Syndax Pharmaceuticals 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 Revuforj as the first and only menin inhibitor to receive FDA approval for this indication.
The approval was based on data from the Phase 1/2 AUGMENT-101 trial, which evaluated the efficacy of Revuforj in patients with R/R acute leukemia with a KMT2A translocation. The study included 104 patients in the efficacy population. The rate of complete remission (CR) plus CR with partial hematological recovery (CRh) was 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). Following treatment with Revuforj, twenty-three percent (24/104 patients) of patients underwent hematopoietic stem cell transplantation (HSCT).
Clinical Impact and Expert Opinion
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."
Safety Profile
The safety evaluation of Revuforj was based on an analysis of 135 patients with R/R acute leukemia with a KMT2A translocation. Common adverse reactions (≥20%) included hemorrhage, nausea, increased phosphate, musculoskeletal pain, infection, increased aspartate aminotransferase, febrile neutropenia, increased alanine aminotransferase, increased parathyroid hormone, bacterial infection, diarrhea, differentiation syndrome, prolonged electrocardiogram QT, decreased phosphate, increased triglycerides, decreased potassium, decreased appetite, constipation, edema, viral infection, fatigue, and increased alkaline phosphatase. Adverse reactions leading to dose reduction or permanent discontinuation were low, at 10% and 12% of patients, respectively.
Disease Context
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.
Availability and Support
Syndax expects 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 specialty 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 who weigh less than 40 kg until the 25 mg tablets are commercially available.
Syndax has established SyndAccess™, a program offering personalized support and resources to U.S. patients prescribed Revuforj, including financial assistance for eligible patients.
Ongoing Development
Revuforj is also in development for R/R acute myeloid leukemia (AML) with a nucleophosmin 1 mutation (mNPM1). Pivotal data from the AUGMENT-101 trial in this population were recently reported. Multiple trials of revumenib in combination with standard-of-care agents in mNPM1 AML or KMT2A-rearranged acute leukemia are ongoing, including in newly diagnosed patients.
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. Treatment with corticosteroids and hemodynamic monitoring should be initiated immediately if differentiation syndrome is suspected.
QTc interval prolongation was also reported in clinical trials. ECG monitoring is recommended, and concomitant use with QTc-prolonging drugs should be avoided. Revuforj can cause fetal harm, and effective contraception is advised during treatment and for 4 months after the last dose.
