Journal: Medical oncology (Northwood, London, England)
This publication reviews the emerging role of menin inhibition as a targeted strategy for acute leukemias characterized by KMT2A rearrangements and NPM1 mutations—biologically defined subsets driven by aberrant HOXA9/MEIS1 transcription.
Key points:
- Biology and rationale:
- KMT2A-rearranged and NPM1-mutated leukemias depend on a menin–KMT2A complex that sustains oncogenic HOXA9/MEIS1 programs.
- Disrupting the menin–KMT2A interaction collapses these transcriptional programs and promotes differentiation of leukemic blasts, making menin a rational therapeutic target.
- Therapeutic agents:
- Selective small-molecule menin inhibitors have been developed, with revumenib and ziftomenib the most clinically advanced.
- Early-phase trials in relapsed/refractory KMT2A-rearranged and NPM1-mutated disease show meaningful clinical responses, including differentiation of blasts.
- The recent regulatory approval of revumenib is highlighted as the first clinical validation of menin inhibition in a genetically defined leukemia subset.
- Toxicities and resistance:
- Key on-target adverse events include differentiation syndrome and QTc prolongation, requiring close monitoring and supportive management.
- Resistance commonly arises through MEN1 pocket mutations that impair drug binding and limit durability of response.
- Future directions:
- Current trials are exploring menin inhibitors in combination regimens, in the frontline setting, and as maintenance therapy.
- The authors position menin inhibition as a transformative, precision epigenetic approach that is reshaping the treatment landscape for these high-risk acute leukemias.