# NPM1-mutated and KMT2A-rearranged acute myeloid leukaemia

Source: https://onco.cc/cancers/aml-npm1-kmt2a/  
OnCo record `aml-npm1-kmt2a` (Cancer). Data CC BY-NC 4.0, attribute "Data from OnCo (onco.cc)"; commercial use needs a licence.

## TL;DR

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.

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.

## Fields

- Kind: Cancer
- Last checked: 2026-09-17
- Also known as: NPM1-mutated AML; KMT2A-rearranged AML; MLL-rearranged AML; Menin-dependent AML
- Tags: subtype-page
- 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

## Sections of this record

The page is a hub with ten sections in reading order; large sections have their own page. The same plan as JSON: https://onco.cc/api/v1/cancers/aml-npm1-kmt2a/sections.json

- Overview (on the hub): The TL;DR, the family this cancer belongs to, the organ, who gets it and what the state of the art is. https://onco.cc/cancers/aml-npm1-kmt2a/#overview [3 state-of-the-art points]
- Types and stages (on the hub): Anatomy, the subtypes and how they differ, how it is staged, and where advanced disease spreads. https://onco.cc/cancers/aml-npm1-kmt2a/#what-it-is [5 subtypes]
- Symptoms and diagnosis (on the hub): How this cancer shows itself, how the diagnosis is confirmed, and the biomarkers clinicians test for. https://onco.cc/cancers/aml-npm1-kmt2a/#finding-it [6 biomarkers]
- Treatment (on the hub): The standard of care by setting, the medicines, surgery and radiotherapy named in it, and the regimens behind them. https://onco.cc/cancers/aml-npm1-kmt2a/#treating-it [3 settings, 3 decisions with options]
- Trials and papers (on the hub): Trials recruiting now, the landmark trials, the trials held by this cancer's subtypes, the key papers and what they mean, the latest literature, and the milestones year by year. https://onco.cc/cancers/aml-npm1-kmt2a/#evidence [7 trials, 4 key papers, 5 milestones]
- Biology and targets (on the hub): The molecular landscape: the targets and how often each appears, the pathways, the mechanics stages and the preclinical models. https://onco.cc/cancers/aml-npm1-kmt2a/#science [6 targets, 1 pathway]
- Countries and centres (own page): Cases by country, the UK and NHS pathway and other country lenses, the expert centres with trials on record, and the centres named on this cancer's subtypes. https://onco.cc/cancers/aml-npm1-kmt2a/where-you-are/
- Decisions and support (on the hub): The decisions you may face, the aids that walk through them, the warnings on record, the first sixty days and the questions to ask. https://onco.cc/cancers/aml-npm1-kmt2a/#living-with-it [17 questions, 6 red cards]
- Pipeline and open problems (own page): Everything in development, the medicines held by this cancer's subtypes, the open problems and what is being done about them, the roadmaps, and what changed on this record. https://onco.cc/cancers/aml-npm1-kmt2a/coming/ [6 medicines, 5 trials, 3 open problems]
- Data (own page): Every connected record, the notes, the JSON, Markdown and RDF twins, and where the record came from and when it was checked. https://onco.cc/cancers/aml-npm1-kmt2a/data/ [42 connected records]

## Standard of care

- 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. ([Cytarabine + anthracycline ('7+3')](https://onco.cc/drugs/cytarabine-7-3/), [Allogeneic stem cell transplantation](https://onco.cc/technologies/allogeneic-hsct/), [NGS-based MRD (clonoSEQ and molecular MRD)](https://onco.cc/technologies/ngs-mrd-clonoseq/), [ELN 2022 risk classification](https://onco.cc/terms/eln-risk/))
- Newly diagnosed, unfit for intensive chemotherapy: Venetoclax plus azacitidine, with a menin inhibitor added in trials. ([Venetoclax](https://onco.cc/drugs/venetoclax/), [Azacitidine](https://onco.cc/drugs/azacitidine/), [VIALE-A](https://onco.cc/trials/viale-a/), [Menin inhibitor + venetoclax + azacitidine](https://onco.cc/pairings/menin-plus-venetoclax-hma/))
- Relapsed or refractory: Revumenib (KMT2A-rearranged or NPM1-mutated) or ziftomenib (NPM1-mutated) as a bridge to allogeneic transplant; menin inhibitor combinations in trials. ([Revumenib](https://onco.cc/drugs/revumenib/), [Ziftomenib](https://onco.cc/drugs/ziftomenib/), [AUGMENT-101](https://onco.cc/trials/augment-101/), [KOMET-001](https://onco.cc/trials/komet-001/), [Allogeneic stem cell transplantation](https://onco.cc/technologies/allogeneic-hsct/))

## State of the art

- 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.

## Open problems

- 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.

## Sources

- Wikipedia: https://en.wikipedia.org/wiki/Nucleophosmin
- Wikipedia: Nucleophosmin: https://en.wikipedia.org/wiki/Nucleophosmin
- NCCN Guidelines: Acute Myeloid Leukemia: https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1411

## Connected records

- cancers: [Acute myeloid leukaemia](https://onco.cc/cancers/aml/), [Acute myeloid leukaemia in children](https://onco.cc/cancers/aml-paediatric/), [Acute myeloid leukaemia in older or unfit patients](https://onco.cc/cancers/aml-older-unfit/), [Acute promyelocytic leukaemia](https://onco.cc/cancers/apl/), [FLT3-mutated acute myeloid leukaemia](https://onco.cc/cancers/aml-flt3/), [IDH1- and IDH2-mutated acute myeloid leukaemia](https://onco.cc/cancers/aml-idh/), [Infant acute lymphoblastic leukaemia (KMT2A-rearranged, under one year)](https://onco.cc/cancers/all-infant/), [Mixed-phenotype acute leukaemia](https://onco.cc/cancers/mixed-phenotype-acute-leukaemia/)
- technologies: [Allogeneic stem cell transplantation](https://onco.cc/technologies/allogeneic-hsct/), [Menin inhibitors](https://onco.cc/technologies/menin-inhibitors/), [NGS-based MRD (clonoSEQ and molecular MRD)](https://onco.cc/technologies/ngs-mrd-clonoseq/)
- targets: [HOXA9](https://onco.cc/targets/hoxa9/), [KMT2A (MLL) rearrangement](https://onco.cc/targets/kmt2a/), [MEIS1](https://onco.cc/targets/meis1/), [Menin](https://onco.cc/targets/menin/), [NPM1 mutation](https://onco.cc/targets/npm1/)
- pathways: [Menin / KMT2A (HOXA9-MEIS1 axis)](https://onco.cc/pathways/menin-kmt2a/)
- terms: [Differentiation syndrome](https://onco.cc/terms/differentiation-syndrome/), [ELN 2022 risk classification](https://onco.cc/terms/eln-risk/), [Minimal / molecular residual disease (MRD)](https://onco.cc/terms/mrd/)
- key papers: [AUGMENT-101: revumenib, the first menin inhibitor, in relapsed leukaemias driven by KMT2A rearrangement or NPM1 mutation](https://onco.cc/key-papers/paper-augment-101-revumenib-menin-nature-2023/), [Cytoplasmic nucleophosmin in acute myeloid leukaemia with a normal karyotype](https://onco.cc/key-papers/paper-falini-npm1-nejm-2005/), [ELN 2022: diagnosis and management of acute myeloid leukaemia in adults](https://onco.cc/key-papers/paper-eln-2022-aml-dohner-blood-2022/), [Molecular measurable residual disease in NPM1-mutated acute myeloid leukaemia (UK NCRI AML17)](https://onco.cc/key-papers/paper-ivey-npm1-mrd-nejm-2016/)
- trials: [A Phase 2 Clinical Study of Ziftomenib in Patients With Relapsed or Refractory NPM1-Mutated Acute Myeloid Leukemia](https://onco.cc/trials/nct07623616/), [A Study of Bleximenib, Venetoclax and Azacitidine For Treatment of Participants With Newly Diagnosed Acute Myeloid Leukemia (AML)](https://onco.cc/trials/nct06852222/), [AUGMENT-101](https://onco.cc/trials/augment-101/), [KOMET-001](https://onco.cc/trials/komet-001/), [myeloMATCH](https://onco.cc/trials/myelomatch/), [Studies to Assess Ziftomenib in Combination With Ven+Aza or 7+3 in Patients With Untreated NPM1-m or KMT2A-r AML](https://onco.cc/trials/nct07007312/), [VIALE-A](https://onco.cc/trials/viale-a/)
- drugs: [Azacitidine](https://onco.cc/drugs/azacitidine/), [Bleximenib](https://onco.cc/drugs/bleximenib/), [Cytarabine + anthracycline ('7+3')](https://onco.cc/drugs/cytarabine-7-3/), [Revumenib](https://onco.cc/drugs/revumenib/), [Venetoclax](https://onco.cc/drugs/venetoclax/), [Ziftomenib](https://onco.cc/drugs/ziftomenib/)
- pairings: [Menin inhibitor + venetoclax + azacitidine](https://onco.cc/pairings/menin-plus-venetoclax-hma/)
- biomarkers: [NPM1 mutation](https://onco.cc/biomarkers/npm1-mutation/)

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JSON: https://onco.cc/api/v1/entities/aml-npm1-kmt2a.json