A novel menin inhibitor has shown promising efficacy in a phase 1 clinical trial for patients with relapsed or refractory acute leukemia harboring specific genetic alterations, potentially offering a new targeted treatment option for these difficult-to-treat malignancies.
Researchers evaluated revumenib (formerly SNDX-5613), an oral, selective inhibitor of the menin-KMT2A interaction, in patients with acute leukemia characterized by KMT2A rearrangements (KMT2Ar) or NPM1 mutations. These genetic subtypes are associated with poor prognosis and currently lack approved targeted therapies.
Mechanism of Action and Scientific Rationale
KMT2A rearrangements occur in approximately 80% of infant acute lymphoblastic leukemia (ALL) and 5-15% of children and adults with acute leukemia. NPM1 mutations represent the most common genetic alteration in adult acute myeloid leukemia (AML), present in up to 30% of patients.
Both genetic alterations lead to aberrant expression of homeobox (HOX) genes and their DNA-binding cofactor MEIS1, creating a gene expression program that blocks normal blood cell differentiation and drives leukemic transformation. In these leukemias, the protein menin serves as a critical oncogenic cofactor.
Revumenib works by blocking the interaction between menin and KMT2A, disrupting the assembly of oncogenic complexes on chromatin. Preclinical studies demonstrated that this inhibition downregulates HOX and MEIS1 transcription and reverses leukemogenesis in relevant models.
Trial Design and Patient Population
The phase 1 dose-escalation study was conducted across nine U.S. sites between November 2019 and March 2022. The trial enrolled 68 patients, including 60 adults and 8 children/adolescents, with a median age of 42.5 years (range 0.8-79).
The study population was heavily pretreated, with a median of four previous lines of therapy, and 46% had relapsed after allogeneic stem cell transplantation. Among participants, 82% had AML, 16% had ALL, and 2% had mixed-phenotype acute leukemia. Genetic analysis showed 68% with KMT2Ar, 21% with NPM1 mutations, and 12% with neither alteration.
Because revumenib is metabolized by cytochrome P450 3A4 (CYP3A4), researchers established two parallel dose-escalation cohorts: Arm A without strong CYP3A4 inhibitors and Arm B with strong CYP3A4 inhibitors. The drug was administered orally every 12 hours in continuous 28-day cycles.
Efficacy Results
Among 60 evaluable patients with KMT2Ar or NPM1 mutations, the complete remission or complete remission with partial hematologic recovery (CR/CRh) rate was 30%. Notably, 78% of patients who achieved CR/CRh had undetectable measurable residual disease (MRD) as assessed by multiparameter flow cytometry.
The overall response rate, which included additional response categories, reached 53%. The median time to CR/CRh was 1.9 months, and the median duration of response was 9.1 months.
Responses were observed across different leukemia subtypes, with morphologic remissions identified in 55% of AML patients, 40% of ALL patients, and in the single patient with mixed-phenotype acute leukemia. Similar response rates were seen in pediatric (50%) and adult (54%) populations.
Twelve patients proceeded to allogeneic stem cell transplantation following response to revumenib, with nine remaining in remission at data cutoff, seven of whom maintained remission for over six months.
An interesting finding was the pattern of cytogenetic clearance in patients with KMT2Ar. While 84% of patients who achieved morphologic remission initially retained detectable KMT2A rearrangements, most later cleared these genetic alterations with continued therapy. This pattern aligns with the mechanism of differentiation agents, where phenotypic differentiation precedes genetic clearance.
Safety Profile
The most common treatment-related adverse event was QT interval prolongation, occurring in 53% of patients. Grade 3 QT prolongation was observed in 13% of patients but resolved with dose interruption or reduction, and no ventricular arrhythmias were reported.
Other common treatment-emergent adverse events included nausea (50%), vomiting (40%), and febrile neutropenia (31%). Differentiation syndrome, a known effect of therapies that induce myeloid differentiation, occurred in 16% of patients (all grade 2) and was successfully managed with corticosteroids and, in some cases, hydroxyurea.
No patients permanently discontinued revumenib due to treatment-related adverse events, and no treatment-related deaths occurred.
Pharmacokinetics and Pharmacodynamics
Pharmacokinetic studies demonstrated dose-proportional exposure in both study arms, with steady-state levels achieved in approximately 48 hours and no evidence of drug accumulation.
Pharmacodynamic analyses of bone marrow cells using RNA sequencing confirmed the mechanism of action. Treatment with revumenib resulted in downregulation of key leukemogenic target genes (MEIS1, HOXA9, PBX3, and CDK6) and increased expression of genes associated with differentiation (CD11b and CD14).
Based on safety, tolerability, and pharmacokinetic data, researchers established recommended phase 2 doses of 226 mg and 276 mg every 12 hours for patients not taking strong CYP3A4 inhibitors, and 113 mg and 163 mg every 12 hours for those taking strong CYP3A4 inhibitors.
Future Directions
These promising results support the continued development of revumenib for patients with KMT2Ar or NPM1-mutated acute leukemia. The drug's ability to induce high rates of MRD-negative remissions in a heavily pretreated population suggests significant potential as a targeted therapy for these genetic subtypes.
Further studies will be needed to determine the optimal duration of therapy, combination strategies, and role in various treatment settings, including frontline therapy and as a bridge to stem cell transplantation.
