OPTI-AML: Prospective Comparison of 28 vs.14 days of Venetoclax Induction with Azacitidine in Older Adults with AML

Azacitidine (Aza) plus venetoclax (Ven) is standard treatment for older/unfit patients with newly diagnosed (ND) acute myeloid leukemia (AML). The approved 28-day (D) Ven schedule is associated with prolonged cytopenias, causing frequent dose reductions and cycle delays. Retrospective studies show similar efficacy and reduced toxicity with abbreviated Ven dosing, but prospective data is lacking. We conducted OPTI-AML(NCT03013998), a prospective randomized phase 2 trial comparing 28D Ven (AV28) versus 14D (AV14) with Aza (75mg/m²x7D) for C1-2 in genomically agnostic ND-AML patients ≥60 years. The primary endpoint was complete remission (CR) rate achieved at any time with two cycles of therapy. Between 2023-2025, 169 patients received AV28 (n=83) or AV14 (n=86). CR across two cycles was 49.4% (AV28) versus 43% (AV14); difference of 6.4% [90%CI:-6.1% to 19.0%], not meeting non-inferiority criteria. Patients with NPM1/ IDH2 mutations had higher CR rates with AV28 (60.9% vs. 33.3%), while CR rates were equivalent (45%) for other subgroups. Composite CR rates were 80.7% (AV28) versus 68.6% (AV14) and MRD negativity was similar (77.6% vs. 76.5%). Although AV28 had more frequent treatment interruptions, count recovery after C2, grade ≥3 adverse events and early mortality were similar. In conclusion, the study did not demonstrate non-inferiority of AV14 compared with AV28 during C1-2 in an unselected ND-AML cohort. However, as the confidence interval for the difference covered 0, CR rate for AV28 was not significantly different than AV14. Certain subgroups may benefit from prolonged Ven exposure, but these findings require validation in larger studies, especially as triplet regimens evolve.

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Journal
Blood
Published
2026-07-28
DOI
https://doi.org/10.1182/blood.2026034611
Primary Topic
Acute Myeloid Leukemia Research
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article
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article

OPTI-AML: Prospective Comparison of 28 vs.14 days of Venetoclax Induction with Azacitidine in Older Adults with AML

Elie Traer, Shivani Handa, Uma Borate, Vu H. Duong et al.
Blood
Acute Myeloid Leukemia Research
article

OPTI-AML: Prospective Comparison of 28 vs.14 days of Venetoclax Induction with Azacitidine in Older Adults with AML

Elie Traer, Shivani Handa, Uma Borate, Vu H. Duong, Alice S. Mims, Brian Druker, Mona Stefanos, Tara L. Lin, Angela D. Nichols, Anand Patel, Molly Martycz, Joshua F. Zeidner, Maria R. Baer, Timothy L. Chen, R. Swords, GJ Schiller, Eytan M. Stein, John C. Byrd, Leonard Rosenberg, Lore Gruenbaum, Colin Vale, Curtis A. Lachowiez, Mary F. Johnson, Yazan F. Madanat, Nyla A. Heerema, William Blum, Ross L Levine, Emily Curran, Lacey Williams, Rebecca L. Olin, Amy Burd, Ashley Yocum, Sonja Marcus, Olatoyosi Odenike, Wendy Stock, Ying Huang, Louis James DeGennaro
article en

Abstract

Azacitidine (Aza) plus venetoclax (Ven) is standard treatment for older/unfit patients with newly diagnosed (ND) acute myeloid leukemia (AML). The approved 28-day (D) Ven schedule is associated with prolonged cytopenias, causing frequent dose reductions and cycle delays. Retrospective studies show similar efficacy and reduced toxicity with abbreviated Ven dosing, but prospective data is lacking. We conducted OPTI-AML(NCT03013998), a prospective randomized phase 2 trial comparing 28D Ven (AV28) versus 14D (AV14) with Aza (75mg/m²x7D) for C1-2 in genomically agnostic ND-AML patients ≥60 years. The primary endpoint was complete remission (CR) rate achieved at any time with two cycles of therapy. Between 2023-2025, 169 patients received AV28 (n=83) or AV14 (n=86). CR across two cycles was 49.4% (AV28) versus 43% (AV14); difference of 6.4% [90%CI:-6.1% to 19.0%], not meeting non-inferiority criteria. Patients with NPM1/ IDH2 mutations had higher CR rates with AV28 (60.9% vs. 33.3%), while CR rates were equivalent (45%) for other subgroups. Composite CR rates were 80.7% (AV28) versus 68.6% (AV14) and MRD negativity was similar (77.6% vs. 76.5%). Although AV28 had more frequent treatment interruptions, count recovery after C2, grade ≥3 adverse events and early mortality were similar. In conclusion, the study did not demonstrate non-inferiority of AV14 compared with AV28 during C1-2 in an unselected ND-AML cohort. However, as the confidence interval for the difference covered 0, CR rate for AV28 was not significantly different than AV14. Certain subgroups may benefit from prolonged Ven exposure, but these findings require validation in larger studies, especially as triplet regimens evolve.

Blood
University of North Carolina at Chapel Hill (US), University of Maryland, Baltimore (US), Memorial Sloan Kettering Cancer Center (US), University of Kansas (US), Emory University (US), University of California, Los Angeles (US), Oregon Health & Science University (US), University of California, San Francisco (US), University of Chicago (US), Southwestern Medical Center (US), Center for Cancer and Blood Disorders (US), UPMC Hillman Cancer Center (US), Leukemia and Lymphoma Society (US), Southwestern Medical Center (US), U-M Rogel Cancer Center (US), UNC Lineberger Comprehensive Cancer Center, OHSU Knight Cancer Institute, The Ohio State University (US), The University of Texas Southwestern Medical Center (US), University of Cincinnati Medical Center (US)
Good health and well-being
Openalex Percentile: Top 9%
Acute Myeloid Leukemia Research
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