NPM1-mutated and KMT2A-rearranged acute myeloid leukaemia
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.
Overview
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.
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.
Red cards
From the labels and guidelines behind the standard of care. Your team's thresholds win.- Emergency services nowBleeding or bruising
Bleeding that will not stop, black or bloody stools, or unexplained bruising when platelets are expected to be low.
- Emergency services nowDifferentiation syndrome
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.
- Emergency services nowTumour lysis syndrome
Nausea, vomiting, muscle cramps, palpitations, seizures, confusion or passing much less urine in the first days of a new dose; the label requires hydration, anti-hyperuricaemic drugs and blood tests around each ramp-up step.
- Check before combiningFood and drink: Venetoclax
Take with a meal and water. Avoid grapefruit, Seville oranges and starfruit.
- Check before combiningHeart rhythm (QT): Revumenib
Known QT prolongation. Avoid other QT-prolonging drugs where possible; check ECG and correct potassium and magnesium before and during treatment.
- Check before combiningLiver: Venetoclax
Reduce by 50% in severe impairment.
See all on the product pages:AzacitidineCytarabine + anthracycline ('7+3')RevumenibVenetoclaxZiftomenib·Printable cards in the navigator
Anatomy and lymph node drainage
- Bone marrow (leukaemia, MDS, MPN, myeloma)
- Lymph node germinal centre (lymphomas)
- Spleen
- Blood (leukaemic phase)
- Lytic bone lesions (myeloma)
- Skin and extranodal sites
- Nodes: cervical
- Nodes: axillary
- Nodes: mediastinal
- Nodes: para-aortic and mesenteric
- Nodes: inguinal
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.
- Bone marrow (leukaemia, MDS, MPN, myeloma)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
- Lymph node germinal centre (lymphomas)
- Spleen
- Blood (leukaemic phase)
- Lytic bone lesions (myeloma)
- Skin and extranodal sites
- cervical
- axillary
- mediastinal
- para-aortic and mesenteric
- inguinal
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: 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
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.
Cases by country
No country-level case numbers. This cancer is not mapped to a GLOBOCAN site.
One section per setting: the options named, what each is for, the trials behind them, the recorded trade-offs and the questions to ask.
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.
Subtypes & biomarkers
top- 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
How often this target appears
- 2005NPM1 mutations described in a third of adult AML
- 2005Menin shown to be required by KMT2A fusion leukaemia
- 2016NPM1 transcript MRD predicts relapse after chemotherapy
- 2024AUGMENT-101: revumenib, the first menin inhibitor, approved for relapsed KMT2A-rearranged leukaemia
- 2025Ziftomenib and revumenib approved for relapsed NPM1-mutated AML
Dated changes read from the records linked to this cancer: approvals, regulatory steps, reported trials, guideline versions and milestones. Newest first; no date is inferred.
All 10 changes by month →- 2026-09-17This recordNPM1-mutated and KMT2A-rearranged acute myeloid leukaemiaFacts on this page last checked
When this page itself was last checked or edited.
- 2025ApprovalZiftomenibZiftomenib approved in US
Relapsed/refractory NPM1-mutated AML with no satisfactory alternative
- 2025Trial resultKOMET-001KOMET-001 reported
CR 23%, ORR 33%, median OS 6.
- 2025MilestoneKOMET-001Ziftomenib and revumenib approved for relapsed NPM1-mutated AML
A milestone in how this cancer is treated.
- 2024Trial resultAUGMENT-101AUGMENT-101 reported
CR+CRh 22.
- 2024MilestoneAUGMENT-101AUGMENT-101: revumenib, the first menin inhibitor, approved for relapsed KMT2A-rearranged leukaemia
A milestone in how this cancer is treated.
What is in development for NPM1-mutated and KMT2A-rearranged acute myeloid leukaemia, drawn from the whole corpus: 5 items. Drugs are grouped by the most advanced trial phase they have reached anywhere; approved treatments sit under standard of care. Technologies are the methods being tested for this cancer, trials are the studies recorded here, and ideas are proposals not yet in a trial.
Drugs in phase 3 · 1
Trials under way · 1
- myeloMATCH · phase platform · NCI / National Clinical Trials Network
Trials reported · 2
- AUGMENT-101 · phase 1/2 · 2024 · positive
- KOMET-001 · phase 1/2 · 2025 · positive
Combinations being explored · 1
Open problems and what is being done
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.
Trials
topTrials recruiting now
Country and place are remembered in this browser only. A postcode is sent to OpenStreetMap's Nominatim service to find coordinates when you press the button; nothing else leaves your device.
Landmark trials
Expert centres
topExpert centres
Bethesda, MD · government | United States | none recorded | 1 | 2,905 | 47,715 | - | |
Miami, FL · cancer center | United States | 0 | 1,607 | 15,145 | - | ||
Madrid · hospital | Spain | none recorded | 0 | 764 | 13,767 | - | |
Pamplona · cancer center | Spain | none recorded | 0 | 751 | 10,993 | - | |
| Spain | none recorded | 0 | 377 | 3,050 | - | ||
Los Angeles, CA · cancer center | United States | 0 | 318 | 3,917 | - | ||
Melbourne · research institute | Australia | none recorded | 0 | 298 | 3,639 | - | |
Toulouse · cancer center | France | none recorded | 0 | 232 | 3,172 | - | |
Indianapolis, IN · cancer center | United States | 0 | 159 | 4,238 | - | ||
Hamilton, ON · cancer center | Canada | none recorded | 0 | 103 | 1,158 | - | |
Baltimore, MD · cancer center | United States | 0 | 101 | 2,306 | - | ||
Sydney · hospital | Australia | none recorded | 0 | 98 | 893 | - | |
Omaha, NE · cancer center | United States | 0 | 37 | 4,159 | - | ||
Rotterdam · consortium | Netherlands | none recorded | 0 | 8 | 207 | - | |
Washington, DC · consortium | United States | none recorded | 0 | 4 | 22 | - |
These are the things we can measure; they are not a ranking of quality. Each column is a field on the institution record or a count over what OnCo has linked; a centre that treats many patients with NPM1-mutated and KMT2A-rearranged acute myeloid leukaemia but is thinly recorded here will look small.
Not known: OnCo holds no case-volume or outcome figures for centres, so none are shown. Where a national audit or registry publishes them, the centre's page links to it. Default order: Newsweek rank, then trials for this cancer, then research output.
Questions to ask
topQuestions to ask your oncologist about NPM1-mutated and KMT2A-rearranged acute myeloid leukaemia
Newly diagnosed
- What is my exact diagnosis, stage, and grade, and which tests established them?Why: Everything else follows from an accurate stage and subtype.
- Which biomarkers have been tested on my tumour (for example NPM1 mutation and NPM1 transcript MRD, KMT2A rearrangement by FISH or RNA sequencing, FLT3-ITD co-mutation, MEN1 mutations, ELN 2022 risk group), and what were the results?Why: These results decide eligibility for targeted therapy, immunotherapy, and trials.
- Which subtype is my cancer, and does that change the recommended treatment?Why: Recognised subtypes for this cancer include NPM1-mutated AML without FLT3-ITD, NPM1-mutated AML with FLT3-ITD, KMT2A-rearranged AML.
- Is germline (inherited) genetic testing recommended for me or my family?Why: Inherited variants can change treatment and matter for relatives.
Newly diagnosed, fit for intensive chemotherapy
- For my situation (newly diagnosed, fit for intensive chemotherapy), which of the standard options do you recommend and why?Why: Guideline options include: 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.
- Am I a candidate for Cytarabine + anthracycline ('7+3'), and what side effects should I expect?Why: Knowing the expected toxicities helps you plan work, family, and supportive care.
Newly diagnosed, unfit for intensive chemotherapy
- For my situation (newly diagnosed, unfit for intensive chemotherapy), which of the standard options do you recommend and why?Why: Guideline options include: Venetoclax plus azacitidine, with a menin inhibitor added in trials.
- Am I a candidate for Venetoclax, Azacitidine, and what side effects should I expect?Why: Knowing the expected toxicities helps you plan work, family, and supportive care.
- How do the results of VIALE-A apply to someone like me?Why: Trial populations differ from individual patients; ask how closely you match.
Relapsed or refractory
- For my situation (relapsed or refractory), which of the standard options do you recommend and why?Why: Guideline options include: Revumenib (KMT2A-rearranged or NPM1-mutated) or ziftomenib (NPM1-mutated) as a bridge to allogeneic transplant; menin inhibitor combinations in trials.
- Am I a candidate for Revumenib, Ziftomenib, and what side effects should I expect?Why: Knowing the expected toxicities helps you plan work, family, and supportive care.
- How do the results of AUGMENT-101 and KOMET-001 apply to someone like me?Why: Trial populations differ from individual patients; ask how closely you match.
Any stage
- Are there clinical trials I could join, for example of Revumenib, Ziftomenib, Bleximenib, Menin inhibitors?Why: Trials are how the next standard of care is set; asking early keeps options open.
- Would a second opinion at a high-volume centre change anything, and can you help arrange it?Why: Rare or high-stakes decisions benefit from a centre that treats many similar patients.
- What supportive care (symptom control, nutrition, exercise, mental health, financial help) is available from the start?Why: Supportive care improves quality of life and helps patients complete treatment.
- I read that “Whether a menin inhibitor added to first-line therapy raises cure rates in NPM1-mutated AML”. How does that affect my plan?Why: Open problems are where trials and second opinions matter most.
- I read that “MEN1 resistance mutations and how to sequence or combine inhibitors around them”. How does that affect my plan?Why: Open problems are where trials and second opinions matter most.
Newly diagnosed? Read the first 60 days with NPM1-mutated and KMT2A-rearranged acute myeloid leukaemia, then print the one-page appointment sheet with room for the answers.
Print this page for your appointment (your browser's print command). These prompts are for discussion; your clinical team knows your case.
Direct links plus the targets, companies, and technologies of this cancer's products.
technologies
7targets
4drugs
6companies
6pathways
1terms
3trials
4pairings
1Latest papers
topQuery 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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