Abstract: 7041 Background: Venetoclax (Ven) is a selective, potent BCL-2 inhibitor. Ven + azacitidine (Aza) were associated with a combined complete remission (CR)/marrow CR (mCR) rate of 79% in a phase 1b study of patients (pts) with HR-MDS. Here we compared two different dose modification strategies to manage expected hematologic toxicities in two safety expansion cohorts with similar follow-up periods. Methods: Pts ≥18y diagnosed with treatment-naïve IPSS intermediate-2 or high-risk MDS with ECOG ≤2 were enrolled. Aza 75 mg/m 2 (iv or subQ daily) was administered for 7 days (d) and Ven was administered at 400 mg for 14d in each 28d cycle. In both cohorts, dose modification during Cycle 1 was not recommended; dose modifications in subsequent cycles were prescribed for AEs. In Safety Expansion Cohort 1 (SE1), either Aza or Ven were initially reduced according to investigator’s choice for significant neutrophil or platelet toxicity. Dose reductions per protocol were 33% for Aza and 50% for Ven (for 14d each cycle). In subsequent cycles, Ven duration could be shortened to 9d of each cycle. In Safety Expansion Cohort 2 (SE2), dose modification guidelines recommended stepwise reductions, first in Aza dose (first to 50 mg/m 2 , then 36 mg/m 2 ) and subsequently in Ven duration to 7d of each cycle (Ven 400 mg). The impact of each dose modification strategy on safety and efficacy in SE1 vs SE2 was compared. Worsening of treatment-emergent adverse events (TEAE) grades from baseline (BL) was analyzed by cycle. Responses were evaluated using IWG 2006 criteria. Analyses included all pts who received ≥1 dose of study drug. Results: We compared 22 pts in SE1 and 21 pts in SE2 with median (range) follow-up of 7.5 (1.0–8.9) and 7.9 (1.8–10.1) mos, respectively. A similar frequency of ≥ G3 hematologic TEAEs (approx %) were reported in SE1 and SE2, respectively, including anemia (14% and 33%), febrile neutropenia (46% and 48%), leukopenia (36% and 19%), neutropenia (55% and 48%) and thrombocytopenia (32% and 38%). Infections (59% and 38%) were more frequent in SE1 than SE2. In a longitudinal analysis, there were more TEAE grade increases from BL to Cycle 1 in SE2 vs SE1. This could be accounted by pts in SE1 and SE2 having unbalanced susceptibility to AEs at BL, as SE1 and SE2 pts received identical Aza + Ven doses in Cycle 1. Response rates were identical: 86% of pts in both SE1 and SE2 had CR or mCR. For pts with mCR, hematologic improvement occurred in 50% of SE1 and 46% of SE2 pts. Conclusions: No obvious hematologic differences were observed when reducing Aza before Ven (SE2) in MDS compared to investigator’s choice (SE1). Both approaches had a similar acceptable safety profile without compromising efficacy for pts with HR-MDS. Clinical trial information: NCT02942290. [Table: see text]

Abstract: Introduction: Patients (pts) with higher-risk myelodysplastic syndromes (MDS) are typically treated with azacitidine (Aza). Venetoclax (Ven) is a selective, potent, oral BCL-2 inhibitor that has demonstrated synergy with Aza in preclinical studies of myeloid malignancies. Higher-risk MDS is associated with mutations in genes involved in RNA splicing, epigenetic regulation, transcription, and cellular signaling. Assessing the dynamics of genetic variants during treatment of higher-risk MDS enables understanding of the molecular determinants of response. This phase 1b study (NCT02942290) evaluates Ven + Aza for treatment-naïve higher-risk MDS, and we report efficacy among mutationally defined subgroups as well as the depth of molecular response. Methods: Pts (≥18 years) with higher-risk MDS enrolled in the study had International Prognostic Scoring System intermediate-2 or high-risk MDS, bone marrow (BM) blasts & lt;20% at baseline, and ECOG ≤2 performance status. Aza 75 mg/m 2 was administered on Days (d) 1-7 of each 28-d cycle. The Ven RP2D was 400 mg x 14 d of each 28-d cycle. Primary objectives were to assess the Ven+Aza safety profile and to establish the RP2D. Key secondary objectives were to assess the overall response rate (ORR), defined as complete remission (CR), marrow CR and partial remission (PR), and overall survival. Analyses were carried out on all pts who received ≥1 dose of study drug and efficacy was evaluated per IWG 2006 response criteria. Molecular responses were quantified by mutation analysis of baseline and serial BM aspirate (BMA) or peripheral blood (PB) samples collected at protocol-specified time points. Mutations were identified in BMA using Archer VariantPlex Myeloid 75-gene panel [limit of detection (LOD) 5%; time points: pre-treatment (n=43), on-treatment (n=32), and treatment completion visit (TCV) (n=25)] or TruSight Myeloid 54-gene Sequencing Panel in PB [LOD 2%; time points: pre-treatment (n=21), on-treatment (n=19), and TCV (n=8)] to assess molecular dynamics during Ven + Aza treatment. Molecular responses were only compared within the same tissue type. Results: At the Dec 15, 2020 cutoff, 78 pts had received Ven+Aza, including 51 who received Ven at the RP2D of 400 mg x 14 d, with median follow up time of 23 mos (range 0.1-44.2). Median age was 70 years (range 26-87); 72% male; and 91% had excess BM blasts ( & gt;5 to ≤10%, n=21; & gt;10 to ≤20%, n=49; & gt;20%, n=1). For the entire population, mORR was 80% (CR 40% and mCR 40%; no PR). 42% with mCR also had hematologic improvement [HI]. Screening mutational profiling was performed on 46/51 pts who received the RP2D of Ven + Aza. The most common mutations were TP53 (26%), ASXL1 (24%), U2AF1 (17%), and RUNX1 (15%), consistent with a higher-risk MDS population. Clinical responses (CR + mCR) were observed across the mutational spectrum, including in pts with poor prognostic mutations in TP53 (83%), ASXL1 (82%), and RUNX1 (71%). Sixty-four pts treated with Ven + Aza (all Ven dosing cohorts) had paired BMA or PB pre-treatment and on-treatment and/or end of study samples available for serial analysis at the Dec 15, 2020 data cutoff. Ven + Aza resulted in robust and rapid molecular responses across the mutational spectrum. Pts who achieved CR at the time of serial sample acquisition had more significant reduction of variant allele frequencies (VAFs) (n=18 pts, mean VAF pre-treatment = 38.3; mean VAF at CR = 11.8) compared to pts who achieved stable disease or HI (n=11 pts, mean VAF pre-treatment = 29.8; mean VAF at SD or HI = 24.0) or progressive disease (n=10 pts, mean VAF pre-treatment = 27.4; mean VAF at PD = 26.9). Reductions of VAFs below the LOD were observed across the mutational spectrum, including in genes that are considered poor prognostic in higher-risk MDS (e.g., TP53, ASXL1 and RUNX1), demonstrating the broad molecular activity of Ven + Aza (Figure). Finally, molecular responses were observed quickly, with VAF reductions below the LOD observed as early as end of Cycle 1, consistent with the mechanism of action of Ven directly activating the mitochondrial apoptotic pathway in cells. Conclusions: Pts with higher-risk MDS treated with Ven + Aza had rapid, durable responses and high remission rates. Pts across key mutational profiles achieved meaningful clinical and molecular responses, supporting an all-comers approach. Updated data will be presented, which will provide more follow up time and durability of responses among mutational subsets. Figure 1 Figure 1. Disclosures Garcia: Genentech: Research Funding; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees; Astellas: 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; AstraZeneca: Research Funding; Prelude: Research Funding; Pfizer: Research Funding. Wei: Novartis, Celgene, AbbVie, Servier, AstraZeneca, and Amgen: Research Funding; Novartis, Janssen, Amgen, Roche, Pfizer, Abbvie, Servier, BMS, Macrogenics, Agios, Gilead: Membership on an entity's Board of Directors or advisory committees; Astellas: Honoraria. Jacoby: Abbvie: Research Funding; Jazz: Research Funding. Fong: Amgen, BMS: Speakers Bureau; AbbVie, Amgen, Novartis, Pfizer, Astellas: Honoraria; Amgen: Research Funding. Borate: Jazz Pharma: Research Funding; Blueprint Medicine: Membership on an entity's Board of Directors or advisory committees; Astellas: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech: Membership on an entity's Board of Directors or advisory committees, Other: Advisory Board; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees; Daiichi-Sankyo: Membership on an entity's Board of Directors or advisory committees; incyte: Membership on an entity's Board of Directors or advisory committees, Research Funding; Rampal: Membership on an entity's Board of Directors or advisory committees; Galecto, Inc.: Consultancy; Promedior: Consultancy. Cunningham: AbbVie, Amgen, Astex, Celgene, Janssen, Novartis, Principia Biopharma, Rigel: Research Funding. Odenike: Celgene, Incyte, AstraZeneca, Astex, NS Pharma, AbbVie, Gilead, Janssen, Oncotherapy, Agios, CTI/Baxalta, Aprea: Research Funding; AbbVie, Celgene, Impact Biomedicines, Novartis, Taiho Oncology, Takeda: Consultancy. Jurcic: AbbVie, BMS/Celgene, Novartis: Consultancy; AbbVie, Arog Pharmaceuticals, Astellas, BMS/Celgene, Forma Therapeutics, Genentech, Gilead Sciences, PTC Therapeutics, Syros Pharmaceuticals: Research Funding. Nowak: Pharmaxis: Current holder of individual stocks in a privately-held company, Research Funding; AbbVie: Other: Investigator on funded clinical trial; Affimed: Research Funding; Tolero Pharma, Pharmaxis, Apogenix: Research Funding; Celgene: Honoraria; Takeda: Honoraria. Platzbecker: Janssen: Honoraria; Celgene/BMS: Honoraria; Geron: Honoraria; AbbVie: Honoraria; Novartis: Honoraria; Takeda: Honoraria. Dunshee: Genentech/Roche: Current Employment, Current equity holder in publicly-traded company. Zhou: AbbVie: Current Employment, Current holder of stock options in a privately-held company. Hoffman: AbbVie: Current Employment, Current holder of stock options in a privately-held company. Sun: AbbVie: Current Employment. Popovic: AbbVie: Current Employment, Current equity holder in publicly-traded company. Ainsworth: AbbVie: Current Employment, Current holder of stock options in a privately-held company. Naqvi: Genentech/Roche: Current Employment, Current holder of stock options in a privately-held company. Kye: AbbVie: Current Employment, Other: May hold equity. Hogdal: AbbVie: Current Employment, Current holder of stock options in a privately-held company.

Abstract: Introduction Hypomethylating agents (HMAs), azacitidine (Aza) or decitabine, are standard treatment (Tx) for patients (pts) with higher-risk myelodysplastic syndrome (HR-MDS) not candidates for immediate allogeneic hematopoietic stem cell transplantation (HSCT). However, complete remission was only reported for 17% receiving Aza, and only half the pts are alive after 2 yrs (Fenaux et. al., 2009). Venetoclax (Ven), a selective, potent, orally bioavailable BCL-2 inhibitor, has been shown to synergize with HMAs in preclinical studies in HR-MDS (Jilg et. al., 2016) and clinical studies in AML (DiNardo et. al., 2016), suggesting that the combination of Ven+Aza may be a promising approach for HR-MDS Tx. This ongoing, open-label, Phase 1b, dose-escalation study is evaluating the safety and preliminary efficacy of Ven+Aza for Tx-naive HR-MDS. Methods The study (NCT02942290) initially included a 3-arm randomized cohort. Data from this cohort included 10 pts treated with Ven (400 mg or 800 mg for 28 days) + Aza and 2 pts treated with Aza alone. Following two deaths (Ven 400 mg=1/5 and Ven 800 mg=1/5), the study was amended to a dose-escalation and safety expansion design to determine the recommended Phase 2 dose (RP2D) of Ven+Aza. Key inclusion criteria were age ≥18 yrs, no prior therapy for MDS, IPSS score of ≥1.5, bone marrow blasts & lt;20%, ECOG score of ≤2, and excluded pts with chronic myelomonocytic leukemia and pts who were candidates for undergoing intensive chemotherapy or allogeneic HSCT. In the dose escalation portion, cohorts were enrolled with escalating doses of Ven administered orally for the first 14 days of each 28-day cycle with cohorts from 100 mg daily up to 400 mg daily. Pts started at 100% of the prescribed Ven dose without intraindividual ramp up. Aza was administered at the std dose (75 mg/m2, subcutaneously or IV) from Day 1-7 per 28-day cycle. Primary study objectives were to evaluate safety and determine the RPTD schedule of Ven+Aza. Key secondary efficacy outcomes include objective response rate (ORR[complete remission (CR) + marrow complete remission (mCR) + partial remission]), progression free survival (PFS), time to response (TTR), duration of response (DOR), and overall survival (OS). Results As of April 9, 2019, 59 pts have been treated and dose-escalation is complete. These included 12 pts in the initial randomized cohort. The dose-escalation cohort included 25 pts (Ven 100 mg=8, Ven 200 mg=9, Ven 400 mg=8) and the safety expansion included 22 pts. Results are presented for all 59 pts [75% male, median age 71 yrs (range 26-85)]. At baseline, 15 (25%) pts had an overall IPSS score of 1.5, 29 (49%) had a score of 2, 8 (14%) had a score of 2.5, 6 (10%) had a score of 3.0, and 1 (2%) pt had a score of 3.5. Eleven (19%) pts had intermediate and 24 (41%) pts had poor baseline cytogenetic risk. In treated pts, the most common treatment-emergent adverse events (TEAE's) were anemia, neutropenia, and thrombocytopenia (Table). Common gastrointestinal symptoms were constipation, nausea, diarrhea, and vomiting. Infection was predominantly febrile neutropenia. Predominant Grade 3 or 4 AEs included neutropenia (61%), thrombocytopenia (39%), leukopenia (31%), and anemia (20%). Major SAEs were febrile neutropenia (31%). There were 10 deaths of which 4 were due to infections (pneumonia-2, neutropenic sepsis-1 and septic shock- 1). Other causes of death were multiorgan failure (n=1), respiratory failure (n=1), progressive disease (n=3), and unexplained death (n=1). Twenty pts discontinued the study including 10 who underwent transplantation. Among 57 pts evaluable for response, the ORR with (CR) was documented in 18, mCR in 22 , and stable disease (SD) in 11. Disease progression was observed in 2 pts. Median TTR for ORR was 1.0 mos (range 0.7-3.5 mos). At this data cut, the median time to FU was 4.3 mos (range 3.3-6.5 months). Median DOR, PFS and OS were not reached. With this short follow up, the 12-mo estimates for DOR for ORR was 74% (95% CI: 34%, 92%) and PFS was 59% (95% CI: 31%, 79%). The 18-mo estimate for OS was 74% (95% CI: 50%, 87%). Among 56 pts eligible for hematological improvement (HI), 28 (50%) patients achieved HI as either HI-erythroid, HI-platelet, or HI-neutrophil. Conclusion The combination therapy of Ven+Aza demonstrated a tolerable safety profile and promising efficacy in pts with HR-MDS. The maximum tolerated dose of Ven without dose-limiting toxicities was determined to be 400 mg in this HR-MDS population. Disclosures Wei: Pfizer: Honoraria; Astellas: former employee, Honoraria; Novartis: Honoraria, Research Funding; AstraZeneca: Honoraria, Research Funding; AbbVie: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Servier: Honoraria, Research Funding; Walter and Eliza Hall Institute: Other: former employee, Patents & Royalties: receives a fraction of its royalty stream related to venetoclax; Macrogenics: Honoraria; Celgene: Honoraria, Research Funding; Genentech: Honoraria; Janssen: Honoraria. Garcia:Abbvie: Research Funding; Genentech: Research Funding. Borate:Pfizer: Consultancy; AbbVie: Consultancy; Takeda: Consultancy; Novartis: Consultancy; Daiichi Sankyo: Consultancy. Fong:Novartis: Speakers Bureau; Pfizer: Consultancy, Speakers Bureau; Amgen: Consultancy, Research Funding, Speakers Bureau; Astellas: Consultancy. Baer:Al Therapeutics: Research Funding; Kite: Research Funding; Takeda: Research Funding; Astellas: Research Funding; Abbvie: Research Funding; Forma: Research Funding; Incyte: Research Funding. Nolte:Novartis: Honoraria, Research Funding; Celgene: Honoraria, Research Funding. Peterlin:AbbVie Inc: Consultancy; Astellas: Consultancy; Jazz Pharma: Consultancy; Daiichi-Sankyo: Consultancy. Jurcic:Incyte: Consultancy; AbbVie Inc: Consultancy; Celgene: Consultancy, Research Funding; Novartis: Consultancy; Astellas: Research Funding; Syros Pharmaceuticals: Research Funding; Actinium Pharmaceuticals: Research Funding; Daiichi Sankyo: Research Funding; Genentech: Research Funding; Forma Therapeutics: Research Funding; Kura Oncology: Research Funding. Garcia-Manero:Amphivena: Consultancy, Research Funding; Helsinn: Research Funding; Novartis: Research Funding; AbbVie: Research Funding; Celgene: Consultancy, Research Funding; Astex: Consultancy, Research Funding; Onconova: Research Funding; H3 Biomedicine: Research Funding; Merck: Research Funding. Hong:Roche: Equity Ownership; Genentech Inc.: Employment, Equity Ownership. Platzbecker:Novartis: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Abbvie: Consultancy, Honoraria. Odenike:Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Agios: Research Funding; Oncotherapy: Research Funding; Astra Zeneca: Research Funding; Incyte: Research Funding; Gilead Sciences: Research Funding; Janssen Oncology: Research Funding; NS Pharma: Research Funding; CTI/Baxalta: Research Funding; Astex Pharmaceuticals: Research Funding; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees. Dunbar:AbbVie Inc: Employment, Other: Stock/stock options. Zhou:AbbVie Inc: Employment, Other: Stock/stock options. Harb:AbbVie Inc: Employment, Other: Stock/stock options. Tanwani:AbbVie Inc: Employment, Other: Stock/stock options. Wolff:AbbVie Inc: Employment, Other: Stock/stock options. Jacoby:Celgene: Speakers Bureau; Novo Nordisk: Consultancy; Jazz Pharma: Membership on an entity's Board of Directors or advisory committees. OffLabel Disclosure: Venetoclax is a BCL-2 inhibitor that is FDA-approved in some indications. This presentation will focus on venetoclax for treatment in myelodysplastic syndromes, which is not an approved indication.

Abstract: Background: Hypomethylating agents (HMA) form the current standard treatment for patients with higher-risk myelodysplastic syndrome (HR-MDS) who are not eligible for allogeneic hematopoietic stem cell transplantation (HSCT). However, overall response rates (ORRs) remain low in patients receiving azacitidine (Aza), and median overall survival (OS) is reported as ~15 months (Sekeres et al. J Clin Oncol. 2017). In addition, there are few data on patient-reported outcomes (PROs) published in this population while on treatment. Venetoclax (Ven) is a selective, potent, orally bioavailable BCL-2 inhibitor, which has demonstrated synergy with HMA in preclinical studies of HR-MDS. From an ongoing, open-label, dose-escalation, Phase 1b study (NCT02942290) evaluating Ven+Aza for the treatment of treatment-naïve HR-MDS, we report the updated safety and efficacy in all treated patients and the exploratory analysis of key PROs in patients who received the recommended Phase 2 dose (RP2D). Methods: Patients aged ≥18 years with treatment-naïve HR-MDS, International Prognostic Scoring System intermediate-2 or high, bone marrow blasts & lt;20% at baseline, and an Eastern Cooperative Oncology Group (ECOG) score ≤2 were enrolled; patients with chronic myelomonocytic leukemia or therapy-related MDS and candidates for intensive chemotherapy or HSCT were excluded. Ven was initially given at a dose of 400 mg or 800 mg for 28 days in a 28-day cycle. Due to intolerance among patients with MDS, this was later amended to an escalating dose (100, 200, and 400 mg) for 14 days in a 28-day cycle. Aza was administered at 75 mg/m2 subcutaneously or intravenously on Days 1-7 of each 28-day cycle. The primary objectives of the study were to assess the Ven+Aza safety profile and to establish the RP2D. Key secondary objectives included assessment of ORR and OS. Safety and efficacy assessments were carried out on all patients who received ≥1 dose of study drug, and efficacy endpoints were evaluated according to the 2006 International Working Group response criteria, with OS analyzed using Kaplan-Meier methodology. PROs were exploratory and included the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core (EORTC QLQ-C30) scale. Results: At data cutoff, December 31, 2019, 57 patients had received Ven+Aza, with a median follow-up of 13.0 months (95% confidence interval [CI] 11.3, 15.6 months). The majority of patients were male (75%); median age was 71 years (range 26-85 years); and 89% had ECOG score 0-1. All patients experienced ≥1 adverse event (AE), the most common being constipation (54%), neutropenia (51%), and nausea (51%). Grade ≥3 AEs were experienced by 97% of patients, with neutropenia (51%), febrile neutropenia (46%), and thrombocytopenia (30%) the most common. Febrile neutropenia was the most common serious AE (42%). The 30-day mortality rate was 2%. The ORR was 77%, including complete remission (CR) and marrow CR (mCR) achieved by 42% and 35% of patients (of whom 40% achieved mCR + hematological improvement), respectively; none achieved partial remission. Median OS was not reached (95% CI 16.2 months, not estimable; Figure 1). Median duration of response was 14.8 months (95% CI 12.9 months, not estimable). Median progression-free survival was 17.5 months (14.5, not estimable). Of the patients who received the RP2D of Ven 400 mg for 14 days/28-day cycle in combination with Aza, physical functioning, as measured by the EORTC QLQ-C30, was maintained through 48 weeks of treatment. In addition, clinically meaningful improvement in fatigue and dyspnea, as measured by the EORTC QLQ-C30, was achieved by the beginning of Cycle 5 and was maintained through Week 48 (Cycle 13; Figure 2). Conclusions: The combination of Ven+Aza demonstrates promising efficacy, including response durability, and an acceptable safety profile for patients with HR-MDS. Maintenance in physical functioning and clinically meaningful improvement in dyspnea and fatigue were observed throughout the first 48 weeks, although these data are not yet mature and low patient numbers beyond Cycle 7 limit conclusions. Additional follow-up data and correlation with disease risk features including mutations will be presented at the meeting. Disclosures Garcia: Pfizer: Research Funding; Eli Lily: Research Funding; Genentech: Research Funding; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Wei:Amgen: Consultancy, Honoraria, Research Funding; MacroGenics: Consultancy, Honoraria; Servier: Consultancy, Honoraria, Research Funding; Walter and Eliza Hall Institute: Other: former employee and receives a fraction of its royalty stream related to venetoclax; Pfizer: Honoraria; Genentech: Honoraria; Astra Zeneca: Honoraria, Research Funding; AbbVie Inc.: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Astellas: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding. Borate:Genentech: Membership on an entity's Board of Directors or advisory committees; Daiichi Sankyo: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Jazz Pharmaceuticals: Research Funding; AbbVie: Other: Investigator in AbbVie-funded clinical trials; Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding. Fong:Astellas: Honoraria; Pfizer: Honoraria; Novartis: Honoraria; Amgen: Honoraria, Research Funding, Speakers Bureau; AbbVie: Honoraria. Baer:Forma: Other: Institutional research funding; Astellas: Other: Institutional research funding; AbbVie: Other: Institutional research funding; Incyte: Other: Institutional research funding; Kite: Other: Institutional research funding; Oscotec: Other: Institutional research funding; Takeda: Other: Institutional research funding. Nolte:AbbVie: Other: Investigator on an AbbVie funded clinical trial. Jurcic:AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Consultancy, Research Funding; Daiichi-Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Arog Pharmaceuticals: Research Funding; Astellas: Research Funding; Forma Therapeutics: Research Funding; Genentech: Research Funding; Kura Oncology: Research Funding; PTC Therapeutics: Research Funding; Syros Pharmaceuticals: Research Funding; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Jacoby:Takeda: Consultancy; AbbVie: Research Funding; Jazz Pharmaceuticals: Research Funding. Hong:F. Hoffmann-La Roche: Current equity holder in publicly-traded company; Genentech, Inc.: Current Employment. Platzbecker:Geron: Consultancy, Honoraria; BMS: Consultancy, Honoraria; Amgen: Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria; Takeda: Consultancy, Honoraria. Odenike:Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Astex Pharmaceuticals, NS Pharma, Gilead Sciences, Janssen Oncology, Oncotherapy, Agios, CTI/Baxalta, Aprea: Other: Institutional research funding; Astra Zeneca: Research Funding; Incyte: Other: Institutional research funding; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Impact Biomedicines: 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. Cunningham:AbbVie: Research Funding; Amgen: Research Funding; Astex: Research Funding; Celgene: Research Funding; Janssen: Research Funding; Novartis: Research Funding; Principia Biopharma: Research Funding; Rigel Ilona: Research Funding. Zhou:AbbVie: Current Employment, Other: may hold stock or other options. Tong:AbbVie, Inc.: Current Employment, Other: may hold stock or other options. Hogdal:AbbVie: Current Employment, Other: may hold stock or other options. Kamalakar:AbbVie: Current Employment, Other: may hold stock or other options. Hutti:AbbVie Inc.: Current Employment, Other: may hold stock or stock options. Kye:AbbVie: Current Employment, Other: may hold stock or other options. Garcia-Manero:Novartis: Research Funding; Merck: Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Amphivena Therapeutics: Research Funding; AbbVie: Honoraria, Research Funding; Helsinn Therapeutics: Consultancy, Honoraria, Research Funding; Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Astex Pharmaceuticals: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; H3 Biomedicine: Research Funding; Jazz Pharmaceuticals: Consultancy; Acceleron Pharmaceuticals: Consultancy, Honoraria; Onconova: Research Funding. OffLabel Disclosure: Venetoclax is a BCL-2 inhibitor approved for use in CLL and in combination with azacitidine, decitabine, or low-dose cytarabine for the treatment of newly-diagnosed AML who are 75 years or older or who have comorbidities that preclude use of intensive induction chemotherapy; the current clinical trial reports use in MDS