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In this multi-institutional retrospective study, we examined characteristics and outcomes of 160 patients with high-grade B-cell lymphoma, not otherwise specified (HGBL-NOS). This rare lymphoma category is defined by high-grade morphologic features, most commonly Burkitt-like, and lack of MYC rearrangements with BCL2 and/or BCL6 rearrangements (so-called double-hit). Our results show that HGBL-NOS tumors are heterogeneous: 83% had a germinal center B-cell immunophenotype, 37% a dual expressor immunophenotype (MYC and BCL2 expression), 28% (single-hit) MYC rearrangement, 13% BCL2 rearrangement, and 11% BCL6 rearrangement. Most patients presented with stage 4 disease, a high serum lactate dehydrogenase, and other high-risk clinical factors. Most frequent first-line regimens included DA-EPOCH-R (43%), R-CHOP (33%), or other intensive chemotherapy programs (11%). We found no significant differences in the rates of complete response (CR, P=0.32), progression-free (PFS, P=0.82), or overall survival (OS, P=0.60) between these chemotherapy regimens. CR was attained by 69% of patients. PFS at 2 years was 55.2% (95%CI, 46.9-62.7), and OS was 68.1% (95%CI, 59.7-75.0). In a multivariable model, the main prognostic factors for PFS and OS were poor performance status, lactate dehydrogenase >3x upper limit of normal, and a dual expressor immunophenotype. Age >60 years or presence of MYC rearrangement were not prognostic, but patients with TP53 alterations had a dismal PFS (13% at 2 years). Presence of MYC rearrangement was not predictive of better PFS in patients treated with DA-EPOCH-R versus R-CHOP. Improvements in the diagnostic criteria and therapeutic approaches beyond dose-intense chemotherapy are needed to overcome the unfavorable prognosis of patients with HGBL-NOS.

Following a similar report on multiple myeloma, Ghione and colleagues report the expected observation that patients with non-Hodgkin lymphoma (NHL) receiving anti-B cell therapies have markedly reduced antibody responses to COVID-19 immunization. Although there is no information regarding T-cell immunity, this suggests that while vaccination is certainly still recommended for this population, patients should be strongly encouraged to maintain social distancing precautions and should be revaccinated after an appropriate interval from the end of their antilymphoma therapy.

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.

Background. BL is a rare, high-grade B-cell lymphoma that is often studied in trials with small sample sizes. Historical definitions of "low-risk BL" vary between studies, use arbitrary cutoffs for lactate dehydrogenase (LDH), and identify a small favorable group, leaving >80-90% of patients (pts) in an undifferentiated "high-risk" category. A validated prognostic index will help compare study cohorts and better define good-prognosis pts for whom reduced treatment would be appropriate vs a poor-prognosis group in need of new approaches. Herein, we constructed and validated a simplified prognostic model for BL applicable to diverse clinical settings across the world. Methods. We derived the BL-IPI from a large real-world evidence cohort of US adults treated for BL in 2009-2018 (Evens A, Blood 2020). Progression-free survival (PFS) from diagnosis until BL recurrence, progression, death, or censoring was the primary outcome. We first determined the best prognostic cutoffs for age, LDH (normalized to local upper limit normal, ULN), hemoglobin (Hgb), and albumin. Independent risk factors were ascertained by forward stepwise selection into Cox regression from candidate variables: age, sex, HIV+ status, ECOG performance status (PS) ≥2, advanced stage (3/4), involvement of >1 extranodal site, bone marrow, central nervous system (CNS), values of LDH, Hgb, and albumin. Derivation models used multiple imputation to mitigate bias from missing data and reported hazard ratios (HR) with 95% confidence interval (CI). BL-IPI groups, defined by inspection of survival curves, were compared using log-rank test for trend. We validated performance of the BL-IPI in an external retrospective dataset of BL pts treated contemporaneously in centers from the United Kingdom, Scandinavia, Canada, and Australia. Results. Characteristics of pts in the derivation (N= 633) and validation (N=457) cohorts are shown in the Table. Age ≥40 years (yr), LDH >3xULN, Hgb 3xULN, low Hgb, and low albumin were associated with inferior PFS in univariate tests. In the multivariable model age ≥40 yr, LDH >3xULN, PS ≥2, and CNS involvement were selected as 4 independent prognostic factors; adding stage did not enhance the model. The model was simplified to 3 groups with 0 (low risk; 18% of pts), 1 (intermediate risk; 36% of pts; HR=3.14; 95%CI, 1.61-6.14), or 2-4 factors (high risk; 46% of pts; HR=6.52; 95%CI, 3.48-12.20; Fig A) with 3 yr PFS of 92%, 72%, and 53%, respectively (P Among pts with stage III/IV (historically classified as "high-risk" and constituting 78% of all pts in the cohort), the BL-IPI further discriminated subgroups with 3 yr PFS of 87%, 71%, and 52%, respectively (P In the international validation cohort, fewer pts had CNS involvement; most received CODOX-M/IVAC+R; and PFS/OS estimates at 3 yr were higher. BL-IPI categories were of similar size (low-risk 15%, intermediate-risk 35%, high-risk 50%), and provided similar risk discrimination (Harrell's C=.65 in both datasets). PFS at 3 yr was 96%, 82%, and 63%, respectively (P Conclusions. BL-IPI is a novel prognostic index specific to BL, which was validated to allow for simplified stratification and comparison of risk distribution in geographically diverse cohorts. The index identified a low-risk group with PFS >90-95%, which could be targeted with future strategies for treatment de-escalation. Conversely, only about 55-60% of pts in the high-risk group achieved cure with currently available immunochemotherapy. Disclosures Olszewski: Spectrum Pharmaceuticals: Research Funding; Genentech, Inc.: Research Funding; TG Therapeutics: Research Funding; Adaptive Biotechnologies: Research Funding. Jakobsen:Takeda: Honoraria. Collins:ADC Therapeutics: Consultancy, Honoraria; Celleron: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Speakers Bureau; Amgen: Research Funding; BeiGene: Consultancy; BMS: Consultancy, Honoraria, Research Funding, Speakers Bureau; Gilead: Consultancy, Honoraria, Speakers Bureau; MSD: Consultancy, Honoraria, Research Funding; Taekda: Consultancy, Honoraria, Other: travel, accommodations, expenses, Speakers Bureau; Roche: Consultancy, Honoraria, Other: travel, accommodations, expenses , Speakers Bureau; Pfizer: Honoraria; Celgene: Research Funding. Cwynarski:Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel Support; Atara: 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, Speakers Bureau; KITE: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel Support, Speakers Bureau; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel Support, Speakers Bureau; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Roche: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel Support, Speakers Bureau. Bachanova:Incyte: Research Funding; Karyopharma: Membership on an entity's Board of Directors or advisory committees; BMS: Research Funding; FATE: Research Funding; Kite: Membership on an entity's Board of Directors or advisory committees; Gamida Cell: Membership on an entity's Board of Directors or advisory committees, Research Funding. Danilov:Abbvie: Consultancy; BeiGene: Consultancy; Nurix: Consultancy; Celgene: Consultancy; Gilead Sciences: Research Funding; Takeda Oncology: Research Funding; Pharmacyclics: Consultancy; Bayer Oncology: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; TG Therapeutics: Consultancy; Astra Zeneca: Consultancy, Research Funding; Verastem Oncology: Consultancy, Research Funding; Karyopharm: Consultancy; Aptose Biosciences: Research Funding; Bristol-Myers Squibb: Research Funding; Rigel Pharmaceuticals: Consultancy. Diefenbach:Trillium: Research Funding; Millenium/Takeda: Research Funding; MEI: Research Funding; Merck: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Genentech, Inc.: Consultancy, Research Funding; Incyte: Research Funding; LAM Therapeutics: Research Funding; Denovo: Research Funding. Epperla:Pharmacyclics: Honoraria; Verastem Oncology: Speakers Bureau. Farooq:Kite, a Gilead Company: Honoraria. Feldman:Pfizer: Research Funding; Portola: Research Funding; Janssen: Speakers Bureau; AstraZeneca: Consultancy; Cell Medica: Research Funding; Seattle Genetics, Inc.: Consultancy, Honoraria, Other: Travel expenses, Research Funding, Speakers Bureau; Viracta: Research Funding; Trillium: 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; Amgen: Research Funding; Pharmacyclics: Honoraria, Other, Speakers Bureau; Abbvie: Honoraria; Bayer: Consultancy, Honoraria; Eisai: Research Funding; Kyowa Kirin: Consultancy, Research Funding. Gerrie:AbbVie: Consultancy, Honoraria, Research Funding; Astrazeneca: Consultancy, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Roche: Research Funding; Sandoz: Consultancy. Jagadeesh:Regeneron: Research Funding; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Debiopharm Group: Research Funding; MEI Pharma: Research Funding; Verastem: Membership on an entity's Board of Directors or advisory committees. Kamdar:BMS: Consultancy; Abbvie: Consultancy; Karyopharm: Consultancy; Celgene: Consultancy; AstraZeneca: Consultancy; Pharmacyclics: Consultancy; Seattle Genetics: Speakers Bureau. Karmali:Takeda: Research Funding; AstraZeneca: Speakers Bureau; BeiGene: Speakers Bureau; Karyopharm: Honoraria; BMS/Celgene/Juno: Honoraria, Other, Research Funding, Speakers Bureau; Gilead/Kite: Honoraria, Other, Research Funding, Speakers Bureau. Khan:Seattle Genetics: Research Funding; Janssen: Honoraria; Pharmacyclics: Honoraria; Bristol Myers Squibb: Research Funding; Celgene: Research Funding. Klein:Takeda: Membership on an entity's Board of Directors or advisory committees. Lossos:Verastem: Consultancy, Honoraria; Stanford University: Patents & Royalties; Seattle Genetics: Consultancy, Other; Janssen Biotech: Honoraria; NCI: Research Funding; Janssen Scientific: Consultancy, Other. Lunning:ADC Therapeutics: Consultancy; Legend: Consultancy; Acrotech: Consultancy; AstraZeneca: Consultancy, Honoraria; Aeratech: Consultancy, Honoraria; Beigene: Consultancy, Honoraria; Verastem: Consultancy, Honoraria; TG Therapeutics: Research Funding; Novartis: Consultancy, Honoraria; Kite: Consultancy, Honoraria; Karyopharm: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Gilead: Consultancy, Honoraria; Curis: Research Funding; Bristol Meyers Squibb: Consultancy, Honoraria, Research Funding. Martin:I-MAB: Consultancy; Celgene: Consultancy; Teneobio: Consultancy; Karyopharm: Consultancy, Research Funding; Janssen: Consultancy; Sandoz: Consultancy; Bayer: Consultancy; Beigene: Consultancy; Cellectar: Consultancy; Incyte: Consultancy; Kite: Consultancy; Morphosys: Consultancy; Regeneron: Consultancy. Martinex-Calle:Abbvie: Other: Travel grant. Naik:Celgene: Other: advisory board; Sanofi: Other: advisory board. Palmisiano:Genentech: Research Funding; AbbVie: Research Funding. Phillips:Beigene: Honoraria; Roche: Research Funding. Phillips:Seattle Genetics: Consultancy; Incyte: Consultancy, Other: travel expenses; AstraZeneca: Consultancy; Karyopharm: Consultancy; Beigene: Consultancy; Bayer: Consultancy, Research Funding; BMS: Consultancy; Pharmacyclics: Consultancy; Abbvie: Consultancy, Research Funding; Cardinal Health: Consultancy. Portell:Roche/Genentech: Consultancy, Research Funding; Infinity: Research Funding; Bayer: Consultancy; Amgen: Consultancy; TG Therapeutics: Research Funding; AbbVie: Research Funding; Pharmacyclics: Consultancy; Janssen: Consultancy; Kite: Consultancy, Research Funding; Acerta/AstraZeneca: Research Funding; Xencor: Research Funding; BeiGene: Consultancy, Research Funding. Reddy:Celgene: Consultancy; BMS: Consultancy, Research Funding; Genentech: Research Funding; Abbvie: Consultancy; KITE Pharma: Consultancy. Yazdy:Abbvie: Consultancy; Genentech: Research Funding; Octapharma: Consultancy; Bayer: Honoraria. Smith:Bristol Meyers Squibb: Research Funding; Ayala: Research Funding; Seattle Genetics: Research Funding; Portola: Research Funding; Pharmacyclics: Research Funding; Merck: Research Funding; Incyte: Research Funding; Ignyta: Research Funding; Genentech: Research Funding; De Novo Biopharma: Research Funding; AstraZeneca: Consultancy; Millenium/Takeda: Consultancy; Beigene: Consultancy; Bayer: Research Funding; AstraZeneca: Research Funding; Acerta Pharma BV: Research Funding; Karyopharm: Consultancy. Cheah:Celgene, F. Hoffmann-La Roche, Abbvie, MSD: Research Funding; Celgene, F. Hoffmann-La Roche, MSD, Janssen, Gilead, Ascentage Pharma, Acerta, Loxo Oncology, TG therapeutics: Honoraria. El-Galaly:F. Hoffmann-La Roche: Current Employment, Other: Support of parent study and funding of editorial support. Evens:Research To Practice: Honoraria, Speakers Bureau; Mylteni: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria, Research Funding; Pharmacyclics: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Merck: Consultancy, Honoraria, Research Funding; Epizyme: Consultancy, Honoraria, Research Funding; MorphoSys: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria.

Background: T cell lymphomas (TCL) have been known to exhibit epigenetic dysregulation and aberrant cell signaling. Tenalisib (RP6530), a highly selective PI3K δ/γ+SIK3 inhibitor has shown clinically promising activity as a single agent in TCL with a differentiated and favorable safety profile. In vitro studies in TCL cell lines showed increased apoptosis when tenalisib was combined with romidepsin (Rhizen data on file). A Phase I/II study of tenalisib in combination with romidepsin was designed to assess safety, pharmacokinetics and efficacy in relapsed/refractory TCL (NCT03770000). Methods: This is a multi-center, open label, Phase I/II study in patients with T cell lymphoma (PTCL and CTCL). The Phase I is a 3+3 dose escalation study to determine the MTD/optimal dose. The Phase II is an expansion cohort at the MTD/optimal dose of the combination. Tenalisib was administered orally at doses of 400, 600 and 800 mg BID in combination with romidepsin (12 &14 mg/m2, Q3W). The objectives of the study are to establish safety, MTD/optimal dose, pharmacokinetics and anti-tumor activity of the combination. We report the dose escalation results and preliminary data from the expansion cohorts. Results: A total 15 patients were enrolled between July 24, 2019 and July 20, 2020. Baseline demographics are presented in Table 1. Patients had a median of 3 (range; 1-17) prior treatments and 11 (73%) were refractory to their last therapy. About 67% (6/9) of CTCL patients had prior mogamulizumab therapy. No DLT was reported in the dose escalation phase and Tenalisib 800 mg BID+ Romidepsin 14 mg/m2, Q3W was considered as the optimal dose for expansion cohorts. PK analysis showed linear and dose-dependent kinetics for tenalisib. Co-administration of romidepsin along with tenalisib did not significantly alter the mutual PK of either agents. Fifteen patients were assessed for safety. Most common treatment emergent adverse events of any grade were nausea (33%), thrombocytopenia (33%) and fatigue (27%). Related ≥ Grade 3 AEs were seen in 5 (33%) patients. These included thrombocytopenia (7%), atrial fibrillation (7%) and pyrexia (7%) which were related to romidepsin while anemia (7%) neutropenia (7%) and rash (7%) were considered related to the combination. There were no instances of transaminitis or colitis. None of the TEAEs led to study discontinuation. Patients from the dose escalation cohorts (n=9) were evaluated for response. Three patients (3/9) showed complete response (CR), 4 patients (4/9) showed stable disease (SD) while 2 patients (2/9) had progressive disease (PD). Out of the three responders, two were PTCL (AITL) patients, one of which is planned for transplantation, while the third patient was a CTCL (Sezary syndrome) patient who had progressed on prior mogamulizumab therapy. This patient showed rapid reduction of Sezary cell count after 2 cycles of treatment. Three patients (2 CR, 1 SD) are currently ongoing with a median duration of response being 9.0 (range; 7.6-10.5+) months. The expansion cohort has 6 patients and is currently enrolling. Conclusions: The combination of tenalisib and romidepsin demonstrates a favorable safety profile and promising indicators of combined anti-tumour activity in patients with R/R TCL. The expansion cohort in CTCL and PTCL is currently underway to validate these encouraging early results. Updated results will be presented during the ASH meeting. Disclosures Iyer: Afffimed: Research Funding; Rhizen: Research Funding; Seattle Genetics, Inc.: Research Funding; Curio Biosciences: Honoraria; Trillium: Research Funding; Daiichi Sankyo: Consultancy; Legend Biotech: Consultancy; Target Oncology: Honoraria; Spectrum: Research Funding; Merck: Research Funding; CRISPR: Research Funding. Huen:Seattle Genetics: Consultancy, Research Funding; Kyowa Kirin: Consultancy, Research Funding; Rhizen: Research Funding; Glaxo Smith Kline: Research Funding; Galderma: Research Funding; Miragen: Research Funding; Helsinn: Consultancy; Medivir: Research Funding. Haverkos:Viracta THerapeutics: Consultancy. Ai:ADC Therapeutics, Kymera: Membership on an entity's Board of Directors or advisory committees; Nurix Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding. Kuzel:Eselixis, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees; Genomic Health: Honoraria; Sanofi/Genzyme: Honoraria; Bioarray: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Marck: Membership on an entity's Board of Directors or advisory committees; Tyme: Membership on an entity's Board of Directors or advisory committees; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Cardinal Health: 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. Alderuccio:ADC Therapeutics: Membership on an entity's Board of Directors or advisory committees; Inovio Pharmaceuticals: Other: Family member; Foundation Medicine: Other: Family member; Puma Biotechnology: Other: Family member; Forma Therapeutics: Other: Family member; Agios Pharmaceuticals: Other: Family member; Oncinfo: Honoraria; OncLive: Honoraria. Stevens:Amgen, MorphoSys: Consultancy. Feldman:Viracta: Research Funding; Portola: Research Funding; Janssen: Speakers Bureau; AstraZeneca: Consultancy; Trillium: Research Funding; Amgen: Research Funding; Pfizer: Research Funding; Kyowa Kirin: Consultancy, Research Funding; Cell Medica: Research Funding; Rhizen: Research Funding; Corvus: Research Funding; BMS: Consultancy, Honoraria, Research Funding; Kite: Honoraria, Other: Travel expenses, Speakers Bureau; Celgene: Honoraria, Research Funding; Seattle Genetics, Inc.: Consultancy, Honoraria, Other: Travel expenses, Research Funding, Speakers Bureau; Takeda: Honoraria, Other: Travel expenses; Pharmacyclics: Honoraria, Other, Speakers Bureau; Abbvie: Honoraria; Bayer: Consultancy, Honoraria; Eisai: Research Funding. Jagadeesh:Seattle Genetics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Regeneron: Research Funding; Verastem: Membership on an entity's Board of Directors or advisory committees; Debiopharm Group: Research Funding; MEI Pharma: Research Funding. Reddy:KITE Pharma, Abbvie, BMS, Celgene: Consultancy; Genentech, BMS: Research Funding. Routhu:Rhizen Pharmaceuticals S.A>.: Current Employment. Barde:Rhizen Pharmaceuticals S.A: Current Employment. Nair:Rhizen Pharmaceuticals S.A.: Current Employment.

Background Primary CNS lymphoma (PCNSL) is a rare non-Hodgkin lymphoma that is often associated with immunosuppressed states. The Epstein-Barr Virus (EBV) may play a role in tumor pathogenicity in some cases. The objective of this study was to examine the patient characteristics, tumor pathology, and survival outcomes associated with EBV tumor status in patients with PCNSL. Methods This was a retrospective subset analysis from 17 academic medical centers that included 439 patients of ages 60 years and above with PCNSL (David K et al. ASH 2020). The associations between EBV status and clinical or demographical variables were tested by Fisher's exact test, Wilcoxon rank-sum test, or CMH trend test. Kaplan-Meier estimator was used to estimate survival probability. Survival difference between groups was tested by log-rank test for statistical significance. Confidence interval of survival rate was calculated using Greenwood's formula. Results A total of 247 patients with available EBV status were included in this analysis. Median age was 71 (range 60-84) and 44.5% were male. Notably, none of the patients were HIV-positive. Twenty-five patients (10.1%) had EBV positive tumors as detected by EBER (EBV-encoded RNA) in-situ hybridization or LMP1 immunohistochemistry (IHC), 17 of which were solid organ transplant (SOT)-related post-transplant lymphoproliferative disorders (PTLD) and 8 of which were not PTLD. All EBV-positive non-PTLDs were diffuse large B-cell lymphoma. Three (15%) SOT-related PTLDs were EBV-negative. Patient characteristics analyzed included age at diagnosis, sex, ECOG performance status, history of prior or concurrent malignancies, history of solid organ transplant or autoimmune disease, history of allogeneic stem cell transplant, and immunosuppressive treatment. Of these, only a history of solid organ transplant or autoimmune disease (P Tumor characteristics analyzed included expression of C-MYC, BCL2, CD5, cell of origin markers (BCL6, MUM1, CD10), and CD20 through IHC, C-MYC and BCL2 translocation through FISH, histology, and involvement of brain parenchyma, CSF, spinal cord, and eyes. EBV-positive tumors were associated with low C-MYC (p=0.047) and BCL6 (p=0.0006) expression on immunohistochemistry, but not other factors. There were no significant differences in tumor characteristics between those with EBV-positive PTLD and EBV-positive non-PTLD. Among patients with PTLD, 30% (n=6) did not receive primary chemotherapy, and the most common treatment regimens were high-dose methotrexate (HD-MTX) with or without rituximab (n=5) and rituximab alone (n=3). However, there was no significant difference in outcomes among PTLD patients who received chemotherapy or those who did not. Among EBV-positive non-PTLD patients, only 12.5% (n=1) did not receive primary chemotherapy and the most common treatment regimens were methotrexate/rituximab/temozolomide (n=3) and HD-MTX with or without rituximab (n=3). There was no difference in overall or progression free survival between patients with EBV-positive and EBV-negative tumors, or in outcomes among SOT-related PTLD patients regardless of EBV status. However, patients with EBV-positive non-PTLD PCNSL had better overall survival compared to patients with EBV-positive PTLD and EBV-negative tumors (p=0.033, Figure). Conclusions In this large observational study of older patients with PCNSL, the incidence of EBV positive tumors was overall low and was most commonly associated with SOT-related PTLD. Mycophenolate mofetil was the most common immunosuppressive medication. In those without PTLD, there were no patient or tumor factors that were associated with EBV status. Unexpectedly, non-PTLD EBV-positive PCNSL had superior outcomes to EBV-positive PTLD and EBV-negative PCNSL. Future studies of EBV-positive non-PTLDs are warranted to further evaluate the potential impact of EBV latency and the immune response on the tumor microenvironment. Disclosures Reddy: BMS: Consultancy, Research Funding; Celgene: Consultancy; Abbvie: Consultancy; Genentech: Research Funding; KITE Pharma: Consultancy. Bachanova:Karyopharma: Membership on an entity's Board of Directors or advisory committees; Kite: Membership on an entity's Board of Directors or advisory committees; BMS: Research Funding; FATE: Research Funding; Incyte: Research Funding; Gamida Cell: Membership on an entity's Board of Directors or advisory committees, Research Funding. Bond:Seattle Genetics: Honoraria. Goldlust:Tocagen: Membership on an entity's Board of Directors or advisory committees, Other: travel; BMS: Membership on an entity's Board of Directors or advisory committees, Other: travel; WEX: Consultancy, Other: travel; Cortice Bio: Consultancy, Other: travel; Boston Biomedical: Consultancy; COTA: Other; Novocure: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: travel, Research Funding, Speakers Bureau. Spurgeon:Gilead: Research Funding; Genentech: Research Funding; Cardinal Health: Honoraria; Bristol-Myers Squibb: Research Funding; VelosBio: Consultancy, Research Funding; Acerta: Research Funding; Janssen: Consultancy, Research Funding; AstraZeneca: Research Funding; Pharmacyclics: Consultancy; Beigene: Research Funding; Verastem: Research Funding; Genmab: Research Funding. Epperla:Verastem Oncology: Speakers Bureau; Pharmacyclics: Honoraria. Karmali:AstraZeneca: Speakers Bureau; Karyopharm: Honoraria; Takeda: Research Funding; BeiGene: Speakers Bureau; Gilead/Kite: Honoraria, Other, Research Funding, Speakers Bureau; BMS/Celgene/Juno: Honoraria, Other, Research Funding, Speakers Bureau. Naik:Celgene: Other: advisory board; Sanofi: Other: advisory board. Smith:Janssen: Consultancy; Celgene: Consultancy, Research Funding; Karyopharm: Consultancy, Research Funding; BMS: Consultancy; FortySeven: Research Funding; Pharmacyclics: Research Funding; Acerta: Research Funding; Genentech/Roche: Consultancy, Other: Support of parent study and funding of editorial support, Research Funding; TG Therapeutics: Consultancy, Research Funding. Rubenstein:Kymera: Research Funding. Kahl:BeiGene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; AstraZeneca Pharmaceuticals LP: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene Corporation: Consultancy; AbbVie: Consultancy; Genentech: Consultancy; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Acerta: Consultancy, Research Funding; ADC Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche Laboratories Inc: Consultancy; Pharmacyclics LLC: Consultancy. Evens:Abbvie: Consultancy, Honoraria; Research To Practice: Honoraria, Speakers Bureau; MorphoSys: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Pharmacyclics: Consultancy, Honoraria; Merck: Consultancy, Honoraria, Research Funding; Epizyme: Consultancy, Honoraria, Research Funding; Mylteni: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria, Research Funding. Martin:Kite: Consultancy; Morphosys: Consultancy; Regeneron: Consultancy; Incyte: Consultancy; Cellectar: Consultancy; Beigene: Consultancy; Bayer: Consultancy; I-MAB: Consultancy; Sandoz: Consultancy; Janssen: Consultancy; Karyopharm: Consultancy, Research Funding; Teneobio: Consultancy; Celgene: Consultancy.

Introduction: Treatment of older patients (pts) with PCNSL is challenging due to the prevalence of comorbidities, frailty, and complexities with delivery of chemotherapy (CT). The optimal induction CT and consolidation regimens for older PCNSL pts is unknown. Moreover, there are few large scale prognostication studies available, including analysis of geriatric assessments (GA). We analyzed detailed characteristics, treatment patterns and outcomes with prognostication across 17 academic centers. Methods: We conducted a large, RW retrospective study of newly diagnosed PCNSL pts (1/2008-1/2019) ages ≥ 60 years (yrs). Survival rates were estimated by Kaplan-Meier with differences assessed by log rank test. We detailed Cumulative Index Rating Scale-Geriatric (CIRS-G) scores & other GAs. Univariate associations were derived via Cox model with variables p Results: Among 491 initial cases, n=450 cases were verified for diagnosis & follow-up. Clinical features included: median age 71 yrs (60-88); male 47%; elevated LDH 30%; creatinine clearance 1 site). Cerebral involvement predominated in 75% with deep structure involvement in 20% & cerebellum in 5%. CSF involvement was documented in 13% of pts (unchecked in 26%). For GA at diagnosis, the median CIRS-G score was 6 (range 0-27) and impaired self-care activities of daily living (ADLs) were noted in 36%. Furthermore, geriatric syndrome (ie, dementia, delirium, depression, and/or falls) was present in 45% of pts. Induction therapy included CT in 91% of pts (of whom 82% had rituximab (Rtx)) and radiation therapy (RT) in 8%. The most common chemotherapy regimens were: high-dose methotrexate (HD MTX) or HD MTX with Rtx (MR) in 38%; HD MTX/procarbazine/vincristine (MPV) +/- Rtx 30%; HD MTX/temozolomide/Rtx (MTR) 22%; Rtx alone 2%; and HD MTX/cytarabine/thiotepa/Rtx (MATRIX) in 2%. Median MTX dosing for all pts was 3.5 g/m2 (range 1-8 g/m2), and by 3 most common regimens (all g/m2): MTR 5.1; MR 5.4; MPV 3.1 (P With 42 month median follow-up (1-125), 3-yr PFS & OS for all pts were 38% & 52%, respectively (Fig 1A/1B). On MVA, factors associated with inferior PFS were: advancing age (continuous HR 1.05, P Conclusions: Older pts with PCNSL have suboptimal outcomes, with 2/3 progressing in the first several years. GA is an important prognostic tool, and could be used to stratify pts in future investigations. In addition, use of Rtx, increasing MTX dose, and the MTR regimen were associated with improved outcomes. Disclosures Reddy: Genentech: Research Funding; Abbvie: Consultancy; KITE Pharma: Consultancy; Celgene: Consultancy; BMS: Consultancy, Research Funding. Bachanova:Gamida Cell: Membership on an entity's Board of Directors or advisory committees, Research Funding; Karyopharma: Membership on an entity's Board of Directors or advisory committees; Kite: Membership on an entity's Board of Directors or advisory committees; FATE: Research Funding; BMS: Research Funding; Incyte: Research Funding. Bond:Seattle Genetics: Honoraria. Goldlust:COTA: Other; BMS: Membership on an entity's Board of Directors or advisory committees, Other: travel; Tocagen: Membership on an entity's Board of Directors or advisory committees, Other: travel; Novocure: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: travel, Research Funding, Speakers Bureau; Boston Biomedical: Consultancy; Cortice Bio: Consultancy, Other: travel; WEX: Consultancy, Other: travel. Spurgeon:Beigene: Research Funding; Janssen: Consultancy, Research Funding; Pharmacyclics: Consultancy; Bristol-Myers Squibb: Research Funding; Genentech: Research Funding; Gilead: Research Funding; Acerta: Research Funding; AstraZeneca: Research Funding; Genmab: Research Funding; VelosBio: Consultancy, Research Funding; Cardinal Health: Honoraria; Verastem: Research Funding. Epperla:Verastem Oncology: Speakers Bureau; Pharmacyclics: Honoraria. Karmali:Takeda: Research Funding; Karyopharm: Honoraria; AstraZeneca: Speakers Bureau; BeiGene: Speakers Bureau; BMS/Celgene/Juno: Honoraria, Other, Research Funding, Speakers Bureau; Gilead/Kite: Honoraria, Other, Research Funding, Speakers Bureau. Naik:Celgene: Other: advisory board; Sanofi: Other: advisory board. Martin:Celgene: Consultancy; Bayer: Consultancy; Janssen: Consultancy; Sandoz: Consultancy; I-MAB: Consultancy; Teneobio: Consultancy; Beigene: Consultancy; Cellectar: Consultancy; Incyte: Consultancy; Kite: Consultancy; Morphosys: Consultancy; Karyopharm: Consultancy, Research Funding; Regeneron: Consultancy. Smith:Genentech/Roche: Consultancy, Other: Support of parent study and funding of editorial support, Research Funding; TG Therapeutics: Consultancy, Research Funding; FortySeven: Research Funding; Karyopharm: Consultancy, Research Funding; Pharmacyclics: Research Funding; BMS: Consultancy; Janssen: Consultancy; Celgene: Consultancy, Research Funding; Acerta: Research Funding. Rubenstein:Kymera: Research Funding. Kahl:ADC Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Consultancy; Celgene Corporation: Consultancy; AstraZeneca Pharmaceuticals LP: Consultancy, Membership on an entity's Board of Directors or advisory committees; Genentech: Consultancy; Pharmacyclics LLC: Consultancy; Roche Laboratories Inc: Consultancy; BeiGene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Acerta: Consultancy, Research Funding. Evens:Merck: Consultancy, Honoraria, Research Funding; Research To Practice: Honoraria, Speakers Bureau; Seattle Genetics: Consultancy, Honoraria, Research Funding; Pharmacyclics: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; Epizyme: Consultancy, Honoraria, Research Funding; MorphoSys: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Mylteni: Consultancy, Honoraria.

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

Background: The term HGBL, NOS was introduced by the World Health Organization (WHO) in 2016 for aggressive B-cell lymphomas with Burkitt lymphoma-like (BLL) or blastoid cytomorphology that lack double-hit genetics and do not meet criteria for other entities. Diagnostic patterns and prognosis of these rare tumors are not well understood. We examined the characteristics and outcomes of patients (pts) with HGBL, NOS diagnosed in 17 academic centers across the United States. Methods: We collected retrospective data on HGBL, NOS cases diagnosed by academic hematopathologists in 2017-2021; 8 centers performed a local review by lymphoma pathology experts to confirm fulfillment of the WHO criteria; pathology reports were reviewed centrally. We excluded pts not tested for MYC rearrangement (MYC-R), any double/triple-hit, diffuse large B-cell, or lymphoblastic lymphomas. Immunohistochemistry (IHC) and cytogenetic tests were done locally. Outcomes included rates of complete response (CR), progression-free (PFS) and overall survival (OS) estimated with 95% confidence intervals (CI). Results: Among 126 pts with HGBL, NOS, median age was 64 years (range 18-91), 67% were male, and 3 were HIV+. Advanced stage was present in 68%, poor performance status (PS, ECOG ≥2) in 21%, high serum lactate dehydrogenase (LDH) in 68%, extranodal (EN) sites in 79%, central nervous system (CNS) involvement in 6%, and International Prognostic Index (IPI) ≥ 3 in 55%. Cytomorphology was reported as BLL in 59 (47%) cases, blastoid in 28 (22%), and unspecified in 39 (31%). By IHC, 83% had germinal center B-cell (GCB) phenotype. Using cases with available data, CD10 was expressed in 79%, BCL6 in 81%, MUM1/IRF4 in 48%, MYC in 73%, BCL2 in 55% (dual MYC/BCL2 expressor [DEL]: 37%), CD5 in 13%, and median Ki-67 was 95%. MYC-R (single-hit) was detected in 27% (Fig A), MYC extra copies (EC) in 9%, BCL2-R in 13%, and BCL6-R in 10%. MYC-EC were present in 16% of cases with BCL2-R or BCL6-R, and BCL2/BCL6-EC in 12% of those with MYC-R. Blastoid tumors were more likely than BLL to involve >1 EN site or to have BCL2-R (Fig B). 9 cases were assessed by next generation sequencing and 5 (56%) had a TP53 mutation. Cases which underwent confirmatory pathology review (N=74) did not differ from others clinically but more often had a well-defined HGBL morphology (77% vs 58%, P=.031) and less often MYC-R (20% vs. 37%, P=.004). The most common first-line regimens (among treated pts, N=121) were DA-EPOCH-R (50%) and RCHOP (35%), with few pts receiving HyperCVAD/MA (5%) or CODOX-M±IVAC (2%); 97% received rituximab, and 44% CNS prophylaxis. Pts selected for DA-EPOCH-R vs. RCHOP were younger (median 61 vs. 68 years, P=.006), more often had stage 3/4 (P=.04), BLL morphology (56% vs. 29%, P=.009) or MYC-R (31% vs. 14%, P=.06). CR was attained in 62% of pts, whereas 20% had progressive disease. The most frequent salvage regimens (± rituximab) included ICE (N=12), DHAP (N=6), and GemOx (N=5). 3 pts underwent autologous, and 3 allogeneic transplant (2/3 subsequently relapsed). 13 received chimeric antigen receptor (CAR) T-cells, with response noted in 7 (54%) and CR in 4 (31%); HGBL relapsed in 3/7 (43%) responders. With median follow-up of 2.7 years, 39% of pts relapsed, and 33% died. Of 49 observed relapses, 13 (27%) involved the CNS. PFS estimate at 2 years was 51% (95% CI, 42-60%) and OS was 68% (95% CI, 58-76%; Fig C). PFS and OS were not significantly associated with age or PS, but stage and LDH were prognostic (Fig D-G). Furthermore, PFS did not differ by BLL/blastoid morphology, MYC-R status or DEL status, but non-GCB tumors had somewhat worse PFS (Fig H-J). We observed no significant PFS (or OS) difference between pts selected for RCHOP vs. DA-EPOCH-R (P=.83 for PFS, Fig K; P=.55 for OS) in aggregate or in any subset, except for de novo tumors with BLL morphology (N=41), where DA-EPOCH-R showed a superior 2-year PFS (73% vs 38% for RCHOP, P=.027; stratified by IPI: P=.040, Fig L). Conclusions: HGBL, NOS, as diagnosed in current academic practice, is highly heterogeneous, highlighting the need to classify high-grade lymphomas using molecular rather than morphologic features. Considering poor survival in all age groups (except for few pts with early stage and normal LDH), lack of prognostic significance of MYC-R, DEL status, or cytomorphology, HGBL, NOS needs prospective trials to delineate prognostic biomarkers, the role of intensified chemotherapy, and novel therapeutic approaches. Figure 1 Figure 1. Disclosures Landsburg: Triphase: Research Funding; Takeda: Research Funding; Curis: Research Funding; Incyte: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees, Other: DSMB member; ADCT: Membership on an entity's Board of Directors or advisory committees; Morphosys: Membership on an entity's Board of Directors or advisory committees. Hughes: Acerta Pharma: Research Funding; AstraZeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Genzyme: Consultancy; Janssen: Consultancy; Karyopharm: Membership on an entity's Board of Directors or advisory committees. Sandoval-Sus: SeaGen, Janssen, MassiveBio, TG: Other: Advisory Board; BMS: Other: Advisory Board, Speakers Bureau. Kothari: Incyte pharmaceuticals: Consultancy, Honoraria; Karyopharm pharmaceuticals: Consultancy, Honoraria. Torka: TG Therapeutics: Membership on an entity's Board of Directors or advisory committees. Smith: Acerta Pharma BV: Research Funding; ADC Therapeutics: Consultancy; AstraZeneca: Consultancy, Research Funding; De Novo Biopharma: Research Funding; Ignyta (spouse): Research Funding; Beigene: Consultancy, Research Funding; Portola Pharmaceuticals: Research Funding; Incyte: Consultancy; Incyte Corporation: Research Funding; Karyopharm: Consultancy; KITE pharm: Consultancy; Merck Sharp & Dohme Corp: Research Funding; Ayala (spouse): Research Funding; Bayer: Research Funding; Genentech: Research Funding; Bristol Myers Squibb (spouse): Research Funding; Millenium/Takeda: Consultancy. Epperla: Genzyme: Honoraria; Karyopharm: Other: Ad Board; Beigene: Speakers Bureau; Verastem: Speakers Bureau. Bond: Kite/Gilead: Honoraria. Naik: Sanofi: Other: Virtual Advisory Board Member ; Takeda: Other: Virtual Advisory Board Member ; Kite: Other: Virtual Advisory Board Member. Kamdar: ADC Therapeutics: Consultancy; AbbVie: Consultancy; KaryoPharm: Consultancy; Kite: Consultancy; Adaptive Biotechnologies: Consultancy; AstraZeneca: Consultancy; Celgene (BMS): Consultancy; TG Therapeutics: Research Funding; Genentech: Research Funding; Genetech: Other; Celgene: Other; SeaGen: Speakers Bureau. Haverkos: Viracta Therapeutics: Consultancy. Karmali: BMS/Celgene/Juno: Consultancy, Research Funding; Takeda: Research Funding; Roche: Consultancy; Epizyme: Consultancy; Janssen/Pharmacyclics: Consultancy; EUSA: Consultancy; Genentech: Consultancy; Karyopharm: Consultancy; AstraZeneca: Speakers Bureau; Kite, a Gilead Company: Consultancy, Research Funding, Speakers Bureau; Morphosys: Consultancy, Speakers Bureau; BeiGene: Consultancy, Speakers Bureau. Vose: Kite, a Gilead Company: Honoraria, Research Funding. Olszewski: PrecisionBio: Research Funding; Celldex Therapeutics: Research Funding; TG Therapeutics: Research Funding; Acrotech Pharma: Research Funding; Genentech, Inc.: Research Funding; Genmab: Research Funding.

Background: Covalent BTK inhibitors (BTKi) have transformed the management of chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), but these treatments are not curative and many patients (pts) will require additional treatment. Covalent BTKi share pharmacologic liabilities (e.g. low oral bioavailability, short half-life) that collectively may lead to suboptimal BTK target coverage, for example in rapidly proliferating tumors with high BTK protein turnover such as accelerating CLL/SLL, ultimately manifesting as acquired resistance in some pts. To address these limitations, pirtobrutinib, a highly selective, non-covalent BTKi that inhibits both wild type (WT) and C481-mutated BTK with equal low nM potency was developed. In the phase 1/2 BRUIN study, pirtobrutinib achieved pharmacokinetic exposures that exceeded its BTK IC96 at trough, was well tolerated and demonstrated promising efficacy in CLL/SLL pts regardless of prior therapy, number of prior lines of therapy, or BTK C481 mutation status(Mato et al. Lancet 2021;397,10277:892-901). Methods: BRUIN is a phase 1/2 multicenter study (NCT03740529) of oral pirtobrutinib monotherapy in pts with advanced B-cell malignancies who have received >2 prior therapies. Pirtobrutinib was dose escalated in a standard 3+3 design in 28-day cycles. The primary objective for phase 1 was to determine the recommended phase 2 dose (RP2D) and the primary objective of phase 2 was overall response rate (ORR); secondary objectives included duration of response (DoR), progression-free survival (PFS), overall survival (OS), safety and tolerability, and pharmacokinetics. Efficacy evaluable pts included all dosed pts who underwent their first response evaluation or discontinued therapy. Response was assessed every 8 weeks from cycle 3, and every 12 weeks from cycle 13 and was measured according to the iwCLL 2018 criteria, including PR with lymphocytosis (PR-L). Safety was assessed in all pts (CLL/SLL and NHL). Results: As of 27 September 2020, 323 pts with B-cell malignancies (170 CLL/SLL, 61 MCL, 26 WM, 26 DLBCL, 13 MZL, 12 FL, 9 RT, and 6 other [other transformation, B-PLL and hairy cell leukemia]) were treated on 7 dose levels (25-300mg QD). Among the 170 pts with CLL/SLL, the median age was 69 (range 36-88) years. Median number of prior lines of therapies was 3 (range 1-11). Majority of the CLL/SLL pts had received a prior BTKi (86%), an anti-CD20 antibody (90%), or a chemotherapy (82%); 21% had received a PI3K inhibitor and 34% a BCL2 inhibitor. High risk molecular features such as 17p deletion, TP53 mutation, and unmutated IGHV were present in 25% (20/81), 30% (27/91), and 88% (71/81) of pts, respectively. No DLTs were reported and MTD was not reached (n=323). 200mg QD was selected as the RP2D. Fatigue (20%), diarrhea (17%), and contusion (13%) were the most frequent treatment-emergent adverse events regardless of attribution or grade seen in >10% of pts (n=323). The most common adverse event of grade ≥3 was neutropenia (10%). Treatment-related hemorrhage and hypertension occurred in 5 (2%) and 4 (1%) pts, respectively. Five (1%) pts discontinued due to treatment-related adverse events. At the efficacy cutoff date, 139 CLL/SLL pts were efficacy-evaluable with a median follow up time of 6 months (range 0.16-17.8+). The ORR was 63% (95% CI 55-71) among the 139 efficacy evaluable pts with 69 PRs (50%), 19 PR-Ls (14%), 45 SDs (32%), and 1 PD (1%), and 5 (4%) pts discontinued prior to first response assessment. Among the 121 BTKi pretreated pts, the ORR was 62% (95% CI 53-71). Responses deepened over time with an ORR of 86% among the pts with at least 10 months follow-up. ORR was similar in pts who discontinued prior BTKi due to progression (67%), or adverse events or other reasons (52%). Of the 88 responding pts, all except 5 remained on therapy (4 progressed and 1 achieved a PR and electively discontinued treatment to undergo transplant). The longest-followed responding patient as of the data cutoff date had been on treatment for 17.8+ months. Conclusion: Pirtobrutinib demonstrated promising efficacy in heavily pretreated CLL/SLL pts following multiple prior lines of therapy, including a covalent BTKi and a BCL2 inhibitor, and in pts with BTK C481 mutations. Pirtobrutinib was well tolerated and exhibited a wide therapeutic index. Updated data, including approximately 100 new pts with CLL and an additional 10 months since the prior data cut will be presented. Disclosures Mato: MSKCC: Current Employment; Acerta/AstraZeneca: Consultancy, Research Funding; AstraZeneca: Consultancy; Johnson and Johnson: Consultancy, Research Funding; AbbVie: Consultancy, Research Funding; Genmab: Research Funding; TG Therapeutics: Consultancy, Other: DSMB, Research Funding; Janssen: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; Adaptive Biotechnologies: Consultancy, Research Funding; DTRM BioPharma: Consultancy, Research Funding; LOXO: Consultancy, Research Funding; Nurix: Research Funding; Pharmacyclics LLC, an AbbVie Company: Consultancy, Research Funding; BeiGene: Consultancy, Research Funding; Sunesis: Consultancy, Research Funding. Pagel: AstraZeneca: Consultancy; Gilead: Consultancy; Pharmacyclics/AbbVie: Consultancy; BeiGene: Consultancy; Epizyme: Consultancy; MEI Pharma: Consultancy; Kite, a Gilead Company: Consultancy; Actinium Pharmaceuticals: Consultancy; Incyte/MorphoSys: Consultancy. Coombs: LOXO: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria; AstraZeneca: Honoraria; AbbVie: Honoraria; Genentech: Honoraria; MEI Pharma: Honoraria. Shah: Incyte: Consultancy; Miltenyi Biotec: Consultancy, Honoraria, Research Funding; Umoja: Consultancy; Lily: Consultancy, Honoraria, Research Funding; Legend: Consultancy; Epizyme: Consultancy; Kite: Consultancy. Lamanna: AstraZeneca: Consultancy, Research Funding; TG Therapeutics, Inc: Research Funding; Juno Therapeutics, Inc.: Research Funding; Genentech, Inc.: Consultancy, Research Funding; Oncternal Therapeutics: Research Funding; AbbVie: Consultancy, Research Funding; BeiGene: Consultancy; Celgene Corporation: Consultancy; Verastem Oncology: Research Funding; Janssen Pharmaceuticals, Inc.: Consultancy; MingSight Pharmaceuticals, Inc.: Research Funding; Pharmacyclics: Consultancy; Gilead Sciences, Inc.: Consultancy. Munir: Janssen, Abbvie, AstraZeneca, Alexion, Apellis, Gilead, Novartis: Honoraria; Janssen, Abbvie, AstraZeneca, Morphosys, Alexion, Gilead, Novartis: Membership on an entity's Board of Directors or advisory committees. Lech-Marańda: Takeda: Membership on an entity's Board of Directors or advisory committees; Janssen-Cilag: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Sanofi: 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; Gilead: 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. Eyre: Janssen: Honoraria; Roche: Consultancy, Honoraria; AstraZeneca: Honoraria, Research Funding; Abbvie: Consultancy, Honoraria, Other: Travel to conferences; Gilead/KITE: Honoraria, Other: Travel support for conferences, Research Funding, Speakers Bureau; Incyte: Consultancy; Secura Bio: Consultancy, Honoraria; Beigene: Honoraria, Research Funding; Loxo Oncology: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Woyach: AbbVie Inc, Loxo Oncology Inc, a wholly owned subsidiary of Eli Lilly & Company: Research Funding; Gilead Sciences Inc: Other: Data & Safety; AbbVie Inc, ArQule Inc, Janssen Biotech Inc, AstraZeneca, Beigene: Other: Advisory Committee; AbbVie Inc, ArQule Inc, AstraZeneca Pharmaceuticals LP, Janssen Biotech Inc, Pharmacyclics LLC, an AbbVie Company,: Consultancy. Wierda: Xencor: Research Funding; Gilead Sciences: Research Funding; Karyopharm: Research Funding; Acerta Pharma Inc.: Research Funding; KITE Pharma: Research Funding; Pharmacyclics LLC, an AbbVie Company: Research Funding; Sunesis: Research Funding; Miragen: Research Funding; Oncternal Therapeutics, Inc.: Research Funding; AbbVie: Research Funding; Loxo Oncology, Inc.: Research Funding; Genzyme Corporation: Consultancy; Juno Therapeutics: Research Funding; GSK/Novartis: Research Funding; Cyclacel: Research Funding; Janssen: Research Funding; Genentech: Research Funding; AstraZeneca: Research Funding. Cheah: TG Therapeutics: Consultancy, Honoraria, Other: advisory; AbbVie: Research Funding; Celgene: Research Funding; AstraZeneca: Consultancy, Honoraria, Other: advisory; MSD: Consultancy, Honoraria, Other: advisory, Research Funding; Janssen: Consultancy, Honoraria, Other: advisory; Roche: Consultancy, Honoraria, Other: advisory and travel expenses, Research Funding; Gilead: Consultancy, Honoraria, Other: advisory; Loxo/Lilly: Consultancy, Honoraria, Other: advisory; Beigene: Consultancy, Honoraria, Other: advisory; Ascentage pharma: Consultancy, Honoraria, Other: advisory. Cohen: Genentech, BMS/Celgene, LAM, BioINvent, LOXO, Astra Zeneca, Novartis, M2Gen, Takeda: Research Funding; Janssen, Adicet, Astra Zeneca, Genentech, Aptitude Health, Cellectar, Kite/Gilead, Loxo, BeiGene, Adaptive: Consultancy. Roeker: Pfizer: Consultancy, Research Funding; TG Therapeutics: Consultancy; Pharmacyclics: Consultancy; Loxo Oncology: Consultancy; Abbot Laboratories: Current equity holder in publicly-traded company; AbbVie, AstraZeneca, Janssen, LOXO, Pharmacyclics, TG Therapeutics, Vaniam Group, Verastem: Consultancy. Patel: H3 Biomedicine: Research Funding; Ribon Therapeutics: Research Funding; Evelo Biosciences: Research Funding; Aileron Therapeutics: Research Funding; Portola Pharmaceuticals: Research Funding; Phoenix Molecular Designs: Research Funding; Jacobio: Research Funding; Placon Therapeutics: Research Funding; Forma Therapeutics: Research Funding; Ciclomed: Research Funding; Clovis: Research Funding; Curis: Research Funding; Cyteir Therapeutics: Research Funding; Daiichi Sankyo: Research Funding; Effector Therapeutics: Research Funding; Eli Lilly: Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Jounce Therapeutics: Research Funding; Klus Pharma: Research Funding; Kymab: Research Funding; Loxo Oncology: Research Funding; LSK Biopartners: Research Funding; Lycera: Research Funding; Mabspace: Research Funding; AstraZeneca: Research Funding; Bicycle Therapeutics: Research Funding; BioNTech: Research Funding; Boehringer Ingelheim: Research Funding; Takeda: Research Funding; Tesaro: Research Funding; TopAlliance: Research Funding; Vedanta: Research Funding; Verastem: Research Funding; Vigeo: Research Funding; Xencor: Research Funding; Exelixis: Membership on an entity's Board of Directors or advisory committees; Bayer: Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees; Alexion, AstraZeneca Rare Disease: Other: Study investigator; Taiho: Research Funding; Stemline Therapeutics: Research Funding; Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding; ORIC Pharmaceuticals: Research Funding; ModernaTX: Research Funding; Mirati Therapeutics: Research Funding; Millennium Pharmaceuticals: Research Funding; Ignyta: Research Funding; Checkpoint Therapeutics: Research Funding; Synthorx: Research Funding; Prelude Therapeutics: Research Funding; Merck: Research Funding; Agenus: Research Funding; ADC Therapeutics: Research Funding; Acerta Pharma: Research Funding; Florida Cancer Specialists: Research Funding; GlaxoSmithKline: Research Funding; Revolution Medicines: Research Funding; Gilead: Research Funding; EMD Serono: Membership on an entity's Board of Directors or advisory committees, Research Funding; Calithera: Research Funding; Artios Pharma: Research Funding; Hutchinson MediPharma: Research Funding; Syndax: Research Funding; Qilu Puget Sound Biotherapeutics: Research Funding; Macrogenics: Research Funding; Incyte: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Seven and Eight Biopharmaceuticals: Research Funding; Hengrui: Research Funding; Genentech/Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding. Fakhri: Loxo/Lilly: Research Funding. Tam: Loxo: Consultancy; Janssen: Consultancy, Honoraria, Research Funding; BeiGene: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria, Research Funding; Roche: Consultancy, Honoraria; Novartis: Honoraria; Pharmacyclics: Honoraria. Lewis: Loxo Oncology at Lilly: Membership on an entity's Board of Directors or advisory committees. Gerson: Abbvie, Genentech: Membership on an entity's Board of Directors or advisory committees; Loxo Oncology at Lilly: Research Funding. Alencar: Amgen: Consultancy; BeiGene: Consultancy; Celgene: Consultancy; Epizyme: Consultancy; Incyte: Consultancy; Janssen: Consultancy; Karyopharm: Consultancy; Kite Pharma: Consultancy; Seattle Genetics: Consultancy. Ujjani: Kite, a Gilead Company: Honoraria; ACDT: Honoraria; Gilead: Honoraria; Janssen: Consultancy; TG Therapeutics: Honoraria; Epizyme: Consultancy, Membership on an entity's Board of Directors or advisory committees; Atara Bio: Consultancy; Loxo: Research Funding; Adaptive Biotechnologies: Research Funding; AstraZeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Consultancy, Research Funding; Pharmacyclics: Consultancy, Research Funding. Flinn: Celgene: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Trillium Therapeutics: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Gilead Sciences: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; BeiGene: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Genentech: Consultancy, Other: All consultancy and 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; AstraZeneca: 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; Iksuda Therapeutics: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Portola Pharmaceuticals: 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; Loxo: 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; Kite, a Gilead Company: Consultancy, Other: All consultancy and 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; Rhizen Pharmaceuticals: Other: All 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; Janssen: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Constellation Pharmaceuticals: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Great Point Partners: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Teva: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Curis: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Forma Therapeutics: 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; Takeda: 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; Juno Therapeutics: 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; Forty Seven: 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; Novartis: 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; Nurix Therapeutics: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; ArQule: 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; Agios: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Verastem: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Unum Therapeutics: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Yingli Pharmaceuticals: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Acerta Pharma: Other: All 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; 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. Ma: Loxo: Research Funding; AstraZeneca: Honoraria, Research Funding, Speakers Bureau; Juno: Research Funding; Beigene: Research Funding, Speakers Bureau; Abbvie: Honoraria, Research Funding; Janssen: Research Funding, Speakers Bureau; TG Therapeutics: Research Funding; Pharmacyclics: Research Funding, Speakers Bureau. Rhodes: Conquer Cancer Foundation Young Investigator Award: Other: Grant/Research Support; AbbVie, Genentech, Pharmacyclics, TG Therapeutics: Other: Consultant. Abdel-Wahab: H3B Biomedicine: Consultancy, Research Funding; Foundation Medicine Inc: Consultancy; Merck: Consultancy; Prelude Therapeutics: Consultancy; LOXO Oncology: Consultancy, Research Funding; Lilly: Consultancy; AIChemy: Current holder of stock options in a privately-held company, Membership on an entity's Board of Directors or advisory committees; Envisagenics Inc.: Current holder of stock options in a privately-held company, Membership on an entity's Board of Directors or advisory committees. Ghia: Gilead: Consultancy, Research Funding; Roche: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria, Research Funding; Acerta/AstraZeneca: Consultancy, Honoraria, Research Funding; ArQule/MSD: Consultancy, Honoraria; AstraZeneca: Consultancy, Honoraria, Research Funding; BeiGene: Consultancy, Honoraria; Celgene/Juno/BMS: Consultancy, Honoraria; Sunesis: Research Funding. Schuster: Abbvie: Consultancy, Research Funding; Incyte: Research Funding; TG Theraputics: Research Funding; Tessa Theraputics: Consultancy; Acerta Pharma/AstraZeneca: Consultancy; Nordic Nanovector: Consultancy; Novartis: Consultancy, Honoraria, Patents & Royalties, Research Funding; Alimera Sciences: Consultancy; BeiGene: Consultancy; Juno Theraputics: Consultancy, Research Funding; Loxo Oncology: Consultancy; Genentech/Roche: Consultancy, Research Funding; Merck: Research Funding; Pharmacyclics: Research Funding; Adaptive Biotechnologies: Research Funding; Celgene: Consultancy, Honoraria, Research Funding. Wang: Loxo Oncology at Lilly: Current Employment. Nair: Loxo Oncology at Lilly: Current Employment, Current equity holder in publicly-traded company. Zhu: Loxo Oncology at Lilly: Current Employment, Current equity holder in publicly-traded company. Tsai: Loxo Oncology at Lilly: Current Employment, Current equity holder in publicly-traded company. Davids: AbbVie: Consultancy; Verastem: Consultancy, Research Funding; MEI Pharma: Consultancy; Surface Oncology: Research Funding; Eli Lilly and Company: Consultancy; Adaptive Biotechnologies: Consultancy; BeiGene: Consultancy; Astra-Zeneca: Consultancy, Research Funding; Pharmacyclics: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; MEI Pharma: Consultancy, Research Funding; Janssen: Consultancy; Celgene: Consultancy; TG Therapeutics: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Merck: Consultancy; Research to Practice: Consultancy; Takeda: Consultancy; Ascentage Pharma: Consultancy, Research Funding. Brown: Genentech/Roche: Consultancy; Invectys: Other: Data Safety Monitoring Committee Service; SecuraBio: Research Funding; Sun: Research Funding; TG Therapeutics: Research Funding; Loxo/Lilly: Research Funding; Eli Lilly and Company: Consultancy; MEI Pharma: Consultancy; Morphosys AG: Consultancy; Nextcea: Consultancy; Janssen: Consultancy; Novartis: Consultancy; Pfizer: Consultancy; Rigel: Consultancy; Acerta/Astra-Zeneca: Consultancy; Beigene: Consultancy; Gilead: Research Funding; Abbvie: Consultancy; Bristol-Myers Squib/Juno/Celegene: Consultancy; Catapult: Consultancy. Jurczak: European Medicines Agency, Sandoz-Novartis, Janssen China R&D, BeiGene, Epizyme, Acerta, AstraZeneca: Consultancy; AstraZeneca, BeiGene, Janssen, Loxo Oncology, Sandoz, Roche: Membership on an entity's Board of Directors or advisory committees; AbbVie, AstraZeneca, Bayer, BeiGene, Celtrion, Celgene, Debbiopharm, Epizyme, Incyte, Janssen, Loxo Oncology, Merck, Mei Pharma, Morphosys, Novo Nordisk, Roche, Sandoz, Takeda, TG Therapeutics, Pharmacyclics, Affirmed, Gilead Sciences, Nordic Nanovecto: Research Funding; Maria Sklodowska-Curie National Research Institute of Oncology: Current Employment; Jagiellonian University: Ended employment in the past 24 months.

Background: Covalent BTK inhibitors (BTKi) have transformed the management of mantle cell lymphoma (MCL), but these treatments are not curative and the majority of patients (pts) will require additional treatment. Covalent BTKi share pharmacologic liabilities (e.g. low oral bioavailability, short half-life) that collectively may lead to suboptimal BTK target coverage, for example in rapidly proliferating tumors with high BTK protein turnover such as MCL. To address these limitations, pirtobrutinib, a highly selective, non-covalent BTKi that inhibits both wild type (WT) and C481-mutated BTK with equal low nM potency was developed. In the phase 1/2 BRUIN study, pirtobrutinib achieved pharmacokinetic exposures that exceeded its BTK IC96 at trough, was well tolerated and demonstrated promising efficacy in heavily pretreated, poor-prognosis MCL pts, most of whom had prior treatment with a covalent BTKi (Mato et al. Lancet 2021;397, 10277:892-901). Methods: BRUIN is a multicenter phase 1/2 study (NCT03740529) of oral pirtobrutinib monotherapy in pts with advanced B-cell malignancies who have received >2 prior therapies. Pirtobrutinib was dose escalated in a standard 3+3 design in 28-day cycles. The primary objective for phase 1 was to determine the recommended phase 2 dose (RP2D) and the primary objective of phase 2 was overall response rate (ORR); secondary objectives included duration of response (DoR), progression-free survival (PFS), overall survival (OS), safety and tolerability, and pharmacokinetics. Efficacy evaluable pts included all dosed pts who underwent their first response evaluation or discontinued therapy. Response was assessed every 8 weeks from cycle 3, and every 12 weeks from cycle 13 and was measured according to Lugano Classification. Safety was assessed in all pts (CLL/SLL and NHL). Results: As of 27 September 2020, 323 pts (170 CLL/SLL, 61 MCL, 26 WM, 26 DLBCL, 13 MZL, 12 FL, 9 RT, and 6 other NHL [other transformation, B-PLL and hairy cell leukemia]) were treated on 7 dose levels (25-300mg QD). Median age was 69 (range 50-87) years for MCL pts. Among the 61 MCL pts, median number of prior lines of therapy was 3 (range, 1-8) and a majority of them had received a prior BTKi (93%), an anti-CD20 antibody (98%) or chemotherapy (92%). No DLTs were reported and MTD was not reached (n=323). 200mg QD was selected as the RP2D. Fatigue (20%), diarrhea (17%), and contusion (13%) were the most frequent treatment-emergent adverse events regardless of attribution or grade seen in >10% of pts (n=323). The most common adverse event of grade ≥3 was neutropenia (10%). Treatment-related hemorrhage and hypertension occurred in 5 (2%) and 4 (1%) pts, respectively. Five (1%) pts discontinued due to treatment-related adverse events. At the efficacy cutoff date, 52 prior BTKi treated MCL pts were efficacy evaluable with an ORR of 52% (95% CI 38-66; 13 CR [25%], 14 PR [27%], 9 SD [17%], 11 PD [21%] and 5 [10%] pts discontinued prior to first response assessment). Median follow up was 6 months (range 0.7-18.3+). Responses were observed in 9/14 pts (64%) with prior autologous or allogeneic stem cell transplant, and 2 of 2 with prior CAR-T cell therapy. Conclusion: Pirtobrutinib demonstrated promising efficacy in heavily pretreated, poor-prognosis MCL following multiple prior lines of therapy, including a covalent BTKi. Pirtobrutinib was well tolerated and exhibited a wide therapeutic index. Updated data, including approximately 60 new pts with MCL and an additional 10 months since the prior data cut will be presented. Disclosures Wang: Juno: Consultancy, Research Funding; Miltenyi Biomedicine GmbH: Consultancy, Honoraria; Lilly: Research Funding; Moffit Cancer Center: Honoraria; Newbridge Pharmaceuticals: Honoraria; VelosBio: Consultancy, Research Funding; OMI: Honoraria; BGICS: Honoraria; Mumbai Hematology Group: Honoraria; BioInvent: Research Funding; CStone: Consultancy; Hebei Cancer Prevention Federation: Honoraria; Celgene: Research Funding; Oncternal: Consultancy, Research Funding; Molecular Templates: Research Funding; Epizyme: Consultancy, Honoraria; InnoCare: Consultancy, Research Funding; Pharmacyclics: Consultancy, Research Funding; Clinical Care Options: Honoraria; AstraZeneca: Consultancy, Honoraria, Research Funding; Chinese Medical Association: Honoraria; Scripps: Honoraria; Imedex: Honoraria; Physicians Education Resources (PER): Honoraria; The First Afflicted Hospital of Zhejiang University: Honoraria; DTRM Biopharma (Cayman) Limited: Consultancy; Dava Oncology: Honoraria; Genentech: Consultancy; Janssen: Consultancy, Honoraria, Research Funding; Anticancer Association: Honoraria; BeiGene: Consultancy, Honoraria, Research Funding; CAHON: Honoraria; Kite Pharma: Consultancy, Honoraria, Research Funding; Bayer Healthcare: Consultancy; Loxo Oncology: Consultancy, Research Funding; Acerta Pharma: Consultancy, Honoraria, Research Funding. Shah: Epizyme: Consultancy; Miltenyi Biotec: Consultancy, Honoraria, Research Funding; Lily: Consultancy, Honoraria, Research Funding; Incyte: Consultancy; Umoja: Consultancy; Kite: Consultancy; Legend: Consultancy. Alencar: Amgen: Consultancy; BeiGene: Consultancy; Celgene: Consultancy; Epizyme: Consultancy; Incyte: Consultancy; Janssen: Consultancy; Karyopharm: Consultancy; Kite Pharma: Consultancy; Seattle Genetics: Consultancy. Gerson: Abbvie, Genentech: Membership on an entity's Board of Directors or advisory committees; Loxo Oncology at Lilly: Research Funding. Patel: Hutchinson MediPharma: Research Funding; Florida Cancer Specialists: Research Funding; Mirati Therapeutics: Research Funding; Lycera: Research Funding; Millennium Pharmaceuticals: Research Funding; Mabspace: Research Funding; Macrogenics: Research Funding; Merck: Research Funding; Daiichi Sankyo: Research Funding; Effector Therapeutics: Research Funding; Cyteir Therapeutics: Research Funding; ADC Therapeutics: Research Funding; Vedanta: Research Funding; Loxo Oncology: Research Funding; Forma Therapeutics: Research Funding; Genentech/Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Research Funding; GlaxoSmithKline: Research Funding; LSK Biopartners: Research Funding; ModernaTX: Research Funding; ORIC Pharmaceuticals: Research Funding; Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding; Phoenix Molecular Designs: Research Funding; Placon Therapeutics: Research Funding; Portola Pharmaceuticals: Research Funding; Prelude Therapeutics: Research Funding; Qilu Puget Sound Biotherapeutics: Research Funding; Revolution Medicines: Research Funding; Ribon Therapeutics: Research Funding; Exelixis: Membership on an entity's Board of Directors or advisory committees; Bayer: Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees; Alexion, AstraZeneca Rare Disease: Other: Study investigator; Evelo Biosciences: Research Funding; EMD Serono: Membership on an entity's Board of Directors or advisory committees, Research Funding; Boehringer Ingelheim: Research Funding; Eli Lilly: Research Funding; Curis: Research Funding; Jacobio: Research Funding; Acerta Pharma: Research Funding; AstraZeneca: Research Funding; Ciclomed: Research Funding; BioNTech: Research Funding; Clovis: Research Funding; Checkpoint Therapeutics: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Calithera: Research Funding; Bicycle Therapeutics: Research Funding; Artios Pharma: Research Funding; TopAlliance: Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Stemline Therapeutics: Research Funding; Seven and Eight Biopharmaceuticals: Research Funding; Taiho: Research Funding; H3 Biomedicine: Research Funding; Vigeo: Research Funding; Tesaro: Research Funding; Aileron Therapeutics: Research Funding; Agenus: Research Funding; Ignyta: Research Funding; Xencor: Research Funding; Syndax: Research Funding; Synthorx: Research Funding; Incyte: Research Funding; Kymab: Research Funding; Hengrui: Research Funding; Verastem: Research Funding; Takeda: Research Funding; Klus Pharma: Research Funding; Jounce Therapeutics: Research Funding. Fakhri: Loxo/Lilly: Research Funding. Jurczak: European Medicines Agency, Sandoz-Novartis, Janssen China R&D, BeiGene, Epizyme, Acerta, AstraZeneca: Consultancy; Jagiellonian University: Ended employment in the past 24 months; AbbVie, AstraZeneca, Bayer, BeiGene, Celtrion, Celgene, Debbiopharm, Epizyme, Incyte, Janssen, Loxo Oncology, Merck, Mei Pharma, Morphosys, Novo Nordisk, Roche, Sandoz, Takeda, TG Therapeutics, Pharmacyclics, Affirmed, Gilead Sciences, Nordic Nanovecto: Research Funding; AstraZeneca, BeiGene, Janssen, Loxo Oncology, Sandoz, Roche: Membership on an entity's Board of Directors or advisory committees; Maria Sklodowska-Curie National Research Institute of Oncology: Current Employment. Lewis: AstraZeneca: Consultancy, Honoraria; Janssen: Honoraria, Patents & Royalties; Novartis: Patents & Royalties; Roche: Consultancy, Honoraria. Fenske: Sanofi: Speakers Bureau; Pharmacyclics: Consultancy; Servier Pharmaceuticals: Consultancy; Kite (Gilead): Speakers Bureau; MorphoSys: Consultancy; TG Therapeutics: Consultancy, Speakers Bureau; Seattle Genetics: Speakers Bureau; KaryoPharm: Consultancy; CSL Therapeutics: Consultancy; Bristol-Myers Squibb: Speakers Bureau; Biogen: Consultancy; Beigene: Consultancy; AstraZeneca: Speakers Bureau; ADC Therapeutics: Consultancy; Adaptive Biotechnologies: Consultancy; AbbVie: Consultancy. Coombs: LOXO: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria; AstraZeneca: Honoraria; AbbVie: Honoraria; Genentech: Honoraria; MEI Pharma: Honoraria. Flinn: Celgene: Other: All 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; Takeda: Consultancy, Other: All consultancy and 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; Kite, a Gilead Company: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Pharmacyclics LLC, an AbbVie Company: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; ArQule: 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; IGM Biosciences: 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; Triphase Research & Development Corp.: Other: All 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; Merck: 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; Juno Therapeutics: 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; Calithera Biosciences: 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; Seagen: 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; Verastem: 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; MorphoSys: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Constellation Pharmaceuticals: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Loxo: 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; Karyopharm Therapeutics: 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; Curis: 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; Pfizer: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Trillium Therapeutics: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Portola 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; Teva: 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; BeiGene: 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; Gilead Sciences: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Great Point Partners: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Iksuda Therapeutics: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Janssen: Consultancy, Other: All consultancy and 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. Lewis: Loxo Oncology at Lilly: Membership on an entity's Board of Directors or advisory committees. Palomba: Pluto: Honoraria; Priothera: Honoraria; Wolters Kluwer: Patents & Royalties; WindMIL: Honoraria; Notch: Honoraria, Other: Stock; Ceramedix: Honoraria; Novartis: Consultancy; Kite: Consultancy; PCYC: Consultancy; Lygenesis: Honoraria; Seres: Honoraria, Other: Stock, Patents & Royalties, Research Funding; Juno: Patents & Royalties; Nektar: Honoraria; Rheos: Honoraria; BeiGene: Consultancy; Magenta: Honoraria. Woyach: AbbVie Inc, ArQule Inc, Janssen Biotech Inc, AstraZeneca, Beigene: Other: Advisory Committee; AbbVie Inc, ArQule Inc, AstraZeneca Pharmaceuticals LP, Janssen Biotech Inc, Pharmacyclics LLC, an AbbVie Company,: Consultancy; AbbVie Inc, Loxo Oncology Inc, a wholly owned subsidiary of Eli Lilly & Company: Research Funding; Gilead Sciences Inc: Other: Data & Safety. Pagel: Pharmacyclics/AbbVie: Consultancy; Epizyme: Consultancy; MEI Pharma: Consultancy; Actinium Pharmaceuticals: Consultancy; Incyte/MorphoSys: Consultancy; AstraZeneca: Consultancy; Kite, a Gilead Company: Consultancy; BeiGene: Consultancy; Gilead: Consultancy. Lamanna: Juno Therapeutics, Inc.: Research Funding; Pharmacyclics: Consultancy; MingSight Pharmaceuticals, Inc.: Research Funding; Janssen Pharmaceuticals, Inc.: Consultancy; TG Therapeutics, Inc: Research Funding; Oncternal Therapeutics: Research Funding; AbbVie: Consultancy, Research Funding; AstraZeneca: Consultancy, Research Funding; BeiGene: Consultancy; Celgene Corporation: Consultancy; Genentech, Inc.: Consultancy, Research Funding; Gilead Sciences, Inc.: Consultancy; Verastem Oncology: Research Funding. Cohen: Genentech, BMS/Celgene, LAM, BioINvent, LOXO, Astra Zeneca, Novartis, M2Gen, Takeda: Research Funding; Janssen, Adicet, Astra Zeneca, Genentech, Aptitude Health, Cellectar, Kite/Gilead, Loxo, BeiGene, Adaptive: Consultancy. Ghia: AbbVie: Consultancy, Honoraria, Research Funding; Sunesis: Research Funding; Roche: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Research Funding; Acerta/AstraZeneca: Consultancy, Honoraria, Research Funding; AstraZeneca: Consultancy, Honoraria, Research Funding; BeiGene: Consultancy, Honoraria; ArQule/MSD: Consultancy, Honoraria; Celgene/Juno/BMS: Consultancy, Honoraria; Gilead: Consultancy, Research Funding. Eyre: Abbvie: Consultancy, Honoraria, Other: Travel to conferences; Loxo Oncology: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Incyte: Consultancy; Gilead/KITE: Honoraria, Other: Travel support for conferences, Research Funding, Speakers Bureau; Secura Bio: Consultancy, Honoraria; Roche: Consultancy, Honoraria; Beigene: Honoraria, Research Funding; Janssen: Honoraria; AstraZeneca: Honoraria, Research Funding. Zinzani: Janssen-Cilag: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celltrion: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Incyte: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Servier: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sandoz: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Bristol Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; TG Therapeutics Inc: Consultancy, Honoraria, 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; BeiGene: 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, Speakers Bureau; Roche: 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; Verastem: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Kyowa Kirin: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; ImmuneDesign: 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; EUSA Pharma: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; ADC Therapeutics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Merck Sharp & Dohme: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Ujjani: Gilead: Honoraria; TG Therapeutics: Honoraria; Janssen: Consultancy; Epizyme: Consultancy, Membership on an entity's Board of Directors or advisory committees; Atara Bio: Consultancy; Loxo: Research Funding; Adaptive Biotechnologies: Research Funding; AstraZeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; ACDT: Honoraria; Kite, a Gilead Company: Honoraria; AbbVie: Consultancy, Research Funding; Pharmacyclics: Consultancy, Research Funding. Koh: Pfizer: Consultancy; Jassen: Honoraria; AstraZeneca: Honoraria; Novartis: Honoraria; GSK: Honoraria; Roche: Honoraria; Takeda: Honoraria. Izutsu: Yakult: Research Funding; Symbio: Honoraria; Takeda: Honoraria, Research Funding; Solasia: Research Funding; Pfizer: Research Funding; Ono Pharmaceutical: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; MSD: Research Funding; Kyowa Kirin: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Incyte: Research Funding; Huya Biosciences: Research Funding; Genmab: Honoraria, Research Funding; Fuji Film Toyama Chemical: Honoraria; Eisai: Honoraria, Research Funding; Daiichi Sankyo: Honoraria, Research Funding; Chugai: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Beigene: Research Funding; Bayer: Research Funding; AstraZeneca: Honoraria, Research Funding; Allergan Japan: Honoraria; AbbVie: Honoraria. Lech-Marańda: Sanofi: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; AbbVie: Membership on an entity's Board of Directors or advisory committees; Janssen-Cilag: Membership on an entity's Board of Directors or advisory committees; Amgen: 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; Novartis: Membership on an entity's Board of Directors or advisory committees. Tam: Loxo: Consultancy; Janssen: Consultancy, Honoraria, Research Funding; BeiGene: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria, Research Funding; Novartis: Honoraria; Roche: Consultancy, Honoraria; Pharmacyclics: Honoraria. Yin: Loxo Oncology at Lilly: Current Employment; AstraZeneca: Ended employment in the past 24 months. Nair: Loxo Oncology at Lilly: Current Employment, Current equity holder in publicly-traded company. Balbas: Nektar Therapeutics: Current equity holder in publicly-traded company, Ended employment in the past 24 months; Loxo Oncology at Lilly: Current Employment, Current equity holder in publicly-traded company. Tsai: Loxo Oncology at Lilly: Current Employment, Current equity holder in publicly-traded company. Mato: LOXO: Consultancy, Research Funding; Genmab: Research Funding; Sunesis: Consultancy, Research Funding; AstraZeneca: Consultancy; MSKCC: Current Employment; Johnson and Johnson: Consultancy, Research Funding; TG Therapeutics: Consultancy, Other: DSMB, Research Funding; Nurix: Research Funding; DTRM BioPharma: Consultancy, Research Funding; Acerta/AstraZeneca: Consultancy, Research Funding; Pharmacyclics LLC, an AbbVie Company: Consultancy, Research Funding; Adaptive Biotechnologies: Consultancy, Research Funding; AbbVie: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; BeiGene: Consultancy, Research Funding; Janssen: Consultancy, Research Funding. Cheah: Novartis: Consultancy, Honoraria; Beigene: Consultancy, Honoraria; TG therapeutics: Consultancy, Honoraria; Lilly: Consultancy, Honoraria; AstraZeneca: Consultancy, Honoraria; Ascentage Pharma: Consultancy, Honoraria; Gilead: Consultancy, Honoraria; MSD: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Abbvie: Research Funding; BMS: Consultancy, Research Funding; Roche: Consultancy, Honoraria, Other: travel, Research Funding.

Background: Patients (pts) with cancer have increased morbidity and mortality associated with the development of SARS-Co-V2 infection. The mRNA vaccines BNT162b2 and mRNA-1273 have robust safety and efficacy with 95-97% prevention of severe COVID-19 disease and development of protective antibody titers in 92 - 100% of healthy individuals. By contrast, some pts with hematological malignancy fail to produce anti-spike antibodies (Ab) despite full courses of vaccination. This is particularly true for pts with non-Hodgkin lymphomas (NHL) and chronic lymphocytic leukemia (CLL) who are actively treated with or have received B cell-directed therapies (BCT). We recently demonstrated that NHL pts who received the COVID-19 vaccine within 9 months from BCT demonstrated markedly lower rates of seroconversion (11%) compared to healthy individuals (100%) or a cohort of older (age >65y) residents of a nursing home (91.5%). NHL pts who had received BCT more than 9 months before the vaccine responded more robustly (88%) (Ghione et al, Blood 2021). Here, we update the results of our earlier study and perform an analysis to identify factors that may help predict for adequate response to COVID-19 vaccines. We hypothesized that neutrophil (N) or lymphocyte (L) counts and/or N/L ratio (NLR) at baseline might predict for adequate Ab production in response to COVID-19 vaccines after receipt of BCT. Methods: This was an observational study performed at Roswell Park Comprehensive Cancer Center. Pts with NHL/CLL who had received COVID-19 mRNA vaccine were included, vaccine response was assessed as previously described (Ghione et al, Blood 2021). For NLR calculation, pts with CLL or NHL with blood involvement were excluded. Clinical variables were analyzed with the t test and Fisher's exact test; validity and cut-off for the L count was obtained with the ROC analysis using GraphPad9 and SPSS. Results: A total of 142 pts with various types of NHL and CLL receiving standard of care treatments were enrolled. Five pts with prior exposure to COVID-19 infection were excluded from the analysis, reaching a total n=137. Of 83 pts with NHL (n=57) and CLL(n=26) in our cohort who were vaccinated within 9 months of BCT, 14 (17%) seroconverted. Baseline N count (p= 0.5), sex (p= 0.2), age (p= 0.8), number of prior lines of treatment (p= 0.4), type of disease (p= 0.7), time from end of BCT to vaccine (p= 0.7) and type of vaccine (p= 0.08), did not affect the rate of seroconversion. For analysis of N and L counts, 37/137 pts with CLL/NHL involving peripheral blood were excluded. Among the remaining 100 pts, 76 had received/were receiving BCT and 24 were either on observation or were on a treatment not including BCT. Only 26/76 (34%) pts on treatment/previously treated with BCT mounted IgG Ab response, while 22/24 (91.6%) patients who were not on BCT mounted the IgG Ab response (p= 0.007). In these NHL pts (N=100), higher L counts and higher NLR were associated with an increased IgG response to the vaccine (p= 0.019). For pts on BCT (N=76) a higher L count (cut-off of 1455 lymphocytes per cubic millimeter of blood [µL] as noted in the ROC) was associated with a higher rate of COVID-19 vaccine response (p= 0.020, with a sensitivity of 84% and specificity 71.5%). Conclusion: In this study, we confirm that pts with NHL/CLL receiving COVID-19 vaccination while on active treatment or within 9 months of treatment with BCT respond poorly to COVID-19 mRNA vaccination (17% seroconversion). Although a higher lymphocyte count and NLR ratio were associated with improved seroconversion rates, these were not powerful predictors. Further study of specific lymphocyte sub-populations that contribute to effective vaccine induced immunity in the context of BCT is ongoing. These studies will help to define optimal strategies for immunization in patients receiving BCT. Figure 1 Figure 1. Disclosures Torka: TG Therapeutics: Membership on an entity's Board of Directors or advisory committees. Griffiths: Takeda Oncology: Consultancy, Honoraria; Alexion Pharmaceuticals: Consultancy, Research Funding; Abbvie: Consultancy, Honoraria; Novartis: Honoraria; Taiho Oncology: Consultancy, Honoraria; Celgene/Bristol-Myers Squibb: Consultancy, Honoraria, Research Funding; Boston Biomedical: Consultancy; Astex Pharmaceuticals: Honoraria, Research Funding; Genentech: Research Funding; Apellis Pharmaceuticals: Research Funding.

Introduction: There are few data about prognostication and outcomes in patients (pts) with HIV-BL treated in the cART era. Optimal treatment strategies to minimize treatment-related mortality (TRM) remain unclear and current recommendations are based on small studies. We conducted a multicenter international analysis to identify prognostic factors and outcomes in pts with HIV-BL treated in the cART era. Methods: This retrospective analysis included a subcohort from a recent study across 30 US sites (Evens et al. Blood 2020) augmented by data from 5 UK centers treated 2009-2018. Progression-free (PFS) and overall survival (OS) were estimated by Kaplan-Meier & differences assessed by log-rank test. Univariate (UVA) associations were derived via Cox model and multivariable (MVA) models were constructed by forward selection of significant variables with P Results: 249 (US: 140 & UK: 109) pts with newly diagnosed HIV-BL were included. Clinical features included median age 43 (IQR 35-50 years [yrs]); male sex: 84%; ECOG PS: 2-4: 48%; elevated LDH: 85% (> 3x upper limit of normal (ULN) 49% & >5xULN 39%); >1 extranodal (EN) site: 60%; any CNS involvement (CNSinv) 25%; and +bone marrow (BM) 46%. MYC rearrangement was reported in 93% of pts with t(8;14) in 49%, break-apart probe in 41% and MYC-light chain in 3%; the rest had classical BL with negative MYC testing (4%) or missing result (3%) (otherwise classical BL). Median CD4 count was 217 (IQR 90-392 cells/µL) with 68% pts having CD4>100 cells/µL. At BL diagnosis, HIV viral load was detectable in 55%; 39% of pts were on cART. Baseline features were similar between the US & UK cohorts with significant differences only in ECOG PS 2-4 (32% vs 65%; P Tx regimens included: CODOX-M/IVAC (Magrath) 60%, DA-EPOCH 25%, HyperCVAD/MA 13%, & other 1%; most pts (87%) received rituximab (R). Similar regimens were used in pts with baseline CNSinv: Magrath 64%, DA-EPOCH 24% & HyperCVAD 12%. In the US, pts most frequently received DA-EPOCH (42%) followed by Magrath (32%) & HyperCVAD/MA (24%), whereas in the UK, 96% received Magrath. R was more frequently given in the US (94% vs 79%, P With median follow-up of 4.5 yrs, 3-yr PFS & OS were 61% & 66%, respectively, and nearly identical in both countries (Fig A). Pts with CD4>100 cells/µL had better 3-yr PFS (Fig B) & OS (68% vs 57% P=0.03). We observed significantly worse outcomes in pts with baseline CNSinv (3-yr PFS 36% vs 69%, P The incidence of CNS recurrence at 3 yr across all Tx was 11%. Higher incidence was observed with DA-EPOCH (P=0.032 vs other regimens; Fig F) with no difference according to CD4 count. Variables associated with PFS & OS on UVA included: ECOG PS 2-4, >1 EN, +BM, baseline CNSinv, LDH>ULN, CD4 5xULN (HR 2.09, P1 EN sites (HR 1.58 P=0.043). The same variables were significant on MVA for OS. Adjusting for all of the prognostic variables, Tx with Magrath was associated with longer PFS (adjusted HR, 0.45, P=0.005). Conclusions: These data represent the largest analysis of HIV-BL to date. There were favorable tolerance and outcomes with intensive R-containing regimens with Magrath being associated with lower TRM and the highest PFS. In addition, prognostic factors for pt outcomes were associated with lymphoma characteristics rather than with HIV-related features. Pts with baseline CNSinv represent a high-risk group with unmet therapeutic needs. Disclosures Alderuccio: Oncinfo: Honoraria; Puma Biotechnology: Other: Family member; ADC Therapeutics: Membership on an entity's Board of Directors or advisory committees; OncLive: Honoraria; Inovio Pharmaceuticals: Other: Family member; Foundation Medicine: Other: Family member; Forma Therapeutics: Other: Family member; Agios Pharmaceuticals: Other: Family member. Olszewski:Spectrum Pharmaceuticals: Research Funding; TG Therapeutics: Research Funding; Adaptive Biotechnologies: Research Funding; Genentech, Inc.: Research Funding. Evens:Epizyme: Consultancy, Honoraria, Research Funding; Pharmacyclics: Consultancy, Honoraria; Merck: Consultancy, Honoraria, Research Funding; Abbvie: Consultancy, Honoraria; Mylteni: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria, Research Funding; MorphoSys: Consultancy, Honoraria; Research To Practice: Honoraria, Speakers Bureau; Novartis: Consultancy, Honoraria. Collins:Gilead: Consultancy, Honoraria, Speakers Bureau; BMS: Consultancy, Honoraria, Research Funding, Speakers Bureau; MSD: Consultancy, Honoraria, Research Funding; Taekda: Consultancy, Honoraria, Other: travel, accommodations, expenses, Speakers Bureau; BeiGene: Consultancy; Roche: Consultancy, Honoraria, Other: travel, accommodations, expenses , Speakers Bureau; Celleron: Consultancy, Honoraria, Research Funding; ADC Therapeutics: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Speakers Bureau; Celgene: Research Funding; Amgen: Research Funding; Pfizer: Honoraria. Danilov:Astra Zeneca: Consultancy, Research Funding; Verastem Oncology: Consultancy, Research Funding; Takeda Oncology: Research Funding; Gilead Sciences: Research Funding; Bayer Oncology: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; TG Therapeutics: Consultancy; Nurix: Consultancy; Celgene: Consultancy; Aptose Biosciences: Research Funding; Bristol-Myers Squibb: Research Funding; Rigel Pharmaceuticals: Consultancy; Karyopharm: Consultancy; Pharmacyclics: Consultancy; BeiGene: Consultancy; Abbvie: Consultancy. Jagadeesh:Seattle Genetics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Debiopharm Group: Research Funding; MEI Pharma: Research Funding; Verastem: Membership on an entity's Board of Directors or advisory committees; Regeneron: Research Funding. Reddy:Genentech: Research Funding; Abbvie: Consultancy; BMS: Consultancy, Research Funding; Celgene: Consultancy; KITE Pharma: Consultancy. Farooq:Kite, a Gilead Company: Honoraria. Bond:Seattle Genetics: Honoraria. Khan:Celgene: Research Funding; Janssen: Honoraria; Pharmacyclics: Honoraria; Bristol Myers Squibb: Research Funding; Seattle Genetics: Research Funding. Yazdy:Bayer: Honoraria; Genentech: Research Funding; Octapharma: Consultancy; Abbvie: Consultancy. Karmali:Karyopharm: Honoraria; Takeda: Research Funding; AstraZeneca: Speakers Bureau; BeiGene: Speakers Bureau; BMS/Celgene/Juno: Honoraria, Other, Research Funding, Speakers Bureau; Gilead/Kite: Honoraria, Other, Research Funding, Speakers Bureau. Martin:Janssen: Consultancy; Regeneron: Consultancy; Bayer: Consultancy; Sandoz: Consultancy; I-MAB: Consultancy; Beigene: Consultancy; Cellectar: Consultancy; Incyte: Consultancy; Kite: Consultancy; Morphosys: Consultancy; Celgene: Consultancy; Teneobio: Consultancy; Karyopharm: Consultancy, Research Funding. Diefenbach:Bristol-Myers Squibb: Consultancy, Research Funding; Denovo: Research Funding; Genentech, Inc.: 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. Klein:Takeda: Membership on an entity's Board of Directors or advisory committees. Haverkos:Viracta THerapeutics: Consultancy. Epperla:Verastem Oncology: Speakers Bureau; Pharmacyclics: Honoraria. Caimi:Amgen: Other: Advisory Board; Bayer: Other: Advisory Board; Kite Pharma: Other: Advisory Board; ADC Therapeutics: Other: Advisory Board, Research Funding; Celgene: Speakers Bureau; Verastem: Other: Advisory Board. Kamdar:Roche: Research Funding. Feldman:Eisai: Research Funding; Pfizer: Research Funding; Kyowa Kirin: Consultancy, Research Funding; Portola: Research Funding; Janssen: Speakers Bureau; AstraZeneca: Consultancy; Trillium: Research Funding; Cell Medica: Research Funding; Amgen: Research Funding; Pharmacyclics: Honoraria, Other, Speakers Bureau; Abbvie: Honoraria; Bayer: Consultancy, Honoraria; 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. Smith:AstraZeneca: Consultancy; Millenium/Takeda: Consultancy; Karyopharm: Consultancy; Beigene: Consultancy; Seattle Genetics: Research Funding; Ayala: Research Funding; Bayer: Research Funding; AstraZeneca: Research Funding; Acerta Pharma BV: Research Funding; Bristol Meyers Squibb: Research Funding; Portola: Research Funding; Pharmacyclics: Research Funding; Merck: Research Funding; Incyte: Research Funding; Ignyta: Research Funding; Genentech: Research Funding; De Novo Biopharma: Research Funding. Portell:Amgen: Consultancy; Pharmacyclics: Consultancy; AbbVie: Research Funding; Janssen: Consultancy; TG Therapeutics: Research Funding; Bayer: Consultancy; BeiGene: Consultancy, Research Funding; Xencor: Research Funding; Kite: Consultancy, Research Funding; Acerta/AstraZeneca: Research Funding; Infinity: Research Funding; Roche/Genentech: Consultancy, Research Funding. Naik:Celgene: Other: advisory board; Sanofi: Other: advisory board. Lossos:Janssen Biotech: Honoraria; Verastem: Consultancy, Honoraria; Stanford University: Patents & Royalties; NCI: Research Funding; Seattle Genetics: Consultancy, Other; Janssen Scientific: Consultancy, Other. Cwynarski:Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel Support, Speakers Bureau; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel Support; Roche: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel Support, Speakers Bureau; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Atara: Consultancy, Membership on an entity's Board of Directors or advisory committees; KITE: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel Support, Speakers Bureau.

Background: The prognosis of relapsed/refractory diffuse large B cell lymphoma (r/r DLBCL) that had progressed after or are ineligible for high dose chemotherapy and autologous stem cell support (HDC-ASCS) is extremely poor (median overall survival of 6.3 months). Cellular based immunotherapy with Chimeric Antigen Receptor T-cell against CD19 (CART-19) has proven high effective in r/r DLBCL with an overall response rate of 52-83% and an overall survival rate of 40%. While r/r DLBCL benefits from CART-19 therapy, a significant number of progress after initial response stresses the need to improve the efficacy of this novel approach. A significant amount of work is being done in improving the manufacturing or activation of CART cells. However, there is few data on lymphoma associated factors that could influence response to CART-19 therapy. Previously we reported an imbalance and dysfunction of pro- and anti-apoptotic proteins, including Bak/Bax, Mcl-1/BCLxL/Survivin and upregulation of inhibitor of apoptosis (IAP) family proteins in rituximab+chemotherapy (R-chemo) resistant DLBCL. Targeting IAPs by small inhibitor LCL161 in lymphoma cells significantly overcame chemotherapy resistance in vitro and in vivo. LCL161 potentiated CART-19 cell cytotoxicity mediated in B-cell acute lymphoblastic leukemia and diffuse large B-cell lymphoma pre-clinical models. Here, we investigate the mechanism of action to enhance immune activation by targeting IAPs in r/r DLBCL. Methods: Primary T-cells were isolated and activated from peripheral blood apheresis samples from consenting adults (healthy human donors or patients with DLBCL) using Pan T-Cell Isolation Kit (MACS) and activated by T-cell Dynabeads human activator CD3/CD28 kit. Cells were expanded in RPMI media supplemented with IL2 for 2 weeks. At day 14, cells phenotype analysis was performed (CD3, CD4, CD8) by flow cytometry. T-cell number was calculated by trypan blue exclusion assay and proliferation was measured by presto blue assay after exposure to LCL161 or control for 48hrs. After exposure, CD4 and CD8 ratios were determined by cellular surface staining. T-cell function assay was determined by intracellular staining with perforin and granzyme B. Regulatory T-cells were determined as CD25+ and FOXP3+ staining cells. T-cell cytolytic activity was accessed by 51Cr release assay using 51Cr labeled rituximab-chemotherapy sensitive (Raji and RL cells) or resistant (Raji 4RH and RL 4RH) cell lines as target cells (effector/target ratio 10/1). To confirm the role of IAP proteins in the effects of LCL161 in T-cell activation, we conducted cytotoxicity assays using XIAP knock out lymphoma cell lines as target cells. Stable XIAP knock out cell lines were generated by CRISPR-Cas9 gene editing system. Lentiviral Cas9 nuclease particles were transduced into Raji and Raji 4RH cells followed by lentiviral XIAP sgRNA transduction. Lentiviral sgRNA non-targeting control was also used as negative control. Result: In vitro exposure of T-cells to LCL161 did not affect cell viability. On the other hand, it led to an increase in CD8+ T-cells and in the CD8:CD4 ratio. In addition, the percentage of regulatory T cells (CD25+ and FOXP3+) was reduced following LCL161 exposure. Using the T-cell function assay, we found that perforin and granzyme B inside T-cell was significantly increased post LCL161 exposure. The presence of LCL161 significantly improved the T-cell killing activity towards rituximab-chemotherapy sensitive and more importantly resistant cell lines. XIAP knock out in target cells resulted in abrogation of the enhance cytotoxicity exhibited by T-cells exposed to LCL161. Conclusion: Our data suggest that besides its previously documented direct anti-tumor activity, LCL161 has dual functions modulating immune cells function. LCL161 improve T-cell function by increasing the number of CD8+ T-cells and intracellular levels of granzyme B and perforin leading to an increase in T-cell cytotoxicity. In addition, LCL161 decreases the number of T-reg cells further enhancing immune activation. Taking together, targeting IAPs would be an attractive approach that potentiate current CART-19 immunotherapy in the clinical setting. Disclosures Hernandez-Ilizaliturri: Astra Zeneca: Consultancy; Karyopharm: Consultancy; Celgene: Consultancy; Takeda: Consultancy; Seattle Genetics: Consultancy; Epyzome: Consultancy; Pharmacyclics: Consultancy; Amgen: Consultancy; Gilead: Consultancy.

Background: The development of drugs targeting BTK and BCL2 has dramatically improved the therapeutic landscape in chronic lymphocytic leukemia (CLL). However, resistance to these agents has been reported due to non-recurrent changes in oncogenic pathways and gene expression signatures. The bromodomain and extra terminal (BET) family proteins (BRD2, BRD3, BRD4 and BRDT) are epigenetic reader proteins that recognize acetylated lysine residues in histones. They play a critical role in mediating gene transcription and have been considered as highly promising targets in several diseases including cancer. Of these, the BRD4 protein is highly enriched in super enhancers and regulates transcription of relevant oncogenes such as MYC, CDK genes, cyclin-D1, BCL2 and MCL-1. BRD4 inhibitors (BRD4i) block the transcription of these key oncogenes through the displacement of BRDs and other epigenetic modifiers from chromatin. In this study, we investigated the preclinical activity of two BRD4i, AZD5153 and PLX51107, and their cooperative role with the BCL2 inhibitor venetoclax and BTK inhibitor ibrutinib in CLL. Methods: Primary tumor cells were isolated from 36 CLL patients. Peripheral blood mononuclear cells were isolated via histopaque-1077 (Sigma-Aldrich, St Louis MO) from peripheral blood apheresis samples from consenting adults under RPCCC protocol CIC-01-16. B-cells were then isolated from enriched lymphocytes by MACS separation using a human B-cell Isolation Kit II. CLL cells were seeded at 3 x106/mL in a 384 well tissue culture plates and exposed to different doses of AZD5153 (1-20uM) or PLX51107 (1-20uM) as a single agent or in combination with venetoclax (1-100nM) or ibrutinib (50-1000nM) for 48 and 72hrs (Selleck Chemicals, Houston TX). Cell viability was assessed using Cell Titer-glo (Promega, Madison WI) with all data being normalized to untreated controls. Synergy was calculated using Calcusyn (Cambridge, UK) software to determine Coefficient of Synergy (CI) values. In addition, CLL cells were plated in 6 well plates and exposed to AZD5153 or PLX51107 alone or in combination with either venetoclax or ibrutinib for 24 hrs. Induction of apoptosis and changes in B-cell receptor signaling, BCL2 and NF-kB pathway related proteins were evaluated by flow cytometry or Western blotting respectively. Results: The study included 33 treatment naïve and 3 relapsed/refractory CLL patients. Deletion 11q was detected in 6 patients and del 17p was seen in 1 patient. Both AZD5153 and PLX51107 displayed time and dose dependent induction of apoptosis of CLL cells. Activity was observed in both treatment naïve and relapsed/refractory samples. Moreover, activity was observed in del 17p or ATM deletion samples. Synergistic activity was observed between BRD4is and venetoclax. PLX51107 exhibited synergy with venetoclax in 83% of the samples tested. Similarly, AZD5153 exhibited synergistic effects when combined with venetoclax in 61% of the samples. To a lesser degree, BRD4is exhibited synergistic activity when combined with ibrutinib, (44% with PLX51107 and 39% with AZD5153). Induction of apoptosis was observed in CLL cells exposed to either BRD4i. Morevoer, an increase in the percentage of apoptosis was observed when BRD4i was combined with venetoclax. Western blotting showed a accumulation of p21, reduced levels of C-MYC, as well as modulation of BCL-2 family member proteins such as BCL2, MCL-1 following BRD4i ex vivo exposure. Conclusions: Our data indicate that BRD4 inhibition results in apoptosis of primary tumor cells isolated from patients with various subtypes of CLL. PLX51107 and AZD5153 exhibit synergistic effects when combined with venetoclax and to a lesser degree with ibrutinib. Modulation of BCL-2 family members following BRD4 inibition could play a role in the synergistic activity observed in our studies. A better understanding of the key signaling pathways involved in proliferation and survival of CLL cells impacted by BRD4i in combination with venetoclax and ibrutinib would provide a proof-of-concept rationale for studies validating BRD4i as epigenetic approach to target BCR signaling in CLL. Disclosures Hernandez-Ilizaliturri: Karyopharm: Consultancy; Celgene: Consultancy; Takeda: Consultancy; Amgen: Consultancy; Gilead: Consultancy; Pharmacyclics: Consultancy; Seattle Genetics: Consultancy; Astra Zeneca: Consultancy; Epyzome: Consultancy.

Introduction: Historically, outcomes for BL have improved in adults using dose intensive chemotherapy regimens and early CNS prophylaxis. More recent data using a less intensive regimen, DA-EPOCH, have been reported. We analyzed detailed patient (pt) & disease characteristics and treatment patterns across 26 US CCs over a recent 9 year (yr) period and also determined survival rates & prognostication. Methods: We conducted a large multicenter retrospective study of newly diagnosed (dx) adult BL pts (6/2009 - 6/2018). Dx was established by institutional expert pathology review; all cases were verified for BL based on 2016 WHO criteria (high grade B cell lymphoma, BL like, etc were excluded). Survival rates were estimated by Kaplan-Meier with differences assessed by log rank test. Univariate (UVA) associations were derived via Cox model with variables P ≤0.05 entered stepwise into a multivariate (MVA) model. Using significant factors from the MVA, a prognostic survival model was constructed. Results: Among N=557 verified BL cases, clinical features included: median age 47 yrs (17-88 yrs; 24% ≥60 yrs); male 76%; HIV+ 22%; ECOG PS 0/1 76%; B symptoms 51%; elevated LDH 78% (3, 5, & 10x elevation: 44%, 29% & 15%, respectively); hemoglobin 1 EN 43%; and 76% stage 3-4 disease (10% stage 1). Additionally, 16% and 3% of pts had baseline leptomeningeal (CSF or cranial nerve palsy) or parenchymal CNS involvement, respectively (see Zayac A et al. ASH 2019 for details). For MYC partner, 68% had t(8;14), 4% light chain, 5% negative FISH (otherwise classic BL) and 23% + break apart probe. HIV+ pts had several clinical differences: CSF+ 23% vs 12% P=0.003; CNS 19% vs 8% P1 EN 60% vs 38% P For all pts, 87% had Tx at an academic CC (13% at community CC). Tx regimens were: CODOX-M/IVAC (Magrath) 31%, HyperCVAD/MA 29%, DA-EPOCH 28%, other 10% (mostly CHOP-based & CALGB Tx) & 1% were never treated. 90% of pts received rituximab as part of Tx (69% inpatient (inpt) & 31% outpatient) & 2% had consolidative autologous SCT. Response among all pts were CR 72%, PR 6%, SD 1%, PD 14%, 7% not evaluable. The treatment related mortality (TRM) rate across all pts was 8.9% (HIV+ vs not: 13% vs 8% P=0.09); most common: sepsis 48%, GI bleed/perforation 14% & respiratory failure 12%. TRM by Tx: hyperCVAD/MA 11.5%, EPOCH 6.4%, Magrath 6.3% & other 18.9%. With 39 month median follow-up, 3 year progression-free survival (PFS) and overall survival (OS) were 65% and 72%, respectively (Fig 1A). Among all pts who experienced disease progression, 90% occurred For prognostication, outcomes were inferior for pts ages ≥40 yrs & LDH >3x normal (Fig 1B/C). Notably, survival rates were not different based on HIV status (Fig 1D) or by the 3 most common Tx regimens (Fig 1E). However, there were important Tx differences based on presence of CNS involvement (see Zayac A et al. ASH 2019). Additionally, use of rituximab was associated with improved PFS & OS (Fig 1F), while outcomes were similar whether rituximab was given inpt vs outpatient (inpt PFS HR 1.25, P=0.19). Furthermore, Tx at an academic CC was associated with improved outcomes, which persisted on MVA (PFS HR 0.54, 95%CI 0.33-0.88 P=0.01; OS HR 0.50, 95%CI 0.29-0.87 P=0.01) & achievement of initial CR was strongly prognostic (Fig 1G). Baseline factors significant on UVA for PFS & OS were: age ≥40 yrs; PS 2-4; LDH >3x; anemia, low albumin; BM involvement; Stage 3-4; CSF+; & >1 EN. On MVA, factors associated with inferior survival were: age ≥40 yrs (PFS HR 1.57, P3x (PFS HR 2.28, P Conclusions: Outcomes for adult BL in this contemporary, large, multicenter RW analysis appear inferior to smaller published series. Interestingly, despite increased adverse prognostic factors, survival rates appeared similar in HIV+ pts. In addition, use of rituximab, achievement of initial CR, and Tx at an academic CC were associated with improved survival. Finally, a novel BL-specific survival model identified pts with markedly divergent outcomes. Disclosures Evens: Seattle Genetics: Consultancy, Honoraria, Research Funding; Epizyme: Consultancy, Honoraria; Pharmacyclics: Consultancy, Honoraria; Tesaro: Research Funding; Verastem: Consultancy, Honoraria. Danilov:Janssen: Consultancy; Seattle Genetics: Consultancy; MEI: Research Funding; Abbvie: Consultancy; Pharmacyclics: Consultancy; Takeda Oncology: Research Funding; Janssen: Consultancy; TG Therapeutics: Consultancy; Curis: Consultancy; Pharmacyclics: Consultancy; Aptose Biosciences: Research Funding; Verastem Oncology: Consultancy, Other: Travel Reimbursement , Research Funding; AstraZeneca: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; Bayer Oncology: Consultancy, Research Funding; Celgene: Consultancy; Bristol-Meyers Squibb: Research Funding; MEI: Research Funding; Gilead Sciences: Consultancy, Research Funding; Abbvie: Consultancy; Bristol-Meyers Squibb: Research Funding. Reddy:KITE Pharma: Consultancy; BMS: Consultancy, Research Funding; Celgene: Consultancy; Genentech: Research Funding; Abbvie: Consultancy. Farooq:Celgene: Honoraria; Kite Pharma: Research Funding. Khan:Janssen: Other: Educational Content/Symposium; Abbvie: Membership on an entity's Board of Directors or advisory committees; Bristol Myers: Other: Research Funds; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees. Yazdy:Genentech: Research Funding; Bayer: Honoraria; Abbvie: Consultancy; Octapharma: Consultancy. Karmali:Gilead/Kite; Juno/Celgene: Consultancy, Speakers Bureau; Astrazeneca: Speakers Bureau; Takeda, BMS: Other: Research Funding to Institution. Martin:Janssen: Consultancy; Teneobio: Consultancy; Celgene: Consultancy; Karyopharm: Consultancy; Sandoz: Consultancy; I-MAB: Consultancy. Diefenbach:LAM Therapeutics: Research Funding; Incyte: Research Funding; Genentech: Consultancy, Research Funding; Trillium: Research Funding; Millenium/Takeda: Research Funding; Seattle Genetics: Consultancy, Research Funding; Merck: Consultancy, Research Funding; MEI: Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Denovo: Research Funding. Epperla:Pharmacyclics: Honoraria; Verastem Oncology: Speakers Bureau. Feldman:Eisai: Research Funding; Amgen: Research Funding; Cell Medica: Research Funding; Roche: Research Funding; Corvus: Research Funding; Kyowa Hakko Kirin: Research Funding; Pfizer: Research Funding; Trillium: Research Funding; Viracta: Research Funding; Bayer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Speakers Bureau; Celgene: Honoraria, Research Funding, Speakers Bureau; Seattle Genetics: Consultancy, Honoraria, Other: Travel expenses, Speakers Bureau; AbbVie: Honoraria, Other: Travel expenses, Speakers Bureau; Pharmacyclics: Honoraria, Other: Travel expenses, Speakers Bureau; Janssen: Honoraria, Speakers Bureau; Kite Pharma: Honoraria, Other: Travel expenses, Speakers Bureau; Portola Pharma: Research Funding; Roche: Research Funding. Lossos:Janssen Scientific: Membership on an entity's Board of Directors or advisory committees; NIH: Research Funding; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees. Naik:Celgene: Other: Advisory board. Kamdar:Celgene: Consultancy; AstraZeneca: Consultancy; Seattle Genetics: Speakers Bureau; University of Colorado: Employment; Pharmacyclics: Consultancy. Portell:AbbVie: Research Funding; Pharmacyclics: Consultancy; Janssen: Consultancy; Genentech: Consultancy, Research Funding; Bayer: Consultancy; BeiGene: Consultancy, Research Funding; Kite: Consultancy, Research Funding; Acerta/AstraZeneca: Research Funding; TG Therapeutics: Research Funding; Xencor: Research Funding; Roche/Genentech: Research Funding; Infinity: Research Funding; Amgen: Consultancy. Olszewski:Spectrum Pharmaceuticals: Research Funding; TG Therapeutics: Research Funding; Genentech: Research Funding; Adaptive Biotechnologies: Research Funding. Alderuccio:Agios: Other: Immediate family member; Puma Biotechnology: Other: Immediate family member; Foundation Medicine: Other: Immediate family member; Targeted Oncology: Honoraria; Inovio Pharmaceuticals: Other: Immediate family member; OncLive: Consultancy.

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.

Objectives: T-cell lymphomas (TCL) pose a significant therapeutic challenge due to their aggressive behavior and poor response to treatment. Significant controversy exists regarding the benefit of intensification of therapy in the frontline and relapse settings due the lack of randomized studies in this rare and heterogenous population. We performed a retrospective analysis of survival outcomes in our cohort of TCL patients (pts) to assess the impact of intensification of therapy and other baseline disease, treatment and response characteristics. Methods: Adult pts with TCL diagnosed between January 2001 to December 2018 at Roswell Park Comprehensive Cancer Center were included in this single institution, retrospective chart review. Pts were classified according to the 2008 WHO classification of lymphomas. Demographics, pathology and treatment data were collected across all subtypes. Survival outcomes were summarized by treatment type using standard Kaplan-Meier methods. Comparisons were made using the log-rank test. All other statistics were descriptive. Results: Eighty-seven pts were included in our study. Histological subtypes of TCL included: 27 (31%) peripheral TCL-unspecified (PTCL-U), 15 (17%) Angioimmunoblastic TCL (AITL), 30 (34.5%) anaplastic large cell lymphoma (ALCL), out of which 10/30(33%) were ALK+ ALCL, 11(12.6%) NK TCL, 4(4.6%) enteropathy associated TCL (EATCL). Median age at diagnosis was 62 yrs (range, 20-92), 39 pts (68%) had stage IV disease, 11 pts (12.6%) had ECOG performance status >2, 21 (24%) with IPI risk of 3-4. Fourteen pts (18.6%) received Hyper-CVAD, 54 pts (72%) received CHOP and 7 pts (9.3%) received CHOEP. Others were treated with either less intensive chemotherapy (n=10), SMILE (n=1) or CMED (n=1). With a median follow up of 94 months (mo), the median OS for the entire cohort was 79 mo (95% CI 45.9-127.4). Complete remission (CR) on interim PET (after 2 cycles of therapy) was seen in 29 pts (53.7%) and this was associated with significantly higher CR rates at the end of treatment as well as improved PFS and OS (NR vs 6.7 mo; p=0.001; NR vs 48 mo; p=0.003) (Figure 1). Impact of frontline therapy was assessed in PTCL pts excluding NK TCL and EATCL (Total n=67). Pts treated with Hyper CVAD or those with CHOP/CHOEP followed by high dose chemotherapy and autologous stem cell transplant (HDC-ASCT) were grouped into the Intensive upfront therapy (IUT) group and compared with less intensive upfront therapy (LIUT) that included CHOP/CHOEP or other chemotherapy (Table 1). IUT (n=17; 25.4%) as compared to LIUT (n=50; 74.6%) had improved PFS (5yr PFS 64 mo vs 33 mo, p=0.037), although OS did not reach statistical significance (5yr OS 70 mo vs 48 mo, p=0.24). (Figure 2). A total of 48 pts (55%) in the entire cohort had relapse/progression(R/P). Pts with early relapse (ER) 12 mo were associated with a significantly lower 5 yr OS (18%; 95% CI 7-33; vs 53%; 95 % CI 29-72). For pts with ER, median OS after progression was only 2.4 mo, as compared to those with LR (14.2 mo). Notably, among pts who received IUT, 4 pts had ER (23.5%); whereas 23 pts (46%) with LIUT had ER. While, this did not meet statistical significance, our cohort may be underpowered to find a true effect. At R/P, 20 pts (41.7%) received multiagent salvage (mostly ICE/CHOP or cytarabine based), 18 pts (37.5%) received single agent therapy (mostly romidepsin), while 10 pts (20.8%) were placed on hospice. As compared to single agent therapy, multiagent salvage was associated with improved median PFS2 and OS2 (calculated from time of R/P to second progression or death) [mPFS 10.4 vs 3.4 mo; p= 0.01; mOS 14.2 vs 5.8 mo; p= 0.004] (Figure 3). Conclusions: While the ideal front-line therapy for TCL continues to be a subject of debate, the use of intensified front-line chemotherapy and/or early HDC-ASCT appears to be associated with better PFS in our cohort of TCL. Attaining an early CR by functional imaging was associated with improved survival. Pts with early relapse of disease or refractoriness to frontline therapy had a dismal overall survival. Use of multiagent intensive salvage therapy over single agent therapy at the time of relapse may improve outcomes. Further analysis on factors influencing choice of salvage treatment strategy at relapse would be important to study. Disclosures No relevant conflicts of interest to declare.

Introduction: T cell lymphomas are heterogenous with an overall poor prognosis. Peripheral T cell lymphoma not otherwise specified (PTCL-NOS) and angioimmunoblastic T cell lymphoma (AITL) are the two most common subtypes in the US accounting for 45% of diagnoses. Based on overlapping recurrent molecular and cytogenetic abnormalities, the WHO created an umbrella category of nodal T-cell lymphomas with T-follicular helper phenotype (TFH lymphoma), which includes AITL and PTCL with TFH phenotype (Swerdlow SH, et al. Blood. 2016). 25-30% of patients (pts) are refractory to initial therapy and even amongst responders to initial therapy, relapse is common. Survival after relapse or progression (R/P) is typically measured only in months. Outcomes have not changed significantly even with the introduction of several new agents in the last 10 years (Chihara D, et al. Br J Haematol. 2017). There remains no standard 2nd line therapy or guidance on sequencing of therapies as interpretation of clinical data in T-cell lymphoma is frequently hampered by the heterogeneity of the patient population and small sample size. The aim of our study was to determine outcomes in a large, well-defined group of pts with either primary refractory PTCL-NOS or TFH lymphoma. Methods: We performed a multi-center retrospective study to determine outcomes to 2nd line therapy for adult pts diagnosed between 1.1.09-6.30.18 with PTCL-NOS or TFH lymphoma, who were primary refractory defined by either induction failure, less than CR to initial therapy, or relapse within 6 months (mo) of completion of initial therapy. We performed time to event analysis using Kaplan-Meier method and compared groups using log-rank test. All other statistics were descriptive. Results: Patient and disease characteristics at diagnosis and relapse are summarized in Table 1. We identified 80 eligible pts from 7 US academic centers. Median FU was 17.2 mo from diagnosis (0.5-70). Overall, pts had mostly advanced stage with multiple high-risk features including bone marrow (BM) or extranodal (EN) involvement and B symptoms at diagnosis and R/P. Most pts received CHOP (52%) or CHOEP (24%) as initial therapy. 60% of patients did not attain a CR, while 40% of pts relapsed after initial CR.14% had received a consolidative transplant in 1st CR prior to relapse (almost all autologous hematopoietic cell transplant [HCT]). At R/P, 48% received single agent therapy [mostly romidepsin (15/38)], while 36% received multi-agent salvage therapy [mostly ICE (9/29)]. 13/80 pts were placed on hospice or only received local therapy after R/P. Median OS from diagnosis and following R/P was 19 mo/12.9 mo respectively. Median PFS2 (defined as time from 2nd line therapy to 2nd progression) for pts receiving systemic therapy was 73 days (d) (range 41-175). On univariate and multivariate analysis, there was no significant difference in PFS2 by histologic subtype (74 d for PTCL and 73 d for TFH lymphoma; p=0.29), platelet count Conclusions: Outcomes in this large, well-defined population of primary refractory PTCL-NOS and TFH lymphoma were poor, but better compared to most other retrospective series in R/R T-cell lymphoma. EN disease and advanced stage were common in this cohort of primary refractory pts. Relapse after HCT in CR1 had a particularly poor prognosis. Our findings suggest that single agent therapy following R/P in primary refractory pts and transplant may be beneficial, though our statistical power was limited due to small sample size. In a next step, we plan to expand the cohort and perform genetic/molecular characterization of available biospecimens following central pathology review. Disclosures Rhodes: DAVA Oncology: Honoraria. Olszewski:Spectrum Pharmaceuticals: Research Funding; Genentech: Research Funding; Adaptive Biotechnologies: Research Funding; TG Therapeutics: Research Funding. Brammer:Verastem, Inc: Research Funding; Viracta Therapeutics, Inc.: Research Funding; Bioniz Therapeutics, Inc.: Research Funding. Ghosh:TG Therapeutics: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Research Funding; Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Forty Seven Inc: Research Funding; AstraZeneca: Honoraria, Speakers Bureau; Pharmacyclics LLC, an AbbVie Company: Consultancy, Honoraria, Research Funding, Speakers Bureau; Genentech: Research Funding; SGN: Consultancy, Honoraria, Research Funding, Speakers Bureau; Bristol-Myers Squibb: Honoraria, Speakers Bureau; Gilead: Consultancy, Honoraria, Speakers Bureau. Dwivedy Nasta:Merck: Membership on an entity's Board of Directors or advisory committees; Roche: Research Funding; 47 (Forty Seven): Research Funding; Rafael: Research Funding; Celgene: Honoraria; ATARA: Research Funding; Aileron: Research Funding; Debiopharm: Research Funding; Millenium/Takeda: Research Funding; Pharmacyclics: Research Funding. Barta:Celgene: Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees; Mundipharma: Honoraria; Seattle Genetics: Honoraria, Research Funding; Takeda: Research Funding; Celgene: Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees; Bayer: Consultancy, Research Funding; Mundipharma: Honoraria; Merck: Research Funding.

Introduction: T-cell lymphomas (TCL) are a heterogenous group of lymphoid malignancies that account for 10-15% of all lymphoproliferative disorders. Histological bone marrow involvement (BMI) ranges between 20-40% of all TCLs at time of diagnosis with bone marrow aspirate and biopsy (BMAB) considered the gold standard test to detect BMI. 18-Fluoro-deoxyglucose positron emission tomography combined with computed tomography (PET-CT) is a standard pretreatment imaging in the staging of TCL. In other lymphomas like DLBCL, PET-CT may obviate the need for BMAB as a component for staging, but this has not been studied in TCL. The aim of this retrospective study is to determine the accuracy of PET-CT in detecting BMI in newly diagnosed TCL. Methods: This is a single institution retrospective medical chart review study. All TCL patients(pts) diagnosed at Roswell Park Cancer Institute between January 2003 to December 2017 and underwent pre-treatment PET-CT and BMAB were included. PET-CT images were visually assessed for BMI. We excluded cases in which BMAB specimens were qualitatively and/or quantitatively insufficient to determine the presence or absence of BMI. Ann Arbor staging was determined using PET-CT and BMAB and the proportion of patients upstaged to Stage IV due to BMI detected by either modality was calculated. The BMAB and PET-CT results were summarized using a 2x2 contingency table. The performance of the PET-CT was evaluated using the sensitivity, specificity, positive predictive value, and negative predictive value. Confidence intervals for these measures were obtained using Jeffrey's prior method. Results: In total 89 pts were included in the analysis. Median age at time of diagnosis was 60 (range 20-92), 52 were male (58%), 20 had elevated LDH (22%), 7 had ECOG greater or equal to 2 (8%), 66 had an IPI score 0-2 (74%) and 23 had an IPI score 3-4 (26%), 7 had >2 extra-nodal sites of involvement (8%). In total, 38 pts (42.6%) had BMI at time of diagnosis, established by either BMAB (n= 25; 28%), PET-CT (n=13; 15%) or by both modalities (n=10 pts; 11%). There were 15 pts (17%) that were negative for BMI on PET-CT but had positive involvement of TCL on BMAB. The sensitivity and specificity of PET-CT to detect BMI by TCL was 40% (95% CI 22.7, 59.4) and 95.3% (95% CI 88.0, 98.7), respectively. Seventy-one pts (79.7%) had concordant results between lymphomatous BMAB and PET-CT (10 pts were positive for both, 61 pts were negative for both) and 18 pts (20.2%) had discordant interpretation (15 pts were negative by PET-CT and positive by BMAB and 3 pts were negative by BMAB and positive on PET-CT). BMAB upstaged 4 out of the 32 (12.5%) stage I-II pts to stage IV; out of these only 1 patient had positive BMI detected by PET-CT. The positive predictive value of PET-CT for detecting BMI was found to be 76.9 % (50.3, 93.0) with a negative predictive value of 80.3 % (70.3, 88.0) (Figure 1). Conclusion:In our cohort of TCL pts, staging PET-CT does not identify all cases with BMI. BMAB upstaged more pts with Stage I/II to Stage IV than PET-CT. Although PET-CT has high negative predictive value for ruling out marrow involvement by TCL, BMAB remains a necessary component in the evaluation of pts with newly diagnosed TCL because of its ability to detect lymphomatous involvement of bone marrow missed by PET-CT which has implications in staging and treatment of TCL. Disclosures No relevant conflicts of interest to declare.

Background: Minimal residual disease (MRD) status is an independent prognostic marker for response duration in patients with mantle cell lymphoma (MCL). Rituximab-based therapy led to a molecular remission (MR) in 48% young MCL patients treated with intense chemo-immunotherapy. More recently, 4 courses of R-DHAP were reported to yield a 66% MRD negativity rate prior to high dose chemotherapy and autologous stem cell transplant (HDC-ASCT). Ofatumumab is a humanized type 1 anti-CD20 mAb that binds to a unique, more membrane-proximal epitope on the CD20 antigen. Pre-clinical studies have demonstrated that ofatumumab (O) is more active than rituximab in eliciting complement-mediated cytotoxicity (CMC) in MCL cell lines, primary tumor cells and murine lymphoma xenograft models. Hence, we evaluated the safety and efficacy of combining ofatumumab with HyperCVAD/MA (O-HyperCVAD) in newly diagnosed MCL (NCT01527149). Study design: This was a single-arm, open-label, multi-center (2 centers), prospective, phase 2 clinical trial. Thirty-seven transplant-eligible patients with newly diagnosed MCL were enrolled. Ofatumumab (1000mg) was given every 3 weeks on day 1, followed by standard doses of alternating HyperCVAD and MA starting on day 3. A total of 6 cycles were given at 3-week intervals followed by HDC-ASCT. Maintenance rituximab 375 mg/m2 every 2 months for 3 years post-ASCT was added after protocol amendment following publication of the LyMa study. Primary objectives were to determine the overall response rate (ORR) and CR rate (CRR) at the end of therapy. Secondary objectives included MRD negativity, progression free survival (PFS), overall survival (OS), feasibility of successful mobilization of autologous stem cells and safety assessment. MRD assessment was performed in peripheral blood (PB) and bone marrow (BM) using high sensitivity multiparametric flowcytometry at baseline, after 2 cycles, after 4 cycles, pre-ASCT, post-ASCT and 6 months post-ASCT. Exploratory endpoints included correlation of MRD with survival, correlation of surface CD20 levels with response and to compare differences in ORR according to Cheson and modified Cheson (MC) criteria. Results: Median age was 60yrs; 73% of patients were male, 92% had an ECOG PS 0-1, majority (81%) had stage 4 disease with 86% having bone marrow involvement; 22% had low risk, 43% had intermediate risk and 35% had high risk MIPI score; 11% had blastoid and 11% had pleiomorphic variants of MCL; 25% harbored p53 deletion. MRD was assessed in 28 of 37 patients; 9 patients from partner site were excluded due to time lag in sample delivery for flowcytometry. MRD positivity was noted in 75% patients in PB and 71.4% patients in BM at baseline. Subsequent samples showed an MRD negativity rate of 82.1% and 64.3% after 2 cycles and 76% and 96% pre-ASCT in PB and BM respectively. Post-ASCT, MRD in BM and PB was found negative in 58% and 90%, respectively. Attainment of early MRD negativity (after 2 cycles) was associated with improved PFS (p=0.04) and OS (p=0.03). Since majority of patients were MRD negative pre-ASCT, we could not demonstrate correlation between pre-ASCT MRD and survival outcomes. The ORR and CRR were 95% and 62% by Cheson and 97% and 84% respectively by modified Cheson criteria. At the end of induction therapy, ORR was 86% and CRR was 62% by Cheson criteria. 73% pts underwent HDC-ASCT. Only one patient failed stem cell collection. The median PFS and OS were 45.5 months and 56 months respectively. There were 3 deaths while on therapy- 2 from sepsis and one from acute myeloid leukemia. Grade 3 and 4 adverse events (AEs) were observed in 22% and 68% of the patients, most of them were hematological AEs related to the chemotherapy regimen. Correlation of surface CD20 expression using mean fluorescent intensity (MFI) and response rates is currently under analysis and will be reported at the meeting. Conclusion: The addition of ofatumumab to HyperCVAD/MA led to high rates of MRD negativity by flowcytometry in patients with newly diagnosed MCL. Early MRD negativity (after 2 cycles) was associated with better PFS and OS. Despite higher ORR, CR and MRD negativity rates, survival outcomes were similar to historical cohorts using rituximab-HypeCVAD/MA. This may be in part due to increased number of patients with high-risk disease in our study. Disclosures Reddy: KITE Pharma: Consultancy; Abbvie: Consultancy; Genentech: Research Funding; Celgene: Consultancy; BMS: Consultancy, Research Funding. Sait:Celgene: Consultancy. OffLabel Disclosure: Ofatumumab was investigated in combination with chemotherapy in newly diagnosed mantle cell lymphoma in this clinical trial.

Background: Laboratory criteria for antiphospholipid antibody syndrome (APS) include lupus anticoagulant (LAC), anti cardiolipin antibodies, and anti-β2 glycoprotein antibodies. International Society of Thrombosis and Hemostasis (ISTH) criteria for the diagnosis of LAC include a positive screening test, positive mixing study, phospholipid dependence and absence of a co-existing factor inhibitor or anti-coagulant drug effect. Patients with test results that fulfill some but not all of the above criteria are considered to have indeterminate LAC. While a positive LAC is an established risk factor for thrombosis, there are limited data about the significance of indeterminate LAC test results. Objective: Our study aimed at determining the prevalence of venous and arterial thrombotic events in patients with indeterminate LAC. Results: We reviewed the clinical course of 500 patients that underwent LAC testing at Cleveland Clinic from 1/11/2008 to 12/28/2010; 346 had indeterminate results. Patients with indeterminate results while on warfarin (n=52) and enoxaparin (n=4) were excluded. Patients treated with heparin at the time of testing (n=50) were included, as heparin in the plasma was neutralized prior to testing. Multivariate logistic regression modeling was performed using XLSTAT software to study the value of various thrombotic risk factors as predictive factors for venous and arterial thrombosis. Associations between categorical variables were tested using the χ2 test or Fisher's exact test. Differences were considered statistically significant at an alpha level of 0.05. In our final cohort of 281 patients with indeterminate results, there were 110 males (39.1%) and 171 females (60.8%), with a median age of 52.5 yrs. Thrombotic manifestations of patients with indeterminate LAC are summarized in Table 1. There were a total of 170 venous thrombotic events in 119 patients (42.5%). Seventy-nine patients had one or more (≥1) instances of deep vein thrombosis (DVT); 45 patients had pulmonary embolism. There were 17 patients with porto-mesenteric thrombosis and 6 patients with other venous thrombotic events. Forty-five patients had concurrent malignancy (16 %) and 22 (8%) had other prothrombotic risk factors including factor V Leiden (n=14), prothrombin G20210A mutation (n=6), elevated homocysteine (n=1), and protein S deficiency (n=1). On multivariate analysis, a relationship was confirmed between the presence of associated prothrombotic disorders and venous thrombosis (OR = 3.36, 95% CI: 1.31- 8.61, P=0.012) (Table 2). Arterial thrombosis was noted in 63 patients, with stroke, myocardial infarction and acute limb ischemia being most common (Table 1). On multivariate analysis, taking into account atherosclerotic risk factors, co-existing hypertension, hyperlipidemia and smoking history were associated with arterial thrombosis (Table 2). Conclusion: Indeterminate results are common among patients referred for LAC testing. In this retrospective cohort, patients with indeterminate LAC had significant rates of venous and arterial thrombosis. Close observation, analysis of other prothrombotic risk factors, and repeat testing of these individuals at a later date should be considered. Disclosures No relevant conflicts of interest to declare.

Background: The presence of the lupus anticoagulant (LA) is an established risk factor for thrombosis especially in the post operative setting. The risk of thrombosis among patients testing indeterminate for lupus anticoagulant is unknown. In our study we aim to estimate the incidence of postoperative thrombosis in this population and determine risk factors. Methods: We studied adult patients undergoing LA testing within 3 months of major surgery at the Cleveland Clinic between 2008 and 2013. The International Society for Thrombosis and Hemostasis (ISTH) defines the following criteria for a positive lupus anticoagulant: 1) a prolonged phospholipid dependent screening test, 2) an inhibitor demonstrated on a mixing study with normal plasma, 3) evidence that the inhibitor is phospholipid dependent, and 4) absence of a coexisting factor inhibitor, direct thrombin inhibitor or heparin. Patients fulfilling some but not all of the ISTH criteria were considered to be LA indeterminate. Patients with previous venous thromboembolism (VTE) and hypercoagulable states were excluded. We collected data on patient demographics, surgery and VTE in the first 30 postoperative days. Patients were divided into different groups based upon the presence of concomitant malignant or rheumatological disease, types of surgery and the utilization of thromboprophylaxis. Associations between categorical variables were determined using Fisher’s exact test. Multivariate logistic regression was performed; variables included age, type of surgery and utilization of pharmacologic thromboprophylaxis. Results: Of 791patients undergoing perioperative lupus anticoagulant testing, 176 were diagnosed LA indeterminate. The median age was 55 years with males comprising 52.3% of the population. Twenty six (14.7%) patients had a concomitant malignancy. Eighteen patients (10.2%) were diagnosed with a rheumatological illness. Seventy four (42.1%) patients underwent cardiac and vascular surgical procedures. General surgery including gastrointestinal surgery accounted for 53 (30.1%) patients. Neurosurgical patients (20) comprised 11.4% of the population studied. Fifteen (8.5%) patients underwent orthopedic surgery and fourteen (8%) patients had urologic procedures. Thirty eight (21.6%,CI 16.1-28.3%) patients developed VTE in the first 30 postoperative days. Of the patients with VTE, 16 (42.1%) had isolated deep vein thrombosis (DVT). Six patients had DVT associated with internal jugular vein (IJV) thrombosis (15.8%). Five patients (13.2%) patients had DVT associated with PE. Two patients (5.2%)had IJV DVT and PE in combination. Thrombosis was also reported at the sites of arteriovenous grafts, portal vein and in the central retinal vein. Twelve (31.5%) clots were related to the presence of indwelling central venous catheters. No significant association between presence of cancer or rheumatological disease and incident thrombosis was identified. Of those tested for beta 2 glycoprotein antibodies and anticardiolipin antibodies, no significant association was observed between presence of post-operative thrombosis and the presence of antibodies. While only 70 patients (39.8%) received any form of pharmacological prophylaxis against VTE, there was significant reduction in the incidence of VTE in patients that received prophylaxis as compared to those that did not. A statistically significant increased odds of thrombosis was observed in the neurosurgical population as compared to the patients undergoing other surgical procedures. On multivariate logistic regression analysis, neurosurgical patients had 3.4 fold increased risk of post operative thrombosis (CI 1.3-9.3) when compared to the rest of the surgical population studied, irrespective of the utilization of thromboprophylaxis. Conclusion: The incidence of thrombosis for patients with an incidental finding of LA indeterminate is 21.6%, comparable to that seen in the general population of patients undergoing similar procedures. This implies that standard guidelines should be used in choosing appropriate post-operative thromboprophylaxis in patients with this laboratory finding. More aggressive anticoagulant regimens do not appear to be necessary, although this remains to be confirmed in a controlled randomized study. Disclosures No relevant conflicts of interest to declare.