Integrating Novel Therapies for NPM1-Mutated AML: The Expanding Role of the Oncology Pharmacist in Precision Treatment and Supportive Care

Mutations in the NPM1 gene are among the most common genetic alterations in acute myeloid leukemia (AML), occurring in approximately 30% of cases. The recent approvals of revumenib (Revuforj; Syndax Pharmaceuticals) and ziftomenib (Komzifti; Kura Oncology) represent the first targeted therapeutic options for patients with (NPM1mt) AML. This article reviews the available clinical data supporting these menin inhibitors and discusses key supportive care considerations to optimize the management of patients receiving menin inhibitor therapy.

Introduction

AML is the most common type of acute leukemia, with an estimated 22,720 new cases in 2026. AML is most commonly diagnosed in older adults, with a median age of diagnosis of 70 years. The treatment landscape has continued to evolve over the last decade, but the 5-year relative survival remains around 30%.¹ NPM1 is the most commonly mutated gene in AML, accounting for ~30% of cases. NPM1 has numerous functions, including, but not limited to, involvement in cell function, DNA repair, and regulation of cell growth.² The approval of menin inhibitors has provided the first targeted treatment for patients with NPM1mt AML. The purpose of this article is to review the 2 currently FDA-approved menin inhibitors, highlight emerging agents in the development pipeline, and discuss evidence-based supportive care strategies to optimize the management of patients receiving menin inhibitor therapy.

Revumenib

Revumenib binds to menin, disrupting its interaction with KMT2A and preventing KMT2A from acting on chromatin. HOXA/MEIS1 expression is downregulated, resulting in restoration of normal hematopoiesis and resumption of differentiation.³ It is indicated for the treatment of relapsed or refractory acute leukemia in patients with KMT2A translocation and NPM1mt who are 1 year or older. For those weighing over 40 kg, the recommended dose is 270 mg twice daily; for those weighing less than 40 kg, 160 mg/m² twice daily. Revumenib is primarily metabolized by CYP3A4, so concomitant use with a strong CYP3A4 inhibitor (CYP3A4i) requires a dose reduction to 160 mg twice daily in those weighing 40 kg or more, or 95 mg/m² twice daily if less than 40 kg. After a strong CYP3A4i is discontinued, the revumenib dose may be increased once at least 5 half-lives of the strong CYP3A4 inhibitor have passed.⁴

Differentiation syndrome (DS) is a potentially life-threatening complication that can occur in patients on revumenib. It occurs in patients with acute leukemia due to the rapid maturation of leukemia cells, resulting in cytokine release. DS occurred in 18% of patients with NPM1mt AML who received revumenib. Severe DS occurred in 12% and was fatal in 2 patients. Median time to onset was 9 days, with a range of 3 to 41 days. To decrease the incidence and severity of DS, the white blood cell count should be less than 25 x 10⁹/L at revumenib initiation. The use of revumenib is associated with the risk of corrected QT interval (QTc) prolongation and torsades de pointes. QTc interval prolongation was observed in 36% of patients and required a dose reduction in 7%. An electrocardiogram (ECG) should be performed weekly for the first 4 weeks of treatment and at least monthly thereafter. Revumenib should not be initiated in patients with a QTc interval greater than 450 milliseconds using the Fridericia formula (QTcF). If the QTc interval increases to greater than 480 to 500 milliseconds, revumenib therapy should be interrupted and restarted at the same dose once the QTc interval decreases to less than or equal to 480 milliseconds. If the QTc interval exceeds 500 milliseconds or increases to more than 60 milliseconds from baseline, therapy should be interrupted and restarted at 1 dose level lower once the QTc interval is less than or equal to 480 milliseconds. To minimize the risk of QTc prolongation and torsades de pointes, ensure that electrolyte abnormalities, including hypokalemia and hypomagnesemia, are corrected before initiation of revumenib and throughout treatment. Common adverse reactions reported in 20% or more of patients on revumenib therapy include nausea, diarrhea, hemorrhage, infection (viral, bacterial, or unidentified pathogen), febrile neutropenia, fatigue, edema, decreased appetite and musculoskeletal pain.⁴

AUGMENT-101 (NCT04065399) was a phase 1/2 open-label, dose-escalation, and expansion study that included adult and pediatric patients with NPM1mt and KMT2A-rearranged (KMT2Ar) acute leukemia. The primary end points were the rate of complete remission and complete remission with partial hematologic recovery (CRh) in addition to safety and tolerability. Revumenib was administered every 12 hours in 28-day continuous cycles until lack of response, unacceptable adverse events (AEs), or disease progression. Sixty-four adult patients with relapsed/refractory NPM1mt AML were evaluated for the primary end point; 15 (23.4%) met the primary end point, achieving CR or CRh. Median time to first response was 1.84 months (range, 0.9-4.6 months) and median time to CR or CRh was 2.76 months (range, 1.8-8.8 months). For patients who met the primary end point, the median duration of CR or CRh was 4.7 months (95% CI, 1.9-8.2). Median overall survival among adult patients was 4.0 months (95% CI, 2.5-7.2), and among CR + CRh responders, it was 23.3 months (95% CI, 7.2-not reached). Grade 3 or higher treatment-related (AEs) that occurred in 10% or more of patients included QTc prolongation, febrile neutropenia, anemia, DS and platelet count decrease.⁵ The approval of revumenib was supported by the results of the AUGMENT-101 trial and showed promising results in relapsed/refractory AML patients who had previously received 1 to 7 lines of therapy, including venetoclax and prior HSCT.

Revumenib is continuing to be evaluated in other treatment settings, including postallogeneic stem cell transplant maintenance. A pooled analysis of patients with KMT2Ar, NUP98r and NPM1mt AML treated with revumenib before hematopoietic stem cell transplantation (HSCT) evaluated 21 patients (11 adult, 10 pediatric). Four patients (19%) had NPM1mt AML. Median time to initiation of revumenib post HSCT was 2.8 months (range, 1.4-5.7 months), and median duration of therapy was 6.7 months (range, 0.5-36 months). At a median follow-up of 18.2 months, 1- and 2-year overall survival was 89%, and median overall survival and event-free survival had not been reached. The cumulative incidence of relapse at 1 year was 11%, and at 2 years, it was 13%. The most common any-grade AE was thrombocytopenia (86%; grade 3 or higher, 43%), which led to dose modifications in 48% of patients and discontinuation in 10%. Graft-vs-host disease occurred in 14% of patients, and of those cases, 5% were grade 3 or higher. Collectively, these findings support continued evaluation of revumenib as a maintenance strategy post HSCT.⁶

SAVE (NCT05360160) was a phase 2 study that evaluated the safety and efficacy of revumenib in combination with decitabine/cedazuridine and venetoclax, as first-line therapy in newly diagnosed AML. The study included pediatric and adult patients with AML or myeloid mixed-phenotype acute leukemia with KMT2Ar, NPM1mt or NUP98r who were not eligible for high-intensity chemotherapy in the frontline setting or who were relapsed/refractory. The primary end point of the phase 2 study was efficacy; revumenib was dosed at 160 mg every 12 hours (dose level 0; DL0) or 270 mg every 12 hours (DL1) without CYP3A4 inhibitors on days 1 to 28. Decitabine/cedazuridine was given daily on days 1 to 5, and venetoclax was given on days 1 to 14; the target dose was 400 mg, but it was adjusted if a patient was on concomitant azole therapy. Among participants, 10 had NPM1mt (38%); the median number of prior lines of therapy was 3 (range, 1-5), with prior exposure to venetoclax, HSCT, and menin inhibitors. The overall response rate was 88%, and the CR + CRh rate was 58%; the rate of minimal residual disease (MRD) negativity among those who achieved CR or CRh was 93% and 74%, respectively. At a median follow-up of 6.6 months, the relapse-free survival was 59%.⁷ Revumenib is also being investigated in combination with intensive chemotherapy. SNDX-5613-0708 (NCT06226571) is a multicenter, open-label, dose-escalation/expansion study that evaluated the dose-limiting toxicities and safety of revumenib in combination with cytarabine plus daunorubicin or idarubicin. Patients who achieved CR or CR with incomplete hematologic recovery received consolidation therapy with high-dose cytarabine in combination with revumenib. As of October 2025, 31 patients were treated in this phase 1 trial (13 DL1 [110 mg/220 mg every 12 hours +/- strong CYP3A4i] and 18 DL2 [160 mg/270 mg every 12 hours +/- strong CYP3A4i]). NPM1mt was detected in 8% of patients in the DL1 dosing arm and 56% in the DL2 dosing arm. Grade 3 or higher treatment-emergent AEs that occurred in both dosing arms include febrile neutropenia, thrombocytopenia, anemia and neutropenia. Preliminary efficacy data suggest that treatment induced deep responses, as evidenced by high rates of MRD-negative CR. These efficacy end points will be further investigated in the ongoing phase 3 REVEAL-ND NPM1 trial (NCT07211958).⁸

Ziftomenib

Ziftomenib is the second FDA-approved menin inhibitor; it is indicated for adult patients with relapsed/refractory AML with NPM1mt. Ziftomenib is available in 200-mg capsules. The recommended dose is 600 mg daily; patients take 3 capsules once daily on an empty stomach, at least 1 hour before or 2 hours after a meal. Patients should avoid concomitant use of proton pump inhibitors (PPIs), as PPIs result in reduced ziftomenib exposure. Histamine-2 receptor antagonists may be given, but ziftomenib should be given 2 hours before or 10 hours after histamine-2 receptor antagonist administration. Locally acting antacids (eg, calcium carbonate) can be administered, but ziftomenib must be administered 2 hours before or after their administration. DS occurred in 26% of patients in the clinical trial and was fatal in 2. Therapy should not be initiated in patients with a WBC count greater than 25 x 10⁹/L. QTc prolongation is also a risk with ziftomenib; electrolyte abnormalities should be corrected, and an electrocardiogram (ECG) should be performed before initiation. Therapy should be initiated only if QTcF is less than 480 milliseconds. An ECG should then be completed once weekly for the first 4 weeks of treatment and monthly thereafter. Interrupt therapy for a QTc interval greater than 500 milliseconds or a change of more than 60 milliseconds from baseline. Ziftomenib is primarily metabolized by CYP3A, and concomitant use with strong or moderate CYP3A4 inhibitors may increase AEs, including QTc prolongation, but no dose adjustments are required. Use with strong or moderate CYP3A4 inducers should be avoided.⁹

KOMET-001 (NCT04067336) was a pivotal phase II trial evaluating ziftomenib in adults with relapsed/refractory NPM1mt AML. Ninety-two patients were evaluated in the phase II portion of the study; ziftomenib was administered at 600 mg daily. The primary end point of CR/CRh was met by 22% of participants; the median time to CR/CRh was 2.8 months (range, 1-15 months), and the median duration was 3.7 months (range, 1.9-7.4 months). Grade 3 or higher treatment-emergent AEs occurring in more than 10% of participants included febrile neutropenia, anemia, thrombocytopenia, DS, neutropenia, pneumonia, and hypokalemia.¹⁰

Ziftomenib is being investigated in combination-based treatment approaches across both relapsed/refractory and newly diagnosed NPM1mt AML. KOMET-007 (NCT05735184) is a phase 1 trial that investigated the combination of ziftomenib, azacitidine and venetoclax; 40 patients were included in the phase 1b arm and received ziftomenib 600 mg daily with standard doses of venetoclax/azacitidine. Composite complete remission occurred in 46%, with 67% achieving MRD negativity.¹¹ Additional studies are ongoing to further evaluate the role of ziftomenib in combination therapy.

JNJ-75276617

JNJ-75276617 (bleximenib; Johnson & Johnson) is an investigational menin inhibitor that has shown promising results in combination with venetoclax and azacitidine in newly diagnosed or relapsed/refractory patients with KMT2Amt or NPM1mt AML who were ineligible for intensive chemotherapy. Blenrep dosing ranged from 50 to 150 mg every 12 hours in relapsed/refractory patients and 50 to 100 mg twice daily in those who were newly diagnosed. Overall response rate (ORR) was evaluated in both populations; in relapsed/refractory patients, it was higher in the 100-mg twice-daily group than in the 50-mg twice-daily group (79% vs 76%), with no further improvement observed in the 150-mg twice-daily group. Similar results were seen in newly diagnosed patients, with higher rates of ORR in those who received 100 mg twice daily than 50 mg twice daily (92% vs 77%). Treatment-emergent AEs that occurred most commonly included nausea, thrombocytopenia, and anemia. DS occurred in 4% of participants, and QTc prolongation was not reported.¹² Studies for bleximenib are ongoing. cAMeLot-1 (NCT04811560) is an ongoing phase 1/2 trial that will seek to evaluate the safety and efficacy of bleximenib in participants with acute leukemia.

Supportive Care

Supportive care is a critical component in the management of patients receiving menin inhibitors and is essential for optimizing treatment outcomes. Pharmacists play a unique role within the interprofessional health care team by proactively identifying, preventing, and managing treatment-related toxicities, educating patients, and coordinating care to help maximize treatment success.

Differentiation Syndrome

The incidence of DS was 4% to 26% among menin inhibitors. Therapy should not be initiated for patients with a white blood cell (WBC) count greater than 25 x 10⁹/L. Patients should be educated on the signs and symptoms of DS, including fever, rapid weight gain, shortness of breath and edema. Oral or intravenous corticosteroids should be initiated if DS is suspected, in addition to supportive care measures. For revumenib, therapy should be held if severe signs and symptoms of DS persist after at least 48 hours of systemic corticosteroids and resumed at the same dosing level once symptoms are grade 1 or lower.² Ziftomenib should be held if DS is suspected and resumed at the same dose level once symptoms are grade 2 or lower.^4,9

QTc Prolongation

Both FDA-approved menin inhibitors carry a risk of QTc prolongation; therapy should not be initiated in patients with a QTc interval greater than 450 milliseconds for revumenib and greater than 480 milliseconds for ziftomenib. Any electrolyte abnormalities, including hypokalemia and hypomagnesemia, should be corrected; electrolytes should be monitored periodically and repleted as indicated. If the QTc interval exceeds 480 milliseconds and is less than 500 milliseconds while taking revumenib, therapy should be held and reinitiated at the same dose level once the QTc interval is less than or equal to 480 milliseconds. If during therapy, the QTc interval exceeds 500 milliseconds or is greater than 60 milliseconds from baseline, hold revumenib therapy and restart at 1 dose level lower when the QTc interval is less than or equal to 480 milliseconds. Therapy with ziftomenib should also be held if the QTc interval exceeds 500 milliseconds or increases by more than 60 milliseconds from baseline, and resumed once grade 2 or lower. ECG monitoring should be performed at baseline, weekly for the first 4 weeks and monthly thereafter.^4,9

Infection

Grade 3 or higher infections, including bacterial, viral and unidentified pathogens, occurred in 17% vs 18%, 6% vs 5% and 30% vs 38% with revumenib and ziftomenib, respectively. Consideration for anti-infective therapy, including antibiotics, antifungals and antivirals, should be evaluated. Keep in mind that revumenib requires a dose adjustment when used in combination with a strong CYP3A4i. Although ziftomenib doesn’t require dose adjustments when used concomitantly with a strong or moderate CYP3A4i, additional monitoring may be warranted due to the risk of increased AEs.^4,9

Administration

Revumenib should be administered on an empty stomach or with a low-fat meal. If patients are unable to take the tablet whole, revumenib may be crushed and dispersed in 10 mL of room-temperature water. The preparation should be drawn up in a 20-mL syringe and taken within 2 hours.⁴

Ziftomenib is also administered on an empty stomach, 1 hour before or 2 hours after a meal. Capsules should be swallowed whole and cannot be broken, opened or chewed. Coadministration with a PPI should be avoided, and if administered with an antacid or histamine-2 receptor antagonists, dosing should be appropriately separated.⁹

Conclusion

Menin inhibitors have transformed the treatment landscape for patients with NPM1mt AML by providing the first targeted therapeutic options for this molecular subtype. Ongoing clinical studies continue to evaluate these agents across additional treatment settings, including combination regimens and frontline therapy, to further improve patient outcomes. As the use of menin inhibitors expands, pharmacists play an integral role within the multidisciplinary health care team by facilitating monitoring of AEs, implementing supportive care strategies, and optimizing treatment adherence to promote the safe and effective delivery of therapy.

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