In a single-center phase I to II trial (SAVE) reported in the Journal of Clinical Oncology, Issa et al found that the all-oral combination of revumenib, decitabine/cedazuridine, and venetoclax was highly active in patients with relapsed or refractory acute myeloid leukemia (AML).
Revumenib is an inhibitor of menin-KMT2A, which is active in AML with KMT2A rearrangement (KMT2Ar), NPM1 mutation (NPM1mt), or NUP98 rearrangement (NUP98r). Preclinical studies indicate synergy of revumenib with BCL2 inhibition.
Study Details
In the study, 42 patients aged 12 years or older were enrolled between October 2022 and January 2026 at MD Anderson Cancer Center. Patients received decitabine/cedazuridine (35 mg/100 mg) once daily on days 1 to 5, venetoclax with ramp-up to 400 mg once daily on days 1 to 14, and revumenib every 12 hours at one of two assigned dose levels (during phase I); the recommended phase II dose was 160 mg twice daily with a strong CYP3A4 inhibitor. Patients had a median age of 40 years and a median of two prior lines of therapy, including venetoclax in 52%. Efficacy was assessed as the composite complete remission (CRc) rate within five cycles, defined as the sum of complete remission (CR), CR with partial hematologic recovery (CRh), and CR with incomplete count recovery (CRi).
Key Findings
The 42 patients included 40% with KMT2Ar, 38% with NPM1mt, and 21% with NUP98r.
Grade ≥ 3 adverse events included febrile neutropenia (36%), lung infection (21%), thrombocytopenia (21%), and elevated aspartate or alanine aminotransferase (21%). Differentiation syndrome occurred in 10% of patients (5% grade 3). QT interval prolongation of any grade occurred in 18 patients (43%), including grade 3 or higher events in two patients.
The CRc rate was 71% and the CR/CRh rate was 60%. Among 37 evaluable responders, 68% (25 patients) had undetectable measurable residual disease on flow cytometry, with 20 (80%) of the 25 having CR/CRh. The median duration of CR/CRh among all patients was 10.5 months, not reached among those with KMT2Ar, 10.7 months in those with NPM1mt, and 5.9 months in those with NUP98r.
The investigators concluded: “This combination was associated with high response rates and durable remissions, with an acceptable safety, in heavily pretreated patients with AML harboring alterations susceptible to menin inhibition.”
Ghayas C. Issa, MD, MS, of the Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, is the corresponding author for the Journal of Clinical Oncology article.
DISCLOSURE: The study was supported by Astex Pharmaceuticals, Taiho Oncology, and Syndax Pharmaceuticals. For full disclosures of the study authors, visit ascopubs.com.
