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Aims To report long-term safety/efficacy of VEN+LDAC. Methods Patients ≥ 60 yrs with previously untreated AML ineligible for standard induction chemotherapy (ECOG performance status: 0–2 [≥75 yrs]; 0–3 [60–74 yrs]) were enrolled. Before dose ramp-up of VEN in cycle 1, patients received prophylaxis to mitigate risk of tumor lysis syndrome (TLS). Patients were treated at recommended phase 2 dose (RP2D): VEN 600 mg per day (QD) orally in 28-day (d) cycles, with subcutaneous LDAC 20 mg/m2 QD on d1–10. Key objectives at RP2D were to assess response rates, duration of response (DOR), overall survival (OS), and safety/tolerability. Results Eighty-two patients received RP2D and ≥1 dose of VEN. Median age was 74 yrs; secondary AML: 49%, prior treatment with a hypomethylating agent (HMA): 29%, poor-risk cytogenetics: 32%. In patients evaluable for molecular analyses, baseline mutations in TP53, FLT3, IDH1/2, and NPM1 were detected in 14%, 21%, 26%, and 13%, respectively. Median treatment duration was 4.2 mo (range 0.2–41.8); 26% received >12.0 mo of treatment. The complete remission (CR)/CR with incomplete blood count recovery (CRi) rate was 54% (CR: 26%; CRi: 28%); median time to first response, 1.4 mo (range 0.8–14.9). Median with 95% confidence interval (CI) DOR (CR/CRi) was 9.8 mo (5.3, 14.9), and median OS was 9.7 mo (5.7, 14.0). Among patients with de novo AML (n=42), CR/CRi rate was 71% (CR: 45%; CRi: 26%); median DOR: 10.8 mo (5.5, 32.8), median OS: 15.7 mo (9.7, 22.4). Patients with prior HMA exposure (n=24), CR/CRi was achieved in 33% (CR: 4%; CRi: 29%); median DOR: 5.3 mo (2.3, 10.2), median OS: 4.1 mo (2.9, 10.1). Longer median OS showed in patients with mutations in NPM1 or IDH1/2 (not reached and 15.9 mo, respectively), intermediate-risk cytogenetic features (14.2 mo), or no prior treatment with HMA (11.7 mo). Common grade 3 or 4 treatment-emergent adverse events (≥30%) were febrile neutropenia (43%), thrombocytopenia (39%), and decreased white blood cell count (34%); 2 patients reported grade ≥3 laboratory TLS event. Conclusion At median 3.5-yr follow-up, VEN+LDAC resulted in median OS of 10 mo. At 2 yrs, 22% of study population remained alive; 32%, 36%, and 64% were alive with IDH1/2, de novo, or NPM1 mutant AML, respectively. Further analyses identifying baseline features predictive of response with prolonged duration are ongoing. Abstract was previously published at EHA25.