On November 13, 2025, the US Food and Drug Administration approved the menin inhibitor ziftomenib (Komzifti) for adult patients with relapsed or refractory acute myeloid leukemia (AML) harboring a susceptible NPM1 mutation and for whom no satisfactory alternative treatments are available.

The approval was based on the phase 1/2 KOMET-001 trial (NCT04067336), an open-label, multicenter study enrolling 112 adults with relapsed or refractory AML and confirmed NPM1 mutation. In the phase 2 cohort (n = 92), the primary endpoint was the combined complete remission (CR) and CR with partial hematologic recovery (CRh) rate. Ziftomenib achieved a CR + CRh rate of 21.4% (95% CI, 14.2–30.2), including CR in 17.0% and CRh in 4.5% of patients. Median duration of CR/CRh was 5.0 months (95% CI, 1.9–8.1). Among 66 patients who were transfusion dependent at baseline, 21.2% achieved transfusion independence for at least 56 days; 26.1% of 46 patients who were transfusion independent at baseline maintained that status.

Adverse reactions included differentiation syndrome (25% overall; 15% grade ≥3), febrile neutropenia (26%), anemia (20%), and thrombocytopenia (20%). QTc prolongation was not clinically significant. Three percent of patients discontinued ziftomenib due to treatment-related adverse events. The prescribing information includes warnings for differentiation syndrome, QTc prolongation, and embryo-fetal toxicity.

Ziftomenib is the first targeted therapy approved specifically for NPM1-mutant AML, a subset representing approximately 25%–30% of adult AML cases. Responses were observed across subgroups regardless of prior venetoclax exposure or hematopoietic stem cell transplant. “In these heavily pretreated, relapsed/refractory patients, similar response rates were seen … regardless of multiple lines of therapy,” said Dr. Eunice Wang, KOMET-001 investigator (OncLive, November 2023).

References:

FDA announcement: https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-ziftomenib-relapsed-or-refractory-acute-myeloid-leukemia-npm1-mutation