Syndax Pharmaceuticals announced that the U.S. Food and Drug Administration (FDA) has approved Revuforj® (revumenib) for the treatment of adult and pediatric patients (one year and older) with relapsed or refractory acute leukemia harboring a lysine methyltransferase 2A (KMT2A) translocation. This marks a significant advancement as Revuforj is the first and only menin inhibitor to receive FDA approval for this indication.
The approval was based on the Phase 1/2 AUGMENT-101 trial, which evaluated the efficacy of Revuforj in 104 patients with relapsed or refractory acute leukemia with a KMT2A translocation. The study demonstrated a complete remission (CR) or complete remission 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). Furthermore, 23% (24/104) of patients underwent hematopoietic stem cell transplantation (HSCT) following Revuforj treatment.
Clinical Impact and 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."
Understanding KMT2A-Rearranged Acute Leukemia
Rearrangements of the KMT2A gene (KMT2Ar) result in an aggressive form of acute leukemia associated with poor prognosis and high relapse rates. It is estimated that over 95% of patients with KMT2Ar acute leukemia have a KMT2A translocation. In these leukemias, the binding of KMT2A fusion proteins with menin drives the activation of a leukemogenic transcriptional pathway. Inhibiting the menin-KMT2A interaction alters the transcription of multiple genes, including differentiation markers.
Safety Profile and Adverse Reactions
The safety evaluation of Revuforj was based on an analysis of 135 patients with relapsed or refractory acute leukemia with a KMT2A translocation. Common adverse reactions (≥20%) included hemorrhage, nausea, increased phosphate levels, musculoskeletal pain, infection, increased aspartate aminotransferase, febrile neutropenia, increased alanine aminotransferase, increased parathyroid hormone, bacterial infection, diarrhea, differentiation syndrome, prolonged electrocardiogram QT interval, decreased phosphate levels, increased triglycerides, decreased potassium levels, decreased appetite, constipation, edema, viral infection, and fatigue. Adverse reactions leading to dose reduction or permanent discontinuation were reported in 10% and 12% of patients, respectively.
Differentiation Syndrome Warning: 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. Immediate corticosteroid therapy and hemodynamic monitoring are required if differentiation syndrome is suspected.
Availability and Support
Syndax anticipates that the 110 and 160 mg tablets of Revuforj will be available for order in the United States through a network of specialty distributors and pharmacies in November. 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 available through an expanded access program for dosing patients under 40 kg prior to the commercial availability of the 25 mg tablets.
Syndax has established SyndAccess™, a program offering personalized support and resources to U.S. patients prescribed Revuforj, including financial assistance for eligible patients.
