Update on a Phase 1/2 First-in-Human Study of the Menin-KMT2A (MLL) Inhibitor Ziftomenib (KO-539) in Patients with Relapsed or Refractory Acute Myeloid Leukemia

Harry Erba, MD, PhD shares an update from the recent ASH 2022 Annual Meeting on a phase 1/2 trial of the menin-KMT2A (MLL) Inhibitor ziftomenib in patients with relapsed or refractory acute myeloid leukemia.


  • In patients with acute myeloid leukemia (AML), KMT2A rearrangements occur in 5% to 10% of patients, and NPM1 mutations occur in 30% of patients. These aberrations cause epigenetic dysregulation in AML.
  • Phase 1a - Dose Escalation
    • This portion of the trial enrolled 30 adults with relapsed/refractory (R/R) AML. Patients received 50 to 1000 mg of ziftomenib orally once daily to assess safety, tolerability, pharmacokinetics, and antileukemic activity.
    • At the 100-mg dose, 1 complete remission (CR) was observed in a patient with SETD2 and RUNX1 mutations. At the 200-mg dose, the 2 patients with the NPM1 mutation responded (1 had a CR without measurable residual disease [MRD-] for > 100 weeks, and 1 had a morphologic leukemic-free state). At a 600-mg dose, 1 of 2 patients with KMT2A rearrangements had stable disease with significantly decreased blast counts lasting more than 4 months.
    • Treatment-emergent adverse events (TEAEs) of grade 3 or greater in at least 10% of all patients (N = 30) were anemia, pneumonia (27% each); neutropenia (17%); thrombocytopenia (13%); febrile neutropenia, and decreased appetite (10% each). Two dose-limiting toxicities (DLTs) occurred: pneumonitis (at the 400-mg dose) and differentiation syndrome (DS; at the 1000-mg dose), which led to dose de-escalation per protocol.
  • Phase 1b - Dose Validation
    • In this portion of the trial, 24 patients with AML and KMT2A rearrangement or NPM1 mutation were randomly assigned to either 200 or 600 mg of ziftomenib (KMT2A rearrangement: 200 mg given to 9 patients, 600 mg given to 3 patients; NPM1 mutation: 200 mg given to 6 patients, 600 mg given to 6 patients) given orally once daily to determine an optimal active dose.
    • At the 200-mg dose, bone marrow (BM) morphology changes and stable/decreasing blast counts were observed. Three patients were dose-escalated to 600 mg with improvement: 1 achieved a BM blast count of less than 5% and significant reduction of high-burden extramedullary disease despite persistence of a small disease focus; 1 had significantly reduced blast counts and disease control; and 1 attained a morphologic leukemic-free state and remains on treatment. At 600 mg, 25% of patients had a best response of CR/CR with partial hematologic recovery (CRh); 33.3% of patients with an NPM1 mutation achieved CR/CRh. Composite CR was 33% with 75% MRD-. Overall response rate (ORR) was 42%. Patients who experienced DS had an ORR of 75%. At data cutoff, 50% of patients remain on treatment.
    • Treatment-emergent adverse events (TEAEs) of at least grade 3 noted in 10% or more of all patients (N = 24) were anemia, febrile neutropenia, neutropenia, thrombocytopenia (25% each); DS, leukocytosis (17% each); sepsis, and leukopenia (13% each). At the 200-mg dose (N = 12), TEAEs of at least grade 3 noted among 10% or more of patients were neutropenia, thrombocytopenia (33% each); febrile neutropenia, anemia, sepsis (25% each); DS, leukocytosis, and respiratory failure (17% each). At the 600-mg dose (N = 12), TEAEs of at least grade 3 seen in 10% or more of patients were febrile neutropenia, anemia (25% each); DS, leukocytosis, neutropenia, thrombocytopenia, leukopenia, and diarrhea (17% each).
    • DS, an on-target effect, occurred in 7 patients. At the 200-mg dose, 3 patients harbored KMT2A rearrangements; and 2 had events of at least grade 3, including 1 death. Of the 4 patients given the 600-mg dose, 1 patient each who had a KMT2A rearrangement or an NPM1 mutation had grade 3 DS; likewise, 1 patient each, respectively, had a grade 2 DS. Since implementation of DS guidance, the reported DS event severity has declined.


  • Overall, these results demonstrated a manageable safety profile and preliminary efficacy of ziftomenib; they warrant further investigation of this agent used alone and in combination.

Erba HP, Fathi AT, Issa GC, et al. Update on a phase 1/2 first-in-human study of the menin-KMT2A (MLL) inhibitor ziftomenib (KO-539) in patients with relapsed or refractory acute myeloid leukemia. Abstract presented at: the 2022 Annual Meeting of the American Society of Hematology; December 10, 2022; New Orleans, LA. Abstract 64.


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