Venetoclax combined with five days of azacitidine for the treatment of previously untreated Acute Myeloid Leukemia (AML): Initial results of the prospective venaza-5S trial

Abstract Background: The combination of Azacitidine (AZA) and Venetoclax (VEN) has become the standard of care frontline treatment for AML patients who are ineligible for intensive treatment due to advanced age or comorbidities, based on the results of the VIALE-A trial. While the combination regimen improved response rate and survival compared to AZA monotherapy, it also resulted in increased hematotoxicity. Among patients who had achieved a response in the VIALE-A trial, which used a standard regimen of 7 days (d) of AZA combined with 28 d of VEN, dose delays due to cytopenias were needed in 78%. Consequently, many clinicians have adopted shortened courses of VEN, either upfront or after a response is achieved, although this approach has not yet been evaluated in prospective trials. We hypothesized that AZA also contributes to the hematotoxicity of the VEN/AZA combination, and that shortening AZA administration from 7 d to 5 d per 28-day cycle could be another strategy to reduce toxicity while maintaining efficacy of the VEN/AZA doublet. Aims: VenAza-5S (NCT05833438)was a single-arm, multicenter Phase II trial designed to obtain initial data on the tolerability and safety of 5d of AZA combined with 28d of VEN in newly diagnosed AML patients ineligible for standard induction therapy. Methods: Eligible patients had newly diagnosed AML and were either ≥75 years of age and/or had comorbidities precluding treatment with intensive induction chemotherapy. Patients with acute promyelocytic leukemia or core binding factor-rearranged AML were excluded. All patients received AZA 75mg/m2 on d1-5 and VEN 400mg on d1-28 of each 28-day cycle. Guidelines for initial VEN ramp-up, VEN dose adjustments in the presence of CYP3A-inhibiting co-medications, and VEN and AZA dose reductions in the case of recurrent episodes of cytopenias corresponded to those used in the VIALE-A trial. The primary endpoint was the composite complete remission (cCR) rate, defined as the rate of complete remission (CR) or CR with incomplete hematopoietic recovery (CRi) after up to 6 cycles of therapy. Secondary endpoints included the overall response rate (ORR, comprising CR, CRh, CRi, and morphologic leukemia-free state [MLFS]), and event-free and overall survival (EFS/OS). Results: Between May 2023 and April 2025, 45 pts were enrolled at 11 sites in Germany. Data cut-off for the present preliminary analysis was June 23, 2025. Median patient age was 81 years (range, 66 to 91 years), and ECOG performance status was ≥2 in 33%. Twenty-two patients (49%) had AML with myelodysplasia-related changes, 21 patients (47%) had de novo AML, and two had AML post cytotoxic therapy. ELN-2022 risk was favorable in 3/45 (6.7%), intermediate in 17/45 (37.8%) and adverse in 22/45 (48.9%) patients (3 pts not evaluable). The median duration of cycles 1, 2 and 3 was 36 d, 30 d and 36 d, respectively. The cCR rate after up to six treatment cycles so far is 53.3% (24/45; 2 pts are not yet evaluable), and the ORR was 60% (27/45). Median time to follow-up was 11.5 months, and median OS is 11.1 months. Hematologic adverse events (i.e. neutropenia, anemia or thrombopenia) of Grade ≥3 occurred in 30 pts (67%). Grade ≥3 infections occurred in 17 participants (38%). Mortality at 30 d from study enrollment was 11% (5/45). Summary/Conclusion: In this high-risk patient population with a median age of over 81 years and nearly 50% myelodysplasia-related AML, the VEN + AZA-5 regimen achieved a cCR-rate of 53%. While in the VIALE-A trial, a cCR-rate of 66% was reported for the combination of VEN with 7d of AZA, a direct comparison is problematic given the differences in baseline patient characteristics. More detailed analysis of prognostic factors, responses in genetic subgroups including the ELN-2022 and 2024 risk categories, and molecular responses will be presented at the meeting. The VenAZA-5 regimen appears to be an effective and well-tolerated front-line treatment option for older or comorbid AML patients, and the 5-day schedule of AZA administration may be attractive for patients and physicians. Furthermore, this regimen may serve as a backbone for future combination therapies.