methods: Eligible pts could receive optional bridging therapy after leukapheresis. Pts received conditioning chemotherapy for 3 d prior to a single axi-cel infusion. Pts received once-daily oral dexamethasone 10 mg on Days 0 (before axi-cel), 1, and 2; corticosteroids and/or tocilizumab for adverse event (AE) management were given earlier vs C1+2. The primary endpoints were incidence and severity of CRS and NEs. Other endpoints included efficacy outcomes and biomarker analyses. To ensure comparability for pts in C6 and C1+2, an exploratory PSM analysis was performed after balancing for key baseline disease characteristics (tumor burden, IPI score, no. of prior lines of chemotherapy, disease stage, and LDH level). Results: As of December 16, 2020, the median follow-up time was 14.9 mo. Gr ≥3 AEs were reported in all 40 treated pts, and the most common were neutropenia (45%), neutrophil count decreased (33%), and white blood cell count decreased (23%). No Gr ≥3 CRS occurred. Gr ≥3 NEs were reported in 15% of pts. Median time to CRS and NE onset was 5 and 6 d, respectively, after axi-cel infusion. Infections of any grade occurred in 50% of pts (20% Gr ≥3). Since the 6-mo analysis, no new cases of CRS were observed. Four new axi-cel-related NEs occurred in 2 pts (pt 1: Gr 2 mental status changes and seizure-like phenomena both on Day 441; pt 2: Gr 1 dementia [occurred on Day 93 but was reported late] and Gr 5 toxic encephalopathy on Day 369 [resultant from a Gr 4 event that started on Day 351]). Two new infections of Gr 2 pneumonia and Gr 1 bronchitis were observed; the latter was axi-cel-related. One death due to progressive disease occurred. The investigator-assessed ORR was 95% (80% CR). Median DOR, PFS, and OS were not reached. Kaplan-Meier estimates of the 12-mo DOR, PFS, and OS rates were 60%, 63%, and 82%, respectively. At data cutoff, 53% of pts were in ongoing response. Median peak CAR T-cell levels were comparably high in pts with ongoing response and relapse (64 cells/µL [n=21] and 66 cells/µL [n=15], respectively) at 12 mo and considerably lower in nonresponders (18 cells/µL [n=2]). In all, 32 matched pts each in C6 and C1+2 were identified during PSM analysis; 8 pts from C6 were not included due to nonavailability of matched pts in C1+2. No Gr ≥3 CRS was observed in C6 vs 13% of pts in C1+2. Incidence of Gr ≥3 NEs was comparable in C6 and C1+2 (19% and 22%, respectively), with median time to onset of 12 d in C6 vs 7 d in C1+2. The ORR was 94% in both C6 and matched C1+2 (75% and 78% CR rates, respectively); 47% and 59% of pts were in ongoing response at 12 mo. The Kaplan-Meier estimate of the 12-mo PFS rate was 61% in both C6 and matched C1+2. Median peak CAR T-cell levels were 65 and 43 cells/µL, respectively, in C6 and C1+2. Serum levels of inflammatory biomarkers associated with CAR T-cell treatment-related AEs (IFN-γ, IL-2, GM-CSF, and ferritin) were lower in C6 vs C1+2. Median cumulative corticosteroid dose including prophylaxis was 1252 mg in C6 (n=32) and 7418 mg in C1+2 (n=6). Conclusion: With ≥1-y follow-up, prophylactic and earlier corticosteroid and/or tocilizumab intervention continued to demonstrate a manageable safety profile, absence of new safety signals, and high, durable response rates, which was corroborated by PSM analysis. Although fewer pts in C1+2 received corticosteroids after matching, the median cumulative corticosteroid dose was 4-fold lower in C6 vs C1+2. These findings suggest that the C6 AE management strategy can improve long-term safety of axi-cel in R/R LBCL without compromising durability of responses. Disclosures Oluwole: Pfizer: Consultancy; Curio Science: Consultancy; Janssen: Consultancy; Kite, a Gilead Company: Consultancy, Research Funding. Forcade: Jazz: Other: Travel Support, Speakers Bureau; MSD: Other: Travel Support; Gilead: Other: Travel Support, Speakers Bureau; Novartis: Consultancy, Other: Travel Support, Speakers Bureau. Muñoz: Targeted Oncology: Honoraria; Seagen: Consultancy, Honoraria, Speakers Bureau; Physicians' Education Resource: Honoraria; Kyowa Kirin: Consultancy, Honoraria, Speakers Bureau; OncView: Honoraria; Pharmacyclics: Consultancy, Speakers Bureau; Bayer: Consultancy, Speakers Bureau; Kite, a Gilead Company: Consultancy, Speakers Bureau; Pfizer: Consultancy; Janssen: Consultancy, Speakers Bureau; Juno/Celgene: Consultancy; Bristol Myers Squibb: Consultancy; Alexion: Consultancy; BeiGene: Consultancy, Speakers Bureau; Fosunkite: Consultancy; Innovent: Consultancy; Debiopharma: Consultancy; Karyopharm: Consultancy; Genmab: Consultancy; ADC Therapeutics: Consultancy; Epizyme: Consultancy; Servier: Consultancy; Acrotech: Speakers Bureau; Verastem: Speakers Bureau; AstraZeneca: Speakers Bureau; Celgene/Bristol Myers Squibb: Speakers Bureau; Genentech: Speakers Bureau; Aurobindo: Speakers Bureau. de Guibert: Gilead: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria; Janssen: Consultancy, Honoraria. Vose: Kite, a Gilead Company: Honoraria, Research Funding. Bartlett: Roche/Genentech: Consultancy; Seagen: Consultancy, Research Funding; Autolus: Research Funding; Bristol Myers Squibb: Research Funding; Celgene: Research Funding; Forty Seven: Research Funding; Genentech: Research Funding; Janssen: Research Funding; Kite, a Gilead Company: Research Funding; Merck: Research Funding; Millennium: Research Funding; Pharmacyclics: Research Funding; ADC Therapeutics: Consultancy, Research Funding. Lin: Juno: Consultancy; Takeda: Research Funding; Gamida Cell: Consultancy; Vineti: Consultancy; Merck: Research Funding; Sorrento: Consultancy; Legend: Consultancy; Celgene: Consultancy, Research Funding; Novartis: Consultancy; Janssen: Consultancy, Research Funding; Bluebird Bio: Consultancy, Research Funding; Kite, a Gilead Company: Consultancy, Research Funding. Deol: Kite, a Gilead Company: Consultancy. McSweeney: Kite, a Gilead Company: Consultancy, Honoraria, Research Funding, Speakers Bureau; Novartis: Research Funding; Autolus: Research Funding; Allovir: Research Funding. Goy: Acerta: Consultancy, Research Funding; AstraZeneca: Membership on an entity's Board of Directors or advisory committees; Xcenda: Consultancy, Honoraria; Vincerx: Honoraria, Membership on an entity's Board of Directors or advisory committees; Elsevier's Practice Update Oncology, Intellisphere, LLC(Targeted Oncology): Consultancy; MorphoSys: Honoraria, Other; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Honoraria; Bristol Meyers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie/Pharmacyclics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; LLC(Targeted Oncology): Consultancy; Kite Pharma: Membership on an entity's Board of Directors or advisory committees; OncLive Peer Exchange: Honoraria; Rosewell Park: Consultancy; Genomic Testing Cooperative: Current holder of stock options in a privately-held company, Membership on an entity's Board of Directors or advisory committees, Other: Leadership role; COTA (Cancer Outcome Tracking Analysis): Current holder of stock options in a privately-held company, Membership on an entity's Board of Directors or advisory committees, Other: Leadership role; Celgene: Consultancy, Honoraria, Research Funding; Xcenda: Consultancy; Gilead: Membership on an entity's Board of Directors or advisory committees; Michael J Hennessey Associates INC: Consultancy; Bristol Meyers Squibb: Membership on an entity's Board of Directors or advisory committees; Medscape: Consultancy; AbbVie/Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; Hoffman la Roche: Consultancy; Infinity/Verastem: Research Funding; Genentech/Hoffman la Roche: Research Funding; Physicians' Education Resource: Consultancy, Other: Meeting/travel support; Janssen: Membership on an entity's Board of Directors or advisory committees; Vincerx pharma: Membership on an entity's Board of Directors or advisory committees; Incyte: Honoraria; AstraZeneca: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Kite, a Gilead Company: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Elsevier PracticeUpdate: Oncology: Consultancy, Honoraria; Janssen: Research Funding; Karyopharm: Research Funding; Phamacyclics: Research Funding; Constellation: Research Funding; Hackensack Meridian Health, Regional Cancer Care Associates/OMI: Current Employment. Kersten: Miltenyi Biotec: Consultancy, Honoraria, Other: Travel support; Roche: Consultancy, Honoraria, Other: Travel support, Research Funding; BMS/Celgene: Consultancy, Honoraria; Takeda: Research Funding; Celgene: Research Funding; Kite, a Gilead Company: Consultancy, Honoraria, Other: Travel support, Research Funding; Novartis: Consultancy, Honoraria, Other: Travel support. Jacobson: Nkarta: Consultancy, Honoraria; Novartis Pharmaceuticals Corporation: Consultancy, Honoraria, Other: Travel support; Humanigen: Consultancy, Honoraria, Other: Travel support; Lonza: Consultancy, Honoraria, Other: Travel support; AbbVie: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria, Other: Travel support, Research Funding; Precision Biosciences: Consultancy, Honoraria, Other: Travel support; Kite, a Gilead Company: Consultancy, Honoraria, Other: Travel support; Celgene: Consultancy, Honoraria, Other: Travel support; Axis: Speakers Bureau; Clinical Care Options: Speakers Bureau. Farooq: Kite, a Gilead Company: Honoraria. Minnema: Cilag: Consultancy; BMS: Consultancy; Janssen: Consultancy; Celgene: Other: Travel expenses; Kite/Gilead: Consultancy; Alnylam: Consultancy. Thieblemont: Bristol Myers Squibb/Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses ; Kyte: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses ; Takeda: 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; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses ; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses , Research Funding; Gilead Sciences: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses ; Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses ; Cellectis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses ; Hospira: Research Funding; Bayer: Honoraria; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses . Timmerman: Spectrum Pharmaceuticals: Research Funding; Bristol Myers Squibb: Research Funding; Kite, a Gilead Company: Consultancy, Research Funding; Bluebird Bio: Current equity holder in publicly-traded company; TG Therapeutics: Current equity holder in publicly-traded company; Marker Therapeutics: Current equity holder in publicly-traded company; Corvus: Current equity holder in publicly-traded company; Genmab: Current equity holder in publicly-traded company; Merck: Research Funding. Stiff: Macrogenics: Research Funding; Amgen: Research Funding; Kite, a Gilead Company: Research Funding; Seagen: Research Funding; Gamida Cell: Research Funding; Janssen: Research Funding; CRISPR Therapeutics: Consultancy, Honoraria; Karyopharm: Consultancy, Honoraria; Cellectar: Research Funding; Bristol Myers Squibb: Research Funding; Incyte: Research Funding; BioLineRX: Research Funding; Cellectar: Research Funding; MorphoSys: Consultancy, Honoraria; Actinium: Research Funding. Avivi: Novartis: Speakers Bureau; Kite, a Gilead Company: Speakers Bureau. Tzachanis: Fate Therapeutics: Research Funding; Incyte: Research Funding; Genentech: Research Funding; Bristol Myers Squibb: Research Funding; Magenta: Consultancy; Kyowa Kirin: Consultancy; Kite, a Gilead Company: Consultancy, Research Funding, Speakers Bureau; EUSA: Consultancy; Takeda: Consultancy, Speakers Bureau; Partner: Consultancy. Kim: Kite, a Gilead Company: Current Employment; Gilead Sciences: Current equity holder in publicly-traded company. Zheng: Kite, a Gilead Company: Current Employment; Gilead Sciences: Current equity holder in publicly-traded company. Shen: Gilead Sciences: Current equity holder in publicly-traded company; Atara: Current Employment, Current equity holder in publicly-traded company, Other: Leadership role, Patents & Royalties; Kite, a Gilead Company: Current Employment, Other: Leadership role, Patents & Royalties. Vardhanabhuti: Kite, a Gilead Company: Current Employment, Other: Travel support, Research Funding; Gilead Sciences: Current equity holder in publicly-traded company. Van Meerten: Kite, a Gilead Company: Honoraria; Janssen: Consultancy.

Background: High grade B-cell Lymphoma with rearrangements of MYC and BCL2 and/or BCL6, also known as double hit lymphoma (DHL), and double expressing lymphomas (DEL; DLBCL with IHC expression of MYC and BCL2, but without double hit cytogenetics) are highly aggressive B cell non-Hodgkin lymphomas and patients (pts) often develop relapsed/refractory disease following standard first-line chemoimmunotherapy. DA-EPOCH-R is widely used in patients with DHL, and a phase 1 trial of venetoclax + DA-EPOCH-R established the dose of 600 mg for 5 days with each cycle as the recommended phase 2 dose (Rutherford, et al. Proc ASCO 2020). A051701 is a phase II/III randomized trial evaluating chemoimmunotherapy +/- the BCL2 inhibitor venetoclax in a DHL cohort (pts with DHL with BCL2 rearrangement and/or expression), and a DEL cohort. Here we report the initial results from the DHL cohort of A051701. Methods: Pts age ≥ 18 years with newly diagnosed DHL were stratified on International Prognostic Index (IPI) score and receipt of a single cycle of chemotherapy prior to registration, which was permitted, and randomized 1:1 to receive DA-EPOCH-R (Arm 1) or DA-EPOCH-R with venetoclax (Arm 2). Enrollment was based on local pathology results which were centrally confirmed. DA-EPOCH-R was administered as previously published. Venetoclax was dosed at 600 mg po daily on days 4-8 of cycle 1 and on days 1-5 of subsequent cycles for up to 6 total cycles. All cycles were supported by GCSF or peg-GCSF. For the interim analysis at the end of phase II, 53 events ensured 90% power to detect an improvement in 24-month progression-free survival (PFS) from 40% in Arm 1 to 60% in Arm 2 (HR=0.557) using a one-sided stratified log-rank test with type I error rate of 20%. The Alliance Data and Safety Monitoring Board approved the data release after accrual was stopped early due to excess toxicity in Arm 2. These data were frozen July 8, 2021. Results: 73 pts were registered (36 in Arm 1 and 37 in Arm 2) between 8/7/19 and 9/18/20. Analyses were performed for the modified intent-to-treat (mITT) population, defined as eligible pts with DHL histology confirmed (n=66; 30 Arm 1, 36 Arm 2). Median age was 65 years in both arms (range 37-80) and baseline demographic factors were well balanced. An allowed pre-protocol chemoimmunotherapy cycle was administered in 60% and 56% of Arm 1 and Arm 2 pts, respectively. The majority of pts had advanced stage disease (Arm 1 87%, Arm 2 86%), GCB immunophenotype (Arm 1 100%, Arm 2 88%), ECOG PS 0-1 (Arm 1 90%, Arm 2 86%), and high-intermediate/high risk IPI score (Arm 1 63%, Arm 2 64%). Therapy was completed per protocol in 70% and 47% of pts, respectively, for Arm 1 and 2, and disease progression on therapy occurred in 10% and 3%. Treatment was discontinued due to adverse events in 7% of pts in Arm 1 and 11% of pts in Arm 2. Consent was withdrawn after beginning treatment in 3% and 11% in Arm 1 and 2, respectively. Death on treatment occurred in 1 patient (3%; PJP pneumonia) in Arm 1 and 6 pts (17%; sepsis (n=4), cardiac arrest (n=2)) in Arm 2. The observation of excess deaths on Arm 2 prompted suspension of accrual to the DHL cohort. Treatment was discontinued for other reasons in 3 (10%) and 4 (11%) pts in Arms 1 and 2, respectively. Venetoclax was dose-reduced and/or omitted in 15 (42%) pts. Grade 4 neutropenia was not significantly different between arms (Arm 1 67%, Arm 2 71%), nor was grade ≥3 neutropenic fever (Arm 1 36%, Arm 2 40%). Sepsis occurred more frequently in Arm 2 (14% vs. 23%). The end of treatment overall and complete response rates in the mITT population were 73% and 67% in Arm 1, and 58% and 50% in Arm 2. The end of treatment overall and complete response rates among only pts evaluated for response (n=52) were 79% and 71% in Arm 1, and 88% and 75% in Arm 2. With a median follow-up of 7.4 months, the median PFS was not reached (NR) in Arm 1 (95% CI 6.1-NR) and was 6.7 months in Arm 2 (95% CI 4.5-NR) (two-sided p=0.13). The median OS was NR in Arm 1 and was 8.5 months in Arm 2 (95% CI 5.2-NR) (two-sided p=0.004). Conclusions: DA-EPOCH-R plus venetoclax in DHL pts resulted in excess treatment-related mortality compared to DA-EPOCH-R alone, prompting early discontinuation of accrual and venetoclax treatment for the study cohort. Based on these data, we recommend against combining venetoclax with DA-EPOCH-R in DHL. Robust accrual to this study shows that prospective trials are feasible in DHL, and the favorable outcome thus far in the DA-EPOCH-R arm may serve as a benchmark for future trials Figure 1 Figure 1. Disclosures Abramson: Astra-Zeneca: Consultancy; Allogene Therapeutics: Consultancy; Incyte Corporation: Consultancy; BeiGene: Consultancy; Kymera: Consultancy; Bluebird Bio: Consultancy; Genmab: Consultancy; EMD Serono: Consultancy; Bristol-Myers Squibb Company: Consultancy, Research Funding; C4 Therapeutics: Consultancy; Morphosys: Consultancy; Kite Pharma: Consultancy; Novartis: Consultancy; Seagen Inc.: Research Funding; AbbVie: Consultancy; Karyopharm: Consultancy; Genentech: Consultancy. Ruppert: Telios Pharma: Consultancy. Hsi: Seattle Genetics: Honoraria; Cytomx: Honoraria; Eli Lilly: Research Funding; AbbVie: Research Funding. Landsburg: Triphase: Research Funding; Takeda: Research Funding; Curis: Research Funding; Karyopharm: Membership on an entity's Board of Directors or advisory committees, Other: DSMB member; ADCT: Membership on an entity's Board of Directors or advisory committees; Incyte: Membership on an entity's Board of Directors or advisory committees; Morphosys: Membership on an entity's Board of Directors or advisory committees. Kahl: AbbVie, Adaptive, ADCT, AstraZeneca, Bayer, BeiGene, Bristol-Myers Squibb, Celgene, Genentech, Incyte, Janssen, Karyopharm, Kite, MEI, Pharmacyclics, Roche, TG Therapeutics, and Teva: Consultancy; AbbVie, Acerta, ADCT, AstraZeneca, BeiGene, Genentech: Research Funding. Friedberg: Acerta: Other: DSMC ; Novartis: Other: DSMC ; Bayer: Other: DSMC . Bartlett: Millennium: Research Funding; Janssen: Research Funding; Kite, a Gilead Company: Research Funding; Merck: Research Funding; Genentech: Research Funding; Celgene: Research Funding; Forty Seven: Research Funding; Bristol Myers Squibb: Research Funding; Roche/Genentech: Consultancy; Autolus: Research Funding; Seagen: Consultancy, Research Funding; Pharmacyclics: Research Funding; ADC Therapeutics: Consultancy, Research Funding. Leonard: ADC Therapeutics, AstraZeneca, Bayer, BMS/Celgene, Epizyme, Inc., Genmab, Gilead/Kite, Karyopharm, BMS/Celgene, Regeneron, MEI Pharma, Miltenyi, Roche/Genentech, Sutro: Consultancy; Roche/Genentech: Consultancy. OffLabel Disclosure: venetoclax in double hit lymphoma

Introduction Adults with Burkitt lymphoma (BL) are at risk for both early toxic death and disease progression. Age is associated with a poor prognosis with highly dose-intensive regimens, but it is unclear if this is driven by disease biology or treatment intolerance. We previously reported that survival for adult BL patients treated with DA-EPOCH-R were poorest with CNS, bone marrow (BM) and/or peripheral blood (PB) involvement, but age was not prognostic (Roschewski et al J Clin Oncol 2020). A retrospective study of patients treated with standard regimens outside of clinical trials identified the Burkitt Lymphoma International Prognostic Index (BL-IPI) which stratified patients into risk categories based on 4 variables: age ≥40y, ECOG ≥2, serum LDH >3x ULN, and CNS involvement (Olszewski J Clin Oncol 2021). We analyzed the prognostic utility of BL-IPI to predict time to progression (TTP) and event-free survival (EFS) for adult patients with BL treated on a prospective multicenter study of risk-adapted DA-EPOCH-R. Methods NCI 9177 was a multicenter study that included pts ≥ age 18 with any HIV status. Treatment was risk-adapted based on LDH, ECOG status, stage, and largest tumor lesion. Low-risk patients received 3 cycles of DA-EPOCH-RR and high-risk patients received 6 cycles of DA-EPOCH-R with either IT chemo prophylaxis or extended IT treatment for active CNS disease. Event-free survival (EFS) was calculated from study entry until progression, last documentation of active disease, death, or last follow-up. Time to progression (TTP) was calculated from study entry until date of progression. Kaplan-Meier estimation and log-tank tests were used to determine the prognostic utility of the BL-IPI including individual factors. Receiver operating characteristic curves were plotted to determine the c-index which measures the predictive ability of a survival model. Results 113 patients were enrolled including 31 (27%) low-risk, 55 (49%) intermediate-risk, and 27 (24%) high-risk by BL-IPI. With a median follow up of living patients of 3.3y, the 5-year TTP for pts with high-risk BL-IPI was 78.3% (95% CI: 55-90) compared to 95.2% (95% CI: 88-98)(p=0.022) for pts with low/intermediate IPI (Figure 1A). Pts with high-risk BL-IPI had a lower 5-year EFS of 66.7% (95% CI: 46-81) compared to 94.2% (95% CI: 83-98) for intermediate-risk and 83.6% (95% CI: 65-93) for low-risk, respectively (p=0.004)(Table 1). Pts aged ≥40y had a similar 5-year TTP and EFS of 93.6% (95% CI: 84-98) versus 88.4% (95% CI: 74-95)(p=0.32) and 86.7% (95% CI: 76-93) versus 81.1% (95% CI: 66-90)(p=0.50) compared to pts under 40y. Pts with ECOG PS ≥2 had a worse 5-year TTP and EFS of 76.5% (95% CI: 49-90) versus 94.4% (95% CI: 87-98)(p=0.01) and 61.9% (95% CI: 38-79) versus 89.8% (95% CI: 81-95)(p=0.0004) compared to pts with ECOG PS 3x ULN. Pts with CNS involvement had worse 5-year TTP and EFS of 62.5% (95% CI: 23-86) versus 93.9% (95% CI: 87-97)(p=0.002) and 45.5% (95% CI: 17-71) versus 88.8% (95% CI: 81-94)(p=0.0001) compared to pts without CNS involvement. Nineteen (70%) pts high-risk by BL-IPI had CNS/BM/PB involvement while 8 (30%) had no CNS/BM/PB involvement. Ten (12%) pts with low/intermediate-risk by BL-IPI had CNS/BM/PB involvement and 76 (88%) had no CNS/BM/PB involvement. Pts without involvement of CNS/BM/PB had an excellent prognosis across BL-IPI groups with 5-year TTP of 97.3% (95% CI: 90-99) for low/intermediate-risk by BL-IPI and 100% for high-risk by BL-IPI. Patient with CNS/BM/PB involvement had 5-year TTP of 80.0% (95% CI: 41-95) for low/intermediate-risk by BL-IPI and 66.7% (95% CI: 38-85) for high-risk by BL-IPI (global p=0.006)(Figure 1B). Compared to BL-IPI (C-index 0.62 p=0.13), CNS/BM/PB involvement had better discrimination between prognostic groups (C-index 0.76, p=0.0005). Conclusion Patients with low-or intermediate risk BL-IPI scores had an excellent 5-year TTP and EFS of 95% and 94% in NCI 9177. Age is not prognostic with DA-EPOCH-R but CNS/BM/PB involvement is prognostic across BL-IPI groups. Future studies in adults with BL should focus on high-risk disease including younger patients. Figure 1 Figure 1. Disclosures Dunleavy: Gebmab: Honoraria; Beigene: Honoraria; Morphosys: Honoraria; Bayer: Honoraria; Pharmacyclics: Honoraria; Genetech: Honoraria; Idec: Honoraria. Abramson: C4 Therapeutics: Consultancy; Allogene Therapeutics: Consultancy; Kymera: Consultancy; Bluebird Bio: Consultancy; BeiGene: Consultancy; Incyte Corporation: Consultancy; Astra-Zeneca: Consultancy; Novartis: Consultancy; Kite Pharma: Consultancy; Genmab: Consultancy; EMD Serono: Consultancy; Bristol-Myers Squibb Company: Consultancy, Research Funding; Morphosys: Consultancy; Seagen Inc.: Research Funding; AbbVie: Consultancy; Karyopharm: Consultancy; Genentech: Consultancy. Link: MEI: Consultancy; Genentech/Roche: Consultancy, Research Funding; Novartis, Jannsen: Research Funding. Friedberg: Novartis: Other: DSMC ; Acerta: Other: DSMC ; Bayer: Other: DSMC . Kahl: AbbVie, Adaptive, ADCT, AstraZeneca, Bayer, BeiGene, Bristol-Myers Squibb, Celgene, Genentech, Incyte, Janssen, Karyopharm, Kite, MEI, Pharmacyclics, Roche, TG Therapeutics, and Teva: Consultancy; AbbVie, Acerta, ADCT, AstraZeneca, BeiGene, Genentech: Research Funding. Bartlett: Pharmacyclics: Research Funding; Millennium: Research Funding; Merck: Research Funding; Kite, a Gilead Company: Research Funding; Janssen: Research Funding; Genentech: Research Funding; Forty Seven: Research Funding; Celgene: Research Funding; Bristol Myers Squibb: Research Funding; Autolus: Research Funding; Seagen: Consultancy, Research Funding; Roche/Genentech: Consultancy; ADC Therapeutics: Consultancy, Research Funding. Noy: Epizyme: Consultancy; Rafael Parhma: Research Funding; Morphosys: Consultancy; Targeted Oncology: Consultancy; Medscape: Consultancy; Pharmacyclics: Consultancy, Research Funding; Janssen: Consultancy, Honoraria.

Introduction: Alliance for Clinical Trials in Oncology A041202 is a NCI National Clinical Trials Network phase 3 study (NCT01886872) comparing BR (Arm 1) with ibrutinib (Arm 2) and the combination of ibrutinib plus rituximab (Arm 3) to determine whether ibrutinib-containing regimens are superior to chemoimmunotherapy (CIT) in terms of progression-free survival (PFS), and whether rituximab adds benefit to ibrutinib therapy. Initial results showed that ibrutinib-containing regimens had superior PFS to CIT, and that rituximab added to ibrutinib did not improve PFS over ibrutinib alone. Pts and Methods: Eligible pts on A041202 were those age ≥ 65 years with previously untreated, symptomatic CLL. Pts had a CrCl > 40 mL/min, bilirubin < 1.5 x ULN, and no significant life-limiting intercurrent illness or need for warfarin treatment. Pts were stratified on Rai stage, Zap-70 methylation performed centrally, and del(17)(p13.1) or del(11)(q22.3) by local interphase cytogenetics and were randomized 1:1:1 to each arm. Pts on Arm 1 who progressed could cross over to Arm 2. Here we present an updated analysis after the third planned interim analysis of Arms 2 and 3 versus Arm 1, and at the second planned interim analysis for Arms 3 vs 2. PFS and OS were estimated using the Kaplan-Meier method and corresponding hazard ratios with p-values were estimated using Cox proportional hazards models. These data encompass patient visits through April 2020 and were locked 15 February 2021. Results: Between 12/9/2013 and 5/16/2016, 547 pts were randomized (Arms 1: 183, 2: 182, and 3: 182). Baseline characteristics have previously been reported; briefly, median age was 71 years, 53% had unmethylated Zap-70, 61% were IGHV unmutated (performed in 66% of patients), 6% had del(17p) and 20% del(11q) by central FISH. Stimulated karyotype was performed centrally and revealed ≥ 3 abnormalities in 27%, and ≥ 5 in 11% of patients. With median follow-up of 55 months (mo), median PFS was 44 mo (95% CI 38-54) in Arm 1 and has not been reached in Arms 2 or 3 [Arm 2 vs 1 hazard ratio (HR): 0.36, 95% CI 0.26-0.52, p The benefit of ibrutinib regimens over CIT, with no additional benefit of rituximab when combined with ibrutinib, was consistent for all subgroups of patients defined by TP53 abnormalities, del(11q), complex karyotype, and IGHV (Figure 3). No significant interaction effects were observed between treatment arm and del(11q), complex karyotype, or IGHV. However, greater benefit of ibrutinib regimens over CIT was observed among patients with TP53 abnormalities than without (p Notable adverse events with ibrutinib include atrial fibrillation or flutter (afib) and hypertension (HTN). All grade afib was seen in 11 pts on BR (6%) and 67 pts on ibrutinib (19%). All grade HTN was seen in 95 pts on BR (54%) and 263 pts on ibrutinib (73%). Conclusions: This update of the A041202 trial continues to show that ibrutinib regimens prolong PFS over BR for older patients with treatment-naïve CLL. With longer follow-up, these benefits continue to be seen across subgroups, including those associated with higher risk disease. Strikingly, within the ibrutinib arms, there does not appear to be inferior PFS for patients with abnormalities in TP53, the highest risk feature seen in CLL, and a predictor of inferior PFS with ibrutinib in relapsed CLL. This differentiates ibrutinib (and perhaps BTKi in general) from other targeted therapy paradigms for treatment-naïve CLL. Similar to prior studies, rates of afib and HTN continue to increase with time on therapy. These data support the use of ibrutinib as initial therapy in CLL, and strengthen the rationale for use of ibrutinib for high risk disease. Support: U10CA180821, U10CA180882, U24CA196171, https://acknowledgments.alliancefound.org, Pharmacyclics, Inc Figure 1 Figure 1. Disclosures Woyach: Gilead Sciences Inc: Other: Data & Safety; AbbVie Inc, ArQule Inc, Janssen Biotech Inc, AstraZeneca, Beigene: Other: Advisory Committee; AbbVie Inc, Loxo Oncology Inc, a wholly owned subsidiary of Eli Lilly & Company: Research Funding; AbbVie Inc, ArQule Inc, AstraZeneca Pharmaceuticals LP, Janssen Biotech Inc, Pharmacyclics LLC, an AbbVie Company,: Consultancy. Ruppert: Telios Pharma: Consultancy. Ding: Merck: Membership on an entity's Board of Directors or advisory committees, Research Funding; DTRM: Research Funding; Octapharma: Membership on an entity's Board of Directors or advisory committees. Bartlett: ADC Therapeutics: Consultancy, Research Funding; Roche/Genentech: Consultancy; Seagen: Consultancy, Research Funding; Autolus: Research Funding; Bristol Myers Squibb: Research Funding; Celgene: Research Funding; Forty Seven: Research Funding; Genentech: Research Funding; Janssen: Research Funding; Kite, a Gilead Company: Research Funding; Merck: Research Funding; Millennium: Research Funding; Pharmacyclics: Research Funding. Brander: Pfizer: Consultancy, Other: Biosimilars outcomes research panel; Genentech: Consultancy, Research Funding; Verastem: Consultancy; Juno Therapeutics/Celgene/Bristol Myers Squibb: Research Funding; LOXO: Research Funding; TG Therapeutics: Consultancy, Research Funding; MEI Pharma: Research Funding; NCCN: Other: panel member; ArQule/Merck: Consultancy; Pharmacyclics LLC, an AbbVie Company: Consultancy, Research Funding; DTRM: Research Funding; BeiGene: Research Funding; AstraZeneca: Research Funding; Ascentage: Research Funding; ArQule: Research Funding; AbbVie: Consultancy, Other: informCLL registry steering committee, Research Funding; Novartis: Research Funding. Barr: Seattle Genetics: Consultancy; Bristol Meyers Squibb: Consultancy; AstraZeneca: Consultancy; Beigene: Consultancy; Genentech: Consultancy; Abbvie/Pharmacyclics: Consultancy; Gilead: Consultancy; Morphosys: Consultancy; TG Therapeutics: Consultancy; Janssen: Consultancy. Rogers: Pharmacyclics LLC: Consultancy; Innate Pharma: Consultancy; Genentech: Consultancy, Research Funding; AstraZeneca: Consultancy; Acerta Pharma: Consultancy; AbbVie Inc.: Consultancy, Research Funding; Janssen Pharmaceuticals, Inc: Research Funding; ovartis Pharmaceuticals Corporation: Research Funding. Parikh: Pharmacyclics, MorphoSys, Janssen, AstraZeneca, TG Therapeutics, Bristol Myers Squibb, Merck, AbbVie, and Ascentage Pharma: Research Funding; Pharmacyclics, AstraZeneca, Genentech, Gilead, GlaxoSmithKline, Verastem Oncology, and AbbVie: Membership on an entity's Board of Directors or advisory committees. Coutre: Acerta: Other: Data Safety Monitoring Committee, Research Funding; Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees; Beigene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Data Safety Monitoring Committee, Research Funding; AstraZeneca: 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; Pharmacyclics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Larson: Epizyme: Consultancy; Astellas: Consultancy, Research Funding; Gilead: Research Funding; CVS/Caremark: Consultancy; Takeda: Research Funding; Novartis: Research Funding; Rafael Pharmaceuticals: Research Funding; Cellectis: Research Funding. Erba: AbbVie Inc: Other: Independent review committee; AbbVie Inc; Agios Pharmaceuticals Inc; ALX Oncology; Amgen Inc; Daiichi Sankyo Inc; FORMA Therapeutics; Forty Seven Inc; Gilead Sciences Inc; GlycoMimetics Inc; ImmunoGen Inc; Jazz Pharmaceuticals Inc; MacroGenics Inc; Novartis; PTC Therapeutics: Research Funding; AbbVie Inc; Agios Pharmaceuticals Inc; Bristol Myers Squibb; Celgene, a Bristol Myers Squibb company; Incyte Corporation; Jazz Pharmaceuticals Inc; Novartis: Speakers Bureau; AbbVie Inc; Agios Pharmaceuticals Inc; Astellas; Bristol Myers Squibb; Celgene, a Bristol Myers Squibb company; Daiichi Sankyo Inc; Genentech, a member of the Roche Group; GlycoMimetics Inc; Incyte Corporation; Jazz Pharmaceuticals Inc; Kura Oncology; Nov: Other: Advisory Committee. Litzow: Jazz: Other: Advisory Board; Pluristem: Research Funding; Actinium: Research Funding; Amgen: Research Funding; Astellas: Research Funding; AbbVie: Research Funding; Omeros: Other: Advisory Board; Biosight: Other: Data monitoring committee. Blachly: INNATE: Consultancy, Honoraria; KITE: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria; AstraZeneca: Consultancy, Honoraria. Owen: Genentech: Research Funding; Gilead: Honoraria; Janssen: Honoraria, Research Funding; AstraZeneca: Honoraria, Research Funding; AbbVie: Honoraria, Research Funding; Roche: Honoraria, Research Funding; Merck: Honoraria; Servier: Honoraria; Incyte: Honoraria; Pharmacyclics: Research Funding. Abramson: Bristol-Myers Squibb Company: Consultancy, Research Funding; C4 Therapeutics: Consultancy; Morphosys: Consultancy; Kite Pharma: Consultancy; Novartis: Consultancy; EMD Serono: Consultancy; Genmab: Consultancy; Bluebird Bio: Consultancy; Kymera: Consultancy; BeiGene: Consultancy; Incyte Corporation: Consultancy; Astra-Zeneca: Consultancy; Allogene Therapeutics: Consultancy; Seagen Inc.: Research Funding; AbbVie: Consultancy; Karyopharm: Consultancy; Genentech: Consultancy. Brown: Abbvie, Acerta/Astra-Zeneca, Beigene, Bristol-Myers Squibb/Juno/Celgene, Catapult, Eli Lilly, Genentech/Roche, Janssen, MEI Pharma, Morphosys AG, Nextcea, Novartis, Pfizer, Rigel: Consultancy; Invectys: Other: Data Safety Monitoring Committee Service; Gilead, Loxo/Lilly, SecuraBio, Sun, TG Therapeutics: Research Funding. Stone: Onconova: Consultancy; Syntrix/ACI: Membership on an entity's Board of Directors or advisory committees; Syndax: Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Research Funding; Elevate Bio: Membership on an entity's Board of Directors or advisory committees; Boston Pharmaceuticals: Consultancy; Bristol Myers Squibb: Consultancy; Jazz: Consultancy; Arog: Consultancy, Research Funding; Gemoab: Membership on an entity's Board of Directors or advisory committees; GlaxoSmithKline: Consultancy; Janssen: Consultancy; Innate: Consultancy; BerGen Bio: Membership on an entity's Board of Directors or advisory committees; Astellas: Membership on an entity's Board of Directors or advisory committees; Foghorn Therapeutics: Consultancy; AbbVie: Consultancy; Actinium: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Aprea: Consultancy; Syros: Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy; Agios: Consultancy, Research Funding; Celgene: Consultancy; Macrogenics: Consultancy. Byrd: Novartis, Trillium, Astellas, AstraZeneca, Pharmacyclics, Syndax: Consultancy, Honoraria; Vincerx Pharmaceuticals: Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; Newave: Membership on an entity's Board of Directors or advisory committees.

Introduction: Burkitt lymphoma (BL) accounts for approximately 50% of all pediatric non-Hodgkin lymphomas compared to 1-2% in adults. Adult BL (aBL) remains a poorly understood entity and its relationship to pediatric BL (pBL) and to DLBCL has not been fully elucidated. The variable treatment outcomes between these entities necessitate a more thorough understanding of the genetic and molecular features underlying their biology to enable better prognostication and more effective treatments. We sought to comprehensively determine genetic features shared with DLBCL and those that are unique to BL, to further delineate genetic subgroupings within each entity. Methods: Samples for this study were collected through the Burkitt Lymphoma Genome Sequencing Project (BLGSP). We sequenced the tumor genomes of 139 pBL and 92 aBL, consisting of both EBV-positive (EBV+) and EBV-negative (EBV-) BLs, and compared these to the genomes of 252 DLBCL patients. All cases were analyzed for simple somatic mutations (SSM), recurrent copy number variations (CNV), structural variations (SV), aberrant somatic hypermutation (aSHM), and SSM hotspots. Mutations were used as features for the identification of genetic subgroups using non-negative matrix factorization (NMF) clustering. Results: Clustering of BL and DLBCL revealed six distinct genetic subgroups (Figure 1) with three primarily representing DLBCLs (DLBCL-1, DLBCL-2, and DLBCL-3) and three predominantly comprising BLs (M53-BL, IC-BL, and DGG-BL). The DLBCL-predominant subgroups partially overlapped with those previously described and resembled features of EZB and ST2-like subgroups. The frequency of aBLs within these subgroups was higher than that of pBL patients (p=0.0005). The new cluster M53-BL consists of both pBL (9/27) and aBL (13/27) samples and is characterized by the highest prevalence of mutations in TP53 accompanied by the paucity of other driver mutations but without the aneuploidy associated with the A53 subgroup described in DLBCL. Enrichment of EBV- samples in this cluster further corroborate our previous findings of TP53 mutations being associated with EBV- BL. IC-BL is characterized by mutations in ID3, CCND3, and SMARCA4. In contrast, DGG-BL, where 65% of the cluster consisted of EBV+ BL samples, had mutations in DDX3X, GNA13, and GNAI2. Using a linear model, we compared the rates of aSHM in BL genomes from all clusters and identified the DLBCL-3 cluster to harbor the highest aSHM rates at common sites while the M53-BL cluster harbored the lowest rates. To further establish the biological basis of unique clusters within BL, we conducted differential gene expression analyses between the two major BL genetic subgroups, DGG-BL and IC-BL. We identified a total of 86 differentially expressed genes between the two clusters (p.adj < 0.01 and |log2foldChange| > 1). Among the genes with the strongest differential expression were IRF4, SERPINA9, and TNFRSF13B. Each of these are notable as their expression is a component of the DLBCL cell-of-origin and double-hit signature classifiers. Further, we found IRF4 expression to be one of the strongest predictors of cluster membership, with high IRF4 expression associated with IC-BL membership. Using TP53 and ID3 mutations as a proxy for M53-BL and IC-BL clusters in aBL, we found mutations in TP53 to be associated with significantly inferior progression free survival (PFS) at 2 year follow up, while mutations in ID3 were associated with overall better PFS at 2 year follow up. Conclusion: This work identifies novel genetic subgroups within BL with characteristic genetic and gene expression differences and some bearing relationship to DLBCL subgroups. The three subgroups with predominantly BL samples (DGG-BL, IC-BL, and M53-BL) each comprised a mixture of aBL and pBL samples, confirming similar molecular features in these entities. The IC-BL cluster is associated with mutations in ID3 and CCND3, high IRF4 expression, and ID3 mutated cases exhibited significantly better outcomes. M53-BL is associated with TP53 mutations and inferior PFS in aBL, representing a subset of patients to be considered for novel treatment approaches. These findings highlight shared pathogenesis between aBL and pBL and establish genetic subtypes within BL that delineate cases with distinct molecular and clinical features. This provides a new framework for new diagnostic and therapeutic strategies. Figure 1 Figure 1. Disclosures Abramson: Seagen Inc.: Research Funding; Allogene Therapeutics: Consultancy; Astra-Zeneca: Consultancy; Incyte Corporation: Consultancy; BeiGene: Consultancy; Kymera: Consultancy; Kite Pharma: Consultancy; Novartis: Consultancy; Bluebird Bio: Consultancy; C4 Therapeutics: Consultancy; Morphosys: Consultancy; Genmab: Consultancy; EMD Serono: Consultancy; Bristol-Myers Squibb Company: Consultancy, Research Funding; AbbVie: Consultancy; Karyopharm: Consultancy; Genentech: Consultancy. Bartlett: Pharmacyclics: Research Funding; Millennium: Research Funding; Merck: Research Funding; Kite, a Gilead Company: Research Funding; Janssen: Research Funding; Genentech: Research Funding; Forty Seven: Research Funding; Celgene: Research Funding; Bristol Myers Squibb: Research Funding; Autolus: Research Funding; Seagen: Consultancy, Research Funding; Roche/Genentech: Consultancy; ADC Therapeutics: Consultancy, Research Funding. Casper: EUSA Pharma: Consultancy. Gerrie: Roche: Research Funding; AbbVie: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Astrazeneca: Honoraria, Research Funding; Sandoz: Honoraria. Grande: Sage Bionetworks: Current Employment. Mullighan: Illumina: Membership on an entity's Board of Directors or advisory committees; Pfizer: Research Funding; AbbVie: Research Funding; Amgen: Current equity holder in publicly-traded company. Noy: Epizyme: Consultancy; Rafael Parhma: Research Funding; Morphosys: Consultancy; Targeted Oncology: Consultancy; Medscape: Consultancy; Pharmacyclics: Consultancy, Research Funding; Janssen: Consultancy, Honoraria. Scott: NanoString Technologies: Patents & Royalties: Patent describing measuring the proliferation signature in MCL using gene expression profiling.; AstraZeneca: Consultancy; Abbvie: Consultancy; Celgene: Consultancy; Incyte: Consultancy; Janssen: Consultancy, Research Funding; Rich/Genentech: Research Funding; BC Cancer: Patents & Royalties: Patent describing assigning DLBCL COO by gene expression profiling--licensed to NanoString Technologies. Patent describing measuring the proliferation signature in MCL using gene expression profiling. . Morin: Foundation for Burkitt Lymphoma Research: Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy; Epizyme: Patents & Royalties.

Background Primary bone diffuse large B cell lymphoma (DLBCL) is a variant of extranodal non-Hodgkin lymphoma (NHL) that is relatively rare, accounting for 3-15% of extranodal NHL and less than 1% of all NHL. Patients often present with pain and swelling or pathologic fracture of the affected area of the skeleton, and B symptoms are often less prevalent. Many cases are limited stage at presentation. Patients are usually treated with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) or similar induction therapy. Based on older studies showing improved outcomes associated with the addition of radiation (many completed prior to the rituximab era), patients often still receive combined-modality therapy today. However, it remains unknown whether consolidative radiation therapy (RT) confers additional benefit following rituximab-based chemoimmunotherapy (CIT) induction. We sought to address this question in a multicenter retrospective study. Methods We conducted a retrospective analysis of outcomes in a modern cohort of patients who underwent treatment for primary bone DLBCL using chemotherapy regimens in the rituximab era either with or without consolidative RT. Data was collected from 13 academic medical centers in the U.S., with patients treated between 2005 and 2019. Patients were identified using each institution's hematologic malignancy registries. Analysis was limited to patients with primary bone DLBCL, with stage I-II disease (primary site +/- locoregional lymph nodes) that could be encompassed in a radiation field. Patients who received CIT alone or CIT followed by RT were included. Treatment selection was at the treating physician's discretion. Electronic medical records were reviewed for: demographics, chemotherapy regimens, radiation treatments, and PET scan data. Local IRB approval was obtained at sites. All data was distributed in a de-identified fashion. The primary outcomes were overall survival (OS), and relapse-free survival (RFS). Secondary outcomes included: response after induction CIT induction and the need for additional therapies. Chi-square test analysis was used to compare categorical variables and the Wilcoxon rank-sum test was used for continuous and ordinal measures. Survival curves were estimated using the Kaplan-Meier method and compared between groups via the log-rank test. Multi-variable analysis (MVA) for OS and RFS was performed using RT vs no RT, PET status post CIT (negative vs positive) and rituximab in induction (Y/N) as variables. Results A total of 127 patients were included: 91 who received CIT and radiation (RT group), and 36 who received CIT alone (no RT group). The median age of patients at diagnosis in the RT group and no RT group was 58.5 and 57.0, respectively. For CIT, the majority of patients received R-CHOP (84%). Despite focusing on 2005-2019, a small percentage of patients (5 - 14%) in each group (RT and no RT) did not receive rituximab with their induction therapy. The OS at 10 years was 74.5% in the RT group and 86.5% in the no RT group (p = 0.29). The RFS at 10 years was 70.9% in the RT group and 78.2% in the no RT group (p = 0.85). Among the 91 patients who received RT, 67 (77.0%) received a dose of 36 Gy or higher. There was no difference in OS (p = 0.63) or RFS (p = 0.90) in patients who received > 36 Gy vs < 36 Gy of radiation. On MVA for OS, RT was not associated with improved OS, although rituximab as part of induction was (p = 0.048). On MVA for RFS, neither RT nor rituximab were associated with improved RFS. For rituximab the trend was in the direction of rituximab benefit (p = 0.11). Conclusion Our results demonstrate that, in the rituximab era, patients with limited stage primary bone DLBCL have excellent outcomes overall. In this study, neither RFS or OS appeared to be improved with the addition of consolidative RT. Rituximab, however, was associated with improved OS on MVA. Outcomes do not appear to differ based on the dose of RT (> 36 Gy vs < 36 Gy). Our data suggests that RT may have less benefit for primary bone DLBCL in the rituximab era, although it is possible that a subset of patients may benefit from consolidative radiation therapy. A larger data set would likely be needed to evaluate this. We plan to present data regarding PET responses at the meeting. Figure 1 Figure 1. Disclosures Lunning: Acrotech: Consultancy; AstraZeneca: Consultancy; Myeloid Therapeutics: Consultancy; Janssen: Consultancy; Morphosys: Consultancy; Novartis: Consultancy; Karyopharm: Consultancy; Kyowa Kirin: Consultancy; Verastem: Consultancy; Kite, a Gilead Company: Consultancy; Celgene, a Bristol Myers Squibb Co.: Consultancy; Spectrum: Consultancy; Daiichi-Sankyo: Consultancy; Beigene: Consultancy; Legend: Consultancy; ADC Therapeutics: Consultancy; TG Therapeutics: Consultancy; AbbVie: Consultancy. Cashen: Secura Bio, ADC Therapeutics: Consultancy. Bartlett: Autolus: Research Funding; Bristol Myers Squibb: Research Funding; Celgene: Research Funding; Forty Seven: Research Funding; Genentech: Research Funding; Janssen: Research Funding; Kite, a Gilead Company: Research Funding; Merck: Research Funding; Millennium: Research Funding; Pharmacyclics: Research Funding; Seagen: Consultancy, Research Funding; Roche/Genentech: Consultancy; ADC Therapeutics: Consultancy, Research Funding. Caimi: XaTek: Patents & Royalties: Royalties from patents (wife); Amgen Therapeutics.: Consultancy; ADC Theraputics: Consultancy, Research Funding; Genentech: Research Funding; TG Therapeutics: Honoraria; Seattle Genetics: Consultancy; Verastem: Consultancy; Kite Pharmaceuticals: Consultancy. Rodgers: MJH Lifesciences: Consultancy. Barr: Morphosys: Consultancy; Gilead: Consultancy; Genentech: Consultancy; TG Therapeutics: Consultancy; Janssen: Consultancy; Beigene: Consultancy; Bristol Meyers Squibb: Consultancy; Seattle Genetics: Consultancy; AstraZeneca: Consultancy; Abbvie/Pharmacyclics: Consultancy. Epperla: Verastem: Speakers Bureau; Beigene: Speakers Bureau; Karyopharm: Other: Ad Board; Genzyme: Honoraria. Hill: AstraZenica: Consultancy, Honoraria; Celgene (BMS): Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Kite, a Gilead Company: Consultancy, Honoraria, Other: Travel Support, Research Funding; Pfizer: Consultancy, Honoraria; Gentenech: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria, Research Funding; Epizyme: Consultancy, Honoraria; Incyte/Morphysis: Consultancy, Honoraria, Research Funding; Beigene: Consultancy, Honoraria, Research Funding; Karyopharm: Consultancy, Honoraria, Research Funding. Karmali: BMS/Celgene/Juno: Consultancy, Research Funding; Epizyme: Consultancy; Karyopharm: Consultancy; Janssen/Pharmacyclics: Consultancy; Morphosys: Consultancy, Speakers Bureau; AstraZeneca: Speakers Bureau; BeiGene: Consultancy, Speakers Bureau; EUSA: Consultancy; Takeda: Research Funding; Genentech: Consultancy; Roche: Consultancy; Kite, a Gilead Company: Consultancy, Research Funding, Speakers Bureau. Portell: Acerta/AstraZeneca: Research Funding; Xencor: Research Funding; Abbvie: Research Funding; Aptitude Health: Honoraria; Morphosys: Honoraria; Targeted Oncology: Honoraria; SeaGen: Research Funding; BeiGene: Honoraria, Research Funding; Merck: Honoraria, Research Funding; Pharmacyclics: Honoraria; Kite: Honoraria, Research Funding; TG Therapeutics: Honoraria, Research Funding; Genentech: Research Funding; VelosBio: Research Funding. Fenske: Pharmacyclics: Consultancy; AstraZeneca: Speakers Bureau; Servier Pharmaceuticals: Consultancy; MorphoSys: Consultancy; Adaptive Biotechnologies: Consultancy; KaryoPharm: Consultancy; CSL Therapeutics: Consultancy; TG Therapeutics: Consultancy, Speakers Bureau; Bristol-Myers Squibb: Speakers Bureau; Sanofi: Speakers Bureau; Seattle Genetics: Speakers Bureau; Biogen: Consultancy; ADC Therapeutics: Consultancy; Kite (Gilead): Speakers Bureau; Beigene: Consultancy; AbbVie: Consultancy.

Background: Immunochemotherapy induction followed by rituximab maintenance is the standard of care in previously untreated symptomatic follicular lymphoma (FL). The phase 3 RELEVANCE study of chemotherapy-free combination immunotherapy with lenalidomide and rituximab (R 2) showed promising activity comparable to standard rituximab + chemotherapy (R-chemo) options (Morschhauser, F and Fowler, NH, et al. N Engl J Med. 2018). Reported here are the results of the second interim analysis. Methods: RELEVANCE is a global, randomized, phase 3 trial (NCT01650701) of R 2 vs R-chemo followed by rituximab in patients with previously untreated grade 1-3a FL requiring therapy according to GELF criteria. Lenalidomide dose was 20 mg/d, d2-22/28 for 6-12 cycles (c), continued in responders at 10 mg/d for a total of 18 c. Rituximab dose was 375 mg/m 2 weekly c1 and d1 c2-6 and continued in responders for 12 additional c (q8wk). R-chemo was given per investigator's choice of standard R + cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP), R + bendamustine (R-B), or R-CVP, followed by 12 c of rituximab (q8wk). Co-primary endpoints were complete response (CR)/CR unconfirmed (CRu) at 120 wk and progression-free survival (PFS) by independent review committee (IRC) based on 1999 IWG criteria. The prespecified second interim analysis was done after 75% of total PFS events were reached. Results: 1030 patients with high tumor burden were randomized to R 2 (n = 513) and R-chemo (n = 517; 72% R-CHOP, 23% R-B, 5% R-CVP); baseline characteristics were similar in both groups. As of October 30, 2020, at median follow-up of 72 mo, 6-year PFS, according to IRC assessment using FDA censoring rules, was 60% for R 2 and 59% for R-chemo with a hazard ratio (HR) of 1.03 (95% CI, 0.84-1.27). Data according to investigator assessment and EMA censoring rules are shown in the table. Median PFS was not reached for both groups. CR/CRu rates at 120 wk by IRC was 48% for R 2 and 53% for R-chemo (P = 0.10). Secondary endpoints, including overall survival, event free survival, and time to next antilymphoma treatment, were also similar in both groups. 162 (32%) R 2 and 166 (32%) R-chemo patients experienced progression/relapse according to investigator assessment of which 107 and 99 patients received additional treatment(s), respectively. Histological transformation was documented in 13/513 patients the R 2 group and 11/517 patients in the R-chemo group over the 72 mo follow-up period. ORR and overall survival after subsequent treatment(s) for relapse/progression were similar in both groups. The overall safety profile in both groups was consistent with the 1st interim analysis. The number of patients with second primary malignancies (SPMs) were similar between both groups, occurring in 57 (11%) R 2-treated and 67 (13%) R-chemo-treated safety population patients. The total number of SPMs was 64 in the R 2 group and 87 in the R-chemo group, with invasive SPM accounting for 43 (67%) and 52 (60%), respectively. Grade 5 adverse events were reported in 9 (2%) R 2 and 6 (1%) R-chemo treated patients. Conclusions: R 2 continues to demonstrate comparable efficacy vs R-chemo in patients with previously untreated grade 1-3a FL requiring therapy with similar 6-year PFS (60% and 59%) and 6-year OS (89% in both groups). Also, response and overall survival after subsequent treatment were similar in both groups. The overall safety profile of both groups was consistent with the previous analysis, with no new safety signals detected. R 2 provides a chemo-free alternative to R-chemo based on immunotherapy/immunomodulation. Figure 1 Figure 1. Disclosures Morschhauser: Chugai: Honoraria; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees; AstraZenenca: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Genmab: Membership on an entity's Board of Directors or advisory committees; Incyte: Membership on an entity's Board of Directors or advisory committees; Servier: Consultancy; Genentech, Inc.: Consultancy; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees; Roche: Consultancy, Speakers Bureau; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; F. Hoffmann-La Roche Ltd: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria; Epizyme: Consultancy, Membership on an entity's Board of Directors or advisory committees. Nastoupil: Bayer: Honoraria; Denovo Pharma: Other: DSMC; Gilead/Kite: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; TG Therapeutics: Honoraria, Research Funding; MorphoSys: Honoraria; Caribou Biosciences: Research Funding; Genentech: Honoraria, Research Funding; ADC Therapeutics: Honoraria; Pfizer: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; IGM Biosciences: Research Funding; Takeda: Honoraria, Other: DSMC, Research Funding; Epizyme: Honoraria, Research Funding; Bristol Myers Squibb/Celgene: Honoraria, Research Funding. Feugier: Gilead: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; Amgen: Honoraria; Astrazeneca: Consultancy, Honoraria; Janssen: Consultancy, Honoraria. Palomba: Wolters Kluwer: Patents & Royalties; Lygenesis: Honoraria; Pluto: Honoraria; Ceramedix: Honoraria; Priothera: Honoraria; Nektar: Honoraria; Novartis: Consultancy; Seres: Honoraria, Other: Stock, Patents & Royalties, Research Funding; Rheos: Honoraria; Magenta: Honoraria; Juno: Patents & Royalties; BeiGene: Consultancy; Kite: Consultancy; WindMIL: Honoraria; Notch: Honoraria, Other: Stock; PCYC: Consultancy. Bachy: Kite, a Gilead Company: Honoraria; Novartis: Honoraria; Daiishi: Research Funding; Roche: Consultancy; Takeda: Consultancy; Incyte: Consultancy. Libby: Genentech: Research Funding; Janssen: Consultancy, Research Funding; BMS: Research Funding; GSK: Research Funding. Casasnovas: Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead Kite: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; MSD: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria. Flinn: Infinity Pharmaceuticals: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Curis: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Karyopharm Therapeutics: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Pfizer: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Novartis: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Genentech: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; TG Therapeutics: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Loxo: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; BeiGene: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Agios: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Great Point Partners: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Yingli Pharmaceuticals: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Nurix Therapeutics: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Kite, a Gilead Company: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Janssen: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Roche: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; ArQule: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Celgene: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Iksuda Therapeutics: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Seagen: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Forma Therapeutics: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Rhizen Pharmaceuticals: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Takeda: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Constellation Pharmaceuticals: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Gilead Sciences: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Pharmacyclics LLC, an AbbVie Company: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; IGM Biosciences: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Incyte: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Forty Seven: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Portola Pharmaceuticals: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Verastem: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Unum Therapeutics: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Acerta Pharma: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; AbbVie: Consultancy, Other: All Consultancy and Research Funding payments made to Sarah Cannon Research Institute, Research Funding; MorphoSys: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; AstraZeneca: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Juno Therapeutics: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Calithera Biosciences: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Merck: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Teva: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Trillium Therapeutics: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Triphase Research & Development Corp.: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Century Therapeutics: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Hutchison MediPharma: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Vincerx Pharma: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Sarah Cannon Research Institute: Current Employment; Servier Pharmaceuticals: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Yingli Pharmaceuticals: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Seagen: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Servier Pharmaceuticals: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Unum Therapeutics: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute, Research Funding; Johnson & Johnson: Current holder of individual stocks in a privately-held company; Seattle Genetics: Research Funding. Haioun: Amgen: Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Roche: Consultancy, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Janssen-Cilag: Consultancy; Miltenyi Biotec: Consultancy; Takeda: Consultancy; Celgene: Consultancy, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Gilead Sciences: Consultancy, Honoraria; Servier/Pfizer: Honoraria; Novartis: Honoraria. Ysebaert: Abbvie, AstraZeneca, Janssen, Roche: Other: Advisory Board, Research Funding. Bartlett: Celgene: Research Funding; Bristol Myers Squibb: Research Funding; Forty Seven: Research Funding; Genentech: Research Funding; Janssen: Research Funding; Kite, a Gilead Company: Research Funding; Merck: Research Funding; Millennium: Research Funding; Pharmacyclics: Research Funding; Autolus: Research Funding; Seagen: Consultancy, Research Funding; Roche/Genentech: Consultancy; ADC Therapeutics: Consultancy, Research Funding. Brice: MSD: Honoraria; BMS: Honoraria; Takeda: Consultancy, Honoraria, Research Funding. Ribrag: Nanostring: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees; PharmaMar: Honoraria, Membership on an entity's Board of Directors or advisory committees; Infinity Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; GSK: Research Funding; Argen-X: Research Funding; Epizyme: Honoraria, Research Funding; Roche: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; Astex Pharmaceuticals: Research Funding; AstraZeneca: Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees; MSD Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Servier: Consultancy, Membership on an entity's Board of Directors or advisory committees; Incyte: Membership on an entity's Board of Directors or advisory committees. Martin Garcia-Sancho: Celgene: Honoraria, Other: travel; Celgene/BMS: Consultancy; Janssen: Honoraria, Research Funding; Incyte: Consultancy; Takeda: Honoraria; Novartis: Consultancy; Kern Pharma: Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Eusa Pharma: Consultancy; Clinigen: Consultancy; Kyowa Kirin: Consultancy; Morphosys: Consultancy; Gilead: Consultancy, Honoraria; Servier: Consultancy, Honoraria, Other: Travel/Accommodations/Expenses; Roche: Consultancy, Honoraria, Other: Travel/Accommodations/Expenses. Lopez-Guillermo: Roche, Gilead/Kite, Celgene, Novartis, Janssen, AbbVie, Spectrum: Consultancy, Honoraria, Research Funding. Larouche: Gilead: Consultancy. Ando: Astellas Pharma: Honoraria; Celgene: Honoraria; Chugai Pharmaceutical: Research Funding; Kyowa Kirin: Research Funding; Novartis: Honoraria; Takeda Pharmaceutical: Research Funding. Maria: Roche: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Gilead: Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding; Astrazeneca: Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Abbvie: Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company). André: Johnson & Johnson: Research Funding; Roche: Other: Travel/accomodation/expenses, Research Funding; Incyte: Consultancy; Gilead: Consultancy, Other: Travel/Accommodations/Expenses; Karyopharm: Consultancy; Bristol-Myers-Squibb: Consultancy, Other: Travel/Accommodations/Expenses; AbbVie: Other: Travel/accomodation/expenses; Celgene: Other: Travel/accomodation/expenses; Takeda: Consultancy, Research Funding. Sehn: Genmab: Consultancy; Novartis: Consultancy; Debiopharm: Consultancy. Izutsu: Takeda: Honoraria, Research Funding; Symbio: Honoraria; Solasia: Research Funding; Pfizer: Research Funding; Ono Pharmaceutical: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; MSD: Research Funding; Kyowa Kirin: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Incyte: Research Funding; Huya Biosciences: Research Funding; Genmab: Honoraria, Research Funding; Fuji Film Toyama Chemical: Honoraria; Eisai: Honoraria, Research Funding; Daiichi Sankyo: Honoraria, Research Funding; Chugai: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Beigene: Research Funding; Bayer: Research Funding; AstraZeneca: Honoraria, Research Funding; Yakult: Research Funding; Allergan Japan: Honoraria; AbbVie: Honoraria. Cartron: Roche, Celgene-BMS: Consultancy; Danofi, Gilead, Novartis, Jansen, Roche, Celgene-BMS, Abbvie, Takeda: Honoraria. Fowler: Bristol Myers Squibb, F. Hoffmann-La Roche Ltd, TG Therapeutics and Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; BostonGene, Corp: Current Employment, Current holder of stock options in a privately-held company. Salles: Velosbio: Consultancy; Epizyme: Consultancy, Honoraria; Morphosys: Consultancy, Honoraria; Loxo: Consultancy; Regeneron: Consultancy, Honoraria; Novartis: Consultancy; Takeda: Consultancy; Incyte: Consultancy; Rapt: Consultancy; Kite/Gilead: Consultancy; Ipsen: Consultancy; Miltneiy: Consultancy; Genmab: Consultancy; Janssen: Consultancy; Genentech/Roche: Consultancy; Debiopharm: Consultancy; Allogene: Consultancy; BMS/Celgene: Consultancy; Beigene: Consultancy; Abbvie: Consultancy, Honoraria; Bayer: Honoraria.

Objective Historically, nearly all relapses in classical Hodgkin lymphoma (cHL) occur within the first 5 years of treatment (Radford et al., BMJ 1997;314:346). In ECHELON-1, brentuximab vedotin, doxorubicin, vinblastine, and dacarbazine (A+AVD) significantly improved modified progression-free survival (PFS) versus doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) in patients with stage III/IV cHL (Connors et al., NEJM 2018;378:331). We report updated efficacy and safety results; median follow-up was 60.9 months. Design This phase 3, open-label study (NCT01712490) randomized patients with previously untreated stage III/IV cHL to receive 6 cycles of A+AVD or ABVD. Patients underwent an interim positron emission tomography scan after cycle 2 (PET2). An exploratory analysis of PFS per investigator was conducted. Results There were 664 and 670 patients randomized to receive A+AVD and ABVD, respectively. 64%, 62%, and 58% of patients had stage IV disease, extranodal involvement at diagnosis, and B symptoms, respectively. Five-year PFS was 82.2% (95% confidence interval [CI]: 79.0–85.0) with A+AVD and 75.3% (95% CI: 71.7–78.5) with ABVD. Overall, PFS favored A+AVD (hazard ratio [HR]: 0.681; 95% CI: 0.534–0.867; P=0.002). PFS benefits were observed regardless of PET2 status and International Prognostic Score. Estimated 5-year PFS with A+AVD versus ABVD was 84.9% versus 78.9% in PET2-negative patients (HR: 0.663; 95% CI: 0.502–0.876; P=0.004), and 60.6% versus 45.9% in PET2-positive patients (HR: 0.702; 95% CI: 0.393–1.255; P=0.229). Treatment-emergent peripheral neuropathy (PN) resolved or improved in 85% (n=375/443) and 86% (n=245/286) of the patients with PN on A+AVD and ABVD, respectively. Secondary malignancies occurred in 19 and 29 patients with A+AVD and ABVD, respectively. A total of 131 female patients or partners of male patients reported a pregnancy; both arms showed similar proportions of ongoing pregnancies or live births. Conclusions At 5 years, A+AVD still demonstrates clinically meaningful improvement in PFS versus ABVD, independent of PET2 status, with a manageable safety profile, including resolution or improvement of PN. The PFS benefit observed with A+AVD at this important milestone suggests that A+AVD is an attractive treatment option for all patients with previously untreated stage III/IV cHL. Funding Millennium Pharmaceuticals and Seagen

Objective Brentuximab vedotin (BV) plus cyclophosphamide, doxorubicin, and prednisone (A+CHP) significantly prolonged progression-free survival (PFS) and overall survival (OS) versus cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) in patients with systemic anaplastic large-cell lymphoma (sALCL) or other CD30-positive peripheral T-cell lymphomas (PTCL) in ECHELON-2 (Horwitz S et al., Lancet 2019). We report updated results; median follow-up was 47.6 months for PFS and 66.8 months for OS. Design This phase 3, double-blind study (NCT01777152) randomized patients aged ≥18 years with previously untreated CD30-positive PTCL (targeting 75% ± 5% with sALCL) to A+CHP or CHOP for 6 or 8 cycles. Primary endpoint of PFS was assessed per investigator in this updated analysis. Key secondary endpoints included OS and PFS in sALCL. BV or BV-containing regimens were permitted as subsequent/retreatment therapies. Results 452 patients were enrolled (226 patients in each arm); 316 (70%) patients had sALCL. Patients with advanced disease were included (stage III [27%] and stage IV [53%]; International Prognostic Index ≥2 [78%]). Data continues to favor A+CHP: HRs were 0.70 (95% CI: 0.53–0.91, P=0.0077) for PFS per investigator and 0.72 (95% CI: 0.53–0.99, P=0.0424) for OS. 5-year PFS was 51.4% (95% CI: 42.8–59.4) with A+CHP versus 43.0% (95% CI: 35.8–50.0) with CHOP; median PFS was 62.3 months (95% CI: 42.0–not evaluable) with A+CHP and 23.8 months (95% CI: 13.6–60.8) with CHOP. 5-year OS was 70.1% (95% CI: 63.3–75.9) and 61.0% (95% CI: 54.0–67.3) with A+CHP and CHOP, respectively. Median OS was not reached in either arm. PFS favored A+CHP (HR: 0.55 [95% CI: 0.39–0.79]) in sALCL. 29 (13%) and 54 (24%) patients with A+CHP and CHOP received subsequent BV, respectively. Treatment-emergent peripheral neuropathy (PN), resolved/improved in 72% (n=84/117) and 78% (n=97/124) of patients with PN on A+CHP and CHOP, respectively; 98% and 97% of ongoing PN events were grade 1/2 with A+CHP and CHOP, respectively. Conclusions At this important 5-year milestone, A+CHP still provides clinically meaningful improvement in both PFS and OS versus CHOP, with a manageable safety profile, including continued resolution/improvement of PN. Funded by NIH/NCI Support Grant P30 CA008748.

Summary Treatment with dose-adjusted EPOCH (etoposide, doxorubicin, cyclophosphamide, vincristine, prednisone) chemotherapy and rituximab (DA-EPOCH-R) has become the standard of care for primary mediastinal B-cell lymphoma (PMBCL) at many institutions despite limited data in the multi-centre setting. We report a large, multi-centre retrospective analysis of children and adults with PMBCL treated with DA-EPOCH-R to characterize outcomes and evaluate prognostic factors. We assessed 156 patients with PMBCL treated with DA-EPOCH-R across 24 academic centres, including 38 children and 118 adults. All patients received at least one cycle of DA-EPOCH-R. Radiation therapy was administered in 14·9% of patients. With median follow-up of 22·6 months, the estimated 3-year event-free survival (EFS) was 85·9% [95% confidence interval (CI) 80·3–91·5] and overall survival was 95·4% (95% CI 91·8–99·0). Outcomes were not statistically different between paediatric and adult patients. Thrombotic complications were reported in 28·2% of patients and were more common in paediatric patients (45·9% vs. 22·9%, P = 0·011). Seventy-five per cent of patients had a negative fluorodeoxyglucose positron emission tomography (FDG-PET) scan at the completion of DA-EPOCH-R, defined as Deauville score 1–3. Negative FDG-PET at end-of-therapy was associated with improved EFS (95·4% vs. 54·9%, P

BACKGROUND There is no clear consensus between pediatric and adult providers about the treatment of adolescents and young adults (AYAs) with Hodgkin lymphoma (HL). METHODS Failure-free survival (FFS) and overall survival (OS) were compared between 114 patients ages 17 to 21 years with HL who were treated on the Eastern Cooperative Oncology Group-American College of Radiology Imaging Network Intergroup adult E2496 study and 391 similarly patients ages 17 to 21 years with HL who were treated on the pediatric Children's Oncology Group (COG) AHOD0031 study. RESULTS Comparing AYAs from the COG and E2496 studies, there were no significant differences in extralymphatic disease, anemia, or hypoalbuminemia. More AYAs in the E2496 trial had stage III and IV disease (63% vs 29%; P < .001) and B symptoms (63% vs 27%; P < .001), and fewer had bulk disease (33% vs 77%; P < .001). More AYAs on the COG trial received radiotherapy (76% vs 66%; P = .03), although in smaller doses. E2496 AYA The 5-year FFS and OS rates were 68% and 89%, respectively in the E2496 AYAs and 81% and 97%, respectively, in the COG AYAs, indicating a statistically superior compared in the COG AYAs (P = .001). In stratified multivariable analyses, E2496 AYAs had worse FFS than COG AYAs in all strata except patients who had stage I and II HL without anemia. Propensity score analysis (based on stage, anemia, and bulk disease) confirmed inferior FFS for E2496 AYAs compared with COG AYAs (P = .004). On the E2496 study, FFS was significantly divergent across age groups (P = .005), with inferior outcomes for those ages 17 to 21 years versus 22-44 years. There was no difference across age on the COG study. CONCLUSIONS Younger AYA patients with HL appear to have better outcomes when treated on a pediatric trial than patients of similar age on an adult trial. Prospective studies examining these differences are warranted. Cancer 2017. © 2017 American Cancer Society.

Compared with solvent-based taxanes, nanoparticle albumin-bound (nab®) paclitaxel has demonstrated improved efficacy and tolerability in several solid tumor malignancies. Studies evaluating nab paclitaxel in patients with lymphoma are lacking. In this planned phase-I/phase-II study, we sought to determine the safety and efficacy of nab-paclitaxel in patients with relapsed/refractory (R/R) lymphoma. Eligible patients (R/R to ≥2 prior systemic therapies) received weekly nab-paclitaxel on days 1, 8 and 15 every 28 days. Dosing was initiated at 100 mg/m2 with dose escalations in 25 mg/m2 increments up to 150 mg/m2 in a classic 3 + 3 design. Twenty heavily pretreated patients (median 5 prior regimens), including 65% with refractory disease, enrolled. The maximum dose tested was well tolerated and grade 3/4 hematologic adverse events (neutropenia 25%, thrombocytopenia 20% and anemia 15%) were modest. The overall response rate was 10% with two partial responses, leading to a decision to close the study p...

Background Lenalidomide and panobinostat have shown single-agent efficacy of 14% to 50% and 27% to 58%, respectively, in Hodgkin lymphoma (HL). This phase I/II study was conducted to determine the maximum tolerated dose (MTD), safety, and efficacy of lenalidomide combined with panobinostat in relapsed/refractory HL. Patients and Methods In the phase I trial, previously treated patients with classical or lymphocyte-predominant HL received escalating doses of lenalidomide on days 1 to 21 and panobinostat 3 times a week (TIW) every 28 days. Dose-limiting toxicity (DLT) was defined during cycle 1. When the MTD was determined, a phase II study was conducted to determine overall response (OR). Results Twenty-four patients enrolled; 11 in the phase I and 13 in phase II portions. No DLTs were observed but 2 patients who received 25 mg lenalidomide and 20 mg panobinostat experienced neutropenia and thrombocytopenia > 14 days in cycle 2, leading to selection of 25 mg lenalidomide on days 1 to 21 and 15 mg panobinostat TIW for the phase II dose. In all 24 patients, Grade 3 to 4 toxicities consisted of neutropenia (58%), thrombocytopenia (42%), lymphopenia (25%), and febrile neutropenia (25%). OR was 16.7% (2 complete response [CR] and 2 partial response). One patient with CR had lymphocyte-predominant HL and received 22 cycles. Median progression-free survival and overall survival were 3.8 and 16.4 months, respectively. Conclusion Although the combination of panobinostat and lenalidomide appears safe in patients with relapsed/refractory HL, the limited efficacy and significant rates of neutropenia and febrile neutropenia observed do not support further evaluation of this combination in HL.

Summary Despite the long history of bendamustine as treatment for indolent non-Hodgkin lymphoma, long-term efficacy and toxicity data are minimal. We reviewed long-term data from three clinical trials to characterize the toxicity and efficacy of patients receiving bendamustine. Data were available for 149 subjects at 21 sites. The median age was 60 years at the start of bendamustine (range 39–84), and patients had received a median of 3 prior therapies. The histologies included grades 1–2 follicular lymphoma (FL; n = 73), grade 3 FL (n = 23), small lymphocytic lymphoma (n = 20), marginal zone lymphoma (n = 15), mantle cell lymphoma (n = 9), transformed lymphomas (n = 5), lymphoplasmacytic lymphoma (n = 2) and not reported (n = 2). The median event-free survival was 14·1 months. Nine of 12 attempted stem cell collections were successful. With a median follow-up of 8·9 years, 23 patients developed 25 cancers, including 8 patients with myelodysplastic syndrome/acute myeloid leukaemia. These data provide important information regarding the long-term toxicity of bendamustine in previously treated patients. A small but meaningful number of patients achieved durable remissions following bendamustine. These rigorously collected, patient-level, long-term follow-up data provide reassurance that bendamustine or bendamustine plus rituximab is associated with efficacy and safety for patients with relapsed or refractory indolent non-Hodgkin lymphoma.

Summary Background A new generation of biological and targeted agents might potentially replace traditional cytotoxic agents in lymphoma. Lenalidomide plus rituximab was felt to be a safe and promising backbone based on available data. Idelalisib is an oral phosphatidylinositol 3-kinase delta (PI3Kδ) inhibitor that has promising activity as a monotherapy in refractory indolent lymphomas. The primary objective of these two trials was to determine the maximum tolerated dose of lenalidomide in combination with rituximab and idelalisib in relapsed follicular and mantle cell lymphoma. Methods A051201 (mantle cell lymphoma) and A051202 (follicular lymphoma) were phase 1 trials. Patients with histologically documented relapsed mantle cell lymphoma who had not received previous lenalidomide or idelalisib (A051201) were started with oral lenalidomide 15 mg on days 1–21 in a 28 day cycle, oral idelalisib 150 mg twice a day with continuous 28-day cycles, and intravenous rituximab 375 mg/m 2 weekly during cycle 1. Patients with histologically documented relapsed follicular lymphoma and time to progression 6 months or longer from last rituximab-containing regimen (A051202) were started with oral lenalidomide 10 mg on days 1–21 every 28 days and oral idelalisib 150 mg twice a day with continuous 28-day cycles, and intravenous rituximab 375 mg/m 2 on cycle 1, day 8, day 15, day 22, and cycle 2, day 1. The primary endpoints of the studies were safety and tolerability of combining idelalisib with lenalidomide and rituximab in patients with relapsed mantle cell lymphoma (A051201) and relapsed follicular lymphoma (A051202). All analyses were by intention to treat. The trials were registered at ClinicalTrials.gov, number NCT01838434 (A051201) and number NCT01644799 (A051202). Findings Between July 9, 2013, and Sept 30, 2014, 11 patients (three with mantle cell lymphoma and eight with follicular lymphoma) were enrolled. Among the first eight patients, four experienced unexpected dose-limiting toxicities: grade 4 sepsis syndrome, grade 4 hypotension with grade 3 rash and fevers, grade 4 aspartate aminotransferase (AST) or alanine aminotransferase (ALT) elevation with fevers, and grade 3 pulmonary infection with grade 3 maculopapular rash. Symptom onset was 9–20 days after treatment initiation, coinciding with rituximab infusions. Both studies were amended to remove rituximab, but two of three additional patients had grade 3 rashes and one had grade 3 AST elevation. Both trials were permanently closed. The most common grade 3–4 adverse events were ALT elevation (two [67%] of three) and rash (two [67%] of three) for patients with mantle cell lymphoma and neutropenia (five [63%] of eight) and rash (four [50%] of eight) for patients with follicular lymphoma. The primary endpoint of safety and tolerability was not met. Interpretation The combination of idelalisib, lenalidomide, and rituximab in these trials is excessively toxic, and these trials serve as cautionary notes as new combinations are proposed. Off-target effects, drug–drug interactions, and emerging toxicities should be carefully assessed when investigating biological agents in combination and should never be done outside of a clinical trial setting. Funding National Cancer Institute of the National Institutes of Health.

Follicular lymphoma (FL) is the most common form of indolent non-Hodgkin lymphoma, yet it remains only partially characterized at the genomic level. To improve our understanding of the genetic underpinnings of this incurable and clinically heterogeneous disease, whole-exome sequencing was performed on tumor/normal pairs from a discovery cohort of 24 patients with FL. Using these data and mutations identified in other B-cell malignancies, 1716 genes were sequenced in 113 FL tumor samples from 105 primarily treatment-naive individuals. We identified 39 genes that were mutated significantly above background mutation rates. CREBBP mutations were associated with inferior PFS. In contrast, mutations in previously unreported HVCN1, a voltage-gated proton channel-encoding gene and B-cell receptor signaling modulator, were associated with improved PFS. In total, 47 (44.8%) patients harbor mutations in the interconnected B-cell receptor (BCR) and CXCR4 signaling pathways. Histone gene mutations were more frequent than previously reported (identified in 43.8% of patients) and often co-occurred (17.1% of patients). A novel, recurrent hotspot was identified at a posttranslationally modified residue in the histone H2B family. This study expands the number of mutated genes described in several known signaling pathways and complexes involved in lymphoma pathogenesis (BCR, Notch, SWitch/sucrose nonfermentable (SWI/SNF), vacuolar ATPases) and identified novel recurrent mutations (EGR1/2, POU2AF1, BTK, ZNF608, HVCN1) that require further investigation in the context of FL biology, prognosis, and treatment.

Outcomes for patients with refractory diffuse large B cell lymphoma (DLBCL) are poor. In the multicenter ZUMA-1 phase 1 study, we evaluated KTE-C19, an autologous CD3ζ/CD28-based chimeric antigen receptor (CAR) T cell therapy, in patients with refractory DLBCL. Patients received low-dose conditioning chemotherapy with concurrent cyclophosphamide (500 mg/m2) and fludarabine (30 mg/m2) for 3 days followed by KTE-C19 at a target dose of 2 × 106 CAR T cells/kg. The incidence of dose-limiting toxicity (DLT) was the primary endpoint. Seven patients were treated with KTE-C19 and one patient experienced a DLT of grade 4 cytokine release syndrome (CRS) and neurotoxicity. Grade ≥3 CRS and neurotoxicity were observed in 14% (n = 1/7) and 57% (n = 4/7) of patients, respectively. All other KTE-C19-related grade ≥3 events resolved within 1 month. The overall response rate was 71% (n = 5/7) and complete response (CR) rate was 57% (n = 4/7). Three patients have ongoing CR (all at 12+ months). CAR T cells demonstrated peak expansion within 2 weeks and continued to be detectable at 12+ months in patients with ongoing CR. This regimen of KTE-C19 was safe for further study in phase 2 and induced durable remissions in patients with refractory DLBCL.

Introduction The management of younger fit patients with mantle cell lymphoma (MCL) varies widely with no consensus on an optimal induction therapy. To date, the treatments with the longest progression-free survival incorporate a chemotherapy backbone that includes high dose cytarabine, followed by consolidation with an autologous stem-cell transplantation (ASCT) (Hermine et al. Lancet 2016, Eskelund et al. Br J Haematol 2016). Recent data showed that a regimen of bendamustine/rituximab followed by cytarabine/rituximab achieved high complete response rates with high minimal residual disease (MRD) negativity (Merryman RW et al. Blood Adv 2020). We hypothesized that adding the Bruton tyrosine kinase inhibitor acalabrutinib to the same chemotherapeutic backbone would be safe and increase complete response rates as well as minimal residual disease (MRD) negativity pre-transplant, and potentially improve clinical outcomes. Methods We conducted a single arm, single institution pilot study registered at clinicaltrials.gov (NCT03623373). Patients with untreated MCL, who were between ages 18-70 and were candidates for ASCT, were eligible. Patients received six 28-day cycles of treatment. Cycles 1-3 consisted of bendamustine 90 mg/m2 on days 1 and 2, rituximab 375 mg/m2 on day 1 and acalabrutinib 100mg BID on days 1 through 28. Cycles 4-6 consisted of rituximab 375 mg/m2 on day 1, cytarabine 2 g/m2 (1.5 g/m2 if age>60) q12 hours on days 1 and 2, and acalabrutinib 100mg BID on days 1 through 7 and 22 through 28. Restaging PET/CT and response assessment based on the Lugano classification were obtained following cycles 3 and 6. After cycle 6 patients underwent leukapheresis and stem-cell collection as preparation for ASCT. Blood for MRD status was collected after cycles 2, 4 and 6 and will be evaluated using the ClonoSeq assay (Adaptive Biotechnologies). The primary objective was to determine the stem cell mobilization success rate. Secondary objectives included safety and tolerability, overall response rate (ORR), pre-transplant complete response rate (CR), and the MRD negativity rate during and after completion of therapy. Results The trial enrolled 14 patients from December 2018 to February 2020. One patient withdrew consent prior to start of treatment and another was found to have an undiagnosed adenocarcinoma shortly after starting MCL treatment. Both are excluded from the analysis. The median age was 57 years (range 52-66). 11 patients were males (92%), all patients had an ECOG performance status of 0-1. 11 patients (92%) presented with stage IV disease. The mean MCL International Prognostic Index (MIPI) score was 6.3 (25% high-risk, 42% intermediate-risk and 33% low-risk). Of the 12 patients who began treatment, 9 completed all 6 cycles. Three patients did not complete therapy due to: insurance issues (n = 1), and thrombocytopenia (n = 2) following cycle 5 and 4. The side effect profile showed expected hematologic toxicities with grade 3-4 cytopenias in all patients, mostly during cytarabine cycles. In total, 100% of patients developed grade 3-4 thrombocytopenia and 83% of patients developed grade 3-4 neutropenia. Three episodes of febrile neutropenia were observed. One patient had a grade 3 transaminase increase, and one patient had grade 3 diarrhea. No bleeding events or treatment related deaths occurred. The remainder of the side effects were low grade and the treatment was generally well tolerated. Of the 12 evaluable patients, 10 responded (ORR 83%) with 9 achieving CR (75%). One patient achieved PR prior to being removed from the study due to thrombocytopenia and then achieved CR off study. Two patients experienced PD during induction. With a median follow up of 9 months, no responding patients have relapsed. The median CD34+ stem cell collection was 3.84x106 cells/kg (range 2.77 - 5.9). MRD results will be presented at the meeting. Conclusions This is the first study attempting to combine BTK inhibition with a high dose cytarabine containing regimen. The addition of acalabrutinib to a regimen of bendamustine/rituximab followed by cytarabine/rituximab appears to be safe. The R-ABC combination will be further tested in the recently activated intergroup trial EA4181. Disclosures Bartlett: Autolus: Research Funding; BMS/Celgene: Research Funding; Forty Seven: Research Funding; Immune Design: Research Funding; Janssen: Research Funding; Kite, a Gilead Company: Research Funding; Merck: Research Funding; Millennium: Research Funding; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics: Research Funding; Seattle Genetics: Consultancy, Research Funding; Roche/Genentech: Consultancy, Research Funding; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees, Research Funding; BTG: Consultancy; Acerta: Consultancy; Affimed Therapeutics: Research Funding; ADC Therapeutics: Consultancy. Fehniger:ImmunityBio: Research Funding; HCW Biologics: Research Funding; Kiadis: Consultancy; Nkarta: Consultancy; Indapta: Consultancy; Wugen: Consultancy; Orca Biosystems: Consultancy; Compass Therapeutics: Research Funding. Ghobadi:Amgen: Consultancy, Research Funding; Kite: Consultancy, Research Funding; Bristol Myers Squibb: Consultancy; EUSA: Consultancy; WuGen: Consultancy. Mehta-Shah:Bristol Myers-Squibb: Research Funding; C4 Therapeutics: Consultancy; Celgene: Research Funding; Genetech/Roche: Research Funding; Innate Pharmaceuticals: Research Funding; Kyowa Hakko Kirin: Consultancy; Verastem: Research Funding; Karyopharm Therapeutics: Consultancy; Corvus: Research Funding. Kahl:Celgene Corporation: Consultancy; AstraZeneca Pharmaceuticals LP: Consultancy, Membership on an entity's Board of Directors or advisory committees; Genentech: Consultancy; Pharmacyclics LLC: Consultancy; Roche Laboratories Inc: Consultancy; BeiGene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Acerta: Consultancy, Research Funding; ADC Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Consultancy.

Introduction: More effective, less toxic treatments with convenient administration are needed for patients (pts) with relapsed/refractory (R/R) B-cell lymphoma (B-NHL). Mosunetuzumab (Mosun) is a full-length, fully humanized IgG1 CD20/CD3 bispecific antibody that redirects T cells to engage and eliminate malignant B cells. In an ongoing Phase I/Ib study (GO29781; NCT02500407), Mosun has shown promising efficacy and tolerable safety in pts with R/R B-NHL when administered intravenously (IV) in step-up doses (Bartlett, et al. ASCO 2019, Schuster, et al. ASH 2019). Subcutaneous (SC) administration of Mosun is an alternative approach to minimize the risk of cytokine release syndrome (CRS), a key adverse event (AE) associated with T-cell engaging immunotherapies. Other potential benefits of SC dosing include reduced healthcare resource utilization and increased convenience. This is the first report of clinical data with Mosun SC in pts with R/R B-NHL. Methods: GO29781 is a Phase I/Ib, open-label, multicenter dose-escalation and expansion study of Mosun in R/R B-NHL. Pts included in this report received single-agent Mosun SC on Day 1 of each 21-day Cycle (Q3W), for 8 cycles in pts with complete response (CR) and up to 17 cycles in pts with partial response or stable disease. Dose escalation used a standard 3+3 design; doses from 1.6-20 mg were assessed. Key outcome measures included best objective response (per Cheson 2007 criteria), tolerability and maximum tolerated dose (MTD). Results: As of January 21 2020, 23 pts had received Mosun SC (diffuse large B-cell lymphoma, n=10; follicular lymphoma [FL], n=5; marginal-zone lymphoma [MZL], n=3; primary mediastinal large B-cell lymphoma, n=2; transformed [tr] FL, n=1; trMZL, n=1; tr nodular lymphocyte-predominant Hodgkin lymphoma, n=1). Median prior systemic therapies was 4 (range: 1-8); five pts (22%) had received prior chimeric antigen receptor T-cell therapy. Thirteen pts (57%) were refractory to last prior therapy and 16 (70%) were refractory to prior anti-CD20 therapy. The MTD was not reached. One dose-limiting toxicity (Grade [Gr] 4 neutropenia; resolved) was observed at dose 1.6mg. Among the 23 safety-evaluable pts, 22 (96%) experienced ≥1 AE; no AEs led to treatment discontinuation. Common (>20%) AEs related to Mosun SC were CRS (n=8, 35%), headache (n=5, 22%; all Gr 1) and injection site reaction (n=5, 22%; all Gr 1). All CRS events, graded by Lee criteria (Lee, et al. Blood 2014), occurred during Cycle 1 and were Gr 1 (n=6, 26%) or Gr 2 (n=2, 9%). In contrast to the Q3W fixed-dosing IV cohort, where 15% of pts experienced Gr 2 CRS at doses 0.05-2.8mg, no Gr 2 CRS occurred in the SC cohort at doses Among the 22 efficacy-evaluable pts across all dose levels, overall response rates and CR rates were 86% (6/7) and 29% (2/7) in indolent NHL pts and 60% (9/15) and 20% (3/15) in aggressive NHL pts, respectively. After a median 6.9 months (range: 1.3-22.1) on study for all SC pts, all but one CR pt remained in remission at the cut-off date. The pharmacokinetic (PK) profile of Mosun SC is characterized by a slow absorption rate (observed Tmax at 72 hours post-dose and Cmax reduced by ~70% versus IV) and high bioavailability (>75%), supporting the use of SC dosing for CRS mitigation. Consistent with reduced CRS, lower peak IL-6 levels were observed with SC dosing, with delayed onset versus Mosun IV. Conclusions: Mosun SC demonstrated a manageable safety profile, encouraging efficacy and a favorable PK profile in heavily pretreated R/R B-NHL pts. CRS events seen in Cycle 1 were mild, transient and required minimal intervention and no Gr ≥3 CRS events were reported. Notably, less frequent Gr 2 CRS events were observed with Mosun SC at 7-fold higher dose levels versus the IV fixed-dosing group. These results support continued dose escalation and optimization of Mosun SC in R/R B-NHL. Updated clinical, PK and biomarker data, including approximately 20 additional pts from an interim expansion cohort, will be presented. Disclosures Matasar: Genentech, Inc.: Consultancy, Honoraria, Research Funding; Daiichi Sankyo: Consultancy; GlaxoSmithKline: Honoraria, Research Funding; IGM Biosciences: Research Funding; Janssen: Honoraria, Research Funding; Pharmacyclics: Honoraria, Research Funding; Immunovaccine Technologies: Honoraria, Research Funding; Merck: Consultancy; Bayer: Consultancy, Honoraria, Research Funding; Juno Therapeutics: Consultancy; F. Hoffmann-La Roche Ltd: Consultancy, Honoraria, Research Funding; Teva: Consultancy; Rocket Medical: Consultancy, Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria. Cheah:Celgene, F. Hoffmann-La Roche, Abbvie, MSD: Research Funding; Celgene, F. Hoffmann-La Roche, MSD, Janssen, Gilead, Ascentage Pharma, Acerta, Loxo Oncology, TG therapeutics: Honoraria. Yoon:Celltrion: Honoraria; Samyang: Research Funding; Amgen, Chongkundang, Celgene, Astrazeneca: Consultancy. Assouline:Takeda: Research Funding; F. Hoffmann-La Roche Ltd: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Speakers Bureau; AstraZeneca: Consultancy, Honoraria, Speakers Bureau; AbbVie: Consultancy, Honoraria, Speakers Bureau; Pfizer: Consultancy, Honoraria; BeiGene: Consultancy, Honoraria, Research Funding. Bartlett:ADC Therapeutics: Consultancy; Kite, a Gilead Company: Research Funding; Immune Design: Research Funding; Janssen: Research Funding; Forty Seven: Research Funding; BMS/Celgene: Research Funding; Autolus: Research Funding; Merck: Research Funding; Millennium: Research Funding; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics: Research Funding; Seattle Genetics: Consultancy, Research Funding; Roche/Genentech: Consultancy, Research Funding; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees, Research Funding; BTG: Consultancy; Acerta: Consultancy; Affimed Therapeutics: Research Funding. Ku:F. Hoffmann-La Roche: Honoraria. Giri:Royal Adelaide Hospital: Current Employment. Johnston:MSD: Membership on an entity's Board of Directors or advisory committees; F. Hoffmann-La Roche: Membership on an entity's Board of Directors or advisory committees. Flinn:Loxo: Research Funding; Unum Therapeutics: Consultancy, Research Funding; Incyte: Research Funding; BeiGene: Consultancy, Research Funding; Gilead Sciences: Consultancy, Research Funding; MorphoSys: Consultancy, Research Funding; Juno Therapeutics: Consultancy, Research Funding; Nurix Therapeutics: Consultancy; Acerta Pharma: Research Funding; Calithera Biosciences: Research Funding; Celgene: Research Funding; TG Therapeutics: Consultancy, Research Funding; Forma Therapeutics: Research Funding; Novartis: Research Funding; Constellation Pharmaceuticals: Research Funding; Great Point Partners: Consultancy; Genentech, Inc.: Research Funding; IGM Biosciences: Research Funding; Agios: Research Funding; Curio Science: Consultancy; Infinity Pharmaceuticals: Research Funding; Trillium Therapeutics: Research Funding; Pfizer: Research Funding; Pharmacyclics LLC, an AbbVie Company: Consultancy, Research Funding; Teva: Research Funding; Seattle Genetics: Consultancy, Research Funding; Portola Pharmaceuticals: Research Funding; ArQule: Research Funding; Takeda: Consultancy, Research Funding; Merck: Research Funding; Curis: Research Funding; AbbVie: Consultancy, Research Funding; Iksuda Therapeutics: Consultancy; Janssen: Consultancy, Research Funding; AstraZeneca: Consultancy, Research Funding; Karyopharm Therapeutics: Research Funding; Kite Pharma: Consultancy, Research Funding; Forty Seven: Research Funding; Triphase Research & Development Corp.: Research Funding; Verastem: Consultancy, Research Funding; Yingli Pharmaceuticals ≠: Consultancy, Research Funding; Rhizen Pharmaceuticals: Research Funding; Johnson & Johnson: Other; Roche: Consultancy, Research Funding; Vincera Pharma: Consultancy; F. Hoffmann-La Roche: Research Funding. Goy:Celgene: Honoraria, Research Funding; Constellation: Research Funding; AbbVie: Research Funding; Hackensack UMC and University of Nebraska: Research Funding; AstraZeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: leadership role, Research Funding; RCCA/OMI: Current Employment; Janssen: Consultancy, Honoraria, Other: leadership role, Research Funding; Regional Cancer Care Associates/OMI: Current Employment; Infinity Verastem: Research Funding; MD Anderson: Research Funding; Kite, a Gilead Company: Consultancy, Current equity holder in publicly-traded company, Honoraria, Other: leadership role, Research Funding; Bayer: Research Funding; CALBG: Research Funding; PracticeUpdate Oncology: Consultancy; Infinity: Research Funding; Karyopharm: Research Funding; Genentech/Roche: Research Funding; Morphosys: Research Funding; Acerta: Consultancy, Honoraria, Other: leadership role, Research Funding; Xcenda: Consultancy; COTA: Consultancy, Current equity holder in publicly-traded company, Other: leadership role. Tzachanis:Fate: Research Funding; Incyte: Research Funding; Genetech: Research Funding; BMS: Research Funding; Takeda: Consultancy, Speakers Bureau; EUSA Pharma: Consultancy; Jazz: Consultancy; Magenta: Consultancy; Kyowa Kirin: Consultancy; Gilead Sciences: Consultancy, Research Funding, Speakers Bureau. O'Hear:Genentech, Inc.: Current Employment; F. Hoffmann-La Roche: Current equity holder in publicly-traded company. Yin:Genentech, Inc.: Current Employment, Current equity holder in publicly-traded company. To:Genentech, Inc.: Current Employment. Sarouei:Genentech, Inc.: Current Employment, Current equity holder in publicly-traded company. Li:F. Hoffmann-La Roche: Current Employment, Current equity holder in publicly-traded company; Genentech, Inc.: Current Employment. Bender:Genentech, Inc.: Current Employment, Current equity holder in private company. Penuel:F. Hoffmann-La Roche: Current equity holder in publicly-traded company; Genentech, Inc./ F. Hoffmann-La Roche: Current Employment. Huang:F. Hoffmann-La Roche: Current Employment. Budde:AstraZeneca: Speakers Bureau; Merck, Amgen, AstraZeneca, Mustang Therapeutics: Research Funding; F. Hoffmann-La Roche, Kite Pharma: Consultancy. OffLabel Disclosure: Mosunetuzumab (RG7828) is a full-length, fully humanized immunoglobulin G1 (IgG1) bispecific antibody targeting both CD3 (on the surface of T cells) and CD20 (on the surface of B cells). Mosunetuzumab redirects T cells to engage and eliminate malignant B cells. Mosunetuzumab is an investigational agent.

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

Background: Hodgkin lymphoma (HL) is a rare lymphoma that often affects young people, with a median age of diagnosis of 39. While the 5-year PFS rate for patients after front-line chemotherapy is 94.6%, those who relapse have a 50% to 60% rate of cure (Alinari and Blum, Blood 2016). We recently discovered that increased abdominal visceral fat normalized to subcutaneous fat (rVFA) is associated with poorer outcomes in females, but not males, with diffuse large B-cell lymphoma (DLBCL). (Teja e tal ASH 2018) Interestingly, increased body mass index overall has been found to be associated with favorable prognosis in DLBCL (Carson et al., Journal of Clinical Oncology 2012). The correlation between these findings and elevated fasting blood glucose further supports a relationship between metabolism and prognosis in lymphoma. Since HL patients are generally younger and healthier than DLBCL patients at diagnosis, we sought to determine if rVFA and other metabolic markers had similar prognostic value in relapsed/refractory HL patients. Methods: We conducted a retrospective study of 95 consecutively treated relapsed/refractory HL patients treated at Washington University in St. Louis, who presented with first relapse between 2004 and 2018. We recorded baseline clinical risk factors such as sex, age, BMI, IPI, diabetes status, extranodal sites at relapse, and duration of response to initial therapy. Treatment and response to therapy by PET/CT were also recorded. In 80 patients, pre-treatment CT images were available to determine areas of subcutaneous and visceral fat at the level of the umbilicus. These values were normalized to total fat to calculate rVFA (Nguyen Radiology, 2018). Thresholds for risk stratification and sex differences were obtained using Cutoff Finder (Budczies PLOS One 2012). Data was analyzed with SPSS. Results: Ninety-five patients were eligible for analysis (54M, 41F) and 50 (53%) had refractory disease to initial therapy. (Table 1) The overall response rate to salvage therapy was 77%. There was no significant difference in overall survival (OS) (p = 0.55) or progression-free survival (PFS) (p = 0.49) between males and females in our study. Patients with higher BMI at diagnosis had a trend towards inferior OS and PFS after relapse. Those with BMI Eighty patients had CT images available for rVFA analysis (45M, 35F). Both males and females had a median rVFA of 28%. Patients with rVFA greater than 34% had inferior OS after relapse (HR= 8.85, 95% CI: 2.38-32.93, p Conclusion: In this cohort, elevated rVFA was associated with inferior OS in all patients with relapsed/refractory HL, which is consistent with our findings in DLBCL as well as other solid tumors. Our results also suggest an association between diabetes and HL prognosis. Given the association of increased BMI, rVFA, diabetes and poorer outcomes in our cohort, there may be an association between a patient's metabolism and prognosis in Hodgkin lymphoma. Further studies should be conducted to examine the relationship between metabolism and cancer prognosis in a larger cohort. Disclosures Bartlett: Seattle Genetics: Consultancy, Research Funding; Immune Design: Research Funding; Forty Seven: Research Funding; Millennium: Research Funding; Merck: Research Funding; BTG: Consultancy; Roche/Genentech: Consultancy, Research Funding; BMS/Celgene: Research Funding; Pharmacyclics: Research Funding; Janssen: Research Funding; Acerta: Consultancy; Kite, a Gilead Company: Research Funding; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Autolus: Research Funding; ADC Therapeutics: Consultancy; Affimed Therapeutics: Research Funding; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Ippolito:Vital Images, Inc: Research Funding. Mehta-Shah:Karyopharm Therapeutics: Consultancy; C4 Therapeutics: Consultancy; Verastem: Research Funding; Celgene: Research Funding; Genetech/Roche: Research Funding; Corvus: Research Funding; Bristol Myers-Squibb: Research Funding; Kyowa Hakko Kirin: Consultancy; Innate Pharmaceuticals: Research Funding.

Introduction Ibrutinib was FDA approved for relapsed or refractory (R/R) marginal zone lymphoma (MZL) based on a phase II clinical trial that showed an overall response rate of 48% (Noy et al, Blood 2017). However, factors associated with response to ibrutinib in R/R MZL and outcomes of patients after progression on ibrutinib are unknown. Given the poor survival in other B-cell lymphomas such as mantle cell lymphoma (MCL) after progression on ibrutinib (Martin P et al, Blood 2016), we sought to evaluate clinicopathologic characteristics predictive of ibrutinib failure in R/R MZL, and describe outcomes of patients who experienced progression on ibrutinib therapy. Methods We performed a multicenter retrospective study of MZL patients treated at 19 US medical centers. Eligible patients were ≥ 18 years diagnosed with MZL from 2010-2019, who received ibrutinib for R/R MZL. Patients achieving a complete response (CR) or partial response (PR) with ibrutinib were considered ibrutinib responders, while those who had stable disease (SD) or progression of disease (PD) were classified as non-responders. The primary endpoint was to evaluate factors predictive of primary progression (PD) on ibrutinib. Secondary endpoints include evaluation of predictors of overall survival (OS) and progression-free survival (PFS) following ibrutinib therapy, assessment of outcomes based on the sequencing of ibrutinib therapy, and evaluation of outcomes following ibrutinib failure. PFS was defined as time from the start of ibrutinib therapy until lymphoma relapse/progression or death from any cause, censoring at last clinical assessment if no progression or death. OS was defined as time from the start of ibrutinib treatment until death or last follow-up. A multivariable Poisson regression analysis was performed to model ibrutinib progression on the clinicopathologic factors (see Table). To identify significant predictors for OS and PFS, we used a multivariable Cox model. Results 101 patients with R/R MZL received ibrutinib, of whom 99 had sufficient data for inclusion in the analysis. Among these patients, 63% (n=62) had CR/PR to ibrutinib (ibrutinib responders, CR=17, PR=45) and 37% (n=37) had no response (ibrutinib non-responders, SD=25, PD=12). The median duration of follow-up was 1.8 years (range=0.1-5.4 years) and 2 years (range=0.2-6.3 years) for ibrutinib responders and non-responders, respectively. Baseline characteristics of the R/R MZL patients stratified by ibrutinib response are shown in the Table. Among all the baseline factors examined for association with ibrutinib progression, only primary refractory disease (refractory to frontline therapy, RR=3.78, 95%CI=1.36-10.45, p=0.01) was predictive of a higher probability of primary progression on ibrutinib on multivariable analysis. The median OS was significantly better for responders (NR [not reached], 95%CI=3.2-NR) compared to non-responders (3.4 years, 95%CI=1.4-NR) (Figure 1A). Achieving CR/PR with ibrutinib (HR=0.22, 95%CI=0.09-0.52) and lack of complex cytogenetics (HR=0.22, 95%CI=0.08-0.59) were predictors of superior PFS. Similarly, ibrutinib response (HR=0.13, 95%CI=0.03-0.53) and lack of complex cytogenetics (HR=0.19, 95%CI=0.04-0.87) were predictors of better OS. There was no difference in PFS or OS based on the timing of ibrutinib administration (second vs third vs fourth line and beyond, Figure 1B and 1C). The median post ibrutinib relapse/progression OS (PROS) for patients who initially responded then progressed on ibrutinib (secondary progression, n=19) was 4 years (Figure 1D). The median PROS for patients who had no response to ibrutinib were stratified according to SD vs PD. The median PROS for those who had SD was NR and those with PD was 0.1 year (Figure 1E). Conclusion This is the largest series of R/R MZL patients treated with ibrutinib. A history of primary refractory disease was predictive of primary progression on ibrutinib, while the presence of complex cytogenetics was associated with inferior PFS and OS. In contrast to MCL, the outcomes of patients who progress on ibrutinib in R/R MZL are not poor except for the primary progression cohort (those with PD as the best response to ibrutinib). Improving therapeutic options for patients who experience PD with ibrutinib treatment represents an urgent unmet need and these patients should be prioritized for evaluation of novel therapeutic approaches. Figure Disclosures Epperla: Verastem Oncology: Speakers Bureau; Pharmacyclics: Honoraria. Reddy:Genentech, BMS: Research Funding; KITE Pharma, Abbvie, BMS, Celgene: Consultancy. Caimi:Genentech: Research Funding; Celgene Corp: Other: Incyte Corporation - Ownership - Pharmacyclics, Inc. - Ownership - Celgene Corp. - Other, Speakers Bureau; ADC Therapeutics: Research Funding. Greenwell:Lymphoma Research Foundation: Research Funding; Acrotech Biopharma LLC, Kyowa Kirin: Consultancy. Janakiram:Takeda, Fate, Nektar: Research Funding. Olszewski:Genentech, Inc.: Research Funding; Spectrum Pharmaceuticals: Research Funding; TG Therapeutics: Research Funding; Adaptive Biotechnologies: Research Funding. Cohen:Genentech, BMS, Novartis, LAM, BioInvent, LRF, ASH, Astra Zeneca, Seattle Genetics: Research Funding; Janssen, Adicet, Astra Zeneca, Genentech, Aptitude Health, Cellectar, Kite/Gilead, Loxo: Consultancy. Palmisiano:AbbVie: Research Funding; Genentech: Research Funding. Awan:Genentech: Consultancy; Janssen: Consultancy; Astrazeneca: Consultancy; Abbvie: Consultancy; Pharmacyclics: Consultancy; Gilead Sciences: Consultancy; Kite Pharma: Consultancy; Dava Oncology: Consultancy; Celgene: Consultancy; Blueprint medicines: Consultancy; Sunesis: Consultancy; Karyopharm: Consultancy; MEI Pharma: Consultancy. Barta:Monsanto: Consultancy; Atara: Honoraria; Seattle Genetics: Honoraria, Research Funding; Janssen: Honoraria; Pfizer: Honoraria. Grover:Genentech: Research Funding; Tessa: Consultancy. Bartlett:Roche/Genentech: Consultancy, Research Funding; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Affimed Therapeutics: Research Funding; Acerta: Consultancy; BTG: Consultancy; Seattle Genetics: Consultancy, Research Funding; Pharmacyclics: Research Funding; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Millennium: Research Funding; Merck: Research Funding; Forty Seven: Research Funding; Immune Design: Research Funding; Janssen: Research Funding; Kite, a Gilead Company: Research Funding; ADC Therapeutics: Consultancy; Autolus: Research Funding; BMS/Celgene: Research Funding. Christian:Acerta: Research Funding; Celgene: Research Funding; Genentech: Research Funding; Merck: Research Funding; Millenium: Research Funding; MorphoSys: Research Funding; F Hoffman-La Roche: Research Funding; Triphase: Research Funding; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Verastem: Membership on an entity's Board of Directors or advisory committees; AstraZenica: Membership on an entity's Board of Directors or advisory committees. Herrera:Pharmacyclics: Research Funding; Immune Design: Research Funding; AstraZeneca: Research Funding; Seattle Genetics: Consultancy, Research Funding; Gilead Sciences: Consultancy, Research Funding; Genentech, Inc./F. Hoffmann-La Roche Ltd: Consultancy, Research Funding; Merck: Consultancy, Research Funding; Bristol Myers Squibb: Consultancy, Other: Travel, Accomodations, Expenses, Research Funding; Karyopharm: Consultancy.

Introduction: Autologous hematopoietic stem cell transplantation (auto-HCT) is the standard treatment for patients with chemo-sensitive relapsed/refractory diffuse large B cell lymphoma (DLBCL). However, post-auto-HCT outcomes are still poor in this population, with 5-year progression free survival (PFS) of 40%. We hypothesize that in patients with DLBCL, blinatumomab consolidation post auto-HCT will eradicate remaining tumor cells, leading to decreased relapse and increased overall survival. Therefore we conducted a pilot study to test blinatumomab as consolidation therapy post auto-HCT for patients with DLBCL. Methods: Adult patients with chemosensitive DLBCL or transformed FL who underwent auto-HCT were included. All patients received one cycle of blinatumomab consolidation starting 42 days post auto-HCT (9 mcg daily as continuous infusion for 7 days, followed by 28 mcg daily for 21 days). Response evaluation was done at day 100 post auto-HCT. Minimal residual disease (MRD) was quantified by immunoglobulin high-throughput sequencing (Ig-HTS) of plasma cell-free DNA on days 42 post auto-HCT (pre-blinatumomab) and on day 100 post auto-HSCT (one month post completion of blinatumomab). Immunophenotyping of T cells in cryopreserved peripheral blood mononuclear cells collected on day 42 (pre-blinatumomab), day 56 (midpoint of blinatumomab treatment cycle), and day 100 (1 month post blinatumomab) was performed using 18-color flow cytometry panels for extracellular and intracellular antigens. Results: As of August 2020, ten patients have been treated with at least 100 days follow up. Patient characteristics and outcomes are summarized in Table 1. Three out of 10 patients (30%) were in partial remission (PR) as determined by CT or PET/CT imaging before auto-HCT. All subjects completed the planned cycle of blinatumomab consolidation. Blinatumomab was well tolerated. Two patients developed grade 1 CRS, with no grade 2 and higher CRS. Immune effector cell-associated neurotoxicity syndrome (ICANS) was not observed. Six patients developed transient tremor (four grade 1, one grade 2, and one grade 3). One subjects developed BCNU pneumonitis and CMV viremia that resolved with steroid and ganciclovir. One hundred days post auto-HCT (one month post blinatumomab consolidation) 10/10 (100%) of patient were in complete remission (CR) as determined by both MRD testing and by CT or PET/CT imaging. Plasma cell free based MRD was positive on day 42 (post auto-HCT and pre-blinatumomab), in two out of ten patients (20%). These two patients achieved MRD negative status after receiving blinatumomab consolidation. With median follow up of 14.5 months (range: 7-34 months), all 10 patients are alive and 6/10 remain in remission.. Interestingly, the 4 patients with disease relapse had lower CD8/CD4 T cell ratio before starting blinatumomab compared with patients who remained in remission (Figure 1A). However, there were no significant differences in the distribution of the major T cell subtypes (naïve, memory, effector and Treg), and expression of markers of T cell activation, proliferation, or exhaustion (Figure 1B-1E). High dimensional analysis with t-stochastic neighbor embedding (tSNE) revealed a cluster of CD8+ and CD4+ T cells characterized by high expression of granzyme B (GB) and perforin that was present in the DLBCL patients before and after blinatumomab treatment but not in a healthy untreated control (Figure 1F-1H). Although further analysis of healthy untreated controls and pre-transplant samples is needed, CD8+ T cells from these DLBCL patients pre-blinatumomab contained very few naïve cells and were enriched for terminally differentiated effector cells. Conclusion: This pilot study shows that blinatumomab consolidation post auto-HCT is safe and well tolerated. MRD response to blinatumomab in all patients with MRD positive disease post auto-HCT is encouraging. Strategies to increase CD8/CD4 ratio and more cycles of consolidation in a larger randomized trial are needed to confirm the efficacy of consolidation with blinatumomab post auto-HCT. Finally, the unusually "high activation" immunophenotype (Teff/GB+) seen in CD8 T cells of DLBCL patients after auto-HCT (compared to those seen in resting peripheral blood) may both impact the response to blinatumomab and provide key insights into optimal timing for administration after auto-HCT. Disclosures Ghobadi: WuGen: Consultancy; Bristol Myers Squibb: Consultancy; Kite: Consultancy, Research Funding; EUSA: Consultancy; Amgen: Consultancy, Research Funding. Mehta-Shah:Bristol Myers-Squibb: Research Funding; Karyopharm Therapeutics: Consultancy; Corvus: Research Funding; Genetech/Roche: Research Funding; Innate Pharmaceuticals: Research Funding; Kyowa Hakko Kirin: Consultancy; Celgene: Research Funding; Verastem: Research Funding; C4 Therapeutics: Consultancy. Kahl:Celgene Corporation: Consultancy; AstraZeneca Pharmaceuticals LP: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics LLC: Consultancy; Roche Laboratories Inc: Consultancy; BeiGene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Acerta: Consultancy, Research Funding; ADC Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech: Consultancy; AbbVie: Consultancy. DiPersio:Magenta Therapeutics: Membership on an entity's Board of Directors or advisory committees.

In this phase I study (NCT01307267), we evaluated safety, pharmacokinetics, clinical activity, and pharmacodynamics of treatment with utomilumab plus rituximab in patients with relapsed/refractory follicular lymphoma (FL) and other CD20Primary objectives were to assess treatment safety and tolerability for estimating the MTD, using a modified time-to-event continual reassessment method, and selecting the recommended phase II dose (RP2D).Sixty-seven patients received utomilumab (0.03-10.0 mg/kg every 4 weeks) and rituximab (375 mg/mUtomilumab in combination with rituximab demonstrated clinical activity and a favorable safety profile in patients with CD20

Single-agent ibrutinib is active in patients with previously treated mantle cell lymphoma (MCL); however, nearly half of all patients experience treatment failure during the first year. We previously demonstrated that prolonged early G1 cell cycle arrest induced by the oral, specific CDK4/6 inhibitor palbociclib can overcome ibrutinib resistance in primary human MCL cells and MCL cell lines expressing wild-type Bruton's tyrosine kinase (BTK). Therefore, we conducted a phase 1 trial to evaluate the dosing, safety, and preliminary activity of palbociclib plus ibrutinib in patients with previously treated mantle cell lymphoma. From August 2014 to June 2016, a total of 27 patients (21 men, 6 women) were enrolled. The maximum tolerated doses were ibrutinib 560 mg daily plus palbociclib 100 mg on days 1 to 21 of each 28-day cycle. The dose-limiting toxicity was grade 3 rash. The most common grade 3 to 4 toxicities included neutropenia (41%), thrombocytopenia (30%), hypertension (15%), febrile neutropenia (15%), and lung infection (11%). The overall and complete response rates were 67% and 37%, and with a median follow-up of 25.6 months, the 2-year progression-free survival was 59.4% and the 2-year response duration was 69.8%. A phase 2 multicenter clinical trial to further characterize efficacy is now ongoing. The current trial was registered at www.clinicaltrials.gov as #NCT02159755.

As part of a randomized, prospective clinical trial in large cell lymphoma, we conducted serial fluorodeoxyglucose positron emission tomography (FDG-PET) at baseline, after 2 cycles of chemotherapy (interim PET [i-PET]), and at end of treatment (EoT) to identify biomarkers of response that are predictive of remission and survival. Scans were interpreted in a core laboratory by 2 imaging experts, using the visual Deauville 5-point scale (5-PS), and by calculating percent change in FDG uptake (change in standardized uptake value [ΔSUV]). Visual scores of 1 through 3 and ΔSUV ≥66% were prospectively defined as negative. Of 524 patients enrolled in the parent trial, 169 agreed to enroll in the PET substudy and 158 were eligible for final analysis. In this selected population, all had FDG-avid disease at baseline; by 5-PS, 55 (35%) remained positive on i-PET and 28 (18%) on EoT PET. Median ΔSUV on i-PET was 86.2%. With a median follow-up of 5 years, ΔSUV, as continuous variable, was associated with progression-free survival (PFS) (hazard ratio [HR] = 0.99; 95% confidence interval [CI], 0.97-1.00; P = .02) and overall survival (OS) (HR, 0.98; 95% CI, 0.97-0.99; P = .03). ΔSUV ≥66% was predictive of OS (HR, 0.31; 95% CI, 0.11-0.85; P = .02) but not PFS (HR, 0.47; 95% CI, 0.19-1.13; P = .09). Visual 5-PS on i-PET did not predict outcome. ΔSUV, but not visual analysis, on i-PET predicted OS in DLBCL, although the low number of events limited the statistical analysis. These data may help guide future clinical trials using PET response-adapted therapy. This trial was registered at www.clinicaltrials.gov as #NCT00118209.

Summary Background Polatuzumab vedotin, an antibody–drug conjugate targeting the CD79b component of the B-cell receptor, has demonstrated activity as a single agent and in combination with rituximab in relapsed or refractory diffuse large B-cell lymphoma. In this study, we evaluated the safety and preliminary activity of polatuzumab vedotin in combination with rituximab or obinutuzumab and cyclophosphamide, doxorubicin, and prednisone (CHP) in patients with previously untreated diffuse large B-cell lymphoma. Methods This was an open-label, non-randomised study composed of a phase 1b dose escalation and a phase 2 dose expansion at 11 hospitals and health centres in the USA and France. Patients aged 18 years or older with B-cell non-Hodgkin lymphoma were eligible. Exclusion criteria included peripheral neuropathy with grade greater than 1, major surgery within 4 weeks before enrolment, known CNS involvement of lymphoma, and uncontrolled heart disease. Phase 1b dose escalation had a three-plus-three design and established the recommended phase 2 dose. Phase 2 expansion evaluated the recommended phase 2 dose of polatuzumab vedotin in patients with newly diagnosed diffuse large B-cell lymphoma with an International Prognostic Index (IPI) of 2–5. Patients received cyclophosphamide 750 mg/m2 on day 1 intravenously, doxorubicin 50 mg/m2 on day 1 intravenously, and prednisone 100 mg once daily on days 1–5 of each 21-day cycle orally (CHP), plus either rituximab 375 mg/m2 intravenously on day 1 of each cycle (R-CHP) or obinutuzumab 1000 mg intravenously on days 1, 8, and 15 of cycle 1 and on day 1 of the following cycles (G-CHP). Polatuzumab vedotin was administered on day 2 of cycles 1 and 2, and on day 1 of the following cycles at 1·0–2·4 mg/kg during the escalation phase and at the recommended phase 2 dose during the expansion phase. Treatment could last six or eight cycles, depending on investigator preference. The primary endpoints of the study were safety and tolerability, and determination of the maximum tolerated dose (or recommended phase 2 dose) of polatuzumab vedotin. All endpoints were analysed per protocol in the safety evaluable population, defined as all patients who received at least one dose of study treatment. This trial is registered with ClinicalTrials.gov, number NCT01992653. Findings Between Dec 4, 2013, and July 26, 2016, 85 patients were enrolled. 82 patients were included in the safety and activity evaluable populations, 25 in phase 1b and 57 in phase 2. In light of information from other studies using polatuzumab vedotin reported during this study, in which the safety profile associated with exposure to polatuzumab vedotin at doses higher than 1·8 mg/kg every 3 weeks was not outweighed by any clinical benefit, the recommended phase 2 dose was set to 1·8 mg/kg in the R-CHP cohort and no higher doses were explored in this study. 66 patients with newly diagnosed diffuse large B-cell lymphoma received the polatuzumab vedotin recommended phase 2 dose (45 R-CHP; 21 G-CHP). In 66 patients with diffuse large B-cell lymphoma who received the recommended phase 2 dose, the most common adverse events of grade 3 or worse were neutropenia (20 [30%]), febrile neutropenia (12 [18%]), and thrombocytopenia (six [9%]). Among the 70 patients (any histology) who received the recommended phase 2 dose, 19 (27%) had grade 1 peripheral neuropathy, eight (11%) grade 2, and two (3%) grade 3. Four deaths were reported during follow-up: two treatment-related (one complication of atrial fibrillation and one septic shock) and two due to disease progression. As of the cutoff date of Dec 29, 2017, median follow-up time was 21·5 months (IQR 16·7–24·3) for the untreated diffuse large B-cell lymphoma cohort treated at the polatuzumab vedotin recommended phase 2 dose. 59 (89%) patients achieved an overall response at end of treatment (51 [77%] patients had a complete response, and eight [12%] patients had a partial response). Interpretation The safety of incorporating polatuzumab vedotin to R-CHP or G-CHP was as expected and managable. Preliminary clinical activity in newly diagnosed diffuse large B-cell lymphoma seems promising and encouraged a phase 3 trial comparing polatuzumab vedotin with R-CHP to R-CHOP. Funding F Hoffmann-La Roche/Genentech.

Background The addition of the anti-CD20 monoclonal antibody rituximab to chemotherapy for diffuse large B-cell lymphoma (DLBCL) has led to improvements in progression-free survival and overall survival, although the exact mechanism of rituximab is not known. Rituximab administration often results in transient, non–life-threatening infusion reactions (IRs). We report a retrospective cohort of patients with DLBCL who received rituximab to determine the significance of IRs on clinical outcomes. Patients and Methods We identified and analyzed a retrospective cohort of 229 patients with DLBCL. They were stratified into 2 cohorts; those who did and did not have an IR. Univariate and multivariate analyses were performed to evaluate the prognostic significance of rituximab-related IRs relative to DLBCL subtype, International Prognostic Index score, c-Myc translocations or amplifications, chemotherapy regimen, and Ki-67 proliferative index. Results Baseline characteristics did not differ significantly between the 2 groups. Rituximab was included as initial treatment in all patients. Patients with an IR had a significantly higher overall survival (hazard ratio, 0.26; 95% confidence interval, 0.07-0.95) at 5 years. In addition, subgroup analysis showed a significantly higher progression-free survival in patients with the germinal center subtype of disease and c-Myc alterations who had a rituximab-related IR (log-rank P Conclusions The presence of a rituximab-related IR is associated with a better overall survival in patients with DLBCL. Although limited by the small sample size and retrospective nature, these results provide rationale for further investigation into the mechanism of action of rituximab in order to optimize the efficacy of CD20 monoclonal antibodies.

In the HELIOS trial, bendamustine/rituximab (BR) plus ibrutinib (BR-I) improved disease outcomes versus BR plus placebo in previously treated chronic lymphocytic leukemia/small lymphocytic lymphoma. Here, we describe the pharmacokinetic (PK) observations, along with modeling to further explore the interaction between ibrutinib and rituximab. 578 subjects were randomized to ibrutinib or placebo with BR (6 cycles). Ibrutinib PK samples and tumor measurements were obtained from all subjects; a subset was evaluated for bendamustine and rituximab PK. Population rituximab PK was assessed using nonlinear mixed-effects modeling. Dose-normalized plasma concentration-time bendamustine data were comparable between the arms. Systemic rituximab exposure was higher with BR-I versus BR; mean trough serum concentrations were 2- to 3-fold higher in the first three cycles and 1.2- to 1.7-fold higher subsequently. No relevant safety differences were observed. In the modeling, including treatment arm as a categorical covariate and tumor burden as a continuous time-varying covariate on overall rituximab clearance significantly improved fitting of the data. BR-I led to higher dose-normalized systemic rituximab exposure versus BR and more rapid steady-state achievement. The modeling data suggest that rituximab disposition is, at least in part, target mediated. Determining the clinical significance of these findings requires further assessments. This study is registered at https://clinicaltrials.gov/ct2/show/NCT01611090 .

Serum soluble chemokines/cytokines produced by Hodgkin cells and the tumor microenvironment might be of value as biomarkers in classic Hodgkin lymphoma (cHL). We assessed serum thymus and activation-related chemokine (TARC), macrophage-derived chemokine (MDC), interleukin-10 (IL-10), and soluble CD163 (sCD163) levels at baseline, time of interim fluorodeoxyglucose positron emission tomography (PET), and after therapy in cHL patients treated on S0816, an intergroup phase 2 response-adapted study evaluating escalated therapy for interim PET (PET2)–positive patients (www.clinicaltrials.gov #NCT00822120). Epstein-Barr virus (EBV) status was assessed, and 559 serum samples were evaluated for TARC, MDC, IL-10, and sCD163 by immunoassay. EBV positivity correlated with higher sCD163 and IL-10 levels but lower TARC levels. While baseline biomarker levels were not associated with outcome, sCD163 levels at the time of PET2 were associated with favorable progression-free survival (PFS), adjusting for PET2 status. After therapy TARC, MDC, and IL-10 correlated with PFS and overall survival (OS) on univariable analysis, which remained significant adjusting for international prognostic score. When also adjusting for end-of-therapy PET results, TARC and IL-10 remained significantly associated with shorter PFS and OS. Exploratory analysis in PET2-negative patients showed that elevated posttherapy TARC and IL-10 levels were associated with PFS. Serum cytokine levels correlate with outcome in cHL and should be investigated further in risk-adapted cHL trials.

Vinca alkaloids are known to cause bilateral jaw pain that occurs once during the chemotherapy course. We report a patient with first bite syndrome (FBS) during active treatment with chemotherapy. A patient with Hodgkin lymphoma presented with unilateral jaw pain after beginning his chemotherapy regimen. Pain was worse with the first bite of each meal and dissipated over subsequent bites. Workup was negative for any lesions in the parotid, parapharyngeal space, or infratemporal fossa. Pain was timed closely with chemotherapy administration and would improve prior to next cycle. A trial of botulinum chemodenervation failed to completely relieve symptoms. The patient noted resolution of symptoms after the completion of chemotherapy. We report a case of FBS, which may represent the jaw pain seen commonly with administration of vinca alkaloids. There appears to be a correlation between onset and duration of first bite symptoms with chemotherapy administration.

Background This multicenter, randomized phase 2 trial evaluated complete responses (CRs), efficacy, and safety with ofatumumab and bendamustine and with ofatumumab, bendamustine, and bortezomib in patients with untreated, high-risk follicular lymphoma (FL). Methods Patients with grade 1 to 3a FL and either a Follicular Lymphoma International Prognostic Index (FLIPI) score of 2 with 1 lymph node >6 cm or an FLIPI score of 3 to 5 were randomized to arm A (ofatumumab, bendamustine, and maintenance ofatumumab) or to arm B (ofatumumab, bendamustine, bortezomib, and maintenance ofatumumab and bortezomib). Results One hundred twenty-eight patients (66 in arm A and 62 in arm B) received treatment. The median age was 61 years, and 61% had disease >6 cm; 29% had an FLIPI score of 2, and 71% had an FLIPI score of 3 to 5. In arm A, 86% completed induction, and 64% completed maintenance. In arm B, 66% and 52% completed induction and maintenance, respectively. Dose modifications were required in 65% and 89% in arms A and B, respectively. Clinically significant grade 3 to 4 toxicities included neutropenia (A, 36%; B, 31%), nausea/vomiting (A, 0%; B, 8%), diarrhea (A, 5%; B, 11%), and sensory neuropathy (A, 0%; B, 5%). The estimated CR rates were 62% (95% confidence interval [CI], 50%-74%) and 60% (95% CI, 47%-72%) in arms A and B, respectively (P = .68). With a median follow-up of 3.3 years, the estimated 2-year progression-free survival (PFS) and overall survival (OS) rates were 80% and 97%, respectively, for arm A and 76% and 91%, respectively, for arm B. Conclusions The CR rates, PFS, and OS were not improved with the addition of bortezomib to ofatumumab and bendamustine in patients with high-risk FL. Although grade 3 to 4 toxicities were similar, more patients treated with bortezomib required dose modifications and early discontinuation.

Therapy for progressive multifocal leukoencephalopathy (PML) remains challenging since there are no anti-viral therapies available for JC virus. Immune reconstitution has improved the prognosis in many settings where PML occurs, but it often is not possible in PML patients with hematologic malignancies. We describe the first biopsy proven PML case where the PD-1 inhibitor nivolumab appears to have stimulated immune activation resulting in effective control of PML in a patient with hematologic malignancy. This report supports further investigation of the utility of checkpoint inhibitors for treating PML where other immune reconstitution options are not available.

BACKGROUND: Based on the encouraging activity and manageable safety profile observed in a phase 1 study, the ECHELON-2 trial was initiated to compare the efficacy and safety of brentuximab vedotin, cyclophosphamide, doxorubicin, and prednisone (A+CHP) versus cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) for the treatment of CD30-positive peripheral T-cell lymphomas.METHODS: ECHELON-2 is a double-blind, double-dummy, randomised, placebo-controlled, active-comparator phase 3 study. Eligible adults from 132 sites in 17 countries with previously untreated CD30-positive peripheral T-cell lymphomas (targeting 75% with systemic anaplastic large cell lymphoma) were randomly assigned 1:1 to receive either A+CHP or CHOP for six or eight 21-day cycles. Randomisation was stratified by histological subtype according to local pathology assessment and by international prognostic index score. All patients received cyclophosphamide 750 mg/m2 and doxorubicin 50 mg/m2 on day 1 of each cycle intravenously and prednisone 100 mg once daily on days 1 to 5 of each cycle orally, followed by either brentuximab vedotin 1·8 mg/kg and a placebo form of vincristine intravenously (A+CHP group) or vincristine 1·4 mg/m2 and a placebo form of brentuximab vedotin intravenously (CHOP group) on day 1 of each cycle. The primary endpoint, progression-free survival according to blinded independent central review, was analysed by intent-to-treat. This trial is registered with ClinicalTrials.gov, number NCT01777152.FINDINGS: Between Jan 24, 2013, and Nov 7, 2016, 601 patients assessed for eligibility, of whom 452 patients were enrolled and 226 were randomly assigned to both the A+CHP group and the CHOP group. Median progression-free survival was 48·2 months (95% CI 35·2-not evaluable) in the A+CHP group and 20·8 months (12·7-47·6) in the CHOP group (hazard ratio 0·71 [95% CI 0·54-0·93], p=0·0110). Adverse events, including incidence and severity of febrile neutropenia (41 [18%] patients in the A+CHP group and 33 [15%] in the CHOP group) and peripheral neuropathy (117 [52%] in the A+CHP group and 124 [55%] in the CHOP group), were similar between groups. Fatal adverse events occurred in seven (3%) patients in the A+CHP group and nine (4%) in the CHOP group.INTERPRETATION: Front-line treatment with A+CHP is superior to CHOP for patients with CD30-positive peripheral T-cell lymphomas as shown by a significant improvement in progression-free survival and overall survival with a manageable safety profile.FUNDING: Seattle Genetics Inc, Millennium Pharmaceuticals Inc, a wholly owned subsidiary of Takeda Pharmacuetical Company Limited, and National Institutes of Health National Cancer Institute Cancer Center.

BACKGROUNDPneumatic tube systems (PTSs) provide rapid transport of patient blood samples, but physical stress of PTS transport can damage blood cells and alter test results. Despite this knowledge, there is limited information on how to validate a hospital PTS.METHODSWe compared 2 accelerometers and evaluated multiple PTS routes. Variabilities in PTS forces over the same routes were assessed. Response curves that demonstrate the relationship between the number and magnitude of accelerations on plasma lactate dehydrogenase (LD), hemolysis index, and potassium in PTS-transported blood from volunteers were generated. Extrapolations from these relationships were used to predict PTS routes that may be prone to false laboratory results. Historical data and prospective patient studies were compared with predicted effects.RESULTSThe maximum recorded g-force was 10g for the smartphone and 22g for the data logger. There was considerable day-to-day variation in the magnitude of accelerations (CV, 4%–39%) within a single route. The linear relationship between LD and accelerations within the PTS revealed 2 PTS routes predicted to increase LD by ≥20%. The predicted increase in LD was similar to that observed in patient results when using that PTS route.CONCLUSIONSHospital PTSs can be validated by documenting the relationship between the concentrations of analytes in plasma, such as LD, with PTS forces recorded by 3-axis accelerometers. Implementation of this method for PTS validation is relatively inexpensive, simple, and robust.

BACKGROUND: Ibrutinib has been approved by the Food and Drug Administration for the treatment of patients with untreated chronic lymphocytic leukemia (CLL) since 2016 but has not been compared with chemoimmunotherapy. We conducted a phase 3 trial to evaluate the efficacy of ibrutinib, either alone or in combination with rituximab, relative to chemoimmunotherapy. METHODS: Patients 65 years of age or older who had untreated CLL were randomly assigned to receive bendamustine plus rituximab, ibrutinib, or ibrutinib plus rituximab. The primary end point was progression-free survival. The Alliance Data and Safety Monitoring Board made the decision to release the data after the protocol-specified efficacy threshold had been met. RESULTS: A total of 183 patients were assigned to receive bendamustine plus rituximab, 182 to receive ibrutinib, and 182 to receive ibrutinib plus rituximab. Median progression-free survival was reached only with bendamustine plus rituximab. The estimated percentage of patients with progression-free survival at 2 years was 74% with bendamustine plus rituximab and was higher with ibrutinib alone (87%; hazard ratio for disease progression or death, 0.39; 95% confidence interval [CI], 0.26 to 0.58; P

TPS7571 Background: The majority of patients (pts) with relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL) who relapse after HSCT, or who are not candidates for HSCT have poor outcomes and are in need of novel therapies. Brentuximab vedotin (BV) is a CD30-directed ADC and preclinical data provide a strong rationale for combining BV, lenalidomide, and rituximab in the treatment of R/R DLBCL. In addition, in a phase 1 trial in which 37 pts with R/R DLBCL were treated with BV + lenalidomide, the ORR was 56.7% (73.3% in CD30+ pts; manuscript in preparation). The median duration of remission was 13.2 months in pts with a CR or PR and 11.7 months in pts with CR, PR, or stable disease > 6 months. The PFS and median OS were 11.2 months and 14.3 months, respectively and results were similar in the CD30+ and CD30 < 1% groups. The clinical activity and manageable safety profiles of BV, lenalidomide, and rituximab as single agents, make the combination a viable option in multiply relapsed and heavily pretreated pts. Methods: This is a randomized, double-blind, placebo-controlled, active-comparator, multicenter phase 3 study designed to evaluate the efficacy of BV vs placebo, in combination with lenalidomide + rituximab, in subjects with R/R DLBCL (NCT04404283). Prior to randomization, there will be a safety and PK run-in period where 6 pts will receive BV, lenalidomide + rituximab, and safety and PK will be evaluated after the first cycle of treatment; 6/6 subjects have been enrolled. Key eligibility criteria include: pts aged ≥18 with R/R DLBCL with an eligible subtype; ≥2 prior lines of therapy and must be ineligible for, or have declined, stem cell transplant, and chimeric antigen receptor T-cell (CAR-T) therapy; ECOG 0 to 2; fluorodeoxyglucose-avid disease by PET and bidimensional measurable disease of at least 1.5 cm by CT. Patients (n = 400) will be randomized 1:1 to receive either BV or placebo in combination with lenalidomide + rituximab and will be stratified by CD30 expression (positive [ ≥1%] versus < 1%), prior allogeneic or autologous stem cell transplant therapy (received or not), prior CAR-T therapy (received or not), and cell of origin (GCB or non-GCB). The primary endpoints are PFS per BICR in the ITT and CD30+ populations. Key secondary endpoints are OS in the ITT and CD30+ populations, and ORR per BICR. Other secondary endpoints include CR rate, duration of response, and safety and tolerability of the combination. Disease response will be assessed by BICR and the investigator according to the Lugano Classification Revised Staging System. Radiographic disease evaluations, including contrast-enhanced CT scans and PET, will be assessed at baseline, then every 6 weeks from randomization until Week 48, then every 12 weeks. PET is not required after CR is achieved. The trial is currently enrolling and will be open in 16 countries. Clinical trial information: NCT04404283.

7503 Background: Optimal initial therapy for mantle cell lymphoma (MCL) remains uncertain. The randomized phase 2 NCTN trial E1411 tested if progression-free survival (PFS) is prolonged by addition of bortezomib (V) (1.6 mg/m2 SC/IV days 1, 8) to bendamustine-rituximab (BVR vs BR) induction and/or by addition of lenalidomide (L) to rituximab (LR vs R) consolidation. Here we report efficacy and toxicity of induction BVR vs BR. Methods: 373 pts, accrued 2012–16, stratified by MIPI and age (≥60) received 1 of 4 arms: A) BR induction x 6 followed by R x 2 yrs, B) BVR followed by R, C) BR followed by LR or D) BVR followed by LR. Eligible pts had untreated MCL, ≥ age 18 (amended from ≥60 when S1106 for < 65 closed), ECOG PS 0-2 and adequate hematologic and organ function. Pts without progressive disease during induction proceeded to consolidation. Primary induction objective was whether adding bortezomib (BVR) (Arms B + D) to BR (Arms A + C) improves PFS, irrespective of consolidation R vs LR. Design of 360 eligible treated pts would provide 93.8% power to detect 10% improvement in 2-yr PFS from 70% hypothesized for BR, corresponding to 37.4% reduction in hazard using stratified log-rank test at 1-sided 10% alpha. Efficacy population was 179 (BVR) and 180 (BR), induction treatment completed in 144 vs 153, progressive disease during induction 6 vs 7 and registration to consolidation 140 vs 145. Results: Baseline demographics did not differ between the groups, with median age 67 (range 42-90) and 13% < 60 yr, 73% men, ECOG PS 0-1 97%, MIPI Low/Med/Hi 37/29/34%. Estimated PFS at 2 yrs 79.6% BVR (95% CI 73.8-85.9) vs 74.5% BR (95% CI 68.2-81.4) (1-sided stratified log-rank p = 0.268). With median PFS follow-up 51 mos, median PFS estimated at 64.1 and 64.0 mos. Overall response rate (ORR) for BVR was 88.9% (CR 65.5%) vs 89.5% (CR 60.5%) BR (z-test 1 sided p = 0.577 for ORR). Treatment related deaths during induction were 2 in BVR (cardiac arrest, hepatitis) and 1 in BR (tumor lysis). Grade ≥ 3 toxicities were 88.1% (163/185) BVR vs 77.5% (145/187) BR. For BVR vs BR grade ≥ 3 neutropenia occurred in 52 vs 39 pts, though febrile neutropenia (7 vs 6), anemia (7 vs 8) and thrombocytopenia (18 vs 16) did not differ. Peripheral neuropathy (PN) grade 2 was 8 sensory for BVR vs 2 sensory/1 motor for BR, while grade 3 PN was 6 sensory/1 motor for BVR vs 0 with BR. The only non-hematologic grade ≥ 3 toxicity in > 5% of pts was rash (9 vs 12 pts). Conclusions: Bortezomib did not significantly improve the primary endpoint of PFS when added to BR as initial MCL therapy. ORR and CR rates at end of induction were also similar. Follow-up continues to assess the entire treatment regimen, including consolidation R vs LR, but the PFS > 5 yrs, high ORR and MRD negativity rate (Smith et al ASH 2019) in this BR-based trial support BR as a platform for MCL induction therapy. Clinical trial information: NCT01415752.

7506 Background: Optimal consolidative therapy for primary central nervous system lymphoma (PCNSL) is not defined. Avoidance of whole brain radiation may reduce risk of neurotoxicity. Non-radiation consolidative options include myeloablative chemotherapy with autologous stem cell transplantation (HDT/ASCT) or non-myeloablative chemotherapy. Methods: This is a randomized phase 2, National Clinical Trials Network study of induction methotrexate (MTX) (8 g/m2 days 1, 15), temozolomide (TMZ) (150-200 mg/m2 D7-11), and rituximab (RTX) (C1 D3, 10, 17, 24 and C2 D3, 10 ) in four 28-day cycles followed by one cycle of cytarabine (ARA-C) (2 g/m2 BID, D1, 2) (MTRA). After induction, patients (pts) received consolidation with thiotepa (5 mg/kg BID, D -5, -4) plus carmustine (400 mg/m2, day -6) and ASCT (Arm A) or one cycle of ARA-C (2 g/m2 BID, D1-4) plus infusional etoposide (40 mg/kg over 96h) (Arm B). Pts were stratified on age and performance status and randomized 1:1 before induction. The primary endpoint was progression-free survival (PFS) from randomization. With 110 pts, there was 84% power to detect an improvement in PFS using a log-rank test (1-sided α= 10%), assuming a median PFS of 3 months for pts who progress during induction, and a median PFS of 2 years (yrs) for Arm B and 4.5 yrs for Arm A consolidation. This report includes the results for the primary endpoint analysis. Results: 113 pts (median age 61 yrs, range 33-75) were randomized (Arm A: 57, Arm B: 56) across 27 centers. 108 eligible pts who received induction therapy were included in the primary endpoint analysis (Arm A: 54, Arm B: 54). 72/108 pts started consolidation and 70/72 completed consolidation per protocol (Arm A: 36, Arm B: 34). With a median follow-up of 3.8 years, median PFS from randomization was 6 yrs (95% CI 3.9-not reached) in Arm A vs 2.4 yrs (95% CI 0.6-not reached) in Arm B (p = 0.02). However, more pts randomized to Arm B went off treatment before consolidation due to progression or death (28% vs 11%, p = 0.05). PFS landmarked at start of consolidation demonstrated a trend for improved PFS favoring Arm A (HR 0.58, 95% CI 0.25-1.36; p = 0.21). Median OS was not reached in either arm, and 3-yr estimates were 83% (95% CI 69-91; Arm A) vs 72% (95% CI 57-82; Arm B). Toxicities were similar between arms with no treatment-related mortality during consolidation. Conclusions: MTRA induction followed by myeloablative consolidation (Arm A) had improved PFS vs MTRA induction followed by non-myeloablative consolidation (Arm B), though more progressions or deaths leading to treatment discontinuation prior to consolidation in Arm B were noted. Both consolidation regimens were well-tolerated with encouraging PFS and OS in newly-diagnosed PCNSL. Support: U10CA180821, U10CA180882; https://acknowledgments.alliancefound.org . Clinical trial information: NCT01511562.

Purpose Four US National Clinical Trials Network components (Southwest Oncology Group, Cancer and Leukemia Group B/Alliance, Eastern Cooperative Oncology Group, and the AIDS Malignancy Consortium) conducted a phase II Intergroup clinical trial that used early interim fluorodeoxyglucose positron emission tomography (FDG-PET) imaging to determine the utility of response-adapted therapy for stage III to IV classic Hodgkin lymphoma. Patients and Methods The Southwest Oncology Group S0816 (Fludeoxyglucose F 18-PET/CT Imaging and Combination Chemotherapy With or Without Additional Chemotherapy and G-CSF in Treating Patients With Stage III or Stage IV Hodgkin Lymphoma) trial enrolled 358 HIV-negative patients between July 1, 2009, and December 2, 2012. A PET scan was performed after two initial cycles of doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) and was labeled PET2. PET2-negative patients (Deauville score 1 to 3) received an additional four cycles of ABVD, whereas PET2-positive patients (Deauville score 4 to 5) were switched to escalated bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone (eBEACOPP) for six cycles. Among 336 eligible and evaluable patients, the median age was 32 years (range, 18 to 60 years), with 52% stage III, 48% stage IV, 49% International Prognostic Score 0 to 2, and 51% score 3 to 7. Results Three hundred thirty-six of the enrolled patients were evaluable. Central review of the interim PET2 scan was performed in 331 evaluable patients, with 271 (82%) PET2-negative and 60 (18%) PET2-positive. Of 60 eligible PET2-positive patients, 49 switched to eBEACOPP as planned and 11 declined. With a median follow-up of 39.7 months, the Kaplan-Meier estimate for 2-year overall survival was 98% (95% CI, 95% to 99%), and the 2-year estimate for progression-free survival (PFS) was 79% (95% CI, 74% to 83%). The 2-year estimate for PFS in the subset of patients who were PET2-positive after two cycles of ABVD was 64% (95% CI, 50% to 75%). Both nonhematologic and hematologic toxicities were greater in the eBEACOPP arm than in the continued ABVD arm. Conclusion Response-adapted therapy based on interim PET imaging after two cycles of ABVD seems promising with a 2-year PFS of 64% for PET2-positive patients, which is much higher than the expected 2-year PFS of 15% to 30%.

Purpose This study investigated the treatment of primary CNS lymphoma with methotrexate, temozolomide (TMZ), and rituximab, followed by hyperfractionated whole-brain radiotherapy (hWBRT) and subsequent TMZ. The primary phase I end point was the maximum tolerated dose of TMZ. The primary phase II end point was the 2-year overall survival (OS) rate. Secondary end points were preirradiation response rates, progression-free survival (PFS), neurologic toxicities, and quality of life. Patients and Methods The phase I study increased TMZ doses from 100 to 150 to 200 mg/m2. Patients were treated with rituximab 375 mg/m2 3 days before cycle 1; methotrexate 3.5 g/m2 with leucovorin on weeks 1, 3, 5, 7, and 9; TMZ daily for 5 days on weeks 4 and 8; hWBRT 1.2 Gy twice-daily on weeks 11 to 13 (36 Gy); and TMZ 200 mg/m2 daily for 5 days every 28 days on weeks 14 to 50. Results Thirteen patients (one ineligible) were enrolled in phase I of the study. The maximum tolerated dose of TMZ was 100 mg/m2. Dose-limiting toxicities were hepatic and renal. In phase II, 53 patients were treated. Median follow-up for living eligible patients was 3.6 years, and 2-year OS and PFS were 80.8% and 63.6%, respectively. Compared with historical controls from RTOG-9310, 2-year OS and PFS were significantly improved (P = .006 and .030, respectively). In phase II, the objective response rate was 85.7%. Among patients, 66% (35 of 53) had grade 3 and 4 toxicities before hWBRT, and 45% (24 of 53) of patients experienced grade 3 and 4 toxicities attributable to post-hWBRT chemotherapy. Cognitive function and quality of life improved or stabilized after hWBRT. Conclusion This regimen is safe, with the best 2-year OS and PFS achieved in any Radiation Therapy Oncology Group primary CNS lymphoma trial. Randomized trials that incorporate this regimen are needed to determine its efficacy compared with other strategies.

Purpose: Additional targeted therapeutics are needed for the treatment of lymphoma. Abexinostat is an oral pan-histone deacetylase inhibitor (HDACi) displaying potent activity in preclinical models. We conducted a multicenter phase I/II study (N = 55) with single-agent abexinostat in relapsed/refractory lymphoma. Experimental Design: In phase I, 25 heavily pretreated patients with any lymphoma subtype received oral abexinostat ranging from 30 to 60 mg/m2 twice daily 5 days/week for 3 weeks or 7 days/week given every other week. Phase II evaluated abexinostat at the maximum tolerated dose in 30 patients with relapsed/refractory follicular lymphoma or mantle cell lymphoma. Results: The recommended phase II dose was 45 mg/m2 twice daily (90 mg/m2 total), 7 days/week given every other week. Of the 30 follicular lymphoma and mantle cell lymphoma patients enrolled in phase II, 25 (14 follicular lymphoma, 11 mantle cell lymphoma) were response-evaluable. Tumor size was reduced in 86% of follicular lymphoma patients with an investigator-assessed ORR of 64.3% for evaluable patients [intent-to-treat (ITT) ORR 56.3%]. Median duration of response was not reached, and median progression-free survival (PFS) was 20.5 months (1.2–22.3+). Of responding follicular lymphoma patients, 89% were on study/drug >8 months. In mantle cell lymphoma, the ORR was 27.3% for evaluable patients (ITT ORR 21.4%), and median PFS was 3.9 months (range, 0.1–11.5). Grade 3–4 treatment-related adverse events (phase II) with ≥10% incidence were thrombocytopenia (20%), fatigue (16.7%), and neutropenia (13.3%) with rare QTc prolongation and no deaths. Conclusions: The pan-HDACi, abexinostat, was overall well tolerated and had significant clinical activity in follicular lymphoma, including highly durable responses in this multiply relapsed patient population. Clin Cancer Res; 22(5); 1059–66. ©2015 AACR.

Purpose: Anti-CD20 monoclonal antibodies (mAb) are an important immunotherapy for B-cell lymphoma, and provide evidence that the immune system may be harnessed as an effective lymphoma treatment approach. ALT-803 is a superagonist IL-15 mutant and IL-15Rα–Fc fusion complex that activates the IL-15 receptor constitutively expressed on natural killer (NK) cells. We hypothesized that ALT-803 would enhance anti–CD20 mAb-directed NK-cell responses and antibody-dependent cellular cytotoxicity (ADCC). Experimental Design: We tested this hypothesis by adding ALT-803 immunostimulation to anti-CD20 mAb triggering of NK cells in vitro and in vivo. Cell lines and primary human lymphoma cells were utilized as targets for primary human NK cells. Two complementary in vivo mouse models were used, which included human NK-cell xenografts in NOD/SCID-γc−/− mice. Results: We demonstrate that short-term ALT-803 stimulation significantly increased degranulation, IFNγ production, and ADCC by human NK cells against B-cell lymphoma cell lines or primary follicular lymphoma cells. ALT-803 augmented cytotoxicity and the expression of granzyme B and perforin, providing one potential mechanism for this enhanced functionality. Moreover, in two distinct in vivo B-cell lymphoma models, the addition of ALT-803 to anti-CD20 mAb therapy resulted in significantly reduced tumor cell burden and increased survival. Long-term ALT-803 stimulation of human NK cells induced proliferation and NK-cell subset changes with preserved ADCC. Conclusions: ALT-803 represents a novel immunostimulatory drug that enhances NK-cell antilymphoma responses in vitro and in vivo, thereby supporting the clinical investigation of ALT-803 plus anti-CD20 mAbs in patients with indolent B-cell lymphoma. Clin Cancer Res; 22(3); 596–608. ©2015 AACR.