Background: The rising incidence of AML in elderly patients poses significant challenges due to adverse biology and comorbidities. Venetoclax (Ven) combined with hypomethylating agents (AZA) or reduced-intensity chemotherapy improves response and survival in unfit/fit elderly AML. Direct comparisons between Ven-based regimens and intensive chemotherapy (IC) in fit elderly AML are lacking. This multicenter, randomized phase II study (NCT06066242) compared efficacy and safety of different induction therapies.

Methods: Patients aged 60–75 years with newly diagnosed, non-M3/CBF AML fit for IC were randomized 1:1:1 (Oct 2023–Jan 2025) to: Arm A (IC): Standard “3+7” (D/IA: daunorubicin 60mg/m² or idarubicin 10 mg/m² d1-3, cyctarabine 100mg/m² d1-7)；Arm B (VA): Ven (100mg d1, 200mg d2, 400mg d3-21/28; on day 21, a bone marrow aspiration will be performed. If the bone marrow morphology indicates that the blast count is <5% or shows severely hypoplastic marrow, venetoclax will be discontinued.) + AZA (75mg/m² d1-7)；Arm C (D/IAV): Ven (100mg d3, 200mg d4, 400mg d5-11) + modified “2+5” (daunorubicin 60mg/m² or idarubicin 10mg/m² d1-2, cyctarabine 100mg/m² d1-5). Patients achieving complete remission/complete remission with incomplete hematologic recovery (CR/CRi) received same consolidation and maintenance therapy. Two cycles of intermediate-dose cytarabine consolidation (cyctarabine 1g/m² q12h d1,3,5), followed by maintenance: 2 cycles of DA/IA (daunorubicin 30mg/m² or idarubicin 8mg/m² d1-2, cyctarabine 100mg/m² d1-5) and 4 cycles of VA (Ven 400mg d1-7, AZA 75mg/m² d1-5). Primary endpoint was event-free survival (EFS). Secondary endpoints included CR/CRh/CRi rates; measurable residual disease (MRD) clearance rate after achieving CR/CRh/CRi; relapse-free survival (RFS); OS and mortality within 30 days after induction therapy.

Results: 102 patients enrolled (median age 65; 55.9% male). ELN 2022 risk: favorable 26%, intermediate 30%, adverse 44%. Arms: A (n=32), B (n=36), C (n=34). Baseline characteristics were balanced across arms. After excluding 2 inevaluable and 9 induction deaths (8.8%), 91 were response-evaluable. The CRc rate for the entire cohort was 55.9% (57/102, CR rate: 50%). With a median follow-up of 12.5 months, the median EFS was 6.4 months, RFS was 9.4 months, and OS was not reached (NR). The 1-year EFS, RFS, OS rate was 36.3±5.2%, 44.6±5.4%, and 55.0±5.4%, respectively. Complete remission (CR) rates following cycle 1 of Arm C was numerically higher than Arm A (A:37.5%,B: 47.2%, C: 61.8%, A vs.C: P= .07), but composite complete remission (CRc) rates had no difference among three arms (A:40.6% , B:60.9%, C:61.8% ; P= .313). Mortality within 30 days after induction therapy was higher in Arm A (12.5%) and Arm C (11.7%) compared to Arm B (2.8%) (P= .281).No significant differences in event-free survival (EFS), relapse-free survival (RFS), or overall survival (OS) were observed across arms overall: median EFS: Arm A: 7.1 months; Arm B: 5.7 months; Arm C: 4.5 months; (P= .602); median RFS: Arm A: 8.6 months ; Arm B: NR; Arm C: 8.1 months; (P= .792); median OS: Arm A (IC): 10.4 months; Arm B (VA): not reached (NR); Arm C (D/IAV): 14.1 months; (P= .407). While subgroup survival analyses across different risk group revealed efficacy variations among treatment regimens.Within the ELN 2022 adverse-risk subgroup (n=44 evaluable), EFS, RFS, and OS were improved in Arm B (VA) compared to Arm A (IC): 1-year EFS: Arm A: 17.9±11.0% vs. Arm B: 59.3±12.1% (P= .005); 1-year RFS: Arm A: 17.3±11.1% vs. Arm B: 65.0±11.7% (P= .043); 1-year OS: Arm A (IC, n=14): 25.7±12.3% vs. Arm B (VA, n=18): 71.3±10.9% (P= .012). No survival differences were observed within the favorable- or intermediate-risk subgroups. Common treatment-emergent non-hematologic adverse events included elevated liver enzymes, creatinine, bilirubin, and hypoalbuminemia; hematologic events included cytopenias and febrile neutropenia. Incidence and severity did not differ significantly between treatment arms.

Conclusion: No significant differences in survival were observed across three regimens. CRc rates were similar between VA and D/IAV regimen, which shows trend better than D/IA. VA improved survival compared to D/IA in patients with ELN 2022 adverse-risk disease. According to our data, Venetoclax-based regimens, particularly Ven+AZA, demonstrate efficacy, especially in high-risk fit older AML patients.

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2025
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