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Central nervous system (CNS) involvement in Burkitt lymphoma (BL) poses a major therapeutic challenge, and the relative ability of contemporary regimens to treat CNS involvement remains uncertain. We described prognostic significance of CNS involvement and incidence of CNS recurrence/progression after contemporary immunochemotherapy using real-world clinicopathologic data on adults with BL diagnosed between 2009 and 2018 across 30 US institutions. We examined associations between baseline CNS involvement, patient characteristics, complete response (CR) rates, and survival. We also examined risk factors for CNS recurrence. Nineteen percent (120/641) of patients (age 18-88 years) had CNS involvement. It was independently associated with HIV infection, poor performance status, involvement of ≥2 extranodal sites, or bone marrow involvement. First-line regimen selection was unaffected by CNS involvement (P=0.93). Patients with CNS disease had significantly lower rates of CR (59% versus 77% without; P

Introduction: Patients (pts) with CLL may be at particular risk of severe COVID-19 given advanced age and immune dysregulation. Two large series with limited follow-up have reported outcomes for pts with CLL and COVID-19 (Scarfò, et al. Leukemia 2020; Mato, et al. Blood 2020). To provide maximal clarity on outcomes for pts with CLL and COVID-19, we partnered in a worldwide effort to describe the clinical experience and validate predictors of survival, including potential treatment effects. Methods: This international collaboration represents a partnership between investigators at 141 centers. Data are presented in two cohorts. Cohort 1 (Co1) includes pts captured through efforts by European Research Initiative on CLL (ERIC), Italian CAMPUS CLL Program, and Grupo Español de Leucemia Linfática Crónica. The validation cohort, Cohort 2 (Co2), includes pts from US (66%), UK (23%), EU (7%), and other countries (4%). There is no overlap in cases between cohorts. CLL pts were included if COVID-19 was diagnosed by PCR detection of SARS-CoV-2 and they required inpatient hospitalization. Data were collected retrospectively 2/2020 - 5/2020 using standardized case report forms. Baseline characteristics, preexisting comorbidities (including cumulative illness rating scale (CIRS) score ≥6 vs. The primary endpoint of this study was to estimate the case fatality rate (CFR), defined as the proportion of pts who died among all pts hospitalized with COVID-19. Chi-squared test was used to compare frequencies; univariable and multivariable analyses utilized Cox regression. Predictors of inferior OS in both Co1 and Co2 were included in multivariable analyses. Kaplan-Meier method was used to estimate overall survival (OS) from time of COVID-19 diagnosis (dx). Results: 411 hospitalized, COVID-19 positive CLL pts were analyzed (Co1 n=281, Co2 n=130). Table 1 describes baseline characteristics. At COVID-19 dx, median age was 72 in Co1 (range 37-94) and 68 in Co2 (range 41-98); 31% (Co1) and 45% (Co2) had CIRS ≥6. In Co1, 48% were treatment-naïve and 26% were receiving CLL-directed therapy at COVID-19 dx (66% BTKi ± anti-CD20, 19% Venetoclax ± anti-CD20, 9.6% chemo/chemoimmunotherapy (CIT), 1.4% PI3Ki, 4% other). In Co2, 36% were never treated and 49% were receiving CLL-directed therapy (65% BTKi ± anti-CD20, 19% Venetoclax ± anti-CD20, 9.4% multi-novel agent combinations, 1.6% CIT, 1.6% PI3Ki, 1.6% anti-CD20 monotherapy, 1.6% other). Most pts receiving CLL-directed therapy had it held at COVID-19 diagnosis (93% in Co1 and 81% in Co2). Frequency of most COVID-19 symptoms/laboratory abnormalities were similar in the two cohorts including fever (88% in both), lymphocytosis (ALC ≥30 x 109/L; 27% vs. 21%), and lymphocytopenia (ALC < 1.0 x 109/L; 18% vs. 28%), while others varied between Co1 and Co2 (p Median follow-up was 24 days (range 2-86) in Co1 and 17 days (1-43) in Co2. CFRs were similar in Co1 and Co2, 30% and 34% (p=0.45). 54% and 43% were discharged while 16% and 23% remained admitted at last follow-up in Co1 and Co2, respectively. The proportion of pts requiring supplemental oxygen was similar (89% vs. 92%) while rate of ICU admission was higher in Co2 (20% vs. 48%, p Conclusions : In the largest cancer dx-specific cohort reported, pts with CLL hospitalized for COVID-19 had a CFR of 30-34%. Advanced patient age at COVID-19 diagnosis was an independent predictor of OS in two large cohorts. This CFR will serve as a benchmark for mortality for future outcomes studies, including therapeutic interventions for COVID-19 in this population. The effect of CLL treatment on OS was inconsistent across cohorts; COVID-19 may be severe regardless of treatment status. While there were no significant differences in distribution of current lines of therapy between cohorts, prior chemo exposure was more common in Co1 vs. Co2, which may account for difference in OS. Extended follow-up will be presented. Disclosures Roeker: American Society of Hematology: Research Funding; Abbott Laboratories: Other: spouse with minority ownership interest ; AbbVie: Other: spouse with minority ownership interest . Scarfo:Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Abbvie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; AstraZeneca: Honoraria; Gilead: Membership on an entity's Board of Directors or advisory committees. Abrisqueta:Celgene: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Speakers Bureau; Roche: Consultancy, Honoraria, Speakers Bureau; AbbVie: Consultancy, Honoraria, Speakers Bureau. Eyre:AbbVie: Consultancy, Honoraria, Other: travel support; Gilead: Consultancy, Honoraria, Other: travel support; Janssen: Consultancy, Honoraria, Other: travel support; KITE, AZ, Loxo Oncology at Lilly: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Muntañola Prat:Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel grants; participated in advisory boards; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel grants; participated in advisory boards; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel grants; participated in advisory boards. Villacampa:AstraZeneca: Other: advisory role; Merck Sharp & Dohme: Honoraria. Leslie:AstraZeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Bayer: Consultancy, Membership on an entity's Board of Directors or advisory committees; ADC therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; BeiGene: Speakers Bureau; KitePharma: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene/BMS: Speakers Bureau; Seattle Genetics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pharmacyclics/Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Epizyme: Speakers Bureau; Karyopharm: Speakers Bureau; TG Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees. Allan:Acerta, Genentech, Abbvie, Sunesis, Ascentage, Pharmacyclics, Janssen, AstraZeneca, BeiGene: Consultancy; Celgene, Genentech, Janssen, TG Therapeutics: Research Funding; Abbvie, Janssen, AstraZeneca, Pharmacyclics: Honoraria. Furman:Incyte: Consultancy; Genentech: Consultancy; Sunesis: Consultancy; Pharmacyclics: Consultancy; Loxo Oncology: Consultancy; Oncotarget: Consultancy; Janssen: Consultancy, Speakers Bureau; TG Therapeutics: Consultancy, Research Funding; Abbvie: Consultancy; Beigene: Consultancy; AstraZeneca: Consultancy, Research Funding; Acerta: Consultancy; Verastem: Consultancy. Pagel:BeiGene, Astrazeneca, Loxo Oncology, Gilead: Consultancy. Hernandez-Rivas:Gilead: Membership on an entity's Board of Directors or advisory committees; Celgene/BMS: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Membership on an entity's Board of Directors or advisory committees; Rovi: Membership on an entity's Board of Directors or advisory committees. Patel:Genentech: Consultancy, Speakers Bureau; Adaptive Biotechnologies: Consultancy; Janssen: Consultancy, Speakers Bureau; Celgene/BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees; BeiGene: Consultancy; Kite: Consultancy; Pharmacyclics: Consultancy, Speakers Bureau; AstraZeneca: Consultancy, Research Funding, Speakers Bureau. Motta:Roche: Honoraria; Janssen: Honoraria. Lamanna:AbbVie: Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees, Research Funding; AstraZeneca: Membership on an entity's Board of Directors or advisory committees; Genentech: Research Funding; Verastem: Research Funding; Bei-Gene: Research Funding; TG Therapeutics: Research Funding; Acerta: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche-Genentech: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees. Vitale:Janssen: Honoraria. Kamdar:Roche: Research Funding. Österborg:BeiGene: Research Funding; Kancera: Current equity holder in publicly-traded company, Research Funding; Sanofi: Consultancy; Karolinska Univeristy Hospital, Stockholm, Sweden: Current Employment. Hanson:Janssen-Cilag: Research Funding; Gilead: Research Funding; AbbVie: Honoraria. Eichhorst:ArQule: Consultancy, Honoraria, Other: travel support, Research Funding; BeiGene: Consultancy, Honoraria, Other: travel support, Research Funding; Gilead: Consultancy, Honoraria, Other: travel support, Research Funding; AstraZeneca: Consultancy, Honoraria, Other: travel support, Research Funding; Oxford Biomedica: Consultancy, Honoraria, Other: travel support, Research Funding; AbbVie: Consultancy, Honoraria, Other: travel support, Research Funding; F. Hoffmann-LaRoche: Consultancy, Honoraria, Other: travel support, Research Funding; Janssen-Cilag: Consultancy, Honoraria, Other: travel support, Research Funding; Celgene: Consultancy, Honoraria, Other: travel support, Research Funding; Novartis: Consultancy, Honoraria, Other: travel support, Research Funding. Reda:Gilead: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees. Varettoni:Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel/accommodations/expenses; AbbVie: Other: Travel/accommodations/expenses; Roche: Consultancy, Membership on an entity's Board of Directors or advisory committees. Marchetti:Gilead: Consultancy; Novartis: Speakers Bureau; Amgen: Speakers Bureau; AbbVie: Other: Sponsored meetings; Takeda: Other: Sponsored meetings; Pfeizer: Other: Sponsored meetings. Munir:F. Hoffmann-La Roche: Consultancy, Other: Medical writing support, furnished by Scott Battle, PhD, of Health Interactions, was funded by F. Hoffmann-La Roche Ltd, Basel, Switzerland; Alexion: Honoraria. Zabalza:Janssen: Honoraria, Other: travel grants; Roche: Other: travel grants; Novartis: Other: travel grants. Janssens:Amgen: Consultancy, Other: travel grants; speaker fees; Abbvie: Consultancy, Other: travel grants; speaker fees; Celgene: Consultancy, Other: travel grants; speaker fees; Janssen: Consultancy, Other: travel grants; speaker fees; Gilead: Consultancy, Other: travel grants; speaker fees; Novartis: Consultancy, Other: travel grants; speaker fees; Sanofi-Genzyme: Consultancy, Other: travel grants; speaker fees; Roche: Consultancy, Other: travel grants; speaker fees. Niemann:AstraZeneca: Honoraria, Research Funding; CSL Behring: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Sunesis: Honoraria, Research Funding; Abbvie: Honoraria, Research Funding; Danish Cancer Society: Honoraria, Research Funding; Novo Nordisk Foundation: Honoraria, Research Funding. Perini:Takeda: Honoraria; Janssen: Honoraria, Speakers Bureau; Abbvie: Speakers Bureau. Patten:AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Honoraria; Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Astra Zeneca: Honoraria. Marasca:Roche: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Shire: Honoraria. Iyengar:Janssen: Honoraria; Gilead: Honoraria. Ferrari:Abbvie: Honoraria. El-Sharkawi:Roche: Other: Conference fees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees. Itchaki:Abbvie Inc: Consultancy, Research Funding. Ma:Novartis: Research Funding; Juno: Research Funding; Pharmacyclics, LLC, an AbbVie Company: Consultancy, Honoraria, Research Funding, Speakers Bureau; Kite: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Gilead: Consultancy, Honoraria; Genentech: Consultancy, Honoraria; Bioverativ: Consultancy, Honoraria; BeiGene: Honoraria, Research Funding, Speakers Bureau; AstraZeneca: Consultancy, Honoraria, Research Funding, Speakers Bureau; AbbVie: Consultancy, Honoraria, Research Funding; TG Therapeutics: Research Funding. Van Der Spek:AMGEN: Other: Teaching activities. Seymour:Seattle Genetics: Research Funding; Merck: Research Funding; Karyopharm: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen/Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; Incyte: Research Funding; Genentech: Research Funding; Bristol-Myers Squibb: Research Funding. Rigolin:Gilead: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Mauro:Roche: Other; Octopharma: Other; Takeda-Shire: Other; Gilead: Other; Janssen: Other; Abbvie: Other. Laurenti:Janssen: Honoraria; Gilead: Honoraria; AbbVie: Honoraria; Roche: Honoraria. Levin:Janssen: Membership on an entity's Board of Directors or advisory committees, Other: travel compensation; Abbvie: Membership on an entity's Board of Directors or advisory committees, Other: travel compensation; Roche: Membership on an entity's Board of Directors or advisory committees, Other: travel compensation. Špaček:Gilead: Honoraria; Abbvie: Honoraria; Janssen: Honoraria. Walewska:AbbVie: Other: sponsored for educational meetings, Speakers Bureau; Janssen: Other: sponsored for educational meetings, Speakers Bureau; Gilead: Speakers Bureau; Astra Zeneca: Membership on an entity's Board of Directors or advisory committees. Wiestner:Pharmacyclics LLC, an AbbVie Company; Acerta, Merck, Nurix, Verastem, and Genmab: Research Funding; National Institutes of Health: Patents & Royalties: and other intellectual property. Broom:Gilead: Other: Travel support, Speakers Bureau. Kater:Abbvie: Research Funding; Roche: Research Funding; Janssen: Research Funding; Celgene: Research Funding; Genentech: Research Funding. Ujjani:AstraZeneca: Consultancy, Honoraria, Research Funding; Abbvie: Consultancy, Honoraria, Research Funding; Verastem Oncology: Consultancy, Honoraria; Gilead/Kite: Consultancy, Research Funding; Atara: Consultancy, Honoraria; Genentech: Consultancy, Honoraria; MorphoSys: Consultancy. Vandenberghe:Celgene: Other: sponsorship to attend Lugano lymphoma meeting in 2019; Gilead: Other: travel grants, Research Funding; Abbvie: Other: travel grants, Research Funding; Janssen: Other: travel grants; Roche: Other: travel grants, Research Funding. Chong:Novartis: Membership on an entity's Board of Directors or advisory committees; Tessa: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; KITE Pharma: Membership on an entity's Board of Directors or advisory committees. Pu:Takeda Pharmaceuticals: Consultancy. Brown:Janssen, Teva: Speakers Bureau; Gilead, Loxo, Sun, Verastem: Research Funding; Abbvie, Acerta, AstraZeneca, Beigene, Invectys, Juno/Celgene, Kite, Morphosys, Novartis, Octapharma, Pharmacyclics, Sunesis, TG Therapeutics, Verastem: Consultancy. Trentin:Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Octapharma: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Shire: Honoraria. Farina:Abbvie: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees. Sanchez:Abbvie: Other: travel grants; Amgem: Other: travel grants; Janssen: Other: travel grants; Celgene: Other: travel grants; Roche: Other: travel grants. Shadman:Abbvie, Genentech, Astra Zeneca, Sound Biologics , Pharmacyclics, Verastem, ADC therapeutics, Beigene, Cellectar, BMS, Morphosys and Atara Biotherapeutics: Consultancy; Mustang Bio, Celgene, Pharmacyclics, Gilead, Genentech, Abbvie, TG therapeutics, Beigene, Astra Zeneca, Sunesis, Beigene: Research Funding. Foglietta:Janssen: Honoraria; Gilead: Honoraria. Jaksic:Roche: Honoraria; Janssen: Honoraria; Abbvie: Honoraria. Sportoletti:AbbVie: Honoraria; Janssen: Honoraria. Barr:Morphosys: Consultancy; Gilead: Consultancy; AstraZeneca: Consultancy, Research Funding; Verastem: Consultancy; Seattle Genetics: Consultancy; TG therapeutics: Consultancy, Research Funding; Abbvie/Pharmacyclics: Consultancy, Research Funding; Celgene: Consultancy; Merck: Consultancy; Genentech: Consultancy; Janssen: Consultancy. Ruchlemer:Abbvie Inc: Consultancy, Research Funding. Kersting:Celgene: Other: travel grant; Janssen: Research Funding; Abbvie: Research Funding. Huntington:Pharmacyclics: Honoraria; AbbVie: Consultancy; Novartis: Consultancy; Genentech: Consultancy; DTRM: Research Funding; Celgene: Consultancy, Research Funding; Bayer: Consultancy, Honoraria; Astrazeneca: Honoraria; TG Therapeutics: Research Funding. Herishanu:Roche: Honoraria; Sanofi: Honoraria; Medison: Honoraria; Janssen: Honoraria; Abbvie: Honoraria; AstraZeneca: Honoraria. Jacobs:TG Therapeutics, Inc.: Research Funding; Astra Zeneca: Consultancy, Speakers Bureau; AbbVie: Consultancy, Speakers Bureau; Pharmacyclics: Research Funding, Speakers Bureau; Seattle Genetics: Consultancy; Verastem: Consultancy; Janssen: Consultancy, Speakers Bureau; Genentech: Speakers Bureau; Sanofi Genzyme: Speakers Bureau. Portell:BeiGene: Consultancy, Research Funding; Pharmacyclics: Consultancy; TG Therapeutics: Research Funding; Infinity: Research Funding; Roche/Genentech: Consultancy, Research Funding; Xencor: Research Funding; Bayer: Consultancy; Amgen: Consultancy; Janssen: Consultancy; Kite: Consultancy, Research Funding; Acerta/AstraZeneca: Research Funding; AbbVie: Research Funding. Rambaldi:Sanofi: Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Astellas: Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); BMS/Celgene: Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); University of Milan: Current Employment; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Support of parent study and funding of editorial support. Received travel support., Research Funding; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support from Gilead.; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company). Research grant from Amgen Inc.; Omeros: Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company). Advisory board and speaker fees from Pfizer.. Brander:Verastem: Consultancy, Honoraria, Other, Research Funding; NCCN: Other; Novartis: Consultancy, Other; Teva: Consultancy, Honoraria; Tolero: Research Funding; NCCN: Other; Novartis: Consultancy, Other; Teva: Consultancy, Honoraria; Tolero: Research Funding; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding; ArQule: Consultancy, Other, Research Funding; Ascentage: Other, Research Funding; AstraZeneca: Consultancy, Honoraria, Other, Research Funding; BeiGene: Other, Research Funding; DTRM: Other, Research Funding; Genentech: Consultancy, Honoraria, Other, Research Funding; Juno/Celgene/BMS: Other, Research Funding; MEI Pharma: Other, Research Funding; Pharmacyclics LLC, an AbbVie Company: Consultancy, Honoraria, Other, Research Funding; Pfizer: Consultancy, Other; TG Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding. Rossi:Abbvie: Membership on an entity's Board of Directors or advisory committees; Daiichi Sankyo: Consultancy, Honoraria; Celgene: Membership on an entity's Board of Directors or advisory committees; Jazz: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Novartis: Other: Advisory board; Astellas: Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria; Pfizer: Membership on an entity's Board of Directors or advisory committees; Alexion: Membership on an entity's Board of Directors or advisory committees; Sanofi: Honoraria; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees. Coscia:Karyopharm Therapeutics: Research Funding; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees; Shire: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Coombs:Abbvie: Consultancy, Honoraria; Genentech: Honoraria; AstraZeneca: Honoraria; MEI Pharma: Honoraria; LOXO Oncology: Honoraria; Octapharma: Honoraria; Novartis: Honoraria. Schuster:Novartis, Genentech, Inc./ F. Hoffmann-La Roche: Research Funding; AlloGene, AstraZeneca, BeiGene, Genentech, Inc./ F. Hoffmann-La Roche, Juno/Celgene, Loxo Oncology, Nordic Nanovector, Novartis, Tessa Therapeutics: Consultancy, Honoraria. Foà:Abbvie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Roche: Membership on an entity's Board of Directors or advisory committees; Novartis: Speakers Bureau; Roche: Membership on an entity's Board of Directors or advisory committees; Incyte: Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Cuneo:Astra Zeneca: Honoraria; Gilead: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Roche: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Abbvie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Bosch:Jansen: Honoraria; Abbvie: Honoraria; Novartis: Honoraria; Astra Zeneca: Honoraria; Takeda: Honoraria; Celgene: Honoraria; Roche: Honoraria. Stamatopoulos:AstraZeneca: Honoraria; Janssen, Gilead, Abbvie: Honoraria, Research Funding. Ghia:Adaptive, Dynamo: Consultancy, Honoraria; Novartis: Research Funding; BeiGene: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding; Celgene/Juno: Consultancy, Honoraria; Lilly: Consultancy, Honoraria; MEI: Consultancy, Honoraria; Sunesis: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding; Gilead: Consultancy, Honoraria, Research Funding; ArQule: Consultancy, Honoraria; Acerta/AstraZeneca: Consultancy, Honoraria. Mato:Adaptive: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; AbbVie: Consultancy, Research Funding; BeiGene: Consultancy; LOXO: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; AstraZeneca: Consultancy, Research Funding; Pharmacyclics LLC, an AbbVie Company: Consultancy, Research Funding; TG Therapeutics: Consultancy, Other: DSMB, Research Funding.

The field of lymphoma oncology is becoming increasingly complex as we transition into the personalized medicine era. Not only are more treatment options becoming available, but lymphomas are being further subclassified with nearly 100 subtypes in the most recent World Health Organization classification [1]. One of the main challenges in iNHL is the absence of identified predictive markers to aide in treatment selection and sequencing. Although chemoimmunotherapy (CIT) remains the preferred frontline option for most patients with FL requiring therapy, there is interest in shifting towards chemotherapy-free approaches. Marginal zone lymphoma subtypes are more variable, with the radiation therapy or rituximab monotherapy as the preferred frontline approach for extranodal (EMZL) and splenic (SMZL), and rituximab monotherapy or CIT the favored approach for treatment-naive nodal marginal zone (NMZL). A continued challenge in the frontline treatment of iNHL in patients with iNHL is the lack of predictive and prognostic markers that can identify those at increased risk of poor outcomes. The FL international prognostic index (FLIPI), FLIPI-2, and m7-FLIPI consider clinical and/or molecular features to help risk-stratify patients; however, significant heterogeneity remains among patients in various risk groups and these prognostic scores have different implications if applied to a patient treated with CIT versus a chemotherapy-free approach [2–4]. In the frontline setting, we are still unable to accurately identify patients at increased risk for early relapse, such as progression of disease within 2 years of frontline CIT (POD24), which remains an area of unmet need. Once these patients can be identified prior to starting therapy, novel approaches can be explored in an attempt to change the natural history of disease for these patients. In the relapsed or refractory (R/R) setting, CIT may be appropriate for a minority of patients, but a targeted approach is preferred for most. From June 2020 through March 2021, the Food and Drug Administration (FDA) granted accelerated approval for three new targeted therapies in R/R FL and one for R/R MZL. Chemotherapy-free options in R/R FL now include lenalidomide-based therapy, four different phosphoinositide 3-kinase (PI3K) inhibitors, tazemetostat, and anti-CD19 chimeric antigen receptor T cell (CAR-T) therapy. It has become clear that responses to targeted therapies are different among iNHL subtypes, and options for R/R MZL differ significantly from R/R FL. For example, ibrutinib is active across most iNHL subtypes and FDA-approved for R/R MZL, SLL, WM, and R/R MCL but due to disappointing efficacy is not approved in FL (Table ​(Table1,1, Figure ​Figure11). Table 1 Targeted therapies in indolent non-Hodgkin lymphomas

Background: Patients with high-risk (HR)CLL, characterized by cytogenetic/molecular abnormalities, are associated with poor prognosis. Although small molecular inhibitor (SMI) therapies have repeatedly demonstrated improved outcomes in patients with HR CLL compared to CIT in the clinical trial setting, CIT use remains common in real-world (RW) practice. There is limited RW evidence of clinical outcomes in HR and non-HR CLL patients based on first-line (1L) treatment. This study describes treatment patterns and time to next treatment (TTNT) in HR and non-HR patients with CLL receiving ibrutinib (IBR) or CIT as 1L therapy. Methods: At 40 US clinical practices (68% community; 32% academic), medical records were abstracted for adult HR and non-HR CLL patients who initiated 1L single-agent IBR or CIT (index date) between 14Feb2014 - 31Dec2016. HR was defined as having one or more of the following prior to 1L initiation: del(17p), del(11q), TP53 mutation, unmutated IGHV, or complex karyotype (≥ 3 chromosomal abnormalities). Non-HR was defined as testing-confirmed absence of above abnormalities. Baseline characteristics were compared by Chi-square, t- / Mann Whitney U tests; TTNT was assessed by Kaplan-Meier (KM) and cox-proportional hazards regression analyses for: (a) IBR HR vs CIT HR, (b) CIT HR vs CIT non-HR, and (c) IBR HR vs IBR non-HR. Log-rank tests were used to assess statistical significance in TTNT comparison. Inverse probability treatment weighting (IPTW) was conducted to balance the baseline characteristics between the IBR HR and CIT HR groups. IPTW was not conducted in HR vs non-HR comparisons as baseline differences may reflect the inherent differences associated with risk status. Results: A total of 516 CLL patients were included in this analysis: 271 HR (IBR: 175; CIT: 96 [49.0% BR, 29.2% FCR, 17.7% G-Clb]) and 245 non-HR (IBR: 82; CIT: 163 [54.0% BR, 34.4% FCR, 9.8% G-Clb]). Baseline demographics and clinical characteristics were balanced within each pair of comparison groups. For both the weighted IBR and CIT HR groups, mean age was ~66 years with ~40% female, >50% Rai Stage 3-4, >85% ECOG 0-1, ~54% del(17p), ~30% del(11q), ~29% TP53mut, and ~33% unmutated IGHV. Median (range) duration of 1L therapy was 28.6 (1.0-58.1) vs 5.5 (0.5-38.4) months, and median (range) follow-up duration was 33.3 (1.4-58.5) vs 35.3 (1.3-59.5) months, for weighted IBR and CIT HR groups, respectively. KM analysis showed that weighted IBR HR patients had significantly longer median TTNT (Figure 1 and Table 1) and were 54% less likely to start a new treatment compared to CIT HR patients (Hazard Ratio [95% CI]: 0.46 [0.34-0.62]; p During the available follow-up, more weighted IBR HR patients had only one line of treatment compared to weighted CIT HR patients (74.7% vs 47.2%), more CIT non-HR patients had only one line of treatment compared to CIT HR patients (69.9% vs 45.8%), and more IBR non-HR had only one line of treatment compared to IBR HR patients (91.5% vs 81.7%). Majority of patients received SMI therapy in 2L. Most common 2L agents were single-agent IBR in the CIT groups (HR: 86.5%; non-HR: 83.7%) and venetoclax (VEN) in the IBR groups, either as monotherapy (HR: 37.5%; non-HR: 28.6%) or in combination with rituximab (HR: 28.1%; non-HR: 28.6%). Conclusions: To the best of our knowledge, this is the largest RW study to date comparing clinical outcomes in HR CLL patients on 1L IBR vs CIT. HR CLL patients treated with single-agent IBR had significantly longer TTNT than those treated with CIT, despite similar demographics and clinical characteristics. This RW study also demonstrated that IBR therapy provided sustained clinical benefit regardless of risk status and supports the use of IBR in 1L setting, with VEN being the most common 2L agent among those who required next line of therapy post-IBR. Finally, this study highlighted the need of cytogenetic/molecular testing before CIT treatment, consistent with clinical treatment guidelines. Disclosures Huang: Janssen Scientific Affairs, LLC: Current Employment; Johnson & Johnson: Current equity holder in publicly-traded company. Deering:EPI-Q, Inc.: Current Employment, Current equity holder in private company. Harshaw:EPI-Q, Inc.: Current Employment. Bhagnani:EPI-Q, Inc.: Ended employment in the past 24 months. Leslie:ADC therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bayer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Karyopharm: Honoraria, Speakers Bureau; Epizyme: Honoraria, Speakers Bureau; AstraZeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pharmacyclics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BeiGene: Honoraria, Speakers Bureau; KitePharma: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; TG Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees; BMS: Speakers Bureau; Celgene: Speakers Bureau; Seattle Genetics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.

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

Introduction: Marginal zone lymphoma (MZL) accounts for approximately 10% of all cases of non-Hodgkin lymphoma and includes 3 clinically distinct subtypes: extranodal (MALT), splenic (SMZL), and nodal (NMZL). Though commonly grouped in trials of iNHL the clinical behavior, molecular features, and response to therapy of MZL is distinct from other iNHL subtypes and varies among MZL subtypes.Areas covered: This review focuses on the contemporary management of NMZL and SMZL. Treatment with monoclonal antibodies, chemoimmunotherapy, BTK inhibitors, PI3K/mTOR inhibitors, Bcl2 inhibitors, lenalidomide, and CAR-T cell therapy will be covered.Expert opinion: In the era of targeted medicine, the need to develop MZL specific clinicogenetic models with prognostic and predictive value in both the frontline and relapsed/refractory setting is becoming increasingly apparent. Due to the relative rarity of each MZL subtype, the use of novel trial design with correlative studies is imperative to advance the field.

BACKGROUND Salvage immunochemotherapy followed by high-dose chemotherapy and autologous stem cell transplantation is the standard-of-care second-line treatment for patients with relapsed/refractory diffuse large B-cell lymphoma after first-line R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone). Outcomes after receipt of second-line immunochemotherapy in patients with aggressive B-cell lymphomas who relapse or are refractory to intensive first-line immunochemotherapy regimens (etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, and rituximab [R-EPOCH], rituximab, hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone alternating with methotrexate and cytarabine [R-HyperCVAD], rituximab, cyclophosphamide, vincristine, doxorubicin, and high-dose methotrexate alternating with ifosfamide, etoposide, and cytarabine [R-CODOX-M/IVAC]) remain unknown. METHODS Outcomes of patients with non-Burkitt, aggressive B-cell lymphomas and relapsed/refractory disease after first-line treatment with intensive immunochemotherapy regimens who received platinum-based second-line immunochemotherapy were reviewed retrospectively. Analyses were performed to determine progression-free survival (PFS) and overall survival (OS) from the time of receipt of second-line immunochemotherapy. RESULTS In total, 195 patients from 19 academic centers were included in the study. The overall response rate to second-line immunochemotherapy was 44%, with a median PFS of 3 months and a median OS of 8 months. Patients with early treatment failure (primary refractory or relapse

PURPOSE Phosphatidylinositol-3-kinase (PI3K) inhibitors have shown activity in relapsed or refractory (R/R) indolent non-Hodgkin lymphoma (iNHL). PI3K inhibitors have been hampered by poor long-term tolerability and toxicity, which interfere with continuous use. Umbralisib, a dual inhibitor of PI3Kδ/casein kinase-1ε, exhibits improved selectivity for PI3Kδ compared with other PI3K inhibitors. This phase IIb trial was designed to evaluate the efficacy and safety of umbralisib in patients with R/R iNHL. PATIENTS AND METHODS In this multicohort, open-label, phase IIb study, 208 patients with R/R marginal zone, follicular, or small lymphocytic lymphoma (MZL, FL, or SLL) unresponsive to prior treatments (≥ 1 MZL; ≥ 2 FL/SLL), including ≥ 1 anti-CD20–based therapy, were administered umbralisib 800 mg orally once daily until disease progression, unacceptable toxicity, or study withdrawal. Primary end point is overall response rate; secondary end points include time to response, duration of response, progression-free survival, and safety. RESULTS The median follow-up is 27.7 months (efficacy) and 21.4 months (safety). The overall response rate was 47.1%, and tumor reduction occurred in 86.4% of patients. The median time to response was 2.7-4.6 months. The median duration of response was not reached for MZL, 11.1 months for FL, and 18.3 months for SLL. Median progression-free survival was not reached for MZL, 10.6 months for FL, and 20.9 months for SLL. At least one grade ≥ 3 treatment-emergent adverse event (TEAE) was reported in 53.4% of patients. TEAEs led to umbralisib discontinuation in 32 patients (15.4%). A total of 31 patients (14.9%) discontinued because of a treatment-related adverse event. Grade ≥ 3 TEAEs reported in ≥ 10% of patients: neutropenia (11.5%) and diarrhea (10.1%). Increased ALT/AST (grade ≥ 3) occurred in 6.7%/7.2% of patients. CONCLUSION Umbralisib achieved meaningful clinical activity in heavily pretreated patients with iNHL. The safety profile was manageable, with a relatively low incidence of immune-mediated toxicities and adverse event–related discontinuations.

Phosphoinositide 3-kinase-δ (PI3Kδ) inhibitors are active in lymphoid malignancies, although associated toxicities can limit their use. Umbralisib is a dual inhibitor of PI3Kδ and casein kinase-1ε (CK1ε). This study analyzed integrated comprehensive toxicity data from 4 open-label, phase 1 and 2 studies that included 371 adult patients (median age, 67 years) with relapsed/refractory non-Hodgkin lymphoma (follicular lymphoma [n = 147]; marginal zone lymphoma [n = 82]; diffuse large B-cell lymphoma/mantle cell lymphoma [n = 74]; chronic lymphocytic leukemia [n = 43]; and other tumor types [n = 25]) who were treated with the recommended phase 2 dose of umbralisib 800 mg or higher once daily. At data cutoff, median duration of umbralisib treatment was 5.9 months (range, 0.1-75.1 months), and 107 patients (28.8%) received umbralisib for ≥12 months. Any-grade treatment-emergent adverse events (AEs) occurred in 366 (98.7%) of 371 patients, with the most frequent being diarrhea (52.3%), nausea (41.5%), and fatigue (31.8%). Grade 3 or higher treatment-emergent AEs occurred in 189 (50.9%) of 371 patients and included neutropenia (11.3%), diarrhea (7.3%), and increased aminotransferase levels (5.7%). Treatment-emergent serious AEs occurred in 95 (25.6%) of 371 patients. AEs of special interest were limited and included pneumonia (29 of 371 [7.8%]), noninfectious colitis (9 of 371 [2.4%]), and pneumonitis (4 of 371 [1.1%]). AEs led to discontinuation of umbralisib in 51 patients (13.7%). Four patients (1.1%) died of AEs, none of which was deemed related to umbralisib. No cumulative toxicities were reported. The favorable long-term tolerability profile and low rates of immune-mediated toxicities support the potential use of umbralisib for the benefit of a broad population of patients with lymphoid malignancies.

Introduction: Data on lymphoma patients with SARS-CoV-2 infection (COVID-19) are lacking. A large cancer cohort study showed that number of comorbidities, active cancer, and worse performance status were associated with increased 30-day mortality (Kuderer 2020). Variables contributing to risk of poor outcomes of COVID-19 in lymphoma patients have not been reported. We aimed to investigate the effect of COVID-19 on lymphoma patients' clinical outcomes including the effect of lymphoma-specific therapies on COVID-19 recovery. Methods: We conducted a multicenter, retrospective, observational cohort study. Data was obtained from 4,302 patients flagged in the electronic health records system with COVID-19, of which 89 lymphoma patients were identified. Presenting clinical information was abstracted from review of unstructured notes as well as structured data. Demographic and baseline parameters were summarized. The differences in the distributions between CD20 antibody treated or non-treated patients were compared using Mann-Whitney's test for continuous variables and Pearson's chi-squared test for categorical variables. The Kaplan-Meier method was utilized to compare the median time from date of diagnosis to date of last follow up or death. Results: 89 lymphoma patients were evaluable. The median age was 67 (range 29-94) with a male predominance (63%). The most common presenting symptoms were fever (54%), shortness of breath (52%), cough (47%), and gastrointestinal (13%). Hypertension and diabetes were present in 51 of 89 (57%) and 19 of 89 (21%) patients, respectively. Laboratory abnormalities included a median absolute neutrophil count of 4.67x103/mcL (range 0-15.9) and lymphocyte count 0.8x103/mcL (range 0-97.7). Inflammatory markers at diagnosis showed median CRP 9.4 mg/dL (0.7-126, n=62) and ferritin of 966 ng/mL (96-14,511, n=42). 76 of 89 (85%) patients required hospitalization, 11 (12%) required mechanical ventilation, and 31 (Case Fatality Rate=35%) died. The overall survival of lymphoma patients is shown in Figure 1A. The presence of hypertension (HR 3.7, p=.005), diabetes (HR 2.6, p=.02), or advanced age ≥70 (HR 2.2, p=.03) were associated with increased COVID-19 related mortality (Figure 1B-D). Lymphoma subtypes included CLL (n=32), DLBCL or Burkitt's (n=18), indolent non-Hodgkin (n=20), Hodgkin (n=6), T cell lymphoma (n=6), and other (n=7). 76% were stage III-IV (n=68), with 40 patients (44%) on active lymphoma treatment at the time of COVID-19 diagnosis. 41 patients (48%) received rituximab within the last 3 years, with 11 requiring chronic immune gamma globulin replacement. 25 patients were tested for seropositivity to COVID-19 at median of 42 days from COVID-19 diagnosis (IQR 32-50). 5 of 9 (55%) patients who did not receive CD20 antibody therapy showed immunity. In contrast, out of 16 patients who received anti-CD20 treatment and had a COVID-19 IGG antibody test, only 2 (12.5%) became seropositive (p =.03). Patients who tested seronegative in the CD20 antibody group and had a second negative IgG antibody test (n=6) were a median of 50 days (range 12-82 days) from COVID-19 diagnosis. The median time from diagnosis until a negative COVID-19 PCR test in CD20 antibody treated patients was 56 days (IQR 29-67.5) compared to 14 days (IQR 13-54) (p=0.037) in CD20 antibody naïve patients. Conclusion: Survival was poor in lymphoma patients with hypertension, diabetes, or age ≥ 70. The rate of seropositivity in patients treated with CD20 antibody therapy was significantly lower (12.5% vs 55%). Patients exposed to anti-CD20 therapy also required significantly more days to clear viral shedding (median 56 days vs 14 days). While limited by sample size, this study merits further validation and suggests anti-CD20 therapy may place lymphoma patients at higher risk of prolonged or repeated COVID-19 infection. Further investigations to determine infectivity of patients with prolonged SARS-CoV2 shedding are needed. Disclosures Mato: Janssen: Consultancy, Research Funding; AbbVie: Consultancy, Research Funding; Adaptive: Consultancy, Research Funding; Loxo: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; Pharmacyclics: Consultancy, Research Funding; TG Therapeutics: Consultancy, Research Funding; AstraZeneca: Consultancy, Research Funding. Leslie:Celgene/BMS: Speakers Bureau; AstraZeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Karyopharm: Speakers Bureau; Seattle Genetics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pharmacyclics/Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BeiGene: Speakers Bureau; TG Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees; KitePharma: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; ADC therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bayer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Epizyme: Speakers Bureau. Goy:Constellation: Research Funding; Genentech/Roche: Research Funding; Infinity: Research Funding; Karyopharm: Research Funding; Morphosys: Research Funding; AbbVie: Research Funding; MD Anderson: Research Funding; Regional Cancer Care Associates/OMI: Current Employment; Infinity Verastem: Research Funding; Xcenda: Consultancy; Hackensack UMC and University of Nebraska: Research Funding; COTA: Consultancy, Current equity holder in publicly-traded company, Other: leadership role; Kite, a Gilead Company: Consultancy, Current equity holder in publicly-traded company, Honoraria, Other: leadership role, Research Funding; Janssen: Consultancy, Honoraria, Other: leadership role, Research Funding; Celgene: Honoraria, Research Funding; AstraZeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: leadership role, Research Funding; Acerta: Consultancy, Honoraria, Other: leadership role, Research Funding; RCCA/OMI: Current Employment; PracticeUpdate Oncology: Consultancy; Bayer: Research Funding; CALBG: Research Funding. Feldman:Kyowa Kirin: Consultancy, Research Funding; Celgene: Honoraria, Research Funding; BMS: Consultancy, Honoraria, Research Funding; Portola: Research Funding; Takeda: Honoraria, Other: Travel expenses; Seattle Genetics, Inc.: Consultancy, Honoraria, Other: Travel expenses, Research Funding, Speakers Bureau; Janssen: Speakers Bureau; AstraZeneca: Consultancy; Corvus: Research Funding; Rhizen: Research Funding; Pfizer: Research Funding; Kite: Honoraria, Other: Travel expenses, Speakers Bureau; Viracta: Research Funding; Trillium: Research Funding; Bayer: Consultancy, Honoraria; Pharmacyclics: Honoraria, Other, Speakers Bureau; Amgen: Research Funding; Eisai: Research Funding; Cell Medica: Research Funding; Abbvie: Honoraria.

Autologous hematopoietic stem cell transplantation (ASCT) is a standard-of-care treatment for many hematologic malignancies. Progression of disease after ASCT is the primary cause of treatment failure. In this Phase Ib trial, we studied the safety and clinical effect of combined checkpoint inhibition therapy (CPIT) with ipilimumab and nivolumab as a consolidation strategy after ASCT for patients with high-risk diffuse large B cell lymphoma (DLBCL), mature T cell lymphoma (TCL), and multiple myeloma (MM). Starting at 14 to 28 days after ASCT, patients received ipilimumab (1 mg/kg i.v. on day 1 of weeks 1, 4, 7, 10, 16, and 22) and nivolumab (3 mg/kg i.v. on day 1 of weeks 1, 4, 7, 10, 12, 14, 16, 18, 20, 22, 24, and 26). Patients received a median of 5 doses of ipilimumab and 8 doses of nivolumab. Thirty-five patients were included in the intent-to-treat population. Ninety-four percent of the patients experienced immune-related adverse events (irAEs) of any grade. Ninety-seven percent of irAEs resolved spontaneously or after holding study drugs and instituting high-dose corticosteroid therapy. Progression-free and overall survival at 18 months post-ASCT for each disease cohort were 85.7% and 100% for primary refractory DLBCL, 28.6% and 57.1% for relapsed DLBCL, not evaluable and 80% for frontline TCL, 25% and 75% for relapsed TCL, 57.1% and 87% for high-risk transplant-naive MM, and 40% and 100% for MM relapsed within 3 years of first ASCT. We conclude that combined CPIT appears to be tolerable as a consolidation strategy after ASCT and in addition to the potential clinical efficacy observed in some subsets of disease, T cell receptor repertoire, T regulatory cell phenotype, and gut microbiota profiles provide a biologic rationale warranting further study of this approach.

Here, we report on a phase IIa study to determine the intubation rate, survival, viral clearance, and development of endogenous Abs in patients with COVID-19 pneumonia treated with convalescent plasma (CCP) containing high levels of neutralizing anti–SARS-CoV-2 Abs. Radiographic and laboratory evaluation confirmed all 51 treated patients had COVID-19 pneumonia. Fresh or frozen CCP from donors with high titers of neutralizing Abs was administered. The nonmechanically ventilated patients (n = 36) had an intubation rate of 13.9% and a 30-day survival rate of 88.9%, and the overall survival rate for a comparative group based on network data was 72.5% (1625/2241). Patients had negative nasopharyngeal swab rates of 43.8% and 73.0% on days 10 and 30, respectively. Patients mechanically ventilated had a day-30 mortality rate of 46.7%; the mortality rate for a comparative group based on network data was 71.0% (369/520). All evaluable patients were found to have neutralizing Abs on day 3 (n = 47), and all but 1 patient had Abs on days 30 and 60. The only adverse event was a mild rash. In this study on patients with COVID-19 disease, we show therapeutic use of CCP was safe and conferred transfer of Abs, while preserving endogenous immune response., Patients with COVID-19 pneumonia receiving high-titer convalescent plasma showed antibody transfer with preservation of endogenous production, and database survival comparison is promising for the early group.

OBJECTIVESTo determine the rate of intubation, overall survival, viral clearance, and the development of endogenous antibodies in patients with COVID-19 pneumonia treated with convalescent plasma containing high levels of neutralizing anti-SARS-CoV-2 antibodies. We also aimed to describe the laboratory parameters of the plasma products.DESIGNThis was a phase IIa, single institution, prospective study in adults hospitalized with SARS-CoV-2 pneumonia.SETTINGHackensack University Medical Center, a 770-bed research and teaching hospital located in Bergen County NJ, 11 km from New York City. The study was conducted between April 15 and June 18, 2020.PARTICIPANTS47 hospitalized adult patients were treated: 32 in the non-mechanically ventilated group and 15 in the mechanically ventilated group. All patients had confirmed SARS-CoV-2 pneumonia by radiographic and laboratory evaluation.INTERVENTIONFresh or frozen convalescent plasma from donors with high titers of viral neutralizing antibodies was administered.MAIN OUTCOME MEASURESIncidence of intubation, overall survival, and discharge rate of patients divided in cohorts based on severity of disease. Description of infused plasma characteristics. Evaluation of recipients’ pre-treatment viral immunity, immunity transfer from convalescent plasma administration, and late immunity 30 and 60 days after treatment. Rates of viral clearance by nasopharyngeal PCR at 10 and 30 days. Outcomes of patients with no pre-treatment immunity. Survival comparison with institutional data for each cohort.RESULTSAnalysis for the non-mechanically ventilated patients showed an intubation rate of 15.6% (95% CI: 5.3%-32.8%) and a day-30 survival rate of 87.5% (28/32; 95% CI:70.2%-96.4%). The overall survival for a comparative group based on institutional data was 66% (675/1023; p=0.012). The rates of negative nasopharyngeal swab by PR-PCR on day+10 and +30 post treatment were 42.9% (95% CI: 24%-63%) and 78% (95% CI: 56%-93%) respectively. Patients mechanically ventilated had a day-30 mortality of 46.7% (95% CI:21.3%-73.4%); the mortality for a comparative group based on institutional data was 68.5% (217/317; p=0.093). The rates of negative nasopharyngeal swab by PR-PCR at day+10 and +30 was 85.7% (95% CI: 42-100%; n=7) and 100% (95% CI: 63-100%; n=8). Seven patients (15%) had no pre-infusion immunity, and all were found to have anti-SARS-CoV-2 neutralizing titers three days post infusion. All evaluable patients were found to have neutralizing antibodies on day+30 (n=30) and on day+60 (n=12) post treatment. There was no difference in outcomes within the ranges of high antiviral neutralizing titers used, mostly greater than 1:1000. There was also no difference between fresh or frozen plasma. The only adverse event was a mild rash in one patient.CONCLUSIONIn this study of adult patients hospitalized with SARS-CoV-2 pneumonia, convalescent plasma was safe and conferred effective transfer of immunity while preserving endogenous immune response. Intubation rates, survival rates compared with institutional data, and viral clearance rates, support the continued evaluation of this antiviral modality.STUDY REGISTRATIONClinicalTrials.gov NTC04343755

There is a Blood Commentary on this article in this issue., Key Points Both watch-and-wait and treated CLL patients have high mortality rates when admitted for COVID-19. Receiving a BTKi for CLL at COVID-19 diagnosis severe enough to require hospitalization did not influence case fatality rate in this study., Given advanced age, comorbidities, and immune dysfunction, chronic lymphocytic leukemia (CLL) patients may be at particularly high risk of infection and poor outcomes related to coronavirus disease 2019 (COVID-19). Robust analysis of outcomes for CLL patients, particularly examining effects of baseline characteristics and CLL-directed therapy, is critical to optimally manage CLL patients through this evolving pandemic. CLL patients diagnosed with symptomatic COVID-19 across 43 international centers (n = 198) were included. Hospital admission occurred in 90%. Median age at COVID-19 diagnosis was 70.5 years. Median Cumulative Illness Rating Scale score was 8 (range, 4-32). Thirty-nine percent were treatment naive (“watch and wait”), while 61% had received ≥1 CLL-directed therapy (median, 2; range, 1-8). Ninety patients (45%) were receiving active CLL therapy at COVID-19 diagnosis, most commonly Bruton tyrosine kinase inhibitors (BTKi’s; n = 68/90 [76%]). At a median follow-up of 16 days, the overall case fatality rate was 33%, though 25% remain admitted. Watch-and-wait and treated cohorts had similar rates of admission (89% vs 90%), intensive care unit admission (35% vs 36%), intubation (33% vs 25%), and mortality (37% vs 32%). CLL-directed treatment with BTKi’s at COVID-19 diagnosis did not impact survival (case fatality rate, 34% vs 35%), though the BTKi was held during the COVID-19 course for most patients. These data suggest that the subgroup of CLL patients admitted with COVID-19, regardless of disease phase or treatment status, are at high risk of death. Future epidemiologic studies are needed to assess severe acute respiratory syndrome coronavirus 2 infection risk, these data should be validated independently, and randomized studies of BTKi’s in COVID-19 are needed to provide definitive evidence of benefit., Visual Abstract

Background: Early reports suggested that cancer patients have a 1.7-fold increased risk of contracting SARS-CoV-2 and higher rates of severe events and mortality compared with general population. Patients with hematologic malignancies may have worse COVID-19 outcomes, due to an impaired humoral immune response from their underlying malignancy and concurrent anticancer therapy. In this multi-center, retrospective, observational study, we evaluate the associations of COVID-19 outcomes with patient and lymphoma disease characteristics. Methods: EMRs at 10 study centers across the USA identified 519 patients with a diagnosis of lymphoma, CLL, or other lymphoid malignancies, who had a documented positive result of SARS-CoV-2 PCR or nucleocapsid antibody testing. Descriptive statistics were used to summarize the demographic and clinical characteristics. Logistic regression was used to evaluate the associations of individual characteristics with COVID-19 outcomes, adjusted for center (NYU vs. other). The interactions between each of the variables was also included in these models; since the interactions were generally small and non-significant, only the main effect of center was included. Two-sided p-values ≤0.05 were considered significant; there were no adjustments for multiple variables or endpoints. Each analysis was based on complete data for that analysis. Results: Tables 1 and 2 provide demographic and clinical characteristics, respectively, of the 519 patients. The mean age was 61.9 years, with 296 (57%) male and 374 (72%) white patients. NYU had the largest cohort (318 patients), with the remaining centers contributing a range of 3 to 69 patients (median 14). Logistic regression models for the association of each COVID-19 outcome with individual clinical and patient characteristics included adjustments for the center (NYU/other). While center effects were statistically significant, center by covariate interaction effects were not and are not included in the final models. The odds ratio (OR) estimates and p-values for each patient and CLL/lymphoma clinical variable are shown in Tables 3 and 4, respectively. The risks of experiencing a severe event, death, and hospital admission increased with age; for each 10 years of age increase, the ORs were 1.58 for experiencing severe events, 1.78 for death, and 1.65 for hospital admission. The risks of poor outcome were higher in males than in females (OR 1.93 for severe events, 1.85 for death, and 1.47 for hospital admission). Patients with Charlson Comorbidity Index (CCI) >5 had a higher risk of severe events (OR 2.46), mortality (3.30) and hospital admission (2.73) compared to patients with CCI ≤5. Compared to patients with HL, patients with aggressive NHL had a higher risk of severe events (OR 4.05), mortality (4.68) and hospital admission (4.65). Patients with CLL similarly had a higher risk of severe events (OR 4.64), mortality (4.65) and hospital admission (5.93) compared to HL patients. Patients with indolent NHL had a higher risk of hospital admission (OR 3.95) but not a higher risk of mortality compared to HL. Patients in remission at the time of COVID-19 diagnosis had a lower risk of severe events (OR 0.42), mortality (0.36) and hospital admission (0.40) relative to those who were not in remission. Patients who received cytotoxic chemotherapy within 28 days of their COVID-19 diagnosis had a higher risk of severe events (OR 2.54), mortality (2.79), and hospital admission (2.31). Patients who received an anti-CD20 monoclonal antibody within 6 months of COVID-19 diagnosis had a higher risk of severe events (OR 2.60), mortality (2.17) and hospital admission (3.28). Conclusions: In addition to demographic and comorbidity risk factors identified in previous studies, our study shows that patients with aggressive NHL and CLL, or patients who have received recent cytotoxic chemotherapy or anti-CD20 mAB, may be at risk for poor COVID-19 outcome. The difference in risk between NHL and HL patients is likely associated with young age of HL patients but may also be related to differences in underlying innate and adaptive immune defects. Patients at high risk for poor outcome should be a priority for studies of monoclonal antibody prophylaxis. If defects in humoral immunity are at the root of poor outcome, this may be compounded by poor response to vaccination. Multivariate analysis of this data will be completed in advance of the meeting. Figure 1 Figure 1. Disclosures Olszewski: Celldex Therapeutics: Research Funding; PrecisionBio: Research Funding; TG Therapeutics: Research Funding; Acrotech Pharma: Research Funding; Genentech, Inc.: Research Funding; Genmab: Research Funding. Barta: Daiichi Sankyo: Honoraria; Seagen: Honoraria; Acrotech: Honoraria; Kyowa Kirin: Honoraria. Hernandez-Ilizaliturri: AbbVie: Other: Advisory Boards; Incyte: Other: Advisory Boards; Celgene: Other: Advisory Boards; BMS: Other: Advisory Boards; Pharmacyclics: Other: Advisory Boards; Amgen: Other: Advisory Boards; Kite: Other: Advisory Boards; Gilead: Other: Advisory Boards; Epyzime: Other: Advisory Boards. Leslie: Janssen: Consultancy, Speakers Bureau; Merck: Consultancy; Abbvie: Consultancy, Honoraria; Epizyme: Consultancy, Honoraria, Speakers Bureau; PCYC/Janssen: Consultancy, Honoraria, Speakers Bureau; Seagen: Consultancy, Honoraria, Speakers Bureau; TG Therapeutics: Consultancy, Honoraria, Speakers Bureau; Celgene/BMS: Consultancy, Honoraria, Speakers Bureau; Kite, a Gilead Company: Consultancy, Honoraria, Speakers Bureau; ADC Therapeutics: Consultancy; BeiGene: Consultancy, Honoraria, Speakers Bureau; Karyopharm Therapeutics: Honoraria, Speakers Bureau; AstraZeneca: Consultancy, Honoraria, Speakers Bureau; Pharmacyclics: Consultancy, Honoraria, Speakers Bureau. Diefenbach: Bristol-Myers Squibb: Consultancy, Honoraria, Research Funding; Merck Sharp & Dohme: Consultancy, Honoraria, Research Funding; Morphosys: Consultancy, Honoraria, Research Funding; Genentech, Inc./ F. Hoffmann-La Roche Ltd: Consultancy, Honoraria, Research Funding; Perlmutter Cancer Center at NYU Langone Health: Current Employment; Incyte: Research Funding; AbbVie: Research Funding; Trillium: Research Funding; IGM Biosciences: Research Funding; IMab: Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Gilead: Current equity holder in publicly-traded company; MEI: Consultancy, Research Funding; Celgene: Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding.

Background: Axi-cel is an autologous anti-CD19 chimeric antigen receptor (CAR) T-cell therapy approved for the treatment of R/R large B-cell lymphoma and follicular lymphoma (FL), both after ≥2 lines of systemic therapy. ZUMA-5 is a Phase 2, multicenter, single-arm study evaluating axi-cel in patients with R/R iNHL (including FL and marginal zone lymphoma [MZL]). In the primary analysis of ZUMA-5 (N=104; 17.5 months median follow-up), the overall response rate (ORR) was 92% (76% complete response [CR] rate), and median peak CAR T-cell levels were numerically greater in patients with FL who were in ongoing response at data cutoff than in those who relapsed (Jacobson et al. ASH 2020. Abstract 700). Here, we report updated clinical and pharmacologic outcomes from ZUMA-5. Methods: Adult patients with R/R FL or MZL after ≥2 lines of therapy (including an anti-CD20 mAb plus an alkylating agent) underwent leukapheresis and conditioning chemotherapy followed by a single axi-cel infusion at 2×10 6 CAR T cells/kg. The primary endpoint was centrally assessed ORR per Lugano classification. The updated efficacy analysis occurred when ≥80 consecutively treated patients with FL had ≥2 years of follow-up post-infusion and included patients with MZL who had ≥4 weeks of follow-up post-infusion. Results: As of March 31, 2021, 149 patients with iNHL (124 FL; 25 MZL) were treated with axi-cel. Of those, 110 patients (86 FL; 24 MZL) were eligible for efficacy analyses. Among eligible patients with FL, median follow-up was 30.9 months (range, 24.7-44.3). Centrally assessed ORR was 94% in patients with FL (79% CR rate). At data cutoff, 57% of eligible patients with FL had ongoing responses; 68% of patients who achieved a CR had ongoing responses. The estimated duration of response (DOR) and progression-free survival (PFS) medians were 38.6 months and 39.6 months in patients with FL, respectively. Among patients with FL who progressed Among eligible patients with MZL, median follow-up was 23.8 months (range, 7.4-39.4). The ORR was 83% in patients with MZL (63% CR rate), with 50% of eligible patients in ongoing response and 73% of patients with a CR in ongoing response at data cutoff. Medians for DOR and TTNT were not reached in patients with MZL; 24-month rates were not estimable and 51%, respectively. Median PFS was 17.3 months in patients with MZL and median OS was not reached (70% OS rate at 24 months). Common Grade ≥3 AEs in all treated patients with iNHL were consistent with prior reporting: neutropenia (33%), decreased neutrophil count (28%), and anemia (25%). Grade ≥3 cytopenias present ≥30 days post-infusion were reported in 34% of patients with iNHL (33% FL; 36% MZL). Consistent with previous reports, Grade ≥3 cytokine release syndrome (CRS) and neurologic events (NEs) occurred in 7% of patients (6% FL; 8% MZL) and 19% of patients (15% FL; 36% MZL), respectively. Most CRS cases (120/121) and NEs (82/87) of any grade resolved by data cutoff. Among patients with FL who had evaluable samples, 76% (65/86) had detectable CAR gene-marked cells at low levels by 12 months post-infusion; 53% (23/43) had detectable cells 24 months post-infusion. Among evaluable patients with MZL, 67% (8/12) had detectable CAR gene-marked cells 12 months post-infusion; 60% (3/5) had detectable cells 24 months post-infusion. B-cell reconstitution was detectable in 59% of evaluable patients with FL (49/83) and 42% of those with MZL (5/12) by 12 months post-infusion. By 24 months, B cells were detectable in 61% of evaluable patients with FL (25/41) and 50% of those with MZL (2/4). Conclusions: With long-term follow-up in ZUMA-5, axi-cel demonstrated substantial and continued benefit in patients with iNHL. In FL, high response rates translated to durability, with a median DOR of 38.6 months and 57% of eligible patients in ongoing response at data cutoff. In MZL, efficacy outcomes appeared to improve with longer follow-up, with the median DOR and OS not yet reached. Axi-cel maintained a manageable safety profile, with no new safety signals . Disclosures Neelapu: Kite, a Gilead Company, Merck, Bristol Myers Squibb, Novartis, Celgene, Pfizer, Allogene Therapeutics, Cell Medica/Kuur, Incyte, Precision Biosciences, Legend Biotech, Adicet Bio, Calibr, Unum Therapeutics and Bluebird Bio: Honoraria; Takeda Pharmaceuticals and related to cell therapy: Patents & Royalties; Kite, a Gilead Company, Bristol Myers Squibb, Merck, Poseida, Cellectis, Celgene, Karus Therapeutics, Unum Therapeutics (Cogent Biosciences), Allogene, Precision BioSciences, Acerta and Adicet Bio: Research Funding; Kite, a Gilead Company, Merck, Bristol Myers Squibb, Novartis, Celgene, Pfizer, Allogene, Kuur, Incyte, Precision BioSciences, Legend, Adicet Bio, Calibr, and Unum Therapeutics: Other: personal fees. Chavez: Merk: Research Funding; MorphoSys, Bayer, Karyopharm, Kite, a Gilead Company, Novartis, Janssen, AbbVie, TeneoBio, and Pfizer: Consultancy; MorphoSys, AstraZeneca, BeiGene, Genentech, Kite, a Gilead Company, and Epizyme: Speakers Bureau; AstraZeneca: Research Funding; ADC Therapeutics: Consultancy, Research Funding; BMS: Speakers Bureau. Sehgal: Juno/Celgene: Research Funding; Kite/Gilead: Research Funding. Epperla: Genzyme: Honoraria; Karyopharm: Other: Ad Board; Beigene: Speakers Bureau; Verastem: Speakers Bureau. Bachy: Kite, a Gilead Company: Honoraria; Novartis: Honoraria; Daiishi: Research Funding; Roche: Consultancy; Takeda: Consultancy; Incyte: Consultancy. Munshi: Kite, a Gilead Company, and Incyte: Honoraria; Kite, a Gilead Company, and Incyte: Speakers Bureau. Casulo: Genentech: Research Funding; BMS: Research Funding; Verastem: Research Funding; Gilead: Research Funding. Maloney: Kite, a Gilead Company, Juno, and Celgene: Research Funding; A2 Biotherapeutics: Consultancy; BioLineRx, Juno, Celgene, Kite, a Gilead Company, Gilead, Novartis, and Pharmacyclics: Honoraria; A2 Biotherapeutics: Divested equity in a private or publicly-traded company in the past 24 months; Juno: Patents & Royalties. Reshef: Bayer: Consultancy; BMS, Regeneron, TScan, Synthekine, Atara, Jasper, Bayer: Consultancy; ilead, BMS, Precision, Immatics, Atara, Takeda, Shire, Pharmacyclics, Incyte: Research Funding; Gilead and Novartis: Honoraria. Leslie: Pharmacyclics: Consultancy, Honoraria, Speakers Bureau; Merck: Consultancy; Abbvie: Consultancy, Honoraria; Kite, a Gilead Company: Consultancy, Honoraria, Speakers Bureau; Epizyme: Consultancy, Honoraria, Speakers Bureau; Celgene/BMS: Consultancy, Honoraria, Speakers Bureau; BeiGene: Consultancy, Honoraria, Speakers Bureau; Janssen: Consultancy, Speakers Bureau; Karyopharm Therapeutics: Honoraria, Speakers Bureau; PCYC/Janssen: Consultancy, Honoraria, Speakers Bureau; AstraZeneca: Consultancy, Honoraria, Speakers Bureau; TG Therapeutics: Consultancy, Honoraria, Speakers Bureau; Seagen: Consultancy, Honoraria, Speakers Bureau; ADC Therapeutics: Consultancy. Oluwole: Pfizer: Consultancy; Curio Science: Consultancy; Kite, a Gilead Company: Consultancy, Research Funding; Janssen: Consultancy. Yakoub-Agha: Jazz Pharmaceuticals: Honoraria. Rosenblatt: Synergys: Patents & Royalties; BioGraph 55: Research Funding. Sherman: Kite, a Gilead Company: Current Employment; Gilead: Current equity holder in publicly-traded company. Dong: Kite, a Gilead Company: Current Employment; Gilead: Current equity holder in publicly-traded company; GliaCure/Tufts: Consultancy, Patents & Royalties. Giovanetti: Kite, a Gilead Company: Current Employment, Current equity holder in publicly-traded company. Yang: Kite, a Gilead Company: Current Employment. Lui: Gilead Sciences: Other: stock or other ownership; Kite, a Gilead Company: Current Employment, Other: travel support. Bashir: Kite, a Gilead Company: Ended employment in the past 24 months; OmniacPharmConsult Ltd: Other: stock or other ownership. Jung: Amgen, Kura, Gilead, and Turning Point: Current equity holder in publicly-traded company; Kite, a Gilead Company: Current Employment. Jacobson: Lonza: Consultancy, Honoraria, Other: Travel support; Kite, a Gilead Company: Consultancy, Honoraria, Other: Travel support; AbbVie: Consultancy, Honoraria; Nkarta: Consultancy, Honoraria; Novartis Pharmaceuticals Corporation: Consultancy, Honoraria, Other: Travel support; Pfizer: Consultancy, Honoraria, Other: Travel support, Research Funding; Precision Biosciences: Consultancy, Honoraria, Other: Travel support; Celgene: Consultancy, Honoraria, Other: Travel support; Humanigen: Consultancy, Honoraria, Other: Travel support; Axis: Speakers Bureau; Clinical Care Options: Speakers Bureau.

Introduction: Liquid biopsy has been reported to be useful in predicting residual disease in patients with diffuse large B-cell lymphoma (DLBCL). Most of the studies focused on quantifying the level of circulating lymphoma-specific DNA. We explored the clinical relevance of the specific mutated genes in predicting progression in patients with DLBCL. Method: Peripheral blood samples were collected from patients with DLBCL based on their visit to clinic without other specific selection. Median age of patients is 69 (range 28-91), with 51% of the patients being male. These patients were treated on multiple protocols including R-CHOP, R-EPOCH, Magrath, HCVAD, CAR-T (#2 patients), and others. cfDNA was extracted and sequenced by next generation sequencing using 177 gene panel. The panel uses single primer extension (SPE) approach with UMI. Sequencing depth is increased to more than 2000X after removing duplicates. Low level mutations are confirmed by inspecting BAM file. Results: A total of 86 sample from 61 patients were collected post clinical remission at different time points (median 28 weeks, range: 1-994 weeks). Of these samples, 56 (65%) from 46 patients (75%) were positive. However, 6 of these samples from 4 patients had germline mutations or mutations in TET2, ASXL1, or DNMT3A that are consistent with CHIP (clonal hematopoiesis of indeterminate potential). The remaining 50 positive samples from 42 patients had 8 repeats on the same patients collected at different time points. Comparing the 19 negative patients with the 42 positive patients post-remission, patients with residual molecular disease were significantly older than patients without residual disease (P=0.01). However, there was no significant difference between the two groups in gender, ethnic background, LDH, cell of origin classification, or TP53 positivity by IHC. Patients with residual disease showed tendency for short progression-free survival (P=0.08). Focusing on patients with specific mutations detected in the cfDNA showed that 14 (23%) patients had mutations either in TP53 or MYD88. There was no significant difference in age between these two groups or any of the other clinical variables. However, patients with TP53/MYD88 mutations had significantly shorter survival (P=0.04). Conclusion: Post-remission residual disease as measured by circulating cfDNA is an independent predictor of potential relapse in patients with DLBCL. However, presence of it is important to determine the aggressiveness of the residual circulating clone. Residual circulating lymphoma DNA with TP53 or MYD88 mutations is a strong predictor of earlier relapse. Figure 1 Figure 1. Disclosures Pecora: Genetic testing cooperative: Other: equity investor; Genetic testing cooperative: Membership on an entity's Board of Directors or advisory committees. Feldman: Alexion, AstraZeneca Rare Disease: Honoraria, Other: Study investigator. Goy: Bristol Meyers Squibb: Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Membership on an entity's Board of Directors or advisory committees; MorphoSys: Honoraria, Other; AbbVie/Pharmacyclics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AstraZeneca: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Honoraria; Acerta: Consultancy, Research Funding; Elsevier's Practice Update Oncology, Intellisphere, LLC(Targeted Oncology): Consultancy; Celgene: Consultancy, Honoraria, Research Funding; Michael J Hennessey Associates INC: Consultancy; Elsevier PracticeUpdate: Oncology: Consultancy, Honoraria; Janssen: Membership on an entity's Board of Directors or advisory committees; Bristol Meyers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Kite, a Gilead Company: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Medscape: Consultancy; Gilead: Membership on an entity's Board of Directors or advisory committees; Genentech/Hoffman la Roche: Research Funding; AbbVie/Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; OncLive Peer Exchange: Honoraria; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Xcenda: Consultancy, Honoraria; Vincerx pharma: Membership on an entity's Board of Directors or advisory committees; Rosewell Park: Consultancy; LLC(Targeted Oncology): 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; Xcenda: Consultancy; Hoffman la Roche: Consultancy; Incyte: Honoraria; Kite Pharma: Membership on an entity's Board of Directors or advisory committees; Infinity/Verastem: Research Funding; Janssen: Research Funding; Karyopharm: Research Funding; Vincerx: Honoraria, Membership on an entity's Board of Directors or advisory committees; Physicians' Education Resource: Consultancy, Other: Meeting/travel support; 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; Phamacyclics: Research Funding; Constellation: Research Funding; Hackensack Meridian Health, Regional Cancer Care Associates/OMI: Current Employment.

Background: While time-limited novel agent combinations have demonstrated high overall response rates and durable responses for patients with chronic lymphocytic leukemia (CLL), they also have high rates of adverse events and possibly overtreat many favorable risk patients. Meanwhile, patients receiving indefinite ibrutinib monotherapy are at risk for cumulative toxicity and acquired resistance with continuous exposure. To address these challenges, we utilized an "add-on" approach to combination therapy after a period of ibrutinib monotherapy exposure. We examined the addition of umbralisib (a selective PI3Kδ and casein kinase-1epsilon [CK1ε] inhibitor) and ublituximab (a novel anti-CD20 monoclonal antibody glycoengineered for enhanced antibody-dependent cellular cytotoxicity; U2) to ibrutinib in CLL patients with detectable minimal residual disease (MRD) after an initial period of treatment with ibrutinib monotherapy. With this strategy, we aimed to induce undetectable MRD (uMRD), minimize the risk of developing BTKi resistance mutations, stop all CLL-directed therapy, and achieve a durable treatment-free observation (TFO) period in CLL patients who would most benefit from combination therapy. Methods: This is a phase II, multicenter, open label clinical trial (NCT04016805). Eligible patients were receiving ongoing ibrutinib, in any line of therapy, for a minimum duration of 6 months and had detectable residual CLL in the peripheral blood via MRD assay (flow cytometry with a cutoff of 10^-4 for uMRD). Umbralisib (administered daily at 800mg) and ublituximab (administered intravenously at 900 mg on Days 1/2 [split 150/750 mg], 8, and 15 of Cycle 1, Day 1 of Cycles 2-6, and on Day 1 every 3 cycles after Cycle 6) were added to ibrutinib, and patients were monitored serially for MRD starting on Cycle 3 Day 1. Once uMRD was achieved and confirmed 4 weeks later, patients entered a period of TFO. Patients who did not attain uMRD continued treatment for up to 24 cycles followed by TFO. The primary objective of the study was rate of uMRD, with a prespecified MRD conversion rate of 25% defined as promising. Secondary endpoints included safety and durability of clinical benefit after treatment discontinuation. Results: In this fully accrued study, U2 was added to ibrutinib in 26 patients. Median age was 63 years (range, 48-81) and 77% were male. Disease characteristics included del(17p) in 8%, del(11q) in 12%, and unmutated IGHV in 31%. Median duration of ibrutinib treatment prior to addition of U2 was 22 months (range 7-66 months). The swimmer plot in Figure 1 depicts time on ibrutinib prior to enrolling in this study, the duration of treatment with triplet therapy, achievement of uMRD, and TFO. MRD has been assessed in 24 patients; 71% (17/24) had uMRD in at least 1 assessment. Median time to first uMRD result was 5 months (range 2 - 12). A total of 16 patients (67%) entered TFO; 15 had 2 consecutive uMRD assessments and 1 completed 24 cycles with detectable MRD. TFO appears durable, with a median of 242 days off therapy (range 5-538 days) as of the data cutoff. 73% remain uMRD at last follow up. No patient has progressed or required re-treatment per iwCLL criteria. U2 plus ibrutinib was well tolerated. All-causality grade 3/4 adverse events of special interest included ALT/AST increase (4%), diarrhea (4%), and hypertension (8%). Two patients discontinued all therapy due to rash; both were uMRD at the time of treatment discontinuation and remain uMRD. One patient died due to complications of COVID-19. Conclusions: This is the first MRD-driven approach utilizing the combination of BTKi, PI3Ki, and anti-CD20 monoclonal antibody. This novel agent combination therapy was well tolerated and effective, with achievement of uMRD in 71% of evaluable patients. This "add-on" approach for patients on continuous ibrutinib resulted in deep remissions that allowed for a tailored, time-limited therapy and sustained treatment-free observation. Figure 1 Figure 1. Disclosures Roeker: Pharmacyclics: Consultancy; TG Therapeutics: Consultancy; Pfizer: Consultancy, Research Funding; AbbVie, AstraZeneca, Janssen, LOXO, Pharmacyclics, TG Therapeutics, Vaniam Group, Verastem: Consultancy; Abbot Laboratories: Current equity holder in publicly-traded company; Loxo Oncology: Consultancy. Leslie: Karyopharm Therapeutics: Honoraria, Speakers Bureau; TG Therapeutics: Consultancy, Honoraria, Speakers Bureau; Epizyme: Consultancy, Honoraria, Speakers Bureau; Abbvie: Consultancy, Honoraria; Merck: Consultancy; Janssen: Consultancy, Speakers Bureau; Kite, a Gilead Company: Consultancy, Honoraria, Speakers Bureau; ADC Therapeutics: Consultancy; BeiGene: Consultancy, Honoraria, Speakers Bureau; Seagen: Consultancy, Honoraria, Speakers Bureau; Celgene/BMS: Consultancy, Honoraria, Speakers Bureau; PCYC/Janssen: Consultancy, Honoraria, Speakers Bureau; Pharmacyclics: Consultancy, Honoraria, Speakers Bureau; AstraZeneca: Consultancy, Honoraria, Speakers Bureau. Soumerai: Abbvie: Consultancy; Adaptive Biotechnologies: Consultancy; AstraZeneca: Consultancy; BeiGene: Consultancy, Research Funding; BMS: Consultancy; BostonGene: Research Funding; GlaxoSmithKline: Research Funding; Seattle Genetics: Consultancy; TG Therapeutics: Consultancy, Research Funding. Zelenetz: MorphoSys: Honoraria; AstraZeneca: Honoraria; Gilead: Honoraria, Research Funding; Verastem: Honoraria; BMS/Celgene/JUNO: Honoraria, Other; NCCN: Other; Gilead: Honoraria; LFR: Other; MEI Pharma: Honoraria, Research Funding; Abbvie: Honoraria, Research Funding; Janssen: Honoraria; Beigene: Honoraria, Other, Research Funding; SecuraBio: Honoraria; Amgen: Honoraria; Pharmacyclics: Honoraria; MethylGene: Research Funding; Genentech/Roche: Honoraria, Research Funding; Novartis: Honoraria. Falchi: Abbvie: Consultancy, Research Funding; Roche: Research Funding; Genetech: Research Funding; Genmab: Consultancy, Research Funding. Park: Curocel: Consultancy; PrecisionBio: Consultancy; BMS: Consultancy; Minerva: Consultancy; Novartis: Consultancy; Affyimmune: Consultancy; Innate Pharma: Consultancy; Kite Pharma: Consultancy; Autolus: Consultancy; Kura Oncology: Consultancy; Servier: Consultancy; Amgen: Consultancy; Artiva: Consultancy; Intellia: Consultancy. Battiato: Janssen Pharmaceutical: Other: Advisory Board July 2020; Abbvie Pharmaceuticals: Other: CLL Steering Committee November 2020-present. Thompson: VJHemOnc: Honoraria; Curio Science: Honoraria; MJH Life Sciences: Honoraria. Miskin: TG Therapeutics, Inc.: Current Employment, Current equity holder in publicly-traded company. Sportelli: TG Therapeutics, Inc.: Current Employment, Current equity holder in publicly-traded company. Mato: Janssen: Consultancy, Research Funding; LOXO: Consultancy, Research Funding; MSKCC: Current Employment; Adaptive Biotechnologies: Consultancy, Research Funding; BeiGene: Consultancy, Research Funding; TG Therapeutics: Consultancy, Other: DSMB, Research Funding; Nurix: Research Funding; AstraZeneca: Consultancy; Acerta/AstraZeneca: Consultancy, Research Funding; Sunesis: Consultancy, Research Funding; Genmab: Research Funding; AbbVie: Consultancy, Research Funding; DTRM BioPharma: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; Johnson and Johnson: Consultancy, Research Funding; Pharmacyclics LLC, an AbbVie Company: Consultancy, Research Funding.

Background: The standard of care (SOC) treatment (Tx) in the curative setting for patients (pts) with relapsed/refractory (R/R) large B-cell lymphoma (LBCL) after 1st-line (1L) chemoimmunotherapy (CIT) is high-dose therapy with autologous stem cell rescue (HDT-ASCT) if responsive to 2L CIT; however, as many pts do not respond to or cannot tolerate 2L CIT, or are not intended for HDT-ASCT, outcomes remain poor. Axi-cel is an autologous anti-CD19 chimeric antigen receptor (CAR) T-cell therapy approved for R/R LBCL after ≥2 prior systemic therapies. Since CAR T-cell therapy may benefit pts in earlier lines of therapy, we conducted ZUMA-7 (NCT03391466), a global, randomized, Phase 3 trial of axi-cel vs SOC in pts with 2L R/R LBCL, and report here the results of the primary analysis (PA). Methods: Eligible pts were ≥18 y with LBCL, ECOG PS 0-1, R/R disease ≤12 mo of adequate 1L CIT (including anti-CD20 monoclonal antibody and an anthracycline), and intended to proceed to HDT-ASCT. Pts were randomized 1:1 to axi-cel or SOC, stratified by 1L Tx response and 2L age-adjusted IPI (sAAIPI). In the axi-cel arm, pts received a single infusion of 2×10 6 CAR T cells/kg after conditioning (3 d; cyclophosphamide 500 mg/m 2/day and fludarabine 30 mg/m 2/day). Optional bridging Tx was limited to corticosteroids (CIT was not allowed). In the SOC arm, pts received 2-3 cycles of an investigator-selected, protocol defined, platinum-based CIT regimen; pts with partial response or complete response (CR) proceeded to HDT-ASCT. Disease assessments by PET-CT per Lugano Classification occurred at timepoints specified from randomization. Although there was no planned trial crossover between arms, pts not responding to SOC could receive CAR T-cell therapy off protocol. Axi-cel was hypothesized to result in a 50% improvement in event-free survival (EFS: time to earliest date of disease progression, death from any cause, or new lymphoma Tx) vs SOC. The PA was event-driven, and the primary endpoint was EFS by blinded central review. Key secondary endpoints, tested hierarchically, were objective response rate (ORR) and overall survival (OS; interim analysis); safety was also a secondary endpoint. Level of CAR T cells was an exploratory endpoint. Results: As of 3/18/21, 359 pts were enrolled globally. The median age was 59 y (range, 21-81; 30% ≥65 y). Overall, 74% of pts had primary refractory disease and 46% had high sAAIPI (2-3). Of 180 pts randomized to axi-cel, 170 (94%) were infused; of 179 pts randomized to SOC, 64 (36%) reached HDT-ASCT after 2L CIT. The primary endpoint of EFS was met (HR: 0.398; P Conclusions: ZUMA-7, the first randomized, global, multicenter Phase 3 study of axi-cel vs 2L SOC in R/R LBCL, demonstrated a statistically significant and clinically meaningful improvement in EFS. Axi-cel showed superiority over SOC with >4-fold greater median EFS, 2.5-fold greater EFS at 2 y, double the CR rate, and more than double the percentage of pts receiving definitive Tx. Safety of axi-cel was manageable and at least consistent with 3L axi-cel therapy. Axi-cel may replace CIT/HDT-ASCT as the SOC for 2L R/R LBCL. These data are reported on behalf of all ZUMA-7 investigators and contributing Kite members. Disclosures Locke: Novartis: Consultancy, Other, Research Funding; Janssen: Consultancy, Other: Scientific Advisory Role; Kite, a Gilead Company: Consultancy, Other: Scientific Advisory Role, Research Funding; Iovance Biotherapeutics: Consultancy, Other: Scientific Advisory Role; GammaDelta Therapeutics: Consultancy, Other: Scientific Advisory Role; Umoja: Consultancy, Other; Wugen: Consultancy, Other; Takeda: Consultancy, Other; Legend Biotech: Consultancy, Other; EcoR1: Consultancy; Emerging Therapy Solutions: Consultancy; Gerson Lehrman Group: Consultancy; Cowen: Consultancy; Calibr: Consultancy, Other: Scientific Advisory Role; Moffitt Cancer Center: Patents & Royalties: field of cellular immunotherapy; Cellular Biomedicine Group: Consultancy, Other: Scientific Advisory Role; BMS/Celgene: Consultancy, Other: Scientific Advisory Role; Bluebird Bio: Consultancy, Other: Scientific Advisory Role; Amgen: Consultancy, Other: Scientific Advisory Role; Allogene Therapeutics: Consultancy, Other: Scientific Advisory Role, Research Funding. Miklos: Pharmacyclics, Amgen, Kite, a Gilead Company, Novartis, Roche, Genentech, Becton Dickinson, Isoplexis, Miltenyi, Juno-Celgene-Bristol Myers Squibb, Allogene, Precision Biosciences, Adicet, Adaptive Biotechnologies: Research Funding; Adaptive Biotechnologies, Novartis, Juno/Celgene-BMS, Kite, a Gilead Company, Pharmacyclics-AbbVie, Janssen, Pharmacyclics, AlloGene, Precision Bioscience, Miltenyi Biotech, Adicet, Takeda: Membership on an entity's Board of Directors or advisory committees; Kite, a Gilead Company, Amgen, Atara, Wugen, Celgene, Novartis, Juno-Celgene-Bristol Myers Squibb, Allogene, Precision Bioscience, Adicet, Pharmacyclics, Janssen, Takeda, Adaptive Biotechnologies and Miltenyi Biotechnologies: Consultancy; Pharmacyclics: Patents & Royalties. Jacobson: Kite, a Gilead Company: Consultancy, Honoraria, Other: Travel support; Lonza: Consultancy, Honoraria, Other: Travel support; Precision Biosciences: Consultancy, Honoraria, Other: Travel support; Novartis Pharmaceuticals Corporation: Consultancy, Honoraria, Other: Travel support; Nkarta: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria, Other: Travel support, Research Funding; Celgene: Consultancy, Honoraria, Other: Travel support; Humanigen: Consultancy, Honoraria, Other: Travel support; Axis: Speakers Bureau; Clinical Care Options: Speakers Bureau. Perales: Cidara: Honoraria; Omeros: Honoraria; Merck: Honoraria; Servier: Honoraria; Medigene: Honoraria; Takeda: Honoraria; Miltenyi Biotec: Honoraria, Other; Sellas Life Sciences: Honoraria; Kite/Gilead: Honoraria, Other; Novartis: Honoraria, Other; Incyte: Honoraria, Other; Equilium: Honoraria; Karyopharm: Honoraria; NexImmune: Honoraria; Celgene: Honoraria; Nektar Therapeutics: Honoraria, Other; MorphoSys: Honoraria; Bristol-Myers Squibb: Honoraria. Kersten: Novartis: Consultancy, Honoraria, Other: Travel support; Kite, a Gilead Company: Consultancy, Honoraria, Other: Travel support, Research Funding; Roche: Consultancy, Honoraria, Other: Travel support, Research Funding; BMS/Celgene: Consultancy, Honoraria; Takeda: Research Funding; Celgene: Research Funding; Miltenyi Biotec: Consultancy, Honoraria, Other: Travel support. Oluwole: Janssen: Consultancy; Kite, a Gilead Company: Consultancy, Research Funding; Pfizer: Consultancy; Curio Science: Consultancy. Ghobadi: Amgen: Consultancy, Research Funding; Kite, a Gilead Company: Consultancy, Honoraria, Research Funding; Atara Biotherapeutics: Consultancy; Wugen: Consultancy; Celgene: Consultancy. McGuirk: Juno Therapeutics: Consultancy, Honoraria, Research Funding; Kite/ Gilead: Consultancy, Honoraria, Other: travel accommodations, expense, Kite a Gilead company, Research Funding, Speakers Bureau; Novartis: Research Funding; Gamida Cell: Research Funding; Pluristem Therapeutics: Research Funding; Bellicum Pharmaceuticals: Research Funding; Allovir: Consultancy, Honoraria, Research Funding; Magenta Therapeutics: Consultancy, Honoraria, Research Funding; EcoR1 Capital: Consultancy; Novartis: Research Funding; Fresenius Biotech: Research Funding; Astelllas Pharma: Research Funding. Pagel: Incyte/MorphoSys: Consultancy; Gilead: Consultancy; AstraZeneca: Consultancy; Actinium Pharmaceuticals: Consultancy; Pharmacyclics/AbbVie: Consultancy; BeiGene: Consultancy; Epizyme: Consultancy; MEI Pharma: Consultancy; Kite, a Gilead Company: Consultancy. Muñoz: Targeted Oncology, OncView, Kyowa, Physicians' Education Resource, and Seagen: Honoraria; Pharmacyclics, Abbvie, Bayer, Kite, a Gilead Company, Pfizer, Janssen, Juno/Celgene, Bristol Myers Squibb, Kyowa, Alexion, Beigene, Fosun Kite, Innovent, Seagen, Debiopharm, Karyopharm, Genmab, ADC Therapeutics, Epizyme, Beigene, and Servier: Consultancy; Kite, a Gilead Company, Kyowa, Bayer, Pharmacyclics, Janssen, Seagen, Acrotech, Aurobindo, Beigene, Verastem, AstraZeneca, Celgene/Bristol Myers Squibb, Genentech, and Roche: Speakers Bureau; Bayer, Kite, a Gilead Company, Celgene, Merck, Portola, Incyte, Genentech, Pharmacyclics, Seagen, and Janssen, Millennium: Research Funding; OncView: Honoraria; Kyowa Kirin: Honoraria; Physicians' Education Resource: Honoraria. Farooq: Kite, a Gilead Company: Honoraria. Van Meerten: Kite, a Gilead Company: Honoraria; Janssen: Consultancy. Reagan: Genentech: Research Funding; Kite, a Gilead Company: Consultancy; Curis: Consultancy; Seagen: Research Funding. Sureda: Kite, a Gilead Company: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sanofi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; GSK: Consultancy, Honoraria, Speakers Bureau; Roche: Other: Support for attending meetings and/or travel; Bluebird: Membership on an entity's Board of Directors or advisory committees; Mundipharma: Consultancy; BMS/Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Support for attending meetings and/or travel, Speakers Bureau; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; MSD: Consultancy, Honoraria, Speakers Bureau; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Support for attending meetings and/or travel, Research Funding, Speakers Bureau. Flinn: Loxo: 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; Gilead Sciences: 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; Pfizer: 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; Kite, a Gilead Company: 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; Juno Therapeutics: 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; Karyopharm Therapeutics: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Nurix Therapeutics: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Great Point Partners: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; BeiGene: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Seagen: 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; Trillium Therapeutics: Other: All 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; Unum Therapeutics: 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; Genentech: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Yingli Pharmaceuticals: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Curis: 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; Novartis: 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; Roche: 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; Iksuda Therapeutics: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Verastem: Consultancy, Other: All consultancy and 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; Infinity Pharmaceuticals: 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; Forty Seven: 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; Agios: 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; TG Therapeutics: Consultancy, Other: All consultancy and 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; Pharmacyclics LLC, an AbbVie Company: 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; 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. Vandenberghe: Bristol Myers Squibb/Celgene: Consultancy; Pfizer: Research Funding; Gilead Sciences: Consultancy, Other: Travel support; Miltenyi Biotec: Consultancy; Novartis: Consultancy; Janssen: Consultancy, Research Funding; Kite, a Gilead Company: Consultancy. Song: GlaxoSmithKline: Honoraria; Takeda: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Janssen: Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Bristol Myers Squibb: Honoraria; Kite, a Gilead Company: Honoraria; Sanofi: Honoraria. Dickinson: Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau; Takeda: Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria; Celgene: Research Funding; Amgen: Honoraria; Roche: Consultancy, Honoraria, Other: travel, accommodation, expenses, Research Funding, Speakers Bureau; Gilead Sciences: Consultancy, Honoraria, Speakers Bureau; MSD: Consultancy, Honoraria, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria. Minnema: Janssen: Consultancy; Alnylam: Consultancy; Kite/Gilead: Consultancy; Cilag: Consultancy; Celgene: Other: Travel expenses; BMS: Consultancy. Riedell: Kite/Gilead: Research Funding, Speakers Bureau; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BeiGene: Consultancy; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Celgene/BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bayer: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Consultancy, Membership on an entity's Board of Directors or advisory committees; Calibr: Research Funding; Tessa Therapeutics: Research Funding; Xencor: Research Funding; MorphoSys: Research Funding. Leslie: Karyopharm Therapeutics: Honoraria, Speakers Bureau; BeiGene: Consultancy, Honoraria, Speakers Bureau; Celgene/BMS: Consultancy, Honoraria, Speakers Bureau; Merck: Consultancy; Abbvie: Consultancy, Honoraria; Kite, a Gilead Company: Consultancy, Honoraria, Speakers Bureau; TG Therapeutics: Consultancy, Honoraria, Speakers Bureau; AstraZeneca: Consultancy, Honoraria, Speakers Bureau; Pharmacyclics: Consultancy, Honoraria, Speakers Bureau; ADC Therapeutics: Consultancy; Epizyme: Consultancy, Honoraria, Speakers Bureau; PCYC/Janssen: Consultancy, Honoraria, Speakers Bureau; Seagen: Consultancy, Honoraria, Speakers Bureau; Janssen: Consultancy, Speakers Bureau. Chaganti: Kite, a Gilead Company: Consultancy, Honoraria, Other: Travel support, Research Funding, Speakers Bureau; Novartis: Consultancy, Honoraria, Other: Travel support, Research Funding, Speakers Bureau; Takeda: Consultancy, Honoraria, Other: travel support, Research Funding, Speakers Bureau; Celgene-BMS: Consultancy, Honoraria, Other: Travel support; Atara Bio: Consultancy, Honoraria, Research Funding, Speakers Bureau; Janssen: Research Funding; Incyte: Honoraria, Speakers Bureau. Yang: Kite, a Gilead Company: Current Employment. Filosto: Tusk Therapeutics: Patents & Royalties: or other intellecular property; Gilead Sciences: Other: stock or other ownership ; Kite, a Gilead Company: Current Employment. Schupp: Gilead Sciences: Current equity holder in publicly-traded company; Kite, a Gilead Company: Current Employment, Honoraria, Other: Travel support. To: NantWorks: Ended employment in the past 24 months; Kite, a Gilead Company: Current Employment, Other: stock or other ownership . Cheng: Kite, a Gilead Company: Current Employment, Other: Travel support; Gilead Sciences: Other: stock or other ownership . Gordon: Bristol Myers Squibb: Honoraria, Research Funding; Zylem Biosciences: Patents & Royalties: Patents, No royalties. Westin: Genentech: Consultancy, Research Funding; Bristol Myers Squibb: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Kite, a Gilead Company: Consultancy, Research Funding; Curis: Research Funding; Iksuda Therapeutics: Consultancy; Umoja: Consultancy; ADC Therapeutics: Consultancy, Research Funding; AstraZeneca: Consultancy, Research Funding; MorphoSys: Consultancy, Research Funding; Morphosys: Research Funding; 47 Inc: Research Funding.

Background: Cirmtuzumab (Cirm) is a humanized monoclonal antibody that inhibits the tumor promoting activity of ROR1 and has demonstrated additive/synergistic activity with many anticancer agents, including ibrutinib (Ibr). Methods: Patients (Pts) with relapsed or refractory (RR) MCL or treatment-naïve (TN) or RR CLL were enrolled. In Part 1 (Dose Escalation), doses of Cirm IV q2wks x5 then q4wks of 2-16 mg/kg and 300 or 600 mg were examined. Safety of Cirm alone was assessed during the first 28 days, then Ibr was started at approved doses for each indication. Cirm 600 mg IV q2wks x3 then q4wks in combination with Ibr starting day 0 was chosen as the recommended dosing regimen for use in Part 2 (Expansion) and Part 3 (CLL only, Cirm/Ibr vs. Ibr). MCL Part 1 is closed, and Part 2 is open for enrollment. CLL Parts 1, 2 & 3 are closed for enrollment. Results: As of 18Jun2021 data cutoff, 28, 34 and 28 pts were treated in MCL Parts 1 & 2, CLL Parts 1 & 2, and CLL Part 3 (Cirm/Ibr (n=18) or Ibr (n=10)). In Parts 1 & 2 MCL, the median number (#) of prior systemic regimens was 1.5 (1-4) including pts relapsing after Ibr (n=4), auto-SCT (n=6), auto-SCT/allo-SCT (n=1), or auto-SCT/CAR-T (n=1). Ki-67 ≥30% and extra-nodal disease was present in 54% and 68% of pts, respectively. The median # of prior systemic regimens for CLL Parts 1 & 2 and CLL Part 3 (RR), was 2 (1-15) including auto-SCT (n=1), and 2 (1-6). Pts entered with Rai staging ≥ Grade 2 in 71% and 64%. Safety (MCL and CLL): Most frequent treatment emergent (TEAEs) (≥30%) for both MCL and CLL pts treated with Cirm/Ibr (N=80), (all grades; regardless of causality) included contusion & fatigue (both 40.0%), and diarrhea (37.5%). Most frequent (≥5%) Grade ≥3 TEAEs, regardless of causality included hypertension (10.0%), fatigue, neutropenia, pneumonia, and atrial fibrillation (all 6.3%), leukocytosis and anemia (both 5.0%). Grade ≥3 TEAEs of myelosuppression, regardless of causality, include anemia (5.0%), thrombocytopenia (1.3%), and neutropenia (6.3%). Most TEAEs in MCL or CLL pts were considered related by Investigator to Ibr alone 64% or 84% vs. Cirm alone 14.3% or 16%. Efficacy (MCL): The best response of 20 evaluable pts in Parts 1 & 2 included CR 35%, PR 45%, SD 10%, and 10% PD. At a median follow-up of 14.9 mos., the objective response rate (ORR), clinical benefit rate (CBR) and median duration of response (DOR) for overall, ≥30% Ki-67, and >1 prior systemic regimen subgroups, were 80%, 90% and (not reached) NR (95% CI: 11.9, NR), 81.8%, 81.8% and 13.8 (95% CI: 8.7, NR), and 90%, 100% and NR (95% CI: 8.7, NR). Responses occurred in all evaluable pts who received prior SCT+/- CAR-T (4CR, 2PR) or prior Ibr (2CR, 2PR). The median PFS (mPFS) for overall, pts achieving CR, and >1 prior systemic regimen subgroups were all NR with varying 95% CI: (16.5, NR), (0.03, NR), and (0.03, NR). Efficacy (CLL): The best response of 34 evaluable pts in Parts 1 & 2 included 94.1% ORR, 11.8% CR, 82.3% PR/PR-L, and 5.9% SD for a CBR of 100%. In Part 3, evaluable Cirm/Ibr TN (n=8) or RR (n=7) and Ibr TN (n=4) or RR (n=3) arms achieved 100% or 85.7% and 100% or 100% ORR, 12.5% or 0% and 0% or 0% CR, 87.5% or 85.7% and 100% or 100% PR/PR-L, 0% or 14.3% and 0% or 0% SD. No pts had PD as best response. All pts had a CBR of 100%. For Parts 1 & 2, at a median follow-up of 24.8 mos., the DOR for overall and >1 prior systemic regimen subgroups, was NR (8.3, 35.9) and NR (12.0, 29.6). In Part 3, at a median follow-up of 14.7 mos., the DOR for TN or RR Cirm/Ibr and Ibr arms is NR (7.7, 18.6) or NR (9.2, 14.8) and NR (11.2, 18.5) or NR (8.3, 14.2). The mPFS (Parts 1 & 2) for overall, pts achieving CR, and >1 prior systemic regimen subgroups were NR (9.1, 35.8), NR (95% CI: 22.5, NR), and NR (9.1, 35.2). In Part 3, mPFS for TN or RR Cirm/Ibr and Ibr arms is all NR. Conclusions: Cirm/Ibr is well-tolerated. ORR, CR, DOR, and mPFS were similar across all subgroups of MCL and CLL pts regardless of number of prior systemic regimens or poor risk factors. Striking responses were observed in patients with MCL as evidenced by a mPFS that was NR (95% CI: 16.5, NR), CR of 35%, and a DOR of NR (95% CI: 11.9, NR) within the study period. These data compare very favorably to the mPFS of 12.8 mos, CR of 20%, and a DOR of 18.6 mos., reported for Ibr alone (Rule 2017). For CLL pts treated with Cirm/Ibr, results continue to be encouraging as they mature. The study is ongoing, with MCL enrollment expanded to include Cirm + Ibr in pts who have had an inadequate response to an Ibr regimen, or who are refractory to approved BTKi agents. Figure 1 Figure 1. Disclosures Lee: Oncternal: Research Funding; Takeda: Research Funding; Celgene: Research Funding; Seagen: Research Funding; BMS: Honoraria, Research Funding; Aptitude Health: Honoraria; Guidepoint: Honoraria; Century Therapeutics: Consultancy; Pharmacyclics: Research Funding; Janssen: Honoraria. Choi: Abbvie: Other: Institution: Research Grant/Funding; Pharmacyclics: Other: Institution: Research Grant/Funding; Oncternal: Other: Institution: Research Grant/Funding; Velosbio: Other: Institution: Research Grant/Funding; Merck: Other: Institution: Research Grant/Funding; Geron: Other: Institution: Research Grant/Funding. Siddiqi: Celgene: Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Juno Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding; BeiGene: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Pharmacyclics LLC, an AbbVie Company: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Kite Pharma: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Speakers Bureau; Oncternal: Research Funding; TG Therapeutics: Research Funding. Wierda: Acerta Pharma Inc.: Research Funding; Pharmacyclics LLC, an AbbVie Company: Research Funding; AstraZeneca: Research Funding; Cyclacel: Research Funding; Karyopharm: Research Funding; Xencor: Research Funding; Oncternal Therapeutics, Inc.: Research Funding; KITE Pharma: Research Funding; Miragen: Research Funding; Janssen: Research Funding; Gilead Sciences: Research Funding; Juno Therapeutics: Research Funding; Genentech: Research Funding; GSK/Novartis: Research Funding; Sunesis: Research Funding; Loxo Oncology, Inc.: Research Funding; Genzyme Corporation: Consultancy; AbbVie: Research Funding. Tuscano: BMS: Research Funding; Seattle Genetics: Research Funding; Takeda: Research Funding; Acrotech: Research Funding; Genentech: Research Funding; Pharmacyclics: Research Funding; Abbvie: Research Funding. Leslie: Abbvie: Consultancy, Honoraria; PCYC/Janssen: Consultancy, Honoraria, Speakers Bureau; Janssen: Consultancy, Speakers Bureau; Pharmacyclics: Consultancy, Honoraria, Speakers Bureau; Karyopharm Therapeutics: Honoraria, Speakers Bureau; AstraZeneca: Consultancy, Honoraria, Speakers Bureau; BeiGene: Consultancy, Honoraria, Speakers Bureau; ADC Therapeutics: Consultancy; Celgene/BMS: Consultancy, Honoraria, Speakers Bureau; TG Therapeutics: Consultancy, Honoraria, Speakers Bureau; Kite, a Gilead Company: Consultancy, Honoraria, Speakers Bureau; Epizyme: Consultancy, Honoraria, Speakers Bureau; Seagen: Consultancy, Honoraria, Speakers Bureau; Merck: Consultancy. Breitmeyer: Oncternal Therapeutics: Current Employment, Membership on an entity's Board of Directors or advisory committees. Yazji: Oncternal Therapeutics: Current Employment. Wang: Oncternal Therapeutics: Current Employment. Wang: OMI: Honoraria; Moffit Cancer Center: Honoraria; Chinese Medical Association: Honoraria; Newbridge Pharmaceuticals: Honoraria; DTRM Biopharma (Cayman) Limited: Consultancy; InnoCare: Consultancy, Research Funding; Scripps: Honoraria; Mumbai Hematology Group: Honoraria; VelosBio: Consultancy, Research Funding; BioInvent: Research Funding; Hebei Cancer Prevention Federation: Honoraria; Epizyme: Consultancy, Honoraria; Anticancer Association: Honoraria; Janssen: Consultancy, Honoraria, Research Funding; Lilly: Research Funding; Physicians Education Resources (PER): Honoraria; Dava Oncology: Honoraria; Clinical Care Options: Honoraria; Molecular Templates: Research Funding; BeiGene: Consultancy, Honoraria, Research Funding; AstraZeneca: Consultancy, Honoraria, Research Funding; Pharmacyclics: Consultancy, Research Funding; Acerta Pharma: Consultancy, Honoraria, Research Funding; Imedex: Honoraria; Juno: Consultancy, Research Funding; Celgene: Research Funding; Genentech: Consultancy; Loxo Oncology: Consultancy, Research Funding; Kite Pharma: Consultancy, Honoraria, Research Funding; Miltenyi Biomedicine GmbH: Consultancy, Honoraria; The First Afflicted Hospital of Zhejiang University: Honoraria; Bayer Healthcare: Consultancy; BGICS: Honoraria; CAHON: Honoraria; Oncternal: Consultancy, Research Funding; CStone: Consultancy. Jamieson: Forty Seven Inc.: Patents & Royalties. Kipps: Genentech-Roche: Consultancy; Gilead Sciences: Consultancy, Honoraria, Other, Speakers Bureau; Janssen: Consultancy, Honoraria, Other, Research Funding, Speakers Bureau; Roche: Honoraria, Other; MD Anderson Cancer Center: Research Funding; Velos: Research Funding; CRIM: Research Funding; Indy Hematology Review: Other; TG Therapeutics: Other; Verstem: Other, Speakers Bureau; University of California, San Diego: Current Employment; Pharmacyclics/AbbVie: Honoraria, Research Funding; Breast Cancer Research Foundation: Research Funding; SCOR - The Leukemia and Lymphoma Society: Research Funding; National Cancer Institute/NIH: Honoraria, Research Funding; Genentech/Roche: Honoraria; European Research Initiative on CLL (ERIC): Honoraria; Genetech: Honoraria, Other; Celgene: Consultancy, Honoraria, Other, Research Funding; Bionest Partner: Other; DAVA Pharmaceuticals: Speakers Bureau; DAVAOncology: Consultancy, Honoraria, Other; AbbVie: Consultancy, Honoraria, Other, Speakers Bureau; Oncternal Therapeutics, Inc.: Current holder of stock options in a privately-held company, Other: Stock or other ownership, Patents & Royalties: Cirmtuzumab was developed by Thomas J. Kipps in the Thomas J. Kipps laboratory and licensed by the University of California to Oncternal Therapeutics, Inc., which provided stock options and research funding to the Thomas J. Kipps laboratory., Research Funding; Moores Cancer Center: Current Employment; MedImmune Inc: Research Funding; GlaxoSmithKline: Research Funding; Gilead Sciences, Inc.: Honoraria, Research Funding; Genentech, Inc.: Honoraria, Research Funding, Speakers Bureau; Pharmacyclics LLC, an Abbvie Company: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses, Research Funding, Speakers Bureau; Celgene Corporation: Consultancy, Honoraria, Research Funding; Abbott Laboratories: Consultancy, Research Funding.

Introduction: Peripheral T-cell lymphomas (PTCL) are a heterogeneous group of lymphomas associated with poor outcomes following anthracycline-based chemotherapy, even when consolidative autologous stem cell transplantation (ASCT) is used. CD30 expression is universal in anaplastic large cell lymphoma (ALCL) and is frequently expressed in other PTCL subtypes. Brentuximab vedotin (BV) is a CD30-directed antibody drug conjugate that prolongs progression-free survival (PFS) and overall survival (OS) when combined with cyclophosphamide, doxorubicin, and prednisone (CHP) as compared to CHOP chemotherapy (Horwitz, 2020). Although a majority of pts treated with BV-CHP remained in durable remission (5y PFS 51%), there is room for improvement. Based on retrospective studies that demonstrated improved outcomes in younger pts, the addition of etoposide to CHOP (CHOEP) is commonly used as initial therapy for PTCL. We performed a multicenter phase 2 trial to evaluate the safety and efficacy of adding etoposide to BV-CHP (CHEP-BV) followed by BV consolidation in pts with newly diagnosed CD30-expressing PTCL. Methods: Adults with newly diagnosed CD30+ (≥ 1% of tumor cells by local pathology) PTCL were eligible, including pts with ALK+ ALCL and IPI score ≥ 2, ALK-negative ALCL, PTCL not otherwise specified (NOS), angioimmunoblastic T-cell lymphoma (AITL), adult T-cell leukemia/lymphoma (ATLL), among others. After accrual of 28 pts, the protocol was amended to allow enrollment of 20 additional pts with CD30+ non-ALCL PTCL (with ALCL allowed in Canada). Pts could receive prephase steroids and/or 1 cycle of CHOP-equivalent chemotherapy prior to study entry. 6 pts were treated in a safety lead-in cohort and all pts received CHEP-BV at the recommended phase 2 dose: 6 x 21-day cycles of CHP+BV (1.8mg/kg) on d1 and etoposide 100mg/m2 on d1-3. G-CSF prophylaxis was mandatory. Pts in response after CHEP-BV could receive BV consolidation (1.8mg/kg q3w) for up to 10 additional cycles (16 total BV cycles) either after ASCT or CHEP-BV if no ASCT was performed. The co-primary endpoints were safety and the CR rate (Deauville score 1-3) by PET-CT after CHEP-BV assessed by investigators according to the 2014 Lugano classification. Secondary endpoints were PFS and OS. Results: Accrual has completed and 48 pts were enrolled; all were evaluable for toxicity, 46 were evaluable for efficacy. 16 pts had ALCL (13 ALK+, 3 ALK-) and 32 had non-ALCL PTCL subtypes, including 18 with AITL, 11 with PTCL NOS, 2 with T-follicular helper PTCL, and 1 with ATLL. Baseline characteristics are shown in Table. 43 pts completed CHEP-BV, 2 had progressive disease (PD) prior to completion, 1 pt discontinued CHEP-BV early (MD discretion), 1 pt died due to COVID-19, and 1 remains on CHEP-BV. Of 43 pts who completed CHEP-BV, 24 proceeded to ASCT and 19 did not. 33 (74%) pts received BV consolidation (20 after ASCT, 13 directly after CHEP-BV) and completed a median 8 of the planned 10 cycles (range, 1-10). 13 pts completed all cycles of consolidation; 19 pts discontinued early - 12 due to adverse events (AE), 5 due to PD, and 2 due to patient/physician choice. The most frequent CHEP-BV related AEs (all grades, G) include fatigue (73%), peripheral sensory neuropathy (67%), anemia (62.5%), nausea (56%), neutropenia (50%), lymphopenia (44%), leukopenia (42%), thrombocytopenia (40%), elevated transaminases (33%). The most common G3+ AEs were neutropenia (37.5%), febrile neutropenia (23%), lymphopenia (21%), anemia (19%), thrombocytopenia (19%). There were 5 deaths, 4 due to PD and 1 due to COVID-19 infection during C3 of CHEP-BV. The interim (n=46) ORR and CR rates (after 3 CHEP-BV cycles, except 1 pt after 2) were 96% and 59% (27 CR, 17 PR), respectively. At completion of CHEP-BV (n=46), the ORR was 91% with 80% CR (37 CR, 5 PR, 4 PD). The ORR/CR rates in ALCL (n=16) vs non-ALCL (n=30) pts were 94%/94% vs 90%/73%, respectively. The ORR/CR rates in pts with CD30 expression 1-9% (n=15) vs 10+% (n=31) were 93%/67% and 90%/87%, respectively. The median follow-up in surviving pts is 16.1 months (range, 0.9-32.5). The overall 18mo PFS and OS were 61% and 89%; 18mo PFS by subgroup: ALCL 81%, non-ALCL 49%, CD30 1-9% 48%, CD30 10+% 67%. Landmark 1y PFS from end of CHEP-BV in responding pts (n=41) was 82% in pts who underwent ASCT vs 48% in pts who did not. Conclusions: In a cohort of pts with mostly non-ALCL CD30-expressing PTCL, CHEP-BV (+/- ASCT) followed by BV consolidation was tolerable and effective. Figure 1 Figure 1. Disclosures Herrera: Genentech: Consultancy, Research Funding; Seagen: Consultancy, Research Funding; Kite, a Gilead Company: Research Funding; Gilead Sciences: Research Funding; Tubulis: Consultancy; Karyopharm: Consultancy; Bristol Myers Squibb: Consultancy, Research Funding; ADC Therapeutics: Consultancy, Research Funding; AstraZeneca: Consultancy, Research Funding; Takeda: Consultancy; Merck: Consultancy, Research Funding. Zain: Secura Bio, DaichiSankyo, Abbvie: Research Funding; Kiyoaw Kirin, Secura Bio, Seattle Genetics: Honoraria; Secura Bio, Ono , Legend, Kiyowa Kirin, Myeloid Therapeutics Verastem Daichi Sankyo: Consultancy. Savage: Astra-Zeneca: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria; Takeda: Other: Institutional clinical trial funding; Roche: Research Funding; Servier: Consultancy, Honoraria; Merck: Consultancy, Honoraria, Other: Institutional clinical trial funding; AbbVie: Consultancy, Honoraria; BMS: Consultancy, Honoraria, Other: Institutional clinical trial funding; Beigene: Other: Institutional clinical trial funding; Genentech: Research Funding. Feldman: Alexion, AstraZeneca Rare Disease: Honoraria, Other: Study investigator. Brammer: Celgene: Research Funding; Kymera Therapeutics: Consultancy; Seattle Genetics: Speakers Bureau. Popplewell: Hoffman La Roche: Other: Food; Novartis: Other: Travel; Pfizer: Other: Travel. Budde: Kite Pharma: Consultancy; Genentech: Consultancy, Research Funding; AstraZeneca: Research Funding. Mei: Morphosys: Research Funding; Janssen: Honoraria; TG Therapeutics: Research Funding; EUSA: Honoraria; BMS: Research Funding; Epizyme: Research Funding; Beigene: Research Funding. Leslie: Merck: Consultancy; Pharmacyclics: Consultancy, Honoraria, Speakers Bureau; Abbvie: Consultancy, Honoraria; PCYC/Janssen: Consultancy, Honoraria, Speakers Bureau; Kite, a Gilead Company: Consultancy, Honoraria, Speakers Bureau; Celgene/BMS: Consultancy, Honoraria, Speakers Bureau; AstraZeneca: Consultancy, Honoraria, Speakers Bureau; Karyopharm Therapeutics: Honoraria, Speakers Bureau; Epizyme: Consultancy, Honoraria, Speakers Bureau; Seagen: Consultancy, Honoraria, Speakers Bureau; BeiGene: Consultancy, Honoraria, Speakers Bureau; TG Therapeutics: Consultancy, Honoraria, Speakers Bureau; Janssen: Consultancy, Speakers Bureau; ADC Therapeutics: Consultancy. Hosing: Nkarta Therapeutics: Membership on an entity's Board of Directors or advisory committees. Forman: Mustang Bio: Consultancy, Current holder of individual stocks in a privately-held company; Lixte Biotechnology: Consultancy, Current holder of individual stocks in a privately-held company; Allogene: Consultancy. Kwak: Pepromene Bio, Inc.: Consultancy, Current equity holder in publicly-traded company.

Background Umbralisib is an oral, once-daily inhibitor of PI3Kδ and CK1e that is highly selective for the delta isoform. The UNITY-NHL trial (NCT02793583) is a multicenter, open-label, Phase 2b study evaluating umbralisib in previously treated NHL patients. Herein, we present results from the UNITY-NHL study. Methods 208 patients with R/R marginal zone, follicular, or small lymphocytic lymphoma (MZL, FL, SLL) unresponsive to prior treatments (≥1 MZL; ≥2 FL/SLL), including ≥1 anti-CD20–based therapy, were administered umbralisib 800mg orally once-daily until disease progression, unacceptable toxicity, or study withdrawal. The primary endpoint of the study was overall response rate (ORR) as assessed by an independent review committee, according to the revised IWG criteria. Results At a median follow up of 27.8 months, MZL patients (n=69) had an ORR of 49.3% (95% CI 37.0% - 61.6%) with 15.9% achieving a complete response (CR), and a Disease Control Rate (DCR: CR+PR+SD) of 82.6%. Median time-to-response (TTR): 2.8 months (95% CI 2.7 - 2.9). No patient who achieved CR has progressed to date. At a median follow up of 27.5 months, FL patients (n=117) had an ORR of 45.3% (95% CI 36.1% - 54.8%) with 5.1% achieving a CR, and a DCR of 79.5%. Median TTR: 4.6 months (95% CI 3.0 - 5.6). At a median follow up of 29.3 months, SLL patients (n=22) had an ORR of 50.0% (95% CI 28.2 - 71.8) with 4.5% achieving a CR, and a DCR of 86.4%. Median TTR: 2.7 months (95% CI 2.4 - 2.8). At least one grade ≥3 treatment-emergent adverse event (TEAE) was reported in 53.4% of patients. TEAEs led to umbralisib discontinuation in 32 patients (15.4%). Grade ≥3 TEAEs reported in ≥10% of patients: neutropenia (11.5%) and diarrhea (10.1%). Increased ALT/AST (grade ≥3) occurred in 6.7%/7.2% of patients. Conclusions Umbralisib achieved meaningful clinical activity in a heavily pretreated iNHL population. The safety profile was manageable, with a relatively low incidence of immune-mediated toxicities and AE-related discontinuations. These results suggest umbralisib has a favorable benefit-risk profile in this patient population and have supported the Accelerated Approval of umbralisib in previously treated MZL and FL patients.

Introduction: Cirmtuzumab (Cirm) is a high-affinity humanized monoclonal antibody designed to inhibit the tumor promoting activity of ROR1. In this study, we examined the safety and efficacy of Cirm in combination with ibrutinib (Ibr) in patients (pts) with MCL or CLL. ROR1 is an onco-embryonic tyrosine kinase-like receptor that is found at high levels on the cell surface of many hematologic and solid cancers. Activation of ROR1 by binding its ligands such as Wnt5a results in increased intracellular signaling, tumor growth and survival, enhanced cancer cell stemness and epithelial mesenchymal transition. Methods: Pts with relapsed or refractory (RR) MCL or treatment naïve (TN) or RR CLL were enrolled and treated in separate groups. In Part 1 Dose Escalation (DE), groups of MCL and CLL pts received Cirm IV q2wks x5 doses then q4wks at assigned doses of 2-16 mg/kg, and in CLL, additional fixed dose levels of 300 or 600 mg were evaluated. The safety and PK of single-agent Cirm was assessed during the first 28 days, and then Ibr was started at 560 mg/day PO for MCL or 420 mg/day PO for CLL. After reviewing the safety and PK data from Part 1, a recommended regimen of fixed dose Cirm 600 mg IV q2wks x3 then q4wks plus Ibr starting D0 was chosen for use in Parts 2 and 3. In Part 3, CLL pts (only) were randomized to either Cirm/Ibr vs. Ibr alone Results: As of April 30, 2020, 12 evaluable MCL pts were enrolled into Part 1 DE. Of these pts, 83% (10) had received ≥ 2 separate prior treatment regimens. In CLL, 34 pts (12 TN and 22 RR pts) enrolled into Part 1 DE (n= 18) or Part 2 Expansion (n= 16). At least 79% of CLL pts in Parts 1 and 2 were high risk as determined by unmutated IGHV, del17p, and/or del11q. Safety: For both MCL and CLL, the most common adverse events (AEs) considered at least possibly related to Cirm alone were grade 1/2 (e.g. fatigue, 6%) with no dose limiting toxicities or discontinuations. The combination of Cirm plus Ibr was well tolerated, with no new or accentuated AEs compared to the known safety profile of Ibr alone. Cirm may be lowering the rates of certain AEs normally seen with Ibr; for example, neutropenic events were 8 mos after stopping all therapy. At a median follow-up of 12.8 mos, 100% of CLL pts were free of disease progression and 82% remained on study. CLL cells collected after the first 28 days of treatment showed a decrease in stemness signature (Choi et al, Cell Stem Cell 2019), with similar reductions seen with single agent Cirm or Cirm + Ibr. Additional pts have been enrolled into Part 2 Expansion MCL and into Part 3 CLL. Early data from these arms are not yet available and will be reported later. Conclusions: Cirmtuzumab in combination with ibrutinib is a well-tolerated and active regimen for RR MCL and TN or RR CLL. The 58% CR/CMR rate for MCL compares favorably to published data with single agent Ibr of 27% (Rule, et al. Haematologica 2019) and it is encouraging that responses occurred in heavily pretreated pts, including those with high Ki-67 expression. In CLL, the high ORR and interim PFS are encouraging; the significance of these observations will be determined with longer follow-up. These data support the continued investigation of this regimen in ROR1-expressing hematologic and solid malignancies. This study is ongoing, and due to the high CR rate in MCL pts, the number of pts to be enrolled in the Part 2 Expansion will be increased to further characterize the safety and efficacy of this combination. Disclosures Lee: Bristol-Myers Squibb: Consultancy, Research Funding; Aptitude Health: Speakers Bureau; Celgene: Research Funding; Guidepoint Blogal: Consultancy; Oncternal Therapeutics: Research Funding; Seattle Genetics: Research Funding; Takeda: Research Funding. Choi:Pharmacyclics/Abbvie: Research Funding; Genentech: Consultancy. Siddiqi:Juno Therapeutics, Pharmacyclics LLC, an AbbVie Company, AstraZeneca, Celgene, Kite Pharma, and BeiGene: Consultancy; Pharmacyclics LLC, an AbbVie Company, Seattle Genetics, Janssen, and AstraZeneca: Speakers Bureau; BeiGene: Other: DMC member; AstraZeneca: Other: Travel/accommodations/expenses; Astrazenca: Membership on an entity's Board of Directors or advisory committees; PCYC: Membership on an entity's Board of Directors or advisory committees; Juno: Membership on an entity's Board of Directors or advisory committees; Kite: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Pharmacyclics LLC, an AbbVie Company, Juno Therapeutics, KITE Pharma, AstraZeneca, TG Therapeutics, Celgene, Oncternal, and BeiGene: Research Funding. Barrientos:Oncternal Therapeutics: Research Funding; Gilead: Consultancy; AstraZeneca: Consultancy; Bayer: Consultancy; Sandoz: Consultancy; Janssen: Honoraria; Genentech: Consultancy. Lamanna:Octapharma: Research Funding; Pharmacyclics: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bei-Gene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Institutional research grants, Research Funding; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees; Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Institutional research grants, Research Funding; Juno: Other: Institutional research grants, Research Funding; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees; MingSight: Other: Institutional research grants, Research Funding; Oncternal, Verastem, TG Therapeutics: Other: Institutional research grants, Research Funding; Astra Zeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Institutional research grants, Research Funding; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Institutional research grants, Research Funding; Columbia University Medical Center: Current Employment; Loxo: Research Funding. Tuscano:Abbvie: Research Funding; Pharmacyclics: Research Funding; Celgene: Honoraria, Research Funding; Amgen: Honoraria; Seattle Genetics: Honoraria; Novartis: Research Funding; Spectrum: Research Funding; Takeda: Research Funding; Genentech: Research Funding. Leslie:KitePharma: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; AstraZeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Epizyme: Honoraria, Speakers Bureau; Karyopharm: Honoraria, Speakers Bureau; Bayer: Consultancy, Membership on an entity's Board of Directors or advisory committees; ADC therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; TG Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Speakers Bureau; BeiGene: Honoraria, Speakers Bureau; Celgene: Speakers Bureau; Seattle Genetics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Ianopulos:Oncternal Therapeutics, Inc.: Current Employment, Current equity holder in publicly-traded company. Breitmeyer:Oncternal Therapeutics, Inc.: Current Employment, Current equity holder in publicly-traded company, Patents & Royalties. Hsu:Oncternal Therapeutics, Inc.: Current Employment, Current equity holder in publicly-traded company; Immune Design: Ended employment in the past 24 months. Wang:Beijing Medical Award Foundation: Honoraria; Lu Daopei Medical Group: Honoraria; MoreHealth: Consultancy; OMI: Honoraria, Other: Travel, accommodation, expenses; Targeted Oncology: Honoraria; Loxo Oncology: Consultancy, Research Funding; Pulse Biosciences: Consultancy; Kite Pharma: Consultancy, Other: Travel, accommodation, expenses, Research Funding; Juno: Consultancy, Research Funding; BioInvent: Research Funding; VelosBio: Research Funding; Acerta Pharma: Research Funding; InnoCare: Consultancy; Oncternal: Consultancy, Research Funding; Nobel Insights: Consultancy; Guidepoint Global: Consultancy; Dava Oncology: Honoraria; Verastem: Research Funding; Molecular Templates: Research Funding; OncLive: Honoraria; Celgene: Consultancy, Other: Travel, accommodation, expenses, Research Funding; AstraZeneca: Consultancy, Honoraria, Other: Travel, accommodation, expenses, Research Funding; Pharmacyclics: Consultancy, Honoraria, Other: Travel, accommodation, expenses, Research Funding; Janssen: Consultancy, Honoraria, Other: Travel, accommodation, expenses, Research Funding. Jamieson:Bristol-Myers Squibb: Other; Forty Seven Inc: Patents & Royalties. Kipps:VelosBio: Research Funding; Pharmacyclics/ AbbVie, Breast Cancer Research Foundation, MD Anderson Cancer Center, Oncternal Therapeutics, Inc., Specialized Center of Research (SCOR) - The Leukemia and Lymphoma Society (LLS), California Institute for Regenerative Medicine (CIRM): Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Gilead: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Genentech/Roche: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Honoraria, Research Funding; Ascerta/AstraZeneca, Celgene, Genentech/F. Hoffmann-La Roche, Gilead, Janssen, Loxo Oncology, Octernal Therapeutics, Pharmacyclics/AbbVie, TG Therapeutics, VelosBio, and Verastem: Membership on an entity's Board of Directors or advisory committees; Oncternal Therapeutics, Inc.: Other: Cirmtuzumab was developed by Thomas J. Kipps in the Thomas J. Kipps laboratory and licensed by the University of California to Oncternal Therapeutics, Inc., which provided stock options and research funding to the Thomas J. Kipps laboratory, Research Funding.

Background: Ibrutinib (I) and venetoclax (V) have each demonstrated modest single-agent activity in relapsed/refractory follicular lymphoma (FL) (Gopal A, JCO 2018; Davids M, JCO 2017). Preclinical data have shown synergy with these agents in B-cell cell lines (Kuo H, Mol Cancer Ther 2017). Based on these observations, we proposed the first trial to combine I and V in FL. Results from the phase Ib portion of this multi-institutional investigator-initiated trial are presented here (NCT02956382). Methods: This phase Ib/II trial is open at Georgetown/Lombardi CCC, Hackensack/John Theurer CC, and University of Washington/Fred Hutchinson/Seattle Cancer Care Alliance. Eligibility criteria include WHO grade 1-3a FL, >1 prior systemic therapy, measurable disease warranting therapy by standard criteria or physician discretion, ECOG performance status < 2, adequate marrow, hepatic, renal function. Patients (pts) were enrolled in a standard phase I 3+3 design at a starting dose level (DL) of I 420 mg daily, V 400 mg daily (DL0). The highest initially planned dose level was DL3: I 560 mg daily, V 800 mg daily. There was no dose ramp up of V based on monotherapy experience in FL. Pts at high risk for tumor lysis syndrome (TLS), defined as node ≥ 8 cm and/or significant lymphocytosis, were hospitalized for initial dose. Pts received study drugs until progression or unacceptable toxicity. Response was assessed by PET-CT and bone marrow biopsy (if marrow involvement present at time of enrollment). Results: Sixteen pts were enrolled between November 2017 - May 2020. Median age was 66 years (range 50-87); 75% were male; 75% were Stage III/IV, 94% had WHO grade 1/2 FL (Table 1). FLIPI score at enrollment was 25% low risk, 44% intermediate risk, 31% high risk. Two pts were considered high risk for TLS. Pts received a median of 2 prior therapies (range 1-8); 19% were refractory to last line of therapy. Cohort enrollment was: DL0 (n=3), DL1 (n=6), DL2 (n=6), DL3 (n=1). The protocol was amended to close DL3 based on pharmacokinetic data from DL2 indicating a 1.8-fold higher mean steady-state ibrutinib plasma exposure compared to ibrutinib 560 mg monotherapy and concern for potential toxicity. Grade 3 adverse events (AE) included neutropenia (25%), thrombocytopenia (13%), lung infection (13%), upper respiratory infection (6%), neutropenic fever (6%), atrial fibrillation (6%), ALT/AST elevations (6%), mucositis (6%), failure to thrive in setting of progression (6%), abdominal pain (6%). There were no grade 4/5 AE. Grade 1/2 AE occurring in > 20% of pts included diarrhea (75%), nausea (63%), bruising (38%), rash (31%), headache (31%), constipation (25%), fatigue (25%). There was no evidence of clinical TLS; 19% had grade 1 hyperuricemia. The pt enrolled at DL3 had grade 1 diarrhea, grade 1 neutropenia. One dose limiting toxicity (DLT) occurred at DL1 (I 560 mg, V 400 mg): grade 3 neutropenia with fever and infection. There were no other DLTs. Therefore, DL2 (I 560 mg, V 600 mg) was determined to be the recommended phase 2 dose (RP2D). The ORR was 69% (0.413, 0.890); CR 25% (0.073, 0.524). The ORR at the RP2D was 83% (CR 33%). Responses by dose level are listed in Table 2. The regimen demonstrated activity in the bone marrow; 2 pts had eradication of involvement and 1 had a decrease from 60% to 0.5% by flow cytometry. Response by lines of prior therapy: 1 (86%, 6/7), > 2 (56%, 5/9). Most pts (91%) had a response by time of first assessment (12 weeks). The median progression-free survival (PFS) was 8.3 months (5.6 months, NA) (Figure 1). Of note, 2 responding pts chose to withdraw from study due to travel and were censored in the PFS analysis at time of discontinuation. One remained in a CR at least 9 months after study withdrawal as documented by PET-CT performed off protocol. No pts discontinued due to toxicity. Conclusion: In the first clinical trial to combine a BTK inhibitor and a BCL-2 inhibitor in relapsed/refractory FL, we found the I-V doublet to demonstrate a toxicity profile similar to that seen in mantle cell lymphoma and CLL. While our sample size is small, there was no evidence of clinical TLS, despite omission of the V ramp up. Preliminary results of anti-tumor activity are encouraging and further evaluation at the RP2D (I 560 mg, V 600 mg) is ongoing in the phase II trial. The combination of ibrutinib and venetoclax may provide an effective option for FL, utilizing a targeted approach distinct from other novel agents currently approved for this malignancy. Disclosures Ujjani: Verastem Oncology: Consultancy, Honoraria; Genentech: Consultancy, Honoraria; MorphoSys: Consultancy; Atara: Consultancy, Honoraria; AstraZeneca: Consultancy, Honoraria, Research Funding; Abbvie: Consultancy, Honoraria, Research Funding; Gilead/Kite: Consultancy, Research Funding. Lai:Agios: Consultancy; Macrogenics: Consultancy; Astellas: Speakers Bureau; Jazz: Speakers Bureau; Abbvie: Consultancy. Leslie:Seattle Genetics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; KitePharma: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Speakers Bureau; Celgene: Speakers Bureau; BeiGene: Honoraria, Speakers Bureau; Pharmacyclics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; AstraZeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Epizyme: Honoraria, Speakers Bureau; Karyopharm: Honoraria, Speakers Bureau; Bayer: Consultancy, Membership on an entity's Board of Directors or advisory committees; ADC therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; TG Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees. Broome:sanofi: Honoraria; argenx: Honoraria; apellis: Honoraria; Alexion: Honoraria. Gopal:IgM bio, BMS, merck: Research Funding; imab bio, takeda,astrazeneca,gilead: Research Funding; Seattle Genetics; Janssen; IMab Bio; TG Therapeutics; Astra Zeneca; Merck; Gilead; ADC Therapeutics; Nurix; TG therapeutics, Cellectar; Actinium: Consultancy; Seattle Genetics; Janssen; Takeda; IgM Bio; IMab Bio; BMS; Astra Zeneca; Merck; Gilead: Research Funding. Smith:Beigene: Consultancy; Millenium/Takeda: Consultancy; AstraZeneca: Consultancy; Portola: Research Funding; Seattle Genetics: Research Funding; Pharmacyclics: Research Funding; Merck: Research Funding; Incyte: Research Funding; Ignyta: Research Funding; Genentech: Research Funding; De Novo Biopharma: Research Funding; Bristol Meyers Squibb: Research Funding; Ayala: Research Funding; Acerta Pharma BV: Research Funding; AstraZeneca: Research Funding; Bayer: Research Funding; Karyopharm: Consultancy. Till:Mustang: Patents & Royalties, Research Funding. Lynch:Morphosys: Consultancy; Takeda: Research Funding; Bayer: Research Funding; TG therapeutics: Research Funding; Incyte: Research Funding; Juno: Research Funding; Cyteir: Research Funding; Genentech: Research Funding; Rhizen: Research Funding. Shadman:Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; TG therapeutics: Research Funding; Celgene: Research Funding; Sunesis: Research Funding; Gilead: Research Funding; AstraZeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol Meyers Squibb: Consultancy, Membership on an entity's Board of Directors or advisory committees; Verastem: Consultancy, Membership on an entity's Board of Directors or advisory committees; ADC Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees; Atara Biotherapeutics: 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; Cellectar: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Mustang Bio: Research Funding; BeiGene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Acerta Pharma: Ended employment in the past 24 months; MophoSys: Consultancy, Membership on an entity's Board of Directors or advisory committees; Sound Biologics: Consultancy, Membership on an entity's Board of Directors or advisory committees. Maloney:Novartis: Consultancy, Honoraria; Bioline Rx: Consultancy, Honoraria; Juno Therapeutics: Consultancy, Honoraria, Patents & Royalties: Patents are pending, but not issued, licensed, no royalties, no licensees., Research Funding; A2 Biotherapeutics: Consultancy, Current equity holder in publicly-traded company, Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Kite, a Gilead Company: Consultancy, Honoraria, Research Funding; Gilead Sciences: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; MorphoSys: Consultancy, Honoraria; Genentech: Consultancy, Honoraria; Pharmacyclics: Consultancy, Honoraria. Cheson:TG Therapeutics: Speakers Bureau; Symbio: Membership on an entity's Board of Directors or advisory committees; Kite: Consultancy; Karyopharm: Consultancy, Membership on an entity's Board of Directors or advisory committees; Morphosys: Consultancy; Trillium: Research Funding; Abbvie: Consultancy, Research Funding; Jannsen: Consultancy; Pharmacyclics: Consultancy, Research Funding; Parexel: Consultancy; GSK: Membership on an entity's Board of Directors or advisory committees. OffLabel Disclosure: We are presenting data regarding the use of venetoclax and ibrutinib in follicular lymphoma.

Background: Umbralisib is an oral, once-daily, dual inhibitor of phosphatidylinositol-3-kinase-delta (PI3Kδ) and casein kinase-1ε (CK1ε) that exhibits improved selectivity for the delta isoform of PI3K. The UNITY-NHL trial (NCT02793583) is a multicenter, open-label, registration directed Phase 2 study designed to evaluate the safety and efficacy of umbralisib in previously treated NHL patients (pts). Previously reported results in pts with relapsed/refractory (R/R) marginal zone lymphoma (MZL) demonstrated that umbralisib was active with a manageable safety profile. In contrast with other PI3K inhibitors, there was a low incidence of immune-mediated toxicities with umbralisib, possibly attributable to enhanced selectivity for the PI3Kδ isoform as well as inhibition of CK1ε. Herein, we present results from the final analysis of the iNHL population treated with single agent umbralisib. Methods: Eligible pts had histologically confirmed iNHL: MZL (splenic, nodal, extranodal), follicular lymphoma (FL; Gr 1, 2, 3a), or small lymphocytic lymphoma (SLL). MZL pts were R/R to ≥1 prior lines of treatment, which must have included an anti-CD20, while FL and SLL pts were R/R to ≥2 prior lines, which had to include an anti-CD20 and an alkylating agent. Umbralisib was administered orally at 800 mg once-daily in 28-day treatment cycles until disease progression or unacceptable tolerability. The primary endpoint of the study was overall response rate (ORR) as assessed by an independent review committee (IRC), according to the revised IWG criteria (Cheson 2007). Secondary endpoints included duration of response (DoR), progression-free survival (PFS), time to response (TTR), and safety. Pneumocystis jiroveci pneumonia (PCP) and anti-viral prophylaxis were mandated for all pts. Results: 208 iNHL pts received at least 1 dose of umbralisib, including 69 MZL, 117 FL, and 22 SLL pts. The median duration of exposure was 8.4 mos (range 0.2 - 27.0), median age was 66, and 56.7% were male. Pts had received a median of 2 prior regimens (range 1 - 10) with 46.1% having received ≥ 3 regimens. FL patients had a median of 3 prior regimens. With a median follow up of 27.8 mos, MZL pts had an ORR of 49.3% (95% CI 37.0% - 61.6%) with 15.9% achieving a complete response (CR), and a Disease Control Rate (DCR: CR+PR+SD) of 82.6%. ORR was consistent amongst MZL subtypes. The median TTR was 2.8 months (95% CI 2.7 - 2.9). The median profession-free survival (PFS) was not reached (95% CI 12.1 mos - not evaluable [NE]) with an estimated 12-month PFS rate of 64.2%. The median DoR was not reached (95% CI 10.3 mos - NE), and no pts who achieved CR have experienced disease progression to date. With a median follow up of 27.5 mos, FL pts had an ORR of 45.3% (95% CI 36.1% - 54.8%) with 5.1% achieving a CR, and a DCR of 79.5%. The median TTR was 4.6 mos (95% CI 3.0 - 5.6). The median PFS was 10.6 mos (95% CI 7.2 - 13.7) with an estimated 12-month PFS rate of 45.9%. The median DoR was 11.1 mos (95% CI 8.3 - 15.6). With a median follow up of 29.3 mos, SLL pts had an ORR of 50.0% (95% CI 28.2 - 71.8) with 4.5% achieving a CR, and a DCR of 86.4%. The median TTR was 2.7 mos (95% CI 2.4 - 2.8). The median PFS was 20.9 mos (95% CI 7.4 - 24.1) with an estimated 12-month PFS rate of 62.6%. The median DoR was 18.3 mos (95% CI 2.4 - NE). Best % change in target lesions form baseline for pts with at least one post-baseline assessment is shown in the figure. At the data cut-off, 60 pts (26 MZL, 27 FL, 7 SLL) remained on treatment. The most common ≥G3 AEs were neutropenia (11.5%), diarrhea (10.1%) and increased ALT/AST (7.2%). Other AEs of interest included pneumonitis (All G 1.4%; ≥G3 1.0%), and colitis (All G 1.4%; ≥G3 0.5%). Serious AEs were reported in 28.1% of pts, with 24.6% ≥G3. One patient with SLL had a fatal myocardial infarction (unrelated to umbralisib); there were no other G5 AEs. A total of 31 pts (14.9%) discontinued due a treatment-related adverse event (AE). Treatment-related AEs leading to dose reductions occurred in 20 (9.6%) pts. Conclusions: In the Phase 2 UNITY-NHL study, umbralisib achieved meaningful clinical activity in a heavily pretreated iNHL population. The safety profile was manageable, with a relatively low incidence of immune-mediated toxicities and AE-related discontinuations. These results suggest umbralisib has a favorable benefit-risk profile in this patient population and further development is ongoing. Figure Disclosures Zinzani: Kirin Kyowa: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Merck: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Kyowa Kirin: Consultancy, Speakers Bureau; MSD: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; ADC Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Immune Design: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Portola: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Eusapharma: Consultancy, Speakers Bureau; Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; TG Therapeutics, Inc.: Honoraria, Speakers Bureau; Servier: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Immune Design: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Verastem: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen-Cilag: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; EUSA Pharma: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sanofi: Consultancy, Membership on an entity's Board of Directors or advisory committees; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Consultancy, Honoraria, Speakers Bureau; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sandoz: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celltrion: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Jurczak:Sandoz-Novartis: Consultancy; Afimed: Research Funding; Acerta: Consultancy, Research Funding; Pharmacyclics: Research Funding; Bayer: Research Funding; Maria Sklodowska-Curie National Research Institute of Oncology, Krakow, Poland: Current Employment; TG Therapeutics, Inc.: Research Funding; Celgene: Research Funding; Servier: Research Funding; Takeda: Research Funding; Roche: Research Funding; Merck: Research Funding; MEI Pharma: Research Funding; Janssen China R&D: Consultancy, Research Funding; BeiGene: Consultancy, Research Funding; AstraZeneca: Consultancy; European Medicines Agency,: Consultancy; Jagiellonian University, Krakow, Poland: Ended employment in the past 24 months; Epizyme: Consultancy; Gilead Sciences: Research Funding; MorphoSys: Research Funding; Nordic Nanovector: Research Funding. Ghosh:Kite/Gilead: Consultancy, Speakers Bureau; Juno/Celgene/Bristol-Myers Squibb: Consultancy, Research Funding; Pharmacyclics LLC, an AbbVie Company: Consultancy, Research Funding, Speakers Bureau; SGN: Consultancy, Research Funding, Speakers Bureau; TG Therapeutics: Consultancy, Research Funding; Roche/Genentech: Research Funding; Karyopharm: Consultancy; Genmab: Consultancy, Speakers Bureau; AbbVie: Speakers Bureau; AstraZeneca: Speakers Bureau; Celgene/Bristol-Myers Squibb: Speakers Bureau; Forty Seven Inc: Consultancy, Other: Research Bureau, Research Funding; Janssen: Consultancy, Research Funding, Speakers Bureau. Derenzini:TG Therapeutics, Inc.: Research Funding. Cheah:Celgene, F. Hoffmann-La Roche, MSD, Janssen, Gilead, Ascentage Pharma, Acerta, Loxo Oncology, TG therapeutics: Honoraria; Celgene, F. Hoffmann-La Roche, Abbvie, MSD: Research Funding. Phillips:Karyopharm: Consultancy; Beigene: Consultancy; Seattle Genetics: Consultancy; BMS: Consultancy; Abbvie: Consultancy, Research Funding; AstraZeneca: Consultancy; Incyte: Consultancy, Other: travel expenses; Cardinal Health: Consultancy; Bayer: Consultancy, Research Funding; Pharmacyclics: Consultancy. Lech-Marańda:Roche, Amgen, Gilead: Speakers Bureau; Roche, Novartis, Takeda, Janssen-Cilag, Amgen, Gilead, AbbVie, Sanofi: Consultancy. Cheson:Abbvie: Consultancy, Research Funding; Kite: Consultancy; TG Therapeutics: Speakers Bureau; Morphosys: Consultancy; Symbio: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Consultancy, Research Funding; Jannsen: Consultancy; Parexel: Consultancy; Trillium: Research Funding; GSK: Membership on an entity's Board of Directors or advisory committees. Caimi:Verastem: Other: Advisory Board; Celgene: Speakers Bureau; Amgen: Other: Advisory Board; Bayer: Other: Advisory Board; Kite Pharma: Other: Advisory Board; ADC Therapeutics: Other: Advisory Board, Research Funding. Leslie:BeiGene: Honoraria, Speakers Bureau; KitePharma: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Seattle Genetics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pharmacyclics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Speakers Bureau; Celgene: Speakers Bureau; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; TG Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; ADC therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bayer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Karyopharm: Honoraria, Speakers Bureau; Epizyme: Honoraria, Speakers Bureau; AstraZeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Chavez:Karyopharm: Consultancy; BeiGene: Speakers Bureau; Bayer: Consultancy; Merck: Research Funding; AbbVie: Consultancy; Genentech: Speakers Bureau; Epizyme: Speakers Bureau; Gilead: Consultancy; Novartis: Consultancy; Kite, a Gilead Company: Consultancy, Speakers Bureau; Celgene: Consultancy; Morphosys: Consultancy, Speakers Bureau; AstraZeneca: Speakers Bureau; Verastem: Consultancy; Pfizer: Consultancy. Fonseca:Bristol-Myers Squibb Company: Speakers Bureau. Babu:Merck: Research Funding; Syndax: Research Funding; AbbVie: Research Funding; Janssen Oncology: Research Funding; TG Therapeutics: Research Funding; Amgen: Research Funding; Sanofi: Research Funding; Lutheran Hospital: Other; Argenx: Consultancy, Research Funding; Nektar: Research Funding; Novartis: Research Funding; Bayer: Honoraria; Lilly: Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding; Alexion Pharmaceuticals: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding, Speakers Bureau; Bristol-Myers Squibb: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding; Fort Wayne Medical Oncology & Hematology: Current Employment, Current equity holder in publicly-traded company; AstraZeneca/MedImmune: Research Funding; AstraZeneca: Consultancy, Honoraria; Genentech, Inc./ F. Hoffmann-La Roche: Research Funding; Boehringer Ingelheim: Consultancy. Hodson:Gilead Sciences: Research Funding. Burke:Bristol Myers Squibb: Consultancy; Verastem: Consultancy; Bayer: Consultancy; Astra Zeneca: Consultancy; Gilead: Consultancy; Seattle Genetics: Speakers Bureau; AbbVie: Consultancy; Morphosys: Consultancy; Adaptive: Consultancy; Epizyme: Consultancy; Kura: Consultancy; Celgene: Consultancy; Adaptive Biotechnologies: Consultancy; Roche: Consultancy. Sharman:TG Therapeutics: Consultancy, Research Funding; Bristol Meyers Squibb: Consultancy, Research Funding; BeiGene: Research Funding; Genentech: Consultancy, Research Funding; AbbVie: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Pharmacyclics: Consultancy, Research Funding; AstraZeneca: Consultancy, Research Funding; Acerta: Consultancy, Research Funding; Roche: Consultancy, Research Funding; Celgene: Consultancy, Research Funding. O'Connor:Kymera Therapeutics: Current equity holder in private company, Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Other: Data Safety Monitoring Committee, Research Funding; TG Therapeutics: Current Employment, Current equity holder in publicly-traded company; Servier: Consultancy; Mundipharma: Other: Consulting; Nomocan: Membership on an entity's Board of Directors or advisory committees; Merck: Research Funding; Astex Pharmaceuticals: Honoraria, Research Funding. Miskin:TG Therapeutics, Inc.: Current Employment, Current equity holder in publicly-traded company. Sportelli:TG Therapeutics, Inc.: Current Employment, Current equity holder in publicly-traded company. Weiss:TG Therapeutics, Inc.: Current Employment, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees. Fowler:Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Research Funding; TG Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding.

Background: Patients with advanced-stage iNHL, including follicular lymphoma (FL) and marginal zone lymphoma (MZL), frequently relapse with standard treatment, underscoring a need for novel therapies. Axi-cel autologous anti-CD19 chimeric antigen receptor (CAR) T cell therapy is approved for the treatment of R/R large B cell lymphoma after ≥ 2 lines of systemic therapy. Here, we present the primary analysis of ZUMA-5, a Phase 2, multicenter, single-arm study of axi-cel in patients with R/R iNHL. Methods: Adults with FL (Grades 1-3a) or MZL (nodal or extranodal) had R/R disease after ≥ 2 lines of therapy (must include an anti-CD20 mAb plus an alkylating agent), and ECOG 0 - 1. Patients underwent leukapheresis followed by conditioning therapy (cyclophosphamide/fludarabine) and a single infusion of axi-cel at 2 × 106 CAR T cells/kg. The primary endpoint was objective response rate (ORR) by central review (per Lugano classification; Cheson, et al. J Clin Oncol. 2014). Secondary endpoints included complete response (CR) rate, duration of response (DOR), progression-free survival (PFS), overall survival (OS), incidence of adverse events (AEs), and levels of CAR T cells in blood and cytokines in serum. The primary efficacy analysis occurred when ≥ 80 treated patients with FL had ≥ 12-months follow-up. Results: As of 3/12/2020, 146 patients with iNHL (124 FL; 22 MZL) received axi-cel; 84 patients with FL had ≥ 12-months follow-up. The median age was 61 years (range, 34 - 79); 57% of patients were male. Thirty-eight percent of patients had ECOG 1, 86% had stage III/IV disease, 47% had ≥ 3 FLIPI, and 49% had high tumor bulk (GELF). Patients had a median 3 prior lines of therapy (range, 1 - 10); 64% had ≥ 3 prior lines. Progression < 2 years after initial chemoimmunotherapy (POD24) occurred in 55% of patients, and 68% were refractory to last prior treatment. Axi-cel was successfully manufactured for all enrolled patients. With a median follow-up of 17.5 months (range, 1.4 - 31.6), the ORR was 92% among efficacy-evaluable patients with iNHL (n = 104), with a 76% CR rate. In patients with FL (n = 84), the ORR was 94% (80% CR rate); in those with MZL (n = 20), the ORR was 85% (60% CR rate). ORR was comparable across key risk groups analyzed by FLIPI, POD24, GELF, refractory status, and prior lines of therapy. As of the data cutoff, 62% of all treated patients had ongoing responses (64% for FL). The medians for DOR, PFS, and OS were not reached; 12-month estimated rates were 72% (95% CI, 61 - 80), 74% (95% CI, 63 - 82), and 93% (95% CI, 86 - 97), respectively. AEs of any grade occurred in 99% of all treated patients. Grade ≥ 3 AEs occurred in 86% of patients with iNHL (85% in FL; 95% in MZL), most commonly neutropenia (33%), decreased neutrophil count (27%), and anemia (23%). Grade ≥ 3 cytokine release syndrome (CRS; per Lee, et al, Blood. 2014) occurred in 7% of patients with iNHL (6% in FL; 9% in MZL). Grade ≥ 3 neurologic events (NEs; per CTCAE v4.03) occurred in 19% of patients with iNHL (15% in FL; 41% in MZL). Most CRS (118/119) and NEs (81/87) of any grade resolved by data cutoff. Grade 5 AEs occurred in 3 patients: multisystem organ failure in the context of CRS (Day 7; related to axi-cel; n = 1 FL), aortic dissection (Day 399; unrelated to axi-cel; n = 1 FL), and coccidioidomycosis infection (Day 327; unrelated to axi-cel; n = 1 MZL). The median peak CAR T cell level was 38 cells/µL (range, 0 - 1415) in all treated patients with iNHL, with 36 cells/µL (range, 0 - 1415) in those with FL and 53 cells/µL (range, 2 - 453) in those with MZL. The AUC0 - 28 was 448 cells/µL × days (range, 6 - 19,900) in all treated patients with iNHL, with 422 cells/µL × days (range, 6 - 19,900) and 552 cells/µL × days (range, 13 - 6468) in those with FL and MZL, respectively. The median time to peak was 9 days (range, 8 - 371) in all patients, 8 days (range, 8 - 371) in patients with FL, and 15 days (range, 8 - 29) in patients with MZL. In efficacy-evaluable patients with FL, median peak CAR T cell levels were numerically greater in those with ongoing response at 12 months than in those who relapsed (P = .057). In all treated patients with FL, CAR T cell peak was associated with Grade ≥ 3 CRS (P = .031) and NEs (P = .005). Conclusions: Axi-cel had considerable and durable clinical benefit in patients with iNHL, with high ORR and CR rates. Axi-cel had a manageable safety profile, with lower rates of Grade ≥ 3 NEs observed in patients with FL vs those in patients with MZL and those previously reported in aggressive NHL (Locke, et al. Lancet Oncol. 2019). Disclosures Chavez: Genentech: Speakers Bureau; Epizyme: Speakers Bureau; Gilead: Consultancy; Verastem: Consultancy; Novartis: Consultancy; Kite, a Gilead Company: Consultancy, Speakers Bureau; Pfizer: Consultancy; Celgene: Consultancy; AstraZeneca: Speakers Bureau; Morphosys: Consultancy, Speakers Bureau; Merck: Research Funding; Bayer: Consultancy; BeiGene: Speakers Bureau; Karyopharm: Consultancy; AbbVie: Consultancy. Sehgal:Juno Therapeutics: Research Funding; TP Therapeutics: Research Funding; Prothena: Research Funding; Gilead Sciences: Research Funding; Bristol-Myers Squibb: Research Funding; Merck: Research Funding. William:Celgene: Consultancy, Honoraria; Incyte: Research Funding; Seattle Genetics: Research Funding; Merck: Research Funding; Dova: Research Funding; Guidepoint Global: Consultancy; Kyowa Kirin: Consultancy, Honoraria. Munoz:Incyte: Research Funding; Fosunkite: Consultancy; Innovent: Consultancy; Acrotech/Aurobindo: Speakers Bureau; Verastem: Speakers Bureau; AstraZeneca: Speakers Bureau; Genentech/Roche: Research Funding, Speakers Bureau; AbbVie: Consultancy, Speakers Bureau; Kyowa: Consultancy, Honoraria, Speakers Bureau; Seattle Genetics: Consultancy, Honoraria, Research Funding, Speakers Bureau; Pharmacyclics: Consultancy, Research Funding, Speakers Bureau; Bayer: Consultancy, Research Funding, Speakers Bureau; Kite, a Gilead Company: Consultancy, Research Funding, Speakers Bureau; Pfizer: Consultancy; Janssen: Consultancy, Research Funding, Speakers Bureau; Juno/Celgene/BMS: Consultancy, Research Funding, Speakers Bureau; Alexion: Consultancy; Beigene: Consultancy, Speakers Bureau; Merck: Research Funding; Portola: Research Funding; Millenium: Research Funding. Salles:BMS/Celgene: Honoraria, Other: consultancy or advisory role; Kite, a Gilead Company: Honoraria, Other: consultancy or advisory role ; Epizyme: Honoraria, Other: consultancy or advisory role; Janssen: Honoraria, Other: consultancy or advisory role; MorphoSys: Honoraria, Other: consultancy or advisory role; Novartis: Honoraria, Other: consultancy or advisory role; Roche: Honoraria, Other: consultancy or advisory role; Abbvie: Other: consultancy or advisory role; Autolos: Other: consultancy or advisory role; Debiopharm: Consultancy, Honoraria, Other: consultancy or advisory role; Genmab: Honoraria, Other; Karyopharm: Honoraria; Takeda: Honoraria. Munshi:Kite, a Gilead Company: Honoraria, Speakers Bureau; Incyte: Honoraria, Speakers Bureau. Maloney:Celgene: Consultancy, Honoraria, Research Funding; Bioline Rx: Consultancy, Honoraria; Juno Therapeutics: Consultancy, Honoraria, Patents & Royalties, Research Funding; Gilead Science: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; A2 Biotherapeutics: Consultancy, Current equity holder in publicly-traded company, Honoraria; Genentech: Consultancy, Honoraria. de Vos:Bayer: Consultancy; Verastem: Consultancy. Reshef:Kiadis: Research Funding; Monsanto: Consultancy; Novartis: Honoraria; Magenta: Consultancy; Atara: Consultancy, Research Funding; Celgene: Consultancy; Bristol-Myers Squibb: Research Funding; Takeda: Research Funding; Incyte: Research Funding; Pharmacyclics: Research Funding; Immatics: Research Funding; Shire: Research Funding; Bluebird: Research Funding; Gilead: Consultancy, Honoraria, Other: Travel support, Research Funding. Leslie:Epizyme: Honoraria, Speakers Bureau; Karyopharm: Honoraria, Speakers Bureau; Bayer: Consultancy, Membership on an entity's Board of Directors or advisory committees; ADC therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; TG Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Speakers Bureau; BMS: Speakers Bureau; KitePharma: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BeiGene: Honoraria, Speakers Bureau; Pharmacyclics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; AstraZeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Yakoub-Agha:Celgene: Honoraria; Novartis: Honoraria; Gilead/Kite: Honoraria, Other: travel support; Janssen: Honoraria; Jazz Pharmaceuticals: Honoraria. Oluwole:Bayer: Consultancy; Spectrum Pharmaceuticals: Consultancy; Pfizer: Consultancy; Kite, a Gilead Company: Consultancy, Honoraria, Research Funding. Fung:AstraZeneca: Honoraria, Other: speakers' bureau, travel support; Genentech: Honoraria, Other: speakers' bureau, travel support; AbbVie: Honoraria, Other: speakers' bureau, travel support; Kite, a Gilead Company: Honoraria, Other: speakers' bureau, travel support; Sanotif: Honoraria, Other: speakers' bureau, travel support; Takeda: Honoraria, Other: speakers' bureau, travel support; Janssen Oncology: Honoraria, Other: speakers' bureau, travel support. Rosenblatt:Merck: Other: consultancy or advisory role ; Biograph55: Other: consultancy or advisory role, Research Funding; Synergy: Patents & Royalties; University of Miami: Other: Leadership. Rossi:Kite, a Gilead Company: Current Employment; Gilead Sciences: Current equity holder in publicly-traded company. Goyal:Kite, a Gilead Company: Current Employment. Plaks:Kite, a Gilead Company: Current Employment, Other: travel support; Gilead Sciences: Other: stock or other ownership . Yang:Kite, a Gilead Company: Current Employment. Lee:Kite, a Gilead Company: Current Employment; Gilead Sciences: Current equity holder in publicly-traded company. Godfrey:IGM Biosciences: Current Employment, Current equity holder in publicly-traded company. Vezan:Kite, a Gilead Company: Current Employment, Honoraria, Other: Travel support; Abbvie: Current equity holder in publicly-traded company; Merck: Current equity holder in publicly-traded company. Avanzi:Kite, a Gilead Company: Current Employment, Other: travel support; Gilead Sciences: Other: stock or other ownership ; MSKCC: Patents & Royalties. Neelapu:N/A: Other; Calibr: Other; Poseida: Research Funding; Cellectis: Research Funding; Merck: Other: personal fees, Research Funding; Kite, a Gilead Company: Other: personal fees, Research Funding; Adicet Bio: Other; Legend Biotech: Other; Precision Biosciences: Other: personal fees, Research Funding; Incyte: Other: personal fees; Cell Medica/Kuur: Other: personal fees; Allogene Therapeutics: Other: personal fees, Research Funding; Pfizer: Other: personal fees; Celgene: Other: personal fees, Research Funding; Novartis: Other: personal fees; Bristol-Myers Squibb: Other: personal fees, Research Funding; Unum Therapeutics: Other, Research Funding; Karus Therapeutics: Research Funding; Acerta: Research Funding; Takeda Pharmaceuticals: Patents & Royalties.

Introduction: Interleukin-1 receptor-associated kinase 4 (IRAK4) is essential for toll-like receptor (TLR) and interleukin-1 receptor (IL-1R) signaling in immune cells including B lymphocytes. It forms the Myddosome complex with the MYD88 adaptor protein, with IRAK4 being essential for downstream signaling, maximal activation of NFkB with inflammatory and immune response and tumor promotion [Treon 2012; Rhyasen 2015]. CA-4948 is a novel small molecule, oral inhibitor of IRAK4, first-in-class and only suppressor of the TLR pathway currently tested in hematological malignancies. When combined with the BTK inhibitor ibrutinib that blocks parallel BCR signaling and NF-kB activating pathway, it has shown synergy in in-vivo B-cell NHL models, providing strong rationale for clinical evaluation [Booher 2018]. Recent preclinical studies demonstrated the role of IRAK4 activation as a driver of secondary, adaptive tumor resistance and survival mechanisms of hematological and solid tumor malignancies [Melgar 2019] that could be blocked by CA-4948 to delay or reverse resistance. Study Design and Methods: This is a multicenter, open-label trial of oral CA-4948 combined with ibrutinib in adult patients with relapsed or refractory hematologic malignancies. (NCT03328078). It has 2 parts: a dose escalation (Part A2), and expansion basket of 4 cohorts (Part B). Part A2: Is a truncated 3+3 design: CA-4948 starting is 200 mg BID with subsequent escalation to 300 mg BID. Both dose are safe and active against NHL as seen in the nearly completed monotherapy Part A1 of this trial Patients will receive CA-4948 with ibrutinib at the labeled dose for the respective NHL subtype (560 mg or 420 mg) until toxicity or progression. Primary objectives are safety/tolerance (MTD, RP2D); 2nd objectives are pharmacokinetics and preliminary efficacy; exploratory objectives include biomarker correlations (e.g., MYD88-L265P mut, IRAK4 pathway, NFκB inhibition). Part B basket has four cohorts: 1 -MZL, 2 - ABC-DLBCL, 3 - PCNSL, and 4 - NHL with adaptive ibrutinib resistance. Cohorts 1-3 must be BTK-inhibitor naïve. Cohort 4 includes ibrutinib treated NHLs after developing adaptive, secondary resistance. All will receive the combination of ibrutinib and CA-4948. Cohort 4 patients will be allowed a Samples sizes, statistical considerations: Approx. 18 patients in Part A2. In Part B, a Simon 2-Step design will be applied to each cohort. Early stopping rule for futility after approx. 20 patients in Stage 1: full accrual with Stage 2 will add about 25 patients. Successful signal efficacy identification in a cohort may support further expansion or a subsequent controlled trial. The safety population will include all patients in the study who received any test dose. The efficacy population will have a valid baseline and post-baseline disease assessment. Safety assessments include TEAEs, safety labs, vitals, physical exams, PK, and ECGs; efficacy assessments: tumor imaging, para-protein determination, and histo/cyto-morphologic examinations. Part A2 inclusion: Histopathologically confirmed B-cell NHL as per the WHO 2016 classification. Eligible NHL subtypes: FL, MZL, MCL, DLBCL (including extranodal lymphomas of leg, testicle, or other sites, excluding mediastinal lymphoma), CLL/SLL, primary or secondary CNS lymphoma, and WM/LPL. Patients with FL, MCL, MZL, WM/LPL, or CLL/SLL should meet clinical treatment criteria. Part B inclusion: Cohorts 1-3 include patients with MZL, ABC-DLBCL, or PCNSL who are BTK-inhibitor naïve. Cohort 4 will include ibrutinib pre-treated MCL, MZL, CLL/SLL, WM/LPL, ABC-DLBCL, or PCNSL with adaptive resistance. Exclusions for both Parts A2 and B: Significant acute or chronic toxicity from prior anti-cancer therapy that has not resolved to Grade ≤ 1, as determined by NCI CTCAE v 4.03 within 7 days prior to start of study or serious co-morbidities. Disclosures Nowakowski: NanoString: Research Funding; Seattle Genetics: Consultancy; Curis: Consultancy; Kymera: Consultancy; Kite: Consultancy; Celgene/BMS: Consultancy, Research Funding; MorphoSys: Consultancy, Research Funding; Ryvu: Consultancy, Membership on an entity's Board of Directors or advisory committees. Leslie:TG Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene/BMS: Speakers Bureau; Seattle Genetics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; KitePharma: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BeiGene: Speakers Bureau; Pharmacyclics/Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; AstraZeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Epizyme: Speakers Bureau; Karyopharm: Speakers Bureau; Bayer: Consultancy, Membership on an entity's Board of Directors or advisory committees; ADC therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees. Joffe:AstraZeneca: Membership on an entity's Board of Directors or advisory committees; Epizyme: Membership on an entity's Board of Directors or advisory committees. Lunning:Kite: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; TG Therapeutics: Research Funding; Verastem: Consultancy, Honoraria; Acrotech: Consultancy; ADC Therapeutics: Consultancy; Legend: Consultancy; Janssen: Consultancy, Honoraria; Karyopharm: Consultancy, Honoraria; Curis: Research Funding; Gilead: Consultancy, Honoraria; Beigene: Consultancy, Honoraria; Aeratech: Consultancy, Honoraria; Bristol Meyers Squibb: Consultancy, Honoraria, Research Funding; AstraZeneca: Consultancy, Honoraria. Patel:Adaptive Biotechnologies: Consultancy; Kite: Consultancy; BeiGene: Consultancy; AstraZeneca: Consultancy, Research Funding, Speakers Bureau; Pharmacyclics: Consultancy, Speakers Bureau; Celgene/BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Speakers Bureau; Genentech: Consultancy, Speakers Bureau. Landsburg:Takeda: Research Funding; Triphase: Research Funding; Seattle Genetics: Speakers Bureau; Morphosys: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Curis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees. Fenske:Medical College of Wisconsin: Current Employment. Ramchandren:Merck, Seattle Genetics, Janssen, Genentech: Research Funding; Seattle Genetics, Sandoz-Novartis, Pharmacyclics, an AbbVie Company, Janssen, Bristol-Myers Squibb: Consultancy. Skarbnik:Alexion: Consultancy; Beigene: Speakers Bureau; Verastem: Speakers Bureau; CLL Society: Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Speakers Bureau; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Kite Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pharmacyclics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Tun:Bristol-Myers Squibb: Research Funding; Celgene: Research Funding; Mundipharma: Research Funding; Curis: Research Funding; TG Therapeutics: Research Funding; Acrotech: Research Funding; DTRM Biopharma: Research Funding.

Introduction. The diagnosis of B-cell lymphoma, unclassifiable, with features intermediate between diffuse large B-cell lymphoma (DLBCL) and classical Hodgkin’s lymphoma (cHL), also referred to as grey zone lymphoma (GZL), is a challenging diagnosis. There are no standardized guidelines; however, evidence strongly suggests that DLBCL-based regimens are effective in the treatment of GZL. Brentuximab vedotin (BV) is an anti-CD30 antibody drug conjugate that has established efficacy in relapsed/refractory Hodgkin and some T-cell lymphomas. There is some evidence that BV has a positive response in non-Hodgkin lymphoma (NHL) with a wide range of CD30 expressions—including GZL.Case. We present a case of a patient initially diagnosed with cHL who underwent repeat biopsy which was revealed to be GZL. Based on PET scanning and immunohistochemical studies, she was classified as a stage IIIA CD20+/CD30+ GZL patient. Given her strong CD30 expression, she underwent 6 cycles of R-BV-CHP (rituximab, brentuximab vedotin, cyclophosphamide, doxorubicin, and prednisone) chemotherapy and achieved complete response (CR) both clinically and radiographically.Discussion. Given the rarity of GZL, this case illustrates the immense challenges in making the diagnosis, discusses the current treatment options, and suggests that BV may be a viable therapeutic candidate in the treatment of GZL.

7556 Background: Cirmtuzumab (Cirm) is a humanized monoclonal antibody that inhibits the tumor promoting activity of ROR1 and had demonstrated additive/synergistic activity with many anti-cancer agents including ibrutinib (Ibr). Methods: Patients (Pts) with relapsed or refractory (RR) MCL or treatment naïve (TN) or RR CLL were enrolled. In Part 1 (Dose Escalation), doses of Cirm IV q2wks x5 then q4wks of 2-16 mg/kg and 300 or 600 mg were examined. Safety of Cirm alone was assessed during the first 28 days, then Ibr was started at approved doses for each indication. Cirm 600 mg IV q2wks x3 then q4wks in combination with Ibr starting day 0 was chosen as the recommended dosing regimen for use in Part 2 (Expansion) and Part 3 (CLL only, Cirm/Ibr vs. Ibr alone). Results: Twelve evaluable MCL pts were enrolled into Part 1, and 5 into Part 2. Median number of prior regimens was 2 (1-5), including pts relapsing after Ibr (4), auto-SCT (3), auto-SCT/ allo-SCT (1), auto-SCT/CAR-T (1). In CLL, 34 evaluable pts (12 TN and 22 RR) enrolled into Part 1 (18) or Part 2 (16). At least 74% of CLL pts in Parts 1 and 2 were high risk as determined by unmutated IGHV, del17p, and/or del11q. In Part 3, 22 evaluable pts received Cirm/Ibr (15) or Ibr (7). As of the 30OCT2020 safety cut-off for MCL and CLL, common TEAEs (all grades) included diarrhea (41%), contusion (39%), fatigue (39%), URI (31%), hypertension (25%) arthralgia (23%). Grade ≥3 neutropenia was 13% and thrombocytopenia 1%. There were no Cirm dose reductions or discontinuations for toxicity. Overall, Cirm did not appear to negatively impact the safety of Ibr. Efficacy (MCL): As of the 02FEB2021 efficacy cutoff, the best response of 17 evaluable pts in Parts 1 and 2 included an objective response rate (ORR) of 82%, 41% CR/CMR, 41% PR, 12% SD, and 6% PD. CR/CMR remain durable from 8-28+ mos. Most responses occurred rapidly after ̃3 mos of Cirm/Ibr. Notably, responses were achieved in all pts who received prior SCT+/- CAR-T (4CR, 1PR) or prior Ibr (2CR, 2PR). At a median follow-up of 14.6 mos, the median PFS (mPFS) had not been reached (NR) (95% CI: 17.5, NA). Efficacy (CLL): The best response of 34 evaluable pts in Parts 1 and 2 included 91% ORR, 3% CR, 88% PR/PR-L, 9% SD, 0% PD. In Part 3, both arms achieved 100% ORR (all PRs). At a median follow-up of 20.2 mos, the mPFS was NR (95% CI: NA, NA), and the PFS estimate at 24 months was 95% for R/R, and 87% for TN, respectively, for evaluable CLL pts receiving Cirm/Ibr. Conclusions: Cirm/Ibr is a well-tolerated, active regimen in both MCL and CLL. For MCL, the mPFS of NR (95% CI: 17.5, NA) and CRR (41%), with all CRs remaining without PD, compare favorably to mPFS of 12.8 mos (95% CI 8.5-16.6) and CRR (20%) reported for single agent Ibr (Rule 2017). For CLL, the high ORR and PFS are encouraging, particularly for RR CLL. The study is ongoing, with MCL enrollment expanded to study Cirm + Ibr in pts who have had a suboptimal response to an Ibr regimen, or who have failed other approved BTKi agents. Clinical trial information: NCT03088878.

e19505 Background: In patients with CLL/SLL, high risk genetic abnormalities are associated with inferior responses to CIT, and the economic burden of this remains uncertain. This study aimed to compare real world clinical and economic outcomes in high risk and perceived non-high risk patients initiating 1L CIT. Methods: This retrospective cohort study identified patients with CLL/SLL from the HealthCore Integrated Research Database representing a national managed care population with over 58 million members. Medical records were obtained for eligible patients who initiated 1L CIT between 1/1/2007 and 7/31/2019 and underwent prognostic testing to classify them as high risk (HR: del17p, TP53 mutation, del11q or unmutated IGHV) or as non-high risk by FISH only (NHR: non-del17p and non-del11q). The first CIT claim date was the index date. Patients were required to have ≥12 months of pre-index and ≥30 days of post-index eligibility. Study outcomes included testing rate, time to next treatment (NT) or death, time to treatment failure (TF; defined as time to change of therapy, non-chemotherapy intervention, hospice care or death), and total plan paid costs (medical + pharmacy) per patient per month (PPPM) in the 1L period. Cox proportional hazard models and generalized linear models were used to calculate adjusted hazard ratio or rate ratio. Results: Among the 1,808 patients with CLL/SLL, 612 were FISH or IGHV tested and the rate of testing increased from 2007 to 2019 (30% to 44%), especially after adding ibrutinib for 1L CLL with del17p in NCCN guidelines v4.2014. Risk status was available for 253 patients (HR: 119; NHR: 134), with 80% of patients initiating 1L BR/FCR-based therapy in both cohorts. Median follow up was 26.4 vs. 25.8 months (HR vs NHR). HR patients had 65% higher risk of NT/death (median time: 2.4 vs 3.7 years), and 65% higher risk of TF (median time: 3.0 vs 4.9 years) compared to NHR patients (Table). The total costs PPPM were also significantly higher for HR patients in the 1L period ($12,194 vs $9,055, p=0.027; Rate Ratio=1.33, p

7515 Background: POD24 is an indicator of poor survival in iNHL (Casulo & Barr. Blood. 2019). In the ZUMA-5 Phase 2 study of axi-cel anti-CD19 CAR T-cell therapy in pts with R/R iNHL, overall response rates (ORR) after 17.5 months median follow-up were similarly high in those with and without POD24 (93% and 92%; Jacobson et al. ASH 2020. #700). Here, we report updated outcomes with longer follow-up in pts with POD24 in ZUMA-5. Methods: Adults with R/R follicular lymphoma (FL) or marginal zone lymphoma (MZL) after ≥2 lines of therapy underwent leukapheresis followed by conditioning therapy and axi-cel infusion (2×106 CAR T cells/kg). Axi-cel–treated pts with available data on progression after an anti-CD20 mAb + alkylating agent were included. The updated efficacy analysis occurred when ≥80 treated pts with FL had ≥18 months follow-up. Results: Of 129 pts at baseline, 81 pts (63%; 68 FL, 13 MZL) had POD24 and 48 pts (37%; 40 FL, 8 MZL) did not have POD24. Median prior lines of therapy in pts with and without POD24 were 3 and 3.5, respectively. High-risk characteristics of pts with and without POD24 included stage III/IV disease, 83% and 94%; ≥3 FLIPI, 44% and 43%; high tumor bulk (GELF), 51% and 44%; and refractory disease, 77% and 63%, respectively. With 23.3 months median follow-up, ORR among efficacy-evaluable pts with POD24 (n = 61) and without POD24 (n = 37) was 92% each (complete response rates, 75% and 86%). At data cutoff, 52% of pts with POD24 and 70% without POD24 had ongoing responses. Median duration of response, progression-free survival, and overall survival were not reached in pts with and without POD24; 18-month estimated rates were 60% and 78%, 55% and 84%, and 85% and 94%, respectively. Incidences of Grade ≥3 adverse events were similar in pts with and without POD24 (84% and 88%), including cytopenias (69% and 65%) and infections (15% and 21%). Grade ≥3 cytokine release syndrome (CRS) occurred in 9% and 2% of pts with and without POD24, respectively; Grade ≥3 neurologic events (NEs) occurred in 17% of pts each. Median times to onset were similar in pts with and without POD24 for CRS (4 days each) and NEs (8 days and 7 days); median durations of CRS (7 days and 5 days) and NEs (11 days and 13 days) were also similar between groups. In efficacy-evaluable pts with FL, median peak CAR T-cell levels were similar in pts with and without POD24 (35.8 cells/μL and 34.5 cells/μL). Peak levels of key inflammatory biomarkers and axi-cel product attributes were generally similar in pts with and without POD24. Conclusions: Axi-cel showed a high rate of durable responses in pts with POD24 iNHL, a population with high-risk disease. Efficacy results, as well as safety and pharmacological profiles, appeared largely comparable between groups, with the exception of PFS rates. Clinical trial information: NCT03105336.

Objective: Here, we report interim results from ZUMA-5, a Phase 2 study of axi-cel, an autologous anti-CD19 chimeric antigen receptor (CAR) T cell therapy, in patients with relapsed/refractory iNHL. Design: Adults with relapsed/refractory follicular lymphoma (FL) or marginal zone lymphoma (MZL) after ≥2 lines of therapy (including an anti-CD20 monoclonal antibody with an alkylating agent) were eligible. Patients were leukapheresed and received conditioning chemotherapy followed by axi-cel at 2 × 106 CAR T cells/kg. The primary endpoint was objective response rate (ORR) by central review (Cheson, et al. J Clin Oncol. 2014). Secondary endpoints included duration of response (DOR), progression-free survival (PFS), overall survival (OS), safety, and blood levels of CAR T cells. Results: As of 8/20/19, 94 patients (80 FL; 14 MZL) received axi-cel (median follow-up, 11.5 months). Median age was 63 years, 51% of patients had ≥3 FLIPI, 59% had high tumor bulk, 66% progressed Conclusions: Axi-cel showed significant clinical benefit, with high response rates, and a manageable safety profile in patients with relapsed/refractory iNHL. Funding provided by Kite, a Gilead Company.

8008 Background: Advanced stage iNHL, including follicular lymphoma (FL) and marginal zone lymphoma (MZL), is considered incurable as most pts experience multiple relapses (Wang, et al. Ther Adv Hematol. 2017), highlighting a need for novel therapies. Here, we present interim results from ZUMA-5, a Phase 2, multicenter study of axi-cel, an autologous anti-CD19 chimeric antigen receptor (CAR) T cell therapy, in pts with R/R iNHL. Methods: Adults with R/R FL (Grades 1-3a) or MZL (nodal or extranodal) after ≥ 2 lines of therapy (including an anti-CD20 monoclonal antibody [mAb] with an alkylating agent), and an ECOG of 0 – 1 were eligible. Pts were leukapheresed and received conditioning chemotherapy followed by axi-cel infusion at 2 × 106 CAR T cells/kg. The primary endpoint was objective response rate (ORR) by central review (Cheson, et al. J Clin Oncol. 2014). Secondary endpoints included duration of response (DOR), progression-free survival (PFS), overall survival (OS), safety, and blood levels of cytokines and CAR T cells. Results: As of 8/20/19, 94 pts (80 FL; 14 MZL) received axi-cel with a median follow-up of 11.5 mo (range, 4.2 – 24.9). Median age was 63 y (range, 34 – 79), 47% of pts were male, 52% had stage IV disease, 51% had ≥ 3 FLIPI, and 59% had high tumor bulk (GELF). Pts had a median 3 prior lines of therapy, 66% progressed < 2 y after initial anti-CD20 mAb-containing therapy (POD24), and 73% were refractory to the last prior treatment. Of 87 pts evaluable for efficacy, ORR was 94% (79% complete response [CR] rate). Pts with FL (n = 80) had an ORR of 95% (80% CR rate). Pts with MZL (n = 7) had an ORR of 86% (71% CR rate). Overall, 68% of pts had ongoing responses as of the data cutoff. Updated data, including DOR, PFS, and OS with longer follow-up, will be included in the presentation. Of 94 pts evaluable for safety, 83% experienced Grade ≥ 3 adverse events (AEs), most commonly neutropenia (33%) and anemia (28%). Grade ≥ 3 cytokine release syndrome (CRS; per Lee et al, Blood 2014) and neurologic events (NEs; per CTCAE v4.03) occurred in 11% and 19% of pts, respectively. Median times to onset of CRS and NEs were 4 and 7 d, with median durations of 6 and 14.5 d. There were 2 Grade 5 AEs: multisystem organ failure in the context of CRS (related to axi-cel) and aortic dissection (unrelated to axi-cel). Median peak and AUC0-28 CAR T cell levels were 44 cells/µL and 490 cells/µL × d, respectively. Conclusions: Axi-cel demonstrated significant and durable clinical benefit, with high rates of ORR and CR, and a manageable safety profile in pts with R/R iNHL. Clinical trial information: NCT03105336 .

Due to recent advancements in the understanding of the molecular pathogenesis of B-cell malignancies, there has been an explosion of innovative agents in development. The purpose of this review is to efficiently summarize novel therapies with activity in indolent non-Hodgkin lymphoma (iNHL) targeting surface antigens, signaling pathways, and the tumor microenvironment. Areas covered: A literature search was performed to identify preclinical data and clinical trials focused on the use of targeted therapies in iNHL subtypes including follicular lymphoma, marginal zone lymphoma, small lymphocytic lymphoma, and lymphoplasmacytic lymphoma/Waldenström macroglobulinemia. Classes reviewed include monoclonal antibodies, antibody-drug conjugates, immunomodulatory agents, B-cell receptor pathway inhibitors, Bcl-2 inhibitors, checkpoint inhibitors, chromatin and epigenetic modulating agents, and CAR T-cells. Expert commentary: Opinions regarding strategies to address the prioritization of novel agents entering clinical development, the determination of rational combination therapy, the development of novel endpoints to expedite clinical development, and the movement towards novel consolidative approaches with immuno- and cellular therapy in an attempt to provide curative treatment options are provided. Also, the economic impact of indefinite therapy is discussed.

Background: BL is associated with a high risk of primary or secondary CNS involvement, warranting intrathecal (IT) and/or systemic therapy that penetrates the blood-brain barrier (BBB). The lower-intensity DA-EPOCH-R regimen has recently shown high survival rates in BL (Dunleavy, NEJM 2013), but it omits drugs traditionally used for CNS prophylaxis (like high-dose methotrexate [HDMTX]). The objective of this multi-institutional retrospective study was to examine treatments, risk factors, and CNS-related outcomes among patients (pts) with BL. Methods: We collected data from 26 US centers on adult BL pts diagnosed (dx) in 6/2009-6/2018. Using institutional expert pathology review and 2016 WHO criteria, we excluded other high-grade lymphomas (including BL-like/unclassifiable), or cases with inadequate clinicopathologic data. We studied factors associated with baseline CNS involvement (CNSinv) using logistic regression reporting odds ratios (OR). Progression-free (PFS), overall survival (OS), and cumulative incidence function of CNS recurrence (in a competing risk analysis) were examined in Cox or Fine-Gray models reporting hazard (HR) or subhazard ratios (SHR), respectively. All estimates report 95% confidence intervals (in square brackets). Results: Among 557 BL pts (median age, 47 years [yr], 24% women, 23% HIV+), 107 (19%) had CNSinv at dx, including 89 (16%) with leptomeningeal, and 15 (3%) with parenchymal CNS disease. In a multivariable model, factors significantly associated with CNSinv at dx included stage 3/4 (OR, 11.2 [1.47-85.9]), poor performance status (PS; OR, 2.12 [1.22-3.69]), ≥2 extranodal sites (OR, 3.77 [2.02-7.03]), or marrow involvement (OR, 2.44 [1.35-4.39]), whereas intestinal involvement conferred low risk of CNSinv (OR, 0.27 [0.11-0.65]). CNSinv at dx was not significantly associated with use of specific chemotherapy regimens (Fig. A,P=.75) or receipt of IT chemotherapy (91% vs 84%, P=.065). Pts with CNSinv were less likely to achieve a complete response (62% vs 76%, P=.005), had worse 3 yr PFS (47% vs 69%; P3x upper limit of normal [LDH>3x]; see Evens AM et al, ASH 2019 for further details). With median follow up of 3.6 yrs, 33 pts (6%) experienced a CNS recurrence (82% within 1 yr from dx; 79% purely in CNS, and 21% with concurrent systemic BL). The cumulative risk of CNS recurrence was 6% [4-8%] at 3y (Fig. D). Univariate significant predictors of CNS recurrence included baseline CNSinv, HIV+ status, stage 3/4, poor PS, LDH>3x, involvement of ≥2 extranodal sites, marrow, or testis. However, in a multivariate model only baseline CNSinv (SHR, 3.35 [1.53-7.31]) and poor PS (SHR, 2.24 [1.03-4.90]) retained significance. The 3 yr risk of CNS recurrence varied from 3% for pts with no risk factor, to 10% with one, and 17% with both factors (Fig. E). In addition, the risk of CNS recurrence differed according to chemotherapy regimen, and was significantly higher for pts treated with DA-EPOCH (12% at 3y [8-18%]; Fig. F) compared with CODOX-M/IVAC (4% [2-8%]) or hyperCVAD/MA (3% [1-6%]; SHR for DA-EPOCH vs. others, 3.50 [1.69-7.22]). All pts recurring after DA-EPOCH had received IT chemotherapy. Higher risk of CNS recurrence persisted with DA-EPOCH regardless of baseline CNSinv (Pinteraction=.70), poor PS (Pint=.14), or HIV status (Pint=.89). Baseline CNSinv was the strongest factor associated with CNS recurrence after DA-EPOCH (3 yr risk, 30% vs 8%, P Conclusions: In adult BL, baseline CNSinv and poor PS predicted subsequent CNS recurrence, an outcome that is associated with a dismal prognosis. Furthermore, treatment with DA-EPOCH was associated with a significantly increased risk of CNS recurrence in this real-world analysis. For BL pts with baseline CNSinv treated in routine clinical practice, regimens with highly BBB-penetrant drugs (e.g. CODOX-M/IVAC, hyperCVAD/MA) may be preferred. Studies should delineate ways to mitigate the risk of CNS recurrence with lower-intensity programs. Disclosures Evens: Seattle Genetics: Consultancy, Honoraria; Research to Practice: Honoraria; Verastem: Consultancy, Honoraria; Affimed: Consultancy, Honoraria; Pharmacyclics: Honoraria, Other: DMC; Bayer: Consultancy, Honoraria; Takeda: Research Funding; Merck: Research Funding. Smith:Incyte Corporation: Research Funding; Seattle Genetics: Research Funding; Portola Pharmaceuticals: Research Funding; Pharmacyclics: Research Funding; Acerta Pharma BV: Research Funding; AstraZeneca: Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech: Research Funding; Ignyta (spouse): Research Funding; Merck Sharp & Dohme Corp: Consultancy, Research Funding; Denovo Biopharma: Research Funding; Bristol-Myers Squibb (spouse): Research Funding; Ayala (spouse): Research Funding. Naik:Celgene: Other: Advisory board. Reddy:KITE Pharma: Consultancy; Abbvie: Consultancy; Genentech: Research Funding; BMS: Consultancy, Research Funding; Celgene: Consultancy. Farooq:Celgene: Honoraria; Kite Pharma: Research Funding. Epperla:Verastem Oncology: Speakers Bureau; Pharmacyclics: Honoraria. Khan:Seattle Genetics: Membership on an entity's Board of Directors or advisory committees; Janssen: Other: Educational Content/Symposium; Abbvie: Membership on an entity's Board of Directors or advisory committees; Bristol Myers: Other: Research Funds. Alderuccio:Puma Biotechnology: Other: Immediate family member; Agios: Other: Immediate family member; Inovio Pharmaceuticals: Other: Immediate family member; Targeted Oncology: Honoraria; OncLive: Consultancy; Foundation Medicine: Other: Immediate family member. Yazdy:Bayer: Honoraria; Genentech: Research Funding; Octapharma: Consultancy; Abbvie: Consultancy. Diefenbach:Bristol-Myers Squibb: Consultancy, Research Funding; Denovo: Research Funding; Genentech: Consultancy, Research Funding; Incyte: Research Funding; LAM Therapeutics: Research Funding; MEI: Research Funding; Merck: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding; Millenium/Takeda: Research Funding; Trillium: Research Funding. Karmali:Astrazeneca: Speakers Bureau; Takeda, BMS: Other: Research Funding to Institution; Gilead/Kite; Juno/Celgene: Consultancy, Speakers Bureau. Martin:Celgene: Consultancy; Teneobio: Consultancy; Karyopharm: Consultancy; Janssen: Consultancy; Sandoz: Consultancy; I-MAB: Consultancy. Magarelli:Tevan Oncology: Speakers Bureau. Kamdar:Seattle Genetics: Speakers Bureau; Pharmacyclics: Consultancy; AstraZeneca: Consultancy; Celgene: Consultancy; University of Colorado: Employment. Portell:Xencor: Research Funding; Roche/Genentech: Research Funding; Infinity: Research Funding; TG Therapeutics: Research Funding; AbbVie: Research Funding; Pharmacyclics: Consultancy; Janssen: Consultancy; Genentech: Consultancy, Research Funding; Amgen: Consultancy; Bayer: Consultancy; BeiGene: Consultancy, Research Funding; Kite: Consultancy, Research Funding; Acerta/AstraZeneca: Research Funding. Lossos:Janssen Scientific: Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees; NIH: Research Funding. Olszewski:Genentech: Research Funding; Adaptive Biotechnologies: Research Funding; TG Therapeutics: Research Funding; Spectrum Pharmaceuticals: Research Funding.

Introduction and Purpose IRAK4 kinase activity is essential for signaling downstream of toll-like receptors (TLR) and the interleukin-1 receptor (IL-1R) family in a variety of myeloid and lymphoid cell types. Dysregulated signaling in these pathways is frequently observed in NHL, particularly in ABC-subtype of Diffuse Large B-Cell Lymphoma (DLBCL) and Waldenström macroglobulinemia (WM). A phase 1 trial in patients with NHL is being conducted to determine safety, pharmacokinetics, and preliminary efficacy of CA-4948 as monotherapy. Patients and Methods At the 18-Jul-2019 data cut-off date, 22 patients have been treated with single-agent CA-4948. Five dose-escalation cohorts from 50 mg QD to 200 mg BID have been tested and cleared; a cohort of patients treated at 400 mg BID dose is currently being evaluated. Patients were diagnosed with relapsed or refractory NHL, including DLBCL (n=13), FL (n=5), HGBL with MYC and BCL2 and/or BCL6 rearrangement (n=1), WM (n=1), LPL (n=1) and MCL (n=1), had a performance status of 0 or 1 (ECOG) at baseline, and were treated in 21-day cycles until progression of disease or unacceptable toxicity, lost to follow-up or death. 5 patients had prior autologous bone marrow transplants. Results CA-4948 has been generally well tolerated. Grade 3/4 treatment-related adverse events included amylase/lipase increased, diarrhea, neutrophil count decreased, rash, rhabdomyolysis. Pharmacokinetics has shown favorable characteristics with dose-proportional increases in exposure. Five patients have been on treatment through the end of Cycle 4, including one patient in Cycle 10 on study for over 7 months. Five patients experienced overall tumor burden decreases of ≥20% from baseline, including at least 2 of 4 patients treated at 200 mg BID. Downstream pharmacodynamic markers of IRAK4 activity are being evaluated. Molecular characteristics including cell-of-origin will be presented. Conclusion CA-4948 demonstrates preliminary clinical activity. Enrollment is on-going and the MTD has not been reached. These encouraging results warrant further clinical testing in patients with advanced hematological malignancies. Clinical trial: NCT03328078. Disclosures Younes: Roche: Consultancy, Honoraria, Research Funding; Takeda: Honoraria; Genentech: Research Funding; Pharmacyclics: Research Funding; Janssen: Honoraria, Research Funding; Merck: Honoraria, Research Funding; Curis: Honoraria, Research Funding; Biopath: Consultancy; Xynomics: Consultancy; Celgene: Consultancy, Honoraria; HCM: Consultancy; BMS: Research Funding; AstraZeneca: Research Funding; Syndax: Research Funding; Abbvie: Honoraria; Epizyme: Consultancy, Honoraria. Nowakowski:Selvita: Membership on an entity's Board of Directors or advisory committees; NanoString: Research Funding; MorphoSys: Consultancy, Research Funding; Genentech, Inc.: Research Funding; F. Hoffmann-La Roche Ltd: Research Funding; Curis: Research Funding; Bayer: Consultancy, Research Funding; Celgene: Consultancy, Research Funding. Tun:Mundi-pharma: Research Funding; DTRM Biopharma: Research Funding; BMS: Research Funding; Celgene: Research Funding; Curis: Research Funding; TG Therapeutics: Research Funding. Lunning:Janssen Scientific Affairs, LLC: Consultancy, Research Funding; Curis: Research Funding; Juno Therapeutics: Consultancy, Research Funding; MiRagen: Research Funding; TG Therapeutics: Consultancy, Research Funding; Spectrum: Consultancy; VANIUM: Consultancy; Verastem: Consultancy; DAVA: Consultancy; Bayer: Consultancy; AbbVie: Consultancy; Kite: Consultancy; Gilead Sciences, Inc.: Consultancy; Seattle Genetics: Consultancy; Portola: Consultancy; OncLive: Consultancy; Novartis: Consultancy. Isufi:Celgene: Consultancy; Novartis: Consultancy; Astra Zeneca: Consultancy. Martell:Curis, Inc.: Employment. Patel:AstraZeneca: Consultancy, Research Funding, Speakers Bureau; Celgene: Consultancy, Speakers Bureau; Genentech: Consultancy, Speakers Bureau; Pharmacyclics/Janssen: Consultancy, Speakers Bureau; Sunesis: Consultancy.

Introduction: Acalabrutinib (acala) is an irreversible, second generation Bruton tyrosine kinase inhibitor (BTKi) approved by the FDA for the treatment of relapsed/refractory (R/R) mantle cell lymphoma, and is in advanced stages of clinical testing for front line (FL) and R/R CLL (Byrd NEJM, Wang NEJM). Ibrutinib (ibr) is a well-established and potent treatment for CLL; however, discontinuation due to intolerance precludes a significant number of patients (pts) in clinical practice from long-term benefit of this targeted therapy (Mato et al Blood 2016, Follows BJH 2017). Acala inhibits BTK more selectively than ibr, and while demonstrating impressive activity, may result in significantly less off-target adverse events (AEs). Although not yet FDA approved, it is being increasingly used in CLL pts with ibr-intolerance or cardiovascular or hematologic comorbidities (atrial fibrillation (AF), hypercoagulable state on long-term anticoagulation, etc.) to potentially avoid ibr-related toxicities. The increasing use of acala in clinical practice provides an opportunity to address various knowledge gaps. Therefore, we conducted a multi-institutional, retrospective analysis in CLL pts treated with acala in the real-world setting. We aimed to report and analyze the main reasons for starting acala, its safety, efficacy, outcome and sequencing. Patients and Methods: This multi-institutional, retrospective analysis included acala-treated CLL pts at 9 US cancer centers. We analyzed and described prior treatments, dosing of acala, discontinuations, toxicities and outcomes. The primary endpoint was progression-free survival (PFS) as predicted by the Kaplan Meier method. Results: 69 CLL pts treated with acala (off clinical trials) were identified. Baseline characteristics are described in Table 1. Median age was 70 years (range 51-89) and 6 (9%) and 63 (91%) pts received acala in the FL and R/R settings, respectively. Of the R/R pts, 49 (78%) had received a prior BTKi, 11 (17%) a phosphoinositide 3-kinase inhibitor (PI3Ki), 14 (22%) venetoclax, 18 (29%) bendamustine, and 17 (27%) fludarabine. Median time from diagnosis of CLL to starting acala was 79.5 months. Most common reasons for choosing acala were prior intolerance to other agents in 47 (68%), disease progression on the prior line of therapy in 19 (28%) and concern for intolerance to other therapies due to age/comorbidities in 9 (13%). Prior intolerance to ibr was the reason for starting acala in 46 (98%) of the intolerant pts; the most common AEs leading to discontinuation of ibr were rash in 10 (22%), AF/flutter in 8 (17%), arthralgia in 8 (17%), bleeding in 6 (13%), infection in 6 (13%) and fatigue in 6 (13%). Almost all pts (99%) started on acala 100 mg orally twice daily, with dose reductions required in 5 (7%). The most common toxicities on acala were fatigue in 9 (13%), infection in 9 (13%), diarrhea/colitis in 7 (10%), nausea/vomiting in 6 (9%), headache in 5 (7%), rash in 5 (7%), bleeding in 2 (3%) and AF/flutter in 1 (1%). The median time from the start of acala to an infection was 3 months. With a median follow-up of 5 months, the acala discontinuation rate was estimated to be 19% (13 pts) with median time to discontinuation of 1 month. The main reason for discontinuation was AEs in 8 pts (12%) (no consistent pattern of AEs), all in R/R pts with median time to discontinuation of 3.5 months; 2 others proceeded to CAR T-cell therapy or allogeneic transplant; 2 died of unrelated causes, 1 from progressive disease off acala. Overall response rate (ORR) was 62% (9% CR, 53% PR, number reported = 66), 50% PR in FL (3/6) and 63% (CR 5%, PR 58%, number reported = 60) in R/R pts. The differences likely reflected small numbers and short follow-up. Median PFS and overall survival were not reached (Figs 1a,b). Conclusion: In this group of largely ibr-intolerant pts, the overall acala discontinuation rate was lower than prior reports from clinical trials, although with relatively short follow up. However, discontinuation rate due to AEs appears to be similar to clinical trial data in an ibr-intolerant pt population (Awan Blood Adv, Rogers ICML 2019). These data demonstrate the need for the results of randomized studies, in order to compare the efficacy and AE profile of acala relative to ibr and other novel agents and Disclosures Yazdy: Genentech: Research Funding; Bayer: Honoraria, Speakers Bureau; Octapharma: Consultancy; Abbvie: Consultancy. Mato:Genentech: Consultancy, Research Funding; Pharmacyclics: Consultancy, Research Funding; Sunesis: Consultancy, Research Funding; Celgene: Consultancy; Johnson & Johnson: Consultancy, Research Funding; TG Therapeutics: Consultancy, Other: DSMB member , Research Funding; Acerta: Consultancy; Janssen: Consultancy; Gilead: Research Funding; DTRM Biopharma: Research Funding; AstraZeneca: Consultancy, Research Funding; AbbVie: Consultancy, Research Funding; LOXO: Consultancy, Research Funding. Roeker:AbbVie: Equity Ownership; Abbott Laboratories: Equity Ownership. Ujjani:Gilead: Consultancy; Atara: Consultancy; Genentech: Honoraria; AbbVie: Honoraria, Research Funding; PCYC: Research Funding; Pharmacyclics: Honoraria; PCYC: Research Funding; Pharmacyclics: Honoraria; Astrazeneca: Consultancy. Shadman:TG Therapeutics: Research Funding; Gilead: Research Funding; Merck: Research Funding; Bigene: Research Funding; Celgene: Research Funding; Acerta: Research Funding; Emergent: Research Funding; Sunesis: Research Funding; Mustang Biopharma: Research Funding; Atara: Consultancy; Pharmacyclics: Consultancy, Research Funding; Verastem: Consultancy; AbbVIe: Consultancy, Research Funding; Genentech, Inc.: Consultancy, Research Funding; AstraZeneca: Consultancy; Sound Biologics: Consultancy; ADC Therapeutics: Consultancy. Skarbnik:Genentech: Honoraria, Speakers Bureau; Seattle Genetics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Acerta: Research Funding; Novartis: Speakers Bureau; Jazz Pharmaceuticals: Speakers Bureau; Abbvie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pharmacyclics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Verastem Oncology: Honoraria, Research Funding, Speakers Bureau; Kite Pharma: Honoraria, Speakers Bureau; Gilead Sciences: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Consultancy, Honoraria, Speakers Bureau; CLL Society: Consultancy, Membership on an entity's Board of Directors or advisory committees. Pagel:AstraZeneca: Consultancy; Gilead Sciences: Consultancy; Pharmacyclics: Consultancy. Patel:Sunesis: Consultancy; Pharmacyclics/Janssen: Consultancy, Speakers Bureau; Celgene: Consultancy, Speakers Bureau; AstraZeneca: Consultancy, Research Funding, Speakers Bureau; Genentech: Consultancy, Speakers Bureau. Jacobs:AstraZeneca: Speakers Bureau; Gilead: Consultancy; Genentech: Speakers Bureau; JUNO: Consultancy; TG Therapeutics: Honoraria, Research Funding; AbbVie: Consultancy, Speakers Bureau; Pharmacyclics LLC, an AbbVie Company: Research Funding, Speakers Bureau. Feldman:Portola Pharma: Research Funding; Roche: Research Funding; Corvus: Research Funding; Eisai: Research Funding; Kyowa Hakko Kirin: Research Funding; Roche: Research Funding; Trillium: Research Funding; Viracta: Research Funding; Pfizer: Research Funding; Bayer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Honoraria, Other: Travel expenses, Speakers Bureau; Janssen: Honoraria, Speakers Bureau; Takeda: Honoraria, Speakers Bureau; Celgene: Honoraria, Research Funding, Speakers Bureau; Seattle Genetics: Consultancy, Honoraria, Other: Travel expenses, Speakers Bureau; AbbVie: Honoraria, Other: Travel expenses, Speakers Bureau; Amgen: Research Funding; Cell Medica: Research Funding; Kite Pharma: Honoraria, Other: Travel expenses, Speakers Bureau. Goy:University of Nebraska: Research Funding; Acerta: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Grants outside of the submitted work, Research Funding; Hakensackumc: Research Funding; Hackensack University Medical Center, RCCA: Employment; Genentech: Other: Grants outside of the submitted work, Research Funding; Pharmacyclics/Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Grants outside of the submitted work, Research Funding; Takeda: Other: Grants outside of the submitted work; Astrazenca: Consultancy, 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, Other: Grants outside of the submitted work; COTA: Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Other: leadership role for profit healthcare company; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Coombs:Pharmacyclics: Honoraria; Loxo: Honoraria; H3 Biomedicine: Honoraria; Octopharma: Honoraria; Dedham Group: Consultancy; Cowen & Co.: Consultancy; Medscape: Honoraria; Abbvie: Consultancy; Covance: Consultancy. Lamanna:Celgene: Consultancy; Infinity/ Verastem: Research Funding; Ming: Research Funding; TG Therapeutics: Research Funding; Oncternal: Research Funding. Weiss:TG Therapeutics: Other: family member with employment and equity) . Cheson:AstraZeneca: Membership on an entity's Board of Directors or advisory committees; Acerta: Consultancy, Research Funding; Pharmacyclics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Morphosys: Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Research Funding; Portola: Research Funding; Kite: Research Funding; Gilead: Research Funding; Epizyme: Research Funding; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Symbios: Equity Ownership, 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; Trillium: Research Funding; TG Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Seattle Genetics: Research Funding; Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. OffLabel Disclosure: Acalabrutinib is an irreversible, second generation Bruton tyrosine kinase inhibitor approved by the FDA for the treatment of relapsed/refractory (R/R) mantle cell lymphoma, and is in advanced stages of clinical development testing for front line (FL) and R/R CLL. Although not yet FDA approved, it is being increasingly used in CLL patients in clinical practice. This highlights the necessity to address various knowledge gaps.

Background: Rituximab (RTX) alone or in combination with chemotherapy has substantially improved treatment outcomes for patients (pts) with marginal zone lymphoma (MZL), but relapse is common and not all pts are acceptable candidates for, or respond to, current salvage therapies. Umbralisib is a novel, next-generation PI3K-delta inhibitor with unique inhibition of casein kinase-1ϵ (CK1ϵ) and, compared to earlier generation PI3K-delta inhibitors, exhibits a differentiated tolerability profile with reduced rates of immune-mediated toxicity (Burris et al, 2018). This registration-directed study evaluates the efficacy and safety of umbralisib in pts with relapsed/refractory (R/R) MZL. Methods: Pts had histologically confirmed MZL, ECOG PS ≤2, and had previously received ≥1 prior therapy including at least one CD20 monoclonal antibody (mAb)-containing regimen. All pts received umbralisib 800 mg orally once daily until progression or unacceptable toxicity. The primary study endpoint was overall response rate (ORR) as assessed by an independent review committee (IRC) according to 2007 IWG criteria. ORR by investigator assessment is reported here, and ORR by IRC is forthcoming. Secondary endpoints included duration of response (DOR), progression-free survival (PFS), and safety. Results: Sixty-nine pts were enrolled; we report on the first 38 who are eligible for at least 6 months (mos) of follow-up as of the data cutoff date. Disease status for the 38 pts: extranodal (n=23), nodal (n=8), and splenic (n=7). Median age was 67 years (range, 34-81). Median number of prior systemic therapies was 2 (range, 1-5). Seven pts (18%) had received monotherapy RTX only, and 26 (68%) had received at least one CD20 mAb-containing chemoimmunotherapy. As of the cut-off date, the median follow-up was 9.6 mos. Per investigator assessment, ORR was 55% (4 CRs and 17 PRs), 29% of pts (n=11) had stable disease (SD) of which 6 of these SD pts remain on study with durations ranging from 7-12+ mos. The clinical benefit rate (CR+PR+SD) was 84%, and 91% of pts with at least 1 post-baseline assessment experienced tumor reductions. The median time to initial response was 2.7 mos, while the median DOR was not reached (95% CI: 8.4-not reached). The 12-month PFS was 71%. The most common (≥20%) adverse events (AE) of any grade included: diarrhea (45%), nausea (29%), fatigue (26%), headache (26%), cough (24%), and decreased appetite (21%). The most common Grade 3/4 events were neutropenia (8%), febrile neutropenia (5%), and diarrhea (5%). As of the cutoff date, 16 pts discontinued treatment (PD: 18%; AEs: 8%; pt decision: 8%; physician decision: 8%) and 58% continue treatment. Conclusions: PI3K-delta inhibition with single-agent umbralisib is active and well tolerated in pts with R/R MZL, achieving durable responses with chemotherapy-free therapy. Citation Format: Nathan H. Fowler, Felipe Samaniego, Wojciech Jurczak, Ewa Lech-Maranda, Nilanjan Ghosh, Bertrand Anz, Piers Patten, James A. Reeves, Lori A. Leslie, Piotr Smolewski, Julio C. Chavez, Paolo Ghia, Corrado Tarella, John M. Burke, Jeff Sharman, Kathryn Kolibaba, Owen A. O'Connor, Chan Y. Cheah, Hari P. Miskin, Peter Sportelli, Michael S. Weiss, Pier Luigi Zinzani. Umbralisib monotherapy demonstrates efficacy and safety in patients with relapsed/refractory marginal zone lymphoma: A multicenter, open-label, registration directed Phase II study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr CT132.

e19055 Background: IRAK4 is a signaling modulator of Toll-like receptors (TLRs) and members of the IL-1R family. TLR/IL-1R activity is frequently dysregulated in NHL, including DLBCL and Waldenström macroglobulinemia (WM). CA-4948, an oral inhibitor of IRAK4, has demonstrated anti-tumor activity in preclinical models. Methods: Dose finding cohorts (3+3 design) will test QD or BID dosing schedule in pts with R/R NHL. Dose expansion will occur in 2 cohorts of R/R NHL with or without MYD88 mutation at the RP2D or MTD. Key eligibility criteria: age ≥ 18 years, ECOG ≤1, and adequate organ function. Objectives: safety, MTD and RP2D (primary); PK and anti-tumor activity (secondary); exploratory biomarkers and PD effects. Plasma cytokine levels are being evaluated post ex-vivo TLR stimulation in whole blood. Results: 13 pts have been treated (6 at 50 mg QD; 3 at 100 mg QD; 4 at 50 mg BID). Tumor types included DLBCL (7), FL (5), WM (1). The most frequent treatment-emergent AEs (≥10% of pts) were fatigue (23%), conjunctivitis, constipation, neutrophil count decrease, white blood cell count decrease (each 15%). One pt treated at 100 mg QD experienced Gr 3 rash which resolved following oral steroid treatment; dose reduction to 50 mg QD was tolerated without flare up. One SAE of disease progression occurred. 9 pts completed the DLT evaluation period thru Cycle 2 including 2 ongoing in Cycle 4 and 6. Preliminary PK showed that CA-4948 is rapidly absorbed with maximum plasma concentration observed 1.0 to 4.0 hrs post administration. T1/2 in plasma was about 6 hrs. Minimal to no accumulation was observed following multiple doses. Plasma exposures were dose proportional. Preliminary PD data showed, similar to murine studies, on target reduction of NF-kB-associated factors such as IL-6 post-treatment from pts with complete sample sets (N = 8). Conclusions: Current dose/schedule is well tolerated with preliminary PK and PD effects at the initial dose level. MTD has not been reached. Clinical trial information: NCT03328078.

Introduction: The therapeutic landscape of chronic lymphocytic leukemia (CLL) has changed significantly since the first targeted therapy, rituximab, was approved for the treatment of symptomatic patients.Areas covered: Multiple monoclonal antibodies (mAbs) and small molecule inhibitors (SMIs) that target the B-cell receptor (BCR) and BCL-2 pathways are now approved treatments for CLL patients. Recent and emerging clinical data investigating the use of targeted therapies in the treatment of CLL patients will be reviewed. The changing role of cytotoxic chemotherapy in the treatment of the CLL patient as a result of the increasing availability of novel targeted therapies will be discussed.Expert commentary: Use of novel therapies is progressively shifting much of the treatment of CLL patients towards a targeted therapeutic approach. Increasing availability of targeted agents such as SMIs will likely reduce the role of cytotoxic chemotherapy in the treatment of both front-line and relapsed/refractory ...

Curative-intent therapy for stage II/III rectal cancer is necessarily complex. Current guidelines by the National Comprehensive Cancer Network recommend preoperative concurrent chemoradiation followed by resection and additional adjuvant chemotherapy. We used standard quality improvement methodology to implement a cost-effective intervention that reduced the time from diagnosis to treatment of patients with stage II/III rectal cancer by approximately 30% in a large public hospital in Houston, Texas. Implementation of the program resulted in a reduction in time from pathologic diagnosis to treatment of 29% overall, from 62 to 44 days. These gains were cost neutral and resulted from improvements in scheduling and coordination of care alone. Our results suggest that: (1) quality improvement methodology can be successfully applied to multidisciplinary cancer care, (2) effective interventions can be cost neutral, and (3) effective strategies can overcome complexities such as having multiple sites of care, high staff turnover, and resource limitations.

Introduction: Cure rate of Mature T/NK cell lymphoma (TCL) is rather low and multiple trials are being conducted to improve frontline therapy outcomes. Consolidation with autologous stem cell transplant is becoming widely used as a mean of improving survival (SCT). Based on data from several retrospective trials, pts who achieve CR may not benefit from consolidative SCT. There is no data available on the role of PET-CR as defined by using Deauville criteria (which became standard in response assessment of NHL (The Lugano Classification 2014)). We performed retrospective analysis of 59 pts with TCL examining the correlation between PFS/OS and iPET and eotPET. Methods: 59 pts newly diagnosed pts with TCL treated between 2008-2016 for whom interim and eotPET scan were available. It was our routine practice to obtain baseline, interim (after 3 cycles of chemotherapy) and eotPET. Pathology slides of outside cases were centrally evaluated by a hematopathologist to confirm diagnosis. Baseline, interim and eotPET were centrally reviewed by a nuclear medicine radiologist blinded to clinical outcomes who assigned Deauville score (DS) to every PET. Responses were recorded according to the Lugano classification 2014. Descriptive statistics and Kaplan Meier method was used to calculate the Progression-free survival (PFS) and Overall survival (OS), two-sided Log-rank test was used to compare OS and PFS between PET groups. Results: Detailed demographic is presented in Table1. Median age at diagnosis is 59, sixty two percent males, 37% female; ALCL 34%, PTCLnos 22%, AITL 19%, and ATLL 10%; most of pts were advanced stage. Most common chemotherapy regimens used were CHOP/CHOEP, HCVAD, and CODOX, SMILE. Median follow up time for the entire cohort was 22.7mo. Forty nine percent of pts progressed and 29% of pts died during follow up. Cause of death for majority of pts was disease progression. Following Deauville scores were assigned on iPET and eotPET respectively: DS1 in 37% and 39%, DS2 in 30% and 35%, DS3 in 15% and 6%, DS4 in 9% and 4%, DS5 in 9% and 16%. We analyzed mPFS and mOS for PET-CR using DS1-2 or DS1-3 to define it. Sixty seven percent and 82% were considered in PET-CR on iPET based on DS 1-2 and DS 1-3 respectively. PET-CR went up to 77% and 83% respectively on eotPET. For final analysis, DS1-2 was used to define PET-CR as no statistically significant difference in mPFS and mOS was noted between DS1-2 and DS1-3. With median follow up of 22.7mo, two-year mPFS and mOS for the cohort were 50% and 74% respectively. Two- year mPFS for iPET-CR and eotPET-CR were 62%. Two-year mOS for iPET-CR and eotPET-CR were 86%% and 83%. Two-year mPFS for iPET-PR and eotPET-PR were 37% and 67%. Two-year mOS for iPET-PR and eotPET-PR were 70% and 100 % (not statistically significant difference with PET-CR mPFS and mOS). None of the pts with PD on iPET were alive at two year. Two-year mOS for eotPET-SD and eotPET-PD are 40%. Negative predictive value of iPET and eotPET is 61%, positive predictive value is 65% and 72% respectively. Conclusion: While PET-SD and PD is quite predictive of poor survivorship, significant number of PET-CR pts will relapse. Even though PET-CR rate to frontline therapy is high, it does not translate into durable responses for significant number of pts with TCL. Thus, PET-CR is not a sensitive enough measure to be considered as a predictor of long-term remission in TCL. It is important to develop response assessment tools which will correlate better with long term survivorship of TCL patients. Figure 1 Overall survival stratified on PET response Figure 1. Overall survival stratified on PET response Figure 2 Progression free survival stratified on PET response Figure 2. Progression free survival stratified on PET response Disclosures Feldman: Pharmacyclics: Speakers Bureau; Celgene: Speakers Bureau; Seattle Genetics: Consultancy, Speakers Bureau; Abbvie: Consultancy, Speakers Bureau. Leslie:Seattle Genetics: Speakers Bureau; Celgene: Speakers Bureau. Skarbnik:Pharmacyclics: Consultancy, Speakers Bureau; Genentech: Consultancy, Speakers Bureau; Abbvie: Consultancy, Speakers Bureau. Mato:Theradex: Research Funding; TG Therapeutics: Research Funding; ProNAi: Research Funding; Gilead Sciences: Research Funding; Acerta Pharma: Research Funding; Abbvie: Research Funding; TG Therapeutics: Consultancy; Pharmacyclics: Consultancy; Gilead Sciences: Consultancy; Abbvie: Consultancy. Chow:Seattle Genetics: Speakers Bureau. Protomastro:COTA: Employment. Leslie:Celgene: Speakers Bureau; Seattle Genetics: Speakers Bureau. Goy:Acerta: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Writing support, Speakers Bureau; Pharmacyclics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Genentech: Research Funding; Infinity: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau.

Background: Allogeneic stem cell transplantation (SCT) remains the only curative option for CLL, in part due to allogeneic graft-vs-leukemia effect (GVL), which can lead to complete suppression of the CLL clone (Schetelig et al, JCO 2003). Management of post-SCT relapse remains challenging, and DLI has been successfully used as salvage, due to its potential to induce GVL (Delgado et al, Blood 2009). We evaluated outcomes of SCT for patients (pts) with a diagnosis of CLL transplanted at our center. Methods: 36 consecutive pts transplanted between 2004 and 2015 were reviewed. Kaplan Meier survival curves were produced to examine overall survival (OS), time to progression (TTP) and post-DLI survival. Univariate Cox Proportionate hazard models were also estimated to assess the impact of pt characteristics on the risk of survival and progression. Bivariate frequencies with Fisher exact tests, correlation analysis, and independent samples t-tests were performed to test associations across outcomes. Results: Sample was 72% male. Median age at time of SCT was 57 yo (range 42-74). Pts had a median time of 70 months (mos) between diagnosis (Dx) of CLL and SCT. Median follow-up post-SCT was 32 mos (range 1-118). Of the 30 pts with known disease status at the time of SCT, 16.7% were in complete remission (CR), 20% had stable disease (SD), 50% were in partial remission (PR) and 13.3% had progressive disease (PD). Median number of lines of therapy pre-SCT was 3 (range 1-8). Thirteen pts (36%) were refractory to their first line of therapy. 10 pts (27.8%) had del(17p), 11 pts (30.6%) had del(11q) and 8 pts (22.2%) had complex cytogenetics. Most patients (72%) received pre-SCT conditioning with FCR (Khouri et al, Exp Hematol 2004). 16 pts (44.4%) received rATG as part of their conditioning regimen. Graft-vs-host disease (GVHD) prophylaxis consisted of methotrexate and tacrolimus. 20 (55.6%) pts had acute GVHD and 19 (52.8%) had chronic GVHD. 5 (13.8%) pts had grade 3/4 acute GVHD and 1 (2.7%) had extensive chronic GVHD. When comparing pts who received SCT from unrelated donors (MUD, 24 pts) vs sibling donors (sib, 10 pts) there were no differences in rates of GVHD, disease progression or overall survival. Twenty-seven pts (75%) were in CR at first disease evaluation after SCT (CR conversion rate of 58.3%) and 2 pts (5.5%) had PD. On follow-up, another 15 pts (41.7%) presented PD. Median TTP was 14 months, with only 3 pts relapsing after 2 years from SCT. Eight pts who had PD and one patient who had a PR post-SCT received short-term anti-CLL therapy for disease debulking, followed by DLI. Six (66.6%) out of the 9 pts who received DLI achieved CR and are currently alive and in CR. Median follow-up post-DLI was 43 months and median duration of response to DLI was 47 mos (range 6-85 mos). Ultimately, 13 (36.1%) pts died, 8 (22.2%) were lost to follow-up, and 15 (41.7%) were alive at last contact. Disease progression was the most common cause of death (5 pts, 13.9%). Transplant-related mortality (TRM) was 13.9% (3 deaths due to infection, 2 deaths due to chronic GVHD). Only 2 deaths (5.5%) occurred during the first 100 days post-SCT, both due to infection. No deaths occurred due to acute GVHD. Median OS was 84 months. PFS (not accounting for pts who relapsed post-SCT but achieved CR with DLI) was 58% in the first year and 25% at five years. The median PFS was 19 months. Univariate and multivariate analysis of pre-SCT pt characteristics (age, time from Dx to SCT, number of therapies, stage, presence of adenopathy, MUD vs sib donor, cytogenetic abnormalities, ABO mismatch, disease status at SCT) did not show any statistically significant correlation with OS, PFS or GVHD rates. Conclusion: SCT remains the only curative option for CLL. Our experience shows that pts may achieve long-term survival with this approach. TRM was low (13.8%) and rates of acute and chronic GVHD were compatible with previous reports (Sorror et al, JCO 2005; Dreger et al, Blood 2010). Type of donor (MUD vs sib) did not impact outcomes, suggesting that patients without a matched sibling should not be denied transplantation if a MUD is available. Although 47% of the patients eventually progressed after transplantation, 66% of patients who received DLI for salvage were able to achieve CR and remain progression-free for a prolonged period of time, underlining the importance of the GVL effect. Most relapses occurred within the first 2 years post SCT and late relapses were rare. Figure 2 Figure 2. Figure 3 Figure 3. Disclosures Skarbnik: Gilead Sciences: Speakers Bureau; Seattle Genetics: Speakers Bureau; Genentech: Speakers Bureau; Abbvie: Consultancy; Pharmacyclics: Consultancy. Vesole:Celgene: Speakers Bureau; Takeda: Speakers Bureau; Janssen: Speakers Bureau; Amgen: Speakers Bureau; Novartis: Speakers Bureau. Goy:Pharmacyclics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Writing support, Speakers Bureau; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech: Research Funding; Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Infinity: Consultancy, Membership on an entity's Board of Directors or advisory committees; Acerta: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Feldman:Pharmacyclics: Speakers Bureau; Celgene: Speakers Bureau; Seattle Genetics: Consultancy, Speakers Bureau; Abbvie: Consultancy, Speakers Bureau. Leslie:Seattle Genetics: Speakers Bureau; Celgene: Speakers Bureau. Leslie:Seattle Genetics: Speakers Bureau; Celgene: Speakers Bureau.

Introduction Primary cutaneous T-cell lymphomas (CTCL) are rare subtypes of extranodal non-Hodgkin lymphoma for which no conventional curative therapies are available. Patients (pts) with early-stage, limited disease typically experience an indolent course. Pts with advanced or progressive disease are more likely to experience an aggressive course characterized by short-lived responses to therapy, debilitating symptoms that significantly impact quality of life,and limited overall survival. Prior retrospective studies have shown allogeneic stem cell transplantation (alloSCT) may lead to durable remissions in pts with advanced CTCL, the largest of which included 47 pts and reported an overall survival (OS) of 51% and progression-free survival (PFS) of 26% at 4-years (Hosing et al. Ann Oncol 2015). We performed a retrospective analysis of pts who underwent alloSCT for advanced CTCL at our institution. Methods We performed a retrospective case analysis of 11 pts with CTCL who underwent alloSCT between 1/1/2008 and 3/1/2016. OS and PFS were estimated using Kaplan-Meier analysis. Other endpoints included transplant-related mortality and morbidity as well as CTCL-related mortality. Results Eleven pts were identified including 5 with mycosis fungoides/Sezary syndrome (MF/SS), 2 with CD4+ CTCL not otherwise specified (NOS), and 1 each with CD8+ CTCL-NOS, ALK-negative cutaneous anaplastic large cell lymphoma (cALCL), sub panniculitis-type T-cell lymphoma, and cutaneous smoldering HTLV-1 associated adult T-cell leukemia/lymphoma (ATLL). The median age at diagnosis was 45.4 yr, median time to alloSCT was 2.4 yr. The median follow-up post-alloSCT was 39.2 mo. Prior to alloSCT, pts received a median of 5 lines of therapy (range 2-11). Total skin electron beam radiation (TSEB) was part of the immediate pre-alloSCT regimen for 6 pts (55%), all of whom had persistent disease. Four pts (67%) converted to CR pre-alloSCT with the addition of TSEB. Nine pts (82%) received reduced-intensity and 2 pts (18%) received myeloablative conditioning. Ten pts received peripheral blood stem cells (PBSC) and 1 received bone marrow: 4 pts (36%) received stem cells from HLA-matched unrelated donors, 2 (18%) from mismatched unrelated donors, 4 (36%) from matched sibling donors, and 1 (9%) from a haploidentical sibling. Nine pts (82%) received tacrolimus/mini methotrexate and 2 pts (18%) received tacrolimus/mycophenolate mofetil for graft-versus-host disease (GvHD) prophylaxis. The pt who received haploidentical stem cells also received post-alloSCT cyclophosphamide. At the time of transplantation, disease status included: complete response (CR) in 8/11 pts (73%), partial response (PR) in 2/11 pts (18%), and progressive disease (PD) in 1/11 pts (9%). At day 100, 9/11 pts (82%) were in CR, 1 pt had PD, and 1 pt with CD8+ CTCL-NOS had died on day 26 of PD. Two of the 9 pts (22%) in CR on day 100 relapsed soon thereafter, one on day 105 and one on day 113. Both achieved CR, 1 with withdrawal of immunosuppression, 1 with salvage brentuximab vedotin, bexarotene and donor lymphocyte infusions (DLI). There were no late relapses. Median OS at 36 mo was 72% (Figure 1): 1 pt died of PD on day 26, 2 pts died of non-alloSCT/non-CTCL adverse events (cerebrovascular accident (CVA), suicide). Median PFS at 36 mo was 64% (Figure 2). Fifty percent (2/4) of pts who relapsed/progressed were in CR at time of alloSCT, 86% (6/7) of pts who did not relapse were in CR at time of alloSCT. The incidence of acute cutaneous GvHD was 100%: 30% grade 1, 70% grade 2-3. The incidence of chronic cutaneous GvHD was 50%: 2 pts (20%) have ongoing severe GvHD, 1 pt with severe DLI-induced GvHD died due to CVA, 2 pts (20%) have completed therapy with no further manifestations of chronic GvHD. There were no other significant long-term toxicities of alloSCT identified. Disease-related mortality was 9% (1/11). Transplant-related mortality was 0%. Conclusion AlloSCT is well-tolerated and may result in long-term remissions for pts with various, heavily pretreated subtypes of CTCL. In our experience relapses were uncommon, occurred early, and durable CR could again be achieved with immunomodulatory approaches. Depth of response pre-alloSCT correlated with long term PFS and OS. It is likely that TSEB may be omitted safely in pts in CR, but should be administered immediately pre-alloSCT to deepen responses in patients with persistent disease. Disclosures Leslie: Seattle Genetics: Speakers Bureau; Celgene: Speakers Bureau. Leslie:Seattle Genetics: Speakers Bureau; Celgene: Speakers Bureau. Feldman:Celgene: Consultancy, Speakers Bureau; Seattle Genetics: Consultancy, Research Funding, Speakers Bureau; Abbvie/Pharmacyclics/Janssen: Speakers Bureau. Vesole:Novartis: Speakers Bureau; Janssen: Speakers Bureau; Takeda: Speakers Bureau; Amgen: Speakers Bureau; Celgene: Speakers Bureau. Goy:Pharmacyclics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Genentech: Research Funding; Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Celgene: 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, Other: Writing support, Speakers Bureau; Acerta: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Infinity: Consultancy, Membership on an entity's Board of Directors or advisory committees.