{"entity":{"id":"aml-npm1-kmt2a","kind":"cancer","name":"NPM1-mutated and KMT2A-rearranged acute myeloid leukaemia","aka":["NPM1-mutated AML","KMT2A-rearranged AML","MLL-rearranged AML","Menin-dependent AML"],"tldr":"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.","summary":"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.\n\nAUGMENT-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.\n\nThe 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.","asOf":"2026-09-17","wikipedia":"https://en.wikipedia.org/wiki/Nucleophosmin","links":[{"label":"Wikipedia: Nucleophosmin","url":"https://en.wikipedia.org/wiki/Nucleophosmin"},{"label":"NCCN Guidelines: Acute Myeloid Leukemia","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1411"}],"tags":["subtype-page"],"related":[],"cancers":[],"sections":[],"technologies":["menin-inhibitors"],"targets":["menin","npm1","kmt2a"],"drugs":[],"companies":[],"institutions":[],"pathways":["menin-kmt2a"],"terms":["differentiation-syndrome","eln-risk","mrd"],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"group":"haematologic","burden":"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.","subtypes":["NPM1-mutated AML without FLT3-ITD (favourable risk)","NPM1-mutated AML with FLT3-ITD","KMT2A-rearranged AML (MLL fusion, any partner gene)","Therapy-related KMT2A-rearranged AML after topoisomerase II inhibitors","Infant KMT2A-rearranged leukaemia"],"biomarkers":["NPM1 mutation and NPM1 transcript MRD","KMT2A rearrangement by FISH or RNA sequencing","FLT3-ITD co-mutation","MEN1 mutations (menin inhibitor resistance)","ELN 2022 risk group","HOXA9 and MEIS1 expression"],"standardOfCare":[{"setting":"Newly diagnosed, fit for intensive chemotherapy","approach":"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.","refs":["cytarabine-7-3","allogeneic-hsct","ngs-mrd-clonoseq","eln-risk"],"guideline":{"version":"NCCN Guidelines: Acute Myeloid Leukemia","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1411"}},{"setting":"Newly diagnosed, unfit for intensive chemotherapy","approach":"Venetoclax plus azacitidine, with a menin inhibitor added in trials.","refs":["venetoclax","azacitidine","viale-a","menin-plus-venetoclax-hma"],"guideline":{"version":"NCCN Guidelines: Acute Myeloid Leukemia","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1411"}},{"setting":"Relapsed or refractory","approach":"Revumenib (KMT2A-rearranged or NPM1-mutated) or ziftomenib (NPM1-mutated) as a bridge to allogeneic transplant; menin inhibitor combinations in trials.","refs":["revumenib","ziftomenib","augment-101","komet-001","allogeneic-hsct"],"guideline":{"version":"NCCN Guidelines: Acute Myeloid Leukemia","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1411"}}],"stateOfArt":["Menin inhibitors are the first targeted therapy for KMT2A-rearranged leukaemia and for NPM1-mutated AML, approved in 2024 and 2025.","NPM1 transcript MRD after two chemotherapy cycles is the best guide to who needs a transplant in favourable-risk disease.","Menin inhibitors with venetoclax and azacitidine are producing high remission rates in early combination trials."],"history":[{"year":2005,"title":"NPM1 mutations described in a third of adult AML","refs":["npm1"]},{"year":2005,"title":"Menin shown to be required by KMT2A fusion leukaemia","refs":["menin","kmt2a"]},{"year":2016,"title":"NPM1 transcript MRD predicts relapse after chemotherapy","refs":["mrd"]},{"year":2024,"title":"AUGMENT-101: revumenib, the first menin inhibitor, approved for relapsed KMT2A-rearranged leukaemia","refs":["augment-101","revumenib"]},{"year":2025,"title":"Ziftomenib and revumenib approved for relapsed NPM1-mutated AML","refs":["komet-001","ziftomenib","revumenib"]}],"pipeline":["revumenib","ziftomenib","bleximenib","menin-inhibitors","myelomatch"],"openProblems":["Whether a menin inhibitor added to first-line therapy raises cure rates in NPM1-mutated AML.","MEN1 resistance mutations and how to sequence or combine inhibitors around them.","Dosing menin inhibitors safely with azoles and other QT-prolonging drugs."],"parent":"aml"},"route":"/cancers/aml-npm1-kmt2a/","neighbours":{"technology":[{"id":"allogeneic-hsct","kind":"technology","name":"Allogeneic stem cell transplantation","route":"/technologies/allogeneic-hsct/"},{"id":"menin-inhibitors","kind":"technology","name":"Menin inhibitors","route":"/technologies/menin-inhibitors/"},{"id":"ngs-mrd-clonoseq","kind":"technology","name":"NGS-based MRD (clonoSEQ and molecular MRD)","route":"/technologies/ngs-mrd-clonoseq/"}],"target":[{"id":"kmt2a","kind":"target","name":"KMT2A (MLL) rearrangement","route":"/targets/kmt2a/"},{"id":"menin","kind":"target","name":"Menin","route":"/targets/menin/"},{"id":"npm1","kind":"target","name":"NPM1 mutation","route":"/targets/npm1/"}],"pathway":[{"id":"menin-kmt2a","kind":"pathway","name":"Menin / KMT2A (HOXA9-MEIS1 axis)","route":"/pathways/menin-kmt2a/"}],"term":[{"id":"differentiation-syndrome","kind":"term","name":"Differentiation syndrome","route":"/terms/differentiation-syndrome/"},{"id":"eln-risk","kind":"term","name":"ELN 2022 risk classification","route":"/terms/eln-risk/"},{"id":"mrd","kind":"term","name":"Minimal / molecular residual disease (MRD)","route":"/terms/mrd/"}],"trial":[{"id":"augment-101","kind":"trial","name":"AUGMENT-101","route":"/trials/augment-101/"},{"id":"komet-001","kind":"trial","name":"KOMET-001","route":"/trials/komet-001/"},{"id":"myelomatch","kind":"trial","name":"myeloMATCH","route":"/trials/myelomatch/"},{"id":"viale-a","kind":"trial","name":"VIALE-A","route":"/trials/viale-a/"}],"drug":[{"id":"azacitidine","kind":"drug","name":"Azacitidine","route":"/drugs/azacitidine/"},{"id":"bleximenib","kind":"drug","name":"Bleximenib","route":"/drugs/bleximenib/"},{"id":"cytarabine-7-3","kind":"drug","name":"Cytarabine + anthracycline ('7+3')","route":"/drugs/cytarabine-7-3/"},{"id":"revumenib","kind":"drug","name":"Revumenib","route":"/drugs/revumenib/"},{"id":"venetoclax","kind":"drug","name":"Venetoclax","route":"/drugs/venetoclax/"},{"id":"ziftomenib","kind":"drug","name":"Ziftomenib","route":"/drugs/ziftomenib/"}],"pairing":[{"id":"menin-plus-venetoclax-hma","kind":"pairing","name":"Menin inhibitor + venetoclax + azacitidine","route":"/pairings/menin-plus-venetoclax-hma/"}],"cancer":[{"id":"aml","kind":"cancer","name":"Acute myeloid leukaemia","route":"/cancers/aml/"},{"id":"aml-paediatric","kind":"cancer","name":"Acute myeloid leukaemia in children","route":"/cancers/aml-paediatric/"},{"id":"all-infant","kind":"cancer","name":"Infant acute lymphoblastic leukaemia (KMT2A-rearranged, under one year)","route":"/cancers/all-infant/"}]}}