The All-Oral Combination of Revumenib, Decitabine and Venetoclax for Relapsed or Refractory Acute Myeloid Leukemia (SAVE).

Abstract

Revumenib is an oral inhibitor of menin-KMT2A, a key dependency in acute myeloid leukemia (AML) with <i>KMT2A</i> rearrangement (<i>KMT2Ar</i>), <i>NPM1</i> mutation (<i>NPM1mt</i>), or <i>NUP98</i> rearrangement (<i>NUP98r</i>). Preclinical studies suggest synergy with BCL2 inhibition. In this phase 1-2 study, we evaluated an all-oral regimen of revumenib, decitabine/cedazuridine, and venetoclax in patients ≥12 years of age with relapsed or refractory AML. Decitabine/cedazuridine was given days 1-5, venetoclax days 1-14, and revumenib twice daily days 1-28. The primary objectives were to determine the recommended phase 2 dose (RP2D) and to assess efficacy according to the composite complete remission (CRc) rate. Forty-two patients were enrolled (median age, 40 years; range, 12-82) including 40% with <i>KMT2Ar,</i> 38% with <i>NPM1mt</i>, and 21% with <i>NUP98r.</i> Patients had a median of 2 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 <i>KMT2Ar</i>, 10.7 months in <i>NPM1mt</i>, and 5.9 months in <i>NUP98r</i>. Emergent mutations in the menin-binding site occurred in 13%. 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.