A phase 3 study of revumenib in combination with intensive chemotherapy in patients with newly diagnosed <i>NPM1</i> -mutated acute myeloid leukemia (REVEAL-ND NPM1).

Abstract

TPS6602 Background: There are currently no approved targeted therapies for newly diagnosed (ND) acute myeloid leukemia (AML) harboring a nucleophosmin-1 mutation ( NPM1 m), which occurs in ~30% of ND adult AML cases. In NPM1 m AML, the NPM1m/XPO1 protein complex binds to DNA to sustain the interaction of menin and wild-type KMT2A that drives upregulation of HOX / MEIS gene expression, resulting in hematopoietic differentiation arrest and leukemogenesis. Revumenib is a first-in-class, oral, potent, and selective inhibitor of the menin-KMT2A interaction. In the phase 1/2 AUGMENT-101 study (NCT04065399), revumenib monotherapy demonstrated clinically meaningful response rates and was generally well tolerated in relapsed/refractory NPM1 m AML, leading to US Food and Drug Administration approval for that patient population on October 24, 2025. Standard AML treatment for younger, non-frail adults is based on intensive chemotherapy (IC) regimens and hematopoietic stem cell transplant (HSCT). The addition of revumenib to standard IC may further improve treatment responses specifically in the ND setting. This study is designed to assess the safety and efficacy of revumenib in combination with IC in patients with ND NPM1 m AML. Methods: REVEAL-ND NPM1 is a phase 3, multicenter, randomized, double-blind, placebo-controlled trial (NCT07211958). Eligible patients are ≥12 years of age, weigh ≥40 kg, and have treatment-naive ND AML with locally determined (centrally confirmed) NPM1 m. Patients will be randomized 1:1 to revumenib or placebo in combination with IC. Induction consists of 1 to 2 cycles of revumenib or placebo (dosed orally) alongside IC with cytarabine and daunorubicin or idarubicin (dosed intravenously). Consolidation consists of 1 to 3 cycles of revumenib or placebo plus cytarabine. HSCT may be performed after initial induction or consolidation. Treatment with revumenib or placebo monotherapy will continue for up to 2 years, with long-term follow-up until death, withdrawal of consent, or study closure. The dual primary endpoints are event-free survival and measurable residual disease-negative complete remission (CR) in the bone marrow, both assessed by independent reviewers. A key secondary endpoint is overall survival. Additional investigator-assessed endpoints include CR rate, composite complete remission (CRc) rate, overall response rate, duration of response (CR, CRc), safety, and quality of life. Overall, ~468 patients will be enrolled. As of January 27, 2026, the study is open to enrollment. Clinical trial information: NCT07211958 .