Phase 1-2 study of the all-oral combination of revumenib, decitabine, and venetoclax for relapsed or refractory acute myeloid leukemia

Revumenib is an oral inhibitor of menin-KMT2a, a key dependency in acute myeloid leukemia with KMT2A rearrangement (KMT2Ar), NPM1 mutation (NPM1mt), or NUP98 rearrangement (NUP98r). Preclinical studies suggest synergy with BCL2 inhibition. The phase 1-2 SAVE study at MD Anderson Cancer Center (Houston, TX) evaluated the all-oral regimen of revumenib, decitabine/cedazuridine, and venetoclax in patient aged 12 year or older with relapsed or refractory acute myeloid leukemia (R/R AML). The primary objectives were to determine the recommended phase 2 dose (RP2D) and to assess efficacy according to the composite complete remissing (CRc) rate. Forty-two patients were enrolled (median age 40 years; range 12-82), including 40% with KMT2Ar, 38% with NPM1mt, and 21% with NUP98r. Patients had a median of 2 prior lines of therapy; 52% had prior venetoclax. The RP2D of revumenib was 160 mg twice daily with venetoclax on days 1-14 and decitabine/cedazuridine on days 1-5 every 28 days. Grade ≥3 adverse events included febrile neutropenia (36%), lung infection (21%), and thrombocytopenia (21%). Differentiation syndrome occurred in 10% (5% grade 3) and resolved with glucocorticoids. The CRc rate was 71%, and the CR or CRh rate was 60%, with measurable residual disease negativity in 80% of these patients. The median duration of CR/CRh was 10.5 months, not reached in KMT2Ar, 10.7 months in NPM1mt, and 5.9 months in NUP98r. Emergent mutations in the menin-binding site occurred in 13%. The authors conclude that this combination was associated with high response rates and durable remissions, with an acceptable safety in heavily pretreated patients with R/R AML harboring alteration susceptible to menin inibition.