All-Oral Combination of Revumenib, Decitabine, and Venetoclax for Relapsed or Refractory AML (SAVE).

PURPOSE: Revumenib is an oral inhibitor of menin-KMT2A, a key dependency in acute myeloid leukemia (AML) with KMT2A rearrangement (KMT2Ar), NPM1 mutation (NPM1mt), or NUP98 rearrangement (NUP98r). Preclinical studies suggest synergy with BCL2 inhibition.

METHODS

In this phase I-II study, we evaluated an all-oral regimen of revumenib, decitabine/cedazuridine, and venetoclax in patients 12 years and older with relapsed or refractory AML. Decitabine/cedazuridine was given on days 1-5, venetoclax on days 1-14, and revumenib twice daily on days 1-28. The primary objectives were to determine the recommended phase II dose (RP2D) and to assess efficacy according to the composite complete remission (CRc) rate.

RESULTS

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 two prior lines of therapy; 52% had prior venetoclax. The RP2D of revumenib was 160 mg twice daily with a strong CYP3A4 inhibitor. 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 complete remission with partial hematologic recovery (CR/CRh) rate was 60%, with measurable residual disease negativity by flow cytometry in 80% of these patients. The median duration of CR/CRh for all patients 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%.

CONCLUSION

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.