Category: AML

  • Oral Menin-Based Triplet Shows Strong Early Activity in ND AML

    The phase II SAVE trial presented at the 2025 American Society of Hematology (ASH) Annual Meeting (Abstract 47) delivered early but compelling results from an all-oral regimen pairing the menin inhibitor revumenib with decitabine/cedazuridine and venetoclax for newly diagnosed acute myeloid leukemia (AML) with mutations in nucleophosmin 1 (NPM1) or rearrangements involving lysine methyltransferase 2A (KMT2A). Among an older, molecularly defined cohort, the combination produced rapid measurable residual disease (MRD)–negative remissions and encouraging early survival signals, raising the possibility that menin inhibition may meaningfully strengthen current low-intensity frontline approaches.

    The newly diagnosed cohort included 21 patients with a median age of 70 years. The NPM1-mutated cohort was older, with a median age of 73 years and 71% aged 70 years or older. Co-mutations were common and included NRAS, KRAS, fms-related tyrosine kinase 3 (FLT3), and isocitrate dehydrogenase 1/2 (IDH1/2). Myelodysplasia-related mutations were present in 43%. Treatment incorporated revumenib through Day 21 of induction to allow confirmation of Day 14 marrow findings before adjustment, and both venetoclax and decitabine/cedazuridine durations were reduced in later cycles as cytopenias emerged. The median cycle length extended to approximately six weeks because of delayed count recovery.

    The overall response rate (ORR) was 86%, and 81% of patients achieved complete remission (CR) or CR with partial hematologic recovery (CRh). All composite remissions were MRD negative by multiparameter flow cytometry with a sensitivity of 10^-4 NPM1-based MRD measured by next-generation sequencing (NGS; sensitivity 5 × 10^-5) showed similar kinetics, and the 2 patients who failed to clear ultimately relapsed. With nine months of median follow-up, the median duration of response (DOR), overall survival (OS), and event-free survival (EFS) had not been reached. Estimated one-year remission rates were 71% in NPM1-mutated AML and 80% in KMT2A-rearranged AML. Most responses occurred within the first cycle, and 33% of patients proceeded to allogeneic hematopoietic stem cell transplantation (HSCT) in first remission, and none of those patients have relapsed.

    Differentiation syndrome (DS) occurred in 19% of patients, including 2 grade 3 events that resolved with corticosteroids. QT interval prolongation occurred in 43% of patients but was limited to grade 2 and did not prompt treatment discontinuation. Infections reflected substantial myelosuppression, with gram-negative rod bacteremia representing the dominant pathogen group. Four deaths occurred including one patient who died post HCT of respiratory failure while receiving revumenib maintenance.

    Taken together, the SAVE trial offers early evidence that integrating a menin inhibitor into an oral hypomethylating agent–venetoclax backbone may produce deep and rapid remissions in newly diagnosed AML with NPM1 mutations or KMT2A rearrangements. Longer follow-up and larger cohorts will be required to define durability, safety in older adults, and the prevalence of resistance mechanisms such as MEN1 mutation.

    References:

    Jen WY, Short NJ, Farhat A, et al. Phase II study of the all-oral combination of revumenib with decitabine/cedazuridine and venetoclax (SAVE) in newly diagnosed AML. Presented at: American Society of Hematology Annual Meeting; 2025; Orlando, FL. Abstract 47.

  • Ziftomenib Approved for NPM1-Mutant R/R AML

    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