Revumenib Shows Activity Across R/R KMT2A-Rearranged Acute Leukemia Subtypes

Revumenib (Revuforj) monotherapy led to clinically meaningful responses in patients with relapsed/refractory acute leukemia harboring a KMT2A rearrangement regardless of leukemia type, according to data from the phase 1/2 AUGMENT-101 trial (NCT04065399) presented during the 2025 ASH Annual Meeting and Exposition.1

Efficacy-evaluable patients with acute myeloid leukemia (AML; n = 78), acute lymphoblastic leukemia (ALL; n = 13), and mixed-phenotype acute leukemia (MPAL; n = 6) achieved overall response rates (ORRs) of 66.7% (95% CI, 55.1%-76.9%), 46.2% (95% CI, 19.2%-74.9%), and 66.7% (95% CI, 22.3%-95.7%), respectively. The respective complete response (CR) rates were 14.1%, 23.1%, and 16.7%. The median durations of treatment were 2.6 months (range, 0.1-14.9), 2.0 months (range, 0.2-4.9), and 1.7 months (range, 0.7-3.9), respectively.

The CR plus CR with partial hematologic recovery (CRh) rates in the AML, ALL, and MPAL cohorts were 23.1% (95% CI, 14.3%-34.0%), 23.1% (95% CI, 5.0%-53.8%), and 16.7% (95% CI, 0.4%-64.1%), respectively. The respective composite CR (CRc) rates were 43.6% (95% CI, 32.4%-55.3%), 30.8% (95% CI, 9.1%-61.4%), and 50.0% (95% CI, 11.8%-88.2%).

“[These] findings emphasize that revumenib is an effective treatment option for patients with relapsed/refractory KMT2A-rearranged acute leukemia, showing its potential to improve outcomes across leukemia types in the difficult-to-treat population,” Ibrahim T. Aldoss, MD, a hematologist-oncologist, an associate professor in the Division of Leukemia, Department of Hematology and Hematopoietic Cell Transplantation, and a member of the Gehr Family Center Leukemia, at City of Hope in Duarte, California, said during the presentation.

In October 2025, the FDA approved revumenib for the treatment of adult and pediatric patients at least 1 year of age with relapsed or refractory AML with a susceptible NPM1 mutation who do not have satisfactory alternative treatment options.2 The regulatory decision was supported by prior data from AUGMENT-101.

How was the study designed?

AUGMENT-101 enrolled adult and pediatric patients with relapsed/refractory acute leukemia with a KMT2A rearrangement or an NPM1 mutation.2 Cohort 2A included patients with ALL or MPAL and cohort 2B included patients with AML; both cohorts enrolled patients with disease harboring a KMT2A rearrangement. Cohort 2C enrolled patients with NPM1-mutated AML.

During the phase 1 dose-escalation portion, the recommended phase 2 dose of oral revumenib was determined to be 160 mg once every 12 hours (95 mg/m2 for patients weighing less than 40 kg) plus a strong CYP3A4 inhibitor in 28-day cycles. In the phase 2 portion, patients who experienced at least a partial response went on to receive optional hematopoietic stem cell transplantation (HSCT) followed by maintenance revumenib in those who achieved a CRc after HSCT.

The primary end points in phase 2 were CR plus CRh rate as well as safety and tolerability. Key secondary end points included CRc rate, ORR, duration of response (DOR), time to response (TTR), and overall survival.

At baseline, the median age in the AML safety population (n = 95) was 37.0 years (range, 1.3-75.0). Most patients were 18 to less than 65 years old (67.4%), female (58.9%), White (69.5%), received prior venetoclax (Venclexta; 70.5%), and received prior HSCT (54.7%). The median number of prior lines of therapy was 2 (range, 1-11).

Patients in the ALL safety population (n = 15) had a median age of 31.0 years (range, 0.6-73.0) at baseline. Most patients were female (60.0%), White (66.7%), and received at least 3 prior lines of therapy (73.3%). The median number of prior lines of therapy was 3 (range, 1-8).

Among patients in the MPAL safety population (n = 6), the median age was 16.0 years (range, 1.0-53.0). Patients were less than 18 years old, 18 to less than 65 years old, and received prior HSCT all at rates of 50.0%. The median number of prior lines of therapy was 2 (range, 1-4).

The median follow-up durations in the AML, ALL, and MPAL cohorts were 5.9 months (range, 0.3-25.7), 3.9 months (range, 0.3-22.3), and 5.4 months (range, 0.9-7.4), respectively.

What were the additional efficacy and safety data?

The median DORs in the AML, ALL, and MPAL cohorts were 7.7 months (95% CI, 3.4-not reached [NR]), NR (95% CI, 0.9-NR), and 1.8 months (95% CI, not evaluable [NE]-NE). The median TTRs were 2.0 months (range, 0.9-4.6), 1.9 months (range, 0.9-2.8), and 3.2 months (range, 3.2-3.2), respectively.

In the AML cohort, most patients who experienced a CR plus CRh (64.3%; n = 9 of 14) or a CRc (60.0%; n = 18 of 30) achieved minimal residual disease (MRD) negativity. The MRD-negativity rates among patients in the ALL arm who had a CR plus CRh or a CRc were 33.3% (n = 1 of 3) and 25.0% (n = 1 of 4), respectively. All patients in the MPAL arm who had a CR plus CRh (n = 1) or a CRc (n = 2) also experienced MRD negativity.

Twenty-one patients overall proceeded to HSCT during remission, including 19 with AML and 2 with MPAL. At the data cutoff, 47.4% of these patients with AML resumed treatment with revumenib after HSCT.

In terms of safety, any-grade adverse effects (AEs) were reported in all patients in the AML, ALL, and MPAL cohorts. Grade 3 or higher AEs (92.6% vs 80.0% vs 100%) also occurred. Any-grade hematologic AEs included febrile neutropenia (37.9% vs 40.0% vs 66.7%) and anemia (28.4% vs 13.3% vs 33.3%). Any-grade revumenib-related AEs were reported in each arm (87.4% vs 53.3% vs 83.3%). Overall, patients discontinued treatment at a rate of 5.2% due to treatment-related AEs.

“The well-characterized safety profile of revumenib is consistent with prior reports and is similar across the different leukemia subtypes,” Aldoss said.

Disclosures: Aldoss received research funding from Novartis, AbbVie, Servier, and JAZZ. He also reported holding consultancy roles with Takeda, Syndax, Asccentage, Autolus, AstraZeneca, JAZZ, Pfizer, KiTE, Servier, and Adaptive.

References

1. Aldoss I, Issa G, Blachly J, et al. Revumenib for patients with relapsed or refractory (R/R) KMT2Ar acute leukemia: outcomes by leukemia type in the phase 2 AUGMENT-101 study. Blood. 2025;146(suppl 1):1001. doi:10.1182/blood-2025-1001
2. FDA approves revumenib for relapsed or refractory acute myeloid leukemia with a susceptible NPM1 mutation. FDA. October 24, 2025. Accessed December 9, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-revumenib-relapsed-or-refractory-acute-myeloid-leukemia-susceptible-npm1-mutation