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: 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) 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: The outcome of patients (pts) with lower-risk myelodysplastic syndrome (MDS) is heterogeneous, with some pts having a particularly poor prognosis. Low doses of hypomethylating agents (HMAs) have been shown to be active in lower-risk MDS. We evaluated the relative safety and efficacy of low-dose decitabine (DAC) and azacitidine (AZA) in pts with lower-risk MDS. Methods: Adult pts with de novo or secondary low- or intermediate-1-risk MDS, CMML or MDS/MPN were eligible for this study. Pts with prior HMA exposure were excluded. Pts were randomized in a Bayesian adaptive design to receive either AZA 75 mg/m2 IV/SC daily or DAC 20 mg/m2 IV daily for 3 consecutive days on a 28-day cycle; pts were more likely to be assigned to the better performing treatment arm. The primary efficacy outcome was the overall improvement rate (OIR) defined as the composite of complete remission (CR), marrow CR, and hematologic improvement. Secondary outcomes included safety profile, cytogenetic response, conversion to transfusion independence, event-free survival (EFS), and overall survival (OS). EFS was defined as the time to HMA failure, progressive disease, transformation to acute myeloid leukemia (AML) or death from any cause. Results: Between 11/2012 and 2/2016, 113 pts with lower-risk MDS have been treated, 40 (39%) with AZA and 73 (71%) with DAC. The median age of the entire cohort was 70 years (range, 44-88 years), and the majority of pts (81%) were intermediate-1-risk by IPSS. Baseline characteristics of the 2 treatment groups were well-balanced and are summarized in Table 1. The median number of cycles received was 9 (range 1-41 cycles). Of the 39 pts in the AZA arm and 70 pts in the DAC arm who have received at least 2 cycles of therapy and were evaluable for response, the OIR was 53% in both groups. The CR rate with AZA and DAC was 38% and 29%, respectively (P=0.29). Among pts with abnormal karyotype at baseline, complete or partial cytogenetic response was observed in 24% of pts in the AZA arm and in 63% of pts in the DAC arm (P=0.01); the rate of complete cytogenetic response was 6% and 26% in the two groups, respectively (P=0.09). Of the 18 pts in the AZA arm and the 38 pts in the DAC arm who were transfusion dependent at baseline and evaluable for response, 17% and 32% achieved transfusion independence, respectively (P=0.24) The median duration of follow-up for the entire cohort was 20 months (range, 2-42 months). Twenty four pts in the AZA arm (60%) and 23 pts in the DAC arm (32%) have come off study due to lack of response or progressive disease. There was a trend toward prolonged EFS with DAC compared to AZA (median EFS: 19.6 months vs. 13.7 months; 1-year EFS rate: 73% vs. 57, respectively; P=0.15; Figure 1A). Twelve pts in the AZA arm (30%) and 17 pts in DAC arm (23%) have died. The median OS was similar between DAC and AZA (median OS not reached for both; 1-year OS rate: 87% vs. 84%, respectively; P=0.80; Figure 1B). Progression to AML occurred in 5 pts (13%) in the AZA arm and 6 pts (8%) in the DAC arm. Both agents were overall well-tolerated. Cycle delays were required in 23% and 37% of pts and dose reductions were required in 5% and 12% of pts treated with AZA and DAC, respectively. Infection or neutropenic fever occurred 2 pts (5%) treated with AZA and in 5 pts treated with DAC (7%). No grade 4 adverse events were observed in either treatment arm. Conclusions: Low-dose AZA and DAC are effective and well-tolerated in pts with lower-risk MDS. Early results suggest that low-dose DAC may result in superior EFS compared to low-dose AZA. A randomized trial comparing low-dose AZA, low-dose DAC, AZA x 5 days, and best supportive care in lower-risk MDS is ongoing. Disclosures Jabbour: ARIAD: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Novartis: Research Funding; BMS: Consultancy. Daver:Otsuka: Consultancy, Honoraria; Sunesis: Consultancy, Research Funding; BMS: Research Funding; Ariad: Research Funding; Pfizer: Consultancy, Research Funding; Kiromic: Research Funding; Karyopharm: Honoraria, Research Funding. DiNardo:Daiichi Sankyo: Other: advisory board, Research Funding; Abbvie: Research Funding; Novartis: Other: advisory board, Research Funding; Celgene: Research Funding; Agios: Other: advisory board, Research Funding. Sekeres:Celgene: Membership on an entity's Board of Directors or advisory committees; Millenium/Takeda: Membership on an entity's Board of Directors or advisory committees. Komrokji:Novartis: Consultancy, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding. Roboz:Agios, Amgen, Amphivena, Astex, AstraZeneca, Boehringer Ingelheim, Celator, Celgene, Genoptix, Janssen, Juno, MEI Pharma, MedImmune, Novartis, Onconova, Pfizer, Roche/Genentech, Sunesis, Teva: Consultancy; Cellectis: Research Funding.