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: Treated secondary acute myeloid leukemia (ts-AML), defined as AML arising from previously treated antecedent hematologic disorder, is a high-risk disease with dismal outcomes. CPX-351 is approved for the treatment of secondary AML, although it did not improve outcomes within the subgroup of patients (pts) with secondary AML with prior exposure to hypomethylating agents (HMAs). In clinical practice, either chemotherapy or HMA plus venetoclax (Ven) are often used for pts with ts-AML, although there are little data to guide the optimal therapy in this setting Methods: We conducted a retrospective analysis of pts with AML arising from either MDS or CMML who received first AML therapy at our institution from 6/2004 to 1/2021 and who had prior HMA exposure for preceding MDS/CMML. Pts treated with prior intensive chemotherapy (IC) or Ven were excluded. Treatment regimens were classified as IC, low-intensity chemotherapy (LIC), or HMA plus Ven. Results: Among 562 pts with ts-AML, 271 (47%) were treated with IC, 237 (41%) with LIC, 54 (9%) with HMA+Ven. Baseline characteristics were similar between pts treated with different treatment regimens (Table 1), although pts treated with IC were significantly younger than those treated with LIC or HMA+Ven (median age: 65 vs. 72 years, P & lt;0.0001). The median number of prior therapies for previous MDS/CMML diagnosis was 1 (range, 1-5). The entire cohort was enriched with adverse risk mutations, including ASXL1 (IC-41%, LIC-28%, HMA+Ven-52%), RUNX1 (IC-22%, LIC-35%, HMA+Ven-56%), and TP53 (IC-45%, LIC-24%, HMA+Ven-40%). In the entire cohort, the CR/CRi rate was 26% and the overall response rate (ORR; defined as CR+CRi+MLFS) was 34%. CR/CRi rates and ORR were similar between IC and LIC (CR/CRi rates: 24% vs 26%; ORR: 30% vs 35%, respectively). Compared with IC/LIC, treatment with HMA+Ven was associated with higher CR/CRi rates (39% vs 25%; P=0.03) and ORR (54% vs 33%; P=0.002). 60-day mortality was similar between the treatment groups (IC-14%, LIC-9%, HMA+Ven-13%). Hematopoietic stem cell transplant rates for pts who received IC, LIC and HMA+Ven were 13%, 5%, and 9%, respectively. In the entire cohort, the median overall survival (OS) was 4.8 months (m), and relapse-free survival (RFS) was 5.9m. OS was similar between those treated with IC or LIC (median OS 4.5m vs. 4.8m; 1-year [yr] OS 14% vs. 22%; P=0.16) but was superior for those who received HMA+Ven compared with those who received IC/LIC (median OS 5.8m vs. 4.7m; 1-yr OS 35% vs. 17%; P=0.05 (Figure 1). RFS was also numerically higher in pts who received HMA+Ven compared with those treated with IC/LIC (median RFS 14.4m vs. 5.4m; 1-yr RFS 59% vs. 29%; P=0.17). The impact of therapies on outcomes in ts-AML was influenced by karyotype. In those with adverse risk karyotype, the outcomes were dismal regardless of treatment approach. ORR was similar between IC/LIC and HMA+Ven (24% vs 28%, P=0.66) and these groups also had similar OS (median OS: 3.3m vs. 4.1m; 1-yr OS 8% vs. 11%; P=0.41). However, among those with non-adverse risk karyotype, HMA+Ven was associated with significantly higher CR/CRi rates (57% vs 30%; P=0.008) and ORR (78% vs 39%, P=0.0003) compared with IC/LIC. HMA+ven also resulted in superior OS in this non-adverse risk group (13.7m vs 5.5m, 1-yr OS 24% vs. 55%, respectively; P=0.04) (Figure 2). The superior outcomes with HMA+Ven were also observed when the comparison was restricted to those treated with IC (P=0.01). Then we evaluated the impact of age specifically in pts treated with IC (stratified into & lt;60 and ≥60 yrs) and HMA+Ven (of any age). Pts treated with HMA+Ven (93% of whom were ≥60 yrs of age) had significantly higher OS compared with pts ≥60 yrs of age who received IC (5.8m vs 4.1m, 1-yr OS 35% vs. 12%; P=0.009) (Figure 3). Although not statistically significant, there was also a trend towards superior OS with HMA+Ven compared to IC in pts & lt;60 yrs of age who received IC (5.8m vs 5.0m, 1-yr OS 35% vs. 16%; P=0.16). Conclusion: For pts with ts-AML and prior HMA exposure, HMA+Ven yielded significantly higher ORR rates and improved OS compared to IC/LIC, particularly in pts with non-adverse risk karyotype and in pts ≥60 yrs of age. These results suggest that HMA+Ven should be preferentially considered for pts with ts-AML and prior HMA exposure, rather than chemotherapy-based approaches. Our results also highlight the very poor outcomes of ts-AML, a poor-risk subgroup of AML for which novel, effective therapies are still needed. Figure 1 Figure 1. Disclosures Kadia: Amgen: Other: Grant/research support; AstraZeneca: Other; Cure: Speakers Bureau; BMS: Other: Grant/research support; Jazz: Consultancy; Genentech: Consultancy, Other: Grant/research support; Liberum: Consultancy; Novartis: Consultancy; Pfizer: Consultancy, Other; Pulmotech: Other; Sanofi-Aventis: Consultancy; Cellonkos: Other; Ascentage: Other; Genfleet: Other; Astellas: Other; Dalichi Sankyo: Consultancy; Aglos: Consultancy; AbbVie: Consultancy, Other: Grant/research support. Ravandi: Amgen: Honoraria, Research Funding; AstraZeneca: Honoraria; Bristol Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Xencor: Honoraria, Research Funding; AbbVie: Honoraria, Research Funding; Jazz: Honoraria, Research Funding; Agios: Honoraria, Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Astex: Honoraria, Research Funding; Novartis: Honoraria; Prelude: Research Funding; Taiho: Honoraria, Research Funding; Syros Pharmaceuticals: Consultancy, Honoraria, Research Funding. DiNardo: ImmuneOnc: Honoraria, Research Funding; GlaxoSmithKline: Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria; Notable Labs: Current holder of stock options in a privately-held company, Membership on an entity's Board of Directors or advisory committees; Agios/Servier: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Research Funding; Novartis: Honoraria; Bristol Myers Squibb: Honoraria, Research Funding; Forma: Honoraria, Research Funding; Foghorn: Honoraria, Research Funding; Celgene, a Bristol Myers Squibb company: Honoraria, Research Funding. Daver: FATE Therapeutics: Research Funding; Glycomimetics: Research Funding; Amgen: Consultancy, Research Funding; Abbvie: Consultancy, Research Funding; Novartis: Consultancy; Novimmune: Research Funding; Bristol Myers Squibb: Consultancy, Research Funding; Gilead Sciences, Inc.: Consultancy, Research Funding; Trovagene: Consultancy, Research Funding; Jazz Pharmaceuticals: Consultancy, Other: Data Monitoring Committee member; Pfizer: Consultancy, Research Funding; Sevier: Consultancy, Research Funding; Hanmi: Research Funding; Trillium: Consultancy, Research Funding; ImmunoGen: Consultancy, Research Funding; Astellas: Consultancy, Research Funding; Daiichi Sankyo: Consultancy, Research Funding; Genentech: 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. Borthakur: Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; University of Texas MD Anderson Cancer Center: Current Employment; GSK: Consultancy; Protagonist: Consultancy; Ryvu: Research Funding; Astex: Research Funding; ArgenX: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees. Konopleva: Rafael Pharmaceuticals: Other: grant support, Research Funding; Cellectis: Other: grant support; Novartis: Other: research funding pending, Patents & Royalties: intellectual property rights; Sanofi: Other: grant support, Research Funding; Reata Pharmaceuticals: Current holder of stock options in a privately-held company, Patents & Royalties: intellectual property rights; AstraZeneca: Other: grant support, Research Funding; AbbVie: Consultancy, Honoraria, Other: Grant Support, Research Funding; Eli Lilly: Patents & Royalties: intellectual property rights, Research Funding; Agios: Other: grant support, Research Funding; Genentech: Consultancy, Honoraria, Other: grant support, Research Funding; Stemline Therapeutics: Research Funding; Ablynx: Other: grant support, Research Funding; F. Hoffmann-La Roche: Consultancy, Honoraria, Other: grant support; KisoJi: Research Funding; Ascentage: Other: grant support, Research Funding; Calithera: Other: grant support, Research Funding; Forty Seven: Other: grant support, Research Funding. Yilmaz: Pfizer: Research Funding; Daiichi-Sankyo: Research Funding. Issa: Syndax Pharmaceuticals: Research Funding; Novartis: Consultancy, Research Funding; Kura Oncology: Consultancy, Research Funding. Kantarjian: Ipsen Pharmaceuticals: Honoraria; NOVA Research: Honoraria; Astellas Health: Honoraria; Immunogen: Research Funding; Novartis: Honoraria, Research Funding; AbbVie: Honoraria, Research Funding; Aptitude Health: Honoraria; Astra Zeneca: Honoraria; KAHR Medical Ltd: Honoraria; Jazz: Research Funding; Pfizer: Honoraria, Research Funding; Daiichi-Sankyo: Research Funding; BMS: Research Funding; Ascentage: Research Funding; Amgen: Honoraria, Research Funding; Precision Biosciences: Honoraria; Taiho Pharmaceutical Canada: Honoraria. Short: Novartis: Honoraria; NGMBio: Consultancy; AstraZeneca: Consultancy; Jazz Pharmaceuticals: Consultancy; Astellas: Research Funding; Takeda Oncology: Consultancy, Research Funding; Amgen: Consultancy, 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) 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: Assessment of measurable residual disease (MRD) provides prognostic information in acute myeloid leukemia (AML). However, the utility of MRD with venetoclax-based lower intensity regimens is unknown. We analyzed the prognostic value of achieving a negative MRD in older/“unfit” patients with AML receiving first-line therapy with 10-day decitabine and venetoclax. MRD was evaluated in bone marrow specimens using multicolor flow cytometry (sensitivity 0.1%). Ninety-seven patients achieving either a complete remission (CR) or CR with incomplete hematologic recovery (CRi) or morphologic leukemia-free state were included. Median age was 72 years (interquartile range, 68-78 years), and 64% had adverse-risk AML. Eighty-three patients achieved CR/CRi, and 52 (54%) became MRD negative. Median time to becoming MRD negative was 2.0 months (interquartile range, 0.9-3.1 months). Patients becoming MRD negative by 2 months had longer relapse-free survival (RFS) compared with those remaining MRD positive (median RFS, not reached vs 5.2 months; hazard ratio [HR], 0.31; 95% confidence interval [CI] , 0.12-0.78; P = .004), longer event-free survival (EFS) (median EFS, not reached vs 5.8 months; HR, 0.25; 95% CI, 0.12-0.55; P & lt; .001), as well as longer overall survival (OS) (median OS, 25.1 vs 7.1 months; HR, 0.23; 95% CI, 0.11-0.51; P & lt; .001). Patients achieving an MRD-negative CR had longer OS compared with those with an inferior response (median OS, 25.1 vs 11.6 months; HR, 0.33; 95% CI, 0.19-0.58; P & lt; .0005). Patients becoming MRD negative within 1 month had an improved OS compared with MRD-positive patients (median OS, 25.1 vs 3.4 months; HR, 0.15; 95% CI, 0.03-0.64; P & lt; .0001). Differential impact of MRD status on survival outcomes persisted at a later 4-month time point of evaluation. In conclusion, MRD-negative status at 1, 2, and 4 months after starting therapy confers significantly better survival in older/unfit patients with AML receiving first-line therapy with 10-day decitabine and venetoclax. This trial was registered at www.clinicaltrials.gov as #NCT03404193.

Abstract: Background: In MDS, hypomethylating agents (HMA) remain the standard of care. ASTX727, an oral formulation of the fixed dose combination of the HMA decitabine and cytidine deaminase inhibitor cedazuridine, was recently approved for the treatment of MDS and CMML. Venetoclax (Ven), an orally bioavailable BCL-2 inhibitor in combination with azacitidine has shown clinical activity in treatment-naïve higher risk MDS. Based on this data, we designed a total oral therapy with Ven+ASTX727 combination to improve the clinical outcomes and quality of life in pts with higher risk MDS or CMML. Methods: This single arm Phase I/II study of orally administered ASTX727 in combination with Ven (NCT04655755) is enrolling pts aged ≥18 years with treatment-naïve higher risk MDS (intermediate-2 or high) per IPSS or CMML with excess blasts ≥5%. Prior bcl2 inhibitor therapy is not allowed. To mitigate tumor lysis syndrome, pretreatment white blood cell count should be less than 10 × 10 9/L. Cytoreduction is allowed. The phase I 3+3 design of venetoclax with ASTX727 has an intended sample size of 12 pts. ASTX727 (cedazuridine/decitabine at 100 mg/35 mg) is administered orally daily on days 1-5 of each treatment cycle and Ven on days 1-14 of the first cycle and thereafter. Three dose levels of venetoclax in combination with ASTX727 will be tested (Table 1) The safety population includes all patients who received any dose of Ven+ ASTX727, and the efficacy population includes patients who have a valid baseline and post-baseline disease assessment and had received at least one dose of the study drug. The primary objective is to determine the safety and tolerability (phase 1) and overall response rate (ORR) (phase 2) of Ven+ASTX727 combination. Results: In phase I portion, seven pts have been enrolled to date (Table 2). The median age is 72 years (range, 54-84) with five pts aged ≥65 yrs. These pts had a median bone marrow blast count of 13% (range,6-15), and harbored a median number of 4 (range,1-7) mutations. Greater than 50% of the cohort harbored adverse risk mutations such as ASXL1(71%), RUNX1 (57%). Three pts were enrolled in dose level 0 and four pts in dose level +1. No DLTs were observed in the initial 6 pt safety lead-in. The 30-day and 60-day mortality rates were 0% each. No tumor lysis syndrome was observed. All seven pts achieved a response (100%) with three pts achieving CR (43%) and four pts achieving marrow CR (57%). Among the responders, two pts achieved MRD negativity (29%). All pts achieved a response within 1 cycle. One pt with TP53mut proceeded to hematopoietic stem cell transplant at the end of 2 cycles and the remaining six pts continue on study. At a median follow up of 3.8 months, the median duration of response was not reached (range,1.8-5.1+ months), and the median overall survival was not reached (range,2.7-6.2+ months). Conclusion: Ven+ASTX727 combination appears safe and demonstrates preliminary efficacy in pts with higher risk MDS or CMML with excess blasts. Total oral therapy of Ven+ASTX727 combination appears to be a promising strategy for HR MDS or CMML pts who often require long term treatment. Figure 1 Figure 1. Disclosures Kantarjian: Daiichi-Sankyo: Research Funding; Jazz: Research Funding; Immunogen: Research Funding; Ascentage: Research Funding; Aptitude Health: Honoraria; Astellas Health: Honoraria; Ipsen Pharmaceuticals: Honoraria; Astra Zeneca: Honoraria; KAHR Medical Ltd: Honoraria; Pfizer: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; NOVA Research: Honoraria; Taiho Pharmaceutical Canada: Honoraria; Precision Biosciences: Honoraria; Amgen: Honoraria, Research Funding; BMS: Research Funding; AbbVie: Honoraria, Research Funding. Short: Novartis: Honoraria; AstraZeneca: Consultancy; Astellas: Research Funding; Jazz Pharmaceuticals: Consultancy; NGMBio: Consultancy; Takeda Oncology: Consultancy, Research Funding; Amgen: Consultancy, Honoraria. Alvarado: CytomX Therapeutics: Consultancy; FibroGen: Research Funding; Sun Pharma: Consultancy, Research Funding; MEI Pharma: Research Funding; Daiichi-Sankyo: Research Funding; Astex Pharmaceuticals: Research Funding; BerGenBio: Research Funding; Jazz Pharmaceuticals: Research Funding. Pemmaraju: ASH Communications Committee: Membership on an entity's Board of Directors or advisory committees; Samus: Other, Research Funding; Novartis Pharmaceuticals: Consultancy, Other: Research Support, Research Funding; MustangBio: Consultancy, Other; Plexxicon: Other, Research Funding; Daiichi Sankyo, Inc.: Other, Research Funding; Dan's House of Hope: 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; Stemline Therapeutics, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding; CareDx, Inc.: Consultancy; Springer Science + Business Media: Other; Celgene Corporation: Consultancy; Aptitude Health: Consultancy; Abbvie Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding; Cellectis S.A. ADR: Other, Research Funding; Affymetrix: Consultancy, Research Funding; HemOnc Times/Oncology Times: Membership on an entity's Board of Directors or advisory committees; Roche Diagnostics: Consultancy; DAVA Oncology: Consultancy; Protagonist Therapeutics, Inc.: Consultancy; Incyte: Consultancy; Sager Strong Foundation: Other; LFB Biotechnologies: Consultancy; Clearview Healthcare Partners: Consultancy; Blueprint Medicines: Consultancy; Bristol-Myers Squibb Co.: Consultancy; ImmunoGen, Inc: Consultancy; Pacylex Pharmaceuticals: Consultancy. Daver: ImmunoGen: Consultancy, Research Funding; Novimmune: Research Funding; Genentech: Consultancy, Research Funding; Trillium: Consultancy, Research Funding; Trovagene: Consultancy, Research Funding; Gilead Sciences, Inc.: Consultancy, Research Funding; Glycomimetics: Research Funding; FATE Therapeutics: Research Funding; Abbvie: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; Astellas: Consultancy, Research Funding; Sevier: Consultancy, Research Funding; Bristol Myers Squibb: Consultancy, Research Funding; Hanmi: Research Funding; Daiichi Sankyo: Consultancy, Research Funding; Pfizer: 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. Kadia: Sanofi-Aventis: Consultancy; AstraZeneca: Other; Ascentage: Other; Genfleet: Other; Amgen: Other: Grant/research support; BMS: Other: Grant/research support; Cure: Speakers Bureau; Jazz: Consultancy; Genentech: Consultancy, Other: Grant/research support; Dalichi Sankyo: Consultancy; Novartis: Consultancy; Liberum: Consultancy; Pfizer: Consultancy, Other; AbbVie: Consultancy, Other: Grant/research support; Aglos: Consultancy; Astellas: Other; Cellonkos: Other; Pulmotech: Other. Borthakur: Astex: Research Funding; Ryvu: Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees; Protagonist: Consultancy; University of Texas MD Anderson Cancer Center: Current Employment; GSK: Consultancy; ArgenX: Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees. Jabbour: Amgen, AbbVie, Spectrum, BMS, Takeda, Pfizer, Adaptive, Genentech: Research Funding.

Abstract: Background: Mutations in the RAS/RAF/MEK/ERK pathway result in resistance to several acute myeloid leukemia (AML) therapies, including hypomethylating agents (HMAs) plus venetoclax. Trametinib is an oral MEK inhibitor that has been studied as monotherapy in relapsed/refractory (R/R) AML with KRAS/NRAS mutations. Preclinical studies have suggested synergy between venetoclax and trametinib in RAS-mutated AML. We therefore sought to evaluate the combination of azacitidine, venetoclax, and trametinib in patients (pts) with R/R AML with Ras pathway-activating mutations. Methods: In this phase II study, adult pts with R/R AML or higher-risk R/R MDS or CMML (intermediate-2 or high-risk by the International Prognostic Scoring System with ≥10% blasts) harboring a Ras pathway-activating mutation involving HRAS/NRAS/KRAS, KIT, BRAF, CBL, PTPN11 or NF1 were eligible). Pts were required to have a performance status ≤2, total bilirubin ≤2.5 x upper limit of normal (ULN), ALT/AST ≤ 3 x ULN, and creatinine clearance ≥30 mL/min. In cycle 1, pts received azacitidine 75 mg/m 2 SC/IV on days 1-7, venetoclax on days 1-28 (100mg on day 1, 200mg on day 2, 400mg on days 3-28), and trametinib 2mg PO on days 1-28. Bone marrow examination was performed on day 21 and if blasts & lt;5% or aplastic marrow, then venetoclax was held. For cycles 2 and beyond, azacitidine 75 mg/m 2 SC/IV was given on days 1-7, venetoclax was given for daily on days 1 - 21 and trametinib 2mg was given continuously. Results: Between 8/2020 and 5/2021, 16 pts were treated. Baseline characteristics are shown in Table 1. The median age was 67 years (range, 28-84 years) and 6 pts (38%) were ≥75 years of age. This was a very heavily pretreated population, and the median number of prior therapies was 4 (range, 1-7). All pts had received prior HMAs, including 13 pts (81%) who had received prior HMA plus venetoclax. Eight pts (50%) had undergone prior hematopoietic stem cell transplant (HSCT). Fourteen pts (88%) had adverse-risk disease, including 6 (38%) with complex karyotype and 3 (19%) with TP53 mutation. Excluding Ras pathway mutations, ASXL1 was the most common co-mutation and was present in 50% of pts. Overall, 4 pts (25%) responded (1 with CR, 1 with CRi and 2 with MLFS). The only pt with CMML responded and attained CR. Two of the 3 pts (67%) who had not previously received HMA plus venetoclax responded (1 CR and 1 MLFS); in contrast, only 2 of the 13 pts (15%) who had previously received HMA plus venetoclax responded (1 CRi and 1 MLFS). Three of the 4 responders had diploid karyotype and one NRAS mutation; the other pt had complex karyotype and an NF1 mutation. Of the 3 responding pts with a NRAS mutations, 2 showed a dramatic decrease in their respective NRAS variant allelic frequencies (0.15 to 0.05 and 0.51 to 0.02). In addition to the 4 pts with formal responses, 4 pts (25%) had a bone marrow blast reduction of ≥50%, including 1 pt with prior treatment with HMA plus venetoclax who had blast reduction from 26% to 6% and who continued on study for 5.5 months. The median duration of follow-up is 7.4 months. One pt who achieved MLFS relapsed after 2 months of remission. The other 3 pts remain in remission. Two of these pts remain on study with ongoing remissions of 3 and 8 months, and the other pt underwent HSCT and has ongoing remission of 7 months. The median overall survival (OS) of the entire cohort was 2.7 months and the 6-month OS rate was 25% (Figure 1A). The median OS for responders and non-responders was not reached and 1.7 months, respectively (P=0.02; Figure 1B). The most common non-hematologic adverse events of any grade were diarrhea (88%) and nausea (63%). Grade 3 non-hematologic adverse events possibly related to study treatment included: mucositis (n=3), diarrhea (n=1), and decreased ejection fraction (EF) (n=1). Six pts (38%) required dose reduction or temporary cessation of trametinib due to mucositis (n=2), retinopathy (n=1), decreased EF (n=1), rash (n=1), and diarrhea (n=1). Conclusion: In this heavily pretreated pt population with poor-risk disease with Ras pathway-activating myeloid malignancies, the triplet combination of azacitidine, venetoclax and trametinib resulted in a response rate of 25%. Two of 3 pts without prior exposure to HMA plus venetoclax responded, and although response rate was modest (15%) in pts with prior HMA plus venetoclax, the activity in this population suggests potential benefit of adding trametinib in these pts. Figure 1 Figure 1. Disclosures Ravandi: Taiho: Honoraria, Research Funding; Prelude: Research Funding; Agios: Honoraria, Research Funding; Astex: Honoraria, Research Funding; Jazz: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Xencor: Honoraria, Research Funding; Novartis: Honoraria; AstraZeneca: Honoraria; AbbVie: Honoraria, Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Syros Pharmaceuticals: Consultancy, Honoraria, Research Funding. Pemmaraju: Novartis Pharmaceuticals: Consultancy, Other: Research Support, Research Funding; Daiichi Sankyo, Inc.: Other, Research Funding; Springer Science + Business Media: Other; ASCO Leukemia Advisory Panel: Membership on an entity's Board of Directors or advisory committees; Plexxicon: Other, Research Funding; Incyte: Consultancy; Affymetrix: Consultancy, Research Funding; CareDx, Inc.: Consultancy; Protagonist Therapeutics, Inc.: Consultancy; Sager Strong Foundation: Other; LFB Biotechnologies: Consultancy; Stemline Therapeutics, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding; Abbvie Pharmaceuticals: 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; Samus: Other, Research Funding; MustangBio: Consultancy, Other; Aptitude Health: Consultancy; Cellectis S.A. ADR: Other, Research Funding; Roche Diagnostics: Consultancy; DAVA Oncology: Consultancy; Dan's House of Hope: Membership on an entity's Board of Directors or advisory committees; Celgene Corporation: Consultancy; HemOnc Times/Oncology Times: Membership on an entity's Board of Directors or advisory committees; Clearview Healthcare Partners: Consultancy; Blueprint Medicines: Consultancy; Bristol-Myers Squibb Co.: Consultancy; ImmunoGen, Inc: Consultancy; Pacylex Pharmaceuticals: Consultancy. Konopleva: Rafael Pharmaceuticals: Other: grant support, Research Funding; Eli Lilly: Patents & Royalties: intellectual property rights, Research Funding; Calithera: Other: grant support, Research Funding; Genentech: Consultancy, Honoraria, Other: grant support, Research Funding; Novartis: Other: research funding pending, Patents & Royalties: intellectual property rights; Forty Seven: Other: grant support, Research Funding; Cellectis: Other: grant support; Agios: Other: grant support, Research Funding; AstraZeneca: Other: grant support, Research Funding; Sanofi: Other: grant support, Research Funding; AbbVie: Consultancy, Honoraria, Other: Grant Support, Research Funding; Stemline Therapeutics: Research Funding; Ascentage: Other: grant support, Research Funding; KisoJi: Research Funding; Ablynx: Other: grant support, Research Funding; F. Hoffmann-La Roche: Consultancy, Honoraria, Other: grant support; Reata Pharmaceuticals: Current holder of stock options in a privately-held company, Patents & Royalties: intellectual property rights. Loghavi: Abbvie: Current equity holder in publicly-traded company; Curio Sciences: Honoraria; Gerson Lehrman Group: Consultancy; Guidepoint: Consultancy; Peerview: Honoraria; Qualworld: Consultancy. Borthakur: Astex: Research Funding; ArgenX: Membership on an entity's Board of Directors or advisory committees; GSK: Consultancy; University of Texas MD Anderson Cancer Center: Current Employment; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Protagonist: Consultancy; Ryvu: Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees. Jabbour: Amgen, AbbVie, Spectrum, BMS, Takeda, Pfizer, Adaptive, Genentech: Research Funding. Daver: Pfizer: Consultancy, Research Funding; Abbvie: Consultancy, Research Funding; Bristol Myers Squibb: Consultancy, Research Funding; Daiichi Sankyo: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; Gilead Sciences, Inc.: Consultancy, Research Funding; Trovagene: Consultancy, Research Funding; ImmunoGen: Consultancy, Research Funding; Novimmune: Research Funding; Novartis: Consultancy; Trillium: Consultancy, Research Funding; Hanmi: Research Funding; Sevier: Consultancy, Research Funding; FATE Therapeutics: Research Funding; Glycomimetics: Research Funding; Genentech: Consultancy, Research Funding; Astellas: Consultancy, Research Funding; 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. Jain: Fate Therapeutics: Research Funding; Genentech: Honoraria, Research Funding; TG Therapeutics: Honoraria; Aprea Therapeutics: Research Funding; Beigene: Honoraria; Servier: Honoraria, Research Funding; Pfizer: Research Funding; Precision Biosciences: Honoraria, Research Funding; Incyte: Research Funding; Janssen: Honoraria; Bristol Myers Squibb: Honoraria, Research Funding; AstraZeneca: Honoraria, Research Funding; ADC Therapeutics: Honoraria, Research Funding; Cellectis: Honoraria, Research Funding; Adaptive Biotechnologies: Honoraria, Research Funding; AbbVie: Honoraria, Research Funding; Pharmacyclics: Research Funding. Kadia: Genfleet: Other; Ascentage: Other; AstraZeneca: Other; Sanofi-Aventis: Consultancy; Cellonkos: Other; Astellas: Other; Pulmotech: Other; Pfizer: Consultancy, Other; Novartis: Consultancy; Liberum: Consultancy; Jazz: Consultancy; Genentech: Consultancy, Other: Grant/research support; Dalichi Sankyo: Consultancy; Cure: Speakers Bureau; BMS: Other: Grant/research support; Amgen: Other: Grant/research support; Aglos: Consultancy; AbbVie: Consultancy, Other: Grant/research support. Kantarjian: BMS: Research Funding; Pfizer: Honoraria, Research Funding; AbbVie: Honoraria, Research Funding; Astellas Health: Honoraria; Amgen: Honoraria, Research Funding; Daiichi-Sankyo: Research Funding; Ascentage: Research Funding; Astra Zeneca: Honoraria; Jazz: Research Funding; Immunogen: Research Funding; Novartis: Honoraria, Research Funding; Aptitude Health: Honoraria; NOVA Research: Honoraria; KAHR Medical Ltd: Honoraria; Ipsen Pharmaceuticals: Honoraria; Precision Biosciences: Honoraria; Taiho Pharmaceutical Canada: Honoraria. Short: Amgen: Consultancy, Honoraria; Takeda Oncology: Consultancy, Research Funding; Astellas: Research Funding; AstraZeneca: Consultancy; Novartis: Honoraria; Jazz Pharmaceuticals: Consultancy; NGMBio: Consultancy. OffLabel Disclosure: Trametinib is a MEK inhibitor working in the RAS/RAF pathway. In patients with relapse/refractory AML with mutations in this pathway, downstream inhibition might provide an avenue for treatment.

Abstract: Background: Pevonedistat is a first-in-class inhibitor of NEDD8-activating enzyme that catalyzes the rate-limiting step of protein neddylation, a critical step in the degradation of cellular proteins that occurs upstream of the proteasome. The combination of azacitidine plus pevonedistat has resulted in high response rates and durable remissions in both myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML), particularly in secondary AML (s-AML). Preclinical studies suggest that pevonedistat synergizes with venetoclax through neutralization of Mcl-1, providing rationale for the triplet combination of azacitidine, venetoclax and pevonedistat. Methods: In this phase I/II study, adult patients (pts) with newly diagnosed s-AML, including pts with therapy-related AML (t-AML) or AML with MDS-related changes, who were unsuitable for intensive chemotherapy were eligible. Pts were required to have a performance status ≤2, total bilirubin ≤ upper limit of normal (ULN), ALT/AST ≤2.5 x ULN, and creatinine clearance ≥30 mL/min. In cycle 1, pts received azacitidine 75 mg/m 2 SC/IV on days 1-7, venetoclax on days 1-28, and pevonedistat 20 mg/m 2 IV on days 1, 3 and 5 on a 28-day schedule. Venetoclax dose ranged from 200mg to 400mg daily during the phase I dose escalation. For cycles 2 and beyond, venetoclax was given on days 1-21. Results: Between 3/2019 and 5/2021, 28 pts were treated (3 pts at venetoclax 200mg daily and 25 pts at 400mg daily). Baseline characteristics are shown in Table 1. The median age was 74 years (range, 61-80), and 12 pts (43%) were ≥75 years of age. The study population was enriched with pts with poor-risk features, including 19 pts (68%) with adverse-risk cytogenetics, 14 (50%) with prior hypomethylating (HMA) or chemotherapy exposure for preceding hematologic malignancy, and 8 (29%) with TP53 mutation. The overall response rate (CR+CRi+MLFS) was 71%, and the CR+CRi rate was 64%. Thirteen pts (46%) achieved CR as best response, 5 (18%) achieved CRi, and 2 (7%) achieved MLFS. Among the 18 pts who achieved CR/CRi, 8 (44%) achieved MRD negativity by multiparameter flow cytometry. Responses were observed across subgroups, including in 8/14 pts (57%) with prior HMA/chemotherapy exposure, 6/8 pts (75%) with TP53 mutation, 12/19 pts (63%) with poor-risk cytogenetics, and 8/9 pts (89%) without non-poor-risk cytogenetics. With a median follow-up of 13.4 months (range 0.4 to 26.3+ months), the median overall survival (OS) was 8.2 months, and the median relapse-free survival was 7.5 months (Figure 1). The median OS for pts with poor-risk and non-poor cytogenetics was 7.9 and 18.0 months, respectively; for pts with and without prior HMA/chemotherapy exposure was 6.2 and 8.9 months, respectively; and for pts with inv(3) AML, TP53-mutated AML, and non-inv(3)/non-TP53-mutated AML was 3.8, 8.9, and 18.0 months, respectively. Four pts (14% of the entire cohort, 20% of responding pts) proceed to hematopoietic stem cell transplantation (HSCT), 3 of whom are still alive and 1 with inv(3) who relapsed post-HSCT and died from progressive AML. The combination was overall well-tolerated with myelosuppression as expected with the combination of HMA plus venetoclax in AML. The median number of cycles received was 2 (range, 1-13 cycles). Non-hematologic grade ≥3 adverse events occurring in ≥2 pts included infection or neutropenic fever in 18 pts (61%), hypophosphatemia in 8 pts (29%), hyperglycemia, hyperbilirubinemia and ALT/AST elevation in 3 pts each (11%), and pneumonitis, acute kidney injury, hypokalemia and vomiting in 2 pts each (7%). One pt developed multiorgan failure on cycle 1, day 1 of therapy, with transaminase elevation, hyperbilirubinemia, renal failure and hyperferritinemia; this pt recovered with holding therapy and supportive care. Hypophosphatemia, which has previously been reported with pevonedistat, was easily managed with oral or intravenous phosphorus supplementation. The 4-week and 8-week mortality rates were 7% and 14%, respectively. Conclusions: The combination of azacitidine, venetoclax and pevonedistat was safe and effective in a very poor-risk population of pts with s-AML, half of whom had prior HMA or chemotherapy exposure for antecedent hematologic malignancy. A randomized study evaluating azacitidine and venetoclax ± pevonedistat (NCT04266795) is ongoing and will help to clarify the potential role of pevonedistat in the frontline treatment of AML. Figure 1 Figure 1. Disclosures Short: AstraZeneca: Consultancy; Jazz Pharmaceuticals: Consultancy; NGMBio: Consultancy; Astellas: Research Funding; Novartis: Honoraria; Takeda Oncology: Consultancy, Research Funding; Amgen: Consultancy, Honoraria. Alvarado: Daiichi-Sankyo: Research Funding; Jazz Pharmaceuticals: Research Funding; FibroGen: Research Funding; BerGenBio: Research Funding; MEI Pharma: Research Funding; Sun Pharma: Consultancy, Research Funding; CytomX Therapeutics: Consultancy; Astex Pharmaceuticals: Research Funding. Konopleva: KisoJi: Research Funding; Ascentage: Other: grant support, Research Funding; AstraZeneca: Other: grant support, Research Funding; Agios: Other: grant support, Research Funding; Ablynx: Other: grant support, Research Funding; Cellectis: Other: grant support; Forty Seven: Other: grant support, Research Funding; AbbVie: Consultancy, Honoraria, Other: Grant Support, Research Funding; Rafael Pharmaceuticals: Other: grant support, Research Funding; Eli Lilly: Patents & Royalties: intellectual property rights, Research Funding; Calithera: Other: grant support, Research Funding; Sanofi: Other: grant support, Research Funding; Stemline Therapeutics: Research Funding; F. Hoffmann-La Roche: Consultancy, Honoraria, Other: grant support; Reata Pharmaceuticals: Current holder of stock options in a privately-held company, Patents & Royalties: intellectual property rights; Genentech: Consultancy, Honoraria, Other: grant support, Research Funding; Novartis: Other: research funding pending, Patents & Royalties: intellectual property rights. Jabbour: Amgen, AbbVie, Spectrum, BMS, Takeda, Pfizer, Adaptive, Genentech: Research Funding. Yilmaz: Pfizer: Research Funding; Daiichi-Sankyo: Research Funding. Jain: Genentech: Honoraria, Research Funding; Cellectis: Honoraria, Research Funding; Precision Biosciences: Honoraria, Research Funding; ADC Therapeutics: Honoraria, Research Funding; Pfizer: Research Funding; Adaptive Biotechnologies: Honoraria, Research Funding; Bristol Myers Squibb: Honoraria, Research Funding; Aprea Therapeutics: Research Funding; Janssen: Honoraria; Incyte: Research Funding; Servier: Honoraria, Research Funding; AstraZeneca: Honoraria, Research Funding; Fate Therapeutics: Research Funding; Beigene: Honoraria; TG Therapeutics: Honoraria; Pharmacyclics: Research Funding; AbbVie: Honoraria, Research Funding. Borthakur: Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Ryvu: Research Funding; ArgenX: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Astex: Research Funding; University of Texas MD Anderson Cancer Center: Current Employment; GSK: Consultancy; Protagonist: Consultancy. DiNardo: ImmuneOnc: 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; Foghorn: Honoraria, Research Funding; Forma: Honoraria, Research Funding; Bristol Myers Squibb: Honoraria, Research Funding; GlaxoSmithKline: Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria; Novartis: Honoraria; Agios/Servier: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Research Funding; Celgene, a Bristol Myers Squibb company: Honoraria, Research Funding. Daver: Astellas: Consultancy, Research Funding; Bristol Myers Squibb: Consultancy, Research Funding; Sevier: Consultancy, Research Funding; Glycomimetics: Research Funding; Gilead Sciences, Inc.: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; FATE Therapeutics: Research Funding; Amgen: Consultancy, Research Funding; Abbvie: Consultancy, Research Funding; Trovagene: Consultancy, Research Funding; Hanmi: Research Funding; Novimmune: Research Funding; Daiichi Sankyo: Consultancy, 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. Pemmaraju: MustangBio: Consultancy, Other; ASH Communications Committee: Membership on an entity's Board of Directors or advisory committees; Aptitude Health: Consultancy; Samus: Other, Research Funding; Plexxicon: Other, Research Funding; Sager Strong Foundation: Other; CareDx, Inc.: Consultancy; Cellectis S.A. ADR: Other, Research Funding; Daiichi Sankyo, Inc.: Other, Research Funding; 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; ASCO Leukemia Advisory Panel: Membership on an entity's Board of Directors or advisory committees; Abbvie Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding; Springer Science + Business Media: Other; Pacylex Pharmaceuticals: Consultancy; Celgene Corporation: Consultancy; Roche Diagnostics: Consultancy; DAVA Oncology: Consultancy; Stemline Therapeutics, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding; LFB Biotechnologies: Consultancy; Novartis Pharmaceuticals: Consultancy, Other: Research Support, Research Funding; Incyte: Consultancy; Affymetrix: Consultancy, Research Funding; Protagonist Therapeutics, Inc.: Consultancy; Clearview Healthcare Partners: Consultancy; Blueprint Medicines: Consultancy; Bristol-Myers Squibb Co.: Consultancy; ImmunoGen, Inc: Consultancy. Sasaki: 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; Novartis: Consultancy, Research Funding. Ravandi: AstraZeneca: Honoraria; Jazz: Honoraria, Research Funding; Taiho: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Agios: Honoraria, Research Funding; Bristol Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Honoraria, Research Funding; Astex: Honoraria, Research Funding; Syros Pharmaceuticals: Consultancy, Honoraria, Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Xencor: Honoraria, Research Funding; Novartis: Honoraria; Prelude: Research Funding. Kadia: Genfleet: Other; Cure: Speakers Bureau; Genentech: Consultancy, Other: Grant/research support; Amgen: Other: Grant/research support; Dalichi Sankyo: Consultancy; Jazz: Consultancy; Novartis: Consultancy; Liberum: Consultancy; Aglos: Consultancy; Pfizer: Consultancy, Other; AbbVie: Consultancy, Other: Grant/research support; Pulmotech: Other; BMS: Other: Grant/research support; Astellas: Other; Sanofi-Aventis: Consultancy; AstraZeneca: Other; Cellonkos: Other; Ascentage: Other. Andreeff: Breast Cancer Research Foundation: Research Funding; Aptose: Consultancy; Daiichi-Sankyo: Consultancy, Research Funding; Karyopharm: Research Funding; 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; Glycomimetics: Consultancy; Senti-Bio: Consultancy; Oxford Biomedica UK: Research Funding; Syndax: Consultancy; AstraZeneca: Research Funding; ONO Pharmaceuticals: Research Funding; Amgen: Research Funding; Reata, Aptose, Eutropics, SentiBio; Chimerix, Oncolyze: Current holder of individual stocks in a privately-held company; Medicxi: 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. Kantarjian: Ipsen Pharmaceuticals: Honoraria; Amgen: Honoraria, Research Funding; Precision Biosciences: Honoraria; Astellas Health: Honoraria; Astra Zeneca: Honoraria; Immunogen: Research Funding; Daiichi-Sankyo: Research Funding; KAHR Medical Ltd: Honoraria; Aptitude Health: Honoraria; Pfizer: Honoraria, Research Funding; Ascentage: Research Funding; NOVA Research: Honoraria; BMS: Research Funding; Jazz: Research Funding; Novartis: Honoraria, Research Funding; AbbVie: Honoraria, Research Funding; Taiho Pharmaceutical Canada: Honoraria. Cortes: Novartis: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Bio-Path Holdings, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees; Sun Pharma: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Bristol Myers Squibb, Daiichi Sankyo, Jazz Pharmaceuticals, Astellas, Novartis, Pfizer, Takeda, BioPath Holdings, Incyte: Consultancy, Research Funding.

Abstract: Background: FLT3 mut confers higher risk of relapse and inferior overall survival (OS) in acute myeloid leukemia (AML). FLT3 inhibitors (FLT3i) show synergism with venetoclax (VEN), and hypomethylating agents (HMA); and clinical studies have shown promising results with HMA+FLT3i, and VEN+FLT3i in FLT3mut AML. We report the results of the first combination of VEN+FLT3i+HMA from a prospective phase 2 study. Methods: We conducted a subgroup analysis of FLT3mut AML pts treated with 10-day decitabine and VEN (DEC10-VEN) on a phase 2 trial. Addition of FLT3i of clinician's choice was allowed. We enrolled newly diagnosed (ND) AML pts & gt;60 yrs and relapsed/refractory (R/R) pts & gt;18 yrs. Pts received DEC 20 mg/m2 for 10 days every 4-6 wks for induction followed by DEC for 5 days after CR/CRi. VEN dose was 400 mg daily or equivalent. Reduction of VEN duration was allowed in cases of myelosuppression. All pts received tumor lysis and antimicrobial prophylaxis during neutropenia. Full protocol of the study has been published previously (DiNardo et al. Lancet Haematol. 2020. In press). CRc (CR + CRp + CRi) responses were graded by the International Working Group for AML criteria (with adapted CRi criteria as presented in ADMIRAL study. NEJM 2019). Results: Between March 2018 and March 2020 we enrolled 30 pts with FLT3mut AML. Among 14 pts with previously treated AML, 13 had R/R AML and 1 had sAML with prior HMA treatment for CMML (Table 1). Among 16 pts with treatment-naïve AML, 15 had ND AML and 1 had sAML with untreated prior MDS. All 14 pts with previously treated AML received FLT3i with DEC10-VEN including sorafenib (SORA, 6), gilteritinib (GILT, 4) and midostaurin (MIDO, 4). Among 16 pts with treatment-naïve AML 11 received a FLT3i including GILT (5), SORA (5) and MIDO (2). 5 pts did not receive a FLT3i due to low ITD ratio (1), insurance non-approval (n=1) and TKD only (3). Median dose and duration of FLT3i during cycle 1 for SORA was 400 mg BID (interquartile range [IQR] 400-400) for 15 days (IQR 14-28), for MIDO was 50 mg BID (IQR 50-50) for 15 days (IQR 14-21) and for GILT was 120 mg daily (IQR 120-120) for 14 days (IQR 14-28). For subsequent cycles, the median dose and duration of SORA was 400 mg BID for 14 days (IQR 14-28), for MIDO was 50 mg BID for 28 days (IQR 28-continuous) and for GILT was 120 mg daily for 14 days (IQR 14-14). 60-day mortality was 7% (n=1) for previously treated pts and 0% in treatment-naïve pts. There were 43 grade 3/4 adverse events, at least possibly related, including infections (with grade 3/4 neutropenia) in 40% pts, febrile neutropenia in 30% and infection (with ANC ≥1.0x109/L) in 27%. Number of treatment-naïve pts with grade 3/4 infections was comparable in those receiving DEC10-VEN vs. FLT3i+DEC10-VEN (2/5 vs 8/11, P=0.2). In treatment-naïve AML, the median time to ANC recovery was 45 days after cycle 1, and 38 days during subsequent cycles, and median time to platelet recovery was 30 days for cycle 1. In previously treated AML the CRc rate was 64% (9/14) and minimal residual disease (MRD) negativity rate by flow cytometry (FCM) was 71% and by PCR/NGS was 88%. Among R/R pts previously exposed to a FLT3i (n=8) the CRc rate was 63%, with FLT3 PCR negativity in 80% (4/5). In treatment-naïve AML the CRc rate was 88% (14/16), MRD negativity by FCM was 82%, by PCR/NGS was 100% (Table 2); and CRc rate in pts not receiving FLT3i was 80% (4/5). After a median follow-up 14.5 months (mo) the median OS and duration of response (DOR) in previously treated pts are 6.1 mo and not reached (NR), respectively; and in treatment-naïve pts are NR and 22.1 mo, respectively, with 2 yr OS of 90% (Fig. 1). 5 previously treated pts underwent stem-cell transplantation (SCT) and 1 pt received DEC + SORA maintenance afterwards with 2-yr OS of 53% in these 5 pts. 4 treatment-naïve pts underwent SCT and 2 pts received FLT3i maintenance post-SCT (SORA [1], crenolanib [1] ). Causes of death (COD) in previously treated pts were pneumonia (2), intracranial hemorrhage (1) and hospice (1) in non-responding pts, and unknown reason (5) and pneumonia post-SCT (1) in responding pts. COD in treatment-naïve pts was pneumonia in CR (1) and refractory disease (1). In 10 pts who were refractory to or relapsed after 'triplet' therapy, the most frequent mutations at screening were DNMT3A (4), IDH1/2 (4), and N/KRAS (3). Conclusion: In our experience, DEC10-VEN + FLT3i is safe and effective for previously treated FLT3mut AML, and an excellent frontline option for older pts with treatment-naïve AML. Disclosures Maiti: Celgene: Research Funding. DiNardo:Notable Labs: Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Honoraria, Research Funding; Daiichi Sankyo: Consultancy, Honoraria, Research Funding; Jazz: Honoraria; MedImmune: Honoraria; Novartis: Consultancy; Syros: Honoraria; Calithera: Research Funding; Takeda: Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Agios: Consultancy, Honoraria, Research Funding; ImmuneOnc: Honoraria. Ravandi:Amgen: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria; Orsenix: Consultancy, Honoraria, Research Funding; Abbvie: Consultancy, Honoraria, Research Funding; Macrogenics: Research Funding; AstraZeneca: Consultancy, Honoraria; Jazz Pharmaceuticals: Consultancy, Honoraria, Research Funding; Xencor: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Honoraria, Research Funding; Astellas: Consultancy, Honoraria, Research Funding. Pemmaraju:Novartis: Honoraria, Research Funding; Cellectis: Research Funding; DAVA Oncology: Honoraria; Plexxikon: Research Funding; Roche Diagnostics: Honoraria; MustangBio: Honoraria; Affymetrix: Other: Grant Support, Research Funding; SagerStrong Foundation: Other: Grant Support; LFB Biotechnologies: Honoraria; Incyte Corporation: Honoraria; AbbVie: Honoraria, Research Funding; Samus Therapeutics: Research Funding; Blueprint Medicines: Honoraria; Pacylex Pharmaceuticals: Consultancy; Daiichi Sankyo: Research Funding; Stemline Therapeutics: Honoraria, Research Funding; Celgene: Honoraria. Borthakur:Argenx: Consultancy; Novartis: Research Funding; GSK: Research Funding; Polaris: Research Funding; AstraZeneca: Research Funding; PTC Therapeutics: Consultancy; BMS: Research Funding; BioLine Rx: Research Funding; Jannsen: Research Funding; Abbvie: Research Funding; BioTherix: Consultancy; Nkarta Therapeutics: Consultancy; Incyte: Research Funding; Cyclacel: Research Funding; BioLine Rx: Consultancy; FTC Therapeutics: Consultancy; Xbiotech USA: Research Funding; Treadwell Therapeutics: Consultancy; Curio Science LLC: Consultancy; Oncoceutics: Research Funding; PTC Therapeutics: Research Funding. Bose:Pfizer, Inc.: Research Funding; CTI BioPharma: Honoraria, Research Funding; Promedior, Inc.: Research Funding; Astellas Pharmaceuticals: Research Funding; NS Pharma: Research Funding; Kartos Therapeutics: Honoraria, Research Funding; Incyte Corporation: Consultancy, Honoraria, Research Funding, Speakers Bureau; Celgene Corporation: Honoraria, Research Funding; Constellation Pharmaceuticals: Research Funding; Blueprint Medicines Corporation: Honoraria, Research Funding. Issa:Novartis: Membership on an entity's Board of Directors or advisory committees; Syndax: Research Funding; Celegene: Research Funding. Kadia:JAZZ: Honoraria, Research Funding; Amgen: Research Funding; BMS: Honoraria, Research Funding; Cellenkos: Research Funding; Ascentage: Research Funding; Celgene: Research Funding; Genentech: Honoraria, Research Funding; Abbvie: Honoraria, Research Funding; Astra Zeneca: Research Funding; Incyte: Research Funding; Pulmotec: Research Funding; Novartis: Honoraria; Pfizer: Honoraria, Research Funding; Cyclacel: Research Funding; Astellas: Research Funding. Short:Takeda Oncology: Consultancy, Honoraria, Research Funding; Astellas: Research Funding; AstraZeneca: Consultancy; Amgen: Honoraria. Yilmaz:Pint Pharma: Honoraria; Daicho Sankyo: Research Funding; Pfizer: Research Funding. Jabbour:Amgen: Other: Advisory role, Research Funding; Takeda: Other: Advisory role, Research Funding; BMS: Other: Advisory role, Research Funding; Pfizer: Other: Advisory role, Research Funding; AbbVie: Other: Advisory role, Research Funding; Adaptive Biotechnologies: Other: Advisory role, Research Funding; Genentech: Other: Advisory role, Research Funding. Jain:BeiGene: 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; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Aprea Therapeutics: 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; Cellectis: Research Funding; Servier: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Incyte: Research Funding; ADC Therapeutics: Research Funding; Pfizer: Research Funding; BMS: Research Funding; AstraZeneca: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech: 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; Pharmacyclics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Thompson:Genentech: Consultancy; Adaptive Biotechnologies: Consultancy, Research Funding; Janssen-Cilag: Honoraria; Pharmacyclics: Research Funding; AbbVie: Research Funding. Kantarjian:BMS: Research Funding; Abbvie: Honoraria, Research Funding; Adaptive biotechnologies: Honoraria; Actinium: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Research Funding; Pfizer: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Jazz: Research Funding; Immunogen: Research Funding; Daiichi-Sankyo: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Delta Fly: Honoraria; Ascentage: Research Funding; Janssen: Honoraria; Oxford Biomedical: Honoraria; BioAscend: Honoraria; Aptitute Health: Honoraria. Daver:Daiichi Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Fate Therapeutics: Research Funding; Trovagene: Research Funding; Gilead: 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; Novimmune: 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; Amgen: 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. Konopleva:Ablynx: Research Funding; Eli Lilly: Research Funding; AbbVie: Consultancy, Research Funding; Calithera: 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; Ascentage: Research Funding; Rafael Pharmaceutical: Research Funding; Cellectis: Research Funding; Sanofi: Research Funding; Forty-Seven: Consultancy, Research Funding; Stemline Therapeutics: Consultancy, Research Funding; Agios: Research Funding; Genentech: Consultancy, Research Funding; F. Hoffmann La-Roche: Consultancy, Research Funding; Kisoji: Consultancy; AstraZeneca: Research Funding; Amgen: Consultancy.

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.