Revumenib for Relapsed or Refractory Acute Leukemia With a KMT2A Translocation

Abstract

Objective: To review the pharmacology, efficacy, and safety of revumenib (Revuforj) for relapsed or refractory (r/r) acute leukemia with a lysine methyltransferase 2A ( KMT2A) gene rearrangement or translocation ( KMT2Ar ). Data Sources: A literature search was conducted using PubMed/MEDLINE, applicable published abstracts, and ongoing studies from ClinicalTrials.gov between January 1, 1981, and April 23, 2025. Keywords included Revuforj, revumenib, SNDX-5613, KMT2A , MLL1 , and menin. Study Selection and Data Extraction: All English-language studies involving revumenib for r/r acute leukemia with a KMT2Ar were included. Data Synthesis: Revumenib, a protein-protein inhibitor that interrupts the interaction between the KMT2A protein and the scaffold protein menin, was granted approval by the Food and Drug Administration (FDA) for r/r acute leukemia with KMT2Ar based on a phase 2 clinical trial in adult and pediatric patients (n = 57), which reported a complete remission or complete remission with partial hematologic recovery of 22.8%. Common grade 3/4 adverse reactions reported for revumenib include infectious (febrile neutropenia 33%; infection 29%; bacterial infection 20%) and hematologic events (differentiation syndrome 13%; hemorrhage 9%; thrombosis 5%). Grade 3/4 QT prolongation, the primary dose-limiting adverse effect, was present in 12% of patients. Differentiation syndrome, related to revumenib’s antileukemic effect, was observed in 29% of patients (grade 3/4: 13%; grade 5: <1%). We also include long-term follow-up for a total of 104 and 135 patients for efficacy and safety results, respectively. Relevance to Patient Care and Clinical Practice in Comparison to Existing Drugs: In the high-risk disease of r/r acute leukemia with KMT2Ar , given limited treatment options, revumenib appears to be a viable, novel treatment option demonstrating clinical efficacy and a manageable adverse effect profile that can be utilized as a bridge to stem cell transplant. Existing therapy options in this setting may include additional traditional chemotherapy, chimeric antigen receptor T-cell therapy (CAR-T), antibody-drug conjugates (eg, gemtuzumab, inotuzumab), bispecific T-cell engager (BiTE) therapies (eg, blinatumomab), DNA methyltransferase inhibitors (eg, azacitidine, decitabine), histone deacetylase inhibitors (eg, vorinostat, panobinostat), and BCL-2 inhibitors (venetoclax). Conclusions: Revumenib is an innovative targeted treatment with promising activity in r/r acute leukemia with KMT2Ar .