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Background: In the Phase 3 randomized, placebo-controlled VIALE-A study, venetoclax (Ven) + azacitidine (Aza) improved overall survival (OS) and complete response (CR) rates vs Aza + placebo (Pbo; DiNardo et al. N Engl J Med. 2020. In Press). Neutropenia and related infections are common in acute myeloid leukemia (AML) and exacerbated by Ven combinations. Antimicrobial prophylaxis is used variably in patients (pts) with AML receiving low-intensity therapies. Ven dose modifications are required for concomitant use of commonly used antimicrobials that are strong or moderate cytochrome P450 3A inhibitors (CYP3Ai). A previous report's findings showed that Ven dose reductions with CYP3Ai do not affect Ven exposure (Wei et al. Blood. 2020;135:2137). This analysis evaluated the use of prophylactic anti-infective CYP3Ai and these agents' effects on infections and efficacy outcomes in the VIALE-A study (NCT02993523). Methods: Pts with newly diagnosed AML, aged ≥75 y or 18-75 yand ineligible for induction therapy were enrolled. Pts were randomized 2:1 to receive Ven (daily, orally) + Aza (75 mg/m2 d 1-7, subcutaneously/intravenously) or Pbo + Aza in 28-d cycles. Anti-infective prophylaxis was required for pts with absolute neutrophil count Results: In total, 286 pts were randomized to Ven + Aza and 145 to Pbo + Aza. Within the first 2 cycles of therapy, concomitant anti-infective prophylaxis agents considered moderate CYP3Ai were received by 41/286 pts (14%) in the Ven + Aza arm and 18/145 (12%) in the Pbo + Aza arm. Concomitant anti-infective prophylaxis agents considered strong CYP3Ai were received in the first 2 cycles by 22/286 pts (8%) treated with Ven + Aza and 13/145 pts (9%) treated with Pbo + Aza. The median duration of each prophylactic CYP3Ai agent use was 12.5 d (range, 1-614) in the Ven + Aza arm and 15 d (range, 1-731) in the Pbo + Aza arm. The rates of CR+CR with incomplete marrow recovery (CRi) as a best response during the study were similar with concomitant use of moderate (61%; CR, 24%; CRi, 37%) or strong (64%; CR, 27%; CRi, 36%) CYP3Ai with adjusted-dose Ven vs no use of CYP3Ai (67%; CR, 39%; CRi, 27%; Table 1). The relatively lower CR and higher CRi rates appear to be due to delay in recovery of peripheral blood counts in pts who received strong CYP3Ai during the first 2 cycles (Table 2). The median time to first CR+CRi was 1.2 mo (range, 0.6-9.9), 1.4 mo (range 1.0-5.5), and 1.4 mo (range, 0.9-5.4) in those receiving no, moderate, and strong CYP3Ai agents, respectively, in the Ven + Aza arm. Median OS was not statistically different regardless of use of moderate or strong CYP3Ai in both arms, as noted by overlapping CIs (Table 1). The 24-month estimated OS was 26.2% (95% CI, 8.1-48.9) for pts receiving strong CYP3Ai vs 37.9% (95% CI, 30.2-45.6) for those receiving no CYP3Ai. Rates of any-grade or Grade 3/4 infections within the first 2 cycles varied between those with or without use of moderate CYP3Ai reported as being given as prophylaxis in both treatment arms (Table 1). Rates of invasive fungal infections were 3%, 12%, and 9% with Ven + Aza and 0%, 0%, and 15% with Pbo + Aza in pts receiving no, moderate, and strong CYP3Ai agents, respectively. Rates of discontinuation from infections were similar in both arms regardless of CYP3Ai use. Conclusions:Antimicrobial prophylaxis with moderate or strong CYP3Ai was used in neutropenic pts in the VIALE-A study, with overall similar composite remission rates with Ven dose reductions. The use of CYP3Ai did not increase rates of discontinuation from infections. Analysis of differences in baseline characteristics, rates of infections, and efficacy outcomes for pts who began anti-infective prophylaxis at the initiation of therapy is ongoing. Disclosures Jonas: Amgen: Consultancy, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding; GlycoMimetics: Consultancy, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding; Celgene: Consultancy, Research Funding; Jazz: Consultancy, Research Funding; Takeda: Consultancy; Tolero: Consultancy; Treadwell: Consultancy; Forty Seven: Research Funding; Accelerated Medical Diagnostics: Research Funding; AROG: Research Funding; Daiichi Sankyo: Research Funding; F. Hoffmann-La Roche: Research Funding; Forma: Research Funding; AbbVie: Consultancy, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding; Genentech/Roche: Research Funding; Sigma Tau: Research Funding; Hanmi: Research Funding; Pfizer: Research Funding; LP Therapeutics: Research Funding; Incyte: Research Funding; Pharmacyclics: Research Funding. Dinardo:Takeda: Honoraria; Notable Labs: Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy; Daiichi Sankyo: Consultancy, Research Funding; Calithera: Research Funding; Celgene: Research Funding; Agios: Consultancy, Research Funding; AbbVie: Consultancy, Research Funding; ImmuneOnc: Honoraria. Fracchiolla: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); Gilead: 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; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Speakers Bureau; Amgen: 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. Pristupa:Beigene: Honoraria, Research Funding; State Institution of Health of the Ryazan Regional Clinical Hospital: Current Employment; Pfizer: Honoraria, Research Funding, Speakers Bureau; Janssen: Honoraria, Research Funding; AbbVie: Honoraria, Research Funding; Takeda: Honoraria, Research Funding, Speakers Bureau; Daiichi Sankyo: Honoraria, Research Funding; Paraxel: Honoraria, Research Funding; Acerta: Honoraria, Research Funding; Pharmacyclics: Honoraria, Research Funding; Geron: Honoraria, Research Funding. Ishizawa:Takeda: Honoraria; Ono: Honoraria; Chugai: Honoraria; Eizai: Honoraria; Novartis: Honoraria, Research Funding; Celgene: Honoraria; SymBio: Research Funding; Bayer: Research Funding; AbbVie: Research Funding. Jin:The First Affiliated Hospital of Zhejiang University: Current Employment. Konopleva:Rafael Pharmaceutical: Research Funding; F. Hoffmann La-Roche: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; Eli Lilly: Research Funding; Sanofi: Research Funding; Calithera: Research Funding; Kisoji: Consultancy; AstraZeneca: Research Funding; AbbVie: Consultancy, Research Funding; Amgen: Consultancy; Ascentage: Research Funding; Reata Pharmaceutical Inc.;: Patents & Royalties: patents and royalties with patent US 7,795,305 B2 on CDDO-compounds and combination therapies, licensed to Reata Pharmaceutical; Ablynx: Research Funding; Forty-Seven: Consultancy, Research Funding; Stemline Therapeutics: Consultancy, Research Funding; Cellectis: Research Funding; Agios: Research Funding. Ofran:AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Astellas: Consultancy; Rambam Health Care: Current Employment; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Roche: Consultancy. Kovacsovics:Pfizer: Research Funding; Novartis: Research Funding; AbbVie: Research Funding; Jazz: Honoraria; Astella: Honoraria; Agios: Honoraria. Kantarjian:Daiichi-Sankyo: Honoraria, Research Funding; BMS: Research Funding; Actinium: Honoraria, Membership on an entity's Board of Directors or advisory committees; Oxford Biomedical: Honoraria; Janssen: Honoraria; Delta Fly: Honoraria; BioAscend: Honoraria; Jazz: Research Funding; Abbvie: Honoraria, Research Funding; Sanofi: Research Funding; Aptitute Health: Honoraria; Adaptive biotechnologies: Honoraria; Pfizer: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Immunogen: Research Funding; Ascentage: Research Funding. Hong:Genentech, Inc.: Current Employment; F. Hoffmann-La Roche: Current equity holder in publicly-traded company. Duan:AbbVie: Current Employment, Other: may hold stock or options. Ainsworth:AbbVie: Current Employment, Current equity holder in publicly-traded company. Potluri:AbbVie: Current Employment, Other: may hold stock or stock options. Werner:AbbVie: Current Employment, Current equity holder in publicly-traded company. Svensson:AbbVie: Current Employment, Current equity holder in publicly-traded company. Pratz:Millennium: Research Funding; Daiichi Sankyo: Research Funding; Agios: Other: Scientific Advisory Board, Research Funding; Jazz Pharmaceutical: Consultancy; Celgene: Other: Scientific Advisory Board; Boston BioMedical: Consultancy; AbbVie: Other: Scientific Advisory Board, Research Funding; Astellas: Other: Scientific Advisory Board, Research Funding.

Introduction The FMS-like tyrosine kinase 3 (FLT3) gene is mutated in ~20% of patients (pts) with AML ≥70 years (Schneider et al, 2012). Both FLT3-ITD and FLT3-TKD mutations (mut) are associated with AML proliferation and potentially targetable with small molecule inhibitors. The presence of a FLT3mut, particularly FLT3-ITD, often correlates with high leukemic burden and risk of relapse despite high response rates (Gale et. al, 2008). There is limited evidence of the effect of currently available therapies on treatment-naïve AML pts unfit for intensive treatment with FLT3mut. We evaluated the efficacy and safety of venetoclax (Ven) and Azacitidine (Aza) combination among treatment-naïve AML pts with co-morbidities and/or age ≥ 75 years, unfit for intensive treatment, and with FLT3mut. Methods Data were pooled from pts enrolled in a phase 3 study (NCT02993523, data cut-off: 04Jan2020) that compared pts treated with Ven+Aza or placebo (Pbo)+Aza, and a prior phase 1b study (NCT02203773, data cut-off: 19Jun2019) where pts were treated with Ven+Aza. Pts on Ven+Aza received Ven 400 mg daily orally (days 1-28) and Aza (75 mg/m2; days 1-7/28-day cycle). Disease assessments were performed per the modified International Working Group response criteria for AML. DNA was isolated from bone marrow aspirates collected from pts prior to the first dose of study drug and analyzed centrally. Pts with positive test results for FLT3; [Leukostrate FLT3 CDx for phase 3 study or MyAML panel (Invivoscribe) for Phase 1b study] were counted as mutation "detected"; pts with a negative test result were counted as mutation "not detected." Pts without a result either due to an inconclusive test or missing specimen were not included in the analyses. Results In this pooled analysis, FLT3mut was detected in 40 pts treated with Ven+Aza and 22 pts treated with Pbo+Aza. At baseline (Ven+Aza/Pbo+Aza), the median age was 75 (range: 49-91)/75 (65-85) years. Cytogenetic risks were: intermediate: 88%/96% and poor: 13%/5%, Eastern Co-operative Oncology Group performance scores were: 0-1: 40%/50% and 2-3: 60%/50%. 78%/86% had de novo AML, while 23%/14% had secondary AML. FLT3-ITD was detected in 28/13 and FLT3-TKD in 13/10 pts, respectively. FLT3-ITD allelic ratios were: Complete response (CR)+CR with partial hematologic recovery (CRh) rates in FLT3mut pts (Ven+Aza/Pbo+Aza) were 65% (95% CI:48%-79%)/18% (5%-40%) (Table) with a median duration of response (mDoR) 18.3 [95% CI: 10.1- not reached (NR)]/15.1 (13.9-NR) mos. Median time to first CR/CRh response was 1.0/3.2 months (mos). 43%/0% achieved CR+CRh by initiation of cycle (C) 2. Median overall survival (mOS) was 13.3 (95% CI: 8.4-23.5)/8.6 (5.9-14.7) mos, respectively. Among pts with FLT3-ITD, CR+CRh rates (Ven+Aza/Pbo+Aza) were 61% (95% CI: 41%-79%)/23% (5%-54%) with mDoR 17.4 (95% CI: 3.7-NR)/14.5 (13.9-15.1) mos. The median time to first CR/CRh response was 1.0/3.5 mos and 39%/0% pts achieved CR+CRh by initiation of C2. The mOS was 11.5 (95% CI: 6.4-23.5)/8.5 (6.1-20.3) mos, respectively. CR+CRh rates in pts with FLT3-TKD were 69% (95% CI: 39%-91%)/20% (3%-56%) with mDoR 18.3 (95% CI: 3.0-NR)/NR (15.1-NR) mos. The median time to first CR/CRh response was 1.0/2.7 mos and 46%/0% achieved a response by initiation of C2. The mOS was 19.2 (95% CI:1.8-NR/10.0 (0.2-14.7) mos, respectively. In pts treated with Ven+Aza, CR+CRh rates among pts with FLT3 detected/FLT3 not detected were 65% (95% CI: 48%-79%)/63% (56%-69%) with mDoR 18.3 (95% CI: 10.1-NE)/18.1 (15.3-NR) mos. The mOS was 13.3 (95%CI: 8.4-23.5)/14.1 (10.6-18.7) mos, respectively (Figure). Among pts treated with Ven+Aza, grade 3/4 hematologic adverse events (AEs) in pts with FLT3 detected/FLT3 not detected was 67%/77%, and included anemia (33%/25%), neutropenia (36%/33%), thrombocytopenia (39%/36%), and febrile neutropenia (36%/43%). Grade 3/4 hematologic AEs among pts with FLT3-ITD/FLT3-TKD treated with Ven+Aza was 67%/69%. Conclusion Ven+Aza compared to Aza monotherapy resulted in significantly higher CR+CRh rates among treatment-naïve pts with FLT3mut ineligible for intensive chemotherapy. In this unselected AML population, insufficient pt numbers in various subgroups limit the ability to draw conclusions regarding DoR and mOS for FLT3-ITD and TKD subgroups. There were no unexpected toxicities in the Ven+Aza arm. Future studies with larger sample sizes are warranted. Disclosures Konopleva: Ascentage: Research Funding; Amgen: Consultancy; Genentech: Consultancy, Research Funding; Stemline Therapeutics: Consultancy, Research Funding; Forty-Seven: Consultancy, Research Funding; Rafael Pharmaceutical: Research Funding; Kisoji: Consultancy; Agios: Research Funding; Calithera: Research Funding; F. Hoffmann La-Roche: Consultancy, Research Funding; Reata Pharmaceutical Inc.;: Patents & Royalties: patents and royalties with patent US 7,795,305 B2 on CDDO-compounds and combination therapies, licensed to Reata Pharmaceutical; AstraZeneca: Research Funding; AbbVie: Consultancy, Research Funding; Sanofi: Research Funding; Eli Lilly: Research Funding; Cellectis: Research Funding; Ablynx: Research Funding. Thirman:AstraZeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Roche/Genentech: 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; Syndax: Research Funding; TG Therapeutics: Research Funding; Tolero: Research Funding; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck: Research Funding; Gilead Sciences: Research Funding. Pratz:Millennium: Research Funding; Celgene: Other: Scientific Advisory Board; AbbVie: Other: Scientific Advisory Board, Research Funding; Astellas: Other: Scientific Advisory Board, Research Funding; Boston BioMedical: Consultancy; Agios: Other: Scientific Advisory Board, Research Funding; Daiichi Sankyo: Research Funding; Jazz Pharmaceutical: Consultancy. Letai:Flash Therapeutics: Membership on an entity's Board of Directors or advisory committees; Dialectic: Membership on an entity's Board of Directors or advisory committees; Chugai: Other: Lecture Fees; Novartis: Research Funding; AbbVie: Consultancy; Zentalis: Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Consultancy. Pullarkat:AbbVie, Inc.: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pfizer: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Dova: Consultancy, Honoraria; Genetech: 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; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Servier: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Kantarjian:Immunogen: Research Funding; Janssen: Honoraria; Sanofi: Research Funding; BioAscend: Honoraria; Abbvie: Honoraria, Research Funding; Oxford Biomedical: Honoraria; Actinium: Honoraria, Membership on an entity's Board of Directors or advisory committees; Aptitute Health: Honoraria; BMS: Research Funding; Daiichi-Sankyo: Honoraria, Research Funding; Delta Fly: Honoraria; Pfizer: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Ascentage: Research Funding; Adaptive biotechnologies: Honoraria; Novartis: Honoraria, Research Funding; Jazz: Research Funding. Dail:Genentech: Current Employment, Current equity holder in publicly-traded company. Duan:AbbVie: Current Employment, Other: may hold stock or options. Chyla:AbbVie: Current Employment, Current equity holder in publicly-traded company. Potluri:AbbVie: Current Employment, Other: may hold stock or stock options. Miller:AbbVie: Current Employment, Current equity holder in publicly-traded company. Dinardo:Takeda: Honoraria; Daiichi Sankyo: Consultancy, Research Funding; Novartis: Consultancy; Notable Labs: Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Research Funding; Celgene: Research Funding; Agios: Consultancy, Research Funding; Calithera: Research Funding; ImmuneOnc: Honoraria. Wei:AbbVie: Honoraria, Research Funding, Speakers Bureau; Servier: Consultancy, Honoraria, Research Funding; Novartis: Honoraria, Research Funding, Speakers Bureau; AstraZeneca: Honoraria, Research Funding; Pfizer: Honoraria; BMS: Consultancy, Honoraria, Research Funding, Speakers Bureau; Janssen: Honoraria; Amgen: Honoraria, Research Funding; Walter and Eliza Hall Institute of Medical Research: Patents & Royalties; Genetech: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Astellas: Honoraria, Membership on an entity's Board of Directors or advisory committees.

Introduction Isocitrate dehydrogenase (IDH) mutations occur in ~20% of acute myeloid leukemia (AML) patients (pts) and are frequently identified in older pts. Pre-clinical data showed that cells with IDH1/2 mutation (mut) were susceptible to Venetoclax (Ven) therapy (Chan et.al., 2015). Clinical studies have demonstrated that pts with IDH1/2mut treated with Ven and azacitidine (Aza) achieved high response rates that were durable, and had longer median overall survival (mOS) (DiNardo et. al., 2020; DiNardo et. al., 2019). Herein, we further evaluated the efficacy and safety of Ven+Aza among treatment-naïve AML pts with IDH1/2 mut unfit for intensive treatment either due to comorbidities and/or age ≥ 75 yrs. Methods Data were pooled from pts enrolled in an ongoing phase 3 study (NCT02993523, data cut-off: 04Jan2020) comparing pts treated with Ven+Aza or placebo (Pbo)+Aza, and a phase 1b study (NCT02203773, data cut-off: 19Jun2019) where pts were treated with Ven+Aza. Pts on Ven+Aza received Ven 400 mg daily orally (days 1-28) and Aza (75 mg/m2; days 1-7/28-day cycle). Disease assessments were performed per modified International Working Group response criteria for AML. DNA was isolated from bone marrow aspirates collected from pts prior to the first dose of study drug and analyzed centrally. Pts with positive test results for IDH1 and 2 [RealTime IDH1 or IDH2 assay (Abbott) for phase 3 study, MyAML panel (Invivoscribe) for phase 1b study] were counted as mutation "detected"; pts with a negative test result were counted as mutation "not detected." Pts without a result either due to an inconclusive test or missing specimen were excluded from the analyses. Results IDH1/2 mut was detected in 79 pts treated with Ven+Aza and 28 pts treated with Pbo+Aza. At baseline (Ven+Aza/Pbo+Aza), median age was 76 (range: 64-90)/78 (62-90) yrs. Cytogenetic risks were intermediate: 79%/68%, and poor:21%/32%. ECOG scores were: 0-1: 56%/68% and 2-3: 44%/32%. 73%/86% had de novo AML, and 27%/14% had secondary AML. IDH1 was detected in 32/11, IDH2 in 49/18, IDH2R140 in 36/15, and IDH2R172 were detected in 13/3 pts, respectively. The median number of treatment cycles received (Ven+Aza/Pbo+Aza) by IDH1/2 pts was 8 (range: 1-37)/2.5 (1-18). Complete response (CR)+CR with partial hematologic recovery (CRh) in Ven+Aza/Pbo+Aza were 72% (95% CI: 61%-82%)/7% (1%-24%) (Table). Median time to first CR/CRh response was 1.0/2.6 months (mos), and 51%/0% achieved CR+CRh by initiation of cycle (C) 2. Median duration of response (mDoR) was 29.5 [95% CI: 16.7-not reached(NR)]/15.5 (NR-NR) mos and mOS was 24.5 [15.2- NR/6.2 (2.3-12.7) mos. The separation of 95% CIs for mOS indicate superior treatment effect of Ven+Aza (Figure). In pts with IDH1, CR+CRh (Ven+Aza/Pbo+Aza) was 59%/9%. Median time to first CR/CRh response was 2.3/3.1 mos, and 25%/0% achieved CR+CRh by initiation of C2. Median DoR and OS were 21.9 (7.8-29.5)/NR and 17.5 (6.3-32.7)/2.2(1.1-5.6) mos. In pts with IDH2, CR+CRh rates were 80%/6%. Median time to first CR/CRh response was 1.0/2.1 mos and 67%/0% achieved CR+CRh by initiation of C2. Median DoR was NR (16.7-NR)/15.5 (NR-NR), and mOS was NR (17.6-NR)/13.0 (95% CI: 3.8-15.8) mos. In pts with IDH2R140, CR+CRh were 75%/7%. Median time to first CR/CRh response was 1.0/2.1 mos, and 58%/0% achieved CR+CRh by initiation of C2. Median DoR and mOS were NR (17.8-NR)/15.5 (NR-NR) and NR (15.0-NR)/12.7 (1.7-15.8) mos, respectively. Response rates in pts with IDH2R172 were 92%/0%. Median time to first CR/CRh response was 1.0/NR mos, and 92%/0% achieved response by initiation of C2. Median DoR and mOS were 16.7 (7.5-NR)/3.5 (NR-NR) and NR (12.2-NR)/13.7 (10.6-NR) mos. IDH1/2 mut pts achieved higher CR+CRh rates with Ven+Aza treatment as compared to pts with IDH not detected (72%/60%). Median DoR and mOS were 29.5 (16.7-NR)/17.5 (10.6-23.5) and 24.5 (15.2-NR)/12.3 (9.7-14.8) mos, respectively. In pts treated with Ven+Aza, grade 3/4 hematologic adverse events (AEs) among pts with IDH1/2 detected/IDH not detected were similar (81%/74%) and included grade 3/4 thrombocytopenia (46%/34%), febrile neutropenia (43%/41%), neutropenia (35%/33%) and anemia (29%/24%). Conclusion Ven+Aza compared to Aza monotherapy resulted in higher response rates, longer DoR, and mOS among treatment-naïve pts with IDH1/2mut ineligible for intensive chemotherapy. The safety profile was acceptable. No unexpected toxicities were noted with Ven+Aza combination. Disclosures Pollyea: Pfizer: Consultancy; Glycomimetics: Other; Takeda: Consultancy; Daiichi Sankyo: Consultancy; Abbvie: Consultancy, Research Funding; Syros: Consultancy; Syndax: Consultancy; Karyopharm: Consultancy; Novartis: Consultancy; Genentech: Consultancy; Amgen: Consultancy; Janssen: Consultancy; 47: Consultancy, Research Funding; Agios: Consultancy; Celgene/BMS: Consultancy. Dinardo:Notable Labs: Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria; Agios: Consultancy, Research Funding; Celgene: Research Funding; Calithera: Research Funding; Daiichi Sankyo: Consultancy, Research Funding; Novartis: Consultancy; AbbVie: Consultancy, Research Funding; ImmuneOnc: Honoraria. Arellano:Gilead Sciences, Inc: Consultancy, Membership on an entity's Board of Directors or advisory committees; Hanmi: Research Funding; Cephalon Oncology: Research Funding. Fiedler:Jazz Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel accomodations; Gilead: Honoraria; BMS: Honoraria; BerGenBio ASA: Research Funding; Servier: Honoraria, Other; Ariad/Incyte: Membership on an entity's Board of Directors or advisory committees; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: support in medical writing; Daiichi Sankyo Oncology: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel accomodations; Morphosys: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: support in medical writing; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel accomodations, support in medical writing, Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees. Konopleva:Reata Pharmaceutical Inc.;: Patents & Royalties: patents and royalties with patent US 7,795,305 B2 on CDDO-compounds and combination therapies, licensed to Reata Pharmaceutical; Calithera: Research Funding; AbbVie: Consultancy, Research Funding; Cellectis: Research Funding; AstraZeneca: Research Funding; Eli Lilly: Research Funding; Sanofi: Research Funding; Stemline Therapeutics: Consultancy, Research Funding; Agios: Research Funding; Ascentage: Research Funding; Ablynx: Research Funding; F. Hoffmann La-Roche: Consultancy, Research Funding; Amgen: Consultancy; Genentech: Consultancy, Research Funding; Kisoji: Consultancy; Rafael Pharmaceutical: Research Funding; Forty-Seven: Consultancy, Research Funding. Rizzieri:Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; abbvie: Membership on an entity's Board of Directors or advisory committees; AROG: Membership on an entity's Board of Directors or advisory committees; Bayer: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees; Teva: Membership on an entity's Board of Directors or advisory committees; Acrobiotech: Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Stemline: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Kite: Honoraria, Speakers Bureau; Karyopharm: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees; Celltrion: Membership on an entity's Board of Directors or advisory committees; Mustang: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Jazz: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Smith:Jazz: Consultancy, Membership on an entity's Board of Directors or advisory committees; Agios: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees. Shinagawa:AbbVie: Research Funding. Lemoli:Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees; BerGenBio ASA: Research Funding; Celgene: Research Funding; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Servier: Consultancy, Membership on an entity's Board of Directors or advisory committees; Daiichi Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees; Jazz: 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. Dail:Genentech: Current Employment, Current equity holder in publicly-traded company. Duan:AbbVie: Current Employment, Other: may hold stock or options. Chyla:AbbVie: Current Employment, Current equity holder in publicly-traded company. Potluri:AbbVie: Current Employment, Other: may hold stock or stock options. Ridgeway:AbbVie: Current Employment, Current equity holder in publicly-traded company. Kantarjian:Janssen: Honoraria; Daiichi-Sankyo: Honoraria, Research Funding; Adaptive biotechnologies: Honoraria; Oxford Biomedical: Honoraria; Abbvie: Honoraria, Research Funding; Ascentage: Research Funding; Amgen: Honoraria, Research Funding; Actinium: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Research Funding; Delta Fly: Honoraria; BMS: Research Funding; Aptitute Health: Honoraria; Novartis: Honoraria, Research Funding; BioAscend: Honoraria; Jazz: Research Funding; Pfizer: Honoraria, Research Funding; Immunogen: Research Funding.

Background: Patients with acute myeloid leukemia (AML) who are older or ineligible for intensive induction chemotherapy have limited treatment options and poor survival. In the VIALE-A study, venetoclax (Ven) + azacitidine (Aza) improved overall survival and response rates compared with placebo (Pbo) + Aza in older or unfit patients with newly diagnosed AML (DiNardo et al. N Engl J Med. 2020). Although cytopenia is common in AML, Ven+Aza was associated with hematologic adverse events in 83% of patients in the VIALE-A study (vs 69% in the Pbo+Aza arm). Here, the frequency and management of cytopenia are analyzed in patients achieving a best response of complete remission (CR) or CR with partial hematologic recovery (CRh) in the VIALE-A study. Methods: This double-blind, Pbo-controlled, multicenter Phase 3 study (NCT02993523) enrolled patients with newly diagnosed AML who were ineligible for intensive chemotherapy due to age ≥75 years or comorbidities. Patients were randomized 2:1 to receive 75 mg/m2 Aza (Days 1-7 of each 28-day cycle) plus either daily 400 mg Ven (Ven+Aza) or Pbo (Pbo+Aza). Disease response was assessed via bone marrow aspirate and biopsy at the end of Cycle 1 and at least every 3 cycles thereafter. After patients achieved blast clearance (bone marrow blasts Results: In total, 186 of 283 (66%) Ven+Aza-treated patients and 33 of 144 (23%) Pbo+Aza-treated patients achieved a best response of CR or CRh (CR/CRh). Of patients with a best response of CR/CRh in the Ven+Aza arm, 77% achieved blast clearance by the end of Cycle 1, 88% by the end of Cycle 2, 92% by the end of Cycle 3, and 98% by the end of Cycle 4. Of patients with a best response of CR/CRh in the Pbo+Aza arm, 33% achieved blast clearance by the end of Cycle 1, 55% by the end of Cycle 2, 76% by the end of Cycle 3, and 91% by the end of Cycle 4. After achieving blast clearance, 75% and 67% of patients in the Ven+Aza and Pbo+Aza arms, respectively, had a delay of the next cycle, with a median duration per cycle delay post-blast clearance (range) of 9.0 (1-39) and 5.5 (1-21) days. Among CR/CRh patients, more patients receiving Ven+Aza versus Pbo+Aza had post-remission cytopenia (87% vs 45%; Table 2). A similar percentage of CR/CRh patients in both arms (Ven+Aza, 26%; Pbo+Aza, 24%) had in-cycle dose interruptions (ie, days without Ven/Pbo exposure between a cycle's first and last Ven/Pbo dose), with a median duration (range) of 2.0 days (1-20) for Ven+Aza and 1.0 (1-13) for Pbo+Aza. A greater proportion of CR/CRh patients experienced post-remission cycle delays due to cytopenia in the Ven+Aza arm (77%) than in the Pbo+Aza arm (30%). Furthermore, a higher percentage of CR/CRh patients had post-remission cycles with a reduction in Ven/Pbo dosing days and/or cycle delays totaling ≥7 days due to cytopenia in the Ven+Aza arm (75%) than in the Pbo+Aza arm (27%). Among these patients, the median percentage of days without Ven/Pbo administration while in remission (out of the total number of days in remission) was 18% (range, 1-69) in the Ven+Aza arm and 13% (3-44) in the Pbo+Aza arm. Ultimately, 129 CR/CRh patients (69%) in the Ven+Aza arm and 10 (30%) in the Pbo+Aza arm received ≤21-day Ven/Pbo dosing post-remission, with a median time from remission to first ≤21-day cycle (range) of 92.0 days (1-480) for Ven+Aza and 74.0 days (6-405) for Pbo+Aza. Conclusion: In the VIALE-A study of older or unfit patients with newly diagnosed AML, the majority of responding patients in the Ven+Aza arm required dosing modifications to manage cytopenia, of which delays between cycles or within-cycle reductions of Ven dosing days were most common. Post-remission cytopenia and dosing modifications were more frequent with Ven+Aza versus Pbo+Aza treatment. The impact of cytopenia and dosing modifications on patient outcomes with Ven+Aza is currently being analyzed and will be reported at a future date. Disclosures Pratz: AbbVie: Other: Scientific Advisory Board, Research Funding; Boston BioMedical: Consultancy; Astellas: Other: Scientific Advisory Board, Research Funding; Jazz Pharmaceutical: Consultancy; Millennium: Research Funding; Daiichi Sankyo: Research Funding; Agios: Other: Scientific Advisory Board, Research Funding; Celgene: Other: Scientific Advisory Board. DiNardo:MedImmune: Honoraria; Agios: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Jazz: Honoraria; Takeda: Honoraria; AbbVie: Consultancy, Honoraria, Research Funding; Syros: Honoraria; Notable Labs: Membership on an entity's Board of Directors or advisory committees; Daiichi Sankyo: Consultancy, Honoraria, Research Funding; ImmuneOnc: Honoraria; Novartis: Consultancy; Calithera: Research Funding. Selleslag:Amgen: Consultancy, Honoraria, Speakers Bureau; Novartis: Consultancy, Honoraria, Speakers Bureau; Astellas: Consultancy, Honoraria, Speakers Bureau; Takeda: Consultancy, Honoraria, Speakers Bureau; Janssen Cilag: Consultancy, Honoraria, Speakers Bureau; AbbVie: Consultancy, Honoraria, Speakers Bureau; Belgian College: Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Speakers Bureau; MSD: Consultancy, Honoraria, Speakers Bureau; Incyte: Consultancy, Honoraria; Alexion: Consultancy, Honoraria; GSK: Consultancy, Honoraria; Teva: Consultancy, Honoraria, Speakers Bureau; Sanofi: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria, Speakers Bureau. Yamamoto:AbbVie: Consultancy, Honoraria, Research Funding; Astra-Zeneca: Consultancy, Research Funding; Zenyaku: Research Funding; Sumitomo Dainippon: Honoraria; Sanofi: Honoraria; Pfizer: Honoraria; Otsuka: Consultancy, Honoraria, Research Funding; Ono: Consultancy, Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Nippon Shinyaku: Honoraria, Research Funding; Mundipharma: Consultancy, Honoraria, Research Funding; MSD: Consultancy, Honoraria, Research Funding; Mochida: Honoraria; Meiji Seika Pharma: Consultancy, Honoraria; Kyowa Kirin: Honoraria; Janssen: Honoraria; Gilead Sciences: Research Funding; IQIVA/Incyte: Research Funding; HUYA: Consultancy; IQIVA/HUYA: Honoraria; Daiichi Sankyo: Consultancy; Eisai: Consultancy, Honoraria, Research Funding; Chugai: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Yakult: Research Funding; Stemline Therapeutics: Consultancy; Solasia Pharma: Research Funding; SymBio: Research Funding; Takeda: Consultancy, Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria; Bayer: Research Funding; Aichi Cancer Center: Current Employment. Konopleva:AbbVie: Consultancy, Research Funding; Cellectis: Research Funding; Agios: Research Funding; Sanofi: Research Funding; Amgen: Consultancy; Reata Pharmaceutical Inc.;: Patents & Royalties: patents and royalties with patent US 7,795,305 B2 on CDDO-compounds and combination therapies, licensed to Reata Pharmaceutical; Ascentage: Research Funding; Eli Lilly: Research Funding; Stemline Therapeutics: Consultancy, Research Funding; Calithera: Research Funding; Forty-Seven: Consultancy, Research Funding; Ablynx: Research Funding; Rafael Pharmaceutical: Research Funding; F. Hoffmann La-Roche: Consultancy, Research Funding; Kisoji: Consultancy; AstraZeneca: Research Funding; Genentech: Consultancy, Research Funding. McDonald:venetoclax advisory board in South Africa (in CLL context): Consultancy; Alberts Cellular Therapy: Current Employment. Babu:Genentech, Inc./ F. Hoffmann-La Roche: Research Funding; Novartis: Research Funding; Janssen Oncology: Research Funding; Syndax: Research Funding; Nektar: Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding; Alexion Pharmaceuticals: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding, Speakers Bureau; Lilly: Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding; Bayer: Honoraria; AstraZeneca: Consultancy, Honoraria; AstraZeneca/MedImmune: Research Funding; Argenx: Consultancy, Research Funding; Boehringer Ingelheim: Consultancy; Merck: Research Funding; AbbVie: Research Funding; TG Therapeutics: Research Funding; Amgen: Research Funding; Lutheran Hospital: Other; Fort Wayne Medical Oncology & Hematology: Current Employment, Current equity holder in publicly-traded company; Sanofi: Research Funding. Stevens:Amgen, MorphoSys: Consultancy. Kantarjian:BioAscend: Honoraria; Delta Fly: Honoraria; Abbvie: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Ascentage: Research Funding; Janssen: Honoraria; Adaptive biotechnologies: Honoraria; Aptitute Health: Honoraria; Oxford Biomedical: Honoraria; Daiichi-Sankyo: Honoraria, Research Funding; BMS: Research Funding; Jazz: Research Funding; Immunogen: Research Funding; Novartis: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; Sanofi: Research Funding; Actinium: Honoraria, Membership on an entity's Board of Directors or advisory committees. Traina:University of São Paulo at Ribeirão Preto Medical School: Current Employment; AbbVie: Other: Principal Investigator for Protocol Number M15-656 . Venditti:Jazz: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); AbbVie: Consultancy, Honoraria, Other: TRAVEL, ACCOMODATIONS, EXPENSES (paid by any for-profit health care company); Janssen: Consultancy, Honoraria, Other: TRAVEL, ACCOMODATIONS, EXPENSES (paid by any for-profit health care company); Amgen: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Pfizer: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Speakers Bureau; Novartis: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company). Mayer:AbbVie: Research Funding; Principia Biopharma: Research Funding. Montez:F. Hoffmann-La Roche: Current equity holder in publicly-traded company; Genentech, Inc.: Current Employment. Ramsingh:Roche: Current equity holder in publicly-traded company, Ended employment in the past 24 months; Genentech: Current Employment, Current equity holder in publicly-traded company. Jin:Genentech: Current Employment. Ainsworth:AbbVie: Current Employment, Current equity holder in publicly-traded company. Duan:AbbVie: Current Employment, Other: may hold stock or options. Svensson:AbbVie: Current Employment, Current equity holder in publicly-traded company. Werner:AbbVie: Current Employment, Current equity holder in publicly-traded company. Potluri:AbbVie: Current Employment, Other: may hold stock or stock options. Jonas:AbbVie: Consultancy, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding; Amgen: Consultancy, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding; GlycoMimetics: Consultancy, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding; Celgene: Consultancy, Research Funding; Jazz: Consultancy, Research Funding; Takeda: Consultancy; Tolero: Consultancy; Treadwell: Consultancy; Forty Seven: Research Funding; Accelerated Medical Diagnostics: Research Funding; AROG: Research Funding; Daiichi Sankyo: Research Funding; F. Hoffmann-La Roche: Research Funding; Forma: Research Funding; Genentech/Roche: Research Funding; Hanmi: Research Funding; Incyte: Research Funding; LP Therapeutics: Research Funding; Pfizer: Research Funding; Pharmacyclics: Research Funding; Sigma Tau: Research Funding.