Menin-KMT2A Inhibitors in Acute Leukaemia

Why the Interaction Matters

In leukaemias with a KMT2A rearrangement, the fusion protein retains the region that binds menin, a small chromatin adaptor. Menin tethers the fusion to target genes such as MEIS1 and HOXA cluster genes, keeping a stem-cell-like transcriptional programme switched on.

Leukaemias with mutated NPM1, and some with other lesions, are also dependent on menin-KMT2A activity at the same target genes, broadening the group of potentially responsive patients.

Breaking It Pharmacologically

Menin inhibitors occupy the pocket on menin that binds KMT2A, displacing the fusion protein from chromatin and switching off the leukaemogenic gene programme. This induces differentiation of the leukaemic blasts rather than immediate cell killing.

In the registration trial of revumenib, about a quarter of heavily pretreated patients with KMT2A-rearranged acute leukaemia achieved complete remission or complete remission with partial haematological recovery, and many of the responders had no detectable residual disease.

Practical Points

Differentiation syndrome and QT-interval prolongation are recognised adverse effects that require monitoring. Resistance can emerge through mutations in menin at the drug-binding site.

Testing for a KMT2A rearrangement or NPM1 mutation is the companion step that identifies candidates, and several other menin inhibitors are in development.

Testing, Sequencing and What Comes Next

Candidates are identified by a KMT2A (MLL) rearrangement test — usually fluorescence in situ hybridisation or a fusion panel — or an NPM1 mutation assay, both routine in the acute leukaemia work-up. Menin inhibitors are currently used mainly in relapsed or refractory disease, but trials are moving them into earlier lines and into combination with chemotherapy or with venetoclax and hypomethylating agents.

Because response works through differentiation, minimal residual disease testing is used to judge depth, and some responders proceed to allogeneic stem-cell transplant to consolidate. Menin binding-site mutations are the main on-target resistance mechanism, and next-generation menin inhibitors are being developed to address them.

Key Takeaways

• ·KMT2A-rearranged and NPM1-mutant leukaemias depend on the menin-KMT2A interaction at HOXA/MEIS1 genes.
• ·Menin inhibitors displace the complex from chromatin and drive leukaemic-cell differentiation.
• ·Revumenib is approved for KMT2A-rearranged acute leukaemia; differentiation syndrome needs monitoring.