Background
AUGMENT-101 was a phase I/II open-label dose-escalation and dose-expansion trial of revumenib (SNDX-5613), an oral inhibitor of the menin–KMT2A protein–protein interaction, in relapsed/refractory acute leukemia harboring KMT2A rearrangements (KMT2A-r) or NPM1 mutations. Menin is a critical cofactor of KMT2A (MLL1) fusion oncoproteins and mutant NPM1 in driving aberrant HOX/MEIS1 transcription; preclinical data showed menin inhibition reverses this program and induces differentiation. AUGMENT-101 was the first trial to clinically validate menin inhibition in acute leukemia.
Interventions and follow up
Regimen: Revumenib (SNDX-5613) oral menin–KMT2A inhibitor BID continuously (phase II dose 163 mg or 226 mg BID depending on concomitant CYP3A4 inhibitor) in R/R acute leukemia with KMT2A rearrangement or NPM1 mutation
Population: Heavily pretreated R/R acute leukemia (AML, ALL, mixed phenotype), median 3 prior lines, pediatric to elderly
Primary endpoint: CR + CRh rate (efficacy population); secondary: ORR, MRD negativity, duration of response, OS, bridging to SCT, safety
mFollow up: 7.5 months (phase II)
Population: Heavily pretreated R/R acute leukemia (AML, ALL, mixed phenotype), median 3 prior lines, pediatric to elderly
Primary endpoint: CR + CRh rate (efficacy population); secondary: ORR, MRD negativity, duration of response, OS, bridging to SCT, safety
mFollow up: 7.5 months (phase II)
Results
ORR: 63% (38/60)
CR + CRh: 30% (18/60)
MRD negativity among CR+CRh responders: 53%
Bridging to allo-SCT: 17% (10/60)
mOS: 8.0 months overall; 10.2 months in KMT2A-r subgroup
CR + CRh: 30% (18/60)
MRD negativity among CR+CRh responders: 53%
Bridging to allo-SCT: 17% (10/60)
mOS: 8.0 months overall; 10.2 months in KMT2A-r subgroup
Adverse events
Mechanism-related: differentiation syndrome 16% all grades, ~6% Grade ≥3 (managed with steroids, hydroxyurea, dose hold)
Cardiac: QTc prolongation ~14% all grades, ~10% Grade ≥3 (ECG monitoring required)
Hematologic/infectious: febrile neutropenia ~24%; cytopenias expected given leukemia context
Other: nausea/vomiting common; no treatment-related deaths attributed to revumenib
Cardiac: QTc prolongation ~14% all grades, ~10% Grade ≥3 (ECG monitoring required)
Hematologic/infectious: febrile neutropenia ~24%; cytopenias expected given leukemia context
Other: nausea/vomiting common; no treatment-related deaths attributed to revumenib
Conclusions
Revumenib achieved a 63% ORR and 30% CR+CRh rate with MRD negativity in 53% of responders in heavily pretreated R/R KMT2A-rearranged and NPM1-mutant acute leukemia, establishing menin inhibition as a clinically validated precision approach in these genetically defined subtypes and providing a novel bridge to transplant for this high-risk population.
Key Limitations
Phase I/II, single-arm, non-randomized with no comparator; small phase II cohort (n=60); heterogeneous population (AML, ALL, mixed phenotype, pediatric to elderly) limits subgroup interpretation; heavily pretreated (median 3 prior lines) so efficacy in less-pretreated settings is unknown; QTc prolongation requires ECG monitoring; CYP3A4 drug interactions (azoles lower required dose); differentiation syndrome demands vigilance; short mOS (8 months) indicates meaningful but non-curative monotherapy effect; emerging menin resistance mutations; no head-to-head comparison to other salvage strategies.
Clinical Context
AUGMENT-101 led to FDA accelerated approval of revumenib for R/R KMT2A-rearranged acute leukemia in November 2024 — the first menin inhibitor approved for human use and the first precision therapy for KMT2A-rearranged leukemia (later expanded to R/R NPM1-mutant AML). KMT2A rearrangements occur in ~5–10% of adult AML and up to 70–80% of infant ALL, one of the most difficult-to-treat subsets. The data are notable for bridging 17% to SCT and MRD negativity in over half of responders. Menin inhibitors (revumenib, ziftomenib) represent a new class; combination strategies with venetoclax, FLT3 inhibitors, and azacitidine are in trials.