Revumenib Plus Azacitidine/Venetoclax Appears Safe in Older NPM1/KMT2Ar AML

“This is the first clinical trial performed on a menin inhibitor plus azacitidine and venetoclax for patients who are newly diagnosed [and] older or unfit with AML who have NPM1 mutations or KMT2Ar,” according to study author Joshua Zeidner, MD.

At all dose levels, revumenib (Revuforj) plus azacitidine (Vidaza) and venetoclax (Venclexta) showed safety and feasibility for patients who are newly diagnosed and older with acute myeloid leukemia (AML) harboring NPM1 mutations or KMT2A rearrangement (KMT2Ar), according to findings from the phase 3 VIALE-A trial (NCT02993523) presented at the 2025 European Hematology Association Congress.

For patients at dose level 1 who were given revumenib at 113 mg every 12 hours on days 1 to 28, the objective response rate (ORR) was 90.5%. At dose level 2 of revumenib at 163 mg every 12 hours for days 1 to 28, the ORR was 86.4%. For patients with KMT2Ar, the ORR was 100% and 85.3% for those with NPM1 mutations. The complete response rates, which included complete responses, hematologic complete responses, and complete remissions with incomplete count recovery, were 81.0%, 81.8%, 88.9%, and 79.4% in the respective cohorts.

After 1 to 2 cycles, no patients had refractory disease. The presentation noted that 84% of evaluable patients achieved remission within 1 cycle of therapy, 100% achieved flow minimal residual disease (MRD)–negative remission, and 31% achieved NPM1 mutation next-generation sequencing–negative remission.

For overall survival (OS), the median follow-up was 6.9 months. For those with KMT2Ar, the median OS was 18.0 months (95% CI, 11.5-not eligible), and for the NPM1-mutated cohort, it was 15.5 months (95% CI, 7.2-19.5). The 1-year overall OS rate was 63% among all patients, 83% for the KMT2Ar group, and 55% for the NPM1 mutation group.

“This is the first clinical trial performed on a menin inhibitor plus azacitidine and venetoclax for patients who are newly diagnosed [and] older or unfit with AML who have NPM1 mutations or KMT2Ar,” Joshua Zeidner, MD, associate professor of medicine and chief of Leukemia Research at the University of North Carolina School of Medicine, said during the presentation. “Azacitidine, venetoclax, and revumenib are highly active [in this population].”

The trial enrolled 43 patients who were 60 years or older, unfit for intensive chemotherapy, and had NPM1 mutations or KMT2Ar. The induction phase included revumenib at dose level 1 or 2 plus azacitidine at 75 mg/m2 once daily on days 1 to 7 plus venetoclax per label on days 1 to 28.

If patients achieved bone marrow remission, they went on to continue treatment indefinitely. If they had morphologic evidence of AML after the first cycle, patients received induction therapy again. If bone marrow remission occurred following retreatment, they continued the treatment. If it did not, they were taken off the study protocol.

In the dose level 1 cohort (n = 21), the median patient age was 74, 47.6% were 75 years or older, and 71.4% were female. A majority of patients had an ECOG performance status of 0 to 1 (71.4%). The European Leukemia Net (ELN) 2024 risk factor criteria showed patients had either favorable- (42.9%), intermediate- (52.4%), or adverse-risk disease (4.8%).

In the dose level 2 cohort (n = 22), the median age was 69.5, 31.8% were 75 years or older, and 36.4% were female, with 68.1% having an ECOG performance status of 0 to 1. Regarding ELN criteria, disease risk was either favorable (59.1%) or intermediate (40.9%); no patient had adverse disease.

For those with KMT2Ar (n = 9), the median patient age was 67, 11.1% were 75 years or older, and 44.4% were female, with 88.9% having an ECOG performance status of 0 to 1. ELN risk included 55.6% of patients with favorable-risk disease, 33.3% with intermediate-risk status, and 11.1% with adverse-risk disease.

For those with NPM1 mutations (n = 34), the median age was 73.5, 47.1% were 75 years or older, 55.9% were female, and 64.7% had an ECOG performance status of 0 to 1. ELN risk included 50.0% having favorable-risk disease, 50.0% had an intermediate risk, and none had an adverse risk.

Overall, the median treatment duration cycle was 38.5 days.

Regarding grade 3 or higher adverse effects (AEs), 26% of patients had febrile neutropenia, 19% had acute kidney injury, 14% had dyspnea, 12% had QTcF prolongation, 12% had hypokalemia, and 12% had muscular weakness.

The most common grade 1/2 AEs included nausea (60%), constipation (53%), and QTcF prolongation (44%).

The 30- and 60-day mortality rate was 7%.

Dose reduction with revumenib occurred following grade 4 neutropenia or thrombocytopenia lasting 14 days to the end of the cycle, with dosing reduced to every 21 days for every cycle thereafter for 10 patients.

Reference

Zeidner J. Azacitidine, venetoclax, and revumenib for newly diagnosed older adults with acute myeloid leukemia (AML) and NPM1 mutation or KMT2A rearrangement: updated results from the BEAT AML consortium. Presented at the 2025 European Hematology Association Congress; Milan, Italy; June 12-15, 2025. Abstract S138.