The U.S. Food and Drug Administration (FDA) has granted approval to revumenib (Revuforj, Syndax Pharmaceuticals Inc.) for the treatment of relapsed or refractory acute leukemia with a lysine methyltransferase 2A gene (KMT2A) translocation in adult and pediatric patients aged one year and older. This approval marks a significant advancement in the treatment landscape for this aggressive form of leukemia.
The approval is based on data from the AUGMENT-101 trial (NCT04065399), a phase 1/2 open-label, multicenter study. The trial enrolled 104 adult and pediatric patients with relapsed or refractory acute leukemia with a KMT2A translocation. Patients were administered revumenib until disease progression, unacceptable toxicity, failure to achieve morphologic leukemia-free state, or hematopoietic stem cell transplantation.
The primary efficacy outcome measures were complete remission (CR) plus CR with partial hematologic recovery (CRh), the duration of CR+CRh, and conversion from transfusion dependence to independence. The CR+CRh rate was 21.2% (95% CI: 13.8, 30.3), with a median duration of 6.4 months (95% CI: 2.7, not estimable). The median time to CR or CRh was 1.9 months (range: 0.9, 5.6 months).
Of the 83 patients dependent on red blood cell (RBC) and/or platelet transfusions at baseline, 12 (14%) achieved transfusion independence during any 56-day post-baseline period. Among the 21 patients independent of both RBC and platelet transfusions at baseline, 10 (48%) remained transfusion independent during any 56-day period after baseline.
Safety Profile
The most 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.
Revuforj carries a Boxed Warning for differentiation syndrome, which can be fatal. Warnings and precautions associated with Revuforj include QTc interval prolongation and embryo-fetal toxicity.
Dosage and Administration
The recommended revumenib dose varies based on patient weight and concomitant use of strong CYP3A4 inhibitors. Due to an anticipated delay in commercial availability of the lowest dose strength, revumenib will be available through an expanded access program for patients weighing less than 40 kg.
Regulatory Information
This application was granted priority review, breakthrough designation, and orphan drug designation. The FDA also utilized the Real-Time Oncology Review pilot program and the Assessment Aid to expedite the approval process. The FDA approved the application six weeks ahead of its goal date.
