The U.S. Food and Drug Administration (FDA) has approved revumenib (Revuforj) for the treatment of adult and pediatric patients, one year and older, with relapsed or refractory acute leukemia harboring a lysine methyltransferase 2A (KMT2A) gene translocation. This marks a significant advancement as revumenib is the first menin inhibitor to receive FDA approval.
Supporting Clinical Data
The approval was based on data from the Phase I/II AUGMENT-101 trial, an open-label, multicenter study. The trial evaluated single-agent revumenib in 104 children and adults with previously treated acute leukemia associated with KMT2A rearrangements. The primary endpoint was complete response (CR) with or without hematologic recovery.
The data showed a complete response rate of 21.2%, with a median response duration of 6.4 months. Furthermore, 12 out of 83 transfusion-dependent patients achieved freedom from red blood cell or platelet transfusions. Among 21 patients who were transfusion independent at baseline, 10 (48%) maintained that status during any 56-day period.
Clinical Significance
"The FDA approval of the first menin inhibitor is a major breakthrough for patients with [relapsed/refractory] acute leukemia with a KMT2A translocation, a genetic alteration associated with a very poor prognosis," said Ghayas C. Issa, MD, of the University of Texas MD Anderson Cancer Center. He further emphasized that the efficacy seen with Revuforj represents a substantial improvement over historical outcomes with available therapies.
Ibrahim Aldoss, MD, of City of Hope in Duarte, California, noted that "after achieving response, 40% of responders were able to go to allogeneic stem cell transplant, which is really our ultimate goal for someone with relapsed/refractory leukemia."
Mechanism of Action
Revuforj functions by interfering with the interaction between menin, a scaffold protein, and histone-lysine N-methyltransferase 2A, a protein encoded by the KMT2A gene. Alterations in the KMT2A gene can lead to the production of leukemia cells. Menin inhibitors bind to menin, halting this process and promoting the production of normal cells.
Adverse Reactions
Common adverse reactions (≥20%) included hemorrhage, nausea, increased phosphate, musculoskeletal pain, infection, increased aspartate aminotransferase, febrile neutropenia, increased alanine aminotransferase, increased intact parathyroid hormone, bacterial infection, diarrhea, differentiation syndrome, electrocardiogram QT prolonged, decreased phosphate, increased triglycerides, decreased potassium, decreased appetite, constipation, edema, viral infection, and fatigue.
Dosing and Availability
The recommended dose of revumenib is 270 mg orally twice a day for patients weighing 40 kg or more who are not receiving strong CYP3A4 inhibitors. For patients weighing less than 40 kg not receiving strong CYP3A4 inhibitors, the recommended dose is based on body surface area and is 160 mg/m2 given orally twice a day. Dosing adjustments are necessary for patients also taking strong CYP3A4 inhibitors.
The 110 mg and 160 mg Revuforj tablets are currently available through specialty distributors and pharmacies, with a monthly cost of approximately $39,500. The 25 mg tablets, intended for patients weighing less than 88 pounds, will be available in late Q1 or early Q2 2025. Until then, an oral solution will be accessible through an expanded access program.
