Articoli di riviste sul tema "Inc Catapult"

Abstract Introduction: Alliance for Clinical Trials in Oncology A041202 is a NCI National Clinical Trials Network phase 3 study (NCT01886872) comparing BR (Arm 1) with ibrutinib (Arm 2) and the combination of ibrutinib plus rituximab (Arm 3) to determine whether ibrutinib-containing regimens are superior to chemoimmunotherapy (CIT) in terms of progression-free survival (PFS), and whether rituximab adds benefit to ibrutinib therapy. Initial results showed that ibrutinib-containing regimens had superior PFS to CIT, and that rituximab added to ibrutinib did not improve PFS over ibrutinib alone. Pts and Methods: Eligible pts on A041202 were those age ≥ 65 years with previously untreated, symptomatic CLL. Pts had a CrCl > 40 mL/min, bilirubin < 1.5 x ULN, and no significant life-limiting intercurrent illness or need for warfarin treatment. Pts were stratified on Rai stage, Zap-70 methylation performed centrally, and del(17)(p13.1) or del(11)(q22.3) by local interphase cytogenetics and were randomized 1:1:1 to each arm. Pts on Arm 1 who progressed could cross over to Arm 2. Here we present an updated analysis after the third planned interim analysis of Arms 2 and 3 versus Arm 1, and at the second planned interim analysis for Arms 3 vs 2. PFS and OS were estimated using the Kaplan-Meier method and corresponding hazard ratios with p-values were estimated using Cox proportional hazards models. These data encompass patient visits through April 2020 and were locked 15 February 2021. Results: Between 12/9/2013 and 5/16/2016, 547 pts were randomized (Arms 1: 183, 2: 182, and 3: 182). Baseline characteristics have previously been reported; briefly, median age was 71 years, 53% had unmethylated Zap-70, 61% were IGHV unmutated (performed in 66% of patients), 6% had del(17p) and 20% del(11q) by central FISH. Stimulated karyotype was performed centrally and revealed ≥ 3 abnormalities in 27%, and ≥ 5 in 11% of patients. With median follow-up of 55 months (mo), median PFS was 44 mo (95% CI 38-54) in Arm 1 and has not been reached in Arms 2 or 3 [Arm 2 vs 1 hazard ratio (HR): 0.36, 95% CI 0.26-0.52, p<0.0001; Arm 3 vs 1 HR 0.36, 95% CI 0.25-0.51, p<0.0001; Arms 3 vs 2 HR 0.99, 95% CI 0.66-1.48, p=0.96]. 48-month PFS estimates were 47%, 76% and 76% in Arms 1, 2, and 3 respectively (Figure 1). At this time, there are no significant differences in overall survival (OS) among arms (p=0.49). 48-month OS estimates were 84%, 85%, and 86% in Arms 1, 2, and 3, respectively (Figure 2). The benefit of ibrutinib regimens over CIT, with no additional benefit of rituximab when combined with ibrutinib, was consistent for all subgroups of patients defined by TP53 abnormalities, del(11q), complex karyotype, and IGHV (Figure 3). No significant interaction effects were observed between treatment arm and del(11q), complex karyotype, or IGHV. However, greater benefit of ibrutinib regimens over CIT was observed among patients with TP53 abnormalities than without (p<0.001). Thus in Arm 1, PFS was significantly worse for those with TP53 abnormalities vs without (HR 5.32, 95% CI 3.05-9.27, p<0.0001), but in Arms 2 and 3 combined, there was no significant difference in PFS by presence/absence of TP53 abnormalities (HR 0.99, 95% CI 0.51-1.91, p=0.98). Notable adverse events with ibrutinib include atrial fibrillation or flutter (afib) and hypertension (HTN). All grade afib was seen in 11 pts on BR (6%) and 67 pts on ibrutinib (19%). All grade HTN was seen in 95 pts on BR (54%) and 263 pts on ibrutinib (73%). Conclusions: This update of the A041202 trial continues to show that ibrutinib regimens prolong PFS over BR for older patients with treatment-naïve CLL. With longer follow-up, these benefits continue to be seen across subgroups, including those associated with higher risk disease. Strikingly, within the ibrutinib arms, there does not appear to be inferior PFS for patients with abnormalities in TP53, the highest risk feature seen in CLL, and a predictor of inferior PFS with ibrutinib in relapsed CLL. This differentiates ibrutinib (and perhaps BTKi in general) from other targeted therapy paradigms for treatment-naïve CLL. Similar to prior studies, rates of afib and HTN continue to increase with time on therapy. These data support the use of ibrutinib as initial therapy in CLL, and strengthen the rationale for use of ibrutinib for high risk disease. Support: U10CA180821, U10CA180882, U24CA196171, https://acknowledgments.alliancefound.org, Pharmacyclics, Inc Figure 1 Figure 1. Disclosures Woyach: Gilead Sciences Inc: Other: Data & Safety; AbbVie Inc, ArQule Inc, Janssen Biotech Inc, AstraZeneca, Beigene: Other: Advisory Committee; AbbVie Inc, Loxo Oncology Inc, a wholly owned subsidiary of Eli Lilly & Company: Research Funding; AbbVie Inc, ArQule Inc, AstraZeneca Pharmaceuticals LP, Janssen Biotech Inc, Pharmacyclics LLC, an AbbVie Company,: Consultancy. Ruppert: Telios Pharma: Consultancy. Ding: Merck: Membership on an entity's Board of Directors or advisory committees, Research Funding; DTRM: Research Funding; Octapharma: Membership on an entity's Board of Directors or advisory committees. Bartlett: ADC Therapeutics: Consultancy, Research Funding; Roche/Genentech: Consultancy; Seagen: Consultancy, Research Funding; Autolus: Research Funding; Bristol Myers Squibb: Research Funding; Celgene: Research Funding; Forty Seven: Research Funding; Genentech: Research Funding; Janssen: Research Funding; Kite, a Gilead Company: Research Funding; Merck: Research Funding; Millennium: Research Funding; Pharmacyclics: Research Funding. Brander: Pfizer: Consultancy, Other: Biosimilars outcomes research panel; Genentech: Consultancy, Research Funding; Verastem: Consultancy; Juno Therapeutics/Celgene/Bristol Myers Squibb: Research Funding; LOXO: Research Funding; TG Therapeutics: Consultancy, Research Funding; MEI Pharma: Research Funding; NCCN: Other: panel member; ArQule/Merck: Consultancy; Pharmacyclics LLC, an AbbVie Company: Consultancy, Research Funding; DTRM: Research Funding; BeiGene: Research Funding; AstraZeneca: Research Funding; Ascentage: Research Funding; ArQule: Research Funding; AbbVie: Consultancy, Other: informCLL registry steering committee, Research Funding; Novartis: Research Funding. Barr: Seattle Genetics: Consultancy; Bristol Meyers Squibb: Consultancy; AstraZeneca: Consultancy; Beigene: Consultancy; Genentech: Consultancy; Abbvie/Pharmacyclics: Consultancy; Gilead: Consultancy; Morphosys: Consultancy; TG Therapeutics: Consultancy; Janssen: Consultancy. Rogers: Pharmacyclics LLC: Consultancy; Innate Pharma: Consultancy; Genentech: Consultancy, Research Funding; AstraZeneca: Consultancy; Acerta Pharma: Consultancy; AbbVie Inc.: Consultancy, Research Funding; Janssen Pharmaceuticals, Inc: Research Funding; ovartis Pharmaceuticals Corporation: Research Funding. Parikh: Pharmacyclics, MorphoSys, Janssen, AstraZeneca, TG Therapeutics, Bristol Myers Squibb, Merck, AbbVie, and Ascentage Pharma: Research Funding; Pharmacyclics, AstraZeneca, Genentech, Gilead, GlaxoSmithKline, Verastem Oncology, and AbbVie: Membership on an entity's Board of Directors or advisory committees. Coutre: Acerta: Other: Data Safety Monitoring Committee, Research Funding; Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees; Beigene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Data Safety Monitoring Committee, Research Funding; AstraZeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Larson: Epizyme: Consultancy; Astellas: Consultancy, Research Funding; Gilead: Research Funding; CVS/Caremark: Consultancy; Takeda: Research Funding; Novartis: Research Funding; Rafael Pharmaceuticals: Research Funding; Cellectis: Research Funding. Erba: AbbVie Inc: Other: Independent review committee; AbbVie Inc; Agios Pharmaceuticals Inc; ALX Oncology; Amgen Inc; Daiichi Sankyo Inc; FORMA Therapeutics; Forty Seven Inc; Gilead Sciences Inc; GlycoMimetics Inc; ImmunoGen Inc; Jazz Pharmaceuticals Inc; MacroGenics Inc; Novartis; PTC Therapeutics: Research Funding; AbbVie Inc; Agios Pharmaceuticals Inc; Bristol Myers Squibb; Celgene, a Bristol Myers Squibb company; Incyte Corporation; Jazz Pharmaceuticals Inc; Novartis: Speakers Bureau; AbbVie Inc; Agios Pharmaceuticals Inc; Astellas; Bristol Myers Squibb; Celgene, a Bristol Myers Squibb company; Daiichi Sankyo Inc; Genentech, a member of the Roche Group; GlycoMimetics Inc; Incyte Corporation; Jazz Pharmaceuticals Inc; Kura Oncology; Nov: Other: Advisory Committee. Litzow: Jazz: Other: Advisory Board; Pluristem: Research Funding; Actinium: Research Funding; Amgen: Research Funding; Astellas: Research Funding; AbbVie: Research Funding; Omeros: Other: Advisory Board; Biosight: Other: Data monitoring committee. Blachly: INNATE: Consultancy, Honoraria; KITE: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria; AstraZeneca: Consultancy, Honoraria. Owen: Genentech: Research Funding; Gilead: Honoraria; Janssen: Honoraria, Research Funding; AstraZeneca: Honoraria, Research Funding; AbbVie: Honoraria, Research Funding; Roche: Honoraria, Research Funding; Merck: Honoraria; Servier: Honoraria; Incyte: Honoraria; Pharmacyclics: Research Funding. Abramson: Bristol-Myers Squibb Company: Consultancy, Research Funding; C4 Therapeutics: Consultancy; Morphosys: Consultancy; Kite Pharma: Consultancy; Novartis: Consultancy; EMD Serono: Consultancy; Genmab: Consultancy; Bluebird Bio: Consultancy; Kymera: Consultancy; BeiGene: Consultancy; Incyte Corporation: Consultancy; Astra-Zeneca: Consultancy; Allogene Therapeutics: Consultancy; Seagen Inc.: Research Funding; AbbVie: Consultancy; Karyopharm: Consultancy; Genentech: Consultancy. Brown: Abbvie, Acerta/Astra-Zeneca, Beigene, Bristol-Myers Squibb/Juno/Celgene, Catapult, Eli Lilly, Genentech/Roche, Janssen, MEI Pharma, Morphosys AG, Nextcea, Novartis, Pfizer, Rigel: Consultancy; Invectys: Other: Data Safety Monitoring Committee Service; Gilead, Loxo/Lilly, SecuraBio, Sun, TG Therapeutics: Research Funding. Stone: Onconova: Consultancy; Syntrix/ACI: Membership on an entity's Board of Directors or advisory committees; Syndax: Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Research Funding; Elevate Bio: Membership on an entity's Board of Directors or advisory committees; Boston Pharmaceuticals: Consultancy; Bristol Myers Squibb: Consultancy; Jazz: Consultancy; Arog: Consultancy, Research Funding; Gemoab: Membership on an entity's Board of Directors or advisory committees; GlaxoSmithKline: Consultancy; Janssen: Consultancy; Innate: Consultancy; BerGen Bio: Membership on an entity's Board of Directors or advisory committees; Astellas: Membership on an entity's Board of Directors or advisory committees; Foghorn Therapeutics: Consultancy; AbbVie: Consultancy; Actinium: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Aprea: Consultancy; Syros: Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy; Agios: Consultancy, Research Funding; Celgene: Consultancy; Macrogenics: Consultancy. Byrd: Novartis, Trillium, Astellas, AstraZeneca, Pharmacyclics, Syndax: Consultancy, Honoraria; Vincerx Pharmaceuticals: Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; Newave: Membership on an entity's Board of Directors or advisory committees.

Background REGN1979 is an anti-CD20 x anti-CD3 bispecific IgG4 antibody (Ab) modified to reduce Fc binding. Engaging both targets results in CD20-specific, local T-cell activation and cytotoxicity, a mechanism of action distinct from standard anti-CD20 Abs. Dose escalation is complete and a recommended Ph 2 dose has been determined. We report Ph 1 safety and efficacy results of REGN1979 in patients (pts) with R/R B-NHL previously treated with anti-CD20 Abs, including pts with progressive disease after anti-CD19 CAR T-cell (CAR T) therapy. Methods Primary objectives are to determine safety, tolerability, and occurrence of dose limiting toxicities (DLTs). Other objectives are to assess antitumor activity, pharmacokinetics (PK), and pharmacodynamics. Eligible pts with R/R B-NHL must have received prior CD20-directed therapy. Treatment consists of 12 weekly intravenous doses of REGN1979 followed by every 2-week dosing for 12 doses (36 weeks total). Results As of June 3, 2019, 96 pts (diffuse large cell B-cell lymphoma [DLBCL] [n=53], follicular lymphoma [FL] grade [Gr] 1-3a [n=25], mantle cell lymphoma [n=6], marginal zone lymphoma [n=6], or other [FL Gr 3b, FL unknown, FL ungraded, or Waldenström macroglobulinemia ] [n=6]) were treated with REGN1979 0.03-320 mg and received a median of 9 doses (range 1-24). Pts had a median of 3 prior lines of therapy (range 1-11); 12 pts with prior CAR T therapy were included in the safety analysis of which 6 were included in the efficacy analysis. Twenty-four pts remain on treatment; 18 completed treatment; 54 discontinued early (35 due to progressive disease [PD]). No pts with B-NHL experienced a DLT. The most common treatment-emergent adverse events (AEs) were pyrexia (n=74), CRS (n=55), chills (n=49), infections and infestations (n=47), fatigue (n=36), increased C-reactive protein (n=32), and anemia (n=32). Seven pts experienced Gr 3 CRS. The severity of CRS symptoms declined through optimized pre-medication even with REGN1979 dose escalation. Most common Gr 3 or 4 AEs were anemia (n=19), decreased lymphocytes/lymphopenia (n=19), infections and infestations (n=18), decreased neutrophils/neutropenia (n=17), and hypophosphatemia/decreased blood phosphorus (n=16). No pts had seizures or grade 4/5 neurologic AEs. Gr 3 neurologic AEs included depressed level of consciousness (unrelated), somnolence, and syncope (n=1 each). Neurological events were transient and none required permanent treatment termination. Five pts discontinued due to AEs: Gr 3 hemolysis; Gr 3 fatigue; Gr 2 and Gr 3 pneumonia; and Gr 3 neck abscess (1 each). Eleven pts died on study: PD (n=6), gastric perforation (n=1), cardiac arrest (n=1), lung infection (n=1), multi-organ failure (n=1), pneumonia (n=1). The Table and Figure show efficacy and duration of response for R/R DLBCL by dose level. Pts who had opportunity for response assessment at Week 12 were included in the analysis of response. Emerging data suggest increasing efficacy with higher doses in R/R DLBCL, with 5 of 8 pts treated at 80/160/320 mg achieving CR; at these doses 2 of 3 pts achieved CR after failure of CAR T therapy. Data also suggest increasing efficacy with increasing doses in R/R FL, but maximum efficacy appears to be achieved at lower doses than in DLBCL; in pts with FL Gr 1-3a treated at ≥5 mg, the ORR was 93% (13/14), and the CR rate was 71.4% (10/14). REGN1979 concentrations in serum increased linearly with dose during the first five weeks. Elevated levels of serum cytokines were observed, mostly in week 1, and no correlation was observed with clinical efficacy. Immunohistological analysis of malignant lymph node tissue demonstrated that pts with high and low CD20 expression achieved clinical response. Relapse among responders was seen with either maintenance or loss of CD20 expression, suggesting antigen-dependent and independent disease escape mechanisms. Conclusions/Summary Tolerability of REGN1979 has been demonstrated at doses up to the final dose level of 320 mg weekly, with no observed DLTs in pts with B-NHL. No pts discontinued due to neurologic AE. Activity was observed broadly in heavily pretreated R/R B-NHL pts treated with REGN1979. With increasing dose, more resistant tumors such as R/R DLBCL are showing benefit, even in pts with prior CAR T therapy failure. Based on these efficacy findings, a global Ph 2 study is underway to evaluate REGN1979 monotherapy in R/R FL Gr 1-3a, R/R DLBCL, and other R/R B-NHL subtypes. Disclosures Bannerji: AbbVie, Inc: Consultancy, travel support; Gilead: Other: travel support; Gilead: Other: travel support; Pharmacyclics: Other: travel support; Merck: Other: travel support, Patents & Royalties: IP rights; AbbVie, Inc: Consultancy; Regeneron Pharmaceuticals, Inc.: Consultancy, Other: travel support, Research Funding; Regeneron Pharmaceuticals, Inc.: Consultancy, Other: travel support, Research Funding; Celgene: Consultancy; Celgene: Consultancy; Merck: Other: travel support, Patents & Royalties: IP rights; Pharmacyclics: Other: travel support. Allan:Acerta Pharma: Consultancy; Sunesis Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; AbbVie, Inc: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics LLC, an AbbVie company: Consultancy; Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bayer: Consultancy; Verastem Oncology, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Honoraria. Arnason:Celgene/Juno: Consultancy; Regeneron Pharmaceuticals, Inc.: Consultancy. Brown:AstraZeneca: Consultancy; Acerta Pharma: Consultancy; Morphosys: Other: Data safety monitoring boards ; Sun Pharmaceuticals, Inc: Research Funding; Sun: Research Funding; Verastem: Consultancy, Research Funding; TG Therapeutics: Consultancy; Teva: Honoraria; Sunesis: Consultancy; Pharmacyclics: Consultancy; Pfizer: Consultancy; Janssen: Honoraria; Invectys: Other: other; Loxo: Consultancy, Research Funding; Novartis: Consultancy; Octapharma: Consultancy; Kite: Consultancy, Research Funding; Dynamo Therapeutics: Consultancy; Catapult Therapeutics: Consultancy; BeiGene: Consultancy; Gilead: Consultancy, Research Funding; Genentech/Roche: Consultancy. Advani:Kyowa Kirin Pharmaceutical Developments, Inc.: Consultancy; Seattle Genetics: Consultancy, Research Funding; Celmed: Consultancy, Membership on an entity's Board of Directors or advisory committees; Forty-Seven: Research Funding; Roche/Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Kura: Research Funding; Bayer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Millennium: Research Funding; Gilead Sciences, Inc./Kite Pharma, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Research Funding; Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Research Funding; Infinity Pharma: Research Funding; Janssen: Research Funding; Merck: Research Funding; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees; Cell Medica, Ltd: Consultancy; Autolus: Consultancy, Membership on an entity's Board of Directors or advisory committees; Agensys: Research Funding; AstraZeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees; Stanford University: Employment, Equity Ownership; Regeneron: Research Funding; Pharmacyclics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Ansell:Seattle Genetics: Research Funding; Trillium: Research Funding; Seattle Genetics: Research Funding; Trillium: Research Funding; Regeneron: Research Funding; Mayo Clinic Rochester: Employment; Regeneron: Research Funding; LAM Therapeutics: Research Funding; Seattle Genetics: Research Funding; Seattle Genetics: Research Funding; Mayo Clinic Rochester: Employment; Mayo Clinic Rochester: Employment; LAM Therapeutics: Research Funding; Bristol-Myers Squibb: Research Funding; Regeneron: Research Funding; Bristol-Myers Squibb: Research Funding; Trillium: Research Funding; Bristol-Myers Squibb: Research Funding; Affimed: Research Funding; Bristol-Myers Squibb: Research Funding; LAM Therapeutics: Research Funding; Seattle Genetics: Research Funding; Affimed: Research Funding; Mayo Clinic Rochester: Employment; Seattle Genetics: Research Funding; Seattle Genetics: Research Funding; Affimed: Research Funding; Affimed: Research Funding; Trillium: Research Funding; LAM Therapeutics: Research Funding; Affimed: Research Funding; Bristol-Myers Squibb: Research Funding; LAM Therapeutics: Research Funding; Regeneron: Research Funding; Regeneron: Research Funding; Affimed: Research Funding; Affimed: Research Funding; Regeneron: Research Funding; Bristol-Myers Squibb: Research Funding; LAM Therapeutics: Research Funding; Bristol-Myers Squibb: Research Funding; LAM Therapeutics: Research Funding; Trillium: Research Funding; Seattle Genetics: Research Funding; Affimed: Research Funding; Regeneron: Research Funding; Trillium: Research Funding; LAM Therapeutics: Research Funding; LAM Therapeutics: Research Funding; Trillium: Research Funding; Mayo Clinic Rochester: Employment; Regeneron: Research Funding; Trillium: Research Funding; Seattle Genetics: Research Funding; Bristol-Myers Squibb: Research Funding; Trillium: Research Funding; Affimed: Research Funding; Bristol-Myers Squibb: Research Funding; Mayo Clinic Rochester: Employment; Mayo Clinic Rochester: Employment; Mayo Clinic Rochester: Employment; Regeneron: Research Funding; Mayo Clinic Rochester: Employment. O'Brien:Pfizer: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria; Acerta: Research Funding; Alexion: Consultancy; Amgen: Consultancy; Aptose Biosciences, Inc: Consultancy; Astellas: Consultancy; Celgene: Consultancy; Eisai: Consultancy; Gilead: Consultancy, Research Funding; GlaxoSmithKline: Consultancy; Kite: Research Funding; Janssen: Consultancy, Honoraria; Pharmacyclics LLC, an AbbVie Company: Consultancy, Research Funding; Regeneron: Research Funding; Verastem: Consultancy; Sunesis: Consultancy, Research Funding; Vaniam Group LLC: Consultancy; TG Therapeutics: Consultancy, Research Funding. Chavez:Janssen Pharmaceuticals, Inc.: Speakers Bureau; Kite Pharmaceuticals, Inc.: Membership on an entity's Board of Directors or advisory committees; Genentech: Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees. Duell:Regeneron Pharmaceuticals, Inc.: Research Funding. Martin:I-MAB: Consultancy; Karyopharm: Consultancy; Celgene: Consultancy; Janssen: Consultancy; Sandoz: Consultancy; Teneobio: Consultancy. Charnas:Regeneron Pharmaceuticals, Inc.: Employment, Equity Ownership. Ambati:Regeneron Pharmaceuticals, Inc.: Employment, Equity Ownership. Adriaens:Regeneron Pharmaceuticals, Inc.: Employment, Equity Ownership. Ufkin:Regeneron Pharmaceuticals, Inc.: Employment, Equity Ownership. Zhu:Regeneron Pharmaceuticals, Inc.: Employment, Equity Ownership. Li:Regeneron Pharmaceuticals, Inc.: Employment, Equity Ownership. Gasparini:Regeneron Pharmaceuticals, Inc.: Employment, Equity Ownership. Ibrahim:Regeneron Pharmaceuticals, Inc.: Employment, Equity Ownership. Jankovic:Regeneron Pharmaceuticals, Inc.: Employment, Equity Ownership. Fiaschi:Regeneron Pharmaceuticals, Inc.: Employment, Equity Ownership. Aina:Regeneron Pharmaceuticals, Inc.: Employment, Equity Ownership. Zhang:Regeneron Pharmaceuticals, Inc.: Employment, Equity Ownership. Deering:Regeneron Pharmaceuticals, Inc.: Employment, Equity Ownership. Hamon:Regeneron Pharmaceuticals, Inc.: Employment, Equity Ownership. Thurston:Regeneron Pharmaceuticals, Inc.: Employment, Equity Ownership. Murphy:Regeneron Pharmaceuticals, Inc.: Employment, Equity Ownership. Weinreich:Regeneron Pharmaceuticals, Inc.: Employment, Equity Ownership. Yancopoulos:Regeneron Pharmaceuticals, Inc.: Employment, Equity Ownership. Lowy:Regeneron Pharmaceuticals, Inc.: Employment, Equity Ownership. Sternberg:Regeneron Pharmaceuticals, Inc.: Employment, Equity Ownership. Topp:Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Boehringer Ingelheim: Membership on an entity's Board of Directors or advisory committees, Research Funding; KITE: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Regeneron Pharmaceuticals, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees. OffLabel Disclosure: The data described in the abstract will report on use REGN1979 in a Phase 1 clinical trial of patients with B-NHL.

Background Studies from the chemoimmunotherapy (CIT) era and more recently with venetoclax have demonstrated the correlation between minimal residual disease (MRD) response measured by at least four-color flow cytometry (FC), and progression free (PFS) and overall survival (OS) in CLL. Despite high overall (ORR) and complete (CR) response rates observed with fludarabine-based combination CIT, the ability to achieve sustained undetectable MRD (uMRD) remission is lacking for the majority of patients treated with these regimens. We have previously reported on the promising combination of ibrutinib plus FCR (iFCR), which demonstrated a 98.8% ORR, 32.9% CR/CRi with bone marrow (BM) uMRD at EOT, and 77.7% BM-uMRD by flow at EOT (83.5% at best response) [Davids et al, Lancet Haematology, 2019]. Adaptive's next generation sequencing (NGS)-MRD assay targets immunoglobulin receptor sequencing with up to 10E-6 sensitivity for detection of B-cell malignancies. Here we present expanded MRD analysis by standard flow cytometry and the first results assessed using NGS-MRD, focusing on mid-FCR (C3) and 2 month post-FCR (EOT) timepoints. Methods iFCR is a multicenter single-arm phase 2 trial at seven sites in the USA. 85 patients aged 65 years or younger with previously untreated CLL were enrolled and treated with iFCR as previously published [Davids, Lancet Haematology, 2019]. Per protocol analyses of MRD in both peripheral blood (PB) and BM by standard four-color FC were performed at local laboratories at C3. Both PB and BM samples were submitted to Adaptive for NGS-MRD evaluation at EOT. Forty-eight patients had paired BM and PB samples with 16 additional PB only samples. NGS-MRD status was evaluated at 10E-5 and 10E-6 levels, and defined as positive if ≥ 1 rearrangement was detected per 100,000 or per million cells, respectively. An indeterminate finding was reported if insufficient cells were assayed, as NGS-MRD testing is limited by the number of cells evaluated, which can often be lower than needed for 10E-6 sensitivity, particularly in PB. Results At the C3 restage, the BM-uMRD rate by flow was 47%, with 100% concordance to flow PB-uMRD status in all patients with BM-uMRD. However, 33% (12/36 evaluable) with detectable cells in marrow had PB-uMRD, demonstrating enhanced sensitivity of BM-MRD testing as shown in Table 1. At EOT, BM-uMRD rates rose to 78%, compared with 86% in PB, including 14/24 patients converted from BM-pos/PB-pos to BM-neg/PB-neg and 7/12 BM-pos/PB-neg to BM-neg/PB-neg. In NGS-MRD analysis from 48 patients with evaluable BM and PB samples at EOT, a larger number of patients were MRD positive in BM (n=21; 43.8%) vs. PB (n=13; 27.1%) (McNemar test: p=0.04). Figure 1 illustrates the improving detection of residual disease in both BM and PB with increasing sensitivity, with greater detection in BM; 54% positive at 10E-6 sensitivity in this cohort, compared with 36% in PB. Evaluation for true negative samples at 10E-6 sensitivity was limited by samples with inadequate cells for evaluation (indeterminate), hence definite uMRD was seen in only 23% BM and 9% PB. Fifty-two patients with PB-uMRD by FC at EOT had associated PB NGS-MRD results: 10 PB-uMRD by FC were positive at 10E-5 with 8 additional positive at 10E-6 (35% greater than FC). Similar results were observed in BM: of forty-four patients with BM-uMRD by FC at EOT, 13 were positive at 10E-5 with 9 additional positive at 10E-6 by NGS-MRD (50% greater than FC), summarized in Table 2. When this higher sensitivity BM-uMRD data is used to define overall clinical response at EOT, the CR/CRi with BM-uMRD rate at 10E-5 is 32.6% (14/43), and at 10E-6 is 16.2% (6/37), compared to 43.8% (21/48) using four-color FC. The rate of BM-uMRD would be 60.5% (26/43) at 10E-5 sensitivity and 29.7% (11/37) at 10E-6, with NGS-MRD. Discussion This first report of NGS-MRD testing after iFCR demonstrates that 50% of patients with BM-uMRD by flow cytometry have detectable CLL cells at the level of detection of ≥ 1 per million cells. While iFCR has improved upon historical uMRD results by four-color flow cytometry, these findings suggest that CLL cells are still frequently present. Longer follow-up will be required to correlate these minimal levels of residual disease with PFS in this setting. Future studies should incorporate NGS-MRD assessment with larger volume cell sampling to ensure adequate sensitivity and evaluate venetoclax-based regimens. Disclosures Brander: Novartis: Consultancy; BeiGene: Research Funding; DTRM Biopharma: Research Funding; AbbVie: Consultancy, Honoraria, Research Funding; Pharmacyclics LLC, an AbbVie Company: Consultancy; MEI: Research Funding; Acerta: Research Funding; Tolero: Research Funding; Teva: Consultancy, Honoraria; TG Therapeutics: Consultancy, Honoraria, Research Funding; Genentech: Consultancy, Honoraria, Research Funding; AstraZeneca: Consultancy, Research Funding. Jacob:Adaptive Biotechnologies: Employment, Other: shareholder. Arnason:Regeneron Pharmaceuticals, Inc.: Consultancy; Celgene/Juno: Consultancy. Abramson:AbbVie Inc, Amgen Inc, Bayer HealthCare Pharmaceuticals, Celgene Corporation, EMD Serono Inc, Genentech, Gilead Sciences Inc, Janssen Biotech Inc, Juno Therapeutics, a Celgene Company, Karyopharm Therapeutics, Kite Pharma Inc, Merck, Novartis, Seattle Gen: Consultancy. Davids:AbbVie, Acerta Pharma, Adaptive, Biotechnologies, Astra-Zeneca, Genentech, Gilead Sciences, Janssen, Pharmacyclics, TG therapeutics: Membership on an entity's Board of Directors or advisory committees; Acerta Pharma, Ascentage Pharma, Genentech, MEI pharma, Pharmacyclics, Surface Oncology, TG Therapeutics, Verastem: Research Funding; AbbVie, Astra-Zeneca, Genentech, Janssen, MEI, Pharmacyclics, Syros Pharmaceuticals, Verastem: Consultancy; Research to Practice: Honoraria. Brown:Novartis: Consultancy; Sunesis: Consultancy; Acerta Pharma: Consultancy; AstraZeneca: Consultancy; BeiGene: Consultancy; Catapult Therapeutics: Consultancy; Dynamo Therapeutics: Consultancy; Genentech/Roche: Consultancy; Gilead: Consultancy, Research Funding; Juno/Celgene: Consultancy; Pfizer: Consultancy; Loxo: Consultancy, Research Funding; Invectys: Other: Data safety monitoring board; Octapharma: Consultancy; Kite, a Gilead Company: Consultancy, Research Funding; AbbVie: Consultancy; Morphosys: Other: Data safety monitoring board; Pharmacyclics: Consultancy; Teva: Honoraria; TG Therapeutics: Consultancy; Verastem: Consultancy, Research Funding; Sun Pharmaceuticals: Research Funding; Janssen: Honoraria.

AbstractConsidering the large and repetitive loads associated with jumping in team sports, automatic detection and quantification of jumping may show promise in reducing injury risks. The aim of this study was to validate commercially available inertial-movement analysis software to detect and quantify jumping in team sports. In addition, the test-retest reliability of the software to quantify jumping was assessed. Seventy-six healthy male participants completed a team sport circuit six times containing seven common movements (including three countermovement and two single-leg jumps) whilst wearing an inertial sensor (Catapult Sports, Australia). Jump detection accuracy was assessed by comparing the known number of jumps to the number recorded by the inertial movement analysis software. A further 27 participants separately performed countermovement and single-leg jumps at 33%, 66% and 100% of maximal jump height over two sessions. Jump height quantification accuracy was assessed by comparing criterion three-dimensional motion analysis-derived heights to that recorded by the inertial movement analysis software. Test-retest reliability was assessed by comparing recorded jump heights between both testing sessions. Catapult’s inertial movement analysis software displayed excellent jump detection accuracy (96.9%) and test-retest jump height quantification reliability (ICC: 0.86 [countermovement jump], 0.88 [single-leg jump]). However, significant mean bias (–2.74 cm [95% LoA –10.44 – 4.96]) was observed for jump height quantification. Overall, Catapult’s inertial movement analysis software appears to be a suitable method of automatically detecting jumping in team sports, and although reliable, caution is advised when using the IMA software to quantify jump height.

Clinical success with the targeted Bruton Tyrosine Kinase (BTK) inhibitors ibrutinib and acalabrutinib has greatly improved the outcome of patients with relapsed chronic lymphocytic leukemia (CLL). However toxic side effects and acquired resistance due to C481S mutations in BTK remain an issue and the prognosis of those developing resistance is poor. Hence better therapeutic options are needed for these patients. Here we characterize a next generation highly selective reversible BTK inhibitor, LOXO-305, and describe its effectiveness in vitro in treatment naïve CLL patients and in those with C481S mutations. Unlike the irreversible BTK inhibitors ibrutinib and acalabrutinib, LOXO-305 does not require the C481 site for binding to the ATP binding domain of BTK. In addition, LOXO-305 is highly selective, with minimal activity against non-BTK kinase and non-kinase off targets, including ITK, TEC and EGFR. We evaluated the efficacy of LOXO-305 in BTK wild-type B cell lymphoma lines most similar to CLL, namely MEC1 and OSU-CLL, and in CLL patient samples, by determining its effect on cell viability, apoptosis and BCR signaling. In both cell lines LOXO-305 reduced cell viability and BCR mediated activation of BTK, PLCg2, ERK and AKT similar to ibrutinib. We measured cellular apoptosis in these cell lines with Annexin V APC and PI staining and showed that after 48 hours LOXO-305 treated cells had a significantly higher percentage of apoptotic cells in comparison with both DMSO (mean increase with LOXO-305: MEC1 21% (p = 0.0005) & OSU-CLL 35% (p = 0.0016)) and ibrutinib (mean increase with LOXO305: MEC1 19% (p=0.0006), OSU-CLL 22% (p=0.0013)). Since LOXO-305's mechanism of BTK inhibition does not involve covalent binding to the C481 site, we tested its efficacy in in vitro ibrutinib resistant models of stably transfected HEK293 cells expressing either wild-type (WT) or C481S BTK. In WT BTK HEK cells, both LOXO-305 and ibrutinib showed comparable inhibitory activity in vitro against wild-type BTK, with IC50 values for phospho-BTK inhibition equal to 5.69 nM and 3.33 nM, respectively. LOXO-305 also inhibited phospho-BTK in BTK-C481S-expressing HEK293 cells at an IC50 equal to 21.2 nM, while ibrutinib had no inhibitory effect at concentrations as high as 300nM. When we extended our analysis to treatment naïve CLL patient cells, we observed that both LOXO-305 and ibrutinib potently inhibited IgM-induced phospho-BTK with IC50 values equal to 1.34 ± 1.23 nM for LOXO-305 (n = 7, p < 0.0001) and 1.04 ± 1.26 nM for ibrutinib (n = 7, p < 0.0001). We also found a significant reduction in phosphorylation of PLCγ2 (Y1217), the immediate downstream effector of BTK (IC50 33 nM for each agent, n = 7, p = 0.02 for LOXO-305, p = 0.0017 for ibrutinib). When we compared the cellular cytotoxicity of LOXO-305 with ibrutinib and acalabrutinib, all three agents demonstrated significant induction of apoptosis (annexin V positive) in BTK wild-type cells compared to DMSO treatment: (LOXO-305: median 63.77% n=3, p = 0.0073, ibrutinib: median 57.76%, n=3, p < 0.0001, acalabrutinib: median 67.11%, n=3, p = 0.0397). In CLL patient cells harboring C481S mutations, we observed a decrease in BCR signaling with 0.6 μM LOXO-305 treatment, with 95% reduction in phospho-BTK (Y223) and 50% reduction in phospho-PLCγ2 vs DMSO (n = 3, phospho-BTK p < 0.0001, phospho-PLCγ2 p = 0.01). In comparison ibrutinib at 0.6 μM demonstrated 50% reduction in phospho-BTK (n = 3, p = 0.01) and no significant change in phospho-PLCγ2. We also observed a 73% reduction in phospho-ERK vs DMSO with 10 μM LOXO-305 treatment (n=3, p = 0.004) while ibrutinib and acalabrutinib showed no significant change. In CLL patient cells with C481S variant allele frequencies (VAF) of 87% and 89%, LOXO-305 was 40-fold more potent at inhibiting phospho-BTK than ibrutinib (IC50 for LOXO305 0.02 μM, for ibrutinib 0.9 μM). Even in patient cells with lower C481S VAF of 9%, LOXO-305 still demonstrated 30-fold higher potency than ibrutinib (IC50 LOXO-305 0.2 μM, ibrutinib 0.6 μM). Our findings show that LOXO-305 potently inhibits cell survival and BCR signaling in both treatment naïve and C481S CLL patient cells, and therefore may prove an effective treatment in both treatment naïve and ibrutinib-resistant CLL patients. A phase 1 clinical trial is ongoing. Disclosures Ebata: LOXO Oncology Inc.: Employment, Equity Ownership. Gomez:LOXO Oncology Inc.: Employment, Equity Ownership. Brandhuber:LOXO Oncology Inc.: Employment, Equity Ownership. Rothenberg:LOXO Oncology Inc.: Employment. Brown:Janssen, Teva Pharmaceuticals: Honoraria; Gilead, Loxo, Sun Pharmaceuticals, Verastem: Research Funding; Morphosys, Invectys (Data Safety Monitoring Board): Membership on an entity's Board of Directors or advisory committees; Abbvie, Acerta, Astra-Zeneca, Beigene, Catapult Therapeutics, Dynamo Therapeutics, Genentech/Roche, Gilead, Juno/Celgene, Kite, Loxo, Octapharma, Novartis, Pfizer, Pharmacyclics, Sunesis, TG Therapeutics, Verastem: Consultancy.

BACKGROUND Novel agents have changed the treatment landscape in chronic lymphocytic leukemia (CLL), however little has been reported about real-world treatment sequence patterns and associated outcomes post-introduction of novel agents. Studies have demonstrated that venetoclax is effective for patients (pts) who have discontinued ibrutinib, however treatments and outcomes post-venetoclax discontinuation remain unclear. The objective of this study was to examine real-world treatment sequence patterns post-introduction of novel agents and specifically understand treatment sequencing following venetoclax. METHODS The CLL Collaborative Study of Real-World Evidence (CORE) is a retrospective, multicenter, collaborative observational study of pts with CLL/small lymphocytic leukemia (SLL). For this analysis, adult pts were eligible for inclusion if they started therapy for CLL/SLL in the relapsed/refractory setting after February 12, 2014 (FDA approval date of first novel agent for CLL/SLL). Interim data are presented; data collection for this analysis is ongoing and is expected to be completed by October 31, 2019. Treatment sequences were characterized specifically focusing on treatment sequencing following venetoclax and other novel agents (i.e., BCRi: e.g., ibrutinib, idelalisib or acalabrutinib). Clinical response, as assessed by physician, was also reported from medical charts (iwCLL criteria were provided as a reference only). RESULTS Of the 267 pts available at the time of interim data analysis, 231 pts (87%) received a novel agent in at least one line of therapy (first-line: 35 pts [15%]; second-line: 133 pts [58%]; third-line or later: 63 pts [27%]). Among novel agents, ibrutinib was the most commonly used first novel agent for 198 pts (86%) followed by venetoclax for 18 pts (8%) and idelalisib for 12 pts (5%). Of those 267 pts, 143 pts (54%) received chemotherapy/chemoimmunotherapy (CT/CIT) followed by a novel agent; 63 pts (24%) received a novel agent followed by a novel agent; 17 (7%) received a novel agent followed by CT/CIT; and 47 (18%) received a CT/CIT followed by CT/CIT. At the time of this interim data cut there were 220 pts (82%) who received BCRi-based regimens (first-line: 33 pts [15%]; second-line: 123 pts [56%]; third-line or later: 64 pts [29%]) and 62 pts (23%) who received venetoclax-based regimens (first-line: 2 pts [3%]; second-line: 22 pts [36%]; third-line or later: 38 pts [61%]). Of the 220 pts who received BCRi-based regimens, 50 (23%) achieved complete remission (CR) and 83 (38%) achieved partial remission (PR) (responses based on physician assessment). Of the 220 pts, 88 (40%) went on to receive a subsequent line of therapy. The most common subsequent treatments administered were venetoclax containing regimens (n= 34, 39%). Of the 88 pts who received a subsequent line of therapy after BCRi-based regimens, 22 pts (25%) achieved CR and 24 pts (27%) achieved PR. Of the 62 pts who received venetoclax-based regimens, 20 pts (32%) achieved CR and 14 pts (23%) achieved PR. Of the 62 pts, 15 pts (24%) went on to receive a subsequent line of therapy. The most common subsequent treatment administered were BCRi containing regimens (n= 10, 67%) primarily ibrutinib-based. Of the 15 pts receiving a subsequent line of therapy after venetoclax-based regimens, 3 pts (20%) achieved CR and 4 pts (27%) achieved PR. While preliminary results are encouraging, further data collection efforts are ongoing and will be included for presentation to confirm the results and outcomes associated with different sequencing options. CONCLUSIONS The treatment paradigm is evolving with the introduction of novel agents. Results from this study will provide a baseline description of treatment sequence patterns enabling clinicians to benchmark the impact of the introduction of novel agents and associated outcomes. Early evidence from these results also suggests that novel agents are most commonly introduced during second line treatment and that other novel agents, including ibrutinib, following venetoclax treatment are being utilized in the real-world settings. Table. Disclosures Mato: Pharmacyclics: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; LOXO: Consultancy, Research Funding; DTRM Biopharma: Research Funding; Johnson & Johnson: Consultancy, Research Funding; TG Therapeutics: Consultancy, Other: DSMB member , Research Funding; Acerta: Consultancy; Janssen: Consultancy; Gilead: Research Funding; AstraZeneca: Consultancy, Research Funding; AbbVie: Consultancy, Research Funding; Sunesis: Consultancy, Research Funding; Celgene: Consultancy. Sail:AbbVie: Employment, Other: may hold stock or stock options. Yazdy:Genentech: Research Funding; Octapharma: Consultancy; Abbvie: Consultancy; Bayer: Honoraria, Speakers Bureau. Hill:Amgen: Research Funding; Seattle Genetics: Consultancy, Honoraria; Celegene: Consultancy, Honoraria, Research Funding; AstraZeneca: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech: Consultancy, Research Funding; Kite: Consultancy, Honoraria; Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; TG therapeutics: Research Funding; Takeda: Research Funding; Pharmacyclics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Shadman:Bigene: Research Funding; TG Therapeutics: Research Funding; AbbVIe: Consultancy, Research Funding; Genentech, Inc.: Consultancy, Research Funding; AstraZeneca: Consultancy; Sound Biologics: Consultancy; Pharmacyclics: Consultancy, Research Funding; ADC Therapeutics: Consultancy; Atara: Consultancy; Verastem: Consultancy; Mustang Biopharma: Research Funding; Gilead: Research Funding; Merck: Research Funding; Acerta: Research Funding; Emergent: Research Funding; Celgene: Research Funding; Sunesis: Research Funding. Manzoor:AbbVie: Employment, Other: and may hold stock or stock options. Tuncer:Abbvie: Membership on an entity's Board of Directors or advisory committees; 2018 Steering Committee: Other: reimbursement for travel to the steering committee at ASH. Allan:Janssen: Consultancy, Honoraria; Acerta Pharma: Consultancy; Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie, Inc: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics LLC, an AbbVie company: Consultancy; Verastem Oncology, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bayer: Consultancy; Sunesis Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees. Ujjani:PCYC: Research Funding; Pharmacyclics: Honoraria; AbbVie: Honoraria, Research Funding; Genentech: Honoraria; Atara: Consultancy; Astrazeneca: Consultancy; Gilead: Consultancy. Sharmokh:AbbVie: Employment, Other: may hold stock or stock options. Jiang:AbbVie: Employment, Other: and may hold stock or stock options. Pena:AbbVie: Employment, Other: and may hold stock or stock options. Marshall:AbbVie: Employment, Other: and may hold stock or stock options. Nielsen:AbbVie: Employment, Other: and may hold stock or stock options. Barr:Janssen: Consultancy; Astra Zeneca: Consultancy, Research Funding; Verastem: Consultancy; Genentech: Consultancy; Seattle Genetics: Consultancy; Merck: Consultancy; Celgene: Consultancy; TG Therapeutics: Consultancy, Research Funding; Pharmacyclics LLC, an AbbVie company: Consultancy, Research Funding; AbbVie: Consultancy; Gilead: Consultancy. Brown:Pfizer: Consultancy; Pharmacyclics: Consultancy; Sunesis: Consultancy; Teva: Honoraria; TG Therapeutics: Consultancy; Verastem: Consultancy, Research Funding; Sun: Research Funding; Sun Pharmaceuticals, Inc: Research Funding; Morphosys: Other: Data safety monitoring boards ; Acerta Pharma: Consultancy; AstraZeneca: Consultancy; BeiGene: Consultancy; Catapult Therapeutics: Consultancy; Dynamo Therapeutics: Consultancy; Genentech/Roche: Consultancy; Gilead: Consultancy, Research Funding; Invectys: Other: other; Janssen: Honoraria; Kite: Consultancy, Research Funding; Loxo: Consultancy, Research Funding; Novartis: Consultancy; Octapharma: Consultancy. Schuh:Pharmacyclics: Consultancy, Speakers Bureau; AbbVie: Consultancy, Speakers Bureau; Genentech: Consultancy, Speakers Bureau; Janssen: Speakers Bureau; Verastem: Speakers Bureau; Kite: Speakers Bureau; Gilead: Speakers Bureau; Seattle Genetics: Speakers Bureau; Jazz Pharmaceuticals: Speakers Bureau; Bristol-Myers Squibb: Research Funding. Eyre:Janssen: Honoraria, Other: travel support; Gilead: Honoraria, Other: travel support; AbbVie: Honoraria, Other: travel support. Wierda:Pharmacyclics LLC: Research Funding; Juno Therapeutics: Research Funding; Gilead Sciences: Research Funding; Miragen: Research Funding; Cyclcel: Research Funding; Oncternal Therapeutics Inc.: Research Funding; GSK/Novartis: Research Funding; Genentech: Research Funding; Xencor: Research Funding; Acerta Pharma Inc: Research Funding; KITE pharma: Research Funding; Sunesis: Research Funding; Loxo Oncology Inc.: Research Funding; Janssen: Research Funding; AbbVie: Research Funding. Skarbnik:Seattle Genetics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pharmacyclics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Verastem Oncology: Honoraria, Research Funding, Speakers Bureau; Kite Pharma: Honoraria, Speakers Bureau; Gilead Sciences: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Consultancy, Honoraria, Speakers Bureau; Acerta: Research Funding; Genentech: Honoraria, Speakers Bureau; CLL Society: Consultancy, Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Speakers Bureau; Novartis: Speakers Bureau; Abbvie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Roeker:Abbott Laboratories: Equity Ownership; AbbVie: Equity Ownership. Bannerji:Gilead: Other: travel support; Celgene: Consultancy; Celgene: Consultancy; Regeneron Pharmaceuticals, Inc.: Consultancy, Other: travel support, Research Funding; Merck: Other: travel support, Patents & Royalties: IP rights; Regeneron Pharmaceuticals, Inc.: Consultancy, Other: travel support, Research Funding; Pharmacyclics: Other: travel support; AbbVie, Inc: Consultancy; Pharmacyclics: Other: travel support; Gilead: Other: travel support; AbbVie, Inc: Consultancy, travel support; Merck: Other: travel support, Patents & Royalties: IP rights. Pauff:AbbVie Inc: Employment, Other: may own stock or stock options. Schuster:Novartis, Nordic Nanovector, and Pfizer: Membership on an entity's Board of Directors or advisory committees; Novartis: Other: a patent (with royalties paid to Novartis) on combination therapies of CAR and PD-1 inhibitors.; Novartis, Celgene, Genentech, Merck, Pharmacyclics, Acerta, and Gilead: Other: Grants, Research Funding; Nordic Nanovector, Pfizer, AstraZeneca, Loxo Oncology, Acerta, and Celgene: Honoraria. Follows:Roche: Consultancy, Honoraria, Speakers Bureau; Janssen: Consultancy, Honoraria, Speakers Bureau; AstraZeneca: Consultancy, Honoraria, Speakers Bureau; Gilead: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Abbvie: Consultancy, Honoraria, Speakers Bureau. Cheson:Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Symbios: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Trillium: Research Funding; Pharmacyclics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Kite: Research Funding; Morphosys: Membership on an entity's Board of Directors or advisory committees; Acerta: Consultancy, Research Funding; Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; TG Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Seattle Genetics: Research Funding; Bristol Myers Squibb: Research Funding; AstraZeneca: Membership on an entity's Board of Directors or advisory committees; Portola: Research Funding; Gilead: Research Funding; Epizyme: Research Funding. Eichhorst:Gilead Sciences, Inc.: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; BeiGene: Research Funding; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; ArQule: Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Brander:Genentech: Consultancy, Honoraria, Research Funding; DTRM Biopharma: Research Funding; TG Therapeutics: Consultancy, Honoraria, Research Funding; AstraZeneca: Consultancy, Research Funding; BeiGene: Research Funding; Novartis: Consultancy; Pharmacyclics LLC, an AbbVie Company: Consultancy; AbbVie: Consultancy, Honoraria, Research Funding; Acerta: Research Funding; Tolero: Research Funding; Teva: Consultancy, Honoraria; MEI: Research Funding. Pivneva:AbbVie: Other: employee of Analysis Group, Inc., which has received consultancy fees from AbbVie. Lamanna:AstraZeneca: Membership on an entity's Board of Directors or advisory committees; Verastem: Research Funding; AbbVie: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees; Bei-Gene: Research Funding; TG Therapeutics: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees; Roche-Genentech: 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.

BACKGROUND The recent approval of novel agents (NAs) has changed the treatment landscape in chronic lymphocytic leukemia (CLL), however, there remains uncertainty regarding treatment discontinuation patterns in real-world (RW) settings. This study assessed patterns of and reasons for discontinuation for patients (pts) treated with chemotherapy/chemoimmunotherapy (CT/CIT) and NAs in first (1L) and second (2L) lines of therapy in CLL. METHODS The CLL Collaborative Study of Real-World Evidence (CORE) study is a retrospective, multicenter, observational study. Adult CLL patients (pts) were included if they were diagnosed with CLL, initiated 1L or 2L therapy for CLL on/after 01/01/2012 (excluding lines of therapy received as part of clinical trials). Discontinuation patterns were assessed among CT/CIT and NAs, more specifically in four treatment cohorts: fludarabine+cyclophosphamide+rituximab (FCR), bendamustine+rituximab (BR), B-cell receptor inhibitors (BCRi)-based (e.g., acalabrutinib, ibrutinib, or idelalisib) and venetoclax-based regimens. Treatment discontinuation was operationally defined as ending therapy for reason(s) other than completion of planned duration of therapy. RESULTS Of 671 pts receiving 1L therapy, 81 (12%) received FCR (median age=58, 70% males); 153 (23%) BR (median age=63, 61% males), 255 (38%) BCRi-based (median age=65, 65% males); and 13 (2%) venetoclax-based (median age=59, 54% males). The remaining 169 pts received other regimens (e.g., other CT/CIT). The most common BCRi-based therapy in 1L was ibrutinib-containing regimens (97%). Median duration of follow-up was 24, 27, 11 and 8 months for FCR, BR, BCRi-based and venetoclax-based regimens, respectively. Treatment discontinuation occurred in 18 (22%), 41 (27%), 51 (20%) and 4/13 pts receiving FCR, BR, BCRi-based and venetoclax-based regimens, respectively. The most common reason for discontinuation in FCR (11/18 pts; 61%), BR (15/41 pts; 37%) and BCRi-based (24/51 pts; 47%) cohorts was adverse events (AEs), with >70% being severe AEs in each cohort. Common AEs leading to discontinuations were hematological abnormalities (e.g., neutropenia, thrombocytopenia) in the FCR (6/18 pts; 33%) and BR (6/41 pts; 15%) cohorts. In the BCRi-based cohort the most common AEs leading to discontinuations were cardiac (4/51 pts; 8%), skin and subcutaneous tissue disorders (e.g., rash; 6/51 pts; 12%), hemorrhage/bleeding (3/51; 6%), and musculoskeletal and connective tissue disorders (3/51; pts; 6%). For the relatively small number of pts treated with venetoclax-based regimens and discontinued, disease progression was the common reason for discontinuations (3/4 pts); no pts discontinued venetoclax-based regimens due to adverse events. In the relapsed/refractory setting specifically in 2L, 15 (7%), 113 (56%) and 16 (8%) pts received BR, BCRi-based and venetoclax-based regimen respectively, of which the most common BCRi-based therapy regimen was ibrutinib-based (95%). Treatment discontinuation occurred in 5/15 pts (33%), 27/113 pts (24%) and 4/16 pts (25%) receiving BR, BCRi-based and venetoclax-based regimens, respectively. The most common reason for discontinuations were severe AEs for BR (3/5 pts) and BCRi-based (13/27 pts) cohorts and disease progression for venetoclax-based regimens (2/4). CONCLUSIONS Despite the relatively short follow-up, in both 1L and 2L, similar discontinuation patterns emerge. CT/CIT is often discontinued prior to completion of planned cycles of therapy, suggesting that these regimens are difficult to tolerate. Additionally, treat to progression BCRi-based regimens are also discontinued for severe AEs, discordant to results from clinical trials. With a small cohort and limited information collected, results on venetoclax discontinuation warrants additional studies. Well tolerated chemotherapy-free combinations with finite treatment duration in treatment naïve and relapsed/refractory settings may limit continuous exposure to treatment and prevent discontinuations due to AEs. Table Disclosures Shadman: Atara: Consultancy; Gilead: Research Funding; TG Therapeutics: Research Funding; Bigene: Research Funding; Celgene: Research Funding; Acerta: Research Funding; Emergent: Research Funding; Sunesis: Research Funding; Merck: Research Funding; AbbVIe: Consultancy, Research Funding; Genentech, Inc.: Consultancy, Research Funding; AstraZeneca: Consultancy; Sound Biologics: Consultancy; Mustang Biopharma: Research Funding; Pharmacyclics: Consultancy, Research Funding; Verastem: Consultancy; ADC Therapeutics: Consultancy. Sail:AbbVie: Employment, Other: and may hold stock or stock options. Manzoor:AbbVie: Employment, Other: and may hold stock or stock options. Yazdy:Genentech: Research Funding; Octapharma: Consultancy; Abbvie: Consultancy; Bayer: Honoraria, Speakers Bureau. Hill:AstraZeneca: Consultancy, Honoraria; Pharmacyclics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; TG therapeutics: Research Funding; Celegene: Consultancy, Honoraria, Research Funding; Seattle Genetics: Consultancy, Honoraria; Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Kite: Consultancy, Honoraria; Genentech: Consultancy, Research Funding; Takeda: Research Funding; Amgen: Research Funding. Tuncer:Abbvie: Membership on an entity's Board of Directors or advisory committees; 2018 Steering Committee: Other: reimbursement for travel to the steering committee at ASH. Allan:Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie, Inc: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics LLC, an AbbVie company: Consultancy; Janssen: Consultancy, Honoraria; Verastem Oncology, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees; Acerta Pharma: Consultancy; Sunesis Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bayer: Consultancy. Ujjani:Atara: Consultancy; Gilead: Consultancy; Astrazeneca: Consultancy; Genentech: Honoraria; PCYC: Research Funding; Pharmacyclics: Honoraria; AbbVie: Honoraria, Research Funding. Emechebe:AbbVie: Employment, Other: and may hold stock or stock options. Kamalakar:AbbVie: Employment, Other: and may hold stock or stock options. Sharmokh:AbbVie: Employment, Other: may hold stock or stock options. Jiang:AbbVie: Employment, Other: and may hold stock or stock options. Pena:AbbVie: Employment, Other: and may hold stock or stock options. Marshall:AbbVie: Employment, Other: and may hold stock or stock options. Nielsen:AbbVie: Employment, Other: and may hold stock or stock options. Barr:Pharmacyclics LLC, an AbbVie company: Consultancy, Research Funding; TG Therapeutics: Consultancy, Research Funding; AbbVie: Consultancy; Janssen: Consultancy; Celgene: Consultancy; Merck: Consultancy; Seattle Genetics: Consultancy; Genentech: Consultancy; Verastem: Consultancy; Gilead: Consultancy; Astra Zeneca: Consultancy, Research Funding. Brown:Dynamo Therapeutics: Consultancy; Catapult Therapeutics: Consultancy; Invectys: Other: other; Janssen: Honoraria; Kite: Consultancy, Research Funding; Loxo: Consultancy, Research Funding; Novartis: Consultancy; Octapharma: Consultancy; Verastem: Consultancy, Research Funding; TG Therapeutics: Consultancy; Teva: Honoraria; Sunesis: Consultancy; Pfizer: Consultancy; Pharmacyclics: Consultancy; Gilead: Consultancy, Research Funding; Genentech/Roche: Consultancy; Sun: Research Funding; Sun Pharmaceuticals, Inc: Research Funding; Morphosys: Other: Data safety monitoring boards ; Acerta Pharma: Consultancy; AstraZeneca: Consultancy; BeiGene: Consultancy. Schuh:AbbVie: Consultancy, Speakers Bureau; Kite: Speakers Bureau; Gilead: Speakers Bureau; Seattle Genetics: Speakers Bureau; Jazz Pharmaceuticals: Speakers Bureau; Janssen: Speakers Bureau; Pharmacyclics: Consultancy, Speakers Bureau; Bristol-Myers Squibb: Research Funding; Verastem: Speakers Bureau; Genentech: Consultancy, Speakers Bureau. Eyre:Janssen: Honoraria, Other: travel support; AbbVie: Honoraria, Other: travel support; Gilead: Honoraria, Other: travel support. Lamanna:Celgene: Membership on an entity's Board of Directors or advisory committees; Roche-Genentech: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Membership on an entity's Board of Directors or advisory committees; Verastem: Research Funding; AbbVie: Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bei-Gene: Research Funding; TG Therapeutics: Research Funding; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees. Wierda:Gilead Sciences: Research Funding; Juno Therapeutics: Research Funding; Oncternal Therapeutics Inc.: Research Funding; Xencor: Research Funding; Janssen: Research Funding; Genentech: Research Funding; AbbVie: Research Funding; GSK/Novartis: Research Funding; Sunesis: Research Funding; Loxo Oncology Inc.: Research Funding; KITE pharma: Research Funding; Acerta Pharma Inc: Research Funding; Miragen: Research Funding; Pharmacyclics LLC: Research Funding; Cyclcel: Research Funding. Skarbnik:Jazz Pharmaceuticals: Speakers Bureau; Kite Pharma: Honoraria, Speakers Bureau; Novartis: Speakers Bureau; CLL Society: Consultancy, Membership on an entity's Board of Directors or advisory committees; Genentech: Honoraria, Speakers Bureau; Gilead Sciences: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Abbvie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Consultancy, Honoraria, Speakers Bureau; Acerta: Research Funding; Seattle Genetics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Verastem Oncology: Honoraria, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Pharmacyclics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Roeker:Abbott Laboratories: Equity Ownership; AbbVie: Equity Ownership. Bannerji:Celgene: Consultancy; Celgene: Consultancy; Pharmacyclics: Other: travel support; Merck: Other: travel support, Patents & Royalties: IP rights; AbbVie, Inc: Consultancy; Gilead: Other: travel support; Regeneron Pharmaceuticals, Inc.: Consultancy, Other: travel support, Research Funding; Merck: Other: travel support, Patents & Royalties: IP rights; Pharmacyclics: Other: travel support; AbbVie, Inc: Consultancy, travel support; Regeneron Pharmaceuticals, Inc.: Consultancy, Other: travel support, Research Funding; Gilead: Other: travel support. Pauff:AbbVie: Employment, Other: and may hold stock or stock options. Schuster:Novartis: Other: a patent (with royalties paid to Novartis) on combination therapies of CAR and PD-1 inhibitors.; Novartis, Celgene, Genentech, Merck, Pharmacyclics, Acerta, and Gilead: Other: Grants, Research Funding; Nordic Nanovector, Pfizer, AstraZeneca, Loxo Oncology, Acerta, and Celgene: Honoraria; Novartis, Nordic Nanovector, and Pfizer: Membership on an entity's Board of Directors or advisory committees. Follows:Gilead: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Abbvie: Consultancy, Honoraria, Speakers Bureau; AstraZeneca: Consultancy, Honoraria, Speakers Bureau; Janssen: Consultancy, Honoraria, Speakers Bureau; Roche: Consultancy, Honoraria, Speakers Bureau. Cheson:Pharmacyclics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Symbios: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Trillium: Research Funding; TG Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Seattle Genetics: Research Funding; Bristol Myers Squibb: Research Funding; Portola: Research Funding; Kite: Research Funding; Gilead: Research Funding; Epizyme: Research Funding; Morphosys: Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Membership on an entity's Board of Directors or advisory committees; Acerta: Consultancy, Research Funding; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Eichhorst:BeiGene: Research Funding; ArQule: Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead Sciences, Inc.: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Brander:DTRM Biopharma: Research Funding; BeiGene: Research Funding; Pharmacyclics LLC, an AbbVie Company: Consultancy; Genentech: Consultancy, Honoraria, Research Funding; Teva: Consultancy, Honoraria; TG Therapeutics: Consultancy, Honoraria, Research Funding; AstraZeneca: Consultancy, Research Funding; Novartis: Consultancy; AbbVie: Consultancy, Honoraria, Research Funding; MEI: Research Funding; Tolero: Research Funding; Acerta: Research Funding. Pivneva:AbbVie: Other: employee of Analysis Group, Inc., which has received consultancy fees from AbbVie. Guerin:AbbVie: Other: employee of Analysis Group, Inc., which has received consultancy fees from AbbVie. Mato:AstraZeneca: Consultancy, Research Funding; AbbVie: Consultancy, Research Funding; Sunesis: Consultancy, Research Funding; Celgene: Consultancy; Johnson & Johnson: Consultancy, Research Funding; Pharmacyclics: Consultancy, Research Funding; Gilead: Research Funding; Acerta: Consultancy; Janssen: Consultancy; LOXO: Consultancy, Research Funding; DTRM Biopharma: Research Funding; Genentech: Consultancy, Research Funding; TG Therapeutics: Consultancy, Other: DSMB member, Research Funding.

Background The pathogenesis of chronic lymphocytic leukemia (CLL) remains unknown, but first-degree relatives of affected patients (pts) have a 3-to-8-fold increased risk of developing CLL, suggesting an inherited component. Previously, we performed an exome-wide comparison of rare germline variants (vts) among CLL pts compared to controls and identified a 1.8X increased risk of any rare germline ATM vt in CLL pts. Certain vts had much higher relative risk; for example, ATM p.L2307F was associated with a 10X increased risk of CLL (Tiao Leukemia 2017). ATM p.F858L and p.P1054R also imparted a 2X increased risk of CLL in a candidate gene association study (Rudd Blood 2006). Most ATM missense vts have not been fully characterized and are classified as vts of uncertain significance (VUS) in clinical testing. We observed that ATM missense vts were common in our CLL clinic and sought to formally test the hypothesis of association by examining the frequency of ATM missense vts identified by next-generation-sequencing (NGS) routinely sent on hematologic malignancy pts seen at our institution. These pts served as a population with well-characterized diagnoses whose genetics had been uniformly determined by a CLIA-certified lab, allowing us to directly ask whether ATM VUS are enriched in CLL compared to other hematologic malignancies, and whether CLL characteristics differ between pts with and without ATM VUS. Methods The Brigham and Women's Hospital Rapid Heme Panel (RHP) is an NGS assay that interrogates 95 cancer-related genes, including the entire coding sequence of ATM. RHP results were aggregated for all 999 pts who had the test sent from the DFCI Lymphoma clinic (excluding T-PLL) between 7/1/2014 and 5/25/2018. RHP data were also aggregated for 876 pts seen by 3 physicians over the same time in the DFCI Leukemia clinic (acute leukemia and other myeloid disorders). Only vts with a total population allelic frequency (PAF) of <1% are included in RHP results, restricting our analysis to less common vts. Statistical analysis was performed in R. Results Out of 384 pts with CLL or monoclonal B lymphocytosis, 99 pts (25.8%, 95% CI 21.5-30.5%) had at least one ATM vt. 71 different ATM vts were seen, with 10 (14%) deemed pathogenic (nonsense mutations, internal insertions or deletions). All remaining 61 vts were missense vts, and the majority were likely germline: 43 are in the gnomAD germline vt database, and of the other 18, 8 had allele frequencies in blood between 40 and 60%. The most common vts were p.S707P (n = 11 pts), p.L2307F (n=9), p.F858L (n=8), and p.D1853V (n=8), all of which are known to be germline. ATM missense vts were more frequent in CLL (97 pts with missense vts out of 384 total, 25.3%) than in non-CLL lymphomas (91 out of 615, 14.8%, p=0.00006). No other individual lymphoma type had a higher frequency of ATM missense vts than CLL. Missense vts were also more frequent in CLL than in pts seen in the myeloid malignancy clinic (143 out of 876, 16.3%, p=0.0003). When restricting analysis to missense vts with PAFs reported in gnomAD, we found a higher percentage of extremely rare vts (PAFs <0.001%) in CLL pts (7 out of 42 vts, 16.7%) compared to the myeloid malignancy group (2 out of 55, 3.6%, p=0.04); the non-CLL lymphoma pts had a similar frequency of extremely rare vts (5 out of 39, 12.8%, p=0.12). Consistent with a biologic role for these vts, 32% of CLL pts with missense vts had 11q-deleted disease, while only 10.5% of pts without missense vts had 11q-deleted disease (p=3*10-6). Pts with missense vts were also significantly less likely to have TP53-aberrant disease, 10.9% vs. 20.7% (p=0.04), consistent with a mutually exclusive role for ATM and TP53. There was no difference in IGHV mutation status between CLL pts with and without missense vts (56.6% vs 53.4% unmutated, respectively). Conclusion One in 4 CLL pts has an ATM missense vt; these are more frequent in CLL than in other lymphoid or myeloid disorders. Most of these are germline and have previously been classified as VUS. CLL pts with missense vts have a higher frequency of 11q-deleted disease. These results highlight an important role for germline ATM missense vts as contributors to the inherited risk for developing CLL and emphasize the importance of analyzing VUS and constitutional data generated by NGS assays, the latter typically not reported by most laboratories. Disclosures Kim: Papgene, Inc: Consultancy; Quanterix, Inc: Consultancy; LabCorp, Inc: Consultancy. Brown:Juno/Celgene: Consultancy; AbbVie: Consultancy; Acerta Pharma: Consultancy; TG Therapeutics: Consultancy; Verastem: Consultancy, Research Funding; Teva: Honoraria; Janssen: Honoraria; Catapult Therapeutics: Consultancy; Dynamo Therapeutics: Consultancy; BeiGene: Consultancy; AstraZeneca: Consultancy; Octapharma: Consultancy; Invectys: Other: Data safety monitoring board; Morphosys: Other: Data safety monitoring board; Sun Pharmaceuticals: Research Funding; Sunesis: Consultancy; Pharmacyclics: Consultancy; Loxo: Consultancy, Research Funding; Novartis: Consultancy; Pfizer: Consultancy; Kite, a Gilead Company: Consultancy, Research Funding; Genentech/Roche: Consultancy; Gilead: Consultancy, Research Funding.

Introduction: The approval of several new, targeted agents has been transformative in the treatment of CLL. Prospective clinical trial data support the use of Ven after Ibr in CLL (Jones JA et al. Lancet Oncol 2018); however, limited data are available on the inverse sequencing of these agents (Mato AR et al. Br J Haematol 2018; Anderson M et al. Blood 2017). Given the recent FDA approval of Ven + obinutuzumab in first-line (1L) CLL, an upsurge in Ibr-naïve pts needing therapy post-Ven is likely; characterizing this sequencing is of the upmost importance. Here we present a US multicentre, retrospective, chart-review analysis to explore outcomes of Ibr post-Ven, in Ibr-naïve pts with CLL. Methods: Efficacy and safety outcomes were investigated for pts with Ibr-naïve CLL, treated with Ven +/- CD20 monoclonal antibody (mAb), who developed progressive disease ([PD] or discontinued Ven) and received Ibr salvage therapy (+/- CD20 mAb). Analyses included pts in 1L or relapsed/refractory setting. Pts were treated between Feb 14, 2012 and Jun 6, 2019, across four institutions (US); data cutoff was Jul 18, 2019. Results: Data were available for 27 pts with CLL who received Ibr post-Ven - the largest cohort to date. Median age was 64 (41-79) years, median time from diagnosis to first therapy was 9.0 (0-117.7) months (mo), and the median number of therapies prior to Ven was 2 (0-9). Prior therapies were varied and included: 1 Bruton's tyrosine kinase inhibitor (BTKi; not Ibr), 3 lenalidomide, 1 pt received 9 lines of therapy (including: idelalisib, lenalidomide, anti-CD22 and temsirolimus), others received chemo- or chemoimmunotherapy, or CD20 mAb only. Median time from diagnosis to initiation of Ven was 56.3 (0-157.7) mo. At baseline, the median lymphocyte count was 2.2 (0.2-220.0) K/µL; 8/24 (33.3%) pts had a lymph node ≥ 5cm. All evaluable pts (26/26) had ≥1 unfavourable prognostic risk factor; 12/20 (60.0%) pts had del17p, 10/16 (62.5%) had del11q, 12/24 (50.0%) had complex karyotype (CK) and 13/15 (86.7%) pts had unmutated IGHV. A complete or partial response (CR or PR) to Ven was achieved in 4/26 (15.4%) and 18/26 (69.2%) evaluable pts, respectively. The median time to PD on Ven was 29.0 (1.0-118.0) mo, with a median treatment duration of 18.0 (0.1-64.3) mo. Pts discontinued Ven due to PD (n=18), consent withdrawal (n=2), non-compliance (n=1), and other (n=6; allogeneic stem cell transplantation n=2, physician decision n=3, not evaluable n=1). Prior to initiation of Ibr, the median lymphocyte count was 1.9 (0.01-179.0) K/µL; 15/26 (57.7%) pts had adenopathy, and 5/13 (38.5%) had a lymph node ≥ 5cm. Risk factors included: del17p (4/10; 40.0%), del11q (4/9; 44.4%), CK (8/17; 47.1%) and unmutated IGHV (11/14; 78.6%). Median time from Ven initiation to Ibr initiation was 31.9 (1.8-60.3) mo; median time to Ibr initiation post-Ven was 0.7 (0-39.7) mo. The overall response rate to Ibr was 56.0% (CR: 1/25, PR: 13/25). The time to progression on Ibr, post-Ven, varied from 3.0 to 53.0 mo (n=10). The median duration of Ibr therapy was 18.3 (3.7-53.2) mo and 20.0 (4.9-44.3) mo for those remaining on Ibr (8/27); the median follow-up time matched the median therapy duration. Nineteen pts discontinued Ibr due to: PD (n=9), physician decision (n=4), adverse events (AEs; n=2), transplant (n=2), symptomatic deterioration and unknown reason (n=1 each). The median number of therapies prior to Ven for the 9 pts who discontinued Ibr due to PD was 2 (1-9); 4/9 pts received novel targeted therapies. Richter's transformation occurred in 1 pt (1/9). The 2 pts who discontinued Ibr due to AEs experienced either atrial fibrillation (AF)/brain abscess or pneumonia after 11.6 and 18.2 mo of Ibr, respectively. Other notable AEs were: major bleeding (n=1), AF (n=2), infection (n=1), neutropenia (n=1), myalgia/arthralgia (n=2), and other cardiac event (n=1). Ibr dose reductions due to fatigue and general malaise occurred in 1 pt. Conclusions: With the limitations of a retrospective series using real-world data, these data suggest that Ibr had substantial clinical activity post-Ven in heavily pre-treated, high-risk CLL pts; no new safety signals arose. Larger, prospective studies are required to fully characterize the efficacy of Ibr after Ven. Meanwhile, salvage therapy with Ibr remains a good option for pts with CLL who relapse after Ven. Disclosures Brown: Sunesis: Consultancy; Pharmacyclics: Consultancy; Pfizer: Consultancy; Novartis: Consultancy; Kite, a Gilead Company: Consultancy, Research Funding; Loxo: Consultancy, Research Funding; Invectys: Other: Data safety monitoring board; Octapharma: Consultancy; Morphosys: Other: Data safety monitoring board; Janssen: Honoraria; Dynamo Therapeutics: Consultancy; Teva: Honoraria; Sun Pharmaceuticals: Research Funding; Genentech/Roche: Consultancy; Gilead: Consultancy, Research Funding; BeiGene: Consultancy; Catapult Therapeutics: Consultancy; AstraZeneca: Consultancy; Acerta Pharma: Consultancy; AbbVie: Consultancy; Juno/Celgene: Consultancy; TG Therapeutics: Consultancy; Verastem: Consultancy, Research Funding. Davids:Research to Practice: Honoraria; AbbVie, Acerta Pharma, Adaptive, Biotechnologies, Astra-Zeneca, Genentech, Gilead Sciences, Janssen, Pharmacyclics, TG therapeutics: Membership on an entity's Board of Directors or advisory committees; AbbVie, Astra-Zeneca, Genentech, Janssen, MEI, Pharmacyclics, Syros Pharmaceuticals, Verastem: Consultancy; Acerta Pharma, Ascentage Pharma, Genentech, MEI pharma, Pharmacyclics, Surface Oncology, TG Therapeutics, Verastem: Research Funding. Chang:Genentech: Research Funding; Celgene: Research Funding; Adaptive Biotechnologies: Research Funding. Ma:Kite: Consultancy; Xeme: Research Funding; Abbvie: Research Funding; Beigene: Research Funding; Bioverativ: Consultancy; Incyte: Research Funding; Genentech: Consultancy; Astra Zeneca: Consultancy, Research Funding, Speakers Bureau; Gilead: Research Funding; Janssen: Consultancy, Speakers Bureau; Novartis: Research Funding; Juno: Research Funding; Acerta: Research Funding; Pharmacyclics: Consultancy, Research Funding, Speakers Bureau. Biondo:Genentech, Inc.: Employment; F. Hoffmann-La Roche Ltd: Equity Ownership. Mun:Genentech: Employment, Equity Ownership. Breuleux:F. Hoffmann - La Roche Ltd: Employment, Equity Ownership; Gilead: Equity Ownership; Basilea Ltd: Equity Ownership. Wierda:Janssen: Research Funding; Xencor: Research Funding; Gilead Sciences: Research Funding; Pharmacyclics LLC: Research Funding; Cyclcel: Research Funding; Sunesis: Research Funding; AbbVie: Research Funding; KITE pharma: Research Funding; Miragen: Research Funding; Juno Therapeutics: Research Funding; GSK/Novartis: Research Funding; Oncternal Therapeutics Inc.: Research Funding; Loxo Oncology Inc.: Research Funding; Genentech: Research Funding; Acerta Pharma Inc: Research Funding.

Venetoclax, the first approved BH3 mimetic targeting BCL2, demonstrates high response rate in chronic lymphocytic leukemia (CLL) but resistant cases are emerging. Aside from BCL2 mutations affecting venetoclax binding, multiple lines of mounting evidence suggest a role for non-mutational mechanisms underlying resistance to this drug. By applying both CRISPR-Cas9 knock-out and ORF overexpression screens in the lymphoma cell line OCI-Ly1, we previously reported the identification of MCL-1 overexpression and of the AMPK/PKA signaling axis in altering energy metabolism underlying venetoclax resistance (Guieze, ASH 2018). Here, we report further in-depth exploration of the impact of these findings, discovered through the analysis of lymphoid cell lines, and of specimens collected from CLL patients developing venetoclax resistance. The resistant lymphoma cell lines that we generated (OCI-Ly1 and SU-DHL4 cells) displayed increased oxidative phosphorylation (OXPHOS) compared to the parental lines, measured by Seahorse assay. We instead observed that venetoclax rapidly perturbs OXPHOS in sensitive cells. This process is dependent on mitochondrial outer membrane permeabilization, as this effect is abrogated in BAX/BAK1 double knockout (KO) cells. Targeting OXPHOS was shown to synergize with venetoclax in vitro and in vivo, as combination of venetoclax and oligomicin (an inhibitor of the ATP synthase, the complex V of the mitochondrial electron transport chain), was more effective than each drug alone in reducing tumor growth of a subcutaneous NSG xenograft model based on OCI-Ly1. Among the candidate markers driving resistance identified from the genome-wide screens, we focused on AMP pathway members (AMPK and PKA) and the ID3 transcriptional regulator, given that ID3 KO cells demonstrated similar transcriptomic changes than the resistant OCI-Ly1 cells. We found that PRKAR2B (encoding a PKA subunit), already highlighted in our ORF screen, was the top transcript overexpressed when knocking out ID3. To clarify how the dominant-negative transcription factor ID3 regulates PRKAR2B expression, we performed ATAC-seq of the ID3 OCI-Ly1 knockout (vs control) lines in order to determine differential signatures of chromatin accessibility and transcription factor engagement. We showed that ID3 repression leads to genome-wide increased accessibility associated with motifs of the lymphoid transcription factor TCF3. TCF3 has previously been shown to interact with ID3 and to be involved in the transcription of ADIPOQ, which was identified in the GOF screen. TCF3 binding sites were confirmed to be present within putative enhancer regions of PRKAR2B in a B cell context. We then investigated whether our findings could be validated in patient samples. By whole-exome sequencing of matched pretreatment and venetoclax-resistant CLL samples collected from 6 patients, we did not detect any recurrent somatic mutations associated with resistance. The resistant samples from three of 6 patients, however, harbored subclones with 1q amplification in a common region encompassing the MCL1 locus. We identified 4 additional CLL cases relapsing on venetoclax with leukemia samples collected before and after relapse. By immunohistochemical staining of 9 of 10 cases for which tissue was available, we detected increased MCL-1 expression at relapse in 6 of 9 cases (p = 0.026). We furthermore confirmed the involvement of AMPK signaling by detecting evidence of AMPK, ACC and p-ACC expression in 4 of 9 patients (all p = 0.0062). ID3 expression was decreased at matched relapse samples (p = 0.0001), supporting the presence of the resistance circuit we identified above. Taken together, our results identified the increased MCL-1 expression and PKA/AMPK activation as underlying mechanisms for venetoclax resistance. Our data support the implementation of combinatorial therapy with metabolic modulators to address venetoclax resistance. Disclosures Guièze: Abbvie: Honoraria; Roche: Honoraria; Janssen: Honoraria; Gilead: Honoraria. Thompson:AbbVie: Research Funding; Amgen: Consultancy, Research Funding; Pfizer: Research Funding; Pharmacyclics: Research Funding; Genentech: Consultancy, Honoraria; Gilead: Consultancy, Honoraria. Davids:AbbVie, Acerta Pharma, Adaptive, Biotechnologies, Astra-Zeneca, Genentech, Gilead Sciences, Janssen, Pharmacyclics, TG therapeutics: Membership on an entity's Board of Directors or advisory committees; Research to Practice: Honoraria; AbbVie, Astra-Zeneca, Genentech, Janssen, MEI, Pharmacyclics, Syros Pharmaceuticals, Verastem: Consultancy; Acerta Pharma, Ascentage Pharma, Genentech, MEI pharma, Pharmacyclics, Surface Oncology, TG Therapeutics, Verastem: Research Funding. Brown:AbbVie: Consultancy; Acerta Pharma: Consultancy; Loxo: Consultancy, Research Funding; BeiGene: Consultancy; Catapult Therapeutics: Consultancy; AstraZeneca: Consultancy; Novartis: Consultancy; Pfizer: Consultancy; Pharmacyclics: Consultancy; Sunesis: Consultancy; TG Therapeutics: Consultancy; Verastem: Consultancy, Research Funding; Sun Pharmaceuticals: Research Funding; Janssen: Honoraria; Teva: Honoraria; Morphosys: Other: Data safety monitoring board; Invectys: Other: Data safety monitoring board; Octapharma: Consultancy; Kite, a Gilead Company: Consultancy, Research Funding; Juno/Celgene: Consultancy; Dynamo Therapeutics: Consultancy; Genentech/Roche: Consultancy; Gilead: Consultancy, Research Funding. Wierda:Xencor: Research Funding; Cyclcel: Research Funding; Genentech: Research Funding; Pharmacyclics LLC: Research Funding; Gilead Sciences: Research Funding; KITE pharma: Research Funding; Oncternal Therapeutics Inc.: Research Funding; Sunesis: Research Funding; AbbVie: Research Funding; Janssen: Research Funding; Acerta Pharma Inc: Research Funding; GSK/Novartis: Research Funding; Miragen: Research Funding; Loxo Oncology Inc.: Research Funding; Juno Therapeutics: Research Funding. Letai:AbbVie, AstraZeneca, Novartis: Consultancy, Research Funding; Zeno Pharmaceuticals, Vivid Bioscience, Flash Therapeutics, Dialectic Therapeutics: Membership on an entity's Board of Directors or advisory committees, Other: Cofounder or Advisory Board member. Neuberg:Pharmacyclics: Research Funding; Madrigal Pharmaceuticals: Equity Ownership; Celgene: Research Funding. Mootha:Jansen Pharmaceuticals: Other: SAB, compensation; 5am Ventures: Other: SAB, compensation; Raze Therapeutics: Other: Founder, SAB, equity. Getz:MuTect, ABSOLTUE, MutSig and POLYSOLVER: Patents & Royalties: MuTect, ABSOLTUE, MutSig and POLYSOLVER; Pharmacyclics: Research Funding; IBM: Research Funding. Wu:Pharmacyclics: Research Funding; Neon Therapeutics: Other: Member, Advisory Board.

Background: Vecabrutinib is a selective, reversible, noncovalent BTK inhibitor (BTKi) with potent in vitro inhibitory activity against both wild type and C481S-mutated BTK, the most common mutation detected in patients (pts) with CLL relapsing on treatment with covalent BTKi (cBTKi). Methods: This is an open-label, modified 3+3 dose-escalation, cohort expansion phase 1b/2 trial to evaluate safety, pharmacokinetics (PK), pharmacodynamics (PD), maximum tolerated dose (MTD) and antitumor activity of oral vecabrutinib in adult pts with relapsed/refractory advanced B-cell malignancies who must have received ≥2 prior regimens and progressed on therapy with a cBTKi where available as an approved indication. Prespecified dose levels are 25 to 500 mg PO BID. Patients continue to receive vecabrutinib until time of progression or intolerable toxicity. The safety period for DLT assessment is Cycle 1 (4 weeks). Activity is monitored throughout study treatment and for survival. Molecular profiles, PK, and PD are also evaluated. Results: To date, 27 pts (chronic lymphocytic leukemia [CLL], n=21; mantle cell lymphoma [MCL], n=2; Waldenström's macroglobulinemia [WM], n=3; marginal zone lymphoma (MZL), n=1) have been treated (Cohort 1, 25 mg BID, n=3; Cohort 2, 50 mg BID, n=10; Cohort 3, 100 mg BID n=7, Cohort 4, 200 mg BID n=4, Cohort 5, 300 mg BID n=3): median age 66 yrs (range: 47-77), 96% ECOG PS 0-1, 73% male, median prior regimens 4 (range: 2-9) all including a cBTKi (23 pts ibrutinib, 4 pts acalabrutinib). At screening, 76% (19/25) had mutated or deleted TP53, 48% (12/25) had BTK C481 mutations and 20% (5/25) had phospholipase C gamma 2 (PLCg2) mutations. BTK C481 mutation was found in 11 CLL pts (C481S n= 8 variant allelic frequency [VAF] 7-93%, C481R n=2, [VAF 49%, 77%], C481P n=1 [VAF 28%]) and in one pt with WM (C481S [VAF 8%]). One CLL pt had both BTK C481S (VAF 20%) and T474I (gatekeeper residue, VAF 32%) mutation. Five pts (3 CLL, 1 WM and 1 MZL) had PLCg2 mutations; only one of the CLL pts had an activating PLCg2 mutation (S707F; VAF 8%). Overall, NGS on a panel of 128 genes known to be recurrently mutated in lymphoid malignancies detected a median of 5 mutations/pt; the most common mutated genes were SF3B1 (24%), NOTCH1 and ATM (20% each). Safety: the MTD has not been reached through Cohort 4. Adverse Events (AEs) are available for 24 pts; the most common all-grade AEs were anemia (37.5%), headache, neutropenia and night sweats (each 25%). Drug-related Grade 3 AEs occurred in 3 pts, all from Cohort 2: increased ALT, neutropenia and worsening anemia (all in 1 pt), and leukocytosis (2 pts). Cohort 2 was expanded per protocol due to a DLT (insufficient doses received due to Grade 3 drug-related ALT increase). There were no drug-related serious AEs. Stable disease (investigator assessed) was seen in 4 pts with CLL, 3 of whom had BTK C481S mutation (Cohort 1, n=1, Cohort 2, n=2, Cohort 3, n=1); these pts remained on treatment 72->196 days. One CLL BTK C481S pt remains on treatment and in Cycle 7 was dose-escalated from 100 to 200 mg BID; two CLL pts with BTK C481S (50 mg, 100 mg BID) showed improvement in B-symptoms and decreased tumor burden (-47%, -16% SPD change). Two pts with CLL (200 mg BID) are in Cycle 3, one with BTK C481S, T474I and one with PLCG2 S707F; 3 pts (300 mg BID; 2 CLL, 1 MZL) are currently in Cycle 1. Cycle 1 Day 8 vecabrutinib median steady-state Cmin values increased with dose: 75 ng/mL (Cohort 1, n=3), 451 ng/mL (Cohort 2, n=10), 873 ng/ml (Cohort 3, n=4) and 1124 ng/ml (Cohort 4, n=4) indicating that doses of ≥200 mg BID should result in consistent and high levels of BTK inhibition (Neuman ASH 2017). PD assessments (BTK phosphorylation; changes in chemokines) confirmed on-target inhibition of BTK. Of 20 pts evaluated, 12 had interpretable pBTK data with decreases seen as early as 1 hour post-first dose (avg 81%; range 37-100%) and sustained inhibition at end of Cycle 1 (avg 80%; range 48-100%). Most pts who completed cycle 1 had a decrease in at least 2 of 3 cytokines (CCL2, CCL3, CCL4). Conclusions: To date, vecabrutinib safety profile in 25-200 mg BID cohorts was acceptable with evidence of clinical activity. Dose levels are under investigation that may result in greater clinical activity in pts whose disease remains adequately sensitive to BTK inhibition. Evaluation of the 300 mg BID cohort is ongoing and updated trial results will be presented. Disclosures Allan: Sunesis Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bayer: Consultancy; Janssen: Consultancy, Honoraria; Acerta Pharma: Consultancy; Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie, Inc: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics LLC, an AbbVie company: Consultancy; Verastem Oncology, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees. Patel:Sunesis: Consultancy; AstraZeneca: Consultancy, Research Funding, Speakers Bureau; Celgene: Consultancy, Speakers Bureau; Genentech: Consultancy, Speakers Bureau; Pharmacyclics/Janssen: Consultancy, Speakers Bureau. Mato:AstraZeneca: Consultancy, Research Funding; AbbVie: Consultancy, Research Funding; Sunesis: Consultancy, Research Funding; Celgene: Consultancy; Johnson & Johnson: Consultancy, Research Funding; TG Therapeutics: Consultancy, Other: DSMB member , Research Funding; LOXO: Consultancy, Research Funding; DTRM Biopharma: Research Funding; Genentech: Consultancy, Research Funding; Pharmacyclics: Consultancy, Research Funding; Gilead: Research Funding; Acerta: Consultancy; Janssen: Consultancy. Wierda:Juno Therapeutics: Research Funding; Gilead Sciences: Research Funding; Acerta Pharma Inc: Research Funding; Pharmacyclics LLC: Research Funding; Genentech: Research Funding; AbbVie: Research Funding; GSK/Novartis: Research Funding; KITE pharma: Research Funding; Sunesis: Research Funding; Miragen: Research Funding; Oncternal Therapeutics Inc.: Research Funding; Cyclcel: Research Funding; Loxo Oncology Inc.: Research Funding; Janssen: Research Funding; Xencor: Research Funding. Pinilla Ibarz:Bayer: Speakers Bureau; Sanofi: Speakers Bureau; Abbvie: Consultancy, Speakers Bureau; TG Therapeutics: Consultancy; Novartis: Consultancy; Bristol-Myers Squibb: Consultancy; Takeda: Consultancy, Speakers Bureau; Janssen: Consultancy, Speakers Bureau; Teva: Consultancy. Choi:Abbvie: Consultancy, Research Funding, Speakers Bureau; Genentech: Consultancy, Speakers Bureau; Pharmacyclics: Consultancy, Research Funding, Speakers Bureau; Rigel: Consultancy, Research Funding; Gilead: Consultancy, Speakers Bureau; Oncternal: Research Funding. O'Brien:Aptose Biosciences, Inc: Consultancy; Amgen: Consultancy; Alexion: Consultancy; Gilead: Consultancy, Research Funding; Janssen: Consultancy, Honoraria; Kite: Research Funding; Sunesis: Consultancy, Research Funding; TG Therapeutics: Consultancy, Research Funding; Vaniam Group LLC: Consultancy; Verastem: Consultancy; Acerta: Research Funding; AbbVie: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria, Research Funding; Regeneron: Research Funding; Pharmacyclics LLC, an AbbVie Company: Consultancy, Research Funding; GlaxoSmithKline: Consultancy; Celgene: Consultancy; Astellas: Consultancy; Eisai: Consultancy. Sharman:AstraZeneca: Consultancy, Honoraria, Research Funding; TG Therapeutics: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria, Research Funding; Pharmacyclics LLC, an AbbVie Company: Consultancy, Honoraria, Research Funding; Genentech: Consultancy, Honoraria, Research Funding; Acerta: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Research Funding. Shadman:Mustang Bio: Research Funding; Genentech: Consultancy, Research Funding; Pharmacyclics: Consultancy, Research Funding; Verastem: Consultancy; Celgene: Research Funding; ADC Therapeutics: Consultancy; Acerta Pharma: Research Funding; Astra Zeneca: Consultancy; AbbVie: Consultancy, Research Funding; Gilead: Consultancy, Research Funding; Sound Biologics: Consultancy; TG Therapeutic: Research Funding; BeiGene: Research Funding; Sunesis: Research Funding; Atara Biotherapeutics: Consultancy. Davids:AbbVie, Astra-Zeneca, Genentech, Janssen, MEI, Pharmacyclics, Syros Pharmaceuticals, Verastem: Consultancy; Acerta Pharma, Ascentage Pharma, Genentech, MEI pharma, Pharmacyclics, Surface Oncology, TG Therapeutics, Verastem: Research Funding; Research to Practice: Honoraria; AbbVie, Acerta Pharma, Adaptive, Biotechnologies, Astra-Zeneca, Genentech, Gilead Sciences, Janssen, Pharmacyclics, TG therapeutics: Membership on an entity's Board of Directors or advisory committees. Pagel:AstraZeneca: Consultancy; Gilead Sciences: Consultancy; Pharmacyclics: Consultancy. Ward:Sunesis Pharmaceuticals: Consultancy. Acton:Sunesis Pharmaceuticals: Consultancy. Taverna:Sunesis Pharmaceuticals: Employment. Fox:Sunesis Pharmaceuticals: Employment. Furman:Acerta Pharma: Consultancy; Beigene: Consultancy; Genentech: Consultancy; Incyte: Consultancy; Janssen: Consultancy; Oncotracker: Consultancy; Pharmacyclics: Consultancy; Sunesis: Consultancy; TG Therapeutics: Consultancy; AstraZeneca: Consultancy; Abbvie: Consultancy; Verastem: Consultancy. Brown:Juno/Celgene: Consultancy; Gilead: Consultancy, Research Funding; Kite, a Gilead Company: Consultancy, Research Funding; Loxo: Consultancy, Research Funding; Dynamo Therapeutics: Consultancy; Genentech/Roche: Consultancy; AbbVie: Consultancy; Acerta Pharma: Consultancy; AstraZeneca: Consultancy; Novartis: Consultancy; Pfizer: Consultancy; Pharmacyclics: Consultancy; Sunesis: Consultancy; TG Therapeutics: Consultancy; Verastem: Consultancy, Research Funding; Sun Pharmaceuticals: Research Funding; Janssen: Honoraria; Teva: Honoraria; Morphosys: Other: Data safety monitoring board; Invectys: Other: Data safety monitoring board; Octapharma: Consultancy; BeiGene: Consultancy; Catapult Therapeutics: Consultancy.

Abstract 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 &gt;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 &gt;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: Targeted inhibition of Bruton tyrosine kinase (BTK) has improved clinical outcomes for patients with chronic lymphocytic leukemia (CLL). Acalabrutinib is a highly selective, covalent BTK inhibitor. A recently completed phase 3 trial showed acalabrutinib improved progression-free survival (PFS) vs idelalisib or bendamustine + rituximab in relapsed/refractory (R/R) CLL patients (ASCEND: Ghia et al. EHA 2019;273259:LB2606). This is an updated analysis with extended follow-up of a phase 1-2 multicenter study (NCT02029443) in patients with R/R CLL/small lymphocytic lymphoma (SLL), to demonstrate the durability of response and long-term tolerability of acalabrutinib. Methods: Patients with CLL or SLL were eligible if they were R/R after ≥1 prior treatment. Eligible patients were ≥18 years of age with an Eastern Cooperative Oncology Group performance status (ECOG PS) ≤2. Oral acalabrutinib 100 mg was administered twice daily. All patients were treated until progressive disease or unacceptable toxicity occurred. Study endpoints included overall response rate (ORR), PFS, duration of response (DOR) and safety, with post hoc analysis of event-free survival (EFS). Response rates were based on the International Workshop on Chronic Lymphocytic Leukemia 2008 criteria (Hallek et al., 2008) with modification for lymphocytosis (Cheson et al., 2012). Nine patients had longitudinal peripheral blood mononuclear cell samples from pre-treatment baseline, during treatment and at progression analyzed for whole exome sequencing, to assess acquired mechanisms of treatment resistance. Results: In total, 134 patients with R/R CLL/SLL received ≥ 1 dose of acalabrutinib. The median age was 66 years (range, 42-85 years). Baseline characteristics included ECOG PS ≤1 (97%), bulky lymph nodes ≥5 cm (39%), unmutated immunoglobulin heavy chain variable region (IGHV; 73%), chromosome 17p13.1 deletion (23%), chromosome 11q22.3 deletion (18%), and complex karyotype (≥3 abnormalities; 35%). The median number of prior therapies was 2 (range, 1-13). Patients received acalabrutinib for a median of 41 months (range, 0.2-58 months). Most adverse events (AEs) were mild to moderate, and most commonly were diarrhea (52%), headache (46%), and upper respiratory tract infection (36%). Grade ≥3 AEs occurred in 66% of patients; most commonly (≥5% of patients) neutropenia (14%), pneumonia (11%), hypertension (7%), anemia (7%) and diarrhea (5%). AEs of interest included atrial fibrillation (7% all grades; 3% Grade ≥3) and major bleeding events (5% all grades; 3% Grade ≥3). Most patients (56%) remained on treatment. The most common reasons for discontinuing treatment were progressive disease (21%) and AEs (11%). AEs leading to discontinuation occurring in ≥1 patient included pneumonia (4 events), anemia, neutropenia, and thrombocytopenia (2 events each). The ORR (partial response with lymphocytosis or above) was 94% (95% confidence interval [CI]: 89-97%); with 4% of patients having complete response, 84% having partial response and 6% having partial response with lymphocytosis (Table). The median DOR, PFS and EFS were not reached; the estimated 42-month DOR was 61% (95% CI: 49-71%), PFS was 68% (95% CI: 59-76%) and EFS was 64% (95% CI: 54-71%). Responses were similar regardless of genomic features, including unmutated IGHV, chromosomal deletions and complex karyotype (Table). Upon relapse during acalabrutinib treatment, whole exome sequencing detected BTK mutations in 6 of 9 (67%) tested patients that were not detectable at baseline. Of the 6 patients with detectable BTK C481X mutations, 4 had expansion to high allele frequency of the BTK mutation at progression (up to 58%). In a longitudinal analysis of patients who had a sample after 6 months of treatment, the BTK mutation was not detectable. No PLCG2 gene mutations were detected using exome analysis in the 9 patients analyzed. Conclusions: These updated results confirm the earlier reports of acalabrutinib efficacy for the treatment of CLL and provide additional data on DOR and long-term tolerability. Reported AEs indicate a tolerable and consistent safety profile, with a low rate of major bleeding events. Genomic profiling in a small subset of patients indicated that acquired mutation of BTK was the most frequent mechanism of acalabrutinib resistance. Disclosures Furman: Genentech: Consultancy. Wierda:Loxo Oncology Inc.: Research Funding; Janssen: Research Funding; Xencor: Research Funding; Cyclcel: Research Funding; Oncternal Therapeutics Inc.: Research Funding; Miragen: Research Funding; Sunesis: Research Funding; KITE pharma: Research Funding; Juno Therapeutics: Research Funding; Gilead Sciences: Research Funding; Acerta Pharma Inc: Research Funding; Pharmacyclics LLC: Research Funding; Genentech: Research Funding; AbbVie: Research Funding; GSK/Novartis: Research Funding. Schuh:Roche: Consultancy, Honoraria; GlaxoSmithKline: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; Gilead: Consultancy, Honoraria. Devereux:Servier: Speakers Bureau; Roche: Consultancy, Other: Travel expenses, Speakers Bureau; GlaxoSmithKline: Consultancy; Gilead: Consultancy, Honoraria, Other: Travel expenses, Speakers Bureau; MSD: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Other: Travel expenses, Speakers Bureau. Brown:Pfizer: Consultancy; Sun: Research Funding; Verastem: Consultancy, Research Funding; TG Therapeutics: Consultancy; Teva: Honoraria; Sunesis: Consultancy; Pharmacyclics: Consultancy; Morphosys: Other: Data safety monitoring boards ; Sun Pharmaceuticals, Inc: Research Funding; Acerta Pharma: Consultancy; AstraZeneca: Consultancy; BeiGene: Consultancy; Catapult Therapeutics: Consultancy; Dynamo Therapeutics: Consultancy; Genentech/Roche: Consultancy; Gilead: Consultancy, Research Funding; Invectys: Other: other; Janssen: Honoraria; Kite: Consultancy, Research Funding; Loxo: Consultancy, Research Funding; Novartis: Consultancy; Octapharma: Consultancy. Hillmen:AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel Expenses, Research Funding; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel Expenses, Research Funding; Pharmacyclics LLC, an AbbVie Company: Consultancy, Honoraria, Research Funding; Roche: Research Funding; Gilead: Research Funding; Apellis: Research Funding; Acerta: Membership on an entity's Board of Directors or advisory committees. Martin:Karyopharm: Consultancy; Teneobio: Consultancy; Celgene: Consultancy; I-MAB: Consultancy; Sandoz: Consultancy; Janssen: Consultancy. Awan:Sunesis: Consultancy; AstraZeneca: Consultancy, Speakers Bureau; Innate Pharma: Research Funding; Gilead: Consultancy; Janssen: Consultancy; Abbvie: Consultancy, Speakers Bureau; Pharmacyclics: Consultancy, Research Funding. Stephens:Acerta: Research Funding; Gilead: Research Funding; Karyopharm: Research Funding. Ghia:Sunesis: Consultancy, Honoraria, Research Funding; Novartis: Research Funding; ArQule: Consultancy, Honoraria; BeiGene: Consultancy, Honoraria; Dynamo: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Research Funding; Juno/Celgene: Consultancy, Honoraria; Gilead: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria, Research Funding; Acerta/AstraZeneca: Consultancy, Honoraria; Pharmacyclics LLC, an AbbVie Company: Consultancy. Barrientos:Bayer: Consultancy; AstraZeneca: Consultancy; AbbVie: Consultancy, Research Funding; Pharmacyclics LLC, an AbbVie Company: Consultancy, Research Funding; Genentech: Consultancy; Gilead: Consultancy; Janssen: Honoraria; Sandoz: Consultancy; Oncternal Therapeutics: Research Funding. Pagel:AstraZeneca: Consultancy; Gilead Sciences: Consultancy; Pharmacyclics: Consultancy. Woyach:Janssen: Consultancy, Research Funding; Pharmacyclics LLC, an AbbVie Company: Consultancy, Research Funding; AbbVie: Research Funding; Karyopharm: Research Funding; Loxo: Research Funding; Morphosys: Research Funding; Verastem: Research Funding. Burke:AstraZeneca: Employment, Equity Ownership. Covey:Acerta Pharma: Employment, Equity Ownership; AstraZeneca: Equity Ownership. Gulrajani:AstraZeneca: Equity Ownership; Acerta Pharma: Employment, Equity Ownership. Hamdy:Acerta Pharma: Employment, Equity Ownership. Izumi:Acerta Pharma: Employment, Equity Ownership. Frigault:Acerta Pharma: Employment; AstraZeneca: Employment, Equity Ownership. Patel:Acerta Pharma: Employment, Equity Ownership. Rothbaum:Acerta Pharma: Employment, Equity Ownership. Wang:AstraZeneca: Equity Ownership; Acerta Pharma: Employment. O'Brien:Eisai: Consultancy; Celgene: Consultancy; TG Therapeutics: Consultancy, Research Funding; Sunesis: Consultancy, Research Funding; GlaxoSmithKline: Consultancy; Gilead: Consultancy, Research Funding; Verastem: Consultancy; Vaniam Group LLC: Consultancy; Astellas: Consultancy; Pfizer: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria; Acerta: Research Funding; Alexion: Consultancy; Amgen: Consultancy; Aptose Biosciences, Inc: Consultancy; Regeneron: Research Funding; Pharmacyclics LLC, an AbbVie Company: Consultancy, Research Funding; Janssen: Consultancy, Honoraria; Kite: Research Funding. Byrd:Ohio State University: Patents & Royalties: OSU-2S; BeiGene: Research Funding; Acerta: Research Funding; Genentech: Research Funding; Janssen: Consultancy, Other: Travel Expenses, Research Funding, Speakers Bureau; BeiGene: Research Funding; Novartis: Other: Travel Expenses, Speakers Bureau; Gilead: Other: Travel Expenses, Research Funding, Speakers Bureau; Gilead: Other: Travel Expenses, Research Funding, Speakers Bureau; Pharmacyclics LLC, an AbbVie Company: Other: Travel Expenses, Research Funding, Speakers Bureau; Novartis: Other: Travel Expenses, Speakers Bureau; TG Therapeutics: Other: Travel Expenses, Research Funding, Speakers Bureau; Pharmacyclics LLC, an AbbVie Company: Other: Travel Expenses, Research Funding, Speakers Bureau; Acerta: Research Funding; Ohio State University: Patents & Royalties: OSU-2S; Janssen: Consultancy, Other: Travel Expenses, Research Funding, Speakers Bureau; Janssen: Consultancy, Other: Travel Expenses, Research Funding, Speakers Bureau; Genentech: Research Funding; Acerta: Research Funding; Ohio State University: Patents & Royalties: OSU-2S; Gilead: Other: Travel Expenses, Research Funding, Speakers Bureau; TG Therapeutics: Other: Travel Expenses, Research Funding, Speakers Bureau; BeiGene: Research Funding; Novartis: Other: Travel Expenses, Speakers Bureau; Genentech: Research Funding; TG Therapeutics: Other: Travel Expenses, Research Funding, Speakers Bureau; Pharmacyclics LLC, an AbbVie Company: Other: Travel Expenses, Research Funding, Speakers Bureau. OffLabel Disclosure: This is a Phase 1/2 investigational study of acalabrutinib in chronic lymphocytic leukemia

Introduction: Venetoclax has demonstrated deep responses and sustained progression-free survival and is well tolerated in patients (pts) with previously untreated or relapsed/refractory (R/R) chronic lymphocytic leukemia/small lymphocytic leukemia (CLL/SLL) in clinical trials. Some early studies provided initial insight of venetoclax utilization in the real-world (RW), but RW evidence focusing on venetoclax effectiveness and safety is still limited. This study assessed venetoclax effectiveness, safety, and treatment patterns in CLL pts treated in clinical practice. Methods: The CLL Collaborative Study of Real-World Evidence (CORE), a large multicenter chart review across 21 institutions in 4 countries, enrolled adult pts who initiated a first line (1L) therapy on/after 01/01/2012 or a new line of therapy (LOT) for R/R CLL/SLL on/after 02/12/2014 (current data cut through 06/08/2020). Clinical responses were abstracted from the medical records as assessed by treating physicians or investigators (iwCLL criteria were provided as reference). Overall response rate (ORR) was calculated as the proportion of pts with complete response (CR) or partial response (PR) out of pts with documented response assessments. Treatment patterns included choice of regimens and sequences, dose interruption, dose reduction, and discontinuation. Treatment discontinuation was defined as ending therapy for any reason(s) other than the completion of planned duration of therapy. Interruption was defined as a gap in the same LOT. All analyses were descriptive. Results: Of the 1231 CLL pts in the CORE data, 155 received venetoclax (21 in 1L and 134 in R/R) and were included in this study. Most of the sample were male (65%) and the median age at venetoclax initiation was 67.5 (range 37-91). For high-risk features among pts with available data, 33% (43/132 pts) had del(17p) or TP53 mutation, 24% (31/131 pts) had complex karyotype (≥ 3 abnormalities), and 77% (61/79 pts) had unmutated IGHV. At venetoclax initiation, 46%, 40%, and 14% of 151 pts with available data had low, medium, and high tumor burden, respectively. Median follow-up time from venetoclax initiation across all lines was 7.0 (0.1-43.1) months. Median number of prior LOT for R/R pts was 2 (1-5); the largest proportion of pts (36%) received venetoclax in 2L followed by 3L (26%). In 1L, venetoclax was most frequently used (62%) in combination (Figure 1), while in R/R setting venetoclax monotherapy was more commonly used (61%) followed by venetoclax + rituximab (25%; Figure 2). Majority of R/R pts (63%) received Bruton's tyrosine kinase inhibitors (BTKi) prior to venetoclax (Figure 2). Response was assessed and documented for 114 pts (74%). Among these, ORR was 75% (CR=40%, PR=35%) overall. Pts ≥65 years old had an ORR of 79% (CR=41%, PR=38%, n=74), and pts &lt;65 years old had an ORR of 70% (CR=40%, PR=30%, n=40). ORR was 77% (CR=40%, PR=37%; n=30) for pts with del(17p) or TP53 mutation and 78% (CR=34%, PR=44%; n=64) for pts without del(17p) or TP53 mutation. ORR was 87% (CR=48%, PR=39%; n=23) for pts with complex karyotype and 74% (CR=32%, PR=42%; n=71) for pts without complex karyotype. ORR was 72% (CR=36%, PR=36%; n=53) for pts with unmutated IGHV and 91% (CR=36%, PR=55%; n=11) for pts with mutated IGHV. Overall, 48% of pts had adverse events (AEs) recorded. Five R/R pts (3.2%) had TLS events (defined by Howard or Cairo-Bishop criteria), of which 3 (1.9%) were clinical. Of the 5 pts, 2 had high tumor burden, and 3 had medium burden. Other AEs of interest include neutropenia (17%), thrombocytopenia (9%), and diarrhea/colitis (5%). Overall, 32% of pts discontinued venetoclax; 13% of all pts discontinued venetoclax due to AEs (primarily neutropenia [n=2] and thrombocytopenia [n=2]), followed by disease progression (8%). Venetoclax interruption rate was 14%, and dose reduction rate was 22% overall. Conclusions: Consistent with trial experiences, venetoclax demonstrates high response rates, including high-risk groups, and a manageable safety profile with low rates of TLS in clinical practice. Despite limitations of RW research, this study provides useful insights into treatment practices with venetoclax. Future research with longer follow-up is warranted to better understand the long-term clinical outcomes associated with venetoclax regimens. Disclosures Zheng: AbbVie: Current Employment. Sail:AbbVie Inc.: Current Employment, Current equity holder in publicly-traded company. Roeker:Abbott Laboratories: Other: spouse with minority ownership interest ; American Society of Hematology: Research Funding; AbbVie: Other: spouse with minority ownership interest . Manzoor:AbbVie: Current equity holder in publicly-traded company. Tuncer:AbbVie: Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees. Allan:Abbvie, Janssen, AstraZeneca, Pharmacyclics: Honoraria; Celgene, Genentech, Janssen, TG Therapeutics: Research Funding; Acerta, Genentech, Abbvie, Sunesis, Ascentage, Pharmacyclics, Janssen, AstraZeneca, BeiGene: Consultancy. Ujjani:Gilead/Kite: Consultancy, Research Funding; AstraZeneca: Consultancy, Honoraria, Research Funding; Genentech: Consultancy, Honoraria; MorphoSys: Consultancy; Atara: Consultancy, Honoraria; Verastem Oncology: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria, Research Funding. Barr:Genentech: Consultancy; Merck: Consultancy; Abbvie/Pharmacyclics: Consultancy, Research Funding; Janssen: Consultancy; Celgene: Consultancy; Seattle Genetics: Consultancy; Verastem: Consultancy; TG therapeutics: Consultancy, Research Funding; Morphosys: Consultancy; Gilead: Consultancy; AstraZeneca: Consultancy, Research Funding. Brown:Novartis: Consultancy; Nextcea: Consultancy; Octapharma: Consultancy; MEI Pharma: Consultancy; Eli Lilly and Company: Consultancy; Astra-Zeneca: Consultancy; TG Therapeutics: Consultancy; Sunesis: Consultancy; Loxo: Consultancy, Research Funding; Sun: Research Funding; Rigel Pharmaceuticals: Consultancy; Pfizer: Consultancy; Catapult: Consultancy; Dynamo Therapeutics: Consultancy; Pharmacyclics: Consultancy; Morphosys: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other; Gilead: Consultancy, Research Funding; Genentech: Consultancy; BeiGene: Consultancy; Invectys: Membership on an entity's Board of Directors or advisory committees, Other: DSMC; Janssen: Honoraria; AbbVie: Consultancy; Kite: Consultancy; Juno/Celgene: Consultancy; Verastem: Consultancy, Research Funding; Acerta: Consultancy. Eyre:AbbVie: 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; Janssen: Consultancy, Honoraria, Other: travel support; Gilead: Consultancy, Honoraria, Other: travel support. Skarbnik:Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Kite Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; CLL Society: Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Alexion: Consultancy; Beigene: Speakers Bureau; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Speakers Bureau; Verastem: Speakers Bureau; Pharmacyclics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Bannerji:Regeneron Pharmaceuticals: Research Funding; F. Hoffmann-La Roche Ltd/Genentech, Inc and Pharmacyclics LLC, an AbbVie Company: Research Funding; Sanofi-Pasteur: Other: Spouse is employee; AbbVie: Research Funding. Eichhorst:BeiGene: Consultancy, Honoraria, Other: travel support, Research Funding; AbbVie: Consultancy, Honoraria, Other: travel support, Research Funding; Janssen-Cilag: Consultancy, Honoraria, Other: travel support, Research Funding; F. Hoffmann-LaRoche: Consultancy, Honoraria, Other: travel support, Research Funding; ArQule: 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; Novartis: Consultancy, Honoraria, Other: travel support, Research Funding; Celgene: Consultancy, Honoraria, Other: travel support, Research Funding. Brander:Verastem: Consultancy, Honoraria, Other, Research Funding; NCCN: Other; 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; NCCN: Other; Novartis: Consultancy, Other; Teva: Consultancy, Honoraria; Tolero: Research Funding; Ascentage: Other, Research Funding; ArQule: Consultancy, Other, Research Funding; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding; Tolero: Research Funding; Teva: Consultancy, Honoraria; Novartis: Consultancy, Other; DTRM: Other, Research Funding; AstraZeneca: Consultancy, Honoraria, Other, Research Funding; BeiGene: Other, Research Funding. Sharmokh:AbbVie: Current Employment, Current equity holder in publicly-traded company. Jiang:AbbVie: Current Employment, Other: may hold stock or options. Pena:AbbVie: Current Employment, Current equity holder in publicly-traded company. Kamalakar:AbbVie: Current Employment, Other: may hold stock or other options. Emechebe:AbbVie: Current Employment, Current equity holder in publicly-traded company. Pivneva:Novartis: Consultancy, Other: Irina Pivneva is an employee of Analysis Group, Inc which received consultancy fees from Novartis.. Burne:Analysis Group, Inc., which has received consultancy fees from AbbVie: Current Employment. Guerin:Abbvie: Consultancy, Other; Novartis Pharmaceuticals Corporation: Consultancy, Other: Annie Guerin is an employee of Analysis Group, Inc. which received consultancy fees from Novartis.; Sanofi Genzyme: Consultancy, Other: Annie Guerin is an employee of Analysis Group, Inc. which received consultancy fees from Sanofi Genzyme.. Davids:Celgene: Consultancy; Research to Practice: Honoraria; AbbVie: Consultancy; Sunesis: Consultancy; Genentech: Consultancy, Research Funding; Pharmacyclics: Consultancy, Research Funding; MEI Pharma: Consultancy, Research Funding; Surface Oncology: Research Funding; BeiGene: Consultancy; Novartis: Consultancy, Research Funding; AstraZeneca: Consultancy, Research Funding; Bristol Myers Squibb: Research Funding; Janssen: Consultancy; Adaptive Biotechnologies: Consultancy; Ascentage Pharma: Consultancy, Research Funding; Gilead Sciences: Consultancy; Eli Lilly: Consultancy; Syros Pharmaceuticals: Consultancy; Zentalis: Consultancy; Merck: Consultancy; TG Therapeutics: Consultancy, Research Funding; Verastem: Consultancy, Research Funding. Mato:AbbVie: Consultancy, Research Funding; Adaptive: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; TG Therapeutics: Consultancy, Research Funding; AstraZeneca: Consultancy, Research Funding; Pharmacyclics: Consultancy, Research Funding; Loxo: Consultancy, Research Funding; Janssen: Consultancy, Research Funding.

The present study aimed to investigate the inter-unit consistency and validity of multiple 10-Hz Catapult Global Navigation Satellite System (GNSS) units in measuring straight-line sprint distances and speeds. A total of 13 participants performed one 45.72-m linear sprint at maximum effort while wearing all eight GNSS units at once. Total run distance and peak speed recorded using GNSS units during the sprint duration were extracted for analysis. Sprint time and peak speed were also obtained from video recordings as reference values. Inter-unit consistency was assessed using intraclass correlation coefficients (ICC) and standard errors of measurements (SEM). For a validity test, one-sample t-tests were performed to compare each GNSS unit’s distance with the known distance. Additionally, Wilcoxon signed-rank tests were performed to compare each unit’s peak speed with the reference peak speed measured using video analysis. Results showed poor inter-unit consistency for both distance (ICC = 0.131; SEM = 8.8 m) and speed (ICC = 0.323; SEM 1.3 m/s) measurements. For validity, most units recorded a total distance (44.50 m to 52.69 m) greater than the known distance of 45.72 m and a lower peak speed (7.25 (0.51) m/s) than the video-based reference values (7.78 (0.90) m/s). The present findings demonstrate that there exist variations in distance and speed measurements among different units of the same GNSS system during straight-line sprint running. Practitioners should be aware of the window of errors associated with GNSS measurements and interpret the results with caution. When making comparisons over a season, players should wear the same unit every time if logistically possible.

Background: Bruton tyrosine kinase (BTK) plays a critical role in B-cell receptor signaling, which mediates B-cell proliferation, migration, and adhesion. Inhibition of BTK has emerged as a strategy for targeting B-cell malignancies including CLL/SLL. Zanubrutinib (BGB-3111) is an investigational, next-generation BTK inhibitor that was designed to maximize BTK occupancy and minimize off-target inhibition of TEC- and EGFR-family kinases. Increased specificity may minimize toxicities reported with ibrutinib potentially due to off-target inhibition such as diarrhea, thrombocytopenia, bleeding, atrial fibrillation, rash, and fatigue (Coutre et al. Blood Advances 2019). In non-clinical studies, zanubrutinib has been shown to be highly potent, selective, bioavailable, and irreversible, with potentially advantageous pharmacokinetic (PK) and pharmacodynamic properties. Complete and sustained BTK occupancy has been observed with zanubrutinib treatment in both peripheral blood mononuclear cells and in lymph nodes (Tam et al. Blood 2019). Based on drug-drug interaction studies and population PK analyses (internal data), zanubrutinib may also be co-administered with strong or moderate CYP3A inhibitors at a reduced dose, proton pump inhibitors, vitamin K antagonists, as well as direct oral anticoagulants. Zanubrutinib does not prolong the QT interval. Pooled clinical data from 6 zanubrutinib monotherapy trials including 682 patients (pts) with either non-Hodgkin lymphoma, Waldenström macroglobulinemia, or CLL/SLL suggests that zanubrutinib has been generally well tolerated amongst pts with B-cell malignancies (Tam et al. EHA 2019). This data further showed that some toxicities often associated with BTK inhibitors were infrequent with zanubrutinib, including 1.9% atrial fibrillation/flutter (0.6% grade ≥3), 2.5% major hemorrhage (2.1% grade ≥3), 10.9% fatigue (0.7% grade ≥3), 18.0% rash (0.1% grade ≥3), 18.3% thrombocytopenia (6.6% grade ≥3), and 19.4% diarrhea (0.9% grade ≥3). Early clinical data in pts with treatment-naïve (TN; n=22) or relapsed/refractory (R/R; n=56) CLL/SLL showed that zanubrutinib was highly active: 96.2% overall response rate (ORR), including 4.5% and 1.8% with complete response in TN and R/R CLL/SLL, respectively (Tam et al. Blood 2019). Study Design and Methods: This ongoing phase 3, randomized, global study (ALPINE; NCT03734016) is designed to compare the efficacy of zanubrutinib to ibrutinib based on ORR in pts with R/R CLL/SLL (Figure). This open-label study randomizes approximately 400 pts 1:1 to each arm, stratified by age (< 65 vs ≥ 65 years), refractory status (yes vs no), geographic region (China vs other), and del(17p)/TP53 mutation status (present vs absent). The study population includes adult pts who have had prior treatment for their CLL/SLL and were either refractory to or relapsed from prior CLL/SLL treatment. Major inclusion criteria include R/R CLL/SLL requiring treatment per International Workshop on CLL (iwCLL) criteria, disease measurable by computed tomography/magnetic resonance imaging, Eastern Cooperative Oncology Group performance status 0-2, and adequate hematologic function. Major exclusion criteria include prior treatment with a BTK inhibitor, current or past history of Richter transformation, clinically significant cardiovascular disease, or history of severe bleeding disorder. Zanubrutinib is dosed at 160 mg twice daily, and ibrutinib is dosed per label at 420 mg daily; treatment in both arms may continue until progression. The primary endpoint is ORR as determined by an independent review committee according to iwCLL guidelines, with modification for treatment-related lymphocytosis for pts with CLL and per 2014 Lugano Classification for pts with SLL. The study is powered to test the non-inferiority, and subsequently the superiority, of the ORR for zanubrutinib vs ibrutinib. Secondary endpoints include progression-free survival, ORR as determined by investigator, safety, duration of response, overall survival, and pt-reported outcomes. Exploratory endpoints include the correlation between clinical outcomes and prognostic and predictive biomarkers. Recruitment began in November 2018 and is ongoing in 14 countries. Disclosures Hillmen: Roche: Research Funding; Gilead: Research Funding; Apellis: Research Funding; Acerta: Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel Expenses, Research Funding; Pharmacyclics LLC, an AbbVie Company: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel Expenses, Research Funding. Brown:AbbVie: Consultancy; Acerta Pharma: Consultancy; AstraZeneca: Consultancy; BeiGene: Consultancy; Catapult Therapeutics: Consultancy; Dynamo Therapeutics: Consultancy; Genentech/Roche: Consultancy; Gilead: Consultancy, Research Funding; Juno/Celgene: Consultancy; Kite, a Gilead Company: Consultancy, Research Funding; Loxo: Consultancy, Research Funding; Novartis: Consultancy; Pfizer: Consultancy; Pharmacyclics: Consultancy; Sunesis: Consultancy; TG Therapeutics: Consultancy; Verastem: Consultancy, Research Funding; Sun Pharmaceuticals: Research Funding; Janssen: Honoraria; Teva: Honoraria; Morphosys: Other: Data safety monitoring board; Invectys: Other: Data safety monitoring board; Octapharma: Consultancy. Byrd:Gilead: Other: Travel Expenses, Research Funding, Speakers Bureau; Acerta: Research Funding; Gilead: Other: Travel Expenses, Research Funding, Speakers Bureau; BeiGene: Research Funding; Janssen: Consultancy, Other: Travel Expenses, Research Funding, Speakers Bureau; BeiGene: Research Funding; Janssen: Consultancy, Other: Travel Expenses, Research Funding, Speakers Bureau; Pharmacyclics LLC, an AbbVie Company: Other: Travel Expenses, Research Funding, Speakers Bureau; Acerta: Research Funding; Novartis: Other: Travel Expenses, Speakers Bureau; Novartis: Other: Travel Expenses, Speakers Bureau; TG Therapeutics: Other: Travel Expenses, Research Funding, Speakers Bureau; Genentech: Research Funding; Pharmacyclics LLC, an AbbVie Company: Other: Travel Expenses, Research Funding, Speakers Bureau; TG Therapeutics: Other: Travel Expenses, Research Funding, Speakers Bureau; Genentech: Research Funding; Ohio State University: Patents & Royalties: OSU-2S; Ohio State University: Patents & Royalties: OSU-2S. Eichhorst:BeiGene: Research Funding; Gilead Sciences, Inc.: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; ArQule: Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Lamanna:Celgene: Consultancy; Oncternal: Research Funding; TG Therapeutics: Research Funding; Ming: Research Funding; Infinity/ Verastem: Research Funding. O'Brien:GlaxoSmithKline: Consultancy; Gilead: Consultancy, Research Funding; AbbVie: Consultancy, Honoraria; Acerta: Research Funding; Alexion: Consultancy; Regeneron: Research Funding; Eisai: Consultancy; Celgene: Consultancy; Aptose Biosciences, Inc: Consultancy; TG Therapeutics: Consultancy, Research Funding; Amgen: Consultancy; Kite: Research Funding; Janssen: Consultancy, Honoraria; Pharmacyclics LLC, an AbbVie Company: Consultancy, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; Verastem: Consultancy; Sunesis: Consultancy, Research Funding; Astellas: Consultancy; Vaniam Group LLC: Consultancy. Salmi:BeiGene: Employment. Hilger:BeiGene: Employment, Equity Ownership. Huang:BeiGene: Employment, Equity Ownership. Tam:AbbVie: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Pharmacyclics LLC, an AbbVie company: Honoraria; Novartis: Honoraria; BeiGene: Honoraria; Roche: Honoraria. OffLabel Disclosure: Zanubrutinib is an investigational agent and has not yet been approved in the US

Introduction: Bruton Tyrosine Kinase inhibitors (BTKis) have transformed the treatment of patients with chronic lymphocytic leukemia (CLL) and other B-cell malignancies by inducing durable responses, improving quality of life and prolonging overall survival. Prolonged use of BTKi in the real-world setting is limited by toxicity and acquired resistance. Discontinuation rates for BTKis may be as high as 40% in relapsed/refractory CLL, with BTK C481-mediated resistance evident in many progressing patients. Alternative therapies such as venetoclax are associated with on-target (BCL2) acquired resistance. We hypothesized that a selective, non-covalent BTKi would benefit patients with B-cell malignancies in the setting of acquired resistance and/ or unacceptable toxicities following an irreversible BTKi. LOXO-305 is a next-generation, highly selective, oral, non-covalent BTKi that inhibits wild-type and C481-mutated BTK preclinically. Here, we report results from a first-in-human, proof-of-concept phase 1 trial in patients with B-cell malignancies. Methods: This multicenter phase 1/2 trial (NCT 03740529) enrolled patients with advanced B-cell malignancies who had failed or were intolerant to &gt; 2 prior therapies. LOXO-305 was dosed orally in 28-day cycles, using a standard 3+3 dose-escalation design with a primary endpoint of MTD/RP2D identification. Results: As of 26 July 2019, 13 patients (9 CLL and 4 MCL) were enrolled to 3 dose levels: 25mg (n=5), 50mg (n=5) and 100mg (n=3) QD. Median age was 65 (range 51-79) years and the median number of prior therapies was 3 (range 2-6). 12 patients (8 CLL, 4 MCL) received prior chemotherapy + anti-CD20 antibody; 2 MCL patients underwent prior autologous stem cell transplantation; 5 CLL patients received prior umbralisib; 10 patients (7 CLL, 3 MCL) received prior ibrutinib (5 intolerant, 5 relapsed), including 1 who had also received venetoclax. 6 CLL patients displayed high-risk genetic features, including unmutated IGHV (4), complex karyotype (4) and del17p (3). Molecular characterization was available in 7 patients (6 CLL, 1 MCL) and revealed: BTK C481S mutations (in 2 CLL patients post-ibrutinib), a BCL2 G101V mutation (in a CLL patient post-venetoclax), and a TP53 mutation (in an MCL patient post-ibrutinib). At doses ≥50 mg QD, LOXO-305 exposure exceeded the calculated IC90 for wild-type and C481S mutated BTK. No DLTs were reported and all TEAEs are grade 1-2. Clinical activity was noted within the first cycle of therapy and at the first dose level of 25mg QD. The first eight patients were evaluable for initial response and 7 tumor responses (87.5%) were observed (by disease-defined criteria): 5/5 CLL patients (1 PR and 4 PR-L including one with BTK C481S mutation after ibrutinib and one with BCL2 G101V mutation after venetoclax) and 2/3 MCL patients (2 PR and 1 PD with a preexisting TP53 mutation). 2 additional CLL patients were awaiting initial radiologic assessment but had already demonstrated treatment-induced lymphocytosis. 12/13 patients remain on therapy, the longest 5+ months. Conclusion: Phase 1 data with LOXO-305 demonstrate a favorable safety profile and provide proof-of-concept evidence of efficacy in heavily pretreated CLL and MCL patients, including patients with acquired resistance to available BTKis and venetoclax. Disclosures Mato: DTRM Biopharma: Research Funding; Genentech: Consultancy, Research Funding; Pharmacyclics: Consultancy, Research Funding; Gilead: Research Funding; Acerta: Consultancy; Janssen: Consultancy; TG Therapeutics: Consultancy, Other: DSMB member , Research Funding; Celgene: Consultancy; Sunesis: Consultancy, Research Funding; AstraZeneca: Consultancy, Research Funding; AbbVie: Consultancy, Research Funding; LOXO: Consultancy, Research Funding; Johnson & Johnson: Consultancy, Research Funding. Flinn:F. Hoffmann-La Roche Ltd: Research Funding; Acerta Pharma, Agios, Calithera Biosciences, Celgene, Constellation Pharmaceuticals, Genentech, Gilead Sciences, Incyte, Infinity Pharmaceuticals, Janssen, Karyopharm Therapeutics, Kite Pharma, Novartis, Pharmacyclics, Portola Pharmaceuticals: Research Funding; TG Therapeutics, Trillum Therapeutics, Abbvie, ArQule, BeiGene, Curis, FORMA Therapeutics, Forty Seven, Merck, Pfizer, Takeda, Teva, Verastem, Gilead Sciences, Astra Zeneca (AZ), Juno Therapeutics, UnumTherapeutics, MorphoSys, AG: Research Funding; TG Therapeutics, Trillum Therapeutics, Abbvie, ArQule, BeiGene, Curis, FORMA Therapeutics, Forty Seven, Merck, Pfizer, Takeda, Teva, Verastem, Gilead Sciences, Astra Zeneca (AZ), Juno Therapeutics, UnumTherapeutics, MorphoSys, AG: Research Funding; AbbVie, Seattle Genetics, TG Therapeutics, Verastem: Consultancy. Pagel:AstraZeneca: Consultancy; Gilead Sciences: Consultancy; Pharmacyclics: Consultancy. Brown:Teva: Honoraria; Janssen: Honoraria; Sunesis: Consultancy; Juno/Celgene: Consultancy; Gilead: Consultancy, Research Funding; Dynamo Therapeutics: Consultancy; Genentech/Roche: Consultancy; Pharmacyclics: Consultancy; Pfizer: Consultancy; Novartis: Consultancy; Loxo: Consultancy, Research Funding; Kite, a Gilead Company: Consultancy, Research Funding; Sun Pharmaceuticals: Research Funding; Verastem: Consultancy, Research Funding; TG Therapeutics: Consultancy; Octapharma: Consultancy; AstraZeneca: Consultancy; BeiGene: Consultancy; Catapult Therapeutics: Consultancy; Acerta Pharma: Consultancy; Invectys: Other: Data safety monitoring board; Morphosys: Other: Data safety monitoring board; AbbVie: Consultancy. Cheah:Roche, Janssen, MSD, Gilead, Loxo Oncology, Acerta, BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene, Roche, Abbvie: Research Funding; Roche: Other: Travel expenses. Coombs:Medscape: Honoraria; Covance: Consultancy; Cowen & Co.: Consultancy; H3 Biomedicine: Honoraria; Dedham Group: Consultancy; Loxo: Honoraria; Abbvie: Consultancy; Octopharma: Honoraria; Pharmacyclics: Honoraria. Rothenberg:LOXO Oncology Inc.: Employment. Tsai:Eli Lilly and Company: Employment. Ku:Eli Lilly and Company: Employment. Wang:BioInvent: Consultancy, Research Funding; VelosBio: Research Funding; Loxo Oncology: Research Funding; Guidepoint Global: Consultancy; Kite Pharma: Consultancy, Research Funding; Pharmacyclics: Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Acerta Pharma: Consultancy, Research Funding; MoreHealth: Consultancy, Equity Ownership; AstraZeneca: Consultancy, Honoraria, Research Funding, Speakers Bureau; Celgene: Honoraria, Research Funding; Juno Therapeutics: Research Funding; Dava Oncology: Honoraria; Aviara: Research Funding.

Abstract Introduction: The rate of early mortality in patients treated for acute myeloid leukemia (AML) reflects a balance of efficacy and safety outcomes. In the randomized phase 3 VALOR trial in patients with first relapsed or refractory AML, rates of 30-day (7.9% vs 6.6%, respectively) and 60-day (19.7% vs 19.4%, respectively) mortality were comparable between vosaroxin plus cytarabine and placebo plus cytarabine arms. The treatment-related mortality (TRM) score is a prognostic scoring system to predict risk of 30-day mortality with intensive treatment protocols in patients with newly diagnosed AML (Walter, 2011, J Clin Oncol 29:4417-4424). The "simplified TRM" score includes age, performance status (PS), platelet count, serum albumin, type of AML (secondary vs primary), white blood cell count, blast percentage in the peripheral blood, and serum creatinine. Here we present a multivariate analysis to identify baseline predictors of 30-day and 60-day mortality and a post hoc analysis of the 30-day mortality by TRM score to inform the assessment of treatment risk in VALOR patients. Methods: In VALOR, patients were randomized 1:1 to receive vosaroxin (90 mg/m2 intravenously [IV] over 10 min in cycle 1 and 70 mg/m2 in subsequent cycles, d 1 and 4) plus cytarabine (1 g/m2 IV, over 2 h, d 1-5) or placebo plus cytarabine. Baseline factors associated with 30-day mortality and 60-day mortality in patients treated with vosaroxin/cytarabine were identified from a univariate logistic regression analysis. Factors with significant associations (P < 0.10 by Type 3 P values) that were considered clinically and biologically relevant were included in a multivariate logistic regression model in the overall safety population. A stepwise selection procedure with entrance and retention criteria set to 0.05 was employed to reduce the risk factors to a parsimonious set. Simplified TRM scores were calculated retrospectively according to Walter 2011. Results: A total of 705 patients were included in the safety population (355 treated with vosaroxin/cytarabine and 350 treated with placebo/cytarabine). Based on multivariate analysis, vosaroxin/cytarabine treatment was not predictive for increased 30-day or 60-day mortality. Eastern Cooperative Oncology Group PS > 1 was predictive (P < 0.05) of 30-day mortality (odds ratio [OR] = 3.2) and 60-day mortality (OR = 2.1). Additional predictive factors identified for 30-day mortality were hemoglobin < 10 g/dL (OR = 3.8) and bilirubin > 1.0 mg/dL (OR = 3.3). For 60-day mortality, other predictive factors were albumin ≤ 3.6 g/dL (OR = 2.0), intermediate or high bone marrow blasts (10% to < 30% [OR = 2.6] or ≥ 30% [OR = 6.3]), prior myelodysplastic syndrome (OR = 2.2), and achievement of complete remission with first-line therapy (OR = 0.66). Age (< 65 y vs 65-69 y vs 70-74 y vs ≥ 75 y) was not a significant predictor of early mortality in the vosaroxin arm in the univariate logistic regression and therefore was not selected for multivariate analysis, although interestingly, age was predictive of 30-day mortality in the control arm. When added to the final multivariate model, age was of borderline significance (P = 0.0606). The median simplified TRM score at baseline was 2.6 (range 0-21) in the vosaroxin/cytarabine arm and 2.6 (range 0-33) in the placebo/cytarabine arm. Most patients (473/554, 85%) for whom a simplified TRM score could be calculated had a score < 8. Patients with lower TRM scores had lower rates of 30-day mortality (Table). Conclusions: Several individual baseline factors independently predicted risk of early mortality in patients with relapsed/refractory AML treated with vosaroxin or placebo plus cytarabine. In addition, the previously validated TRM score for predicting early mortality in newly diagnosed AML also predicted mortality in this relapsed/refractory population. In future studies of vosaroxin (and other intensive regimens), patient selection based upon these predictors of early mortality should be considered. Table. Thirty-Day Mortality by TRM Simplified Score TRM Simplified Score 30-Day Mortality, n/N (%) Pla/Cyt (n = 350) Vos/Cyt (n = 355) Total (N = 705) < 8 7/228 (3.1) 10/245 (4.1) 17/473 (3.6) 8 to < 16 6/31 (19.4) 5/31 (16.1) 11/62 (17.7) ≥ 16 3/10 (30.0) 5/9 (55.6) 8/19 (42.1) Missing 7/81 (8.6) 8/70 (11.4) 15/151 (9.9) Disclosures Lancet: Seattle Genetics: Consultancy; Kalo-Bios: Consultancy; Amgen: Consultancy; Pfizer: Consultancy; Celgene: Consultancy, Research Funding; Boehringer-Ingelheim: Consultancy. Ritchie:Onyx: Speakers Bureau; Incyte: Speakers Bureau; Novartis: Speakers Bureau; Ariad: Other: Advisory Board; Celgene: Speakers Bureau. Strickland:Amgen: Other: Advisory Board Particpation; Sunesis Pharmaceuticals: Other: Steering Committee and Advisory Board Participation; Boehringer-Ingelheim: Other: Advisory Board Particpation; Alexion Pharmaceuticals: Other: Advisory Board Particpation; Daiichi-Sankyo: Other: Advisory Board Particpation. Schiller:Sunesis: Honoraria, Research Funding. Vey:Sunesis: Other: Steering Committee Member. Erba:Sunesis; Pfizer; Daiichi Sankyo; Ariad: Consultancy; GlycoMimetics; Janssen: Other: Data Safety & Monitoring Committees; Seattle Genetics; Amgen: Consultancy, Research Funding; Millennium/Takeda; Celator; Astellas: Research Funding; Novartis; Incyte; Celgene: Consultancy, Patents & Royalties. Recher:Celgene; Amgen; Chugai: Research Funding; Janssen; Novartis; Amgen: Other: Travel, accommodations, expenses; Sunesis; Celgene: Consultancy. Odenike:Sunesis: Membership on an entity's Board of Directors or advisory committees, Research Funding. Kell:Sunesis: Consultancy, Honoraria. Krug:Boehringer Ingelheim: Research Funding; Novartis; BMS; Roche; Boehringer Ingelheim; Bayer: Honoraria; Sunesis: Speakers Bureau; Sunesis; Clavis Pharma; usa Pharma, Catapult Cell Therapy, Gilead, Roche: Membership on an entity's Board of Directors or advisory committees. Page:Sunesis: Employment. DeVault:Sunesis: Consultancy. Hwang:Sunesis: Consultancy. Craig:Sunesis: Employment, Equity Ownership. Stuart:Sunesis: Honoraria, Other: Advisory Board, Research Funding; Astellas Pharma, Inc: Research Funding.

The factors mediating GvL resistance following allogeneic stem cell transplant (SCT) in lymphoid malignancies remain incompletely characterized. Because cell-intrinsic features shape chemotherapeutic relapse, we hypothesized that they also shape GvL outcomes by influencing evolutionary trajectories of CLL relapse after reduced intensity conditioning SCT (RIC). We identified 9 heavily pre-treated patients (pts) (range: 1-5 therapies, median: 3) with various times to CLL relapse after RIC (range: 83-1825 days), of which 8 had at least partial responses before relapse. To define evolutionary trajectories, we generated paired whole-exome and RNA sequencing data from purified CLL cells pre/post-RIC, using MuTect2 and ABSOLUTE algorithms to identify somatic alterations (SAs) and corresponding cancer cell fractions (CCFs). 5 pts had clonal SAs in TP53 and/or SF3B1 pre-SCT, and no single SA was specific to post-RIC. Furthermore, we found no SAs nor altered expression of HLA class I/II or b2M in either baseline or post-RIC samples. However, we found 6 relapse pairs to exhibit complex branched evolution involving CCF shifts of at least 0.2 in subclonal and clonal SAs whereas 3 pairs showed genomic stability. Clonal evolution was associated with longer time to relapse (Wilcoxon, p=0.02; median 798 versus 304 days) as well as complete response (p=0.05), suggesting that GvL immune escape may be facilitated by clonal evolution. To determine the phenotypic consequences of clonal evolution, we examined single cell transcriptomes using scRNAseq from paired pre/post-RIC CLL cells from 2 pts with early (304, 442 days; "ERs") and 2 pts with late (1801, 1825 days; "LRs") relapses after RIC. Using the inDrop platform, we profiled a median of 3560 CLL cells/pt (range: 2254-5278). Clustering using Seurat revealed marked transcriptional stability after RIC in ERs whereas dramatic shifts in gene expression programs were observed in LRs. Single cell trajectory analysis using Monocle identified ordered biological processes through which LRs, but not ERs, progressed. Branched expression analysis revealed multiple patient specific pathways defining LRs, including within chromatin regulators (EBF1, BANK1), oncogenic pathways (AFF3, DENND4A) and ribosomal biosynthesis (EEF1G, NACA). Thus, genetic evolution in LRs results in distinct phenotypic consequences. To directly link SAs with transcriptional outcomes, we interrogated scRNAseq data for known SAs identified by WES. In one LR, loss of a CLL cancer driver (RPS15mut) was observed in two of three post-RIC transcriptional clusters, either through deletion of chr.19p (where RPS15 resides) or reversion to the wildtype allele (implying loss of heterozygosity). In addition, genomic and transcriptional loss of HLA genes were detectable in pre-RIC clusters that failed to expand at relapse in both LRs, suggesting that pre-existing HLA loss does not provide a selective advantage for CLL relapse after RIC, consistent with our bulk analyses. These data highlight how scRNAseq can delineate genetic selection pressures within subpopulations of a single patient. To investigate whether epigenetic dysregulation underlies these genetic changes, we measured locally disordered methylation (LDM), a known epigenetic mechanism of CLL genetic variability. Genome-wide methylome profiles revealed increases in LDM in LRs compared to ERs for various genomic regions (Kruskal-Wallis (KW), p&lt;0.05 for promoters, genes, distal regulatory modules); no increases in LDM were observed in an independent cohort of late CLL relapse after chemotherapy alone (n=7; time between samples: 496-1511 days). Moreover, we controlled for time between samples by calculating the rate of change in LDM and still found significant differences only during LR after RIC (versus ER or late relapse after chemotherapy; KW, p&lt;10-13). Finally, genes with increased LDM were enriched for multiple stem cell gene sets (q&lt;0.01), implicating a common stem-like state in LRs. Altogether, these data highlight important features of GvL resistance in CLL: 1) GvL selective pressure, shown by LRs, can shape evolutionary trajectories through genotypic alterations that directly exert phenotypic consequences; 2) alterations in HLA genes have less influence in CLL than in myeloid malignancies; and 3) GvL immune editing may select for epigenetic variability that facilitates evasion through stem-like states. Disclosures Brown: Octapharma: Consultancy; Novartis: Consultancy; Loxo: Consultancy, Research Funding; Kite: Consultancy, Research Funding; Janssen: Honoraria; Invectys: Other: other; Gilead: Consultancy, Research Funding; Genentech/Roche: Consultancy; Dynamo Therapeutics: Consultancy; Catapult Therapeutics: Consultancy; BeiGene: Consultancy; AstraZeneca: Consultancy; Acerta Pharma: Consultancy; Morphosys: Other: Data safety monitoring boards ; Sun Pharmaceuticals, Inc: Research Funding; Sun: Research Funding; Verastem: Consultancy, Research Funding; TG Therapeutics: Consultancy; Teva: Honoraria; Sunesis: Consultancy; Pharmacyclics: Consultancy; Pfizer: Consultancy. Getz:MuTect, ABSOLTUE, MutSig and POLYSOLVER: Patents & Royalties: MuTect, ABSOLTUE, MutSig and POLYSOLVER; IBM: Research Funding; Pharmacyclics: Research Funding. Ho:Jazz Pharmaceuticals: Consultancy; Jazz Pharmaceuticals: Research Funding; Omeros Corporation: Membership on an entity's Board of Directors or advisory committees. Neuberg:Celgene: Research Funding; Pharmacyclics: Research Funding; Madrigal Pharmaceuticals: Equity Ownership. Soiffer:Gilead, Mana therapeutic, Cugene, Jazz: Consultancy; Jazz: Consultancy; Kiadis: Other: supervisory board; Mana therapeutic: Consultancy; Cugene: Consultancy; Juno, kiadis: Membership on an entity's Board of Directors or advisory committees, Other: DSMB. Ritz:TScan Therapeutics: Consultancy; Equillium: Research Funding; Merck: Research Funding; Kite Pharma: Research Funding; Aleta Biotherapeutics: Consultancy; Celgene: Consultancy; Avrobio: Consultancy; LifeVault Bio: Consultancy; Draper Labs: Consultancy; Talaris Therapeutics: Consultancy. Wu:Neon Therapeutics: Other: Member, Advisory Board; Pharmacyclics: Research Funding.

Background: Zanubrutinib is a highly selective, next-generation Bruton tyrosine kinase (BTK) inhibitor designed to maximize BTK occupancy and minimize off-target effects. Zanubrutinib has been associated with improved specificity and durable clinical responses in patients with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL; Tam, Blood 2019;134:851-9). Early clinical data from Arm C of the SEQUOIA trial suggested that zanubrutinib was active and well-tolerated in treatment-naïve (TN) CLL/SLL patients with the high-risk characteristic deletion of chromosome 17p13.1 [del(17p)] (Tam ASH 2019 #499). In that cohort, an overall response rate (ORR) of 92.7% was reported, and the most common adverse events (AEs; 20.1% contusion, 15.6% upper respiratory tract infection, 13.8% rash) and most common grade ≥3 AEs (10.1% neutropenia, 3.7% pneumonia, 2.8% hypertension) were consistent with those in previous reports of zanubrutinib treatment in patients with various B-cell malignancies. Venetoclax is a B-cell lymphoma 2 protein (BCL-2) inhibitor approved for the treatment of adult patients with CLL or SLL. Results of several phase 2 CLL trials of BCL-2 inhibitor and BTK inhibitor combinations have suggested that combination treatment is tolerable and may have synergistic activity (Hillmen JCO 2019;37:2722-9. Jain, NEJM 2019;380:2095-103. Siddiqi, EHA 2020 #S158.). Combination treatment given for a finite duration as determined by undetectable minimal residual disease (uMRD) is of significant interest and has the potential to alter the CLL/SLL treatment landscape if shown to induce deeper responses with a fixed duration of therapy. In the BOVen study, zanubrutinib was given in combination with venetoclax and obinutuzumab to TN CLL patients, and uMRD in the peripheral blood and bone marrow was used to determine treatment discontinuation (Soumerai, ASCO 2020 #8006.) Preliminary data showed that 62% of patients met the uMRD endpoint and successfully discontinued treatment after a median of 8 months (6 months of triplet therapy), and 100% of patients had a best response of partial response or higher (43% complete response/complete response with incomplete marrow recovery). The most common grade ≥3 AEs (15.4% neutropenia, 5.1% thrombocytopenia, 5.1% lung infection, 2.6% infusion-related reaction, 2.6% rash, 2.6% bleeding) were consistent with those previously reported in combination treatment studies, and no events of tumor lysis syndrome (TLS) were reported. Study Design and Methods : The SEQUOIA trial (NCT03336333) is an open-label, global, multicenter, phase 3 study that includes a nonrandomized cohort (Arm D) of up to 50 TN patients with del(17p) CLL/SLL. Arm D is designed to provide combination treatment of zanubrutinib and venetoclax and use serial monitoring of uMRD to determine treatment discontinuation. Patients are treated with zanubrutinib (160 mg twice daily) for 3 months followed by the combination of zanubrutinib (same dosing) and venetoclax (ramp-up cycle followed by 400 mg once daily). Combination treatment is given for 12-24 cycles until disease progression, unacceptable toxicity, or requirements for uMRD at &lt;10−4 sensitivity (uMRD4) by flow cytometry are met (Figure). Adult patients with CLL/SLL who met International Workshop on CLL (iwCLL) criteria for treatment (Hallek, Blood 2008;111:5446-56) are eligible if they have central verification of del(17p) by fluorescence in situ hybridization with &gt;7% aberrant nuclei present. Initial safety and tolerability of zanubrutinib and venetoclax combination therapy will be assessed, including the risk of TLS at baseline and before initiation of venetoclax. Responses will be assessed by investigator for CLL per modified iwCLL criteria (Hallek, Blood 2008;111:5446-56. Cheson, JCO 2012;30:2820-2) and for SLL per Lugano criteria (Cheson, JCO 2014;32:3059-68). Secondary endpoints include ORR, progression-free survival, duration of response, rate of uMRD4 at various time points, safety, and pharmacokinetics of zanubrutinib and venetoclax. Exploratory endpoints include overall survival, patient-reported outcomes, and time to recurrence of detectable MRD after discontinuation of zanubrutinib and/or venetoclax. Recruitment began in November 2019 and is ongoing in 8 countries. Figure 1 Disclosures Tam: Janssen: Honoraria, Research Funding; AbbVie: Honoraria, Research Funding; BeiGene: Honoraria. Flinn:Novartis: Research Funding; Nurix Therapeutics: Consultancy; Portola Pharmaceuticals: Research Funding; Gilead Sciences: Consultancy, Research Funding; Forty Seven: Research Funding; Trillium Therapeutics: Research Funding; TG Therapeutics: Consultancy, Research Funding; F. Hoffmann-La Roche: Research Funding; Incyte: Research Funding; Curis: Research Funding; Calithera Biosciences: Research Funding; Karyopharm Therapeutics: Research Funding; Juno Therapeutics: Consultancy, Research Funding; Acerta Pharma: Research Funding; Great Point Partners: Consultancy; Genentech, Inc.: Research Funding; Loxo: Research Funding; Celgene: Research Funding; MorphoSys: Consultancy, Research Funding; Curio Science: Consultancy; Merck: Research Funding; Constellation Pharmaceuticals: Research Funding; Forma Therapeutics: Research Funding; Verastem: Consultancy, Research Funding; Yingli Pharmaceuticals ≠: Consultancy, Research Funding; Rhizen Pharmaceuticals: Research Funding; Johnson & Johnson: Other; Roche: Consultancy, Research Funding; Vincera Pharma: Consultancy; ArQule: Research Funding; Agios: Research Funding; AstraZeneca: Consultancy, Research Funding; BeiGene: Consultancy, Research Funding; Kite Pharma: Consultancy, Research Funding; IGM Biosciences: Research Funding; Takeda: Consultancy, Research Funding; Infinity Pharmaceuticals: Research Funding; Unum Therapeutics: Consultancy, Research Funding; Triphase Research & Development Corp.: Research Funding; Teva: Research Funding; Seattle Genetics: Consultancy, Research Funding; Iksuda Therapeutics: Consultancy; Janssen: Consultancy, Research Funding; AbbVie: Consultancy, Research Funding; Pfizer: Research Funding; Pharmacyclics LLC, an AbbVie Company: Consultancy, Research Funding. Tedeschi:Department of Hematology Niguarda Hospital Milano: Current Employment; Janssen spa: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; AstraZeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees; BeiGene: 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, Speakers Bureau; Sunesis: Consultancy. Ferrant:AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees. Brown:BeiGene: Consultancy; Genentech: Consultancy; Gilead: Consultancy, Research Funding; Acerta: Consultancy; Sun: Research Funding; Loxo: Consultancy, Research Funding; Verastem: Consultancy, Research Funding; TG Therapeutics: Consultancy; Sunesis: Consultancy; Rigel Pharmaceuticals: Consultancy; Pfizer: Consultancy; Octapharma: Consultancy; Novartis: Consultancy; Nextcea: Consultancy; MEI Pharma: Consultancy; Invectys: Membership on an entity's Board of Directors or advisory committees, Other: DSMC; Astra-Zeneca: Consultancy; Janssen: Honoraria; Morphosys: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other; Catapult: Consultancy; Dynamo Therapeutics: Consultancy; Eli Lilly and Company: Consultancy; Juno/Celgene: Consultancy; Kite: Consultancy; AbbVie: Consultancy; Pharmacyclics: Consultancy. Robak:GSK: Research Funding; Bristol Meyers Squibb: Research Funding; Roche: Consultancy, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding; AstraZeneca: Honoraria, Research Funding; Acerta: Research Funding; Janssen: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding; BioGene: Honoraria, Research Funding; Pharmacyclics LLC, an AbbVie Company: Honoraria, Research Funding; UCB: Honoraria, Research Funding; Medical University of Lodz: Current Employment; Momenta: Consultancy; Takeda: Consultancy; Octapharma: Honoraria; Morphosys: Research Funding; Novartis: Honoraria, Research Funding; Sandoz: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding; UTX-TGR: Research Funding; Pfizer: Research Funding. Ghia:Gilead: Consultancy, Honoraria, Research Funding; ArQule: Consultancy, Honoraria; Acerta/AstraZeneca: Consultancy, Honoraria; 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; Adaptive, Dynamo: Consultancy, Honoraria; Novartis: Research Funding; AbbVie: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding. Kuwahara:BeiGene: Current Employment, Current equity holder in publicly-traded company, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company). Paik:BeiGene: Current Employment, Current equity holder in publicly-traded company. Hua:BeiGene USA Ltd.: Current Employment, Current equity holder in publicly-traded company, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Agios Pharmaceuticals Inc.: Current equity holder in publicly-traded company, Ended employment in the past 24 months; Vertex: Current equity holder in publicly-traded company. Cohen:BeiGene: Current Employment, Current equity holder in publicly-traded company, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company). Huang:BeiGene: Current Employment, Current equity holder in publicly-traded company, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company). Hillmen:Janssen: 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 Funding, Speakers Bureau; AbbVie: 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 Funding, Speakers Bureau; Astra Zeneca: Honoraria; F. Hoffmann-La Roche: Honoraria, Research Funding; Pharmacyclics: Research Funding; Gilead: Research Funding. OffLabel Disclosure: Zanubrutinib has not been approved for TN CLL/SLL with del(17p) in the US

Background: Chronic lymphocytic leukemia (CLL) is the most prevalent type of adult leukemia. In many countries, chemoimmunotherapy (CIT) remains the standard of care for frontline treatment of patients without high-risk cytogenetics. Although in most patients the disease responds initially, CIT can be associated with early and late toxicity and limited progression-free survival (PFS), requiring subsequent treatment. Novel chemotherapy-free targeted agents are highly effective but need to be taken continuously, which is associated with development of resistance clones and considerable medical and financial toxicities. Therefore, there is a need to evaluate potentially less toxic frontline chemotherapy-free regimens that could improve outcomes with a fixed duration of treatment. Acalabrutinib is a highly selective, potent, covalent Bruton tyrosine kinase inhibitor (BTKi), which has shown promising efficacy and safety in CLL. In a phase 1/2 trial of 99 patients with untreated CLL, the overall response rate (ORR) was 99% after a median time on study of 33 (1-39) months (Byrd et al.Blood 2018;132:692). Recently completed phase 3 trials showed acalabrutinib ± obinutuzumab (obi) improved PFS vs chemotherapy in untreated patients (ELEVATE TN: AstraZeneca Press release 06/06/2019), and acalabrutinib improved PFS vs idelalisib or bendamustine + rituximab in relapsed/refractory patients (ASCEND: Ghia et al. EHA 2019;273259:LB2606). Combining a BTKi with an anti-CD20 antibody (obi) and a BCL-2 inhibitor (venetoclax [ven]) has the potential to achieve deeper responses and enhance rates of undetectable minimal residual disease (uMRD). In the phase 3 CLL-14 trial in untreated patients with CLL, fixed duration treatment with obi (6 months) + ven (12 months) was more efficacious than obi (6 months) + chlorambucil (12 months), achieving a longer PFS and higher rate of uMRD (Fischer et al. NEJM 2019;380:2225-36). Study design and methods: ACE-CL-311 (NCT03836261) is a 3-arm phase 3, randomized (1:1:1), global, multicenter, open-label trial evaluating the efficacy and safety of acalabrutinib + ven (Arm A) vs acalabrutinib + ven + obi (Arm B) vs CIT (Arm C: fludarabine/cyclophosphamide/rituximab [FCR; only for patients ≤ 65 years of age] or bendamustine/rituximab [BR]). The trial opened in February 2019 and is recruiting adult patients with untreated CLL without del(17p) or TP53 mutation. The enrollment target is 780 patients across about 250 sites. Patients must have an Eastern Cooperative Oncology Group performance status of ≤2 and fulfill iwCLL 2018 criteria for CLL diagnosis and treatment (Hallek et al. Blood 2018;131:2745-60). Adequate organ function requirements include serum aspartate aminotransferase and alanine aminotransferase ≤2.5× upper limit of normal (ULN); total bilirubin ≤2× ULN; and estimated creatinine clearance of ≥50 mL/min (≥70 mL/min for FCR). Key exclusion criteria include stroke or intracranial hemorrhage, significant cardiovascular disease (asymptomatic or controlled atrial fibrillation allowed), bleeding disorders, or a requirement for treatment with warfarin or equivalent vitamin K antagonists or a strong cytochrome P450 inhibitor. Patients will be randomized to receive oral acalabrutinib 100 mg twice daily in 28-day cycles for up to 14 cycles + once-daily oral ven (cycles 3-14; ramp-up followed by 400 mg/day) ± infusions of obi (cycles 2-7), or up to 6 cycles of FCR or BR. Patients will be evaluated for efficacy per iwCLL 2018 guidelines and observed until progressive disease, with survival followed post-progression. The primary efficacy endpoint is independent review committee (IRC)-assessed PFS in Arm A vs Arm C. Secondary efficacy endpoints include IRC- and investigator-assessed PFS, uMRD rates, ORR, event-free survival, duration of response, time-to-next therapy, and overall survival. Safety objectives include incidence and severity of adverse events. Exploratory efficacy endpoints include patient-reported outcomes. The study is powered to achieve ~90% power to detect a hazard ratio of 0.65 in PFS comparing Arm A to Arm C, assuming median PFS of 44.7 months in FCR/BR at the 2-sided significance level of 0.05. Patients will be stratified based on age (>65 vs ≤65 years), IGHV mutational status (mutated vs unmutated), Rai stage risk (high [≥3] vs non-high [<3]), and geographic location (North America vs Europe vs Other). Disclosures Brown: Teva Pharmaceuticals: Honoraria; Investys: Membership on an entity's Board of Directors or advisory committees; Genentech/Roche: Consultancy; AstraZeneca: Consultancy; Morphosys: Membership on an entity's Board of Directors or advisory committees; Verastem: Consultancy, Research Funding; Loxo: Consultancy, Research Funding; Juno/Celgene: Consultancy; Pfizer: Consultancy; Beigene: Consultancy; Kite: Consultancy; Sunesis: Consultancy; Acerta: Consultancy; Gilead: Consultancy, Research Funding; Novartis: Consultancy; Catapult Therapeutics: Consultancy; Pharmacyclics: Consultancy; Abbvie: Consultancy; Octapharma: Consultancy; Sun Pharmaceuticals: Research Funding; Dynamo Therapeutics: Consultancy; Janssen: Honoraria; TG Therapeutics: Consultancy. Eichhorst:Gilead Sciences, Inc.: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Consultancy, Honoraria, 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, Research Funding, Speakers Bureau; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; ArQule: Membership on an entity's Board of Directors or advisory committees; BeiGene: Research Funding. Ghia:Janssen: Consultancy, Honoraria, Research Funding; Juno/Celgene: Consultancy, Honoraria; Sunesis: Consultancy, Honoraria, Research Funding; Novartis: Research Funding; ArQule: Consultancy, Honoraria; BeiGene: Consultancy, Honoraria; Dynamo: Consultancy, Honoraria; Pharmacyclics LLC, an AbbVie Company: Consultancy; Gilead: Consultancy, Honoraria, Research Funding; Acerta/AstraZeneca: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria, Research Funding. Kater:Abbvie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche/Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Research Funding; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Acerta: Membership on an entity's Board of Directors or advisory committees, Research Funding. Khurana:Acerta Pharma: Employment. Elhamy:Acerta Pharma: Employment. Wang:Acerta Pharma: Employment; AstraZeneca: Equity Ownership. Seymour:Takeda: Consultancy. OffLabel Disclosure: Yes, this is phase 3 trial for an indication (CLL) that is currently unapproved

Introduction: Duvelisib (DUV), an oral inhibitor of PI3K-δ/γ, and venetoclax (VEN), an oral inhibitor of BCL-2, are both approved for relapsed/refractory (R/R) CLL. We previously found that PI3K-δ inhibition sensitizes CLL cells to ex vivo BCL-2 inhibition (Davids et al., Blood, 2012). We hypothesized that DUV plus VEN would lead to deep remissions that allow for an all oral, time-limited therapy. Here, we report for the first time on a phase I study of DUV plus VEN for patients (pts) with R/R CLL/SLL. Methods: This is an investigator-initiated phase I trial with primary endpoints: DLTs, MTD, and RP2D of VEN plus DUV in pts with R/R CLL/SLL. Secondary endpoints: PK, preliminary efficacy. Pts are treated as per Figure 1, with a 7-day lead-in of DUV 25 mg BID. On day 8, DUV was continued and VEN initiated at 10 mg QD, with weekly ramp-up to 20/50/100 (dose level 1), 200 mg (dose level 2), and 400 mg (dose level 3). The last 3 pts initiated VEN at 20 mg. A 3+3 design was used, and the DLT observation period was the first cycle. Eligibility criteria: ≥1 prior therapy, requiring therapy by 2008 iwCLL criteria, ECOG PS ≤2, adequate hematologic and organ function, no prior VEN or DUV. CTCAE v5 and 2008 iwCLL were used to evaluate toxicity and efficacy. PK testing was performed at each VEN dose escalation and just prior to cycle 2. MRD was assessed by 8-color flow at a sensitivity of 10-4 (Mayo Laboratories) in the peripheral blood (PB) and bone marrow (BM). Results: As of July 12, 2019, 12 pts were evaluable. Median age 69 yrs (range 50 to 78). Del(17p): 3/12 (25%), del(11q): 1/12 (8%), unmutated IGHV: 12/12 (100%), mutation in NOTCH1: 7/12 (58%) and TP53: 5/12 (42%) pts. Median prior treatments: 3 (range 1-6), including 2 pts relapsed after alloHCT. Ten pts had prior BTKi, including 3 who progressed on therapy. No DLTs were observed, and the RP2D of VEN in combination with DUV was the approved dose of 400 mg. Most pts had baseline cytopenias, with a median ANC of 3 (range 1.19-7.78), Hgb 7 (range 7.6-13.5), PLT 43 (range 21-221). Heme toxicities were common and included: neutropenia (100%, 83% ≥ gr3), anemia (100%, 33% ≥ gr3), and thrombocytopenia (75%, 8% ≥ gr3). Nine pts required G-CSF support. All grade non-heme tox in >25% of pts: fatigue (92%, all gr1/2), hyperglycemia (100%, 25% gr1, 58% gr2, 17% gr3), hypocalcemia (100%, 50% ≥ gr3), hypophosphatemia (67%, 25% ≥ gr3), elevated alk phos (58%, all gr1/2), elevated AST (58%, all gr1/2), hypokalemia (50%, 17% ≥ gr3), hypomagnesemia (50%, all gr1/2), rash (50%, 8% ≥ gr3), diarrhea (42%, 8% ≥ gr3), and hyponatremia (42%, 8% ≥ gr3). SAEs: gr3 amylase/lipase, and gr3 febrile neutropenia (n=1 each). No laboratory or clinical tumor lysis syndrome (TLS) was observed per Cairo-Bishop criteria. One pt with medium TLS risk who initiated VEN at 20 mg had an increase in LDH prompting a brief VEN hold; a second pt with medium TLS risk had an early rise in K rapidly responsive to intervention and later LDH increase prompting a brief VEN hold. Five patients required DUV holds for asymptomatic elevation in amylase and/or lipase (n=4), rash (n=2), bronchitis (n=1), or diarrhea (n=1). Four pts required steroids for toxicity management. PK analyses demonstrated that VEN exposure increased with increasing doses in the presence of DUV. After receiving 25 mg DUV BID, 4h VEN plasma concentrations following 200 mg and 400 mg VEN were 1,803±819 ng/mL and 2,363±1134 ng/mL, respectively. These VEN concentrations are similar to values in the literature, suggesting no significant drug/drug interaction. At data cutoff, median number of treatment cycles was 6 (range 1-9), and the first 9 pts were evaluable for response (6 had 2 response assessments). Eight of the 9 pts achieved response, with 3 CRs and 5 PRs. Two pts had undetectable MRD (uMRD) in PB and BM (including 1 pt with CR and 1 pt with minimal nodes with SD). One pt with a CR was PB-uMRD only. Three pts have discontinued (1 electively moved to alloHCT, 2 with PD (including 1 ibrutinib progressor who developed Richter's Syndrome (RS)). Conclusions: DUV plus VEN is feasible in pts with R/R CLL/SLL, with no DLTs observed, and a RP2D of VEN 400 mg with DUV 25 mg BID. Although high rates of neutropenia were observed, infections were infrequent. Early efficacy data for this 1-year time-limited, all oral regimen are promising, with CRs and uMRD already observed despite short follow-up. Updated results will be presented at the meeting, and a phase II trial, which includes a cohort for RS, will further evaluate efficacy. Disclosures Montegaard: Pharmacyclics: Consultancy; Janssen: Consultancy. Soumerai:AbbVie: Consultancy; Verastem: Consultancy; BostonGene: Research Funding; Genentech/Roche: Research Funding; TG therapeutics: Research Funding; BeiGene: Research Funding. Arnason:Regeneron Pharmaceuticals, Inc.: Consultancy; Celgene/Juno: Consultancy. Brown:Sun Pharmaceuticals: Research Funding; Janssen: Honoraria; Teva: Honoraria; Morphosys: Other: Data safety monitoring board; Invectys: Other: Data safety monitoring board; Octapharma: Consultancy; Pharmacyclics: Consultancy; Sunesis: Consultancy; TG Therapeutics: Consultancy; Verastem: Consultancy, Research Funding; AbbVie: Consultancy; Acerta Pharma: Consultancy; AstraZeneca: Consultancy; BeiGene: Consultancy; Catapult Therapeutics: Consultancy; Dynamo Therapeutics: Consultancy; Genentech/Roche: Consultancy; Gilead: Consultancy, Research Funding; Juno/Celgene: Consultancy; Kite, a Gilead Company: Consultancy, Research Funding; Loxo: Consultancy, Research Funding; Novartis: Consultancy; Pfizer: Consultancy. Davids:Research to Practice: Honoraria; AbbVie, Acerta Pharma, Adaptive, Biotechnologies, Astra-Zeneca, Genentech, Gilead Sciences, Janssen, Pharmacyclics, TG therapeutics: Membership on an entity's Board of Directors or advisory committees; AbbVie, Astra-Zeneca, Genentech, Janssen, MEI, Pharmacyclics, Syros Pharmaceuticals, Verastem: Consultancy; Acerta Pharma, Ascentage Pharma, Genentech, MEI pharma, Pharmacyclics, Surface Oncology, TG Therapeutics, Verastem: Research Funding. OffLabel Disclosure: Duvelisib and venetoclax are approved for the treatment of CLL, but not in combination

Background: While autologous stem cell transplantation (ASCT) can be curative for patients (pts) with relapsed or refractory diffuse large B-cell lymphoma (DLBCL), relapse remains common. With the emergence of novel effective therapies, it is even more important to identify pts at high risk of treatment failure who may not benefit from ASCT, and pts with impending post-ASCT relapse who may be candidates for pre-emptive interventions. We assembled cohorts of DLBCL pts who underwent ASCT and had apheresis stem cell (ASC) samples or serially collected post-ASCT peripheral blood mononuclear cell (PBMC) and plasma samples. We hypothesized that circulating tumor DNA (ctDNA) identified using immunoglobulin-based next generation sequencing (IgNGS) in ASC or PB samples could predict relapse. Methods: Samples from 3 cohorts were analyzed. Pts in cohort 1 (C1) underwent ASCT at Dana-Farber Cancer Institute (DFCI) from 2003-2013 (Herrera, ASH 2015). Archival tumor tissue and ASC samples were retrospectively collected for analysis. Pts in cohort 2 (C2) were prospectively enrolled on a banking protocol at DFCI and underwent ASCT from 2014-2016. Pts in cohort 3 (C3) underwent ASCT from 2015-2016 and participated in a multicenter phase II trial of post-ASCT pembrolizumab maintenance (PM) (Frigault, Blood Adv 2020). Pts in C2/C3 had tumor tissue and serially collected post-ASCT PBMC and plasma samples as mandated by protocol, and a subset had available pre-ASCT PB or ASC samples. Because PM did not demonstrate a clear benefit in the trial, all cohorts were analyzed together. IgNGS (Adaptive Biotechnologies; Seattle, WA) was performed, as previously described (Armand, BJH 2013). In all cases, ctDNA testing was not performed in real-time or used to drive clinical decisions. Results: 152 pts were enrolled. Among 141 pts with sufficient DNA for testing, a clonotype was identified in 112 (78%) with a higher detection rate in more recent cohorts - C2 (93%) and C3 (90%) vs C1 (67%). Among 97 pts with an available ASC sample, 23 (24%) were ctDNA-positive (pos). With a median follow-up among survivors of 69 months (m) (range 13-185), the 5-year (y) progression-free survival (PFS) for ASC ctDNA-pos and ASC ctDNA-negative (neg) pts were 13% (95% CI 3-30%) and 52% (95% CI 40-63%), respectively (HR 2.8, p&lt;0.001), while the 5y cumulative incidences of relapse were 83% (95% CI 66-99%) and 39% (95% CI 27-50%), respectively (HR 3.1, p&lt;0.001). The sensitivity and specificity of ASC ctDNA for progression or death were 36% and 95%, respectively. ASC ctDNA (HR 2.5, p=0.002) was the only significant predictor of PFS in a multivariable model that included pre-ASCT positron emission tomography (PET), lines of therapy, age, and primary refractory status. Inferior overall survival was observed for ASC ctDNA-pos pts (HR 2.1 p=0.037). In an exploratory analysis, we examined 14 pts with an available pre-ASCT plasma sample. 2/14 were ctDNA-pos (14%) and both pts relapsed (HR for PFS 9.4, p=0.03). Among 13 pts with both pre-ASCT PB and ASC samples (drawn a median of 19 days apart [range 11-47]), results were concordant in 12/13 pts (92%). 56 pts had a median of 3 (range 1-8) post-ASCT plasma samples available for analysis. Within this cohort, 25 pts relapsed and 2 pts died in remission. 21 pts (38%) had detectable ctDNA in a median of 2 post-ASCT samples (range 1-5); among them, 18 (86%) relapsed with a median lead time from first ctDNA detection to relapse of 52 days (range 0-518). Among the 3 ctDNA-pos pts who did not relapse, 2 had detectable ctDNA at a single time point and subsequently became ctDNA-neg, and 1 developed acute myeloid leukemia and underwent allogeneic transplantation. Among 20 pts who relapsed and had ≥1 plasma sample available within 100 days of relapse, 18 (90%) had detectable ctDNA. PBMC testing had inferior performance characteristics (Table). Conclusions: Identification of ctDNA using IgNGS within an ASC sample is a powerful predictor of post-ASCT relapse and provides (at least in this cohort) a better way to predict relapse than pre-ASCT PET. Detection of ctDNA in pre-ASCT plasma also appears to be predictive of relapse. In ctDNA-pos pts, given the dismal PFS, strong consideration could be given to alternative treatment strategies, e.g. CAR-T cell therapy. Furthermore, detection of ctDNA in post-ASCT plasma samples is closely associated with impending relapse, which provides an attractive platform for pre-emptive therapeutic intervention. Figure Disclosures Brown: Dynamo Therapeutics: Consultancy; Morphosys: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other; Octapharma: Consultancy; Pfizer: Consultancy; Acerta: Consultancy; Sun: Research Funding; Genentech: Consultancy; Rigel Pharmaceuticals: Consultancy; Eli Lilly and Company: Consultancy; Juno/Celgene: Consultancy; Invectys: Membership on an entity's Board of Directors or advisory committees, Other: DSMC; Gilead: Consultancy, Research Funding; Astra-Zeneca: Consultancy; Janssen: Honoraria; Sunesis: Consultancy; Novartis: Consultancy; Loxo: Consultancy, Research Funding; Nextcea: Consultancy; MEI Pharma: Consultancy; Kite: Consultancy; Pharmacyclics: Consultancy; AbbVie: Consultancy; Catapult: Consultancy; BeiGene: Consultancy; Verastem: Consultancy, Research Funding; TG Therapeutics: Consultancy. Crombie:AbbVie: Research Funding; Bayer: Research Funding. Davids:Gilead Sciences: Consultancy; Zentalis: Consultancy; Sunesis: Consultancy; Syros Pharmaceuticals: Consultancy; Research to Practice: Honoraria; Merck: Consultancy; Bristol Myers Squibb: Research Funding; Janssen: Consultancy; Genentech: Consultancy, Research Funding; Eli Lilly: Consultancy; Celgene: Consultancy; AstraZeneca: Consultancy, Research Funding; BeiGene: Consultancy; Ascentage Pharma: Consultancy, Research Funding; Adaptive Biotechnologies: Consultancy; AbbVie: Consultancy; Novartis: Consultancy, Research Funding; Verastem: Consultancy, Research Funding; MEI Pharma: Consultancy, Research Funding; Surface Oncology: Research Funding; Pharmacyclics: Consultancy, Research Funding; TG Therapeutics: Consultancy, Research Funding. Fisher:Kyowa Kirin: Membership on an entity's Board of Directors or advisory committees. Jacobsen:Merck, Pharmacyclics, F. Hoffmann-LaRoche, Novartis: Research Funding; Takeda: Honoraria; Acerta, AstraZeneca, Merck: Consultancy. LaCasce:BMS: Consultancy; Research to Practice: Speakers Bureau; UptoDate: Patents & Royalties. Dahi:Kite: Consultancy. Nieto:Secura Bio: Other: Grant Support; Novartis: Other: Grant Support; Affimed: Consultancy, Other: Grant Support; Astra Zeneca: Other: Grant Support. Chen:Incyte Corporation: Consultancy; Takeda: Consultancy; Magenta: Consultancy; Kiadis: Consultancy; Actinium: Other: Data and Safety Monitoring Board Member; Equillium: Other: Data and Safety Monitoring Board Member; AbbVie: Other: Data and Safety Monitoring Board Member. Herrera:Pharmacyclics: Research Funding; Bristol Myers Squibb: Consultancy, Other: Travel, Accomodations, Expenses, Research Funding; Karyopharm: Consultancy; Merck: Consultancy, Research Funding; Genentech, Inc./F. Hoffmann-La Roche Ltd: Consultancy, Research Funding; Gilead Sciences: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding; Immune Design: Research Funding; AstraZeneca: Research Funding. Armand:IGM: Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria, Research Funding; Affimed: Consultancy, Research Funding; ADC Therapeutics: Consultancy; Celgene: Consultancy; Pfizer: Consultancy; Infinity: Consultancy; Otsuka: Research Funding; Genentech: Research Funding; Roche: Research Funding; Tensha: Research Funding; Merck: Consultancy, Honoraria, Research Funding; Adaptive: Consultancy, Research Funding; Sigma Tau: Research Funding.

Abstract Background: Bruton's tyrosine kinase (BTK) inhibition is a key component in B-cell receptor signaling and is one of the most prominent therapeutic targets in hematologic malignancies. Acalabrutinib is a highly selective, covalent, potent next-generation inhibitor of BTK (Barf et al, 2017) and is approved for the treatment of mantle cell lymphoma and chronic lymphocytic leukemia (CLL). However, a small subset of patients develop resistance to acalabrutinib over time. While the major mechanism of resistance to covalent BTK inhibitors is explained by acquired mutations in BTK-Cys481 and its downstream target PLCg2, additional mechanisms are under investigation. Previously, we presented that high surface expression of CD49d (VLA-4) and CD79B correlates with acalabrutinib resistance in CLL patients (Bibikova et al, 2019). In the present study, we performed optimized whole genome methylation sequencing on 42 clinical samples from 22 patients in the ACE-CL-001 clinical trial (NCT02029443) to better understand novel mechanisms of acalabrutinib resistance at an epigenetic level in CLL patients. Methods: DNA was extracted from peripheral blood mononuclear cells of patients with available samples at baseline (n=20), following acalabrutinib treatment at the time of progressive disease (n=8), or at 6 months post treatment start (n=14, used as non-progressor controls). While bisulfite conversion has been the gold standard for DNA methylation analysis for decades, it damages DNA and performs suboptimally with clinical FFPE and cfDNA samples that are often in limited quantity. Enzymatic methods have recently been reported that do not induce DNA damage, making them more suitable to routine clinical samples that are already DNA-damaged (eg, by formalin fixation) and often have limited DNA amounts. Before performing methylome analysis, we conducted a comprehensive comparison of bisulfite and enzymatic DNA methylation assays in reference cell lines and clinically relevant samples . This revealed that enzymatic methods outperformed bisulfite in several library quality metrics and resulted in increased library yield with the same DNA input and PCR amplification cycles. Enzymatic methods also captured a larger fraction of GC-rich regions, including CpG islands, in all comparisons. Prior to interrogating the full CLL 22 patient sample set, the enzymatic methods were validated in a subset of 6 CLL samples. We conducted a comprehensive analysis of methylation data sets with previously established RNA-seq analysis from paired samples. Results: Analysis of the acalabrutinib posttreatment samples revealed that the non-progressed patients had significantly higher methylation of 440 genes, whereas progressed samples had higher methylation of only 2 genes. CDKN1C, IL15, and AXL were significantly more methylated in non-progressed samples (Figure 1A), and these genes have been shown to be related to proliferation, survival, or response to BTK inhibition in CLL (De Totero et al, 2008; Sinha et al, 2018; Gupta et al, 2019; Lu et al, 2021; Kagiyama et al, 2021). Using RNA-seq data from paired samples, we showed that, as expected, IL15 methylation negatively correlated with IL15 expression (Figure 1B; R=−0.73, p=7.1e-09). IL15 is a proinflammatory cytokine that has downstream signaling targets in the NF-kB pathway, similar to BTK, indicating that alternative methods of NF-kB signaling may affect response. To support this hypothesis, we found that IL15 methylation significantly correlated with BIRC2 (R=0.59, p=1.4e-5) and RELA (R=0.42, p=0.0034) expression. Both genes play a role in NF-kB signaling, where BIRC2 encodes for the protein cIAP1 that regulates NF-kB activation and RELA encodes for p65, a member of the NF-kB transcription factor family. To our knowledge, it is not known if DNA methylation of IL15-induced expression plays a role in CLL resistance to BTK inhibition, and this finding may have important implications for future combination treatments. To note, CDKN1C, IL15, and AXL methylation were also significantly different between the progressed and non-progressed patients before acalabrutinib treatment, indicating they may be playing a role in innate resistance to acalabrutinib treatment. Conclusions: Using EM-seq to analyze DNA methylation, we found that reduced IL15 methylation and increased IL15 expression correlates with acalabrutinib innate resistance in CLL patients. Figure 1 Figure 1. Disclosures Burke: AstraZeneca: Current Employment, Current equity holder in publicly-traded company, Current holder of stock options in a privately-held company, Divested equity in a private or publicly-traded company in the past 24 months. Nuttall: AstraZeneca: Current Employment, Current holder of individual stocks in a privately-held company. Karl: AstraZeneca: Current Employment, Current equity holder in publicly-traded company. Callahan: AstraZeneca: Current Employment; Veritas Genetics: Current holder of individual stocks in a privately-held company. Mendler: AstraZeneca: Current Employment, Divested equity in a private or publicly-traded company in the past 24 months; BISC Global, Inc.: Ended employment in the past 24 months. Criscione: AstraZeneca: Current Employment, Current holder of individual stocks in a privately-held company, Divested equity in a private or publicly-traded company in the past 24 months. Naumenko: AstraZeneca: Consultancy. Bibikova: AstraZeneca: Current Employment, Current equity holder in publicly-traded company, Ended employment in the past 24 months; Acerta Pharma: Current holder of stock options in a privately-held company, Ended employment in the past 24 months. Bloecher: AstraZeneca: Current Employment, Current equity holder in publicly-traded company, Current holder of individual stocks in a privately-held company. Dougherty: AstraZeneca: Current Employment, Current equity holder in publicly-traded company, Research Funding; Pfizer: Current equity holder in publicly-traded company. Barrett: AstraZeneca: Current Employment, Current holder of individual stocks in a privately-held company, Research Funding. Scaltriti: AstraZeneca: Current Employment, Current holder of stock options in a privately-held company; MSKCC: Research Funding. Cingolani: AstraZeneca: Current Employment, Divested equity in a private or publicly-traded company in the past 24 months. Byrd: Novartis, Trillium, Astellas, AstraZeneca, Pharmacyclics, Syndax: Consultancy, Honoraria; Vincerx Pharmaceuticals: Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; Newave: Membership on an entity's Board of Directors or advisory committees. Furman: Oncotracker: Consultancy; Sunesis: Consultancy; Janssen: Consultancy, Honoraria; Acerta/AstraZeneca: Consultancy; Beigene: Consultancy; Genentech: Consultancy; Pharmacyclics: Consultancy; Loxo Oncology: Consultancy; TG Therapeutics: Consultancy; Verastem: Consultancy; Incyte: Consultancy; Abbvie: Consultancy, Honoraria, Other: Expert testimony; AstraZeneca: Honoraria; Morphosys: Consultancy; Sanofi: Consultancy; X4 Pharmaceuticals: Consultancy. Brown: Invectys: Other: Data Safety Monitoring Committee Service; TG Therapeutics: Research Funding; Beigene: Consultancy; Genentech/Roche: Consultancy; MEI Pharma: Consultancy; Morphosys AG: Consultancy; Bristol-Myers Squib/Juno/Celegene: Consultancy; Rigel: Consultancy; Pfizer: Consultancy; Novartis: Consultancy; Catapult: Consultancy; Acerta/Astra-Zeneca: Consultancy; Eli Lilly and Company: Consultancy; Abbvie: Consultancy; Janssen: Consultancy; Nextcea: Consultancy; Loxo/Lilly: Research Funding; Sun: Research Funding; SecuraBio: Research Funding; Gilead: Research Funding. Mortlock: ARTICA Therapeutics B.V.: Membership on an entity's Board of Directors or advisory committees; Anavo Therapeutics: Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Current Employment, Current equity holder in publicly-traded company. Hadfield: AstraZeneca: Current Employment, Current holder of individual stocks in a privately-held company, Divested equity in a private or publicly-traded company in the past 24 months. Munugalavadla: AstraZeneca: Current Employment, Current equity holder in publicly-traded company.

Abstract Background: The combination of venetoclax (Ven), a selective oral B-cell lymphoma-2 inhibitor, and obinutuzumab (Obi), a type II anti-CD20 monoclonal antibody, is approved as a 12-cycle fixed duration treatment for adult patients (pts) with previously untreated chronic lymphocytic leukemia (CLL). In the CLL14 study, pts with CLL and coexisting conditions treated with Ven-Obi achieved high rates of undetectable minimal residual disease (uMRD), translating into a 4-year progression free survival (PFS) of 74%. Despite these favorable results, disease relapse may occur after cessation of the fixed duration therapy, particularly for those with higher risk genetics, such as TP53 aberrancy and unmutated IgHV. A key unanswered question in the field is, for pts who initially had a clinical response after first-line (1L) Ven-Obi treatment, how much clinical benefit would they receive from retreatment with Ven-Obi after developing progressive disease (PD)? Retreatment with Ven-Obi would provide a line of treatment in addition to other regimens such as BTK inhibitors. In patients with relapsed/refractory (R/R) CLL, one of the current standard therapies is the combination of Ven and rituximab (R). Updated results from the phase 3 MURANO trial of 24-cycle fixed duration Ven-R demonstrated that patients with disease progression after treatment completion and clinical response had a best overall response rate (ORR) of 72.2% upon Ven-R retreatment. The results of the MURANO study and the favorable safety profile of Ven-Obi suggest that retreatment with Ven-Obi after initial therapy with Ven-Obi may be effective in pts with relapsed CLL. The present study is the first prospective clinical trial to evaluate the efficacy and safety of retreatment with Ven-Obi at the time of PD in pts who had initially responded to 1L Ven-Obi for at least 12 months (mo) after completing therapy. Study Design and Methods: Pts are eligible for this multicenter, open-label, non-randomized, phase 2 study (NCT04895436) if they have a diagnosis of CLL according to iwCLL criteria, were treated with Ven-Obi fixed duration therapy, and achieved a best response of either complete remission (CR), CR with incomplete marrow recovery (CRi), nodular partial remission (nPR), or partial remission (PR). Pts must also have had at least 12 mo of remission between the last dose of Ven and PD. Pts will be divided into two cohorts: PD more than 2 years after completing 1L treatment (Co-1), and pts with PD between 1-2 years post 1L therapy (Co-2). Pts receive Obi (100 mg intravenously [IV] on Day [D] 1 and additional 900mg on either D1 or D2, then 1000mg on D8 and D15 of Cycle [C] 1 and subsequently on D1C2-6). Ven is administered orally once daily (QD) beginning on C1D22, including a 5-week ramp-up period (weekly dose increases from 20, 50, 100, 200, to 400mg QD), followed by 400mg QD thereafter on 28-day cycles, for a total of 12 or 24 cycles in Co-1 and Co-2, respectively. Pts in Co-2 with detectable MRD (≥10 -4) after 15 months of therapy may continue Ven monotherapy beyond mo 24 at the investigator's discretion. The primary objective is to assess the efficacy of Ven-Obi in Co-1 as measured by ORR, defined as a proportion of pts achieving a best response of PR/nPR or CR/CRi at the end of combination therapy (EOCT) assessment (EOCT + 3 mo). Key secondary objectives are CR/CRi at EOCT, CR/CRi rate at end of therapy (EOT), ORR at EOT, time to response (TTR), duration of response (DOR), PFS, overall survival (OS), time to next treatment (TTNT), and uMRD (10 -4)rate at EOCT and EOT. Safety endpoints include the type, frequency, and severity of treatment-emergent adverse events (AEs), and serious AEs. Prespecified exploratory biomarker endpoints include MRD kinetics up to 12 mo post-treatment, and correlations of baseline characteristics of IgHV, TP53 mutation, and del (17p) status with outcomes. Point and interval estimates will be used to characterize the efficacy of Ven-Obi retreatment; exact binomial (Clopper-Pearson) 95% confidence intervals will be provided alongside the corresponding point estimates for the response rates of interest (ORR, CR rate, and uMRD rate), while Kaplan-Meier methodology will be used to summarize the time-to-event endpoints (DOR, PFS, OS, and TTNT). Finally, descriptive statistical summaries will be reported for several patient-reported outcome (PRO) measures, including the EORTC QLQ-CLL-17, EQ-5D-5L, and FACIT-F. Figure 1 Figure 1. Disclosures Davids: Takeda: Consultancy; Novartis: Consultancy, Research Funding; Janssen: Consultancy; AbbVie: Consultancy; Merck: Consultancy; MEI Pharma: Consultancy; Adaptive Biotechnologies: Consultancy; Pharmacyclics: Consultancy, Research Funding; Research to Practice: Consultancy; Ascentage Pharma: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Surface Oncology: Research Funding; Astra-Zeneca: Consultancy, Research Funding; Eli Lilly and Company: Consultancy; Genentech: Consultancy, Research Funding; Celgene: Consultancy; MEI Pharma: Consultancy, Research Funding; BeiGene: Consultancy; TG Therapeutics: Consultancy, Research Funding; Verastem: Consultancy, Research Funding. Fischer: Abbvie: Honoraria; Roche: Honoraria, Other: Travel Grants. Porro Lurà: F. Hoffmann - La Roche Ltd: Current Employment, Current holder of individual stocks in a privately-held company. Sinai: AbbVie Inc.: Current Employment, Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company. Chyla: AbbVie: Current Employment, Current equity holder in publicly-traded company. Sail: AbbVie: Current Employment, Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company. Pesko: AbbVie: Current Employment, Current equity holder in publicly-traded company. Pai: AbbVie: Current Employment, Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company. Komlosi: AbbVie: Current Employment, Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company. Hallek: Roche: Honoraria, Speakers Bureau; Gilead: Honoraria, Speakers Bureau; Mundipharma: Honoraria, Speakers Bureau; Janssen: Honoraria, Speakers Bureau; Celgene: Honoraria, Speakers Bureau; Pharmacyclics: Honoraria, Speakers Bureau. Brown: Beigene: Consultancy; Janssen: Consultancy; Pfizer: Consultancy; Eli Lilly and Company: Consultancy; Nextcea: Consultancy; Genentech/Roche: Consultancy; Bristol-Myers Squib/Juno/Celegene: Consultancy; Novartis: Consultancy; Morphosys AG: Consultancy; MEI Pharma: Consultancy; Acerta/Astra-Zeneca: Consultancy; Abbvie: Consultancy; Invectys: Other: Data Safety Monitoring Committee Service; TG Therapeutics: Research Funding; Sun: Research Funding; SecuraBio: Research Funding; Loxo/Lilly: Research Funding; Gilead: Research Funding; Rigel: Consultancy; Catapult: Consultancy. Al-Sawaf: AbbVie: Honoraria, Research Funding; Adaptive: Honoraria; AstraZeneca: Honoraria; Beigene: Honoraria, Research Funding; Gilead: Honoraria; Janssen: Honoraria, Research Funding; Roche: Honoraria, Research Funding. OffLabel Disclosure: Venetoclax is a B-cell lymphoma 2 inhibitor approved in combination with Obinutuzumab, a type II anti-CD20 monoclonal antibody, for first-line therapy for chronic lymphocytic leukemia.

Backgound Venetoclax (V) plus obinutuzumab (O) regimen is active as frontline CLL treatment; a little over half of patients (pts) will achieve undetectable minimal residual disease in the bone marrow (BM-uMRD) with one year of time-limited therapy (Fischer et al. NEJM 2019). Novel strategies may further augment the efficacy of VO. Ibrutinib was previously combined with VO, but relatively high rates of infusion reactions and neutropenia were observed, as were the characteristic toxicities of ibrutinib including diarrhea and bruising (Rogers et al. Blood 2018). Acalabrutinib (A), a more selective BTK inhibitor, is well-tolerated and active as monotherapy or with O, and we previously found that it sensitizes CLL cells to V (Deng et al. Leukemia 2017). We hypothesized that a time-limited triplet combination of A, V, and O (AVO) could achieve a high rate of BM-uMRD with good tolerability. For the first time we now report on the safety and preliminary efficacy data of AVO in previously untreated CLL pts. Methods This ongoing open-label, single arm, phase 2 investigator-initiated study (NCT03580928) enrolled pts with previously untreated CLL without restriction by prognostic marker status. Eligibility: requiring treatment by iwCLL criteria, ECOG PS ≤ 2, creatinine clearance ≥50ml/min, absolute neutrophil count ≥500/mm3, and platelets ≥30,000/mm3. A, V, and O are started sequentially (see figure), with one 28-day cycle lead-in with A at 100 mg bid, then 2 cycles of AO (with O at standard dosing), then V ramp-up beginning at C4, followed by 3 more cycles of triplet AVO therapy. After 6 months of O, the AV doublet continues through C15; pts with BM-uMRD-negative CR after C15 may discontinue therapy, while all others continue AV until completing C24, with the option to discontinue therapy if in BM-uMRD CR at that time. Response is assessed by 2018 iwCLL criteria, including bone marrow biopsy with MRD testing in the BM and peripheral blood (PB) by 8-color flow cytometry at a sensitivity of at least 10-4. The primary endpoint is the rate of BM-uMRD CR after 15 cycles. Non-hematologic adverse events (AEs) are assessed by CTCAE v5.0, with hematologic toxicity determined by iwCLL criteria. Results The data cut for this interim analysis was July 11, 2019. The study is fully accrued at 37 pts. Median age: 63 years (range: 41-78), 73% male. Baseline prognostic features: unmutated IGHV in 23 (62%) pts, TP53 aberrant disease (defined as either del(17p) and/or TP53 mutation) in 10 (27%) pts, del(11q) in 10 (27%) pts, and complex karyotype in 7 (19%) pts. Thirty-six pts remain on study drugs with a median time on therapy of 8 months (range: 2-11). One pt withdrew consent after 6 cycles due to gastrointestinal symptoms. The overall response rate for the 24 pts who have completed re-staging at C8 is 100%, 18 (75%) PR and 5 (25%) CR. At C8 restaging, 65% of pts were PB-uMRD, 50% of pts were BM-uMRD, and 3 pts (13%) had BM-uMRD CRs. In 8 pts with TP53-aberrant disease who have reached C8, 6 had PR and 2 had CR, with 3 pts BM-uMRD. The most frequent AEs have been fatigue (81% total, 78% gr 1+2, 3% gr ≥3) and headache (76% total, 73% gr 1+2, 3% gr ≥3). Bruising was reported by 16 pts (43%, all gr 1+2). The most frequent gr 3/4 AE has been neutropenia (68% total, 32% gr ≥3). Infusion-related reactions were seen in 8 pts (22%, 19% gr 1+2, 3% gr ≥3). Laboratory tumor lysis syndrome (TLS) occurred in 2 pts (5%), both gr 3 immediately after starting O and prior to any V; both pts continued O. Out of 32 pts, 31 (97%) were medium-to-high risk for TLS on C1D1 but only 3 (9%) were medium-to-high risk at V initiation on C4D1, with 4 medium-to-low risk pts electively admitted for V initiation. One case of gr 3 atrial fibrillation and no cases of hemorrhage or febrile neutropenia were observed. Conclusion Our preliminary data suggest that even at an early response evaluation after 8 cycles of therapy (including only 4 months of V), AVO as frontline CLL therapy leads to a high proportion of pts achieving BM-uMRD and CR, including pts with TP53-aberrant disease. The AE profile is favorable, with a low rate of infusion reactions and no significant cardiac or bleeding toxicities. Updated data will be presented at the meeting for this ongoing study. Based on our initial results we have opened an expansion cohort to further characterize the efficacy and safety of AVO. AVO will also be studied head-to-head against chemoimmunotherapy and the AV doublet in the phase 3 trial CL-311 (NCT03836261), which is currently enrolling. Figure Disclosures Montegaard: Pharmacyclics: Consultancy; Janssen: Consultancy. Jacobson:Kite, a Gilead Company: Consultancy, Honoraria, Other: Travel Expenses, Research Funding; Novartis: Consultancy, Honoraria, Other: Travel Expenses; Pfizer: Consultancy, Research Funding; Humanigen: Consultancy, Other: Travel Expenses; Bayer: Consultancy, Other: Travel Expenses; Precision Biosciences: Consultancy, Other: Travel Expenses; Celgene: Consultancy, Other: Travel Expenses. Jacobsen:Astra-Zeneca: Consultancy; Novartis: Research Funding; F. Hoffmann-LaRoche: Research Funding; Takeda: Honoraria; Pharmacyclics: Research Funding; Merck: Consultancy, Research Funding; Acerta: Consultancy. LaCasce:Seattle Genetics: Consultancy, Research Funding; BMS: Consultancy; Research to Practice: Speakers Bureau; Humanigen: Consultancy. Arnason:Regeneron Pharmaceuticals, Inc.: Consultancy; Celgene/Juno: Consultancy. Armand:Merck: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Bristol-Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Adaptive: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Affimed: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Research Funding; Otsuka: Research Funding; Sigma Tau: Research Funding; Infinity: Consultancy; Genentech: Research Funding; Pfizer: Consultancy; ADC Therapeutics: Consultancy; Tensha: Research Funding. Brown:BeiGene: Consultancy; AbbVie: Consultancy; Catapult Therapeutics: Consultancy; Dynamo Therapeutics: Consultancy; Genentech/Roche: Consultancy; Kite, a Gilead Company: Consultancy, Research Funding; Loxo: Consultancy, Research Funding; Novartis: Consultancy; Juno/Celgene: Consultancy; Acerta Pharma: Consultancy; AstraZeneca: Consultancy; Gilead: Consultancy, Research Funding; Pfizer: Consultancy; Pharmacyclics: Consultancy; Sunesis: Consultancy; TG Therapeutics: Consultancy; Verastem: Consultancy, Research Funding; Sun Pharmaceuticals: Research Funding; Janssen: Honoraria; Teva: Honoraria; Morphosys: Other: Data safety monitoring board; Invectys: Other: Data safety monitoring board; Octapharma: Consultancy. Davids:AbbVie, Acerta Pharma, Adaptive, Biotechnologies, Astra-Zeneca, Genentech, Gilead Sciences, Janssen, Pharmacyclics, TG therapeutics: Membership on an entity's Board of Directors or advisory committees; AbbVie, Astra-Zeneca, Genentech, Janssen, MEI, Pharmacyclics, Syros Pharmaceuticals, Verastem: Consultancy; Acerta Pharma, Ascentage Pharma, Genentech, MEI pharma, Pharmacyclics, Surface Oncology, TG Therapeutics, Verastem: Research Funding; Research to Practice: Honoraria. OffLabel Disclosure: Acalabrutinib, venetoclax, obinutuzumab - combination therapy for previously untreated CLL

Abstract Introduction FCR remains the only therapy other than allo transplant proven to provide a significant chance of functional cure with very long term follow-up for young, fit patients with mutated IGHV CLL. Given the excellent efficacy and tolerability of ibrutinib in a broad population of young, fit CLL patients, we designed the frontline iFCR study to investigate whether time-limited novel agent plus chemoimmunotherapy could provide durable remission for CLL patients irrespective of IGHV status. We previously reported that with a median follow-up of 16.5 months, the rate of CR with bone marrow undetectable minimal residual disease (BM-uMRD) 2 months post-FCR (primary endpoint) was 33%, and that 84% of patients achieved BM-uMRD as best response (Davids et al., Lancet Haem, 2019). Here, we report updated data with longer follow-up, with all patients having had the opportunity to complete 2 years of ibrutinib maintenance following iFCR. Methods This is a multicenter, single arm, phase 2 investigator sponsored trial (NCT02251548) which enrolled CLL patients age ≤65 years without restriction by IGHV mutation status, all of whom met iwCLL treatment criteria. Ibrutinib 420 mg daily was given for 7 days, then combination ibrutinib with FCR for up to 6 cycles. Responders continued on ibrutinib maintenance, and patients with BM-uMRD after 2 years of maintenance discontinued therapy. Response was assessed by 2008 iwCLL criteria, and toxicity by CTCAE v4.03 and iwCLL criteria. The primary objective was to determine the rate of CR/CRi with BM-uMRD 2 months after iFCR combination. Secondary objectives were to assess response rates, PFS/OS, rates of BM-uMRD after 2 years of ibrutinib maintenance, and safety/tolerability. Results Between October, 2014, and April, 2018, 85 patients were enrolled at 9 US sites.As previously reported, the median age was 55 years (range 38-65). IGHV was unmutated in 46/79 patients (58.2%). Deletion of 17p and TP53 mutation were present in 4/83 (4.8%) and 3/81 (3.7%) patients, respectively; 2 of these patients had both. The median number of FCR cycles completed was 6 (range 1-6). Median follow-up is now 40.3 months (range 3.1-76). Median number of ibrutinib maintenance cycles is 24 (range 0-81). By ITT analysis, the rate of CR with BM-uMRD at any point on study is now 55% (47/85 patients), and best rate of BM-uMRD remained 84% (71/85). After 2 years of ibrutinib maintenance, the rates of CR/CRi, BM-uMRD, and PB-uMRD in patients with available data were 77% (44/57), 81% (50/62), and 81% (55/68), respectively, with no differences based on IGHV status. At the median follow-up time of 40 months, PFS and OS for all patients were 97% and 99%, respectively (see Figure, below). Thirteen of 61 patients (21.3%) who completed iFCR and started ibrutinib maintenance in a BM-uMRD state have had recurrent BM-MRD, with median time to MRD recurrence not yet reached. Seven patients underwent retreatment with ibrutinib monotherapy (5 due to clinical progression and 2 due to recurrent BM-MRD without clinical progression), and all 7 achieved PR with re-treatment. Median time on re-treatment is 12.8 months (range 4.2-26.2), and none of these 7 patients have progressed on re-treatment. One patient died 17 months into ibrutinib maintenance due to presumed sudden cardiac death. In the updated safety analysis, the most common treatment-emergent Gr 3/4 adverse events were hematologic, including neutropenia 40% (up from 35%), thrombocytopenia 32% (unchanged), and anemia 11% (unchanged). Ten patients (12%, up from 9%) experienced Gr ≥3 febrile neutropenia, and 20 patients (24%, up from 11%) had Gr ≥3 infection. Any Gr atrial fibrillation was observed in 8%, and ventricular arrhythmia in 1 patient. No major bleeding events occurred. Two patients developed MDS, and both are now in CR for CLL and MDS after undergoing allo transplant. No patients developed Richter's syndrome. Conclusions With longer term follow-up (median of 40.3 months), most patients treated with iFCR have continued to maintain deep responses, including patients with unmutated IGHV. The safety profile remains consistent with the individual toxicities of ibrutinib and FCR. Among the few patients with recurrence after this time-limited therapy, all have responded to re-treatment with ibrutinib monotherapy. iFCR is worthy of exploring in comparative studies in younger, fit CLL patients who desire the possibility of functional cure with time-limited therapy. Figure 1 Figure 1. Disclosures Davids: Ascentage Pharma: Consultancy, Research Funding; Celgene: Consultancy; Eli Lilly and Company: Consultancy; Janssen: Consultancy; MEI Pharma: Consultancy; Merck: Consultancy; Research to Practice: Consultancy; Takeda: Consultancy; Novartis: Consultancy, Research Funding; BeiGene: Consultancy; Adaptive Biotechnologies: Consultancy; Astra-Zeneca: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; MEI Pharma: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Pharmacyclics: Consultancy, Research Funding; TG Therapeutics: Consultancy, Research Funding; Verastem: Consultancy, Research Funding; Surface Oncology: Research Funding; AbbVie: Consultancy. Brander: NCCN: Other: panel member; Verastem: Consultancy; MEI Pharma: Research Funding; Juno Therapeutics/Celgene/Bristol Myers Squibb: Research Funding; ArQule: Research Funding; Pharmacyclics LLC, an AbbVie Company: Consultancy, Research Funding; Pfizer: Consultancy, Other: Biosimilars outcomes research panel; DTRM: Research Funding; ArQule/Merck: Consultancy; LOXO: Research Funding; AbbVie: Consultancy, Other: informCLL registry steering committee, Research Funding; TG Therapeutics: Consultancy, Research Funding; AstraZeneca: Research Funding; Novartis: Research Funding; Genentech: Consultancy, Research Funding; Ascentage: Research Funding; BeiGene: Research Funding. Montegaard: AbbVie: Consultancy; AstraZeneca*-: Consultancy; Janssen: Consultancy; Pharmacyclics: Consultancy. Alencar: Seattle Genetics: Consultancy; Kite Pharma: Consultancy; Karyopharm: Consultancy; Janssen: Consultancy; Incyte: Consultancy; Epizyme: Consultancy; Celgene: Consultancy; BeiGene: Consultancy; Amgen: Consultancy. Jacobson: Humanigen: Consultancy, Honoraria, Other: Travel support; Pfizer: Consultancy, Honoraria, Other: Travel support, Research Funding; Kite, a Gilead Company: Consultancy, Honoraria, Other: Travel support; Novartis Pharmaceuticals Corporation: Consultancy, Honoraria, Other: Travel support; Celgene: Consultancy, Honoraria, Other: Travel support; AbbVie: Consultancy, Honoraria; Axis: Speakers Bureau; Lonza: Consultancy, Honoraria, Other: Travel support; Clinical Care Options: Speakers Bureau; Precision Biosciences: Consultancy, Honoraria, Other: Travel support; Nkarta: Consultancy, Honoraria. Armand: Infinity: Consultancy; Pfizer: Consultancy; Kite: Research Funding; Tensha: Research Funding; IGM: Research Funding; Roche: Research Funding; Genentech: Consultancy, Research Funding; AstraZeneca: Consultancy; Epizyme: Consultancy; Enterome: Consultancy; Regeneron: Consultancy; C4: Consultancy; GenMab: Consultancy; Tessa Therapeutics: Consultancy; Miltenyi: Consultancy; Morphosys: Consultancy; Daiichi Sankyo: Consultancy; Otsuka: Research Funding; Sigma Tau: Research Funding; Celgene: Consultancy; ADC Therapeutics: Consultancy; Adaptive: Consultancy, Research Funding; Affimed: Consultancy, Research Funding; BMS: Consultancy, Honoraria, Research Funding; Merck: Consultancy, Honoraria, Research Funding. Crombie: Roche: Research Funding; Merck: Research Funding; Abbvie: Research Funding; Bayer: Research Funding; Karyopharm: Consultancy; Incyte: Consultancy. LaCasce: Bristol-Myers Squibb Company.: Other: Data Safetly and Monitoring. Arnason: Juno/BMS: Honoraria. Hochberg: Trapelo Health: Consultancy; Leuko: Consultancy. Abramson: Bristol-Myers Squibb Company: Consultancy, Research Funding; Kite Pharma: Consultancy; Novartis: Consultancy; Morphosys: Consultancy; C4 Therapeutics: Consultancy; EMD Serono: Consultancy; Genmab: Consultancy; Bluebird Bio: Consultancy; Kymera: Consultancy; BeiGene: Consultancy; Incyte Corporation: Consultancy; Astra-Zeneca: Consultancy; Allogene Therapeutics: Consultancy; Seagen Inc.: Research Funding; AbbVie: Consultancy; Karyopharm: Consultancy; Genentech: Consultancy. Brown: Gilead, Loxo/Lilly, SecuraBio, Sun, TG Therapeutics: Research Funding; Invectys: Other: Data Safety Monitoring Committee Service; Abbvie, Acerta/Astra-Zeneca, Beigene, Bristol-Myers Squibb/Juno/Celgene, Catapult, Eli Lilly, Genentech/Roche, Janssen, MEI Pharma, Morphosys AG, Nextcea, Novartis, Pfizer, Rigel: Consultancy. OffLabel Disclosure: Ibrutinib being used to enhance the efficacy of FCR

Abstract Background: The phase 3 head-to-head trial of acalabrutinib (acala) vs ibrutinib (ibr) (NCT02477696) demonstrated noninferior efficacy and improved tolerability with acala in previously treated CLL (Byrd J Clin Oncol 2021). We now report additional data to further characterize BTKi-related adverse events (AEs) and the safety profile of acala and ibr, including measures of AE burden that account for frequency, duration, and drug exposure, which are not captured by incidence alone. Methods: Patients (pts) received oral acala 100 mg BID or ibr 420 mg QD until disease progression or unacceptable toxicity. Overall incidence, exposure-adjusted (exp-adj) incidence, and exp-adj time with event (sum of event durations [all grades]*100/sum of treatment-emergent period [for all pts in each arm]) were assessed for the most common BTKi-related AEs. Atrial fibrillation (afib)/flutter, hypertension (htn), and bleeding events were further characterized by time to onset, cumulative incidence by Kaplan-Meier method, pt subgroup, and AE management. Results: A total of 533 pts (acala, n=268; ibr, n=265) were randomized; median treatment exposures were 38.3 and 35.5 mo, respectively. Incidence and exp-adj incidence and time with event are reported for the most common AEs and events of clinical interest (ECIs) (Table). Among cardiovascular (CV) ECIs, incidences of any-grade afib/flutter, htn, and bleeding were statistically higher with ibr, with higher exp-adj incidence (2.0-, 2.8-, and 1.6-fold, respectively) and exp-adj time with event (2.8-, 3.7-, and 1.8-fold). Ventricular arrhythmias were reported in 3 ibr-treated pts vs 0 pts in the acala arm. Among other BTKi-related AEs, incidences of any-grade diarrhea, arthralgia, contusion, urinary tract infection (UTI), back pain, muscle spasms and dyspepsia were statistically higher with ibr, with a 1.5- to 4.1-fold higher exp-adj incidence, and a 1.4- to 13.1-fold higher exp-adj time with event (except for UTI, which had a 1.4-fold lower exp-adj time with event for ibr). Incidences of headache and cough were statistically higher with acala, with a 1.6- and 1.2-fold higher exp-adj incidence, respectively, and a 1.4- and 1.1-fold higher exp-adj time with event. The total exp-adj time with event for all any-grade AEs was 37% higher with ibr (234 [acala] vs 320 [ibr] mo/100 person-mo). For any-grade afib/flutter, median time to onset was longer for acala vs ibr (28.8 vs 16.0 mo), and cumulative incidence was lower for acala at 6 mo (2% vs 6%), 12 mo (3% vs 8%), 18 mo (4% vs 10%), and 24 mo (5% vs 12%). Afib/flutter also occurred less frequently with acala vs ibr in subgroups of age (&lt;65 y: 3% vs 7%; ≥65 y: 15% vs 23%), prior line of therapy (1-3: 10% vs 16%; ≥4: 7% vs 19%), and among pts without prior history (6% vs 15%). Cox proportional-hazards (PH) analysis of new-onset afib/flutter showed a 63% rate reduction favoring acala (Figure 1). Among all pts, concomitant medication use for afib/flutter was less common for acala (8%) vs ibr (14%), with antithrombotic use reported in 5% vs 9% of pts, respectively. For any-grade htn, median time to onset was similar for acala and ibr (8.1 vs 7.0 mo), but cumulative incidence was lower for acala at 6 mo (5% vs 12%), 12 mo (6% vs 16%), 18 mo (8% vs 20%), and 24 mo (8% vs 23%). Htn also occurred less frequently with acala vs ibr in subgroups of age (&lt;65 y: 9% vs 23%; ≥65 y: 10% vs 23%), prior line of therapy (1-3: 10% vs 25%; ≥4: 4% vs 11%), and among pts without prior history (7% vs 23%). Cox PH analysis of new-onset htn showed a 77% rate reduction favoring acala (Figure 2). No dose reductions or treatment discontinuations due to htn occurred in either arm. Concomitant medication use for htn was less common for acala (5%) vs ibr (19%). For any-grade bleeding events, the median time to onset was similar for acala vs ibr (1.2 vs 1.2 mo), and cumulative incidence was lower for acala at 6 mo (29% vs 42%), 12 mo (32% vs 45%), 18 mo (34% vs 49%), and 24 mo (38% vs 51%). Bleeding events also occurred less frequently with acala vs ibr in most subgroups of age (&lt;65 y: 26% vs 47%; ≥65 y: 49% vs 55%) and prior line of therapy (1-3: 39% vs 54%; ≥4: 32% vs 30%). Bleeding events were associated with dose reduction in 3 vs 2 pts in the acala vs ibr arms, respectively, and led to treatment discontinuation in 2 vs 4 pts. Conclusions: In this head-to-head trial of BTKis in CLL, event-based analyses demonstrated a higher BTKi-related toxicity burden with ibr, with a lower impact of CV-related toxicity with acala across subgroups. Figure 1 Figure 1. Disclosures Seymour: AstraZeneca: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees; Mei Pharma: Honoraria, Membership on an entity's Board of Directors or advisory committees; Morphosys: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sunesis: Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; F. Hoffmann-La Roche Ltd: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene: Consultancy, Research Funding, Speakers Bureau. Byrd: Novartis, Trillium, Astellas, AstraZeneca, Pharmacyclics, Syndax: Consultancy, Honoraria; Newave: Membership on an entity's Board of Directors or advisory committees; Vincerx Pharmaceuticals: Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees. Hillmen: Janssen: Honoraria, Other: Travel, Accommodations, Expenses, Research Funding; AbbVie: Honoraria, Other: Travel, Accommodations, Expenses, Research Funding; Pharmacyclics: Honoraria, Research Funding; Roche: Research Funding; Gilead: Research Funding; AstraZeneca: Honoraria; SOBI: Honoraria; BeiGene: Honoraria. Ghia: Acerta/AstraZeneca: Consultancy, Honoraria, Research Funding; AstraZeneca: Consultancy, Honoraria, Research Funding; Sunesis: Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Gilead: Consultancy, Research Funding; Celgene/Juno/BMS: Consultancy, Honoraria; ArQule/MSD: Consultancy, Honoraria; BeiGene: Consultancy, Honoraria; Roche: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria, Research Funding. Kater: Genmab, LAVA: Other: Ad Board, Steering Committee; Janssen, AstraZeneca: Other: Ad Board, steering committee, Research Funding; Abbvie: Honoraria, Other: Ad Board, Research Funding; BMS, Roche/Genentech: Other: Ad Board, , Research Funding. Chanan-Khan: Ascentage: Research Funding; Alpha2 Pharmaceuticals, NonoDev, Starton: Current holder of stock options in a privately-held company; Cellectar: Current equity holder in publicly-traded company; Alpha2 Pharmaceuticals: Patents & Royalties: Tabi; BeiGene, Jansen, Ascentage: Honoraria; Ascentage, Starton, Cellectar, NonoDev, Alpha2 Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; BieGene, Jansen, Ascentage: Consultancy. Furman: Genentech: Consultancy; Sanofi: Consultancy; Morphosys: Consultancy; Incyte: Consultancy; Beigene: Consultancy; Loxo Oncology: Consultancy; TG Therapeutics: Consultancy; X4 Pharmaceuticals: Consultancy; Sunesis: Consultancy; Acerta/AstraZeneca: Consultancy; Abbvie: Consultancy, Honoraria, Other: Expert testimony; Pharmacyclics: Consultancy; Oncotracker: Consultancy; Janssen: Consultancy, Honoraria; Verastem: Consultancy; AstraZeneca: Honoraria. O'Brien: Amgen, Astellas, Celgene, GlaxoSmithKline, Janssen Oncology, Aptose Biosciences Inc., Vaniam Group LLC, AbbVie, Alexion, Verastem, Juno Therapeutics, Vida Ventures, Autolus, Johnson and Johnson, Merck, Bristol Myers Squibb, NOVA Research Company, Eli Lill: Consultancy; Kite, Regeneron, Acerta, Caribou, Gilead, Pharmacyclics, TG Therapeutics, Pfizer, Sunesis: Research Funding. Brown: Gilead, Loxo/Lilly, SecuraBio, Sun, TG Therapeutics: Research Funding; Invectys: Other: Data Safety Monitoring Committee Service; Abbvie, Acerta/Astra-Zeneca, Beigene, Bristol-Myers Squibb/Juno/Celgene, Catapult, Eli Lilly, Genentech/Roche, Janssen, MEI Pharma, Morphosys AG, Nextcea, Novartis, Pfizer, Rigel: Consultancy. Mato: Genmab: Research Funding; Janssen: Consultancy, Research Funding; LOXO: Consultancy, Research Funding; Nurix: Research Funding; TG Therapeutics: Consultancy, Other: DSMB, Research Funding; Pharmacyclics LLC, an AbbVie Company: Consultancy, Research Funding; Adaptive Biotechnologies: Consultancy, Research Funding; Sunesis: Consultancy, Research Funding; AstraZeneca: Consultancy; BeiGene: Consultancy, Research Funding; MSKCC: Current Employment; Acerta/AstraZeneca: Consultancy, Research Funding; Johnson and Johnson: Consultancy, Research Funding; AbbVie: Consultancy, Research Funding; DTRM BioPharma: Consultancy, Research Funding; Genentech: Consultancy, Research Funding. Stilgenbauer: AbbVie, Amgen, AstraZeneca, Celgene, Gilead, GSK, Hoffmann-La Roche, Janssen, Novartis, Sunesis: Honoraria; AbbVie, Amgen, AstraZeneca, Celgene, Gilead, GSK, Hoffmann-La Roche, Janssen, Novartis, Sunesis: Other: Research Support; AbbVie, Amgen, AstraZeneca, Celgene, Gilead, GSK, Hoffmann-La Roche, Janssen, Novartis, Sunesis: Consultancy; AbbVie, Amgen, AstraZeneca, Celgene, Gilead, GSK, Hoffmann-La Roche, Janssen, Novartis, Sunesis: Research Funding. Kuptsova-Clarkson: AstraZeneca: Current Employment, Current equity holder in publicly-traded company; AbbVie: Current holder of individual stocks in a privately-held company. Miranda: ASTRAZENECA: Current Employment; ASTRAZENECA: Current equity holder in publicly-traded company. Wagner: AstraZeneca: Current Employment. Higgins: AstraZeneca: Current Employment; PROMETRIKA, LLC: Ended employment in the past 24 months. Sohoni: AstraZeneca: Current equity holder in publicly-traded company, Ended employment in the past 24 months; Revolution Medicines: Current Employment, Current equity holder in publicly-traded company; Theravance: Current equity holder in publicly-traded company. Jurczak: 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; Jagiellonian University: Ended employment in the past 24 months; European Medicines Agency, Sandoz-Novartis, Janssen China R&D, BeiGene, Epizyme, Acerta, AstraZeneca: Consultancy.

Abstract Background: Zanubrutinib is a selective next-generation Bruton tyrosine kinase (BTK) inhibitor designed to have high specificity for BTK and minimize off-target effects (J Med Chem 2019;62:7923-40). Data from several phase 2 CLL trials assessing BCL-2 and BTK inhibitor combination treatment suggested that undetectable minimal residual disease (uMRD)-driven fixed-duration combination treatment was tolerable and enabled durable responses after treatment discontinuation (JAMA Oncol 2021;1649.; EHA 2021 S147). However, a limited number of patients with the high-risk feature, deletion of chromosome 17p13.1 [del(17p)], have been included in these studies. Preliminary data from Arm C of the SEQUOIA trial suggested that zanubrutinib monotherapy was active (18-mo progression-free survival: 90.6%) and well-tolerated in CLL/SLL patients with del(17p) (ASH 2020 1306). Here, we present early results for patients with TN del(17p) CLL/SLL receiving zanubrutinib + venetoclax in Arm D of the SEQUOIA trial (NCT03336333). Methods: SEQUOIA is an open-label, global, multicenter, phase 3 study that includes a nonrandomized cohort (Arm D) of patients with TN del(17p) CLL/SLL (Blood 2020;136 [supplement 1]:24-5). Patients in Arm D were treated with zanubrutinib (160 mg twice daily) for 3 mos followed by zanubrutinib (same dosing) + venetoclax (ramp-up cycle followed by 400 mg once daily) combination treatment for 12-24 cycles until progressive disease (PD), unacceptable toxicity, or achievement of uMRD at &lt;10 -4 sensitivity by flow cytometry (whichever occurred first). Adult patients with CLL/SLL who met International Workshop on CLL (iwCLL) criteria for treatment (Blood 2008;111:5446-56) were eligible if they had central verification of del(17p) by fluorescence in situ hybridization with &gt;7% aberrant nuclei present. Initial safety and tolerability of zanubrutinib + venetoclax was assessed, including the risk of tumor lysis syndrome (TLS) both at baseline and prior to initiation of venetoclax. Responses for CLL and SLL were investigator-assessed per modified iwCLL criteria (Blood 2008;111:5446-56; J Clin Oncol 2012;30:2820-2) and Lugano criteria (J Clin Oncol 2014;32:3059-68), respectively. Bone marrow exams to confirm a suspected complete response (CR) or CR with incomplete hematological recovery were required starting at the end of Cycle 9. Results: As of 1 JUN 2021 (data cutoff), 35 of approximately 80 planned patients with centrally confirmed del(17p) were enrolled. Median follow-up was 9.7 mos. In the safety analysis population (n=35), 94.3% had CLL and high-risk characteristics including Binet stage C (51.5%), bulky disease ≥5 cm (42.9%), unmutated immunoglobulin heavy chain variable locus (85.3%, n=34), median del(17p) frequency of 81.5%, and elevated β 2-microglobulin (71.4%). At data cutoff, 29 patients had started combination therapy and 27 patients completed ramp-up venetoclax dosing. Thirty-two patients remained on study treatment and 3 patients ended treatment due to withdrawal of consent, PD, or adverse event (AE of lung cancer), all n=1. The patient with lung cancer had lung nodules present at screening and died due to lung adenocarcinoma. AEs and serious AEs were reported in 29 patients (82.9%) and 4 patients (11.4%), respectively. AEs reported in ≥10% of patients included diarrhea (n=5), neutropenia (n=5), fatigue (n=4), nausea (n=4), and petechiae (n=4). Thirteen patients (37.1%) had grade ≥3 AEs; most frequently neutropenia (n=4) and diarrhea (n=2). One patient with ongoing grade 2 atrial fibrillation at baseline reported grade 3 atrial fibrillation on study. To date, no AEs of TLS have been reported. At baseline, the TLS risk categories were high, medium, and low in 12 (34.3%), 22 (62.9%), and 1 (2.9%) patients, compared with 0 (0%), 21 (67.7%), and 10 (32.3%) patients, respectively, prior to initiation of venetoclax. For the 31 patients who reached the initial efficacy assessment at 3 mos after starting zanubrutinib, the overall response rate was 96.8% (30/31); one patient reported PD after having an initial partial response while on combination therapy. Conclusion: Preliminary safety data with the 9.7-mo median follow-up suggest that zanubrutinib + venetoclax was generally well tolerated in this high-risk population, with no new safety signals identified and no TLS reported. Enrollment is ongoing; updated safety, efficacy, and biomarker data will be presented. Figure 1 Figure 1. Disclosures Tedeschi: AbbVie: Honoraria, Other: Advisory Board and Travel, Accommodations, Expenses, Speakers Bureau; Janssen: Honoraria, Other: Advisory Board and Travel, Accommodations, Expenses, Speakers Bureau; BeiGene: Honoraria, Other: Advisory Board, Speakers Bureau; AstraZeneca: Honoraria, Other: Advisory Board, Speakers Bureau. Ferrant: Janssen: Other: Travel, Accommodations, Expenses; AbbVie: Honoraria, Other: Travel, Accommodations, Expenses; AstraZeneca: Honoraria. Flinn: Calithera Biosciences: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Celgene: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Triphase Research & Development Corp.: 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; Portola Pharmaceuticals: Other: All 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; Genentech: 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; Kite, a Gilead Company: Consultancy, Other: All consultancy and 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; Incyte: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; BeiGene: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Forty Seven: 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; Janssen: 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; Loxo: 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; Rhizen 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; Trillium Therapeutics: Other: All 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; Verastem: Consultancy, Other: All consultancy and 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; TG Therapeutics: 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; Nurix Therapeutics: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Gilead Sciences: 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; Forma Therapeutics: 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; IGM Biosciences: Other: All 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; Unum Therapeutics: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; MorphoSys: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; 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; Merck: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Constellation Pharmaceuticals: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Curis: 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; Iksuda Therapeutics: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; 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. Tam: Roche: Consultancy, Honoraria; Novartis: Honoraria; Pharmacyclics: Honoraria; Janssen: Consultancy, Honoraria, Research Funding; Loxo: Consultancy; AbbVie: Consultancy, Honoraria, Research Funding; BeiGene: Consultancy, Honoraria. Ghia: Acerta/AstraZeneca: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria, Research Funding; ArQule/MSD: Consultancy, Honoraria; Celgene/Juno/BMS: Consultancy, Honoraria; BeiGene: Consultancy, Honoraria; Gilead: Consultancy, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Roche: Consultancy, Honoraria; Sunesis: Research Funding; AstraZeneca: Consultancy, Honoraria, Research Funding. Robak: Biogen, Abbvie, Octapharma, Janssen: Honoraria, Other: Advisory board; AstraZeneca, Abbvie, Janssen, Octapharma, Gilead,Oncopeptides AB, Pharmacyclics, Pfizer, GlaxoSmithKline, Biogen: Research Funding; Medical University of Lodz: Current Employment. Brown: MEI Pharma: Consultancy; Bristol-Myers Squib/Juno/Celegene: Consultancy; Pfizer: Consultancy; Abbvie: Consultancy; Sun: Research Funding; Gilead: Research Funding; Rigel: Consultancy; Catapult: Consultancy; Eli Lilly and Company: Consultancy; Genentech/Roche: Consultancy; Novartis: Consultancy; Invectys: Other: Data Safety Monitoring Committee Service; Beigene: Consultancy; Nextcea: Consultancy; Morphosys AG: Consultancy; TG Therapeutics: Research Funding; Acerta/Astra-Zeneca: Consultancy; Janssen: Consultancy; SecuraBio: Research Funding; Loxo/Lilly: Research Funding. Ramakrishnan: BeiGene: Current Employment, Current equity holder in publicly-traded company, Divested equity in a private or publicly-traded company in the past 24 months, Other: Travel, Accommodations, Expenses. Tian: AbbVie: Ended employment in the past 24 months; BeiGene: Current Employment. Kuwahara: BeiGene: Current Employment, Current equity holder in publicly-traded company, Divested equity in a private or publicly-traded company in the past 24 months. Paik: BeiGene USA, Inc.: Current Employment, Current equity holder in publicly-traded company. Cohen: BeiGene: Current Employment, Current equity holder in publicly-traded company, Other: Travel, Accommodations, Expenses. Huang: BeiGene: Current Employment, Current equity holder in publicly-traded company, Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company, Divested equity in a private or publicly-traded company in the past 24 months, Other: Travel, Accommodations, Expenses; Protara Therapeutics: Current holder of individual stocks in a privately-held company, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company). Hillmen: BeiGene: Honoraria; Janssen: Honoraria, Other: Travel, Accommodations, Expenses, Research Funding; AbbVie: Honoraria, Other: Travel, Accommodations, Expenses, Research Funding; Pharmacyclics: Honoraria, Research Funding; Roche: Research Funding; Gilead: Research Funding; AstraZeneca: Honoraria; SOBI: Honoraria. OffLabel Disclosure: Zanubrutinib is an investigational agent and has not been approved for TN del(17p) CLL/SLL in the US

Background: Patients (pts) with CLL/SLL whose tumor exhibits the deletion of chromosome 17p13.1 [del(17p)] have an unfavorable prognosis and respond poorly to standard chemoimmunotherapy. Zanubrutinib (BGB-3111) is an investigational, next-generation Bruton tyrosine kinase (BTK) inhibitor. In the ASPEN study of pts with Waldenström macroglobulinemia, zanubrutinib was associated with important safety advantages compared to ibrutinib, especially regarding cardiovascular toxicity (Blood; in press). The initial results from Arm C of the SEQUOIA (BGB-3111-304) trial of zanubrutinib in a large cohort of TN CLL/SLL pts with del(17p) were recently presented with a median follow-up of 10 months (Blood 2019;134:851). Presented here is an updated analysis for safety and efficacy in this cohort. Methods : The SEQUOIA trial (NCT03336333) is an open-label, global, multicenter, phase 3 study that includes a nonrandomized cohort (Arm C) of TN pts with del(17p) CLL/SLL treated with zanubrutinib (160 mg twice daily). Adult pts with CLL/SLL who met International Workshop on CLL (iwCLL) criteria for treatment (Blood 2008;111:5446) were eligible if they were aged ≥65 y or unsuitable for treatment with fludarabine, cyclophosphamide, and rituximab. Use of long-term anticoagulation was permitted. Central verification of del(17p) by fluorescence in situ hybridization with a minimum of 7% aberrant nuclei present was required for entry into Arm C. Response was evaluated by investigator for CLL per modified iwCLL criteria (Blood 2008;112:5259; J Clin Oncol. 2012;30:2820) and for SLL per Lugano criteria (J Clin Oncol. 2014;32:3059). Results : As of 15 Apr 2020 (data cutoff), median follow-up was 18.2 mo (range, 5.0-26.3) for the 109 pts enrolled; 97 pts (89.0%) remained on treatment with zanubrutinib. The best overall response rate (ORR) was 94.5% (3.7% complete response [CR] or CR with incomplete bone marrow recovery, 87.2% partial response [PR], 3.7% PR with lymphocytosis, 4.6% stable disease, 0.9% progressive disease). Five pts (4.6%) met clinical CR criteria but did not undergo bone marrow biopsy. Median progression-free survival (PFS), duration of response (DoR), and overall survival (OS) were not reached. Estimated 18-mo PFS (Figure), 18-mo DoR, and 18-mo OS were 88.6% (95% CI, 79.0-94.0), 84.0% (95% CI, 67.5-92.6), and 95.1% (95% CI, 88.4-97.9), respectively. Investigator-reported transformation occurred in 5 pts (4.6%), of whom 4 had histologic confirmation. Median time to transformation was 13.6 mo (time to transformation for each pt: 3.9, 7.0, 13.6, 13.8, and 15.7 mo). In an exploratory analysis, 37.2% and 26.7% of pts with evaluable karyotypes had at least 3 or 5 distinct karyotypic abnormalities, respectively; no differences in ORR or PFS were observed between pts with or without complex karyotype. With extended follow-up, adverse events (AEs) reported in ≥10% of treated pts included contusion (20.2%), upper respiratory tract infection (19.3%), neutropenia/neutrophil count decreased (17.4%), diarrhea (16.5%), nausea (14.7%), constipation (13.8%), rash (13.8%), back pain (12.8%), cough (11.9%), arthralgia (11.0%), and fatigue (10.1%). Grade ≥3 AEs occurring in &gt;2% of pts included neutropenia/neutrophil count decreased (12.9%) and pneumonia (3.7%). AEs of interest (pooled terms) included infections (64.2%), bleeding (47.7%; 5.5% grade ≥3 or serious), headache (8.3%), hypertension (8.3%), and myalgia (4.6%). Skin tumors were reported in 9.2%, and non-skin second malignancies were reported in 4.6% of pts. Three pts (2.8%) reported an AE of atrial fibrillation or flutter of which 2 events occurred in the setting of sepsis. Four pts (3.7%) discontinued zanubrutinib due to AEs (including pneumonia, sepsis secondary to Pseudomonas, melanoma, and acute kidney injury [in the context of disease progression]), of which 2 pts have died. Three additional pts died, 2 due to disease progression and 1 from sepsis after progression. No sudden or unknown deaths were reported. Conclusions : Extended follow-up of zanubrutinib monotherapy in TN CLL/SLL pts with del(17p) showed the durability of responses in this high-risk cohort, with an estimated 18-mo PFS of 88.6% and estimated 18-mo OS of 95.1%. Zanubrutinib was generally well tolerated, with low rates of discontinuation due to AEs. These data support the potential utility of zanubrutinib in the frontline management of pts with high-risk disease. Disclosures Brown: TG Therapeutics: Consultancy; Sunesis: Consultancy; MEI Pharma: Consultancy; Nextcea: Consultancy; Novartis: Consultancy; Octapharma: Consultancy; Pfizer: Consultancy; Rigel Pharmaceuticals: Consultancy; Verastem: Consultancy, Research Funding; Kite: Consultancy; Acerta: Consultancy; Genentech: Consultancy; Pharmacyclics: Consultancy; Morphosys: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other; Sun: Research Funding; Loxo: Consultancy, Research Funding; Dynamo Therapeutics: Consultancy; Catapult: Consultancy; BeiGene: Consultancy; Gilead: Consultancy, Research Funding; Invectys: Membership on an entity's Board of Directors or advisory committees, Other: DSMC; Eli Lilly and Company: Consultancy; Astra-Zeneca: Consultancy; Janssen: Honoraria; AbbVie: Consultancy; Juno/Celgene: Consultancy. Robak:Bristol Meyers Squibb: Research Funding; Sandoz: Consultancy, Honoraria; Pfizer: Research Funding; Momenta: Consultancy; UCB: Honoraria, Research Funding; AstraZeneca: Honoraria, Research Funding; Octapharma: Honoraria; BioGene: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding; Roche: Consultancy, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding; Acerta: Research Funding; GSK: Research Funding; Medical University of Lodz: Current Employment; Morphosys: Research Funding; AbbVie: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding; Takeda: Consultancy; UTX-TGR: Research Funding; Pharmacyclics LLC, an AbbVie Company: Honoraria, Research Funding. Ghia:Novartis: Research Funding; ArQule: Consultancy, Honoraria; Acerta/AstraZeneca: Consultancy, Honoraria; 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; Adaptive, Dynamo: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding; Gilead: Consultancy, Honoraria, Research Funding. Kahl:ADC Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech: Consultancy; Pharmacyclics LLC: Consultancy; Roche Laboratories Inc: Consultancy; Celgene Corporation: Consultancy; AbbVie: Consultancy; AstraZeneca Pharmaceuticals LP: Consultancy, Membership on an entity's Board of Directors or advisory committees; BeiGene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Acerta: Consultancy, Research Funding. Walker:Alfred health: Current Employment; Peninsula Health: Current Employment; Roche: Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company). Janowski:Celgene: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Consultancy. Chan:Amgen: Other: TRAVEL, ACCOMODATIONS, EXPENSES (paid by any for-profit health care company); Janssen: Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding, Speakers Bureau; AbbVie: Membership on an entity's Board of Directors or advisory committees; Roche: Other: TRAVEL, ACCOMODATIONS, EXPENSES (paid by any for-profit health care company); Celgene: Other: TRAVEL, ACCOMODATIONS, EXPENSES (paid by any for-profit health care company). Shadman:AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Sound Biologics: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Cellectar: Consultancy, Membership on an entity's Board of Directors or advisory committees; Atara Biotherapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees; ADC Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees; Verastem: Consultancy, Membership on an entity's Board of Directors or advisory committees; Sunesis: Research Funding; AstraZeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol Meyers Squibb: Consultancy, Membership on an entity's Board of Directors or advisory committees; Mustang Bio: Research Funding; BeiGene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Research Funding; Acerta Pharma: Ended employment in the past 24 months; Gilead: Research Funding; MophoSys: Consultancy, Membership on an entity's Board of Directors or advisory committees; Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; TG therapeutics: Research Funding. Laurenti: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; Gilead: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Opat:F. Hoffmann-La Roche Ltd: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AstraZenca: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BeiGene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; CSL Behring: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Epizyme: Research Funding. Ciepluch:Copernicus Wojewodzkie centrum Onkologii: Current Employment. Verner:Cilag Pty Ltd: Research Funding; Concord Repatriation General Hospital: Current Employment; Janssen: Research Funding. Šimkovič:University Hospital Hradec Kralove: Current Employment; Acerta Pharma: Consultancy; Gilead Sciences: Consultancy, Other: Travel, Accommodations, Expenses; Janssen-Cilag: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Speakers Bureau; AbbVie: 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), Speakers Bureau. Österborg:Sanofi: Consultancy; Kancera: Current equity holder in publicly-traded company, Research Funding; BeiGene: Research Funding; Karolinska Univeristy Hospital, Stockholm, Sweden: Current Employment. Trněný:Takeda: Consultancy, Honoraria, Other: TRAVEL, ACCOMODATIONS, EXPENSES (paid by any for-profit health care company); Amgen: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); 1st Faculty of Medicine, Charles University, General Hospital in Prague: Current Employment; MorphoSys: Consultancy, Honoraria; Incyte: Consultancy, Honoraria; Roche: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding; Bristol Meyers Squibb: Consultancy, Honoraria, Other: TRAVEL, ACCOMODATIONS, EXPENSES (paid by any for-profit health care company); Janssen: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Gilead Sciences: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Celgene: Consultancy. Tedeschi:BeiGene: Consultancy, Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen spa: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sunesis: Consultancy; Department of Hematology Niguarda Hospital Milano: Current Employment. Blombery:Invivoscribe: Honoraria; Janssen: Honoraria; Amgen: Consultancy; Novartis: Consultancy. Paik:BeiGene: Current Employment, Current equity holder in publicly-traded company. Yin:BeiGene: Current Employment, Current equity holder in publicly-traded company; Arcus Biosciences: Current equity holder in publicly-traded company; Cornell University: Patents & Royalties: A genetically modified mouse model, licensed to pharmaceutical companies. Feng:BeiGene: Current Employment, Current equity holder in publicly-traded company. Ramakrishnan:BeiGene: Current Employment, Current equity holder in publicly-traded company. Huang:BeiGene: Current Employment, Current equity holder in publicly-traded company, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company). Hillmen:F. Hoffmann-La Roche: Honoraria, Research Funding; Astra Zeneca: Honoraria; Gilead: Research Funding; Janssen: 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 Funding, Speakers Bureau; AbbVie: 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 Funding, Speakers Bureau; Pharmacyclics: Research Funding. Tam:BeiGene: Honoraria; AbbVie: Honoraria, Research Funding; Janssen: Honoraria, Research Funding. OffLabel Disclosure: Zanubrutinib has not been approved for TN CLL/SLL with del(17p) in the US

Abstract Background: Zanubrutinib (zanu) is a selective next-generation Bruton tyrosine kinase (BTK) inhibitor designed to have high specificity for BTK and minimize off-target effects (Guo, J Med Chem 2019;62:7923-40). In a phase 1/2 study, zanu demonstrated complete and sustained BTK occupancy in both peripheral blood mononuclear cells and lymph nodes and was associated with durable clinical responses in patients (pts) with CLL/SLL (Tam, Blood 2019;134:851-9). Here, we present interim results for the phase 3 SEQUOIA (BGB-3111-304; NCT03336333) trial, which evaluated the efficacy and safety of zanu vs BR in TN pts with CLL/SLL. Methods: SEQUOIA is an open-label, global phase 3 study that randomized TN pts with CLL/SLL without del(17p) to receive zanu 160 mg twice daily until progressive disease or unacceptable toxicity, or bendamustine 90 mg/m 2 on day 1 and 2 and rituximab 375 mg/m 2 in cycle 1, 500 mg/m 2 in cycles 2-6 for 6 × 28-day cycles. Adult pts with CLL/SLL who met International Workshop on CLL (iwCLL) criteria for treatment (Hallek, Blood 2008;111:5446-56) were eligible if they were either ≥65 y or unsuitable for treatment with fludarabine, cyclophosphamide and rituximab. Central verification of del(17p) status by fluorescence in situ hybridization was required. Pts were stratified by age (&lt;65 y vs ≥65 y), Binet Stage (C vs A/B), IGHV mutational status, and geographic region. The primary endpoint was independent review committee (IRC)-assessed progression-free survival (PFS) for zanu vs BR. Secondary endpoints included PFS by investigator assessment (INV), overall response rate (ORR; by IRC and INV), overall survival (OS), and safety. Responses for CLL and SLL were assessed per modified iwCLL criteria (Hallek, Blood 2008;111:5446-56; J Clin Oncol 2012;30:2820-2) and Lugano criteria (Cheson, J Clin Oncol 2014;32:3059-68), respectively. Adverse events (AEs) were recorded until disease progression to support safety evaluation over an equivalent time period. Results: From 31 Oct 2017-22 Jul 2019, 479 pts without del(17p) were randomized to zanu (n=241) and BR (n=238). Treatment groups were well balanced for demographic and disease characteristics (zanu vs BR): median age, 70.0 y vs 70.0 y; unmutated IGHV, 53.4% (125/234) vs 52.4% (121/231); and del(11q), 17.8% vs 19.3%. At median follow-up (26.2 mo), PFS by IRC was significantly prolonged with zanu vs BR (HR 0.42, 95% CI 0.28-0.63, 1-sided and 2-sided P&lt;0.0001; Figure); similar results were observed by INV (HR 0.42, 95% CI 0.27-0.66, 1-sided P&lt;0.0001, 2-sided P=0.0001). Treatment benefit for zanu was observed across subgroups for age, Binet stage, bulky disease, and del(11q) status. Treatment benefit was also observed for pts with unmutated IGHV (HR 0.24, 1-sided and 2-sided P&lt;0.0001), but not for mutated IGHV (HR 0.67, 1-sided P=0.0929). Estimated 24-mo PFS (IRC) for zanu vs BR was 85.5% (95% CI 80.1%- 89.6%) vs 69.5% (95% CI 62.4%-75.5%). ORR by IRC for zanu vs BR was 94.6% (95% CI 91.0%-97.1%) vs 85.3% (95% CI 80.1%-89.5%). Complete response rate was 6.6% with zanu and 15.1% with BR. ORR by INV for zanu vs BR was 97.5% (95% CI 94.7%-99.1%) vs 88.7% (95% CI 83.9%-92.4%) Estimated 24-mo OS for zanu vs BR was 94.3% (95% CI 90.4%-96.7%) and 94.6% (95% CI 90.6%-96.9%). The most common AEs are shown in the Table. AEs of interest occurring during the full reporting period (pooled terms, zanu vs BR) included atrial fibrillation (any grade [gr]: 3.3% vs 2.6%), bleeding (any gr/gr≥3: 45.0%/3.8% vs 11.0%/1.8%), hypertension (any gr: 14.2% vs 10.6%), infection (any gr/gr≥3: 62.1%/16.3% vs 55.9%/18.9%), and neutropenia (any gr/gr≥3: 15.8%/11.7% vs 56.8%/51.1%). Treatment discontinuation due to AEs occurred in 20 pts (8.3%) receiving zanu vs 31 pts (13.7%) receiving BR; 85.5% of pts receiving zanu remain on treatment. AEs leading to death occurred in 11 pts (4.6%) receiving zanu vs 12 pts (5.3%) receiving BR. No sudden deaths were reported. Conclusions: In this global registrational trial, zanu demonstrated statistically significant improvement in PFS compared to BR as assessed by IRC. Superiority was also observed in PFS by INV as well as ORR by both IRC and INV. Zanu was generally well tolerated, with low rates of atrial fibrillation consistent with those observed in the phase 3 ASPEN (Tam, Blood 2020;136:2038-2050) and ALPINE studies (Hillmen, EHA 2021 #LB1900). These data support the potential utility of zanu in the frontline management of pts with TN CLL/SLL. Figure 1 Figure 1. Disclosures Tam: AbbVie: Consultancy, Honoraria, Research Funding; BeiGene: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Research Funding; Pharmacyclics: Honoraria; Novartis: Honoraria; Loxo: Consultancy; Roche: Consultancy, Honoraria. Giannopoulos: Polish Myeloma Consortium, Next Generation Hematology Association: Membership on an entity's Board of Directors or advisory committees; Sandoz: Consultancy, Honoraria; Pfizer: Honoraria; Teva: Honoraria; TG Therapeutics: Research Funding; Abbvie: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Astra-Zeneca: Consultancy, Honoraria, Research Funding; Bei-Gene: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Sanofi-Genzyme: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; Roche: Consultancy, Honoraria, Research Funding; Karyopharm: Consultancy, Honoraria, Research Funding; GSK: Consultancy, Honoraria, Research Funding; Gilead: Honoraria, Research Funding. Jurczak: Astra Zeneca: Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: Research Funding; Bayer: Research Funding; BeiGene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celtrion: Research Funding; Celgene: Research Funding; Debbiopharm: Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Loxo Oncology: Membership on an entity's Board of Directors or advisory committees; Sandoz: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding; Epizyme: Research Funding; Incyte: Research Funding; Merck: Research Funding; Takeda: Research Funding; TG Therapeutics: Research Funding. Šimkovič: Janssen, Gilead, Roche, AstraZeneca, and AbbVie: Other: consultancy fees, advisory board participation fees, travel grants, and honoraria; University Hospital Hradec Kralove: Current Employment; AbbVie: Consultancy, Current equity holder in publicly-traded company, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses; AstraZeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen-Cilag: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses; Merck: Current equity holder in publicly-traded company; Eli Lilly: Current equity holder in publicly-traded company; J&J: Current equity holder in publicly-traded company; Gilead: Other: Travel, Accommodations, Expenses. Shadman: Abbvie, Genentech, AstraZeneca, Sound Biologics, Pharmacyclics, Beigene, Bristol Myers Squibb, Morphosys, TG Therapeutics, Innate Pharma, Kite Pharma, Adaptive Biotechnologies, Epizyme, Eli Lilly, Adaptimmune , Mustang Bio and Atara Biotherapeutics: Consultancy; Mustang Bio, Celgene, Bristol Myers Squibb, Pharmacyclics, Gilead, Genentech, Abbvie, TG Therapeutics, Beigene, AstraZeneca, Sunesis, Atara Biotherapeutics, GenMab: Research Funding. Österborg: BeiGene: Research Funding; Gilead: Research Funding. Laurenti: Janssen: Consultancy, Honoraria; AstraZeneca: Consultancy, Honoraria; Gilead: Honoraria; Roche: Honoraria, Research Funding; AbbVie: Consultancy, Honoraria, Research Funding; BeiGene: Honoraria. Walker: BeiGene: Consultancy; Acerta: Consultancy. Opat: Abbvie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Astra Zeneca: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BeiGene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics: Research Funding; Sandoz: Research Funding; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; CSL Behring: Honoraria, Membership on an entity's Board of Directors or advisory committees; Merck: Honoraria, Membership on an entity's Board of Directors or advisory committees; Monash Health: Current Employment. Chan: AbbVie: Membership on an entity's Board of Directors or advisory committees; Eusa: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; GSK: Membership on an entity's Board of Directors or advisory committees; Amgen: Other: Travel, Accommodations, Expenses; Celgene: Other: Travel, Accommodations, Expenses; Roche: Speakers Bureau. Ciepluch: Copernicus Wojewodzkie Centrum Onkologii: Current Employment. Greil: Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses, Research Funding; AstraZeneca: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses, Research Funding; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses, Research Funding; Sandoz: Honoraria, Research Funding; Amgen: Honoraria, Other: Travel, Accommodations, Expenses, Research Funding; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses, Research Funding; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses, Research Funding; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses, Research Funding; Merck: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Sankyo: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses, Research Funding; Daiichi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses, Research Funding; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses; MSD: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses, Research Funding; Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses, Research Funding. Trněný: AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses; Portola: Honoraria, Membership on an entity's Board of Directors or advisory committees; MorphoSys: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses; 1st Faculty of Medicine, Charles University, General Hospital in Prague: Current Employment; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses; Celgene: Consultancy; Amgen: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses; Gilead Sciences: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses; Incyte: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses; AstraZeneca: Honoraria. Brander: Verastem: Consultancy; ArQule: Research Funding; Genentech: Consultancy, Research Funding; TG Therapeutics: Consultancy, Research Funding; Juno Therapeutics/Celgene/Bristol Myers Squibb: Research Funding; MEI Pharma: Research Funding; Novartis: Research Funding; LOXO: Research Funding; Ascentage: Research Funding; AstraZeneca: Research Funding; BeiGene: Research Funding; DTRM: Research Funding; AbbVie: Consultancy, Other: informCLL registry steering committee, Research Funding; Pfizer: Consultancy, Other: Biosimilars outcomes research panel; NCCN: Other: panel member; ArQule/Merck: Consultancy; Pharmacyclics LLC, an AbbVie Company: Consultancy, Research Funding. Flinn: Loxo: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Juno Therapeutics: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Nurix Therapeutics: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; IGM Biosciences: 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; Forty Seven: 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; Roche: 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; Novartis: Consultancy, Other: All consultancy and 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; Great Point Partners: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Genentech: 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; AbbVie: Consultancy, Other: All Consultancy and Research Funding payments made to Sarah Cannon Research Institute, Research Funding; Gilead Sciences: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Celgene: 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; Infinity Pharmaceuticals: 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; Kite, a Gilead Company: Consultancy, Other: All consultancy and 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; Merck: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; BeiGene: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Calithera Biosciences: 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; TG Therapeutics: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Iksuda Therapeutics: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Constellation Pharmaceuticals: 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; ArQule: 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; 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; Acerta Pharma: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Yingli Pharmaceuticals: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Trillium Therapeutics: 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; Rhizen Pharmaceuticals: 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; Pfizer: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Triphase Research & Development Corp.: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Century Therapeutics: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Hutchison MediPharma: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Vincerx Pharma: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Sarah Cannon Research Institute: Current Employment; Servier Pharmaceuticals: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Yingli Pharmaceuticals: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Seagen: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Servier Pharmaceuticals: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Unum Therapeutics: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute, Research Funding; Johnson & Johnson: Current holder of individual stocks in a privately-held company; Seattle Genetics: Research Funding. Verner: Janssen-Cilag Pty Ltd: Research Funding. Brown: Janssen: Consultancy; MEI Pharma: Consultancy; Rigel: Consultancy; Bristol-Myers Squib/Juno/Celegene: Consultancy; Novartis: Consultancy; Invectys: Other: Data Safety Monitoring Committee Service; TG Therapeutics: Research Funding; Abbvie: Consultancy; Acerta/Astra-Zeneca: Consultancy; Beigene: Consultancy; Catapult: Consultancy; Loxo/Lilly: Research Funding; Sun: Research Funding; Nextcea: Consultancy; Gilead: Research Funding; SecuraBio: Research Funding; Eli Lilly and Company: Consultancy; Genentech/Roche: Consultancy; Pfizer: Consultancy; Morphosys AG: Consultancy. Kahl: AbbVie, Adaptive, ADCT, AstraZeneca, Bayer, BeiGene, Bristol-Myers Squibb, Celgene, Genentech, Incyte, Janssen, Karyopharm, Kite, MEI, Pharmacyclics, Roche, TG Therapeutics, and Teva: Consultancy; AbbVie, Acerta, ADCT, AstraZeneca, BeiGene, Genentech: Research Funding. Ghia: Sunesis: Research Funding; Roche: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Research Funding; Gilead: Consultancy, Research Funding; Celgene/Juno/BMS: Consultancy, Honoraria; BeiGene: Consultancy, Honoraria; ArQule/MSD: Consultancy, Honoraria; AstraZeneca: Consultancy, Honoraria, Research Funding; Acerta/AstraZeneca: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria, Research Funding. Tian: BeiGene: Current Employment; AbbVie: Ended employment in the past 24 months. Marimpietri: BeiGene USA: Current Employment, Current equity holder in publicly-traded company, Divested equity in a private or publicly-traded company in the past 24 months. Paik: BeiGene USA, Inc.: Current Employment, Current equity holder in publicly-traded company. Cohen: BeiGene: Current Employment, Current equity holder in publicly-traded company, Other: Travel, Accommodations, Expenses. Huang: BeiGene: Current Employment, Current equity holder in publicly-traded company, Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company, Divested equity in a private or publicly-traded company in the past 24 months, Other: Travel, Accommodations, Expenses; Protara Therapeutics: Current holder of individual stocks in a privately-held company, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company). Robak: Biogen, Abbvie, Octapharma, Janssen: Honoraria, Other: Advisory board; AstraZeneca, Abbvie, Janssen, Octapharma, Gilead,Oncopeptides AB, Pharmacyclics, Pfizer, GlaxoSmithKline, Biogen: Research Funding; Medical University of Lodz: Current Employment. Hillmen: Pharmacyclics: Honoraria, Research Funding; Roche: Research Funding; Gilead: Research Funding; AstraZeneca: Honoraria; SOBI: Honoraria; BeiGene: Honoraria; AbbVie: Honoraria, Other: Travel, Accommodations, Expenses, Research Funding; Janssen: Honoraria, Other: Travel, Accommodations, Expenses, Research Funding. OffLabel Disclosure: Zanubrutinib is an investigational agent and has not been approved for TN CLL/SLL without del(17p) in the US

This study aimed to compare the agreement of total distance (TD), high-speed running (HSR) distance, and sprint distance during 16 official soccer matches between a global navigation satellite system (GNSS) and an optical-tracking system. A total of 24 male soccer players, who are actively participating in the Polish Ekstraklasa professional league, were included in the analysis conducted during official competitions. The players were systematically monitored using Catapult GNSS (10-Hz, S7) and Tracab optical-tracking system (25-Hz, ChyronHego). TD, HSR distance, sprint distance, HSR count (HSRC), and sprint count (SC) were collected. The data were extracted in 5-min epochs. A statistical approach was employed to visually examine the relationship between the systems based on the same measure. Additionally, R2 was utilized as a metric to quantify the proportion of variance accounted for by a variable. To assess agreement, Bland–Altman plots were visually inspected. The data from both systems were compared using the estimates derived from the intraclass correlation (ICC) test and Pearson product–moment correlation. Finally, a paired t-test was employed to compare the measurements obtained from both systems. The interaction between Catapult and Tracab systems revealed an R2 of 0.717 for TD, 0.512 for HSR distance, 0.647 for sprint distance, 0.349 for HSRC, and 0.261 for SC. The ICC values for absolute agreement between the systems were excellent for TD (ICC = 0.974) and good for HSR distance (ICC = 0.766), sprint distance (ICC = 0.822). The ICC values were not good for HSRCs (ICC = 0.659) and SCs (ICC = 0.640). t-test revealed significant differences between Catapult and Tracab for TD ( p < 0.001; d = −0.084), HSR distance ( p < 0.001; d = −0.481), sprint distance ( p < 0.001; d = −0.513), HSRC ( p < 0.001; d = −0.558), and SC ( p < 0.001; d = −0.334). Although both systems present acceptable agreement in TD, they may not be perfectly interchangeable, which sports scientists and coaches must consider when using them.

Performance tracking devices in the form of wrist-worn watches are common in rowing; however, the accuracy of relevant output variables (i.e. stroke rate [SR] and velocity) during on-water training is unknown. To assess the quality of wrist-watch data output, 16 rowing athletes recorded 118 on-water rowing sessions using a Garmin Forerunner 735XT, which was compared to a Catapult Optimeye R4 tracking device. Garmin recording function was set to ‘Every Second’ ( N = 68 sessions) or ‘Smart’ ( N = 50 sessions). Catapult velocity was calculated as the average velocity per stroke, while a 15 s velocity moving average was determined for Garmin data. Catapult and Garmin were filtered for training-specific data (SR = 14–50 strokes per minute [spm]; velocity = 2.1–7.0 m/s−1). Efficacy and reliability of the Garmin was assessed via the difference between devices (% error), intra-class correlation coefficient (ICC ± 95% confidence interval (CI)) and coefficient of variation (CV%). Error in 15 s smoothed velocity was 3.8% (‘Every Second’) and 8.2% (‘Smart’). Both recording functions demonstrated ‘good’ reliability (ICC = 0.75–0.9, CV < 10%) for SR and velocity; the exception was SR using ‘Smart’ recording. Our data suggests that when using the ‘Every Second’ recording function, data is filtered and velocity is smoothed over 15 s, the Garmin device can be reliable for SR and velocity measurement within 1 spm and <0.20 m/s−1 respectively.

Abstract Funding Acknowledgements Type of funding sources: Private grant(s) and/or Sponsorship. Main funding source(s): AK has been funded by the Egyptian cultural centre and educational bureau of the Egyptian embassy in London and the Ministry of higher education in Egypt. SEP acknowledges support from the “SmartHeart” EPSRC programme grant (www.nihr.ac.uk; EP/P001009/1) and the London Medical Imaging and AI Centre for Value-Based Healthcare. This new centre is one of the UK Centres supported by a £50m investment from the Data to Early Diagnosis and Precision Medicine strand of the government’s Industrial Strategy Challenge Fund, managed and delivered by UK Research and Innovation (UKRI). SEP acknowledges support from the CAP-AI programme, London’s first AI enabling programme focused on stimulating growth in the capital’s AI Sector. CAP-AI is led by Capital Enterprise in partnership with Barts Health NHS Trust and Digital Catapult and is funded by the European Regional Development Fund and Barts Charity. SEP also acts as a paid consultant to Circle Cardiovascular Imaging Inc., Calgary, Canada and Servier onbehalf Barts Heart Centre, St Bartholomew’s Hospital, Barts Health NHS Trust, West Smithfield, London, UK Background Manual contouring of cardiovascular magnetic resonance (CMR) cine images remains common practice and the reference standard for left ventricular (LV) volumes and mass evaluation. However, it is time-consuming and machine learning (ML) may significantly reduce the time required for contouring. Accurate LV contours are the basis for reliable LV strain analysis using tissue tracking. Purpose To assess the impact of a ML contouring tool alone versus expert adjusted contours on LV strain. Methods We retrospectively selected 402 CMR studies with diagnoses of myocardial infarction (n = 108), myocarditis (n = 130) and healthy controls (n = 164) from the Barts BioResource between January 2015 to June 2018. CMR examinations were obtained using 1.5T and 3T scanners (Siemens Healthineers, Germany). We excluded 32 cases due to phase inconsistency between short (SAX) and long axes (LAX) cine images or suboptimal cine image quality. For the remaining 370 cases, steady state free precession cine images for LAX and SAX were analysed by the ML contouring tool (using CVI42 research prototype software 5.11). Manual expert adjustment for the contours was done for each case if considered suboptimal for strain analysis in the reference end-diastolic phase. Strain results from ML and expert adjusted ML methods were compared for strain agreement. Times taken by these methods were recorded and compared against the time taken for standard manual contouring. Results SAX and LAX derived strains by ML and expert adjusted ML methods showed good agreement by Bland-Altman analysis (Figure 1) with excellent coefficient of concordance using Kendall W which is 0.98 for global SAX, radial and circumferential strains (mean difference(MD) = -1.7% (lower and upper limits of agreement (UL,LL) -6.6,3.2), MD = 0.5% (-1.0,2.1)) and is 0.95 for global LAX derived strain (radial and longitudinal, MD = 0.7% (UL,LL -8.7 ,7.4),MD= 0.2% (-1.9,2.5), respectively). Time taken for adjustment of ML contours was significantly shorter than manual contouring (1.35 minutes vs 8.0 minutes, around 590% time saving in ML adjusted method). Conclusions ML contouring compared to expert manual adjustment has a clinically reasonable agreement when used for measuring LV strain. Also, using the ML tool with expert adjustment shows significant time saving for analysis and reporting time compared to entirely manual analysis, favouring its application in routine clinical practice. Abstract Figure.

What creative techniques of resistance are available to a female filmmaker when she is the victim of a violent event and filmed at her most vulnerable? This article uses an autoethnographic lens to discuss my experience of a serious car crash my family and I were inadvertently involved in due to police negligence and a criminal act. Employing Creative Analytical Practice (CAP) ethnography, a reflexive form of research which recognises that the creative process, producer and product are “deeply intertwined” (Richardson, “Writing: A Method” 930), I investigate how the crash’s violent affects crippled my agency, manifested in my creative praxis and catalysed my identification of latent forms of institutionalised violence in film culture, its discourse and pedagogy that also contributed to my inertia. The article maps my process of writing a feature length screenplay during the aftermath of the crash as I set out to articulate my story of survival and resistance. Using this narrative inquiry, in which we can “investigate how we construct the world, ourselves, and others, and how standard objectifying practices...unnecessarily limit us” (Richardson, “Writing: A Method” 924), I outline how I attempted to disrupt the entrenched power structures that exist in dominant narratives of violence in film and challenge my subjugated positioning as a woman within this canon. I describe my engagement with the deconstructionist practices of writing the body and militant feminist cinema, which suggest subversive opportunities for women’s self-determination by encouraging us to embrace our exiled positioning in dominant discourse through creative experimentation, and identify some of the possibilities and limitations of this for female agency. Drawing on CAP ethnography, existentialism, film feminism, and narrative reframing, I assert that these reconstructive practices are more effective for the creative enfranchisement of women by not relegating us to the periphery of social systems and cultural forms. Instead, they enable us to speak back to violent structures in a language that has greater social access, context and impact.My strong desire to tell screen stories lies in my belief that storytelling is a crucial evolutionary mechanism of resilience. Narratives do not simply represent the social world but also have the ability to change it by enabling us to “try to figure out how to live our lives meaningfully” (Ellis 760). This conviction has been directly influenced by my personal story of trauma and survival when myself, my siblings, and our respective life partners became involved in a major car crash. Two police officers attending to a drunken brawl in an inner city park had, in their haste, left the keys in the ignition of their vehicle. We were travelling across a major intersection when the police car, which had subsequently been stolen by a man involved in the brawl – a man who was wanted on parole, had a blood alcohol level three times over the legal limit, and was driving at speeds exceeding 110kms per hour - ran a red light and crossed our path, causing us to crash into his vehicle. From the impact, the small four-wheel drive we were travelling in was catapulted metres into the air, rolling numerous times before smashing head on into oncoming traffic. My heavily pregnant sister was driving our vehicle.The incident attracted national media attention and our story became a sensationalist spectacle. Each news station reported erroneous and conflicting information, one stating that my sister had lost her unborn daughter, another even going so far as to claim my sister had died in the crash. This tabloidised, ‘if it bleeds, it leads’, culture of journalism, along with new digital technologies, encourages and facilitates the normalisation of violent acts, often inflicted on women. Moreover, in their pursuit of high-rating stories, news bodies motivate dehumanising acts of citizen journalism that see witnesses often inspired to film, rather than assist, victims involved in a violent event. Through a connection with someone working for a major news station, we discovered that leading news broadcasters had bought a tape shot by a group of men who call themselves the ‘Paparazzi of Perth’. These men were some of the first on the scene and began filming us from only a few metres away while we were still trapped upside down and unconscious in our vehicle. In the recording, the men are heard laughing and celebrating our tragedy as they realise the lucrative possibilities of the shocking imagery they are capturing as witnesses pull us out of the back of the car, and my pregnant sister incredibly frees herself from the wreckage by kicking out the window.As a female filmmaker, I saw the bitter irony of this event as the camera was now turned on me and my loved ones at our most vulnerable. In her discussion of the male gaze, a culturally sanctioned form of narrational violence against women that is ubiquitous in most mainstream media, Mulvey proposes that women are generally the passive image, trapped by the physical limits of the frame in a permanent state of powerlessness as our identity is reduced to her “to-be-looked-at-ness” (40). For a long period of time, the experience of performing the role of this commodified woman of a weaponised male gaze, along with the threat of annihilation associated with our near-death experience, immobilised my spirit. I felt I belonged “more to the dead than to the living” (Herman 34). When I eventually returned to my creative praxis, I decided to use scriptwriting as both my “mode of reasoning and a mode of representation” (Richardson, Writing Strategies 21), test whether I could work through my feelings of alienation and violation and reclaim my agency. This was a complex and harrowing task because my memories “lack[ed] verbal narrative and context” (Herman 38) and were deeply rooted in my body. Cixous confirms that for women, “writing and voice...are woven together” and “spring from the deepest layers of her psyche” (Moi 112). For many months, I struggled to write. I attempted to block out this violent ordeal and censor my self. I soon learnt, however, that my body could not be silenced and was slow to forget. As I tried to write around this experience, the trauma worked itself deeper inside of me, and my physical symptoms worsened, as did the quality of my writing.In the early version of the screenplay I found myself writing a female-centred film about violence, identity and death, using the fictional narrative to express the numbness I experienced. I wrote the female protagonist with detachment as though she were an object devoid of agency. Sartre claims that we make objects of others and of ourselves in an attempt to control the uncertainty of life and the ever-changing nature of humanity (242). Making something into an object is to deprive it of life (and death); it is our attempt to keep ourselves ‘safe’. While I recognise that the car crash’s reminder of my mortality was no doubt part of the reason why I rendered myself, and the script’s female protagonist, lifeless as agentic beings, I sensed that there were subtler operations of power and control behind my self-objectification and self-censorship, which deeply concerned me. What had influenced this dea(r)th of female agency in my creative imaginings? Why did I write my female character with such a red pen? Why did I seem so compelled to ‘kill’ her? I wanted to investigate my gender construction, the complex relationship between my scriptwriting praxis, and the context within which it is produced to discover whether I could write a different future for myself, and my female characters. Kiesinger supports “contextualizing our stories within the framework of a larger picture” (108), so as to remain open to the possibility that there might not be anything ‘wrong’ with us, per se, “but rather something very wrong with the dynamics that dominate the communicative system” (109) within which we operate: in the case of my creative praxis, the oppressive structures present in the culture of film and its pedagogy.Pulling FocusWomen are supposed to be the view and when the view talks back, it is uncomfortable.— Jane Campion (Filming Desire)It is a terrible thing to see that no one has ever taught us how to develop our vision as women neither in the history of arts nor in film schools.— Marie Mandy (Filming Desire)The democratisation of today’s media landscape through new technologies, the recent rise in female-run production companies (Zemler) in Hollywood, along with the ground-breaking #MeToo and Time’s Up movements has elevated the global consciousness of gender-based violence, and has seen the screen industry seek to redress its history of gender imbalance. While it is too early to assess the impact these developments may have on women’s standing in film, today the ‘celluloid ceiling’ still operates on multiple levels of indoctrination and control through a systemic pattern of exclusion for women that upholds the “nearly seamless dialogue among men in cinema” (Lauzen, Thumbs Down 2). Female filmmakers occupy a tenuous position of influence in the mainstream industry and things are not any better on the other side of the camera (Lauzen, The Celluloid Ceiling). For the most part, Hollywood’s male gaze and penchant for sexualising and (physically or figuratively) killing female characters, which normalises violence against women and is “almost inversely proportional to the liberation of women in society” (Mandy), continues to limit women to performing as the image rather than the agent on screen.Film funding bodies and censorship boards, mostly comprised of men, remain exceptionally averse to independent female filmmakers who go against the odds to tell their stories, which often violate taboos about femininity and radically redefine female agency through the construction of the female gaze: a narrational technique of resistance that enables reel woman to govern the point of view, imagery and action of the film (Smelik 51-52). This generally sees their films unjustly ghettoised through incongruent classification or censorship, and forced into independent or underground distribution (Sexton-Finck 165-182). Not only does censorship propose the idea that female agency is abject and dangerous and needs to be restrained, it prevents access to this important cinema by women that aims to counter the male gaze and “shield us from this type of violence” (Gillain 210). This form of ideological and institutional gatekeeping is not only enforced in the film industry, it is also insidiously (re)constituted in the epistemological construction of film discourse and pedagogy, which in their design, are still largely intrinsically gendered institutions, encoded with phallocentric signification that rejects a woman’s specificity and approach to knowledge. Drawing on my mutually informative roles as a former film student and experienced screen educator, I assert that most screen curricula in Australia still uphold entrenched androcentric norms that assume the male gaze and advocate popular cinema’s didactic three-act structure, which conditions our value systems to favour masculinity and men’s worldview. This restorative storytelling approach is argued to be fatally limiting to reel women (Smith 136; Dancyger and Rush 25) as it propagates the Enlightenment notion of a universal subjectivity, based on free will and reason, which neutralises the power structures of society (and film) and repudiates the influence of social positioning on our opportunity for agency. Moreover, through its omniscient consciousness, which seeks to efface the presence of a specific narrator, the three-act method disavows this policing of female agency and absolves any specific individual of responsibility for its structural violence (Dyer 98).By pulling focus on some of these problematic mechanisms in the hostile climate of the film industry and its spaces of learning for women, I became acutely aware of the more latent forms of violence that had conditioned my scriptwriting praxis, the ambivalence I felt towards my female identity, and my consequent gagging of the female character in the screenplay.Changing Lenses How do the specific circumstances in which we write affect what we write? How does what we write affect who we become?— Laurel Richardson (Fields of Play 1)In the beginning, there is an end. Don’t be afraid: it’s your death that is dying. Then: all the beginnings.— Helene Cixous (Cixous and Jensen 41)The discoveries I made during my process of CAP ethnography saw a strong feeling of dissidence arrive inside me. I vehemently wanted to write my way out of my subjugated state and release some of the anguish that my traumatised body was carrying around. I was drawn to militant feminist cinema and the French poststructuralist approach of ‘writing the body’ (l’ecriture feminine) given these deconstructive practices “create images and ideas that have the power to inspire to revolt against oppression and exploitation” (Moi 120). Feminist cinema’s visual treatise of writing the body through its departure from androcentric codes - its unformulaic approach to structure, plot, character and narration (De Lauretis 106) - revealed to me ways in which I could use the scriptwriting process to validate my debilitating experience of physical and psychic violence, decensor my self and move towards rejoining the living. Cixous affirms that, “by writing her self, woman will return to the body which has been more than confiscated from her, which has been turned into…the ailing or dead figure” (Cixous, The Laugh of the Medusa 880). It became clear to me that the persistent themes of death that manifested in the first draft of the script were not, as I first suspected, me ‘rehearsing to die’, or wanting to kill off the woman inside me. I was in fact “not driven towards death but by death” (Homer 89), the close proximity to my mortality, acting as a limit, was calling for a strengthening of my life force, a rebirth of my agency (Bettelheim 36). Mansfield acknowledges that death “offers us a freedom outside of the repression and logic that dominate our daily practices of keeping ourselves in order, within the lines” (87).I challenged myself to write the uncomfortable, the unfamiliar, the unexplored and to allow myself to go to places in me that I had never before let speak by investigating my agency from a much more layered and critical perspective. This was both incredibly terrifying and liberating and enabled me to discard the agentic ‘corset’ I had previously worn in my creative praxis. Dancyger and Rush confirm that “one of the things that happens when we break out of the restorative three-act form is that the effaced narrator becomes increasingly visible and overt” (38). I experienced an invigorating feeling of empowerment through my appropriation of the female gaze in the screenplay which initially appeased some of the post-crash turmoil and general sense of injustice I was experiencing. However, I soon, found something toxic rising inside of me. Like the acrimonious feminist cinema I was immersed in – Raw (Ducournau), A Girl Walks Home at Night (Amirpour), Romance (Breillat), Trouble Every Day (Denis), Baise-Moi (Despentes and Thi), In My Skin (Van), Anatomy of Hell (Breillat) – the screenplay I had produced involved a female character turning the tables on men and using acts of revenge to satisfy her needs. Not only was I creating a highly dystopian world filled with explicit themes of suffering in the screenplay, I too existed in a displaced state of rage and ‘psychic nausea’ in my daily life (Baldick and Sartre). I became haunted by vivid flashbacks of the car crash as abject images, sounds and sensations played over and over in my mind and body like a horror movie on loop. I struggled to find the necessary clarity and counterbalance of stability required to successfully handle this type of experimentation.I do not wish to undermine the creative potential of deconstructive practices, such as writing the body and militant cinema, for female filmmakers. However, I believe my post-trauma sensitivity to visceral entrapment and spiritual violence magnifies some of the psychological and physiological risks involved. Deconstructive experimentation “happens much more easily in the realm of “texts” than in the world of human interaction” (hooks 22) and presents agentic limitations for women since it offers a “utopian vision of female creativity” (Moi 119) that is “devoid of reality...except in a poetic sense” (Moi 122). In jettisoning the restorative qualities of narrative film, new boundaries for women are inadvertently created through restricting us to “intellectual pleasure but rarely emotional pleasure” (Citron 51). Moreover, by reducing women’s agency to retaliation we are denied the opportunity for catharsis and transformation; something I desperately longed to experience in my injured state. Kaplan acknowledges this problem, arguing that female filmmakers need to move theoretically beyond deconstruction to reconstruction, “to manipulate the recognized, dominating discourses so as to begin to free ourselves through rather than beyond them (for what is there ‘beyond’?)” (Women and Film 141).A potent desire to regain a sense of connectedness and control pushed itself out from deep inside me. I yearned for a tonic to move myself and my female character to an active position, rather than a reactive one that merely repeats the victimising dynamic of mainstream film by appropriating a reversed (female) gaze and now makes women the violent victors (Kaplan, Feminism and Film 130). We have arrived at a point where we must destabilise the dominance-submission structure and “think about ways of transcending a polarity that has only brought us all pain” (Kaplan, Feminism and Film 135). I became determined to write a screen narrative that, while dealing with some of the harsh realities of humanity I had become exposed to, involved an existentialist movement towards catharsis and activity.ReframingWhen our stories break down or no longer serve us well, it is imperative that we examine the quality of the stories we are telling and actively reinvent our accounts in ways that permit us to live more fulfilling lives.— Christine Kiesinger (107)I’m frightened by life’s randomness, so I want to deal with it, make some sense of it by telling a film story. But it’s not without hope. I don’t believe in telling stories without some hope.— Susanne Bier (Thomas)Narrative reframing is underlined by the existentialist belief that our spiritual freedom is an artistic process of self-creation, dependent on our free will to organise the elements of our lives, many determined out of our control, into the subjective frame that is to be our experience of our selves and the world around us (107). As a filmmaker, I recognise the power of selective editing and composition. Narrative reframing’s demand for a rational assessment of “the degree to which we live our stories versus the degree to which our stories live us” (Kiesinger 109), helped me to understand how I could use these filmmaking skills to take a step back from my trauma so as to look at it objectively “as a text for study” (Ellis 108) and to exercise power over the creative-destructive forces it, and the deconstructive writing methods I had employed, produced. Richardson confirms the benefits of this practice, since narrative “is the universal way in which humans accommodate to finitude” (Writing Strategies 65).In the script’s development, I found my resilience lay in my capacity to imagine more positive alternatives for female agency. I focussed on writing a narrative that did not avoid life’s hardships and injustices, or require them to be “attenuated, veiled, sweetened, blunted, and falsified” (Nietzsche and Hollingdale 68), yet still involved a life-affirming sentiment. With this in mind, I reintroduced the three-act structure in the revised script as its affectivity and therapeutic denouement enabled me to experience a sense of agentic catharsis that turned “nauseous thoughts into imaginations with which it is possible to live” (Nietzsche 52). Nevertheless, I remained vigilant not to lapse into didacticism; to allow my female character to be free to transgress social conventions surrounding women’s agency. Indebted to Kaplan’s writing on the cinematic gaze, I chose to take up what she identifies as a ‘mutual gaze’; an ethical framework that enabled me to privilege the female character’s perspective and autonomy with a neutral subject-subject gaze rather than the “subject-object kind that reduces one of the parties to the place of submission” (Feminism and Film 135). I incorporated the filmic technique of the point of view (POV) shot for key narrative moments as it allows an audience to literally view the world through a character’s eyes, as well as direct address, which involves the character looking back down the lens at the viewer (us); establishing the highest level of identification between the spectator and the subject on screen.The most pertinent illustration of these significant scriptwriting changes through my engagement with narrative reframing and feminist film theory, is in the reworking of my family’s car crash which became a pivotal turning point in the final draft. In the scene, I use POV and direct address to turn the weaponised gaze back around onto the ‘paparazzi’ who are filming the spectacle. When the central (pregnant) character frees herself from the wreckage, she notices these men filming her and we see the moment from her point of view as she looks at these men laughing and revelling in the commercial potential of their mediatised act. Switching between POV and direct address, the men soon notice they have been exposed as the woman looks back down the lens at them (us) with disbelief, reproaching them (us) for daring to film her in this traumatic moment. She holds her determined gaze while they glance awkwardly back at her, until their laughter dissipates, they stop recording and appear to recognise the culpability of their actions. With these techniques of mutual gazing, I set out to humanise and empower the female victim and neutralise the power dynamic: the woman is now also a viewing agent, and the men equally perform the role of the viewed. In this creative reframing, I hope to provide an antidote to filmic violence against and/or by women as this female character reclaims her (my) experience of survival without adhering to the culture of female passivity or ressentiment.This article has examined how a serious car crash, being filmed against my will in its aftermath and the attendant damages that prevailed from this experience, catalysed a critical change of direction in my scriptwriting. The victimising event helped me recognise the manifest and latent forms of violence against women that are normalised through everyday ideological and institutional systems in film and prevent us from performing as active agents in our creative praxis. There is a critical need for more inclusive modes of practice – across the film industry, discourse and pedagogy – that are cognisant and respectful of women’s specificity and our difference to the androcentric landscape of mainstream film. We need to continue to exert pressure on changing violent mechanisms that marginalise us and ghettoise our stories. As this article has demonstrated, working outside dominant forms can enable important emancipatory opportunities for women, however, this type or deconstruction also presents risks that generally leave us powerless in everyday spaces. While I advocate that female filmmakers should look to techniques of feminist cinema for an alternative lens, we must also work within popular film to critique and subvert it, and not deny women the pleasures and political advantages of its restorative structure. By enabling female filmmakers to (re)humanise woman though encouraging empathy and compassion, this affective storytelling form has the potential to counter violence against women and mobilise female agency. Equally, CAP ethnography and narrative reframing are critical discourses for the retrieval and actualisation of female filmmakers’ agency as they allow us to contextualise our stories of resistance and survival within the framework of a larger picture of violence to gain perspective on our subjective experiences and render them as significant, informative and useful to the lives of others. This enables us to move from the isolated margins of subcultural film and discourse to reclaim our stories at the centre.ReferencesA Girl Walks Home at Night. Dir. Ana Lily Amirpour. Say Ahh Productions, 2014.Anatomy of Hell. Dir. Catherine Breillat. Tartan Films, 2004. Baise-Moi. Dirs. Virginie Despentes and Coralie Trinh Thi. FilmFixx, 2000.Baldick, Robert, and Jean-Paul Sartre. Nausea. 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