Ziftomenib, a menin inhibitor, is an antineoplastic agent.1
Ziftomenib is used for the treatment of adult patients with relapsed or refractory acute myeloid leukemia (AML) with a susceptible nucleophosmin 1 ( NPM1 ) mutation who have no satisfactory alternative treatment options.1, 3 Ziftomenib has been designated an orphan drug by FDA for the treatment of AML.2
The current indication for ziftomenib in the treatment of AML with an NPM1 mutation is based on the results of an open-label, single-arm, phase 1/2, multicenter clinical trial in 112 adult patients.1, 5, 6 Patients received ziftomenib 600 mg once daily until disease progression or unacceptable toxicity.1 Patients were permitted to resume treatment with ziftomenib following hematopoietic stem cell transplant (HSCT).1 Outcomes assessed for efficacy were complete remission (CR; defined as <5% blasts in bone marrow, absolute neutrophil count [ANC] >1 x 109/L, and platelet count >100 x 109/L); complete remission with partial hematologic recovery (CRh; defined as <5% blasts in bone marrow, ANC >0.5 x 109/L, and platelet count >50 x 109/L); duration of remission (CR plus CRh); and rate of conversion from transfusion-dependent to transfusion-independent.1
The median age of patients was 69 years; 63% were female; 79% were White, 2% were Black or African American, and 4% were Asian.1 Of the 112 patients included in the analysis, 4 (3.6%) patients underwent stem cell transplantation following ziftomenib treatment.1 Disease was categorized as primary refractory, refractory relapse, or untreated relapse in 6, 33, or 61% of patients, respectively.1 The median number of prior lines of therapy was 2 (range, 1-7) and the median follow-up was 4.2 months (range, 0.1-41.2).1 CR was observed in 17% of patients, with a median duration of response of 5 months.1 CRh was observed in 4.5% of patients.1 CR plus CRh was achieved in 21.4% of patients, with a median duration of response of 5 months.1 For patients who achieved a CR or CRh, the median time to first response was 2.7 months (range, 0.9-15).1 Of the 24 patients who achieved CR or CRh, 21 (88%) responded within 6 months of starting ziftomenib.1 Among the 66 patients who were dependent on red blood cell (RBC) and/or platelet transfusions at baseline, 14 (21.2%) became independent of transfusions during any 56-day post-baseline period.1 Of the 46 patients who were independent of both RBC and platelet transfusions at baseline, 12 (26.1%) patients remained transfusion independent during any 56-day post-baseline period.1
Ziftomenib is administered orally as capsules.1 Swallow the capsules whole; do not break, open, or chew.1
Administer ziftomenib on an empty stomach, at least 1 hour before or 2 hours after a meal, at approximately the same time each day.1
If a dose is missed, administer it as soon as possible on the same day, at least 12 hours before the next scheduled dose.1 Resume the regular schedule the following day.1 Do not administer 2 doses within 12 hours.1
Store capsules at 20-25°C (excursions permitted between 15-30°C).1
The recommended dosage of ziftomenib for the treatment of relapsed or refractory AML with a susceptible NPM1 mutation in adult patients is 600 mg once daily until disease progression or unacceptable toxicity.1 Do not start treatment until the WBC count is reduced to <25 x 109/L.1 Treat for a minimum of 6 months to allow time for clinical response in patients without disease progression or unacceptable toxicity.1
Dosage Modification for Adverse Reactions
If adverse events occur during therapy, temporary interruption, dosage reduction, and/or discontinuance of ziftomenib may be necessary.1 For patients receiving 600 mg once daily, an initial reduction to 400 mg once daily is recommended.1 If further dosage reduction is necessary, the dosage should be reduced to 200 mg once daily.1 If a dosage of 200 mg once daily is not tolerated, discontinue ziftomenib permanently.1
Manage any abnormalities promptly.1
The recommended dosage modifications for adverse reactions are present in Table 1.1
Adverse Reaction | Recommended Action |
|---|---|
Differentiation syndrome | If differentiation syndrome is suspected, interrupt ziftomenib. Administer systemic corticosteroids, initiate hemodynamic monitoring for a minimum of 3 days or until symptom resolution, and provide supportive care. Resume at same dose level when signs and symptoms improve and are Grade ≤2. |
Noninfectious leukocytosis (e.g., sudden or significant WBC increase, including WBC doubling within the first 2 weeks of administration or an absolute increase of 10 x 109/L) | Evaluate for differentiation syndrome. Initiate treatment with hydroxyurea, as per standard institutional practices, and leukapheresis if clinically indicated. Taper hydroxyurea only after leukocytosis improves or resolves. Interrupt ziftomenib if leukocytosis is not controlled with hydroxyurea within 48 hours. If interrupted, resume at same dose level once WBC counts are controlled. |
Nonhematological adverse reactions: Grade ≥3 | Interrupt ziftomenib until recovery to Grade ≤2. Resume at the same dose level. If same Grade ≥3 toxicity recurs, interrupt ziftomenib until recovery to Grade ≤2. Restart at a reduced dose. |
Dosage Modifications for Concomitant Use of Acid-Reducing Agents
Avoid concomitant use of proton pump inhibitors (PPIs), H2 receptor antagonists (H2RAs), or locally acting antacids with ziftomenib.1 If coadministration with a H2RA cannot be avoided, administer ziftomenib 2 hours before or 10 hours after the H2RA.1 If coadministration with a locally acting antacid cannot be avoided, administer ziftomenib 2 hours before or 2 hours after the antacid.1
The manufacturer makes no specific dosage recommendations for geriatric patients or patients with hepatic or renal impairment.1, 3
A boxed warning about the risk of differentiation syndrome is included in the prescribing information for ziftomenib.1 Ziftomenib can cause life threatening or fatal differentiation syndrome.1
Differentiation syndrome occurred in 29 (26%) of 112 patients with relapsed or refractory acute myeloid leukemia (AML) receiving ziftomenib, including Grade 3 in 13% of patients and fatal in 2 patients.1 In all patients with any genetic form of AML treated with ziftomenib monotherapy in clinical trials, differentiation syndrome occurred in 25% of patients.1 Among the 39 patients with KMT2A -rearranged AML treated with ziftomenib, 4 fatal cases of differentiation syndrome occurred.1 Ziftomenib is not approved for use in patients with KMT2A -rearranged AML.1
Among 112 patients with an NPM1 mutation, differentiation syndrome occurred with and without concomitant hyperleukocytosis, as early as 3 days and up to 46 days after initiation of ziftomenib.1 The median time to onset was 15 days.1 Multiple events occurred in 2 patients.1 Treatment was interrupted and subsequently resumed in 15 (13%) patients and permanently discontinued in 2 (2%) patients.1
Prior to starting treatment with ziftomenib, reduce the WBC counts to <25 x 109/L.1 If differentiation syndrome is suspected, interrupt treatment with ziftomenib, and initiate oral or IV corticosteroids (e.g., dexamethasone 10 mg every 12 hours) for a minimum of 3 days with hemodynamic and laboratory monitoring.1 Resume ziftomenib at the same dose level when signs and symptoms improve and are Grade 2 or lower.1 Taper corticosteroids over a minimum of 3 days after adequate control or resolution of symptoms.1 Symptoms of differentiation syndrome may recur with premature discontinuation of corticosteroid treatment.1
QT interval corrected for rate (QTc) prolongation has been reported in 12% of 112 patients treated with ziftomenib for relapsed or refractory AML with a NPM1 mutation, including Grade 3 in 8% of patients.1 The heart-rate corrected QT interval (using Fridericia's method; QTcF) was >500 in 9% of patients, and the increase from baseline QTcF was >60 msec in 12% of patients.1 Dose reduction was required in 1% of patients due to QTc interval prolongation.1 QTc prolongation occurred in 14% of the 42 patients <65 years of age and in 10% of the 70 patients ≥65 years of age.1
Correct electrolyte abnormalities, including hypokalemia and hypomagnesemia, prior to treatment with ziftomenib.1 Perform an ECG prior to initiation of treatment, and do not initiate ziftomenib in patients with QTcF >480.1 Perform an ECG at least once weekly for the first four weeks on treatment, and at least monthly thereafter.1 Interrupt ziftomenib if the QTc interval is >500 or the change from baseline is >60 (Grade 3).1 In patients with congenital long QTc syndrome, congestive heart failure, electrolyte abnormalities, or those who are taking medications known to prolong the QTc interval, more frequent ECG monitoring may be necessary.1 Concomitant use of ziftomenib with drugs known to prolong the QTc interval may increase the risk of QTc interval prolongation.1
Fetal/Neonatal Morbidity and Mortality
Based on findings of animal reproductive studies and its mechanism of action, ziftomenib can cause embryo-fetal harm when administered to a pregnant woman.1 In animal reproduction studies, oral administration of ziftomenib to pregnant mice during the period of organogenesis caused adverse developmental outcomes, including embryo-fetal mortality, structural abnormalities, and altered fetal growth at approximately 0.3 times the steady-state clinical exposure based on the AUC at the recommended human dose.1
Advise pregnant women of the potential risk to the fetus.1 Advise females of reproductive potential to use effective contraception during treatment with ziftomenib and for 6 months after the last dose.1 Advise males with female partners of reproductive potential to use effective contraception during treatment with ziftomenib and for 3 months after the last dose.1
There are no available human data on ziftomenib use in pregnant women; however, based on animal studies and its mechanism of action, ziftomenib can cause fetal harm when administered during pregnancy.1
In animal reproduction studies, oral administration of ziftomenib to pregnant mice during organogenesis resulted in adverse developmental outcomes, including embryo-fetal mortality, structural abnormalities, and altered fetal growth at maternal exposures approximately 0.3 times the human exposure (AUC) at the recommended dose.1 Advise pregnant women of the potential risk to a fetus.1
It is not known whether ziftomenib is distributed into human milk, or if the drug has any effects on the breastfed infant or on milk production.1 Due to the potential for adverse reactions in the breastfed child, advise women not to breastfeed during treatment with ziftomenib and for 2 weeks after the last dose.1
Females and Males of Reproductive Potential
Based on findings in animals and its mechanism of action, ziftomenib can cause fetal harm when administered to a pregnant woman.1
Verify pregnancy status in females of reproductive potential prior to initiating ziftomenib.1 Advise females of reproductive potential to use effective contraception during treatment and for 6 months after the last dose.1 Advise males with female partners of reproductive potential to use effective contraception during treatment and for 3 months after the last dose.1
Animal studies indicate that ziftomenib may impair fertility in males and females of reproductive potential; these effects were not reversible after a 4-week recovery period.1
Safety and efficacy of ziftomenib have not been established in pediatric patients.1
Among the 112 patients with relapsed or refractory AML with an NPM1 mutation treated with ziftomenib, 70 (63%) patients were ≥65 years of age and 31 (28%) were >75 years of age.1 No overall differences in effectiveness, safety, or pharmacokinetics of ziftomenib were observed between patients aged ≥65 years and younger patients.1
No clinically significant differences in the pharmacokinetics of ziftomenib were observed in patients with mild or moderate hepatic impairment.1, 3 The pharmacokinetics of ziftomenib have not been studied in patients with severe hepatic impairment.1
No clinically significant differences in the pharmacokinetics of ziftomenib were observed in patients with mild or moderate renal impairment.1, 3 The pharmacokinetics of ziftomenib have not been studied in patients with severe renal impairment.1
The most common adverse reactions (≥20%) reported with ziftomenib in clinical studies were infection without an identified pathogen, hemorrhage, diarrhea, nausea, fatigue, edema, bacterial infection, musculoskeletal pain, differentiation syndrome, pruritus, increased transaminases, and febrile neutropenia.1
The most common laboratory abnormalities (≥10%) reported with ziftomenib in clinical studies were increased aspartate aminotransaminase, decreased potassium, decreased albumin, increased alanine aminotransferase, decreased sodium, increased creatinine, increased alkaline phosphatase, increased bilirubin, and increased potassium.1
Ziftomenib is metabolized primarily by cytochrome P-450 (CYP) 3A.1
Ziftomenib is a substrate of P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP).1
Ziftomenib induces CYP1A2, but not CYP2B6 or CYP3A4.1
Ziftomenib does not inhibit CYP1A2 or CYP2D6.1
Ziftomenib inhibits UDP-glucuronosyltransferase (UGT) 1A9 and UGT2B17.1 Ziftomenib does not inhibit P-gp, BCRP, organic anion transporter (OAT) 1, OAT3, organic cation transporter (OCT) 2, multidrug and toxin extrusion transporter (MATE) 1, MATE2-K, organic anion transporting polypeptide (OATP) 1B1, OATP1B3, bile salt export pump (BSEP), or multidrug resistance-associated protein (MRP) 2.1
Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes
Ziftomenib is not predicted to have clinically significant effects on the exposure of repaglinide (CYP2C8 substrate), (S)-warfarin (CYP2C9 substrate), and omeprazole (CYP2C19 substrate).1
Ziftomenib is predicted to increase the AUC and peak plasma concentrations of midazolam (a CYP3A4 substrate) by up to 1.9- and 1.4-fold, respectively, when administered alone.1
Concomitant use of ziftomenib with strong or moderate CYP3A4 inhibitors increases the exposure of ziftomenib, which may increase the risk of adverse reactions such as QT prolongation.1
Itraconazole, voriconazole, and posaconazole (strong CYP3A4 inhibitors) are estimated to increase ziftomenib AUC by up to 3-fold and peak plasma concentrations by up to 2-fold.1 Erythromycin, fluconazole, and isavuconazole (moderate CYP3A4 inhibitors) are estimated to increase ziftomenib AUC by up to 2-fold and peak plasma concentrations by up to 2-fold.1 Cimetidine (weak CYP3A inhibitor) is estimated to increase ziftomenib AUC and peak plasma concentrations by up to 1.4-fold.1
Monitor patients more frequently for ziftomenib-associated adverse reactions when concomitantly taking strong or moderate CYP3A4 inhibitors with ziftomenib.1
Concomitant use of ziftomenib with strong or moderate CYP3A4 inducers may decrease the exposure of ziftomenib, which may reduce the efficacy of ziftomenib.1
Rifampin (strong CYP3A4 inducer) is estimated to decrease ziftomenib AUC by up to 80% and peak plasma concentrations by up to 70%.1 Efavirenz (moderate CYP3A4 inducer) is estimated to decrease ziftomenib AUC and peak plasma concentrations by up to 70%.1 Dexamethasone (weak CYP3A4 inducer) is estimated to decrease ziftomenib AUC and peak plasma concentrations by up to 40%.1
Avoid concomitant use of ziftomenib with strong or moderate CYP3A4 inducers.1
Drugs Affecting or Affected by Transport Systems
Ziftomenib is not predicted to have clinically significant effects on the exposure of raltegravir (UGT1A1 substrate).1
Drugs Affecting Gastric Acidity
Concomitant administration of ziftomenib with proton pump inhibitors (PPIs) decreases the exposure of ziftomenib, which may reduce the efficacy of ziftomenib.1 Administration of PPIs reduced ziftomenib AUC by 53% and peak plasma concentration by 70%.1
Avoid concomitant use of ziftomenib with PPIs, H2 receptor antagonists (H2RAs), and locally acting antacids.1 If concomitant use cannot be avoided with H2RAs and locally acting antacids, modify the administration time of ziftomenib (see Dosage Modifications for Concomitant Use of Acid-Reducing Agents under Dosage and Administration).1
Ziftomenib causes QT interval corrected for rate (QTc) prolongation.1 Concomitant use of ziftomenib with other QTc-prolonging agents may further increase the QTc interval and the risk of associated adverse reactions, including torsades de pointes, other serious arrhythmias, and sudden death.1
Avoid concomitant use of ziftomenib with products known to prolong the QTc interval.1 If coadministration cannot be avoided, obtain ECGs at initiation, during concomitant use, and as clinically indicated.1 Interrupt ziftomenib if the QTc interval exceeds 500 msec or increases >60 msec from baseline.1
Ziftomenib blocks the interaction of menin and lysine [K]-specific methyltransferase 2A (KMT2A).1 Acute leukemias may be driven by NPM1 mutations that recruit the wild-type menin-KMT2A complex to promoters of leukemogenic genes.1 Susceptible NPM1 mutations result in loss of the nucleolar localization signal and insertion of a nuclear export signal, leading to cytoplasmic accumulation of mutant NPM1 protein, disruption of normal cellular function, and leukemogenesis through altered gene expression.1 Pharmacologic disruption of the menin-KMT2A protein-protein interaction by ziftomenib blocks the oncogenic activity of mutant NPM1 and induces differentiation of leukemic cells, as evidenced by increased expression of differentiation markers.1 In nonclinical studies, ziftomenib demonstrated in vitro and in vivo antitumor activity in models of NPM1 -mutant leukemia.1
In patients with relapsed or refractory acute myeloid leukemia (AML) receiving ziftomenib 600 mg once daily, interval corrected for rate (QTc) prolongation was concentration dependent, with a predicted mean increase of 7.7 ms from baseline.1
The absolute bioavailability of ziftomenib is 12.9%.1 Following administration of a dosage of 600 mg once daily with a high-fat meal, ziftomenib AUC and peak plasma concentrations increased 4-fold.1 Protein binding of the drug is 99%.1 Ziftomenib is primarily metabolized by cytochrome P450 (CYP) 3A.1 The half-life of ziftomenib is 189.8 hours with concomitant use of strong CYP3A4 inhibitors and 93.6 hours without concomitant CYP3A4 inhibitors.1 Following oral administration of ziftomenib 600 mg once daily, 86% of the drug is excreted in feces (73% as unchanged drug) and 0.5% in urine (0.03% as unchanged drug).1
Additional Information
The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer's labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care. For further information on the handling of antineoplastic agents, see the ASHP Guidelines on Handling Hazardous Drugs at [Web].
Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.
Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.
Ziftomenib is available only from designated specialty pharmacies.4 Contact the manufacturer or consult the ziftomenib website ([Web]) for more information.4
Routes | Dosage Forms | Strengths | Brand Names | Manufacturer |
|---|---|---|---|---|
Oral | Capsules | 200 mg | Komzifti® | Kura Oncology |
AHFS® Drug Information. © Copyright, 1959-2026, Selected Revisions June 10, 2026. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, MD 20814.
Only references cited for selected revisions after 1984 are available electronically.
1. Kura Oncology, Inc. KOMZIFTI (ziftomenib) ORAL prescribing information. 2025 Nov.
2. US Food and Drug Administration. Search orphan drug designations and approvals. From FDA website. Accessed 2026 Feb 27.
3. US Food and Drug Administration. Center for Drug Evaluations and Research Application Number: 220305Orig1s000 Multi-Discipline Review. From the FDA website. Accessed 2026 Feb 27.
4. We're here for you. Accessed 2026 Mar 3. [Web]
5. Wang ES, Montesinos P, Foran J, et al. Ziftomenib in relapsed or refractory NPM1-mutated AML. J Clin Oncol. 2025;43(31):3381-3390. doi:10.1200/JCO-25-01694
6. Wang ES, Issa GC, Erba HP, et al. Ziftomenib in relapsed or refractory acute myeloid leukaemia (KOMET-001): a multicentre, open-label, multi-cohort, phase 1 trial. Lancet Oncol. 2024;25(10):1310-1324. doi:10.1016/S1470-2045(24)00386-3