Azacitidine-Venetoclax in Elderly and Unfit Acute Myeloid Leukemia: Real-World Outcomes Outside Clinical Trials

Background: Azacitidine plus venetoclax (AZA+VEN) is the current standard first-line treatment for elderly or medically unfit patients with acute myeloid leukemia (AML). However, patients treated in real-world settings often differ from those enrolled in clinical trials due to frailty, comorbidities, secondary AML, and prior exposure to hypomethylating agents. Materials and Methods: We retrospectively analyzed 21 consecutive AML patients who received frontline AZA+VEN between October 2020 and May 2026. Patient fitness was assessed according to SIE/SIES/GITMO criteria. Data on treatment responses, toxicities, treatment modifications, survival outcomes, ELN 2022/2024 risk categories, and comorbidity burden, including HCT-CI and augmented HCT-CI scores, were collected. Results: Median age was 77.2 years, and 95.2% of patients were considered unfit for intensive chemotherapy. Secondary AML was observed in 42.9% of cases, including 23.8% arising from myelodysplastic syndromes (MDSs) previously treated with azacitidine. The overall response rate was 57.1% (12/21), with a composite complete remission (CR/CRi) rate of 42.9%. The median time to response was 1.8 months. Venetoclax schedule modifications were required in 66.7% of patients, while azacitidine dose/schedule reductions were necessary in 57.1%. The augmented HCT-CI was significantly associated with OS, supporting further investigation of its potential prognostic value in this setting. Conclusions: AZA+VEN demonstrated meaningful clinical activity and manageable toxicity in elderly or unfit AML patients. Frailty and comorbidity burden had a substantial impact on outcomes, supporting the integration of biological and fitness-based risk assessment in the management of AML in real-world clinical practice.