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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.
The next phase is combination: menin inhibitors with venetoclax and azacitidine in unfit patients, with 7+3 in fit patients, and as maintenance after transplant, together with bleximenib and other second-generation inhibitors. Whether adding a menin inhibitor to first-line therapy raises cure rates in NPM1-mutated AML, where chemotherapy already cures many, is the trial question of the decade.
NPM1 is the commonest mutation in adult acute myeloid leukaemia, in about three in ten patients; KMT2A rearrangements are found in about one in twenty adults, in most infants with leukaemia, and in leukaemia that follows chemotherapy.
Leukaemias, myeloma and MDS live in the marrow and blood; lymphomas grow in lymph nodes and spleen. The node stations are the disease map, not a route of spread, and staging counts them.
In lymphoma the node stations are the disease itself; staging (Ann Arbor / Lugano) counts how many regions and sides of the diaphragm are involved.
Same organ: High-grade B-cell lymphoma with MYC and BCL2 rearrangements (double-hit lymphoma), Mediastinal grey zone lymphoma, Primary effusion lymphoma, Plasmablastic lymphoma, T-cell/histiocyte-rich large B-cell lymphoma, EBV-positive diffuse large B-cell lymphoma, Primary large B-cell lymphoma of the testis, Gastric MALT lymphoma, Ocular adnexal MALT lymphoma, Extranodal NK/T-cell lymphoma, Adult T-cell leukaemia/lymphoma, ALK-positive anaplastic large cell lymphoma, ALK-negative anaplastic large cell lymphoma, Breast implant-associated anaplastic large cell lymphoma, Primary cutaneous anaplastic large cell lymphoma, Lymphomatoid papulosis, Mycosis fungoides, Enteropathy-associated T-cell lymphoma, Monomorphic epitheliotropic intestinal T-cell lymphoma, Extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma), Splenic marginal zone lymphoma, Nodal marginal zone lymphoma, Primary cutaneous marginal zone lymphoma, Primary cutaneous follicle centre lymphoma, Sezary syndrome, Nodal T-follicular helper cell lymphoma, angioimmunoblastic type (angioimmunoblastic T-cell lymphoma), Hepatosplenic T-cell lymphoma, Intravascular large B-cell lymphoma, Lymphomatoid granulomatosis, T-cell prolymphocytic leukaemia, Splenic B-cell lymphoma/leukaemia with prominent nucleoli (formerly B-cell prolymphocytic leukaemia and hairy cell leukaemia variant), T-cell large granular lymphocytic leukaemia, Mixed-phenotype acute leukaemia, Myeloid leukaemia of Down syndrome, Burkitt leukaemia, Marginal zone lymphoma, Cutaneous T-cell lymphoma (mycosis fungoides and Sezary syndrome), Primary mediastinal (thymic) large B-cell lymphoma, Leukaemia (all types), Acute myeloid leukaemia, Acute lymphoblastic leukaemia, Chronic lymphocytic leukaemia, Chronic myeloid leukaemia (CML), Diffuse large B-cell lymphoma, Follicular lymphoma, Hodgkin lymphoma, Mantle cell lymphoma, Multiple myeloma, Non-Hodgkin lymphoma (all types), Myelodysplastic syndromes / neoplasms (MDS), Myeloproliferative neoplasms (PV, ET, myelofibrosis), Polycythaemia vera (PV), Essential thrombocythaemia (ET), Waldenström macroglobulinaemia, Hairy cell leukaemia, Peripheral T-cell lymphomas (including cutaneous T-cell lymphoma), Blastic plasmacytoid dendritic cell neoplasm (BPDCN), Burkitt lymphoma, HIV-associated (AIDS-related) lymphomas, Chronic myelomonocytic leukaemia and MDS/MPN overlap neoplasms, Systemic mastocytosis, Erdheim-Chester disease, Rosai-Dorfman disease and other histiocytic neoplasms, Langerhans cell histiocytosis (LCH), Post-transplant lymphoproliferative disorder (PTLD), FLT3-mutated acute myeloid leukaemia, IDH1- and IDH2-mutated acute myeloid leukaemia, Secondary and therapy-related acute myeloid leukaemia, Acute promyelocytic leukaemia, Acute myeloid leukaemia in older or unfit patients, Smouldering multiple myeloma, Newly diagnosed multiple myeloma, transplant-eligible, Newly diagnosed multiple myeloma, transplant-ineligible, Relapsed or refractory multiple myeloma, Plasma cell leukaemia, Lower-risk myelodysplastic syndromes, Higher-risk myelodysplastic syndromes, Chronic lymphocytic leukaemia, first treatment, Relapsed or refractory chronic lymphocytic leukaemia, Richter transformation of chronic lymphocytic leukaemia, Chronic myeloid leukaemia, chronic phase, Chronic myeloid leukaemia, accelerated and blast phase, Primary myelofibrosis, Standard-risk B-cell acute lymphoblastic leukaemia in children, High-risk acute lymphoblastic leukaemia in children (high-risk B-ALL and T-ALL), Philadelphia chromosome-positive acute lymphoblastic leukaemia in children (Ph-positive ALL), Philadelphia chromosome-like acute lymphoblastic leukaemia (Ph-like or BCR::ABL1-like ALL), Infant acute lymphoblastic leukaemia (KMT2A-rearranged, under one year), Relapsed and refractory acute lymphoblastic leukaemia in children, Acute myeloid leukaemia in children, Erdheim-Chester disease, Rosai-Dorfman-Destombes disease, Single-system Langerhans cell histiocytosis (bone, skin or one other organ), Multisystem Langerhans cell histiocytosis (with or without risk-organ involvement), Indolent and smouldering systemic mastocytosis, Advanced systemic mastocytosis (aggressive SM, SM with an associated haematological neoplasm, mast cell leukaemia), Early-stage classical Hodgkin lymphoma (stage I to II), Advanced-stage classical Hodgkin lymphoma (stage III to IV), Nodular lymphocyte-predominant Hodgkin lymphoma (nodular lymphocyte-predominant B-cell lymphoma), Relapsed and refractory classical Hodgkin lymphoma
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.
Venetoclax plus azacitidine, with a menin inhibitor added in trials.
Revumenib (KMT2A-rearranged or NPM1-mutated) or ziftomenib (NPM1-mutated) as a bridge to allogeneic transplant; menin inhibitor combinations in trials.
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Revumenib proved that a transcriptional dependency, rather than a kinase, can be drugged in leukaemia, opening treatment for two genetic subgroups that together cover roughly a third of AML plus most infant ALL. It is now approved and is being combined with venetoclax-azacitidine and intensive chemotherapy in front-line trials. Single-agent remissions are often short without transplant.
The risk category on an AML report, and therefore whether a patient is steered towards transplant in first remission, comes from these recommendations.
Molecular monitoring of NPM1 now decides whether a patient with otherwise favourable-risk disease should go to transplant in first remission, and molecular relapse can be treated pre-emptively.
NPM1-mutated AML is now its own WHO category. The mutation is a stable target for measurable residual disease monitoring and the disease is one of the two indications for menin inhibitors.
Query for this cancer: (TITLE:"NPM1-mutated and KMT2A-rearranged acute myeloid leukaemia" OR ABSTRACT:"NPM1-mutated and KMT2A-rearranged acute myeloid leukaemia" OR TITLE:"NPM1-mutated AML" OR ABSTRACT:"NPM1-mutated AML" OR TITLE:"KMT2A-rearranged AML" OR ABSTRACT:"KMT2A-rearranged AML" OR TITLE:"MLL-rearranged AML" OR ABSTRACT:"MLL-rearranged AML" OR TITLE:"Menin-dependent AML" OR ABSTRACT:"Menin-dependent AML") AND (treatment OR therapy OR trial OR survival OR diagnosis). Results are unfiltered search hits about NPM1-mutated and KMT2A-rearranged acute myeloid leukaemia, not a curated reading list.
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Bleeding that does not stop by itself, bleeding from more than one site, or new bruising in several places or one large area.
Fever, cough or breathlessness, rapid weight gain or swelling, bone pain, low blood pressure or reduced urine; the labels say to start steroids and monitor at the first suspicion, and the syndrome has been fatal.
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Take with a meal and water. Avoid grapefruit, Seville oranges and starfruit.
Known QT prolongation. Avoid other QT-prolonging drugs where possible; check ECG and correct potassium and magnesium before and during treatment.
Reduce by 50% in severe impairment.
See all on the product pages:AzacitidineCytarabine + anthracycline ('7+3')RevumenibVenetoclaxZiftomenib·Printable cards in the navigator
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