Background: ASTX727, is an oral formulation of the fixed dose combination of decitabine and cytidine deaminase inhibitor cedazuridine (100 mg/35 mg). We investigated whether a total oral therapy regimen of ASTX727+ven is feasible and safe. Methods: Pts aged ≥18 years (yrs) with relapsed/refractory AML (R/R) or pts with AML aged ≥ 75 or 18 -74 with comorbid conditions prohibiting intensive chemotherapy were eligible to participate (frontline-FL). Other eligibility criteria included adequate renal and hepatic function, and an ECOG performance status (PS) of≤2. ASTX727 is administered daily on days 1‐5 of each cycle and ven on days 1‐28 of the first cycle after a dose ramp up of 100-200-400 mg over 3 days (with tumor lysis prophylaxis precautions and with ven dose adjustments as needed). A bone marrow exam is performed on day 21±3 days and ven is held if blasts < 5% to allow count recovery. Cycles are repeated every 4-8 weeks and ven is administered for 21 days in subsequent cycles. Results: Between March 2021 and January 2022, 28 pts (15 FL and 13 R/R) have been treated on the study. The median age is 75 yrs (range, 47-90) with FL cohort 81 and R/R cohort 72. 9 FL pts (60%) were ≥80 and 5 (30%) 70-80 yrs. In R/R cohort 9 pts (69%) were 70-80 yrs. The median PS is 2 (range 0-3) and in the R/R cohort, the median number of prior treatments is 2 (range, 1-4). In the FL cohort 5 (33%) had normal and 6 (40%) a complex karyotype; 3 had other. In the R/R cohort, 15% had normal karyotype, 46% complex and 31% others. Mutations of note in the frontline cohort were RUNX1 (33%), ASXL1 (33%), DNMT3A (7%), TET2 (40%) and TP53 (20%). The overall response rate (ORR) including complete response (CR), CR with incomplete count recovery (CRi) and morphological leukemia free state (MLFS) in the FL cohort is 61% (4 CR, 4 CRi, 1 MLFS and 3 non-responders). 3 pts received only one day of therapy for severe adverse events unrelated to therapy (1 due to ischemic stroke, 1 septic shock and 1 debilitation) and were not evaluable for response. In the R/R cohort, the ORR was 45% (2 CR, 2 CRi, 2 MLFS with 5 non-responders and 2 not evaluable). The median number of cycles received is 2 (range, 1-5) for both cohorts. With a median follow-up of 5 months, the median survival for the FL cohort has not been reached (range, 0.6 – 7.3) and is 7.2 (range, 0.8-7.3) months for the R/R cohort. Grade 3 or higher adverse events directly attributable to therapy were mainly myelosuppression-related and included neutropenic infections in 3 (11%) and elevation of liver enzymes in 1 (4%) pt. Conclusions: Total oral therapy of ASTX727+ven is safe and feasible, particularly in the advanced elderly population, and demonstrates significant efficacy in pts unfit for chemotherapy both in the FL and R/R settings. Clinical trial information: NCT04746235.