A new combination of azacitidine, venetoclax, and revumenib demonstrated high rates of complete response and clinical activity in older adults with newly diagnosed acute myeloid leukemia (AML) and an NPM1 mutation or KMT2A rearrangement. The regimen was also shown to be safe in updated results from a phase I trial presented at the 2025 European Hematology Association (EHA) Annual Meeting and published in the Journal of Clinical Oncology.
“The promising findings from our phase I safety trial have directly led to the design and implementation of a randomized phase III study to determine whether the addition of revumenib to standard azacitidine and venetoclax improves overall survival in people with NPM1-mutant or KMT2A-rearranged acute myeloid leukemia,” stated lead study author Joshua F. Zeidner, MD, Associate Professor of Medicine, UNC School of Medicine, and Chief of Leukemia Research, UNC Lineberger Comprehensive Cancer Center. “This regimen has the potential to be practice-changing for patients whose acute myeloid leukemia harbors the specific gene alterations we focused on.”
Background and Study Methods
This was the first clinical trial to assess whether adding a menin inhibitor to standard therapy is effective for treating newly diagnosed patients with AML. Revumenib is an oral inhibitor that was approved by the U.S. Food and Drug Administration in November 2024 for treating patients with relapsed or refractory AML who have a KMT2A translocation.
This study was part of the Leukemia and Lymphoma Society’s Beat AML Master Clinical Trial protocol that tests for genomic alterations that are then considered in creating an individual treatment plan for each patient with AML. NPM1 mutations are found in about 30% of patients with AML, compared with 5% of patients harboring a KMT2A rearrangement.
The phase I dose-escalation and -expansion study, conducted with the Beat AML Consortium, explored the use of azacitidine, venetoclax, and revumenib at two different dose levels (113 mg [n = 21] or 163 mg [n = 22] every 12 hours with strong cytochrome P450 inhibitor azoles) in patients aged 60 or older with newly diagnosed AML with an NPM1 mutation or a KMT2A rearrangement. A total of 43 patients were enrolled across 12 U.S. centers.
Study Findings
The overall response rate in the intention-to-treat population was 88.4%, including 85.3% in the group of patients with NPM1 mutations and 100% in the group with KMT2A rearrangements. Composite complete remissions were reported in 81.4% of all patients, 79.4% of patients with NPM1 mutations, and 88.9% of patients with KMT2A rearrangements.
After one to two cycles of treatment, no patient had refractory disease. The median time to first response was 28 days. Of 37 evaluable patients, all had no evidence of measurable residual disease.
The median overall survival was 15.5 months, but the median was notably 18 months for patients with KMT2A rearrangements. The median duration of composite complete remission was 12 months.
According to the investigators, the regimen was able to be administered safely, with similar treatment-related adverse events seen at both dose levels.
Differentiation syndrome was observed in 19% of patients, including two patients with grade 3 differentiation syndrome, and QTc Fridericia prolongation in 44%, including five patients with grade 3 events. None of these events required permanent discontinuation of treatment. Mortality at 30 days and 60 days was 7%, reportedly because of sepsis.
Disclosure: For full disclosures of the study authors, visit ascopubs.org.
