Pharmacy Logistics, Emerging Safety and Efficacy Data, and Future Directions for Menin Inhibitors in Acute Leukemias

Despite recent advances in targeted therapies, certain subsets of acute leukemias (ALs), such as those driven by KMT2A rearrangements (also known as MLL1) or NPM1 high-risk mutations, remain challenging to manage, especially in relapsed or refractory (R/R) settings.^1,2 KMT2A rearrangements are rare in adult patients, occurring in approximately 3% of newly diagnosed acute myeloid leukemia (AML) cases.³ Contrarily, in pediatric patients diagnosed with AML, KMT2A rearrangements are more common, with a global incidence of 55% for infants and 11% for children and adolescents.⁴ NPM1 mutations occur more commonly than KMT2A rearrangements and are found in approximately 30% of AML cases.⁵ Given the historic lack of targeted treatment options for these patients, this is a promising area for novel drug development.

Menin inhibitors provide a new targeted therapy option for patients with ALs. They disrupt the interaction between menin, a protein involved in myeloid proliferation, and KMT2A, an oncogene involved in hematopoiesis.^6-8 When KMT2A fusion proteins bind with menin, leukemogenic transcriptional pathways are activated, leading to the development and proliferation of leukemic cells; this is a known mechanism of leukemia development.

On November 15, 2024, the FDA approved revumenib (Revuforj; Syndax Pharmaceuticals, Inc), a first-in-class menin inhibitor, for patients 1 year and older with R/R AL with a KMT2A translocation.⁹ On October 24, 2025, revumenib also became the first agent approved for patients 1 year and older with R/R AML with a susceptible NPM1 mutation who have no satisfactory alternative treatment options.¹⁰ Shortly after, on November 13, 2025, ziftomenib (Komzifti; Kura Oncology, Inc) was similarly approved for adults with R/R AML with a susceptible NPM1 mutation who have no satisfactory alternative treatment options.¹¹

Other menin inhibitors under investigation in clinical trials include bleximenib (JNJ-75276617; Johnson & Johnson) and enzomenib (DSP-5336; Sumitomo Pharma). The anticipated upcoming approval of several agents in the menin inhibitor class suggests a potential paradigm shift for the treatment of patients with high-risk leukemias.^12-14 As these agents become increasingly used in practice, it is important for oncology pharmacists to learn how to optimize care and support patients receiving them.

Menin Inhibitors Logistics

At the time of writing, published prescribing information is only available for revumenib and ziftomenib.^15,16 Practical considerations regarding dosage, drug-drug interactions (DDIs), and hold and monitoring parameters are summarized in Table 1.^15,16 Details regarding the administration of bleximenib and enzomenib, and the management of their adverse effects, are limited to clinical trial protocols.

The recommended phase 2 dose (RP2D) for bleximenib monotherapy is 100 mg twice daily following a step-up dose of 50 mg twice daily.¹⁷ This dose was selected based on similar overall response rates (ORRs) compared with the 150-mg twice-daily regimen, but with a more favorable safety profile.¹⁷ Information about CYP3A4 interactions with bleximenib is still emerging.

The RP2D for enzomenib has not been established. However, results from a phase 1/2 study (NCT04988555) demonstrated encouraging activity in patients with R/R KMT2A rearrangements or NPM1-mutated AL at doses of 140 to 300 mg twice daily. Furthermore, current data suggest that azole coadministration does not significantly alter enzomenib exposure.¹⁸

Emerging Efficacy and Safety Data

Clinical trial protocols with emerging results are summarized in Table 2.

Revumenib

Revumenib’s approval was based on positive data from AUGMENT-101 (NCT04065399), a phase 1/2, open-label, dose-escalation and expansion study in heavily pretreated patients with R/R leukemias with KMT2A rearrangements or NPM1 mutations. In the efficacy-evaluable population with KMT2A rearrangements (n = 57), the complete remission and complete remission with partial hematologic recovery (CR/CRh) rate was 22.8%, with a median duration of 6.4 months. Among patients who achieved a response, 14 (38.9%) underwent allogeneic hematopoietic stem cell transplant.¹⁹

Adverse effects (AEs) of interest include QTc prolongation and differentiation syndrome (DS). Asymptomatic prolongation of the QT interval was the only dose-limiting toxicity, although no patients discontinued revumenib due to QTc prolongation. QTc prolongation occurred in 25.5% of patients, with 13.8% at grade 3 and no grade 4 occurrences. Because targeting the menin-KMT2A axis inhibits blast proliferation and promotes cellular differentiation, DS remains an AE of interest across the menin inhibitor class. In the safety population of KMT2A-rearrangement AL, any-grade DS was observed in 27.7% of patients, with grade 3 or higher DS in 16.0%. All cases were treated with steroids and hydroxyurea, and there were no discontinuations. The most common AEs were nausea (44.7%), febrile neutropenia (FN; 38.3%), and diarrhea (35.1%). The most common AEs grade 3 or higher were FN (37.2%), neutropenia (28.7%), and thrombocytopenia (21.3%). The data support promising results with a manageable safety profile.¹⁹

Revumenib was also the first menin inhibitor approved for patients with AML harboring NPM1 mutations, based on results from the AUGMENT-101 trial. Main efficacy outcomes included a CR/CRh rate of 23.1%, with a median duration of 4.5 months, and a 17% rate of transfusion independence in patients previously dependent on red blood cell (RBC) and/or platelet transfusions during any 56-day postbaseline period.¹⁰ Treatment-emergent DS occurred in 16 patients (19.0%), with 13.1% at grade 3 or higher. The median time to onset was 10 days (range, 4-34), and the median duration of the initial event was 14.5 days (range, 3-57). Treatment-emergent QTc prolongation occurred in 42.9% of patients, with 22.6% at grade 3 or higher. The median time to onset was 8 days (range, 1-84), and the median duration of the initial event was 4 days (range, 1-14).²⁰

Revumenib is also being studied as a combination therapy in both R/R and newly diagnosed settings. In R/R AML or myeloid mixed-lineage AL, revumenib is being studied in combination with decitabine/cedazuridine (Inqovi; Taiho Oncology, Inc) and venetoclax (Venclexta; AbbVie Inc) as an all-oral option in patients 12 years and older.²¹ Dual BCL-2 and menin inhibition led to synergistic activity in models for KMT2A rearrangements or NPM1-mutation leukemias, which are highly susceptible to induction of apoptosis by BCL-2 inhibition. Data updates from the 2024 American Society of Hematology Annual Meeting and Exposition showed a CR/CRh rate of 58% (15/26), a measurable residual disease (MRD) negativity rate among patients with CR/CRh of 93% (13/14 patients), and a 6-month overall survival (OS) rate of 74%. Twelve patients (46%) proceeded to transplant.²¹

Lastly, in newly diagnosed patients, revumenib is being studied in combination with venetoclax and azacitidine (Vidaza; Bristol Myers Squibb) in patients 60 years and older with AML and mNPM1 mutations or KMT2A rearrangements.²¹ As of a November 2024 data cutoff, the rate of composite complete remission (CRc) was 95% (35/37), the MRD-negativity rate was 95% (35/37), and 27% of patients (10/37) proceeded to transplant.²³

Ziftomenib

Based on results from the phase 1/2 KOMET-001 (NCT04067336) trial, ziftomenib was approved in November 2025 for adults with R/R AML with a susceptible NPM1 mutation who have no satisfactory alternative treatment options. With a median follow-up of 4.2 months, the CR/CRh rate was 21.4%, with a CR/CRh duration of 5 months. Among the patients dependent on RBC or platelet transfusions at baseline, 21.2% became independent during any 56-day postbaseline period. Ziftomenib-related QTc prolongation was observed in 3 patients, all of whom were taking other medications known to prolong QTc. Differentiation syndrome occurred in 25% of patients, of whom 15% had grade 3 events (no grade 4 or 5). The most common grade 3 or higher treatment-emergent AEs were febrile neutropenia (26%), anemia (20%), and thrombocytopenia (20%).²⁴

Ziftomenib is also being studied in combination with standard-of-care therapies in both ND and R/R AML in the phase 1 KOMET-007 trial (NCT05735184). In patients with newly diagnosed AML, interim phase 1a results of ziftomenib in combination with cytarabine and daunorubicin showed the most common grade 3 or higher treatment-emergent AEs as FN and cytopenias. At the 200-mg and 400-mg doses, there were no cases of DS, ziftomenib-associated QTc prolongation, or dose-limiting toxicities. No additional ziftomenib-related myelosuppression was observed with the combination. Of the 33 evaluable patients, CRc rates for those with NPM1 mutations (n = 15) were 100% (8/8) at 200 mg and 86% (6/7) at 400 mg. For those with KMT2A rearrangements, CRc rates were 90% (9/10) at 200 mg and 63% (5/8) at 400 mg.²⁵

In R/R AML, interim phase 1a results of ziftomenib in combination with azacitidine and venetoclax included 74% of patients (25/34) who were menin inhibitor naive, 68% (17/25) of whom had prior venetoclax exposure. In those with NPM1 mutations, CRc rates were 80% (4/5) at 200 mg and 50% (3/6) at 400 mg. In patients with KMT2A rearrangements, CRc rates were 29% (2/7) at 200 mg and 17% (1/6) at 400 mg. No dose-limiting toxicities or ziftomenib-related QTc prolongation were reported, and all cases of DS (12%) were manageable per DS guidance.²⁶ These data support robust clinical outcomes and consistent and manageable safety profiles of ziftomenib. Emerging safety profiles from these 3 trials are listed in Table 3.^{16-21,23-25,27}

Bleximenib

Bleximenib is under investigation in early-phase clinical trials. This agent is being studied in patients with AL and KMT2A rearrangements and/or NPM1 mutations, in the newly diagnosed and R/R settings. The cAMeLot-1 trial (NCT04811560) is an ongoing phase 1/2 dose-escalation and expansion study evaluating beximenib monotherapy in adult patients with R/R KMT2A rearrangements or NPM1-altered AL.²⁷ A phase 2 study evaluating the efficacy of bleximenib monotherapy in R/R KMT2A rearrangement or NPM1-mutated AML is planned once the recommended phase 2 dose of bleximenib is identified.

Bleximenib is also being studied in combination with other AML-directed therapies in an ongoing phase 1 trial (NCT05453903).²⁸ In the phase 1b portion of this trial, newly diagnosed patients with AML received bleximenib in combination with intensive cytarabine and daunorubicin or idarubicin (the 7 + 3 regimen). This regimen demonstrated an ORR of 93%, with a median time to CR of 30 days. Two episodes of grade 1 QTc prolongation not related to bleximenib were reported.²⁸

In patients unfit for intensive chemotherapy, bleximenib in combination with azacitidine and venetoclax demonstrated preliminary antileukemic efficacy and an acceptable safety profile.²⁹ Bleximenib was evaluated at multiple dose levels, with 100 mg twice daily demonstrating higher efficacy and a safety profile comparable to that of other dose levels. Patients with R/R achieved an ORR of 82%. The ORR among newly diagnosed patients was 90%.³⁰

Finally, the phase 3 cAMeLot-2 study (NCT06852222) is investigating bleximenib combined with venetoclax and azacitidine in adult patients with newly diagnosed AML with KMT2A rearrangements or NPM1 mutations who are ineligible for intensive chemotherapy.³¹

Enzomenib

Enzomenib is in an early phase of study. This agent is designed to minimize off-target toxicity by having low lipophilicity and basicity. A phase 1/2 dose escalation and expansion study (NCT04988555) is evaluating enzomenib in adult patients with R/R AL with KMT2A rearrangements, NPM1 mutations, and/or other HOXA9/MEIS1 leukemia-driven subsets.¹⁸ Enzomenib is being studied with and without strong CYP3A4 inhibitor azole antifungals to assess for significant DDIs. Thirty-five patients were treated with enzomenib at doses of 140 mg or greater twice daily. The ORR for 22 patients with KMT2A rearrangement leukemia was 59.1%. Of the 13 patients with NPM1-mutated AML, the ORR was 53.8%. In addition, no significant impact on enzomenib exposure was observed when combined with azole antifungals. There were no reports of grade 3 or higher QTc prolongation events related to enzomenib. Possible DS was reported in 11.1% of patients.¹⁸

Menin Inhibitors in Pediatric Populations

The role of menin inhibitors in pediatric cancers is an emerging field offering a promising treatment option. Pediatric cancers often exhibit specific genetic and epigenetic features, making targeted therapies beneficial. Menin inhibitors have potential in mixed-lineage leukemias. Patients with KMT2A-rearrangement leukemias are at risk of resistance to standard therapies and higher relapse rates, so directed therapy with menin inhibitors provides a promising alternative.

The AUGMENT-101 trial assessed the efficacy and safety of revumenib in adults and pediatric patients with this condition and had promising outcomes.¹⁹ The efficacy population included 13 pediatric patients, of whom 5 achieved complete remission. Other menin inhibitors are still being researched in pediatrics. Bleximenib in vitro studies used pediatric cell lines to assess activity.²⁷ Ziftomenib is being studied in a phase 1, single-center trial (NCT06397027) in combination with venetoclax and azacitidine.³² As further data are released, the availability of treatment options for children will expand.

Future Directions

Resistance to anticancer therapies, like drug resistance in other settings, occurs when the disease becomes tolerant to pharmacotherapies. In this case, the cancer cells develop ways to evade the drug’s effect, which can lead to treatment failure. Multiple possible mechanisms are noted for resistance, including increased inhibition of apoptosis, drug inactivation, alterations to the drug target, and changes to the cancer cell either intrinsically via mutations or extrinsically due to changes in the microenvironment.^33,34

Menin is a key regulator of gene expression and plays an essential role in various cellular processes, such as differentiation, proliferation, and survival. In cancers such as AL, mutations in the MLL family can lead to proteins that engage menin. Menin inhibitors disrupt this menin-MLL interaction. However, resistance to menin inhibitors has been reported. One such mechanism of resistance that has been investigated is due to changes in the menin protein caused by mutations in MEN1. These structural alterations to the menin-binding site on the protein can reduce the affinity of menin inhibitors for their target, leading to treatment failure. For example, several patients previously treated with revumenib were found to have MEN1 mutations after initial successful treatment that were not detected prior to treatment. Further investigation confirmed that, after approximately 2 cycles of revumenib, MEN1 mutations were detected.³⁵

Cancer cells can also develop resistance by activating compensatory signaling pathways, therefore bypassing the menin-MLL interaction.³⁵ Some strategies that could help overcome this resistance to menin inhibitors include the development of newer-generation menin inhibitors that may have a higher potency or the ability to target mutations to MEN1. For example, emerging data show that bleximenib has a unique binding mode that allows it to retain antiproliferative activity in the presence of common MEN1 resistance mutations.³⁶ Additionally, combination therapies are being explored as multidrug treatments that may help counteract resistance and provide synergistic benefit. For example, bleximenib in vitro has shown improved effects in combination with gilteritinib (Xospata; Astellas Pharma US, Inc), as well as with venetoclax and azacitidine.²⁷

Furthermore, menin inhibitors are being explored in combination with chemotherapy and other targeted therapies in both the newly diagnosed and R/R settings. The phase 1 AUGMENT-102 trial (NCT05326516) is studying revumenib in combination with fludarabine/cytarabine in patients with R/R AML with NPM1 mutations, KMT2A rearrangements, or NUP98 rearrangements.³⁷ The phase 1 KOMET-008 trial (NCT06001788) will study ziftomenib plus fludarabine, cytarabine, idarubicin, and granulocyte colony-stimulating factor or low-dose ara-C/cytarabine chemotherapy in patients with NPM1 mutations or KMT2A rearrangement in R/R AML, as well as ziftomenib plus gilteritinib in patients with NPM1 mutations and FLT3-mutated R/R AML.⁴ Finally, it is believed that menin inhibitors may have a synergistic effect with other targeted agents, such as venetoclax and FLT3 inhibitors, and future studies may involve studying combinations of menin inhibitors with various targeted agents in AML.

Menin inhibitors remain an exciting and expanding therapeutic area of AL in both pediatric and adult populations, with significant clinical data promising additional treatment options. The approvals of revumenib and ziftomenib, and preliminary clinical data for additional menin inhibitors, support the notion that disrupting menin’s interactions with the KMT2A complex offers a novel approach in a challenging area of AL management. Notable toxicities include cytopenias, QTc prolongation, and DS, but these appear to be manageable, with menin inhibitors avoiding major off-target effects. As the menin portfolio grows in both indications and agents, it is important to organize the distinguishing differences among the available options. Notable examples include revumenib’s black box warning for QTc prolongation and dose reductions for strong CYP3A4 inhibitors, which are absent with ziftomenib. In contrast, ziftomenib has drug interactions with acid-reducing agents, which are absent with revumenib. Additionally, revumenib is unique in that it can be crushed and is approved for patients 1 year and older. The clinical application of these agents is expected to grow, both as monotherapy and in combination, especially as data emerge on overcoming resistance and on potential synergies when used in combination.

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