Azacitidine, Venetoclax, and Revumenib for Newly Diagnosed NPM1-Mutated or KMT2A-Rearranged AML

Abstract

Purpose: Azacitidine and venetoclax is a standard frontline treatment regimen for newly diagnosed older adults with AML; however, long-term outcomes remain poor. Revumenib is an oral menin inhibitor with clinical activity in AML patients with nucleophosmin-1 mutation (NPM1m) or lysine methyltransferase 2A rearrangements (KMT2Ar).

Methods: We conducted a phase I dose-escalation and expansion study of azacitidine, venetoclax, and revumenib at two dose levels (113 mg or 163 mg orally every 12 hours in combination with strong cytochrome P450 inhibitor azoles) in patients aged 60 years and older newly diagnosed with AML with NPM1m or KMT2Ar (ClinicalTrials.gov identifier: NCT03013998).

Results: Overall, 43 patients were enrolled and treated. There was no maximal tolerated dose identified. Differentiation syndrome was present in eight (19%) patients and QTc Fridericia prolongation was present in 19 (44%) patients, and neither required permanent discontinuation of revumenib. The overall response rate with an intention-to-treat population was 88.4% (95% CI, 74.9 to 96.1; NPM1m: 85.3%; KMT2Ar: 100%), the rate of composite complete remission (complete remission [CR] + CR with partial or incomplete hematologic recovery) was 81.4% (95% CI, 66.6 to 91.6; NPM1m: 79.4%; KMT2Ar: 88.9%), and the rate of CR was 67.4% (95% CI, 51.5 to 80.9; NPM1m: 65%; KMT2Ar: 78%). No patient had refractory disease after 1-2 cycles of treatment. The median time to first response was 28 days, and 84% of responders achieved remission within the first cycle. All 37 patients evaluated had no evidence of measurable residual disease by a centralized flow cytometry assay.

Conclusion: In older adults newly diagnosed with NPM1m or KMT2Ar AML, the combination of azacitidine, venetoclax, and revumenib was able to be safely administered with high rates of CR and clinical activity.

FIG 1.

Study schema and CONSORT diagram. (A) Patients are allowed up to three induction cycles to achieve a marrow remission before going onto continuation-phase cycles. Continuation-phase cycles can only be started after achieving hematologic recovery. (B) Forty-three patients were treated in this study between DL1 and DL2 across multiple dose expansions. DL1, Dose Level 1; DL2, Dose Level 2; PO, orally.

FIG 2.

Clinical response rates by patient subgroups' clinical response rates by categories including dose levels, age, mutation group, and ELN 2024 risk. Only 1 patient was ELN2024 adverse risk and is included with the intermediate-risk group. CRc rate includes CR/CRh/CRi. CR, complete remission; CRc, composite CR; CRh, CR with partial hematologic recovery; CRi, CR with incomplete recovery; DL1, Dose Level 1; DL2, Dose Level 2; ELN, European Leukemia Net; KMT2Ar, lysine methyltransferase 2A rearrangements; MLFS, morphologic leukemia-free state; NPM1m, nucleophosmin-1 mutations.

FIG 3.

Overall and event-free survival. (A) Median overall survival in KMT2Ar was 18.0 months (95% CI, 11.5 to not reached) and that in NPM1m was 15.5 months (95% CI, 7.2 to 19.5). (B) Median event-free survival in KMT2Ar was not reached and that in NPM1m was 13.3 months (95% CI, 7.2 to 19.5). (C) Swimmer plot describing response, relapse, transplant, and death. CR, complete remission; CRh, CR with partial hematologic recovery; CRi, CR with incomplete recovery; KMT2Ar, lysine methyltransferase 2A rearrangements; MLFS, morphologic leukemia-free state; KMT2Ar, lysine methyltransferase 2A rearrangements; NE, not reached; NPM1m, nucleophosmin-1 mutations.

FIG A1.

Duration of response. Median duration of response in KMT2Ar was 11.2 months (95% CI, 5.2 to not reached) and that in NPM1m was 12.0 months (95% CI, 7.7 to not reached). KMT2Ar, lysine methyltransferase 2A rearrangements; NE, not reached; NPM1m, nucleophosmin-1 mutations.