Clinical trialPhase 2Leukaemia

Ziftomenib in Relapsed or Refractory NPM1 -Mutated AML

J Clin Oncol · 202592 patients

Wang ES, Montesinos P, Foran J, Erba H, Rodríguez-Arbolí E, Fedorov K, et al. J Clin Oncol. 2025. 43:3381-3390

Study type: Clinical trial
Study name: KOMET-001
Phase: Phase 2
Design: Phase 2 part (registration-enabling stage) of the KOMET-001 study; single-arm trial in which all patients received ziftomenib
Sample size: 92 patients
Source: J Clin Oncol · 2025

In plain words

Ziftomenib is a tablet taken by mouth that was tested in patients with acute myeloid leukaemia with an NPM1 mutation whose disease had come back after earlier treatments or had not responded to treatment. In this study, about a fifth of patients (22%) went into complete or almost complete remission, and some kind of response was seen in about 1 in 3 (33%). Side effects such as fever with low white blood cell counts, and anaemia, occurred. A special side effect called “differentiation syndrome” happened in a quarter of patients and could be controlled with medical care. Decisions about this drug should be made together with your own doctor.

Key results

22%

CR/CRh rate (primary endpoint)

95% CI 14–32; P = 0.0058

61%

Measurable residual disease (MRD) negativity

33%

Overall response rate

95% CI 23–43

4.6 months

Median duration of response

95% CI 2.8–7.4

6.6 months

Median overall survival

95% CI 3.6–8.6

Comparable CR/CRh regardless of previous treatment (including venetoclax) or type of co-mutations

Subgroup analysis

Prespecified subgroup analyses

Dose and schedule cards

Ziftomenib (KOMET-001)

Relapsed or refractory NPM1-mutated AML in adults with no other satisfactory optionCycle length: ContinuousOn the page “Leukaemia” · Regimens and dosing in relapsed or refractory AML

Relapsed or refractory NPM1-mutated AML in adults with no other satisfactory option

Drug	Dose	Route	Schedule
Ziftomenib	600 mg once daily	Oral, on an empty stomach (1 hour before or 2 hours after a meal)	Continuous

Cycle length: Continuous
Duration: Until progression or unacceptable toxicity; at least 6 months in the absence of progression

Avoid proton pump inhibitors; if an H2 antagonist cannot be avoided, take ziftomenib 2 hours before or 10 hours after it. If differentiation syndrome is suspected: interrupt the drug; systemic corticosteroids and haemodynamic monitoring for at least 3 days; control noninfectious leukocytosis with hydroxyurea. Dose reduction for recurrent grade ≥3 toxicity: 400 mg and then 200 mg; inability to tolerate 200 mg: discontinue permanently.

On the page “Leukaemia” · Regimens and dosing in relapsed or refractory AML

Ziftomenib (KOMET-001)

Relapsed or refractory NPM1-mutated AML in adults with no satisfactory alternativeCycle length: ContinuousOn the page “Acute myeloid leukaemia (AML): 2022 classification, ELN genetic risk and treatment” · Targeted treatment in relapsed or refractory AML

Relapsed or refractory NPM1-mutated AML in adults with no satisfactory alternative

Drug	Dose	Route	Schedule
Ziftomenib	600 mg once a day	Oral, fasting (1 hour before or 2 hours after food)	Continuous

Cycle length: Continuous
Duration: At least 6 months in the absence of progression

Boxed warning for differentiation syndrome: if suspected, stop the drug and start oral or IV corticosteroids with haemodynamic monitoring. Avoid proton pump inhibitors; if an H2 antagonist is unavoidable, take ziftomenib 2 hours before or 10 hours after it. Differentiation syndrome occurred in 25% of patients (15% grade 3).

On the page “Acute myeloid leukaemia (AML): 2022 classification, ELN genetic risk and treatment” · Targeted treatment in relapsed or refractory AML

Doses follow the trial protocol, guideline or official drug label (source given in the notes of each regimen). Before prescribing, check blood counts, renal and hepatic function, drug interactions and the patient’s condition, and adjust the dose according to the drug label.

Treatment arms and regimens

1Ziftomenib (single arm)

Ziftomenib 600 mg orally once daily, continuously.

Per the FDA label: on an empty stomach (1 hour before or 2 hours after a meal); start only with a white blood cell count below 25×10⁹/L; continue until progression or unacceptable toxicity and for at least 6 months in the absence of progression; dose reduction for adverse events to 400 and then 200 mg; avoid proton pump inhibitors.

Source of the regimen details: Abstract of the paper (600 mg once daily) and the FDA label for ziftomenib (DailyMed)

Doses are given for the information of specialists, as in this study’s protocol, and are not a prescription. Every drug must be prescribed by the treating physician for the individual patient.

Study population

Patients with relapsed or refractory acute myeloid leukaemia (AML) with an NPM1 mutation (NPM1-m). Median age was 69 years (range 33 to 84 years). Patients started treatment between 26 January 2023 and 13 May 2024. Patients were heavily pretreated and some had received venetoclax. Other eligibility criteria are not given in the abstract.

Endpoints

Primary endpoint: rate of complete remission with full haematological recovery (CR) or complete remission with partial haematological recovery (CRh). Secondary and exploratory endpoints reported in the abstract: rate of measurable residual disease (MRD) negativity, overall response rate, duration of response, overall survival, prespecified subgroup analyses and safety.

Safety and side effects

Common treatment-emergent grade 3 or higher adverse events: febrile neutropenia (26%), anaemia (20%) and thrombocytopenia (20%). Differentiation syndrome occurred in 25% of patients (15% grade 3; no grade 4 or 5) and was manageable with the risk-mitigation measures set out in the protocol. Three patients (3%) discontinued treatment because of ziftomenib-related adverse events. The authors note the absence of clinically significant QTc prolongation and low rates of myelosuppression.

Clinical significance and place in guidelines

These results show that menin inhibition with ziftomenib can lead to clinical responses and MRD negativity in relapsed/refractory NPM1-mutated AML, even in patients previously treated with venetoclax. This study is a single-arm cohort and has no direct comparison with standard treatment. Regulatory approval status (for example FDA or EMA) and the drug's place in clinical guidelines should be checked separately, as the abstract does not mention them.

Limitations

The study is single-arm with no control group. Median duration of response (4.6 months) and median overall survival (6.6 months) are short. The sample is small (92 patients) and only patients with NPM1 mutations were enrolled in this phase 2 part. The findings therefore cannot be generalised to patients with KMT2A rearrangements, and the effect on survival needs to be examined in further studies.

Original article (DOI)PubMed

This summary was prepared by the editorial team from the published paper; the original paper is the final reference. Read the original abstract on PubMed.