Prospective comparison of 28 vs 14 days of venetoclax induction with azacitidine in older adults with untreated AML: OPTI-AML trial

Azacitidine (Aza) plus venetoclax (Ven) is standard treatment for older/unfit patients with newly diagnosed (ND) acute myeloid leukemia (AML). The approved 28-day Ven schedule is associated with prolonged cytopenias and frequent treatment modifications. Retrospective studies show similar efficacy and reduced toxicity with abbreviated Ven dosing, but prospective data are lacking. OPTI-AML is a prospective randomized phase 2 trial comparing 28-day Ven (AV28) vs 14-day (AV14) with Aza (75 mg/m2 for 7 days) for cycles 1-2 in genomically agnostic patients with ND-AML aged ≥60 years. The primary end point was complete remission (CR) rate within 2 cycles. Between 2023 and 2025, 169 patients received AV28 (n = 83) or AV14 (n = 86). CR rate was 49.4% (AV28) vs 43% (AV14); difference of 6.4% (90% confidence interval: −6.1% to 19.0%), not meeting noninferiority criteria. Patients with NPM1/ IDH2 mutations had higher CR rates with AV28 (60.9% vs 33.3%), whereas rates were equivalent (45%) for other subgroups. Composite CR rates were 80.7% (AV28) vs 68.6% (AV14), and measurable residual disease negativity was similar (77.6% vs 76.5%). Although AV28 had more frequent treatment interruptions, count recovery after cycle 2, grade ≥3 adverse events, and early mortality were similar. In conclusion, AV14 did not demonstrate noninferiority compared with AV28 during cycles 1-2 in an unselected ND-AML cohort. Although the difference in CR rates was not significantly different between arms, these findings do not support routine abbreviation of Ven to 14 days during initial therapy. Certain subgroups may benefit from prolonged Ven exposure, warranting validation in larger studies, especially as triplet regimens evolve. This trial was registered at www.clinicaltrials.gov as NCT03013998.