Abstract: Background: Acute myeloid leukemia (AML) remains a therapeutic challenge in elderly or unfit patients (pts) and high-risk subgroups. DEC10-VEN has shown high efficacy in these pts. However, outcomes in specific mutational subgroups are unknown. Here we present the results in mutational subgroups and resistance patterns in pts treated with DEC10-VEN (NCT03404193). Methods: This single-institution phase II study enrolled pts with newly diagnosed (ND) AML ( & gt;60 years) ineligible for intensive chemotherapy, relapsed or refractory (R/R) AML, and secondary AML (sAML) with or without prior therapy. DEC was given 20 mg/m2 IV daily on day 1-10 until CR/CRi, followed by 5-day cycles. VEN was given for 21-28 days in cycle 1 and day 1-21 or shorter duration thereafter. BCR-ABL1 and FLT3 inhibitors (FLT3i) were allowed as appropriate. Amplicon-based next-generation sequencing targeting the entire coding regions of 81 myeloid genes was performed on screening bone marrow aspirate with a MiSeq platform. The analytical sensitivity was established at 5% mutant reads in a background of wild type reads. Previously described somatic mutations registered in COSMIC were considered as potential driver mutations. Results: High response rates were noted across mutational subgroups of both previously untreated and previously treated AML (Table 1 and 2). The median follow-up for the entire cohort was 8.1 months (mo). In previously untreated AML (ND AML and untreated sAML, n=49), the CR/CRi rate in NPM1mut pts was 100% (n=13), in RUNX1mut pts was 100% (n=8), in IDH1/2mut pts was 92% (n=12), in TP53mut pts was 85% (n=13), and in N/KRASmut pts was 77% (n=13, Table 1). The median overall survival (OS) among previously untreated NPM1mut pts was not reached (NR), for RUNX1mut pts was NR, for IDH1/2mut pts was 12.4 mo, for TP53mut pts was 5.8 mo, and for N/KRASmut was 12.4 mo. The median DOR for NPM1mut pts was 8.5 mo, for RUNX1mut pts was NR, for IDH1/2mut pts was NR, for TP53mut pts was 5.7 mo, and for N/KRASmut pts was 6.7 mo (Table 1). The one pt with NPM1mut who relapsed had co-occurring ASXL1mut and NRASmut at screening. In previously treated AML (treated sAML and R/R AML, n=52), the CR/CRi rate in NPM1mut pts was 60% (n=10), in IDH1/2mut pts was 50% (n=8), and in TP53mut pts was 21% (n=14, Table 2). The median OS for NPM1mut pts was NR, for IDH1/2mut pts was 7.8 mo, and for TP53mut pts was 4.5 mo. The median DOR for NPM1mut pts was NR, for IDH1/2mut pts was NR, and for TP53mut pts was 3.2 mo (Table 2). The only grade 4 TLS event occurred in a pt with NPM1mut and IDH2mut and baseline WBC of 28x109/L. 2 other pts with high % of PB blasts and FLT3mut experienced grade 3 TLS. Among 15 pts with FLT3-ITD/TKD, 8 pts received sorafenib, 5 pts received midostaurin, and 2 pts did not receive FLT3i (1 insurance non-approval and 1 very low ITD ratio). Among ND FLT3mut AML pts (n=7), the CR/CRi rate was 100% (n=5) in pts receiving FLT3i with negative MRD by flow cytometry (FCM) in 80% pts, with median OS of 8.8 mo and median DOR not reached (Table 1). Of the 2 FLT3-ITD pts not receiving FLT3i, 1 pt with FLT3-ITD of 0.47 did not respond, and 1 pt with low FLT3-ITD of 0.02 achieved CR MRD-. Among previously treated FLT3mut pts (n=8), all received FLT3i with a CR/CRi rate of 38% (n=5) and negative MRD by FCM in 75% pts tested (3/4). The median OS was 6.4 mo and the median DOR was 6.6 mo (Table 2). 2 pts had received prior FLT3i, 1 pt achieved morphologic leukemia-free state (MLFS), and the other pt did not respond. 1 pt with new t(9;22) identified at 4th relapse achieved a MLFS after 1 cycle with addition of ponatinib and transitioned to allogeneic transplant. Overall, pts with durable CR/CRi/MLFS sustained without relapse till data cut-off, had significantly higher proportion of mutations in NPM1 and DNA methylation pathways (DNMT3A, TET2, IDH1/2) compared to pts refractory to, or relapsing after DEC10-VEN (Table 3, Fig. 1). Pts with relapsed or refractory disease to DEC10-VEN had significantly higher frequency of N/KRASmut, ASXL1mut, and TP53mut compared to pts with durable CR/CRi/MLFS (Table 3, Fig. 1). TP53mut associated with worse OS on multivariable analysis (HR 2.9, 95% CI 1.4-5.7, p=0.003). Conclusion: DEC10-VEN is an effective regimen for AML. Addition of FLT3i to DEC10-VEN was safe and may improve upon responses in FLT3mut pts. Mutations in NPM1 and DNA methylation pathways were associated with more durable responses while mutations in ASXL1, RAS and TP53 were associated with refractory disease or relapse. Disclosures Maiti: Celgene: Other: research funding. Cortes:BiolineRx: Consultancy; Forma Therapeutics: Consultancy, Honoraria, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Daiichi Sankyo: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; Astellas Pharma: Consultancy, Honoraria, Research Funding; Jazz Pharmaceuticals: Consultancy, Research Funding; Sun Pharma: Research Funding; Immunogen: Consultancy, Honoraria, Research Funding; Merus: Consultancy, Honoraria, Research Funding; Biopath Holdings: Consultancy, Honoraria. Pemmaraju:samus: Research Funding; celgene: Consultancy, Honoraria; abbvie: Consultancy, Honoraria, Research Funding; incyte: Consultancy, Research Funding; mustangbio: Consultancy, Research Funding; cellectis: Research Funding; Stemline Therapeutics: Consultancy, Honoraria, Research Funding; novartis: Consultancy, Research Funding; plexxikon: Research Funding; Daiichi-Sankyo: Research Funding; sagerstrong: Research Funding; affymetrix: Research Funding. Daver:Servier: Research Funding; Agios: Consultancy; Abbvie: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Agios: Consultancy; Celgene: Consultancy; Hanmi Pharm Co., Ltd.: Research Funding; Forty-Seven: Consultancy; Forty-Seven: Consultancy; Immunogen: Consultancy, Research Funding; Immunogen: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Astellas: Consultancy; BMS: Consultancy, Research Funding; Astellas: Consultancy; Daiichi Sankyo: Consultancy, Research Funding; Daiichi Sankyo: Consultancy, Research Funding; Jazz: Consultancy; Jazz: Consultancy; NOHLA: Research Funding; Karyopharm: Consultancy, Research Funding; Incyte: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; Servier: Research Funding; Genentech: Consultancy, Research Funding; Incyte: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Karyopharm: Consultancy, Research Funding; Abbvie: Consultancy, Research Funding; Glycomimetics: Research Funding; Sunesis: Consultancy, Research Funding; Otsuka: Consultancy; NOHLA: Research Funding; Celgene: Consultancy; Otsuka: Consultancy; Glycomimetics: Research Funding; Novartis: Consultancy, Research Funding; Sunesis: Consultancy, Research Funding; Hanmi Pharm Co., Ltd.: Research Funding; Pfizer: Consultancy, Research Funding. Ravandi:Cyclacel LTD: Research Funding; Macrogenix: Consultancy, Research Funding; Xencor: Consultancy, Research Funding; Menarini Ricerche: Research Funding; Selvita: Research Funding; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, 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. Borthakur:Cyclacel: Research Funding; AbbVie: Research Funding; Eli Lilly and Co.: Research Funding; Xbiotech USA: Research Funding; Merck: Research Funding; Bayer Healthcare AG: Research Funding; Agensys: Research Funding; Janssen: Research Funding; NKarta: Consultancy; BioTheryX: Membership on an entity's Board of Directors or advisory committees; Arvinas: Research Funding; Incyte: Research Funding; Tetralogic Pharmaceuticals: Research Funding; Strategia Therapeutics: Research Funding; Oncoceutics: Research Funding; BioLine Rx: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Oncoceutics, Inc.: Research Funding; GSK: Research Funding; BMS: Research Funding; Cantargia AB: Research Funding; FTC Therapeutics: Membership on an entity's Board of Directors or advisory committees; Argenx: Membership on an entity's Board of Directors or advisory committees; PTC Therapeutics: Consultancy; Novartis: Research Funding; Eisai: Research Funding; Polaris: Research Funding; AstraZeneca: Research Funding. Short:Takeda Oncology: Consultancy, Research Funding; AstraZeneca: Consultancy; Amgen: Honoraria. Alvarado:Jazz Pharmaceuticals: Research Funding; Abbott: Honoraria. Kadia:AbbVie: Consultancy, Research Funding; Amgen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding; Jazz: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Research Funding; Bioline RX: Research Funding; BMS: Research Funding; Genentech: Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees. Takahashi:Symbio Pharmaceuticals: Consultancy. Jain:Janssen Pharmaceuticals, Inc.: Consultancy, Honoraria, 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; Pharmacyclics, an AbbVie company: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Research Funding; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; ADC Therapeutics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Incyte: Research Funding; AstraZeneca: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Servier: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Cellectis: Research Funding; Verastem: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Precision Biosciences: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Adaptive Biotechnologies: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Sasaki:Otsuka: Honoraria; Pfizer: Consultancy. Andreeff:NIH/NCI: Research Funding; CPRIT: Research Funding; Breast Cancer Research Foundation: Research Funding; Oncolyze: Equity Ownership; Oncoceutics: Equity Ownership; Senti Bio: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Eutropics: Equity Ownership; Aptose: Equity Ownership; Reata: Equity Ownership; 6 Dimensions Capital: Consultancy; Center for Drug Research & Development: Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy; AstaZeneca: Consultancy; Daiichi Sankyo, Inc.: Consultancy, Patents & Royalties: Patents licensed, royalty bearing, Research Funding; Jazz Pharmaceuticals: Consultancy; Celgene: Consultancy; Cancer UK: Membership on an entity's Board of Directors or advisory committees; NCI-CTEP: Membership on an entity's Board of Directors or advisory committees; German Research Council: Membership on an entity's Board of Directors or advisory committees; Leukemia Lymphoma Society: Membership on an entity's Board of Directors or advisory committees; NCI-RDCRN (Rare Disease Cliln Network): Membership on an entity's Board of Directors or advisory committees; CLL Foundation: Membership on an entity's Board of Directors or advisory committees; BiolineRx: Membership on an entity's Board of Directors or advisory committees. Bose:CTI BioPharma: Research Funding; Promedior: Research Funding; NS Pharma: Research Funding; Incyte Corporation: Consultancy, Research Funding, Speakers Bureau; Celgene Corporation: Consultancy, Research Funding; Blueprint Medicine Corporation: Consultancy, Research Funding; Kartos: Consultancy, Research Funding; Constellation: Research Funding; Pfizer: Research Funding; Astellas: Research Funding. Jabbour:Pfizer: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; AbbVie: Consultancy, Research Funding; Adaptive: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; Cyclacel LTD: Research Funding; BMS: Consultancy, Research Funding. Thompson:AbbVie: Research Funding; Amgen: Consultancy, Research Funding; Pfizer: Research Funding; Pharmacyclics: Research Funding; Genentech: Consultancy, Honoraria; Gilead: Consultancy, Honoraria. Zhang:The University of Texas M.D.Anderson Cancer Center: Employment. Kantarjian:Daiichi-Sankyo: Research Funding; BMS: Research Funding; Cyclacel: Research Funding; Ariad: Research Funding; AbbVie: Honoraria, Research Funding; Takeda: Honoraria; Novartis: Research Funding; Pfizer: Honoraria, Research Funding; Jazz Pharma: Research Funding; Immunogen: Research Funding; Amgen: Honoraria, Research Funding; Astex: Research Funding; Agios: Honoraria, Research Funding; Actinium: Honoraria, Membership on an entity's Board of Directors or advisory committees. Konopleva:Genentech: Honoraria, Research Funding; Ascentage: Research Funding; Kisoji: Consultancy, Honoraria; Reata Pharmaceuticals: Equity Ownership, Patents & Royalties; Ablynx: Research Funding; Astra Zeneca: Research Funding; Eli Lilly: Research Funding; Cellectis: Research Funding; Amgen: Consultancy, Honoraria; F. Hoffman La-Roche: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria, Research Funding; Forty-Seven: Consultancy, Honoraria; Stemline Therapeutics: Consultancy, Honoraria, Research Funding; Calithera: Research Funding; Agios: Research Funding. DiNardo:agios: Consultancy, Honoraria; medimmune: Honoraria; notable labs: Membership on an entity's Board of Directors or advisory committees; syros: Honoraria; jazz: Honoraria; abbvie: Consultancy, Honoraria; celgene: Consultancy, Honoraria; daiichi sankyo: Honoraria. OffLabel Disclosure: FLT3 inhibitors, used in combination with decitabine and venetoclax

Abstract: Background: Elderly patients (pt) with acute myeloid leukemia (AML) or pts with relapsed/refractory (R/R) AML have dismal outcomes. Venetoclax (VEN) synergizes with hypomethylating agents (HMA) and is now an approved combination for newly diagnosed (ND) AML in older/intensive chemotherapy (IC)-ineligible patients. We hypothesized that VEN with 10-day decitabine (DEC) may offer superior efficacy in AML. Methods: Between January and November 2018 we enrolled 101 pts with ND AML (n=40), untreated secondary AML (sAML, n=9), treated sAML (n=19) and R/R AML (n=33). Eligibility included ECOG PS ≤3, WBC ≤10 x109/L, and adequate organ function. DEC was given 20 mg/m2 IV daily on day 1-10 until CR/CRi, followed by 5-day cycles. VEN was given on day 1-28 in cycle 1 but was interrupted on C1D21 until count recovery if the day 21 bone marrow (BM) had ≤5% blasts. VEN could be reduced further to 14, 10 or 7 days in subsequent cycles for pts with ongoing cytopenias/myelosuppression. VEN dose was 400 mg PO daily (reductions allowed for concomitant CYP3A4 inhibitors) All pts received tumor lysis syndrome (TLS) prophylaxis. Cytoreduction prior to start, and concomitant BCR-ABL1 (n=1) and FLT3 inhibitors (n=15) were allowed as indicated. Primary objective was overall response rate and secondary objectives included safety and overall survival. The data cut-off date was 03.08.19. Results: This high-risk cohort included 52% of pts ≥70 yrs (interquartile range [IQR], 61-74), 54% pts were men, 28% pts had ECOG PS ≥2, and 67% pts had adverse-risk AML (Table 1). 30 and 60-day mortality were both 2.5% for ND pts, and 5% and 9%, respectively, for all pts. Notable treatment-emergent adverse events were infections with grade 3/4 neutropenia (61%), febrile neutropenia (35%), and TLS (4%, Table 2). Four pts developed grade 3 or 4 reversible TLS; their median WBC count was 7.1x109/L (1.6, 2.1, 12, 28) and median peripheral blasts was 64% (IQR 39-83) and led to a subsequent requirement for WBC ≤10 x109/L prior to start. The CR/CRi rate in ND AML was 95%, in untreated sAML was 67%, in treated sAML was 37%, and in R/R AML was 27% (Table 3). Out of 67 pts with C1D21±3 BM, ≤5% blasts was achieved in 57%, and 74% of ND pts. In previously untreated AML (defined as ND AML + untreated sAML), CR/CRi rate in ELN favorable, intermediate and adverse risk pts were 100% (n=11), 100% (n=6), and 84% (n=32). CR/CRi rate in t-AML was 100% (n=7). In previously treated AML (treated sAML + R/R AML), CR/CRi rate in HMA refractory pts was 39% (n=18), in pts with prior IC was 21% (n=33), in pts with prior HMA and IC was 17% (n=12), in pts with prior stem cell transplantation (SCT) was 22% (n=18). At median follow-up of 8.1 months (mo), the 6-mo OS in ND AML was 90%, in untreated sAML was 56%, in treated sAML was 62%, and R/R AML was 53% (Fig. 1). Among all pts, achievement of CR conferred better duration of response (DOR) and OS compared to CRi/MLFS (median DOR not reached [NR] vs 4.0 mo, censored at SCT, hazard ratio [HR] 0.21, 95% confidence interval [CI] 0.09-0.49, p=0.002, and median OS NR vs 7.8 mo, censored at SCT, HR 0.31, 95% CI 0.13-0.74). 70% of all responding pts were minimal residual disease negative (MRD-) by flow cytometry and MRD- status was associated with longer OS (NR vs 7.8 mo, censored at SCT, HR 0.35, 95% CI 0.14-0.88, p=0.01, Fig. 2a). Median DOR in pts achieving CR/CRi in ND AML was 8.5 mo, in the untreated sAML was 6.3 mo, in treated sAML was 4.8 mo, and in R/R AML was 6.6 mo. Among ND AML pts achieving CR/CRi, median time to count recovery after 1st, 2nd and 3rd cycles for ANC 〉 0.5x109/L was 42 days (95% CI 37-46), 40 days (95% CI 35-44), and 38 days (95% CI 32-NR), respectively; and for platelet ≥50 x109/L was 28 days (95% CI 25-32), 25 days (95% CI 0-34), and 26 days (95% CI 19-33), respectively. 78 pts (77%) discontinued treatment, and 59 pts (58%) are alive. Common reasons for discontinuation were non-response in 24 pts (24%), SCT in 20 pts (20%), and relapse in 18 pts (18%). Pts receiving SCT (n= 20) had excellent outcomes with 100-day post-SCT mortality of 0% (Fig 2b and c). Baseline BCL2 expression in CD34+ blasts showed a trend between higher BCL2 expression and MRD- rate (Fig. 2d). Conclusions: DEC10-VEN is an effective therapy for ND elderly pts, as well as in R/R AML as an effective bridge to SCT. Trial continues to accrue (NCT03404193). Disclosures Maiti: Celgene: Other: research funding. DiNardo:jazz: Honoraria; medimmune: Honoraria; abbvie: Consultancy, Honoraria; daiichi sankyo: Honoraria; celgene: Consultancy, Honoraria; agios: Consultancy, Honoraria; notable labs: Membership on an entity's Board of Directors or advisory committees; syros: Honoraria. Cortes:Astellas Pharma: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; Daiichi Sankyo: Consultancy, Honoraria, Research Funding; Forma Therapeutics: Consultancy, Honoraria, Research Funding; Biopath Holdings: Consultancy, Honoraria; BiolineRx: Consultancy; Immunogen: Consultancy, Honoraria, Research Funding; Sun Pharma: Research Funding; Jazz Pharmaceuticals: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Merus: Consultancy, Honoraria, Research Funding. Pemmaraju:mustangbio: Consultancy, Research Funding; abbvie: Consultancy, Honoraria, Research Funding; samus: Research Funding; celgene: Consultancy, Honoraria; cellectis: Research Funding; Stemline Therapeutics: Consultancy, Honoraria, Research Funding; novartis: Consultancy, Research Funding; plexxikon: Research Funding; Daiichi-Sankyo: Research Funding; sagerstrong: Research Funding; affymetrix: Research Funding; incyte: Consultancy, Research Funding. Daver:Pfizer: Consultancy, Research Funding; Servier: Research Funding; Hanmi Pharm Co., Ltd.: Research Funding; Novartis: Consultancy, Research Funding; Abbvie: Consultancy, Research Funding; Jazz: Consultancy; Servier: Research Funding; Daiichi Sankyo: Consultancy, Research Funding; Karyopharm: Consultancy, Research Funding; Astellas: Consultancy; Incyte: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Immunogen: Consultancy, Research Funding; Sunesis: Consultancy, Research Funding; NOHLA: Research Funding; Forty-Seven: Consultancy; Novartis: Consultancy, Research Funding; Glycomimetics: Research Funding; Agios: Consultancy; Otsuka: Consultancy; Abbvie: Consultancy, Research Funding; Celgene: Consultancy; Genentech: Consultancy, Research Funding; Hanmi Pharm Co., Ltd.: Research Funding; Incyte: Consultancy, Research Funding; NOHLA: Research Funding; Glycomimetics: Research Funding; Celgene: Consultancy; Agios: Consultancy; Genentech: Consultancy, Research Funding; Sunesis: Consultancy, Research Funding; Karyopharm: Consultancy, Research Funding; Otsuka: Consultancy; Pfizer: Consultancy, Research Funding. Ravandi:Menarini Ricerche: Research Funding; Cyclacel LTD: Research Funding; Macrogenix: Consultancy, Research Funding; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Selvita: Research Funding; Xencor: Consultancy, Research Funding. Garcia-Manero:AbbVie: Research Funding; Celgene: Consultancy, Research Funding; Astex: Consultancy, Research Funding; Onconova: Research Funding; H3 Biomedicine: Research Funding; Merck: Research Funding; Amphivena: Consultancy, Research Funding; Helsinn: Research Funding; Novartis: Research Funding. Borthakur:BMS: Research Funding; Argenx: Membership on an entity's Board of Directors or advisory committees; Eisai: Research Funding; Tetralogic Pharmaceuticals: Research Funding; Novartis: Research Funding; Strategia Therapeutics: Research Funding; Cyclacel: Research Funding; BioLine Rx: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; AstraZeneca: Research Funding; PTC Therapeutics: Consultancy; Arvinas: Research Funding; Oncoceutics: Research Funding; GSK: Research Funding; Janssen: Research Funding; Incyte: Research Funding; AbbVie: Research Funding; Xbiotech USA: Research Funding; Merck: Research Funding; Bayer Healthcare AG: Research Funding; BioTheryX: Membership on an entity's Board of Directors or advisory committees; Eli Lilly and Co.: Research Funding; Cantargia AB: Research Funding; NKarta: Consultancy; Agensys: Research Funding; Polaris: Research Funding; Oncoceutics, Inc.: Research Funding; FTC Therapeutics: Membership on an entity's Board of Directors or advisory committees. Short:Takeda Oncology: Consultancy, Research Funding; AstraZeneca: Consultancy; Amgen: Honoraria. Alvarado:Jazz Pharmaceuticals: Research Funding; Abbott: Honoraria. Kadia:Amgen: Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Research Funding; Bioline RX: Research Funding; Celgene: Research Funding; Jazz: Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Consultancy, Research Funding; Genentech: Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees. Takahashi:Symbio Pharmaceuticals: Consultancy. Jain:Pharmacyclics, an AbbVie company: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen Pharmaceuticals, Inc.: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Precision Biosciences: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Research Funding; Genentech: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Verastem: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; ADC Therapeutics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AstraZeneca: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Servier: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Cellectis: Research Funding; Adaptive Biotechnologies: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Incyte: Research Funding; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Sasaki:Otsuka: Honoraria; Pfizer: Consultancy. Andreeff:Daiichi Sankyo, Inc.: Consultancy, Patents & Royalties: Patents licensed, royalty bearing, Research Funding; Celgene: Consultancy; Jazz Pharmaceuticals: Consultancy; Amgen: Consultancy; AstaZeneca: Consultancy; 6 Dimensions Capital: Consultancy; Reata: Equity Ownership; Aptose: Equity Ownership; Eutropics: Equity Ownership; Senti Bio: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Oncoceutics: Equity Ownership; Oncolyze: Equity Ownership; Breast Cancer Research Foundation: Research Funding; CPRIT: Research Funding; NIH/NCI: Research Funding; Center for Drug Research & Development: Membership on an entity's Board of Directors or advisory committees; Cancer UK: Membership on an entity's Board of Directors or advisory committees; NCI-CTEP: Membership on an entity's Board of Directors or advisory committees; German Research Council: Membership on an entity's Board of Directors or advisory committees; Leukemia Lymphoma Society: Membership on an entity's Board of Directors or advisory committees; NCI-RDCRN (Rare Disease Cliln Network): Membership on an entity's Board of Directors or advisory committees; CLL Foundation: Membership on an entity's Board of Directors or advisory committees; BiolineRx: Membership on an entity's Board of Directors or advisory committees. Bose:Blueprint Medicine Corporation: Consultancy, Research Funding; Incyte Corporation: Consultancy, Research Funding, Speakers Bureau; Celgene Corporation: Consultancy, Research Funding; Kartos: Consultancy, Research Funding; Constellation: Research Funding; Pfizer: Research Funding; Astellas: Research Funding; NS Pharma: Research Funding; Promedior: Research Funding; CTI BioPharma: Research Funding. Jabbour:Cyclacel LTD: Research Funding; Pfizer: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; AbbVie: Consultancy, Research Funding; Adaptive: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Takeda: Consultancy, Research Funding. Thompson:AbbVie: Research Funding; Amgen: Consultancy, Research Funding; Pfizer: Research Funding; Pharmacyclics: Research Funding; Genentech: Consultancy, Honoraria; Gilead: Consultancy, Honoraria. Zhang:The University of Texas M.D.Anderson Cancer Center: Employment. Kantarjian:Amgen: Honoraria, Research Funding; Actinium: Honoraria, Membership on an entity's Board of Directors or advisory committees; Cyclacel: Research Funding; BMS: Research Funding; Daiichi-Sankyo: Research Funding; Novartis: Research Funding; Jazz Pharma: Research Funding; Astex: Research Funding; Immunogen: Research Funding; AbbVie: Honoraria, Research Funding; Agios: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; Takeda: Honoraria; Ariad: Research Funding. Konopleva:Forty-Seven: Consultancy, Honoraria; Genentech: Honoraria, Research Funding; Ablynx: Research Funding; Kisoji: Consultancy, Honoraria; Astra Zeneca: Research Funding; Ascentage: Research Funding; Cellectis: Research Funding; Amgen: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria, Research Funding; Reata Pharmaceuticals: Equity Ownership, Patents & Royalties; F. Hoffman La-Roche: Consultancy, Honoraria, Research Funding; Calithera: Research Funding; Agios: Research Funding; Stemline Therapeutics: Consultancy, Honoraria, Research Funding; Eli Lilly: Research Funding.

Abstract: Background: Acute myeloid leukemia (AML) outcomes in the elderly, particularly intensive chemotherapy (IC)-ineligible patients (pts), are poor. Venetoclax (VEN), a BCL2 inhibitor, in combination with low-intensity regimens has shown excellent efficacy in AML and is approved for IC-ineligible pts as frontline therapy. Outcomes and expectations of AML after failure of frontline VEN-based regimens are unknown. Methods: We conducted a retrospective study to determine pt outcomes after failure of frontline therapy with VEN and hypomethylating agents (HMA). Newly diagnosed (ND) AML pts enrolled on 2 clinical trials of VEN+HMA (NCT02203773, NCT03404193) with refractory AML or relapse after initial response to VEN+HMA were included. In 1 trial, ND IC-ineligible AML pts (≥65 years [yr]) received VEN 400-1200 mg daily with decitabine (DEC) for 5 days or azacitidine (AZA) for 7 days. The other trial enrolled ND IC-ineligible AML pts ( & gt;60 yrs) who received VEN 400 mg daily or equivalent with DEC for 10 days until CR/CRi, followed by 5-day cycles. FLT3 inhibitors (FLT3i) were allowed in FLT3mut pts. Overall survival (OS) was measured from date of diagnosis of refractory AML or relapse after VEN+HMA therapy, till death or censored at last follow-up. The data cut-off date was 07.08.19. Results: Between November 2014 and February 2019, out of 103 ND AML pts treated with VEN+HMA, 41 pts were identified to have refractory AML, or relapse after VEN+HMA. The median age was 74 yrs (range 62-85), 12 pts (29%) had sAML, 7 pts (17%) had therapy-related AML, 33 pts (81%) had ELN adverse risk AML, 16 pts (39%) had TP53mut, 12 pts (29%) had N/KRASmut, and 5 pts (12%) had FLT3-ITD (Table 1, Fig 1). Pts had received a median of 4 cycles of VEN+HMA (range 1-29). The median follow-up duration for all pts was 21.2 months (mo). With frontline VEN+ HMA, 19 pts (46%) achieved CR, 11 pts (27%) achieved CRi, 3 pts (7%) achieved morphologic leukemia free state (MLFS), and 8 pts (20%) had primary refractory disease. Pts obtaining initial response relapsed after a median duration of response (DOR) of 5.3 mo (range 0.9-34.1). After VEN+ HMA failure, median OS for all 41 pts was 2.4 mo (range 0.1-21.2, Fig 2a). Pts who received salvage therapy (n=24) had longer OS compared to pts who did not receive salvage therapy (n=17, 2.9 vs 1.3 mo, HR=0.41, 95% CI 0.19-0.88, p=0.003, Fig 2b). Median OS for de novo AML at relapse/failure was 2.5 mo, for sAML was 2.8 mo, and for t-AML was 1.1 mo (Fig 2c). Pts with primary refractory AML vs relapsed AML had comparable OS of 1.7 mo vs 2.3 mo, respectively (Fig 2d). Of the 24 pts who received salvage therapy (Table 2, Fig 2e), 5 pts (21%) responded; CR in 1 pt, CRi in 2 pts and MLFS in 2 pts. Among 3 pts with primary refractory AML, 1 pt achieved CR and 1 pt achieved MLFS. Among 21 pts with relapse after VEN+HMA, 2 pts achieved CRi and 1 pt achieved MLFS. 8 pts received IC, and 2/8 pts (notably both with NRASmut) achieved CR and CRi with CLIA, and CLIA + gemtuzumab ozogamicin, respectively. 7 pts received HMA-based regimens, and 2/7 pts responded with CRi and MLFS with AZA + quizartinib, and AZA + nivolumab + ipilimumab, respectively. The former pt had FLT3-ITD and NRASmut and the latter pt had TP53mut. Of the remaining 9 pts receiving other therapies, 1 pt with FLT3-ITD achieved a MLFS with quizartinib + low-dose ara-c. These 5 responding pts continue in remission with median DOR not reached (NR, range 0.7-20.1, Fig 2f) and OS also NR (range, 2-21.2). All pts with NPM1mut and IDH1/2mut who relapsed had adverse-risk cytogenetics or co-occurring mutations in TP53, N/KRAS, FLT3, and/or KIT. Of FLT3-ITDmut pts, 2 of 5 pts (40%) responded to salvage therapy including a FLT3i. Of 11 RASmut pts, 3 pts (27%) responded to salvage therapy including both IC and HMA-based regimens. 1 of 6 TP53mut pts receiving salvage therapy achieved MLFS with AZA + nivolumab + ipilimumab. This pt was also the only one among 7 pts with complex cytogenetics who responded to salvage therapy. Conclusion: Older IC-ineligible pts with ND AML who fail frontline VEN+HMA have high-risk disease biology including t-AML, sAML, complex cytogenetics, FLT3-ITD, TP53mut, N/KRASmut. These known high-risk features decrease likelihood of response and confer poor OS, confirmed in this analysis. The median OS after frontline VEN+HMA failure was 2.4 mo. Notably some pts with FLT3-ITD responded well to salvage regimens with FLT3i. Novel therapies to abrogate VEN resistance, especially in high risk genotypes, are urgently needed. Disclosures Maiti: Celgene: Other: research funding. Cortes:Takeda: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Forma Therapeutics: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; Jazz Pharmaceuticals: Consultancy, Research Funding; Daiichi Sankyo: Consultancy, Honoraria, Research Funding; Astellas Pharma: Consultancy, Honoraria, Research Funding; Sun Pharma: Research Funding; Biopath Holdings: Consultancy, Honoraria; BiolineRx: Consultancy; Novartis: Consultancy, Honoraria, Research Funding; Immunogen: Consultancy, Honoraria, Research Funding; Merus: Consultancy, Honoraria, Research Funding. Pemmaraju:mustangbio: Consultancy, Research Funding; abbvie: Consultancy, Honoraria, Research Funding; samus: Research Funding; celgene: Consultancy, Honoraria; cellectis: Research Funding; Stemline Therapeutics: Consultancy, Honoraria, Research Funding; novartis: Consultancy, Research Funding; plexxikon: Research Funding; Daiichi-Sankyo: Research Funding; sagerstrong: Research Funding; affymetrix: Research Funding; incyte: Consultancy, Research Funding. Daver:Immunogen: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Hanmi Pharm Co., Ltd.: Research Funding; Jazz: Consultancy; Daiichi Sankyo: Consultancy, Research Funding; Servier: Research Funding; Abbvie: Consultancy, Research Funding; Forty-Seven: Consultancy; Glycomimetics: Research Funding; Celgene: Consultancy; Astellas: Consultancy; Immunogen: Consultancy, Research Funding; Daiichi Sankyo: Consultancy, Research Funding; Astellas: Consultancy; Celgene: Consultancy; NOHLA: Research Funding; Agios: Consultancy; Otsuka: Consultancy; BMS: Consultancy, Research Funding; Sunesis: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Servier: Research Funding; Glycomimetics: Research Funding; Pfizer: Consultancy, Research Funding; NOHLA: Research Funding; Genentech: Consultancy, Research Funding; Sunesis: Consultancy, Research Funding; Incyte: Consultancy, Research Funding; Abbvie: Consultancy, Research Funding; Karyopharm: Consultancy, Research Funding; Agios: Consultancy; Karyopharm: Consultancy, Research Funding; Forty-Seven: Consultancy; Otsuka: Consultancy; Jazz: Consultancy; Incyte: Consultancy, Research Funding; Hanmi Pharm Co., Ltd.: Research Funding. Ravandi:Xencor: Consultancy, Research Funding; Macrogenix: Consultancy, Research Funding; Selvita: Research Funding; Cyclacel LTD: Research Funding; Menarini Ricerche: Research Funding; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, 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. Borthakur:AstraZeneca: Research Funding; BioLine Rx: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; NKarta: Consultancy; Cyclacel: Research Funding; Janssen: Research Funding; Incyte: Research Funding; Novartis: Research Funding; Xbiotech USA: Research Funding; Eisai: Research Funding; Tetralogic Pharmaceuticals: Research Funding; Polaris: Research Funding; Arvinas: Research Funding; Merck: Research Funding; Cantargia AB: Research Funding; FTC Therapeutics: Membership on an entity's Board of Directors or advisory committees; Argenx: Membership on an entity's Board of Directors or advisory committees; BioTheryX: Membership on an entity's Board of Directors or advisory committees; PTC Therapeutics: Consultancy; Strategia Therapeutics: Research Funding; Bayer Healthcare AG: Research Funding; Agensys: Research Funding; Oncoceutics: Research Funding; GSK: Research Funding; BMS: Research Funding; Oncoceutics, Inc.: Research Funding; Eli Lilly and Co.: Research Funding; AbbVie: Research Funding. Short:Takeda Oncology: Consultancy, Research Funding; Amgen: Honoraria; AstraZeneca: Consultancy. Alvarado:Jazz Pharmaceuticals: Research Funding; Abbott: Honoraria. Kadia:Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bioline RX: Research Funding; BMS: Research Funding; Amgen: 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; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Research Funding; Celgene: Research Funding; Jazz: Membership on an entity's Board of Directors or advisory committees, Research Funding. Takahashi:Symbio Pharmaceuticals: Consultancy. Jain:Adaptive Biotechnologies: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen Pharmaceuticals, Inc.: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Servier: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Cellectis: Research Funding; Verastem: 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; Pharmacyclics, an AbbVie company: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Precision Biosciences: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; ADC Therapeutics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Incyte: Research Funding; AstraZeneca: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Research Funding; Genentech: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Sasaki:Otsuka: Honoraria; Pfizer: Consultancy. Andreeff:BiolineRx: Membership on an entity's Board of Directors or advisory committees; Leukemia Lymphoma Society: Membership on an entity's Board of Directors or advisory committees; CLL Foundation: Membership on an entity's Board of Directors or advisory committees; German Research Council: Membership on an entity's Board of Directors or advisory committees; NCI-CTEP: Membership on an entity's Board of Directors or advisory committees; Cancer UK: Membership on an entity's Board of Directors or advisory committees; Center for Drug Research & Development: Membership on an entity's Board of Directors or advisory committees; NIH/NCI: Research Funding; CPRIT: Research Funding; Breast Cancer Research Foundation: Research Funding; Oncolyze: Equity Ownership; Oncoceutics: Equity Ownership; Senti Bio: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Eutropics: Equity Ownership; Aptose: Equity Ownership; Daiichi Sankyo, Inc.: Consultancy, Patents & Royalties: Patents licensed, royalty bearing, Research Funding; Jazz Pharmaceuticals: Consultancy; Celgene: Consultancy; Amgen: Consultancy; AstaZeneca: Consultancy; 6 Dimensions Capital: Consultancy; Reata: Equity Ownership; NCI-RDCRN (Rare Disease Cliln Network): Membership on an entity's Board of Directors or advisory committees. Bose:Incyte Corporation: Consultancy, Research Funding, Speakers Bureau; Celgene Corporation: Consultancy, Research Funding; Blueprint Medicine Corporation: Consultancy, Research Funding; Kartos: Consultancy, Research Funding; Constellation: Research Funding; Pfizer: Research Funding; Astellas: Research Funding; NS Pharma: Research Funding; Promedior: Research Funding; CTI BioPharma: Research Funding. Jabbour:Takeda: Consultancy, Research Funding; Cyclacel LTD: Research Funding; Pfizer: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Adaptive: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; AbbVie: Consultancy, Research Funding. Thompson:AbbVie: Research Funding; Amgen: Consultancy, Research Funding; Pfizer: Research Funding; Pharmacyclics: Research Funding; Genentech: Consultancy, Honoraria; Gilead: Consultancy, Honoraria. Zhang:The University of Texas M.D.Anderson Cancer Center: Employment. Kantarjian:Agios: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Immunogen: Research Funding; Daiichi-Sankyo: Research Funding; Pfizer: Honoraria, Research Funding; Ariad: Research Funding; Cyclacel: Research Funding; Jazz Pharma: Research Funding; Actinium: Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Honoraria, Research Funding; Novartis: Research Funding; Takeda: Honoraria; Astex: Research Funding; BMS: Research Funding. Konopleva:Calithera: Research Funding; Stemline Therapeutics: Consultancy, Honoraria, Research Funding; Forty-Seven: Consultancy, Honoraria; Kisoji: Consultancy, Honoraria; Ascentage: Research Funding; Eli Lilly: Research Funding; AbbVie: Consultancy, Honoraria, Research Funding; Cellectis: Research Funding; Amgen: Consultancy, Honoraria; Genentech: Honoraria, Research Funding; F. Hoffman La-Roche: Consultancy, Honoraria, Research Funding; Astra Zeneca: Research Funding; Agios: Research Funding; Reata Pharmaceuticals: Equity Ownership, Patents & Royalties; Ablynx: Research Funding. DiNardo:jazz: Honoraria; abbvie: Consultancy, Honoraria; celgene: Consultancy, Honoraria; medimmune: Honoraria; syros: Honoraria; notable labs: Membership on an entity's Board of Directors or advisory committees; agios: Consultancy, Honoraria; daiichi sankyo: Honoraria.

Abstract: Background: Older patients (pt) with acute myeloid leukemia (AML) and patients with high-risk myelodysplastic syndrome / chronic myelomonocytic leukemia (HR MDS/CMML) have poor outcomes. We showed that 10-day decitabine with venetoclax (DEC10-VEN) is a safe and effective strategy and offers potentially better outcomes compared to intensive chemotherapy in older pts with newly diagnosed (ND) AML, as well as relapsed or refractory (R/R) AML (DiNardo et al. Lancet Haematol 2020; Maiti et al. Am J Hematol 2021; Maiti et al. Cancer 2021). We here in present updated results of this prospective phase II trial (NCT03404193). Methods: Eligibility criteria included ECOG PS ≤3, WBC ≤10 x10 9/L, and adequate organ function. Decitabine dose was 20 mg/m 2 IV daily on D1-10 until CR/CRi, followed by 5-day cycles. Venetoclax was given on D1-28 in cycle 1 but was interrupted on C1D21 until count recovery if the D21 bone marrow (BM) had ≤5% blasts. Venetoclax dose was 400 mg PO daily or equivalent with concomitant azole antifungals as previously described (DiNardo et al. Lancet Haematol. 2020). Venetoclax duration could be reduced to 14 to 7 days in subsequent cycles in cases of prolonged myelosuppression. All pts received cytoreduction prior to start, tumor lysis syndrome (TLS) prophylaxis and antimicrobial prophylaxis. Concomitant FLT3 tyrosine kinase inhibitors were allowed in FLT3-mutated AML. Pts could proceed to allogeneic stem-cell transplantation (SCT) after response, if eligible. Primary objective was overall response rate and secondary objectives included safety and overall survival. Outcomes and endpoints were defined per ELN2017 criteria. Measurable residual disease (MRD) was assessed using multiparametric flow cytometry (sensitivity 0.1%) and reported for all responding pts with evaluable MRD sample. Results: Between January 2018 and April 2021 we enrolled 219 pts with ND AML (n=83), untreated sAML (n=20), treated sAML (n=25), R/R AML (n=71) and HR MDS/CMML (n=20). This high-risk cohort included 54% of pts ≥70 yrs (n=119), 57% pts were men, 29% pts had ECOG PS ≥2, and 57% pts had adverse-risk AML (Table 1). The 30 mortality was 1% for ND pts and 3.6% for all pts. There were 346 treatment-related adverse events in 181 patients including infections with grade 3/4 neutropenia (40%), febrile neutropenia (29%), and infection with unknown ANC (17%, Table 2). There were 11 grade 5 events including infections with grade 3/4 neutropenia (n=6), infections with unknown ANC (n=4), and renal failure (n=1). The CR/CRi rate in ND AML was 83%, in untreated sAML was 65%, in treated sAML was 40%, in R/R AML was 42% and in HR-MDS/CMML was 20% (Table 3). Rates of negative measurable residual disease (MRD) by flow cytometry (0.1%) in ND AML was 73%, in untreated sAML was 53%, in treated sAML was 65%, and in R/R AM was 58%. After a median follow-up of 24.7 months (mo), the median OS in ND AML was 16.2 mo, in untreated sAML was 10.7 mo, in treated sAML was 5.8 mo, in R/R AML was 7.8 mo, and in HR-MDS/CMML was 10.1 mo (Fig. 1a). The 1-yr OS in ND AML was 54%, in untreated sAML was 41%, in treated sAML was 36%, in R/R AML was 41%, and in HR MDS/CMML was 35%. Median RFS for pts with ND AML was 10.9 mo, in the untreated sAML was 6.7 mo, in treated sAML was 11.4 mo, and in R/R AML was 8.4 mo (Fig. 1b). 44 pts underwent SCT after achieving response including ND AML (n=17), untreated sAML (n=4), treated sAML (n=3), R/R AML (n=16), and HR-MDS/CMML (n=4). The 100-day post-SCT mortality was 9% (n=4). Median OS after SCT in pts with previously untreated AML was 31.1 mo and in previously treated AML was 15.0 mo (Fig. 1c) 199 pts (91%) have discontinued treatment and 69 pts (32%) are alive. The most common reasons for treatment discontinuation included refractory disease in 49 pts (22%), relapse in 45 pts (21%), SCT in 44 pts (20%). Conclusions: DEC10-VEN is an effective therapy for older pts with ND and R/R AML. Transition to SCT after response with DEC10-VEN may offer long-term survival advantage in this older/unfit population with both ND and R/R AML. The trial continues to accrue. Based on these findings we have initiated a phase II trial of 10-day oral decitabine (ASTX727) with venetoclax in R/R AML (NCT04975919). Figure 1 Figure 1. Disclosures DiNardo: GlaxoSmithKline: Membership on an entity's Board of Directors or advisory committees; Notable Labs: Current holder of stock options in a privately-held company, Membership on an entity's Board of Directors or advisory committees; ImmuneOnc: Honoraria, Research Funding; Forma: Honoraria, Research Funding; Bristol Myers Squibb: Honoraria, Research Funding; AbbVie: Consultancy, Research Funding; Agios/Servier: Consultancy, Honoraria, Research Funding; Takeda: Honoraria; Novartis: Honoraria; Foghorn: Honoraria, Research Funding; Celgene, a Bristol Myers Squibb company: Honoraria, Research Funding. Pemmaraju: DAVA Oncology: Consultancy; ASCO Leukemia Advisory Panel: Membership on an entity's Board of Directors or advisory committees; Dan's House of Hope: Membership on an entity's Board of Directors or advisory committees; HemOnc Times/Oncology Times: Membership on an entity's Board of Directors or advisory committees; Sager Strong Foundation: Other; Cellectis S.A. ADR: Other, Research Funding; CareDx, Inc.: Consultancy; Springer Science + Business Media: Other; MustangBio: Consultancy, Other; Stemline Therapeutics, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding; LFB Biotechnologies: Consultancy; Daiichi Sankyo, Inc.: Other, Research Funding; Affymetrix: Consultancy, Research Funding; Roche Diagnostics: Consultancy; Samus: Other, Research Funding; Blueprint Medicines: Consultancy; Clearview Healthcare Partners: Consultancy; Novartis Pharmaceuticals: Consultancy, Other: Research Support, Research Funding; Celgene Corporation: Consultancy; Incyte: Consultancy; Protagonist Therapeutics, Inc.: Consultancy; Abbvie Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding; Plexxicon: Other, Research Funding; Aptitude Health: Consultancy; ASH Communications Committee: Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb Co.: Consultancy; ImmunoGen, Inc: Consultancy; Pacylex Pharmaceuticals: Consultancy. Daver: Novartis: Consultancy; Jazz Pharmaceuticals: Consultancy, Other: Data Monitoring Committee member; Trovagene: Consultancy, Research Funding; Abbvie: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; FATE Therapeutics: Research Funding; Hanmi: Research Funding; Amgen: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Bristol Myers Squibb: Consultancy, Research Funding; Novimmune: Research Funding; Astellas: Consultancy, Research Funding; Daiichi Sankyo: Consultancy, Research Funding; Sevier: Consultancy, Research Funding; ImmunoGen: Consultancy, Research Funding; Glycomimetics: Research Funding; Gilead Sciences, Inc.: Consultancy, Research Funding; Trillium: Consultancy, Research Funding; Dava Oncology (Arog): Consultancy; Celgene: Consultancy; Syndax: Consultancy; Shattuck Labs: Consultancy; Agios: Consultancy; Kite Pharmaceuticals: Consultancy; SOBI: Consultancy; STAR Therapeutics: Consultancy; Karyopharm: Research Funding; Newave: Research Funding. Issa: Kura Oncology: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Syndax Pharmaceuticals: Research Funding. Borthakur: Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; GSK: Consultancy; ArgenX: Membership on an entity's Board of Directors or advisory committees; Ryvu: Research Funding; University of Texas MD Anderson Cancer Center: Current Employment; Astex: Research Funding; Protagonist: Consultancy. Ravandi: Astex: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Taiho: Honoraria, Research Funding; Bristol Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Xencor: Honoraria, Research Funding; Agios: Honoraria, Research Funding; AstraZeneca: Honoraria; Prelude: Research Funding; Novartis: Honoraria; AbbVie: Honoraria, Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Jazz: Honoraria, Research Funding; Syros Pharmaceuticals: Consultancy, Honoraria, Research Funding. Alvarado: MEI Pharma: Research Funding; Astex Pharmaceuticals: Research Funding; FibroGen: Research Funding; Jazz Pharmaceuticals: Research Funding; Daiichi-Sankyo: Research Funding; BerGenBio: Research Funding; CytomX Therapeutics: Consultancy; Sun Pharma: Consultancy, Research Funding. Kadia: AbbVie: Consultancy, Other: Grant/research support; Cure: Speakers Bureau; Genfleet: Other; Cellonkos: Other; Sanofi-Aventis: Consultancy; Liberum: Consultancy; Astellas: Other; AstraZeneca: Other; Jazz: Consultancy; Genentech: Consultancy, Other: Grant/research support; BMS: Other: Grant/research support; Dalichi Sankyo: Consultancy; Ascentage: Other; Pulmotech: Other; Novartis: Consultancy; Pfizer: Consultancy, Other; Aglos: Consultancy; Amgen: Other: Grant/research support. Short: Takeda Oncology: Consultancy, Research Funding; Amgen: Consultancy, Honoraria; Astellas: Research Funding; AstraZeneca: Consultancy; Jazz Pharmaceuticals: Consultancy; NGMBio: Consultancy; Novartis: Honoraria. Jabbour: Amgen, AbbVie, Spectrum, BMS, Takeda, Pfizer, Adaptive, Genentech: Research Funding. Jain: Bristol Myers Squibb: Honoraria, Research Funding; AstraZeneca: Honoraria, Research Funding; Pfizer: Research Funding; Servier: Honoraria, Research Funding; Janssen: Honoraria; Incyte: Research Funding; Adaptive Biotechnologies: Honoraria, Research Funding; Precision Biosciences: Honoraria, Research Funding; Aprea Therapeutics: Research Funding; Fate Therapeutics: Research Funding; Beigene: Honoraria; Cellectis: Honoraria, Research Funding; ADC Therapeutics: Honoraria, Research Funding; TG Therapeutics: Honoraria; Genentech: Honoraria, Research Funding; AbbVie: Honoraria, Research Funding; Pharmacyclics: Research Funding. Wierda: Janssen: Research Funding; Karyopharm: Research Funding; Genentech: Research Funding; Xencor: Research Funding; Pharmacyclics LLC, an AbbVie Company: Research Funding; Acerta Pharma Inc.: Research Funding; AstraZeneca: Research Funding; Juno Therapeutics: Research Funding; Gilead Sciences: Research Funding; Cyclacel: Research Funding; Oncternal Therapeutics, Inc.: Research Funding; Miragen: Research Funding; Sunesis: Research Funding; GSK/Novartis: Research Funding; KITE Pharma: Research Funding; Loxo Oncology, Inc.: Research Funding; Genzyme Corporation: Consultancy; AbbVie: Research Funding. Sasaki: Novartis: Consultancy, Research Funding; Pfizer: Membership on an entity's Board of Directors or advisory committees; Daiichi-Sankyo: Membership on an entity's Board of Directors or advisory committees. Takahashi: Novartis: Consultancy; Celgene/BMS: Consultancy; GSK: Consultancy; Symbio Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees. Yilmaz: Daiichi-Sankyo: Research Funding; Pfizer: Research Funding. Burger: AstraZeneca: Consultancy; Gilead: Consultancy, Other: Travel/Accommodations/Expenses, Research Funding, Speakers Bureau; Pharmacyclics LLC: Consultancy, Other: Travel/Accommodations/Expenses, Research Funding, Speakers Bureau; TG Therapeutics: Other: Travel/Accommodations/Expenses, Research Funding, Speakers Bureau; Novartis: Other: Travel/Accommodations/Expenses, Speakers Bureau; Beigene: Research Funding, Speakers Bureau; Janssen: Consultancy, Other: Travel/Accommodations/Expenses, Speakers Bureau. Verstovsek: CTI BioPharma: Research Funding; Ital Pharma: Research Funding; Incyte Corporation: Consultancy, Research Funding; Gilead: Research Funding; Genentech: Research Funding; PharmaEssentia: Research Funding; Promedior: Research Funding; Protagonist Therapeutics: Research Funding; Roche: Research Funding; NS Pharma: Research Funding; Blueprint Medicines Corp: Research Funding; Celgene: Consultancy, Research Funding; Sierra Oncology: Consultancy, Research Funding; AstraZeneca: Research Funding; Novartis: Consultancy, Research Funding; Constellation: Consultancy; Pragmatist: Consultancy. Andreeff: Glycomimetics: Consultancy; Aptose: Consultancy; AstraZeneca: Research Funding; Oxford Biomedica UK: Research Funding; Amgen: Research Funding; Syndax: Consultancy; Medicxi: Consultancy; Novartis, Cancer UK; Leukemia & Lymphoma Society (LLS), German Research Council; NCI-RDCRN (Rare Disease Clin Network), CLL Foundation; Novartis: Membership on an entity's Board of Directors or advisory committees; Breast Cancer Research Foundation: Research Funding; Reata, Aptose, Eutropics, SentiBio; Chimerix, Oncolyze: Current holder of individual stocks in a privately-held company; ONO Pharmaceuticals: Research Funding; Karyopharm: Research Funding; Daiichi-Sankyo: Consultancy, Research Funding; Senti-Bio: Consultancy. Bose: Pfizer: Research Funding; Constellation Pharmaceuticals: Research Funding; Novartis: Honoraria; Sierra Oncology: Honoraria; Kartos Therapeutics: Honoraria, Research Funding; Blueprint Medicines: Honoraria, Research Funding; CTI BioPharma: Honoraria, Research Funding; Celgene Corporation: Honoraria, Research Funding; BMS: Honoraria, Research Funding; Incyte Corporation: Honoraria, Research Funding; Astellas: Research Funding; NS Pharma: Research Funding; Promedior: Research Funding. Ferrajoli: AstraZeneca: Other: Advisory Board, Research Funding; BeiGene: Other: Advisory Board, Research Funding; Janssen: Other: Advisory Board . Thompson: Adaptive Biotechnologies: Other: Institution: Advisory/Consultancy, Honoraria, Research Grant/Funding, Expert Testimony; Pharmacyclics: Other: Institution: Advisory/Consultancy, Honoraria, Research Grant/Funding; Janssen: Consultancy, Honoraria; Gilead: Other: Institution: Advisory/Consultancy, Honoraria; AbbVie: Other: Institution: Advisory/Consultancy, Honoraria, Research Grant/Funding; Genentech: Other: Institution: Advisory/Consultancy, Honoraria, Research Grant/Funding; Amgen: Other: Institution: Honoraria, Research Grant/Funding. Kantarjian: AbbVie: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Immunogen: Research Funding; BMS: Research Funding; Jazz: Research Funding; Ascentage: Research Funding; Daiichi-Sankyo: Research Funding; Ipsen Pharmaceuticals: Honoraria; Astra Zeneca: Honoraria; KAHR Medical Ltd: Honoraria; Aptitude Health: Honoraria; Pfizer: Honoraria, Research Funding; Astellas Health: Honoraria; Novartis: Honoraria, Research Funding; NOVA Research: Honoraria; Precision Biosciences: Honoraria; Taiho Pharmaceutical Canada: Honoraria. Konopleva: Agios: Other: grant support, Research Funding; Calithera: Other: grant support, Research Funding; Rafael Pharmaceuticals: Other: grant support, Research Funding; KisoJi: Research Funding; Eli Lilly: Patents & Royalties: intellectual property rights, Research Funding; Reata Pharmaceuticals: Current holder of stock options in a privately-held company, Patents & Royalties: intellectual property rights; Novartis: Other: research funding pending, Patents & Royalties: intellectual property rights; Cellectis: Other: grant support; Ascentage: Other: grant support, Research Funding; AstraZeneca: Other: grant support, Research Funding; Sanofi: Other: grant support, Research Funding; Ablynx: Other: grant support, Research Funding; Genentech: Consultancy, Honoraria, Other: grant support, Research Funding; Forty Seven: Other: grant support, Research Funding; AbbVie: Consultancy, Honoraria, Other: Grant Support, Research Funding; Stemline Therapeutics: Research Funding; F. Hoffmann-La Roche: Consultancy, Honoraria, Other: grant support.

Abstract: Background: DEC10-VEN is an effective regimen and offers better outcomes compared to intensive chemotherapy in older pts with newly diagnosed (ND) or relapsed/refractory (R/R) AML (Maiti. Am J Hematol 2021; Maiti. Cancer 2021). We report long term outcomes in major genomic subgroups. Methods: Pts received decitabine 20 mg/m 2 on D1-10 until CR/CRi, followed by 5-day cycles. VEN dose was 400 mg daily but held on C1D21 if D21 bone marrow (BM) had ≤5% blasts. VEN could be reduced to & lt;14 days in cases of myelosuppression (DiNardo. Lancet Haematol 2020). Treatment-naïve group included pts with ND and secondary AML (sAML) without therapy for antecedent hematological disorder (AHD). Previously treated AML included sAML with prior therapy for AHD and R/R AML. Concomitant TKIs included gilteritinib (18), sorafenib (13), midostaurin (5), enasidenib (3) and ponatinib (1). Eligible pts could proceed to stem cell transplantation (SCT) after response. Endpoints were defined per ELN2017. NGS targeting entire coding regions of 81 myeloid genes was performed on screening BM sample with an analytical sensitivity of 5%. Measurable residual disease (MRD) was tested by multiparametric flow cytometry (sensitivity 0.1%). Results: Between January 2018 and April 2021 we enrolled 199 pts with ND AML (n=83), untreated sAML (n=20), treated sAML (n=25), and R/R AML (n=71). Median age of treatment-naïve pts was 72 yrs (range 61-72) and of previously treated pts was 67 yrs (range 18-85, Table 1). No pts had favorable risk cytogenetics. Median no. of prior therapies in previously treated pts was 2 (range 1-8) and 24% pts (23/96) had prior SCT. 21 treatment-naïve and 20 previously treated pts underwent SCT after response. Median follow-up for all pts was 25.4 mo. Among treatment-naïve pts, CR/CRi rates were high in all mutations subgroups ranging from 70-88% in pts with NPM1mut, FLT3mut, IDH1/2mut, TP53mut, RUNX1mut, K/NRASmut. Pts with ASXL1mut had modest CR/CRi rate of 56% (Table 2). FLT3 TKI was used in 71% FLT3mut pts (n=15/21). MRD negative rate among responding pts were high across all mutational subgroups ranging from 62-91%, except 55% in pts with ASXL1mut and 50% in pts with TP53mut. Median overall survival (OS) for treatment-naïve pts with NPM1mut was not reached (NR), IDH1/2mut was 29.6 mo, FLT3mut was 24.5 mo, RUNX1mut was 16.2 mo, ASXL1mut was 15.2 mo, K/NRASmut was 12.1 mo and TP53mut was 5.4 mo (Fig 1a-b). The median relapse-free survival (RFS) among treatment-naïve pts with NPM1mut was NR, IDH1/2mut was NR, FLT3mut was 20.0 mo, RUNX1mut was 9.7 mo, ASXL1mut was 8.5 mo, K/NRASmut was 6.5 mo and TP53mut was 3.1 mo (Fig 1c-d). Among NPM1+FLT3 co-mutated pts, outcomes in treatment-naïve pts (n=26) included ORR of 96%, CR/CRi in 88%, MRD negative in 92% (22/24), median OS NR and median RFS NR. Among previously treated NPM1+FLT3 pts (n=9), ORR was 78%, CR/CRi in 56%, MRD negative in 86% (6/7), median OS 12.4 mo and median RFS 6.6 mo. Among NPM1+DNMT3A co-mutated pts, outcomes in treatment-naïve pts (n=28) included ORR of 93%, CR/CRi in 89%, MRD negative in 79% (19/24), median OS 15.2 mo and median RFS 9.0 mo. Among previously treated NPM1+DNMT3A pts (n=6), ORR was 75%, CR/CRi in 50%, MRD negative in 75% (3/4), median OS was 4.7 mo and median RFS was 5.2 mo. Among previously treated pts CR/CRi rates in pts with NPM1mut was 68%, IDH1/2mut 50%, FLT3mut 42%, RUNX1mut 45%, ASXL1mut 38%, TP53mut 30%, and K/NRASmut was 26% (Table 2). FLT3 TKI used in 95% of FLT3mut pts (n=18/19). MRD negative rate among responding pts were high for pts with NPM1mut, FLT3mut, IDH1/2mut, RUNX1mut and ASXL1mut ranging from 60-87%, but were low for pts with K/NRASmut at 56% and TP53mut at 37%. The median OS among previously treated pts with IDH1/2mut was 16.9 mo, RUNX1mut was 13.7 mo, NPM1mut was 12.4 mo, ASXL1mut was 9.0 mo, FLT3mut was 6.4 mo, K/NRASmut was 6.0 mo, and for TP53mut was 4.5 mo (Fig 1e-f). The median RFS among treatment-naïve pts with K/NRASmut was 18.9 mo, NPM1mut was 15.6 mo, IDH1/2mut was 15.3, RUNX1mut was 12.9 mo, ASXL1mut was 10.7 mo, TP53mut was 9.4 mo, and for FLT3mut was 6.6 mo (Fig 1g-h). Conclusions: DEC10-VEN offered high rates of CR/CRi, negative MRD, favorable OS and RFS across several genomic subgroups of treatment-naïve AML including NPM1, FLT3, IDH1/2 and modest outcomes in pts with these mutations in salvage setting. Outcomes in pts with TP53, RUNX1, ASXL1 and K/NRAS were suboptimal. Outcomes with FLT3 VEN HMA triplet was encouraging, particularly for frontline FLT3mut pts. Figure 1 Figure 1. Disclosures DiNardo: Novartis: Honoraria; Takeda: Honoraria; ImmuneOnc: Honoraria, Research Funding; Bristol Myers Squibb: Honoraria, Research Funding; Notable Labs: Current holder of stock options in a privately-held company, Membership on an entity's Board of Directors or advisory committees; GlaxoSmithKline: Membership on an entity's Board of Directors or advisory committees; Agios/Servier: Consultancy, Honoraria, Research Funding; Foghorn: Honoraria, Research Funding; AbbVie: Consultancy, Research Funding; Forma: Honoraria, Research Funding; Celgene, a Bristol Myers Squibb company: Honoraria, Research Funding. Pemmaraju: Affymetrix: Consultancy, Research Funding; Cellectis S.A. ADR: Other, Research Funding; Samus: Other, Research Funding; Blueprint Medicines: Consultancy; Celgene Corporation: Consultancy; Clearview Healthcare Partners: Consultancy; Dan's House of Hope: Membership on an entity's Board of Directors or advisory committees; Protagonist Therapeutics, Inc.: Consultancy; Aptitude Health: Consultancy; Incyte: Consultancy; Novartis Pharmaceuticals: Consultancy, Other: Research Support, Research Funding; LFB Biotechnologies: Consultancy; Stemline Therapeutics, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding; ASH Communications Committee: Membership on an entity's Board of Directors or advisory committees; ASCO Leukemia Advisory Panel: Membership on an entity's Board of Directors or advisory committees; HemOnc Times/Oncology Times: Membership on an entity's Board of Directors or advisory committees; Sager Strong Foundation: Other; Plexxicon: Other, Research Funding; CareDx, Inc.: Consultancy; Daiichi Sankyo, Inc.: Other, Research Funding; Springer Science + Business Media: Other; DAVA Oncology: Consultancy; Roche Diagnostics: Consultancy; MustangBio: Consultancy, Other; Abbvie Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding; Bristol-Myers Squibb Co.: Consultancy; ImmunoGen, Inc: Consultancy; Pacylex Pharmaceuticals: Consultancy. Daver: Amgen: Consultancy, Research Funding; Trovagene: Consultancy, Research Funding; FATE Therapeutics: Research Funding; Sevier: Consultancy, Research Funding; Astellas: Consultancy, Research Funding; Hanmi: Research Funding; Genentech: Consultancy, Research Funding; Abbvie: Consultancy, Research Funding; Gilead Sciences, Inc.: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Daiichi Sankyo: Consultancy, Research Funding; Bristol Myers Squibb: Consultancy, Research Funding; Novimmune: Research Funding; Glycomimetics: Research Funding; Trillium: Consultancy, Research Funding; ImmunoGen: Consultancy, Research Funding; Novartis: Consultancy; Jazz Pharmaceuticals: Consultancy, Other: Data Monitoring Committee member; Dava Oncology (Arog): Consultancy; Celgene: Consultancy; Syndax: Consultancy; Shattuck Labs: Consultancy; Agios: Consultancy; Kite Pharmaceuticals: Consultancy; SOBI: Consultancy; STAR Therapeutics: Consultancy; Karyopharm: Research Funding; Newave: Research Funding. Issa: Syndax Pharmaceuticals: Research Funding; Novartis: Consultancy, Research Funding; Kura Oncology: Consultancy, Research Funding. Borthakur: Astex: Research Funding; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; University of Texas MD Anderson Cancer Center: Current Employment; Ryvu: Research Funding; Protagonist: Consultancy; Takeda: Membership on an entity's Board of Directors or advisory committees; ArgenX: Membership on an entity's Board of Directors or advisory committees; GSK: Consultancy. Ravandi: Taiho: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Agios: Honoraria, Research Funding; Xencor: Honoraria, Research Funding; Bristol Myers Squibb: 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, Research Funding; Astex: Honoraria, Research Funding; Jazz: Honoraria, Research Funding; Prelude: Research Funding; AbbVie: Honoraria, Research Funding; AstraZeneca: Honoraria; Novartis: Honoraria; Syros Pharmaceuticals: Consultancy, Honoraria, Research Funding. Alvarado: BerGenBio: Research Funding; Jazz Pharmaceuticals: Research Funding; Sun Pharma: Consultancy, Research Funding; MEI Pharma: Research Funding; FibroGen: Research Funding; CytomX Therapeutics: Consultancy; Daiichi-Sankyo: Research Funding; Astex Pharmaceuticals: Research Funding. Kadia: BMS: Other: Grant/research support; Dalichi Sankyo: Consultancy; Cure: Speakers Bureau; Jazz: Consultancy; Liberum: Consultancy; Aglos: Consultancy; Amgen: Other: Grant/research support; Novartis: Consultancy; AbbVie: Consultancy, Other: Grant/research support; Genentech: Consultancy, Other: Grant/research support; Pfizer: Consultancy, Other; Pulmotech: Other; Sanofi-Aventis: Consultancy; Cellonkos: Other; Ascentage: Other; Genfleet: Other; Astellas: Other; AstraZeneca: Other. Jabbour: Amgen, AbbVie, Spectrum, BMS, Takeda, Pfizer, Adaptive, Genentech: Research Funding. Short: Novartis: Honoraria; Jazz Pharmaceuticals: Consultancy; NGMBio: Consultancy; Astellas: Research Funding; AstraZeneca: Consultancy; Takeda Oncology: Consultancy, Research Funding; Amgen: Consultancy, Honoraria. Jain: Adaptive Biotechnologies: Honoraria, Research Funding; Janssen: Honoraria; Aprea Therapeutics: Research Funding; Genentech: Honoraria, Research Funding; Bristol Myers Squibb: Honoraria, Research Funding; Precision Biosciences: Honoraria, Research Funding; Fate Therapeutics: Research Funding; Servier: Honoraria, Research Funding; ADC Therapeutics: Honoraria, Research Funding; TG Therapeutics: Honoraria; Beigene: Honoraria; Incyte: Research Funding; Cellectis: Honoraria, Research Funding; Pfizer: Research Funding; AstraZeneca: Honoraria, Research Funding; Pharmacyclics: Research Funding; AbbVie: Honoraria, Research Funding. Wierda: Juno Therapeutics: Research Funding; KITE Pharma: Research Funding; Pharmacyclics LLC, an AbbVie Company: Research Funding; Cyclacel: Research Funding; Loxo Oncology, Inc.: Research Funding; Acerta Pharma Inc.: Research Funding; Genzyme Corporation: Consultancy; Miragen: Research Funding; Oncternal Therapeutics, Inc.: Research Funding; Sunesis: Research Funding; GSK/Novartis: Research Funding; Genentech: Research Funding; Gilead Sciences: Research Funding; Xencor: Research Funding; Janssen: Research Funding; Karyopharm: Research Funding; AbbVie: Research Funding; AstraZeneca: Research Funding. Sasaki: Daiichi-Sankyo: Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Research Funding; Pfizer: Membership on an entity's Board of Directors or advisory committees. Takahashi: GSK: Consultancy; Celgene/BMS: Consultancy; Symbio Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy. Yilmaz: Daiichi-Sankyo: Research Funding; Pfizer: Research Funding. Burger: Beigene: Research Funding, Speakers Bureau; Pharmacyclics LLC: Consultancy, Other: Travel/Accommodations/Expenses, Research Funding, Speakers Bureau; Gilead: Consultancy, Other: Travel/Accommodations/Expenses, Research Funding, Speakers Bureau; TG Therapeutics: Other: Travel/Accommodations/Expenses, Research Funding, Speakers Bureau; AstraZeneca: Consultancy; Novartis: Other: Travel/Accommodations/Expenses, Speakers Bureau; Janssen: Consultancy, Other: Travel/Accommodations/Expenses, Speakers Bureau. Verstovsek: Incyte Corporation: Consultancy, Research Funding; PharmaEssentia: Research Funding; Promedior: Research Funding; AstraZeneca: Research Funding; NS Pharma: Research Funding; Ital Pharma: Research Funding; Celgene: Consultancy, Research Funding; Protagonist Therapeutics: Research Funding; Roche: Research Funding; Sierra Oncology: Consultancy, Research Funding; Gilead: Research Funding; Genentech: Research Funding; CTI BioPharma: Research Funding; Blueprint Medicines Corp: Research Funding; Novartis: Consultancy, Research Funding; Constellation: Consultancy; Pragmatist: Consultancy. Andreeff: Karyopharm: Research Funding; Syndax: Consultancy; Medicxi: Consultancy; Oxford Biomedica UK: Research Funding; Amgen: Research Funding; ONO Pharmaceuticals: Research Funding; Glycomimetics: Consultancy; Novartis, Cancer UK; Leukemia & Lymphoma Society (LLS), German Research Council; NCI-RDCRN (Rare Disease Clin Network), CLL Foundation; Novartis: Membership on an entity's Board of Directors or advisory committees; Daiichi-Sankyo: Consultancy, Research Funding; Breast Cancer Research Foundation: Research Funding; Aptose: Consultancy; Senti-Bio: Consultancy; AstraZeneca: Research Funding; Reata, Aptose, Eutropics, SentiBio; Chimerix, Oncolyze: Current holder of individual stocks in a privately-held company. Bose: CTI BioPharma: Honoraria, Research Funding; Incyte Corporation: Honoraria, Research Funding; Astellas: Research Funding; Kartos Therapeutics: Honoraria, Research Funding; Sierra Oncology: Honoraria; NS Pharma: Research Funding; Celgene Corporation: Honoraria, Research Funding; BMS: Honoraria, Research Funding; Blueprint Medicines: Honoraria, Research Funding; Novartis: Honoraria; Constellation Pharmaceuticals: Research Funding; Pfizer: Research Funding; Promedior: Research Funding. Ferrajoli: BeiGene: Other: Advisory Board, Research Funding; Janssen: Other: Advisory Board ; AstraZeneca: Other: Advisory Board, Research Funding. Thompson: Gilead: Other: Institution: Advisory/Consultancy, Honoraria; Janssen: Consultancy, Honoraria; AbbVie: Other: Institution: Advisory/Consultancy, Honoraria, Research Grant/Funding; Pharmacyclics: Other: Institution: Advisory/Consultancy, Honoraria, Research Grant/Funding; Adaptive Biotechnologies: Other: Institution: Advisory/Consultancy, Honoraria, Research Grant/Funding, Expert Testimony; Genentech: Other: Institution: Advisory/Consultancy, Honoraria, Research Grant/Funding; Amgen: Other: Institution: Honoraria, Research Grant/Funding. Welch: Janssen: Research Funding; Notable Labs: Research Funding. Kantarjian: Ipsen Pharmaceuticals: Honoraria; Immunogen: Research Funding; Pfizer: Honoraria, Research Funding; Aptitude Health: Honoraria; Jazz: Research Funding; NOVA Research: Honoraria; KAHR Medical Ltd: Honoraria; Astellas Health: Honoraria; Daiichi-Sankyo: Research Funding; BMS: Research Funding; AbbVie: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Astra Zeneca: Honoraria; Amgen: Honoraria, Research Funding; Ascentage: Research Funding; Precision Biosciences: Honoraria; Taiho Pharmaceutical Canada: Honoraria. Konopleva: Ablynx: Other: grant support, Research Funding; Agios: Other: grant support, Research Funding; Rafael Pharmaceuticals: Other: grant support, Research Funding; AbbVie: Consultancy, Honoraria, Other: Grant Support, Research Funding; AstraZeneca: Other: grant support, Research Funding; Reata Pharmaceuticals: Current holder of stock options in a privately-held company, Patents & Royalties: intellectual property rights; Ascentage: Other: grant support, Research Funding; Calithera: Other: grant support, Research Funding; Forty Seven: Other: grant support, Research Funding; F. Hoffmann-La Roche: Consultancy, Honoraria, Other: grant support; Cellectis: Other: grant support; KisoJi: Research Funding; Genentech: Consultancy, Honoraria, Other: grant support, Research Funding; Novartis: Other: research funding pending, Patents & Royalties: intellectual property rights; Eli Lilly: Patents & Royalties: intellectual property rights, Research Funding; Sanofi: Other: grant support, Research Funding; Stemline Therapeutics: Research Funding. OffLabel Disclosure: Off-label use - venetoclax in relapsed/refractory AML

Abstract: Background: Detection of measurable residual disease (MRD) has been shown to provide important prognostic information in patients (pt) with acute myeloid leukemia (AML) receiving standard cytotoxic chemotherapy. The predictive value of MRD detection after low intensity regimens is less well established. Methods: We conducted a post-hoc analysis of a phase 2 trial to determine the prognostic value of MRD after frontline therapy with venetoclax (VEN) plus decitabine (DEC; DiNardo CD, et al, Lancet Haematology, 2020). MRD was assessed on bone marrow (BM) specimens using 8-color multiparametric flow cytometry (FCM) that was validated to a sensitivity level of 0.01-0.1%. Negative results were considered valid only if there had been acquisition of at least 200,000 events or a minimum of 200 CD34+ myeloid precursors. Pts were treated with DEC 20 mg/m2 for 10 days for induction followed by DEC for 5 days after CR/CRi with cycles repeated every 4-6 wks. Response and relapse were defined using the ELN 2017 criteria. Overall survival (OS) was determined from start of treatment until death or censored at last follow-up (LFU). Relapse-free survival (RFS) was determined from date of CR/CRi till morphologic relapse, death, or censored at LFU. Results: Between January 2018 and April 2020 we enrolled 121 pts in the frontline cohort including de novo AML (n=74), untreated secondary AML (sAML, n=16) and sAML with prior therapy for antecedent hematological disorder (n=31). No pts had received prior therapy for AML. The median age was 72 yrs (interquartile range [IQR] 68-77) and 34 pts (28%) had ECOG PS ≥2 (Table 1). The overall response rate was 81% with CR/CRi rate of 71%. Over half (53%) of responding pts achieved MRD negative status at any time point. (Table 2). The median time to response was 1.4 mo (IQR 1.1-2.6) and median time to MRD negativity was 2.0 mo (IQR 0.9-3.1). 16 pts (13%) underwent allogeneic hematopoietic stem cell transplant after achievement of response. The median OS was 11.7 mo (95% CI 9.1, 14.8) and the median RFS was 9.0 mo (95% CI 6.7, 15.0). After a median FU of 20.2 mo (95% CI 15.7, 23.0) 51 pts are alive. Pts achieving negative MRD at the time of morphologic response (CR/CRi/MLFS) had significantly longer OS compared to pts who were MRD positive, median OS 25.1 vs 11.6 mo, respectively, hazard ratio (HR) 0.45, 95% confidence interval (CI) 0.24, 0.85, p=.02. Pts achieving CR MRD- per ELN guidelines at any time point had longer OS compared to those with an inferior response i.e. CR MRD+ or CRi/MLFS MRD± (median OS 25.1 mo vs 10.9 mo, HR 0.31, 95% CI 0.18, 0.55, p & lt;.001; Fig. 1a) and better RFS (median not reached [NR] vs. 6.7, HR 0.26, 95% CI 0.14, 0.47, p & lt;.001). Pts achieving any response who became MRD negative by 1 mo after starting therapy had a 85% reduction in risk of death compared to pts who achieved a response but remained MRD positive, median OS 25.1 vs 3.4 mo, respectively, HR 0.15, 95% CI 0.03, 0.63, p & lt;.001 (Fig. 1b). Pts achieving any response who became MRD negative by 2 mo after starting therapy also had a significantly improved OS compared to those who remained MRD positive (median OS of 25.1 mo vs. 8.0 mo, HR 0.24, 95% CI 0.12, 0.47, p & lt;.001; Fig. 1c) and RFS (median RFS NR vs 6.7 mo, HR 0.28, 95% Ci 0.13, 0.60, p & lt;.001). Conclusion: Achievement of negative MRD status at 1- and 2-month time points is associated with significantly better OS and RFS in older pts with AML receiving frontline therapy with VEN and DEC. Disclosures Maiti: Celgene: Research Funding. DiNardo:Novartis: Consultancy; Calithera: Research Funding; Celgene: Consultancy, Honoraria, Research Funding; MedImmune: Honoraria; Agios: Consultancy, Honoraria, Research Funding; ImmuneOnc: Honoraria; AbbVie: Consultancy, Honoraria, Research Funding; Notable Labs: Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria; Jazz: Honoraria; Syros: Honoraria; Daiichi Sankyo: Consultancy, Honoraria, Research Funding. Kadia:Cyclacel: Research Funding; Astra Zeneca: Research Funding; Astellas: Research Funding; Pulmotec: Research Funding; Cellenkos: Research Funding; Amgen: Research Funding; JAZZ: Honoraria, Research Funding; BMS: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; Novartis: Honoraria; Ascentage: Research Funding; Incyte: Research Funding; Celgene: Research Funding; Abbvie: Honoraria, Research Funding; Genentech: Honoraria, Research Funding. Daver:Fate Therapeutics: Research Funding; ImmunoGen: Research Funding; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol-Myers Squibb: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Karyopharm: Research Funding; Servier: Research Funding; Genentech: Research Funding; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novimmune: Research Funding; Celgene: 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; Trillium: Consultancy, Membership on an entity's Board of Directors or advisory committees; Syndax: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; KITE: Consultancy, Membership on an entity's Board of Directors or advisory committees; Agios: 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, Research Funding; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Trovagene: Research Funding. Short:AstraZeneca: Consultancy; Takeda Oncology: Consultancy, Honoraria, Research Funding; Astellas: Research Funding; Amgen: Honoraria. Yilmaz:Pint Pharma: Honoraria; Daicho Sankyo: Research Funding; Pfizer: Research Funding. Pemmaraju:LFB Biotechnologies: Honoraria; Plexxikon: Research Funding; DAVA Oncology: Honoraria; Pacylex Pharmaceuticals: Consultancy; Blueprint Medicines: Honoraria; Roche Diagnostics: Honoraria; AbbVie: Honoraria, Research Funding; MustangBio: Honoraria; Celgene: Honoraria; Stemline Therapeutics: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Affymetrix: Other: Grant Support, Research Funding; Daiichi Sankyo: Research Funding; Cellectis: Research Funding; Incyte Corporation: Honoraria; SagerStrong Foundation: Other: Grant Support; Samus Therapeutics: Research Funding. Borthakur:Argenx: Consultancy; Treadwell Therapeutics: Consultancy; Nkarta Therapeutics: Consultancy; BioTherix: Consultancy; FTC Therapeutics: Consultancy; GSK: Research Funding; Jannsen: Research Funding; Abbvie: Research Funding; Cyclacel: Research Funding; BioLine Rx: Research Funding; BMS: Research Funding; AstraZeneca: Research Funding; Incyte: Research Funding; PTC Therapeutics: Consultancy; PTC Therapeutics: Research Funding; BioLine Rx: Consultancy; Polaris: Research Funding; Xbiotech USA: Research Funding; Oncoceutics: Research Funding; Curio Science LLC: Consultancy; Novartis: Research Funding. Bose:Promedior, Inc.: Research Funding; Pfizer, Inc.: Research Funding; Constellation Pharmaceuticals: Research Funding; NS Pharma: Research Funding; CTI BioPharma: Honoraria, Research Funding; Astellas Pharmaceuticals: Research Funding; Incyte Corporation: Consultancy, Honoraria, Research Funding, Speakers Bureau; Kartos Therapeutics: Honoraria, Research Funding; Blueprint Medicines Corporation: Honoraria, Research Funding; Celgene Corporation: Honoraria, Research Funding. Issa:Novartis: Membership on an entity's Board of Directors or advisory committees; Syndax: Research Funding; Celegene: Research Funding. Jabbour:Pfizer: Other: Advisory role, Research Funding; BMS: Other: Advisory role, Research Funding; Takeda: Other: Advisory role, Research Funding; Amgen: Other: Advisory role, Research Funding; AbbVie: Other: Advisory role, Research Funding; Genentech: Other: Advisory role, Research Funding; Adaptive Biotechnologies: Other: Advisory role, Research Funding. Jain:Servier: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Fate Therapeutics: Research Funding; Precision Bioscienes: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Adaptive Biotechnologies: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Verastem: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Incyte: Research Funding; ADC Therapeutics: Research Funding; Pharmacyclics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Research Funding; BeiGene: 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; TG Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Cellectis: Research Funding; Pfizer: Research Funding; Genentech: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Aprea Therapeutics: Research Funding; AstraZeneca: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Garcia-Manero:Novartis: Research Funding; Helsinn Therapeutics: Consultancy, Honoraria, Research Funding; H3 Biomedicine: Research Funding; Merck: Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Amphivena Therapeutics: Research Funding; Acceleron Pharmaceuticals: Consultancy, Honoraria; Astex Pharmaceuticals: Consultancy, Honoraria, Research Funding; Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Honoraria, Research Funding; Jazz Pharmaceuticals: Consultancy; Onconova: Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding. Burger:Pharmacyclics, an AbbVie company: Consultancy, Research Funding, Speakers Bureau; Janssen Pharmaceuticals: Consultancy, Speakers Bureau; Gilead Sciences: Consultancy, Research Funding; Beigene: Research Funding, Speakers Bureau; TG Therapeutics: Research Funding, Speakers Bureau; AstraZeneca: Consultancy. Thompson:AbbVie: Research Funding; Pharmacyclics: Research Funding; Genentech: Consultancy; Janssen-Cilag: Honoraria; Adaptive Biotechnologies: Consultancy, Research Funding. Verstovsek:Protagonist Therapeutics: Research Funding; ItalPharma: Research Funding; AstraZeneca: Research Funding; PharmaEssentia: Research Funding; Novartis: Consultancy, Research Funding; Sierra Oncology: Consultancy, Research Funding; Blueprint Medicines Corp: Research Funding; Genentech: Research Funding; CTI Biopharma Corp: Research Funding; Promedior: Research Funding; Gilead: Research Funding; Celgene: Consultancy, Research Funding; Incyte Corporation: Consultancy, Research Funding; Roche: Research Funding; NS Pharma: Research Funding. Sasaki:Daiichi Sankyo: Consultancy; Otsuka: Honoraria; Pfizer Japan: Consultancy; Novartis: Consultancy, Research Funding. Andreeff:Centre for Drug Research & Development; Cancer UK; NCI-CTEP; German Research Council; Leukemia Lymphoma Foundation (LLS); NCI-RDCRN (Rare Disease Clin Network); CLL Founcdation; BioLineRx; SentiBio; Aptose Biosciences, Inc: Membership on an entity's Board of Directors or advisory committees; Amgen: Research Funding; Daiichi-Sankyo; Jazz Pharmaceuticals; Celgene; Amgen; AstraZeneca; 6 Dimensions Capital: Consultancy; Daiichi-Sankyo; Breast Cancer Research Foundation; CPRIT; NIH/NCI; Amgen; AstraZeneca: Research Funding. Kantarjian:BioAscend: Honoraria; Abbvie: Honoraria, Research Funding; BMS: Research Funding; Immunogen: Research Funding; Aptitute Health: Honoraria; Adaptive biotechnologies: Honoraria; Actinium: Honoraria, Membership on an entity's Board of Directors or advisory committees; Daiichi-Sankyo: Honoraria, Research Funding; Ascentage: Research Funding; Jazz: Research Funding; Sanofi: Research Funding; Pfizer: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Janssen: Honoraria; Oxford Biomedical: Honoraria; Delta Fly: Honoraria; Amgen: Honoraria, Research Funding. 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; Genentech: Consultancy, Research Funding; F. Hoffmann La-Roche: Consultancy, Research Funding; Ablynx: Research Funding; Calithera: Research Funding; Cellectis: Research Funding; Eli Lilly: Research Funding; Rafael Pharmaceutical: Research Funding; Forty-Seven: Consultancy, Research Funding; Amgen: Consultancy; AstraZeneca: Research Funding; Agios: Research Funding; Sanofi: Research Funding; Stemline Therapeutics: Consultancy, Research Funding; Kisoji: Consultancy; AbbVie: Consultancy, Research Funding; Ascentage: Research Funding. Ravandi:Abbvie: Consultancy, Honoraria, Research Funding; Macrogenics: Research Funding; AstraZeneca: Consultancy, Honoraria; Xencor: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria; Orsenix: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Astellas: Consultancy, Honoraria, Research Funding; Jazz Pharmaceuticals: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Honoraria, Research Funding.

Abstract: Background: Low-dose dasatinib was shown to be safe and effective in patients with newly diagnosed chronic myeloid leukemia in chronic phase (CML-CP). There is no randomized clinical trials to compare the outcome with the standard-dose dasatinib. The aim of this study is to compare responses and outcome of patients with newly diagnosed CML-CP treated with frontline dasatinib 50 mg/day with those who received standard-dose dasatinib 100 mg/day. Method: We analyzed 233 patients with newly diagnosed CML-CP who were treated with low-dose dasatinib 50 mg/day (N=83) or standard-dose dasatinib 100 mg/day (N=150). Responses criteria were previously defined. Failure-free survival (FFS) was calculated from the start date of therapy to the dates of treatment discontinuation for any reason except of treatment-free remission; event-free survival (EFS), to the date of any of the events while on study as defined in the IRIS study; transformation-free survival (TFS), to the date of transformation to accelerated or blast phases during study; overall survival (OS), to the date of death from any cause at any time or date of last follow-up. Patients on low-dose dasatinib who had suboptimal response by European LeukemiaNet criteria had an option to increase the dose to 100 mg/day. Propensity score analysis with 1:1 matching was performed with the nearest neighbor matching method using calipers of width equal to 0.2. Multiple imputation was performed to minimize the bias. Propensity scores were calculated with logistic regression from baseline covariates including age, spleen size by examination, white blood cell count, hemoglobin, platelet count, percentage of basophils, percentage of blasts in peripheral blood and bone marrow, the presence of clonal evolution, and Sokal risk classification to minimize difference. Results: Propensity score matching identified 77 patients in each cohort without significant baseline difference (Table 1). The overall median follow-up was 60 months: 48 months and 131 months for low-dose and standard-dose, respectively. The 12-month major molecular response (MMR) rates were 82% and 75% for low-dose and standard-dose groups, respectively (P=0.229). The cumulative incidence of molecular response (MR)4, MR4.5, and complete molecular response (CMR) rates within 1 year were higher in the low-dose dasatinib group compared with the standard-dose group (63% and 43%, 53% and 36%, and 46% and 33% for each)(P=0.009; P=0.031; P=0.060). The incidence of pleural effusion was 6% and 21% in the low-dose and standard-dose, respectively (P=0.016). The 4-year FFS rates were 89% and 77% in the low-dose dasatinib and standard-dose dasatinib, respectively (P=0.041) (Figure 1). The 4-year TFS rates were 100% and 100%, respectively (P=1.000); the 4-year EFS rates were 95% and 92%, respectively (P=0.556); the 4-year OS rates were 97% and 96%, respectively (P=0.781). Conclusions: The low-dose dasatinib is as effective as standard-dose dasatinib with less intolerance, resulting in favorable outcome. Figure 1 Figure 1. Disclosures Sasaki: Novartis: Consultancy, Research Funding; Daiichi-Sankyo: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees. Jabbour: Amgen, AbbVie, Spectrum, BMS, Takeda, Pfizer, Adaptive, Genentech: Research Funding. Issa: Syndax Pharmaceuticals: Research Funding; Novartis: Consultancy, Research Funding; Kura Oncology: Consultancy, Research Funding. Yilmaz: Pfizer: Research Funding; Daiichi-Sankyo: Research Funding. Ferrajoli: Janssen: Other: Advisory Board ; AstraZeneca: Other: Advisory Board, Research Funding; BeiGene: Other: Advisory Board, Research Funding. Bose: Incyte Corporation: Honoraria, Research Funding; Pfizer: Research Funding; Astellas: Research Funding; Constellation Pharmaceuticals: Research Funding; Blueprint Medicines: Honoraria, Research Funding; CTI BioPharma: Honoraria, Research Funding; Sierra Oncology: Honoraria; Kartos Therapeutics: Honoraria, Research Funding; Novartis: Honoraria; NS Pharma: Research Funding; BMS: Honoraria, Research Funding; Celgene Corporation: Honoraria, Research Funding; Promedior: Research Funding. Thompson: Janssen: Consultancy, Honoraria; AbbVie: Other: Institution: Advisory/Consultancy, Honoraria, Research Grant/Funding; Gilead: Other: Institution: Advisory/Consultancy, Honoraria; Genentech: Other: Institution: Advisory/Consultancy, Honoraria, Research Grant/Funding; Amgen: Other: Institution: Honoraria, Research Grant/Funding; Adaptive Biotechnologies: Other: Institution: Advisory/Consultancy, Honoraria, Research Grant/Funding, Expert Testimony; Pharmacyclics: Other: Institution: Advisory/Consultancy, Honoraria, Research Grant/Funding. Alvarado: Sun Pharma: Consultancy, Research Funding; Jazz Pharmaceuticals: Research Funding; FibroGen: Research Funding; BerGenBio: Research Funding; CytomX Therapeutics: Consultancy; MEI Pharma: Research Funding; Daiichi-Sankyo: Research Funding; Astex Pharmaceuticals: Research Funding. Jain: ADC Therapeutics: Honoraria, Research Funding; Cellectis: Honoraria, Research Funding; Janssen: Honoraria; Aprea Therapeutics: Research Funding; Pfizer: Research Funding; Beigene: Honoraria; Precision Biosciences: Honoraria, Research Funding; Servier: Honoraria, Research Funding; Fate Therapeutics: Research Funding; Bristol Myers Squibb: Honoraria, Research Funding; Incyte: Research Funding; TG Therapeutics: Honoraria; Adaptive Biotechnologies: Honoraria, Research Funding; AstraZeneca: Honoraria, Research Funding; Genentech: Honoraria, Research Funding; AbbVie: Honoraria, Research Funding; Pharmacyclics: Research Funding. Takahashi: GSK: Consultancy; Novartis: Consultancy; Symbio Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene/BMS: Consultancy. Borthakur: GSK: Consultancy; Astex: Research Funding; Protagonist: Consultancy; University of Texas MD Anderson Cancer Center: Current Employment; ArgenX: Membership on an entity's Board of Directors or advisory committees; Ryvu: Research Funding; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees. Pemmaraju: HemOnc Times/Oncology Times: Membership on an entity's Board of Directors or advisory committees; Roche Diagnostics: Consultancy; Abbvie Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding; LFB Biotechnologies: Consultancy; Cellectis S.A. ADR: Other, Research Funding; Dan's House of Hope: Membership on an entity's Board of Directors or advisory committees; DAVA Oncology: Consultancy; CareDx, Inc.: Consultancy; Incyte: Consultancy; Daiichi Sankyo, Inc.: Other, Research Funding; Springer Science + Business Media: Other; ASH Communications Committee: Membership on an entity's Board of Directors or advisory committees; Novartis Pharmaceuticals: Consultancy, Other: Research Support, Research Funding; Aptitude Health: Consultancy; Stemline Therapeutics, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding; Samus: Other, Research Funding; Plexxicon: Other, Research Funding; ASCO Leukemia Advisory Panel: Membership on an entity's Board of Directors or advisory committees; MustangBio: Consultancy, Other; Sager Strong Foundation: Other; Celgene Corporation: Consultancy; Affymetrix: Consultancy, Research Funding; Protagonist Therapeutics, Inc.: Consultancy; Clearview Healthcare Partners: Consultancy; Blueprint Medicines: Consultancy; Bristol-Myers Squibb Co.: Consultancy; ImmunoGen, Inc: Consultancy; Pacylex Pharmaceuticals: Consultancy. Cortes: Sun Pharma: Consultancy, Research Funding; Bio-Path Holdings, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb, Daiichi Sankyo, Jazz Pharmaceuticals, Astellas, Novartis, Pfizer, Takeda, BioPath Holdings, Incyte: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Takeda: Consultancy, Research Funding. Kantarjian: Precision Biosciences: Honoraria; Immunogen: Research Funding; Jazz: Research Funding; Taiho Pharmaceutical Canada: Honoraria; Ascentage: Research Funding; Pfizer: Honoraria, Research Funding; Astra Zeneca: Honoraria; Daiichi-Sankyo: Research Funding; BMS: Research Funding; AbbVie: Honoraria, Research Funding; Astellas Health: Honoraria; Novartis: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Aptitude Health: Honoraria; NOVA Research: Honoraria; KAHR Medical Ltd: Honoraria; Ipsen Pharmaceuticals: Honoraria.

Abstract: Background: Blockade of PD-1/PD-L1 pathways enhances anti-leukemic responses in pre-clinical studies. PD1 inhibition alone had limited clinical activity in AML. CLTA4 inhibition demonstrated encouraging single-agent CR's in postASCT patients (pts), especially for extra-medullary (EMD) relapses (Davis M et al, NEJM 2016). AZA+Nivo up-regulated CTLA4 on bone marrow (BM) CD8 cells in both responders (R) and non-responders (NR) on treatment (Daver N, et al, Cancer Discovery 2019), suggesting a triplet of AZA+Nivo+Ipi may abrogate PD-1 mediated resistance. Methods: Pts were eligible for the AZA+Nivo (cohort 1, n=59) if they had R/R AML, ECOG ≤ 2, and adequate organ function. This cohort has completed enrollment. A cohort of AZA+Nivo+Ipi was opened (cohort 2), with the same eligibility criteria. Ipi 1mg/kg Q6 weeks was added to the established AZA+Nivo schedule and found to be safe in a lead-in dose cohort. Results: Cohort 1 (59 R/R AML) pts were treated with Aza+Nivo (Daver et al., Cancer Discovery 2019). CR/CRi and OS were superior to contemporary historic HMA-based clinical trial controls at MDACC (Table 1). Pts with low pretherapy BM blasts ( & lt;20% BM blasts) and early salvage (salvage 1) had encouraging median (med) OS 11 months (mos), indicating progressive T-cell exhaustion with multiple relapses. Importantly, on 40-parametric CYTOF assessment, Rs to AZA+Nivo had a higher frequency of pre-therapy BMA CD3+ and CD8+ cells compared with NRs (optimal CD3+ cutoff 13.2%: ORR 56% versus 23%), suggesting pre-existing BM T-cell infiltration may be a pre-requisite of response to PD1 based therapies, as PD1 inhibitors have limited ability to mobilize peripheral T-cells (Fig 1A). The pre-therapy BM CD4 polyfunctional strength index (PSI) defined as percentage of polyfunctional cells in the sample, multiplied by the intensities of the secreted cytokines, assessed by single cell cytokine analysis was dramatically different between Rs and NRs (P=0.03). Single-cell RNA-seq on 113,394 BM cells collected longitudinally from 8 pts (3R, 2 stable disease (SD), 3NR) demonstrated that deletion 7/7q, LSC signature enrichment, and activated metabolic/oxidative pathways, were associated with resistance to AZA+Nivo (Abbas H et al, ASH 2020). Importantly, AZA+Nivo induced novel and expanded T cell clonotypes, almost exclusively in Rs. Cohort 2 (36 R/R AML) pts were treated with Aza+Nivo+Ipi, with med age 67 years (25-83), secondary AML (50%), ELN unfavorable cytogenetics (67%), TP53 (36%), med salvage 2 (range, 1-3), and prior HMA based therapies in 67%. All 36 pts are evaluable. Per ELN 2017, CR/CRi was noted in 7 (19%) and PR in 1 (3%). Five (14%) pts had durable stable disease (SD) (defined as absence of CR, CRi, PR; with SD on treatment for ≥6 months), and 23 (64%) were NRs (Table 1). Interestingly, 4 pts with EMD were enrolled and 3 had CR/PR [med DOR 8 (5-13) mos]. The 4- and 8-week mortalities were 0 and 6%, respectively. Grade 3/4 immune toxicities noted in 8 pts (19%), including rash, pneumonitis, colitis, pyrexia. One pt required ICU stay, but no deaths attributed to immune toxicity. Other grade ≥2 toxicities were as expected for R/R AML population and were mostly infections/febrile neutropenia. Converse to AZA+Nivo, on CYTOF, R did not have a higher frequency of pre-therapy BM CD8+ infiltration, but did have progressive BM CD8+ infiltration on therapy, compared with NRs, demonstrating that Ipi (unlike Nivo) may be able to mobilize peripheral T-cells to the BM (Fig 1B). Expansion of a cluster of antigen experienced CD8+ T cells was associated with response (Fig 1B). In all salvage the med OS with Aza+Ipi+Nivo versus Aza+Nivo versus contemporary HMA-controls in R/R AML, were 7.6, 5.9, and 4.6 mos, respectively (P=0.01) (Fig 1C). The 1-year OS in R/R AML pts with AZA+Nivo+Ipi was 25%. The med OS with Aza+Ipi+Nivo was comparable to med OS 6-8 mos reported with HMA+VEN salvage in numerous studies. Conclusion: The OS with Aza+Nivo+Ipi was modestly improved over AZA+Nivo and HMA-controls in R/R AML. Single-cell cytokine profiling and single-cell RNA-seq from Aza+Nivo showed striking pre- and on-treatment differences among R and NR not only in T-cell fitness and clonality, but also in the tumor microenvironment. Ipi may be uniquely able to mobilize peripheral T-cell to BM and EMD. This underappreciated immune diversity suggests a critical need for biomarker-based trials (as we are doing with molecular therapies) for immunotherapies in AML. Disclosures Daver: Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Trovagene: Research Funding; Fate Therapeutics: Research Funding; ImmunoGen: Research Funding; Novartis: 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; Jazz: Consultancy, Membership on an entity's Board of Directors or advisory committees; Trillium: Consultancy, Membership on an entity's Board of Directors or advisory committees; Syndax: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; KITE: Consultancy, Membership on an entity's Board of Directors or advisory committees; Agios: 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, Research Funding; Bristol-Myers Squibb: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Karyopharm: Research Funding; Servier: Research Funding; Genentech: Research Funding; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novimmune: Research Funding; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Garcia-Manero:Merck: Research Funding; Onconova: Research Funding; Novartis: Research Funding; Jazz Pharmaceuticals: Consultancy; Helsinn Therapeutics: Consultancy, Honoraria, Research Funding; H3 Biomedicine: Research Funding; AbbVie: Honoraria, Research Funding; Acceleron Pharmaceuticals: Consultancy, Honoraria; Amphivena Therapeutics: Research Funding; Astex Pharmaceuticals: Consultancy, Honoraria, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Konopleva:Eli Lilly: Research Funding; Rafael Pharmaceutical: Research Funding; Genentech: Consultancy, Research Funding; Stemline Therapeutics: Consultancy, Research Funding; Agios: Research Funding; Cellectis: Research Funding; Calithera: Research Funding; AstraZeneca: Research Funding; 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; Sanofi: Research Funding; Kisoji: Consultancy; Amgen: Consultancy; F. Hoffmann La-Roche: Consultancy, Research Funding; AbbVie: Consultancy, Research Funding; Ablynx: Research Funding; Forty-Seven: Consultancy, Research Funding. Kadia:Pulmotec: Research Funding; Astellas: Research Funding; Cellenkos: Research Funding; Amgen: Research Funding; Genentech: Honoraria, Research Funding; BMS: Honoraria, Research Funding; Cyclacel: Research Funding; JAZZ: Honoraria, Research Funding; Celgene: Research Funding; Incyte: Research Funding; Astra Zeneca: Research Funding; Ascentage: Research Funding; Pfizer: Honoraria, Research Funding; Novartis: Honoraria; Abbvie: Honoraria, Research Funding. DiNardo:AbbVie: Consultancy, Honoraria, Research Funding; Takeda: Honoraria; Agios: Consultancy, Honoraria, Research Funding; Daiichi Sankyo: Consultancy, Honoraria, Research Funding; Calithera: Research Funding; Jazz: Honoraria; MedImmune: Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Syros: Honoraria; Notable Labs: Membership on an entity's Board of Directors or advisory committees; ImmuneOnc: Honoraria; Novartis: Consultancy. Borthakur:Abbvie: Research Funding; Novartis: Research Funding; Incyte: Research Funding; PTC Therapeutics: Research Funding; Curio Science LLC: Consultancy; FTC Therapeutics: Consultancy; Argenx: Consultancy; PTC Therapeutics: Consultancy; BioLine Rx: Consultancy; BioTherix: Consultancy; Nkarta Therapeutics: Consultancy; Treadwell Therapeutics: Consultancy; Oncoceutics: Research Funding; Xbiotech USA: Research Funding; Polaris: Research Funding; AstraZeneca: Research Funding; BMS: Research Funding; BioLine Rx: Research Funding; Cyclacel: Research Funding; GSK: Research Funding; Jannsen: Research Funding. Pemmaraju:AbbVie: Honoraria, Research Funding; Daiichi Sankyo: Research Funding; Stemline Therapeutics: Honoraria, Research Funding; DAVA Oncology: Honoraria; Incyte Corporation: Honoraria; Celgene: Honoraria; Novartis: Honoraria, Research Funding; SagerStrong Foundation: Other: Grant Support; Plexxikon: Research Funding; LFB Biotechnologies: Honoraria; Blueprint Medicines: Honoraria; Samus Therapeutics: Research Funding; Affymetrix: Other: Grant Support, Research Funding; Pacylex Pharmaceuticals: Consultancy; MustangBio: Honoraria; Roche Diagnostics: Honoraria; Cellectis: Research Funding. Jabbour:Takeda: Other: Advisory role, Research Funding; Adaptive Biotechnologies: Other: Advisory role, Research Funding; Pfizer: Other: Advisory role, Research Funding; BMS: Other: Advisory role, Research Funding; Amgen: Other: Advisory role, Research Funding; AbbVie: Other: Advisory role, Research Funding; Genentech: Other: Advisory role, Research Funding. Sasaki:Novartis: Consultancy, Research Funding; Otsuka: Honoraria; Pfizer Japan: Consultancy; Daiichi Sankyo: Consultancy. Yilmaz:Pint Pharma: Honoraria; Pfizer: Research Funding; Daicho Sankyo: Research Funding. Issa:Syndax: Research Funding; Celegene: Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees. Short:AstraZeneca: Consultancy; Amgen: Honoraria; Astellas: Research Funding; Takeda Oncology: Consultancy, Honoraria, Research Funding. Andreeff:Amgen: Research Funding; Centre for Drug Research & Development; Cancer UK; NCI-CTEP; German Research Council; Leukemia Lymphoma Foundation (LLS); NCI-RDCRN (Rare Disease Clin Network); CLL Founcdation; BioLineRx; SentiBio; Aptose Biosciences, Inc: Membership on an entity's Board of Directors or advisory committees; Daiichi-Sankyo; Breast Cancer Research Foundation; CPRIT; NIH/NCI; Amgen; AstraZeneca: Research Funding; Daiichi-Sankyo; Jazz Pharmaceuticals; Celgene; Amgen; AstraZeneca; 6 Dimensions Capital: Consultancy. Cortes:Novartis: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Sun Pharma: Research Funding; BioPath Holdings: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Telios: Research Funding; Astellas: Research Funding; Amphivena Therapeutics: Research Funding; Arog: Research Funding; BiolineRx: Consultancy, Research Funding; Bristol-Myers Squibb: Research Funding; Daiichi Sankyo: Consultancy, Research Funding; Jazz Pharmaceuticals: Consultancy, Research Funding; Immunogen: Research Funding; Merus: Research Funding. Ravandi:Jazz Pharmaceuticals: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Honoraria, Research Funding; Abbvie: Consultancy, Honoraria, Research Funding; Astellas: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria; Macrogenics: Research Funding; Orsenix: Consultancy, Honoraria, Research Funding; AstraZeneca: Consultancy, Honoraria; Xencor: Consultancy, Honoraria, Research Funding. Allison:BioAlta: Consultancy, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; Apricity Health: Consultancy, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; Achelois: Consultancy, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; Codiak BioSciences: Consultancy, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; Dragonfly Therapeutics: Consultancy, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; Forty-Seven Inc.: Consultancy, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; Hummingbird: Consultancy, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; ImaginAB: Consultancy, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; Jounce Therapeutics: Consultancy, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties; Lava Therapeutics: Consultancy, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; Lytix Biopharma: Consultancy, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; Marker Therapeutics: Consultancy, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; Polaris: Consultancy, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; BioNTech: Consultancy, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologies: Consultancy, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees. Kantarjian:Cyclacel: Research Funding; BMS: Research Funding; Takeda: Honoraria; Agios: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; Astex: Research Funding; AbbVie: Honoraria, Research Funding; Jazz Pharma: Research Funding; Amgen: Honoraria, Research Funding; Daiichi-Sankyo: Research Funding; Actinium: Honoraria, Membership on an entity's Board of Directors or advisory committees; Immunogen: Research Funding; Novartis: Research Funding; Ariad: Research Funding. Sharma:Achelois: Consultancy, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; Apricity Health: Consultancy, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; BioAlta: Consultancy, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; Codiak BioSciences: Consultancy, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; Constellation: Consultancy, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; Dragonfly Therapeutics: Consultancy, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; Forty-Seven Inc.: Consultancy, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; Hummingbird: Consultancy, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; ImaginAb: Consultancy, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; Jounce Therapeutics: Consultancy, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties; Lava Therapeutics: Consultancy, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; Lytix Biopharma: Consultancy, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; Marker Therapeutics: Consultancy, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; Oncolytics: Consultancy, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; Infinity Pharma: Consultancy, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; BioNTech: Consultancy, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologies: Consultancy, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; Glympse: Consultancy, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; Polaris: Consultancy, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees. OffLabel Disclosure: Nivolumab and Ipilimumab based combinations for AML, will be discussed. These agents do not have an on label indication for AML at this time.