By William Elliott, MD, FACP, and James Chan, PharmD, PhD
The U.S. Food and Drug Administration has approved the first menin inhibitor, revumenib, for the treatment of relapsing or refractory acute leukemia with a lysine methyltransferase 2A (KMT2A) gene (also known as the mixed lineage leukemia [MLL] gene) translocation in adults and pediatric patients.
Revumenib is a selective, orally active drug that blocks menin KMT2A interaction. Its review used the Real-Time Oncology Review, which streamlined data submission prior to filing of the clinical application.1 Revumenib was granted a priority review as well as breakthrough and orphan designations. It is distributed by Syndax Pharmaceuticals, Inc as Revuforj.
Indications
Revumenib is indicated for the treatment of relapsed or refractory acute leukemia with KMT2A translocation in adult and pediatric patients 1 year of age and older.2
Dosage
The recommended dose is based on patient weight and concomitant use of strong CYP3A4 inhibitors.2 For those weighing 40 kg or more, the dose is 270 mg orally twice daily. Patients weighing less than 40 kg should receive 160 mg/m2 twice daily. Revumenib is administered until there is disease progression, unacceptable toxicity, failure to achieve morphological leukemia-free state by four cycles of treatment, or the patient receives a hematopoietic stem cell transplantation.
Patients without disease progression or unacceptable toxicity should be treated for a minimum of six months to allow time for clinical response. The emergence of differentiation syndrome and QTc interval prolongation requires interruption of revumenib treatment.2
Concurrent use of standard intrathecal chemotherapy prophylaxis is recommended for patients with risk of central nervous system relapse.1 Concomitant use of strong or moderate CYP3A4 inducers are not recommended because they will result in reduced systemic expose of revumenib with increased exposure to the active metabolites (M1) that may prolong QTc.2 Revumenib is available as 25-mg, 110-mg, and 160-mg tablets.
Potential Advantages
Revumenib is the first menin inhibitor specifically for the treatment of relapsed or refractory acute leukemia with KMT2A translocation.
Potential Disadvantages
Most frequent adverse reactions (> 25%) include differentiation syndrome, QTc interval prolongation, hemorrhage, musculoskeletal pain, infection, febrile neutropenia, elevated phosphate levels, and elevation of liver enzymes (alanine transaminase, aspartate transaminase). Based on animal data, revumenib can cause embryo-fetal toxicity. Female patients of reproductive potential as well as male partners should use effective contraception. Patients with acquired resistance to menin inhibition have been reported.3
Comments
Translocation is a form of genetic rearrangement where a piece of a chromosome breaks off and attaches to another chromosome, creating a new combination of aberrant genetic material. Translocation of KMT2A (KMR2Ar) results in upregulation of critical leukemogenic target genes (e.g., HOX, MEIS1) and acute leukemia. Menin is a critical oncogenic cofactor in the pathogenesis of KMT2Ar leukemia.4,5 Inhibition of menin down regulates these genes and blocks leukamogenesis.
The efficacy of revumenib was evaluated in a single-arm, open-label study in adult and pediatric participants (n = 104) with relapsed or refractory acute leukemia with KMT2A translocation.2,4 Study participants had a median age of 37 years (interquartile range [1,79]), 64% were female, and 72% were white. Of the participants, 83% had acute myeloid leukemia (AML), 15% had acute lymphoblastic leukemia (ALL), 2% had mixed phenotype acute leukemia (MPAL), and 59% had refractory relapse disease. Forty-four percent had prior stem cell transplantation.
Treatment with revumenib was continued until lack of response after up to four cycles, disease progression, unacceptable toxicity, or withdrawal of consent. The primary efficacy endpoints were the rate of complete remission (CR) plus CR with partial hematologic recovery (CR+CRh), the duration of CR+CRh, and the rate of conversion from transfusion dependence to transfusion independence. The median follow-up was 5.73 months (range, 0.3 to 26.9 months). CR+CRh was achieved in 21% of patients with AML, 19% with ALL, and 50% with MPAL. For those who achieved CR+CRh, the median time to achievement was 1.9 months (range, 0.9, 5.6 months). The median duration of CR+CRh was 6.4 months. Fourteen percent (12 of 84) who were dependent on red blood cell (RBC) and/or platelet transfusion became independent of RBC and platelet transfusion during any 56-day postbaseline period. Twenty-three percent of participants underwent hematopoietic stem cell transplantations.
Clinical Implications
The prognosis of acute leukemias that harbor rearrangement of the gene (KMT2Ar) is poor, with a < 25% five-year survival rate.4 KMT2Ar occurs in 80% of infant ALL patients and 5% to 15% of children and adults with acute leukemia (AML, ALL, or MPAL). There is no standard treatment for refractory or recurrent AML, but treatment generally includes combination chemotherapy, targeted therapy, and stem cell transplant using donor stem cells.6 Revumenib is the first targeted treatment option for adult and pediatric patients with KMT2A translocation. The cost for revumenib is $658 per tablet regardless of the strength. Therefore, for ≥ 40 kg patients (270 mg [160 mg tablet + 110 mg tablet]), the cost for twice daily tablets would be $2,632 per day.
References
- U.S. Food and Drug Administration. FDA approves revumenib for relapsed or refractory acute leukemia with a KMT2A translocation. Nov. 15, 2024. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-revumenib-relapsed-or-refractory-acute-leukemia-kmt2a-translocation
- Syndax Pharmaceuticals, Inc. Revuforj prescribing information. Revised November 2024. https://www.accessdata.fda.gov/drugsatfda_docs/label/2024/218944s000lbl.pdf
- Perner F, Stein EM, Wenge DV, et al. MEN1 mutations mediate clinical resistance to menin inhibition. Nature. 2023;615(7954):913-919.
- Issa GC, Aldoss I, Thirman MH, et al. Menin inhibition with revumenib for KMT2A-rearranged relapsed or refractory acute leukemia (AUGMENT-101). J Clin Oncol. 2025;43(1):75-84.
- Dempke WCM, Desole M, Chiusolo P, et al. Targeting the undruggable: Menin inhibitors ante portas. J Cancer Res Clin Oncol. 2023;149(11):9451-9459.
- American Cancer Society. Chemotherapy for acute myeloid leukemia (AML). Revised June 5, 2024. https://www.cancer.org/cancer/types/acute-myeloid-leukemia/treating/chemotherapy.html
The U.S. Food and Drug Administration has approved the first menin inhibitor, revumenib, for the treatment of relapsing or refractory acute leukemia with a lysine methyltransferase 2A gene (also known as the mixed lineage leukemia gene) translocation in adults and pediatric patients.
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