The FDA has granted accelerated approval to revumenib (Revuforj; Syndax Pharmaceuticals) for the treatment of adult and pediatric patients (1 year and older) with relapsed or refractory acute leukemia harboring KMT2A (also known as mixed-lineage leukemia) rearrangements. This approval marks a significant advancement in precision oncology, offering a targeted therapy for a challenging subset of acute leukemia. The FDA granted revumenib breakthrough therapy and orphan drug designations, underscoring its potential to address a critical unmet need.
Understanding KMT2A-Rearranged Acute Leukemia
Acute leukemia is an aggressive blood cancer characterized by the rapid proliferation of immature lymphocytes in the bone marrow. KMT2A rearrangements, present in approximately 10% of acute leukemia cases, lead to a particularly aggressive disease course. Standard treatments like chemotherapy and hematopoietic cell transplantation often yield suboptimal outcomes, with high relapse rates. Revumenib offers a novel approach by targeting the underlying genetic driver of this leukemia subtype.
Mechanism of Action
Revumenib is an oral, small-molecule inhibitor that specifically targets menin, a protein essential for the pathologic interaction with the KMT2A protein. By disrupting the menin-KMT2A interaction, revumenib interferes with the abnormal cellular signaling that fuels disease progression in KMT2Ar leukemia. This mechanism distinguishes revumenib from traditional therapies, providing a precision-based treatment option.
Clinical Efficacy
The approval was based on data from the AUGMENT-101 phase 1/2 clinical trial (NCT04065399), which demonstrated promising efficacy in patients with relapsed or refractory KMT2Ar acute leukemia. Interim analysis showed a complete remission (CR) and CR with partial hematologic recovery rate of 22.8% (95% CI, 12.7%-35.8%) and an overall response rate of 63.2%. These results are particularly significant given that less than 10% of patients with R/R KMT2Ar acute leukemia achieve remission with existing therapies. Eytan M. Stein, MD, of Memorial Sloan Kettering Cancer Center, noted that revumenib "gives hope to those with relapsed and refractory KMT2Ar disease."
Safety Profile and Management
While revumenib has demonstrated a tolerable safety profile, health care providers should monitor for potential adverse events (AEs), including QTc prolongation and differentiation syndrome. In the AUGMENT-101 trial, QTc prolongation occurred in 25.5% of patients (grade 3, 13.8%; grade 4, 0%), and differentiation syndrome occurred in 27.7% of patients (grade 3, 14.9%; grade 4, 1.1%). The median time to onset of differentiation syndrome was 10 days (range, 3-41 days). Management of these AEs typically involves supportive care and dose adjustments. Diarrhea, edema, febrile neutropenia, nausea, and vomiting were also common AEs, occurring in more than 30% of patients.
The Pharmacist's Role
Pharmacists play a crucial role in the safe and effective administration of revumenib. This includes assessing a patient’s blood counts, electrolyte levels, and liver enzyme levels, as well as performing a baseline electrocardiogram to monitor for QTc prolongation. Dosing adjustments are necessary for patients on strong CYP3A4 inhibitors, such as voriconazole and posaconazole. The recommended dose for these patients is 160 mg (95 mg/m2 if < 40 kg) every 12 hours. For patients not requiring strong CYP3A4 inhibitors, the recommended dose is 270 mg (95 mg/m2 if < 40 kg) every 12 hours. It is also important to counsel patients to administer revumenib on an empty stomach or with a low-fat meal to optimize absorption.
Future Directions
Ongoing trials, such as the phase 1/2 SAVE study (NCT05360160), are evaluating the combination of revumenib with BCL2 inhibitors, FLT3 inhibitors, and hypomethylating agents. Additionally, revumenib has shown promise in patients with NPM1-mutated (NPM1m) acute myeloid leukemia (AML), another challenging disease lacking approved targeted therapies. Recent data from the AUGMENT-101 trial’s NPM1m AML cohort indicate that revumenib achieved significant clinical responses in R/R NPM1m AML, further reinforcing its role in precision oncology.
