Syndax Pharmaceuticals today announced that the U.S. Food and Drug Administration (FDA) has approved Revuforj® (revumenib) for the treatment of relapsed or refractory (R/R) acute leukemia with a lysine methyltransferase 2A gene (KMT2A) translocation in adult and pediatric patients one year and older. This marks the first and only menin inhibitor to receive FDA approval for this indication. The FDA had previously granted Breakthrough Therapy and Fast Track designations, as well as Priority Review for Revuforj, and the approval was processed through the FDA's Real Time Oncology Review (RTOR) program.
Clinical Efficacy and Safety
The approval of Revuforj was based on data from the Phase 1/2 AUGMENT-101 trial, which evaluated the efficacy of Revuforj in 104 patients with R/R acute leukemia with a KMT2A translocation. The study demonstrated a complete remission (CR) plus CR with partial hematological recovery (CRh) rate of 21% (22/104 patients; 95% CI: 13.8%, 30.3%). The median duration of CR+CRh was 6.4 months (95% CI: 2.7, not estimable), and the median time to CR or CRh was 1.9 months (range: 0.9, 5.6 months). Notably, 23% (24/104) of patients underwent hematopoietic stem cell transplantation (HSCT) following treatment with Revuforj.
The safety evaluation was based on 135 patients with R/R acute leukemia with a KMT2A translocation. Common adverse reactions (≥20%) included hemorrhage (53%), nausea (51%), and increased phosphate (50%). Serious adverse reactions were reported in 73% of patients, with infection (24%), febrile neutropenia (19%), and bacterial infection (17%) being the most frequent. Differentiation syndrome, a potentially fatal condition, occurred in 29% of patients.
Expert Commentary
Ghayas C. Issa, M.D., Associate Professor of Leukemia at The University of Texas MD Anderson Cancer Center, stated, "The FDA approval of the first menin inhibitor is a major breakthrough for patients with R/R acute leukemia with a KMT2A translocation, a genetic alteration associated with a very poor prognosis. The significant clinical benefit and robust efficacy seen with Revuforj represents a substantial improvement over what has been historically observed in these patients with previously available therapies and has the potential to be an important new treatment option for patients."
Disease Context and Unmet Need
Rearrangements of the KMT2A gene (KMT2Ar) are associated with an aggressive form of acute leukemia, characterized by poor prognosis and high relapse rates. It is estimated that over 95% of patients with KMT2Ar acute leukemia have a KMT2A translocation. More than half of these patients relapse after conventional frontline therapies, with a median overall survival (OS) of less than one year. In third-line treatment or beyond, only 5% of patients achieve complete remission, and the median OS is less than three months.
Dosing and Availability
Syndax anticipates that Revuforj will be available for order in the United States this month through a network of specialty distributors and pharmacies. The available tablet strengths will be 110 mg and 160 mg. The 25 mg tablets, intended for patients weighing less than 40 kg, are expected to be available in late first quarter or early second quarter of 2025. An oral solution of revumenib will be accessible through an expanded access program for these smaller patients until the 25 mg tablets are commercially available.
Warnings and Precautions
Revuforj carries a boxed warning for differentiation syndrome, which can be fatal. Symptoms may include fever, dyspnea, hypoxia, pulmonary infiltrates, pleural or pericardial effusions, rapid weight gain or peripheral edema, hypotension, and renal dysfunction. The white blood cell count should be reduced to less than 25 Gi/L prior to starting Revuforj. If differentiation syndrome is suspected, immediate corticosteroid therapy and hemodynamic monitoring are required.
QTc interval prolongation is another significant risk, with 29% of patients in clinical trials experiencing this adverse reaction. ECG monitoring is recommended, and concomitant use with QTc-prolonging drugs should be avoided. Revuforj is also associated with embryo-fetal toxicity, necessitating effective contraception during treatment and for 4 months after the last dose.
