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10 slides generated from the cancer page, with a quiz from the open benchmark and speaker notes that cite the sources. Arrow keys move between slides; Print gives one slide per page.
NPM1-mutated and KMT2A-rearranged leukaemias depend on a protein called menin to keep leukaemia genes switched on. Menin inhibitors, revumenib and ziftomenib, are the first drugs to exploit this, and they produce remissions in patients whose leukaemia had come back after everything else.
Both leukaemias run on the same circuit. A KMT2A fusion protein, or the mislocated mutant nucleophosmin, needs the chromatin adaptor menin to hold the HOXA9 and MEIS1 programme open; without it the blasts differentiate. NPM1-mutated AML without FLT3-ITD sits in the ELN favourable group and is cured by chemotherapy in about half of patients, with NPM1 transcript MRD after two cycles the strongest predictor of relapse. KMT2A-rearranged AML, whichever partner gene, is adverse or intermediate risk and is treated with intensive chemotherapy and transplant.
AUGMENT-101 reported revumenib in heavily pretreated relapsed KMT2A-rearranged leukaemias in 2023 and 2024: complete remission with full or partial count recovery in 22.8 percent and an overall response rate of 63.2 percent, leading to approval in November 2024 for relapsed or refractory KMT2A-rearranged acute leukaemia from the age of one, the first menin inhibitor and the first drug approved for this genotype. KOMET-001 followed with ziftomenib in relapsed NPM1-mutated AML, complete remission in 23 percent, and 2025 brought approvals for both drugs in relapsed NPM1-mutated disease. Differentiation syndrome and QT prolongation are the class toxicities; MEN1 mutations that stop menin inhibitor binding were the first resistance mechanism described.
| Setting | Approach | Guideline |
|---|---|---|
| Newly diagnosed, fit for intensive chemotherapy | 7+3 induction with consolidation; NPM1 MRD monitoring decides transplant in favourable-risk disease; transplant in first remission for KMT2A-rearranged and FLT3-ITD co-mutated disease. | not mapped |
| Newly diagnosed, unfit for intensive chemotherapy | Venetoclax plus azacitidine, with a menin inhibitor added in trials. | not mapped |
| Relapsed or refractory | Revumenib (KMT2A-rearranged or NPM1-mutated) or ziftomenib (NPM1-mutated) as a bridge to allogeneic transplant; menin inhibitor combinations in trials. | not mapped |