Background: Patients (pt) with relapsed or refractory (R/R) acute myeloid leukemia (AML) have poor outcomes. Pts without actionable mutations (e.g. FLT3, IDH1/2) do not have standard approved treatments, and outcomes with available salvage therapies are poor (Roboz et al. J Clin Oncol. 2014). While venetoclax with azacitidine is now the standard for older or unfit pts with newly diagnosed AML, it is unknown how venetoclax-based lower intensity regimens compare to intensive chemotherapy (IC) for salvage therapy in adult pts with AML. Methods: We compared outcomes of adult pts (>18 yrs) with R/R AML treated on a prospective phase 2 trial of 10-day decitabine and venetoclax (DEC10-VEN) with a historical cohort of patients treated with intensive chemotherapy (IC) using a propensity score matched analysis (PSMA). Pts treated with DEC10-VEN received decitabine 20 mg/m2 daily for 10 days with daily venetoclax for induction followed by decitabine for 5 days with venetoclax for consolidation (NCT03404193); prior exposure to venetoclax was exclusion criteria. Patients in the IC cohort received either CLIA, CIA, or FIA without venetoclax on 2 prospective clinical 1b/2 trials (NCT02115295, NCT01289457). CLIA regimen included cladribine 5 mg/m2 IV on days (D) 1-5, ara-C 1-2 g/m2 IV on D1-5 and idarubicin 10 mg/m2 IV on D1-3. CIA and FIA included idarubicin 10 mg/m2 IV daily on D1-3, ara-C 1 g/m2 IV daily on D1-5, and clofarabine 15 mg/m2 IV daily on D1-5 or fludarabine 30 mg/m2 IV on D1-5, respectively. PSM with nearest neighbor method was used to select the IC comparison group using a 1:1 matching with caliper control of 0.3. Propensity scores were calculated from baseline characteristics including age, ECOG performance status, European LeukemiaNet risk group and number of prior lines of therapies received. SPSS 24, R Essentials for SPSS 24, R 3.2, and PSMATCHING3.03 package were used to conduct the PSM. Chi-square, Student's t, and log-rank were used to compare categorical, continuous, and time-to-event variables, respectively. Results: 54 out of 55 pts treated with DEC10-VEN were best matched to 54 out of 197 pts treated with IC. The standardized mean differences of variables selected for PSM before and after matching was low, ranging from -0.067 to 0.042 suggesting significant reduction of bias between the two intervention groups. Pts in DEC10-VEN cohort were treated between January 2018 and December 2019 while pts in IC cohort received treatment between February 2011 and January 2018. The median age of the DEC10-VEN cohort was 62 years and baseline characteristics were well balanced between the two groups (Table 1). The median no. of prior lines of therapy was similar in DEC10-VEN and IC cohorts at 2 (range 1-8) vs 2 (range 1-7), respectively (p=.8). In the IC group, 26 pts received CLIA, 20 pts received CIA and 8 pts received FIA. The median follow-up for the DEC10-VEN cohort was 12.5 months (mo) and for IC cohort was 22.5 mo. In DEC10-VEN cohort, pts received a median of 2 cycles of therapy (range 1-12) and in IC cohort pts had received a median of 1 cycle of therapy (range 1-7). CR/CRi were comparable with DEC10-VEN and IC (41% vs 30%, odds ratio [OR] , 95% CI 0.74, 3.62, p=.23, Table 2). The rate of primary refractory disease was significantly lower with DEC10-VEN (28% vs 54%, OR 0.33, 95% CI 0.15, 0.74, p<.01). The median no. of cycles to best response in DEC10-VEN cohort was 1 (range 1-4) and in IC cohort was 1 (range 1-2). The 30-day mortality was 7% (n=4) with DEC10-VEN and 9% (n=5) with IC (OR 0.78, 95% CI 0.20, 3.09, p=.73). The median overall survival (OS) with DEC10-VEN was 7.1 mo compared to 5.5 mo with IC (hazard ratio [HR] 0.72, 95% CI 0.46, 1.14, p=.16, Fig. 1). 10 pts in DEC10-VEN cohort and 8 pts in IC cohort proceeded to stem-cell transplantation (SCT). The median OS after SCT was comparable in DEC10-VEN and IC cohorts (median OS 19.3 vs 13.5 mo, HR 1.21, 95% CI 0.35, 4.22, p=.1, Fig. 2). Among FLT3-mutant pts, the median OS with DEC10-VEN + FLT3 inhibitor was 6.8 mo (n=10) and with IC + sorafenib was 8.8 mo (n=8; HR 0.84, 95% CI 0.27, 2.60, p=.1). Additional subgroup analyses by clinical, cytogenetic, and molecular characteristics will be presented. Conclusion: DEC10-VEN represents an appropriate salvage therapy comparable to non-venetoclax based intensive chemotherapy regimens in younger pts with R/R AML and can serve as a bridge to SCT. This regimen provides an appropriate backbone for adding novel therapies in the R/R setting. Disclosures Maiti: Celgene: Research Funding. DiNardo:Syros: Honoraria; ImmuneOnc: Honoraria; Takeda: Honoraria; Agios: Consultancy, Honoraria, Research Funding; Calithera: Research Funding; Novartis: Consultancy; Daiichi Sankyo: Consultancy, Honoraria, Research Funding; Notable Labs: Membership on an entity's Board of Directors or advisory committees; Jazz: Honoraria; AbbVie: Consultancy, Honoraria, Research Funding; MedImmune: Honoraria; Celgene: Consultancy, Honoraria, Research Funding. Kadia:Genentech: Honoraria, Research Funding; Pulmotec: Research Funding; JAZZ: Honoraria, Research Funding; Abbvie: Honoraria, Research Funding; Incyte: Research Funding; Ascentage: Research Funding; Cellenkos: Research Funding; Astra Zeneca: Research Funding; Astellas: Research Funding; Cyclacel: Research Funding; Amgen: Research Funding; Celgene: Research Funding; Pfizer: Honoraria, Research Funding; BMS: Honoraria, Research Funding; Novartis: Honoraria. Jabbour:BMS: Other: Advisory role, Research Funding; Pfizer: Other: Advisory role, Research Funding; Genentech: Other: Advisory role, Research Funding; Adaptive Biotechnologies: Other: Advisory role, Research Funding; AbbVie: Other: Advisory role, Research Funding; Amgen: Other: Advisory role, Research Funding; Takeda: Other: Advisory role, Research Funding. Daver:Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; 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; Bristol-Myers Squibb: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Karyopharm: Research Funding; Servier: Research Funding; Genentech: Research Funding; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novimmune: Research Funding; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Trovagene: Research Funding; Fate Therapeutics: Research Funding; ImmunoGen: Research Funding; Syndax: Consultancy, Membership on an entity's Board of Directors or advisory committees; Daiichi Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; 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. Borthakur:BioLine Rx: Consultancy; BioLine Rx: Research Funding; GSK: Research Funding; Cyclacel: Research Funding; Oncoceutics: Research Funding; Jannsen: Research Funding; Curio Science LLC: Consultancy; Polaris: Research Funding; Novartis: Research Funding; Argenx: Consultancy; FTC Therapeutics: Consultancy; BMS: Research Funding; Xbiotech USA: Research Funding; AstraZeneca: Research Funding; PTC Therapeutics: Research Funding; Incyte: Research Funding; BioTherix: Consultancy; Nkarta Therapeutics: Consultancy; Treadwell Therapeutics: Consultancy; Abbvie: Research Funding; PTC Therapeutics: Consultancy. Pemmaraju:MustangBio: Honoraria; SagerStrong Foundation: Other: Grant Support; AbbVie: Honoraria, Research Funding; LFB Biotechnologies: Honoraria; Roche Diagnostics: Honoraria; Pacylex Pharmaceuticals: Consultancy; Affymetrix: Other: Grant Support, Research Funding; Cellectis: Research Funding; Celgene: Honoraria; Stemline Therapeutics: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Blueprint Medicines: Honoraria; Incyte Corporation: Honoraria; Samus Therapeutics: Research Funding; DAVA Oncology: Honoraria; Plexxikon: Research Funding; Daiichi Sankyo: Research Funding. Short:Takeda Oncology: Consultancy, Honoraria, Research Funding; AstraZeneca: Consultancy; Amgen: Honoraria; Astellas: Research Funding. Yilmaz:Pfizer: Research Funding; Pint Pharma: Honoraria; Daicho Sankyo: Research Funding. Alvarado:Sun Pharma: Research Funding; Astex Pharmaceuticals: Research Funding; FibroGen: Research Funding; Tolero Pharmaceuticals: Research Funding; BerGenBio ASA: Research Funding; Jazz Pharmaceuticals: Research Funding; MEI Pharma: Research Funding; Daiichi-Sankyo: Research Funding. Ravandi:Amgen: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria; Astellas: Consultancy, Honoraria, Research Funding; 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. Kantarjian:Ascentage: Research Funding; Abbvie: Honoraria, Research Funding; BMS: Research Funding; Daiichi-Sankyo: Honoraria, Research Funding; Immunogen: Research Funding; Jazz: Research Funding; Novartis: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; Sanofi: Research Funding; Actinium: Honoraria, Membership on an entity's Board of Directors or advisory committees; Adaptive biotechnologies: Honoraria; Aptitute Health: Honoraria; BioAscend: Honoraria; Delta Fly: Honoraria; Janssen: Honoraria; Oxford Biomedical: Honoraria; Amgen: Honoraria, Research Funding. Konopleva:Eli Lilly: Research Funding; Amgen: Consultancy; AbbVie: Consultancy, Research Funding; Reata Pharmaceutical Inc.;: Patents & Royalties: patents and royalties with patent US 7,795,305 B2 on CDDO-compounds and combination therapies, licensed to Reata Pharmaceutical; Cellectis: Research Funding; Kisoji: Consultancy; Sanofi: Research Funding; Agios: Research Funding; Rafael Pharmaceutical: Research Funding; Ablynx: Research Funding; Stemline Therapeutics: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; Forty-Seven: Consultancy, Research Funding; AstraZeneca: Research Funding; Ascentage: Research Funding; Calithera: Research Funding; F. Hoffmann La-Roche: Consultancy, Research Funding.