# IDH1- and IDH2-mutated acute myeloid leukaemia

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

## TL;DR

IDH-mutated acute myeloid leukaemia has a faulty metabolic enzyme that floods cells with a chemical that blocks maturation. Pills that shut the enzyme off, ivosidenib for IDH1 and enasidenib or olutasidenib for IDH2 and IDH1, let the leukaemia cells mature, and ivosidenib with azacitidine tripled survival in older patients.

## Summary

Mutant isocitrate dehydrogenase 1 or 2 makes the oncometabolite 2-hydroxyglutarate, which jams the DNA-demethylating enzymes that blood cells need to differentiate. IDH2 mutations (R140, R172) occur in roughly one in eight adult AML and IDH1 (R132) in about one in twelve. They co-occur with NPM1 and DNMT3A mutations and are enriched in older patients. Blocking the mutant enzyme does not kill the blast directly; it restores differentiation over weeks, and the price is differentiation syndrome in around a fifth of patients.

Enasidenib, approved in 2017 for relapsed or refractory IDH2-mutated AML on a phase 1/2 study, was the first IDH inhibitor; its phase 3 IDHENTIFY trial against conventional care in older relapsed patients did not lengthen survival. Ivosidenib followed in 2018 for relapsed IDH1-mutated disease and, after AGILE (2022), for newly diagnosed patients unfit for intensive chemotherapy: ivosidenib plus azacitidine gave a median overall survival of 24.0 months against 7.9 months with azacitidine alone (hazard ratio 0.44). Olutasidenib, a second IDH1 inhibitor, was approved for relapsed disease in 2022.

IDH-mutated leukaemias also respond unusually well to venetoclax with azacitidine, the VIALE-A subgroup showing the largest survival gain of any genotype, so the field now debates ivosidenib-azacitidine against venetoclax-azacitidine and tests triplets of all three. Resistance comes through second-site IDH mutations, isoform switching from IDH1 to IDH2, and emergence of RAS-pathway clones.

## Fields

- Kind: Cancer
- Last checked: 2026-09-17
- Also known as: IDH-mutant AML; IDH1-mutated AML; IDH2-mutated AML
- Tags: subtype-page
- Group: haematologic
- Burden: About one in five adults with acute myeloid leukaemia carries a mutation in IDH1 or IDH2, more often in older patients and in leukaemia arising from a prior marrow disorder.
- Subtypes: IDH1 R132-mutated AML (ivosidenib, olutasidenib); IDH2 R140- and R172-mutated AML (enasidenib); IDH-mutated AML with NPM1 co-mutation; IDH-mutated secondary AML from myelodysplastic syndromes
- Biomarkers: IDH1 R132 and IDH2 R140/R172 mutations; 2-hydroxyglutarate level; NPM1, DNMT3A and RAS co-mutations; ELN 2022 risk group; IDH mutation clearance as MRD

## 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-idh/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-idh/#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-idh/#what-it-is [4 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-idh/#finding-it [5 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-idh/#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-idh/#evidence [5 trials, 4 key papers, 4 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-idh/#science [3 targets]
- 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-idh/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-idh/#living-with-it [16 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-idh/coming/ [6 medicines, 3 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-idh/data/ [34 connected records]

## Standard of care

- Newly diagnosed IDH1-mutated, unfit for intensive chemotherapy: Ivosidenib plus azacitidine (AGILE) or venetoclax plus azacitidine; triplets in trials. ([Ivosidenib](https://onco.cc/drugs/ivosidenib/), [Azacitidine](https://onco.cc/drugs/azacitidine/), [AGILE](https://onco.cc/trials/agile/), [Venetoclax](https://onco.cc/drugs/venetoclax/), [VIALE-A](https://onco.cc/trials/viale-a/))
- Newly diagnosed, fit for intensive chemotherapy: 7+3 induction with consolidation and transplant by ELN risk; IDH inhibitors added in trials. ([Cytarabine + anthracycline ('7+3')](https://onco.cc/drugs/cytarabine-7-3/), [Allogeneic stem cell transplantation](https://onco.cc/technologies/allogeneic-hsct/), [Ivosidenib](https://onco.cc/drugs/ivosidenib/))
- Relapsed or refractory: Ivosidenib or olutasidenib for IDH1, enasidenib for IDH2; venetoclax-based combinations; transplant in responders. ([Ivosidenib](https://onco.cc/drugs/ivosidenib/), [Olutasidenib](https://onco.cc/drugs/olutasidenib/), [Enasidenib](https://onco.cc/drugs/enasidenib/), [Venetoclax](https://onco.cc/drugs/venetoclax/), [Allogeneic stem cell transplantation](https://onco.cc/technologies/allogeneic-hsct/))

## State of the art

- Ivosidenib plus azacitidine is a first-line standard for unfit IDH1-mutated patients after AGILE tripled median survival.
- Three approved IDH inhibitors cover both genes in relapsed disease.
- Venetoclax-azacitidine is especially active in IDH-mutated leukaemia, so two targeted options compete in the same patients.

## Open problems

- Ivosidenib-azacitidine or venetoclax-azacitidine first, or all three together.
- Managing differentiation syndrome without stopping an effective drug.
- Isoform switching and second-site mutations that escape a single IDH inhibitor.

## Sources

- Wikipedia: https://en.wikipedia.org/wiki/Isocitrate_dehydrogenase
- Wikipedia: Isocitrate dehydrogenase: https://en.wikipedia.org/wiki/Isocitrate_dehydrogenase
- 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 older or unfit patients](https://onco.cc/cancers/aml-older-unfit/), [FLT3-mutated acute myeloid leukaemia](https://onco.cc/cancers/aml-flt3/), [NPM1-mutated and KMT2A-rearranged acute myeloid leukaemia](https://onco.cc/cancers/aml-npm1-kmt2a/), [Secondary and therapy-related acute myeloid leukaemia](https://onco.cc/cancers/aml-secondary/)
- technologies: [Allogeneic stem cell transplantation](https://onco.cc/technologies/allogeneic-hsct/), [Epigenetic drugs (HDAC, DNMT, EZH2, IDH, menin, BET)](https://onco.cc/technologies/epigenetic-drugs/)
- targets: [IDH1 / IDH2](https://onco.cc/targets/idh/), [TET2](https://onco.cc/targets/tet2/)
- terms: [Differentiation syndrome](https://onco.cc/terms/differentiation-syndrome/), [ELN 2022 risk classification](https://onco.cc/terms/eln-risk/), [Hypomethylating agents (azacitidine, decitabine)](https://onco.cc/terms/hma/)
- trials: [A Study to Assess the Safety and Efficacy of Two Combinations of Isocitrate Dehydrogenase (IDH) Mutant Targeted Therapies Plus Azacitidine in Participants With Newly Diagnosed Acute Myeloid Leukemia (AML) Harboring IDH Mutations Who Are Not Candidates to Receive Intensive Induction Chemotherapy](https://onco.cc/trials/nct02677922/), [A Study to Evaluate HMPL-306 in Patients With IDH1or IDH2-mutated Acute Myeloid Leukemia](https://onco.cc/trials/nct06387069/), [AGILE](https://onco.cc/trials/agile/), [myeloMATCH](https://onco.cc/trials/myelomatch/), [VIALE-A](https://onco.cc/trials/viale-a/)
- key papers: [AGILE: ivosidenib plus azacitidine for newly diagnosed IDH1-mutated AML in patients unfit for intensive chemotherapy](https://onco.cc/key-papers/paper-agile-ivosidenib-azacitidine-nejm-2022/), [Durable remissions with ivosidenib in IDH1-mutated relapsed or refractory acute myeloid leukaemia](https://onco.cc/key-papers/paper-ivosidenib-idh1-dinardo-nejm-2018/), [ELN 2022: diagnosis and management of acute myeloid leukaemia in adults](https://onco.cc/key-papers/paper-eln-2022-aml-dohner-blood-2022/), [Enasidenib in mutant IDH2 relapsed or refractory acute myeloid leukaemia](https://onco.cc/key-papers/paper-enasidenib-idh2-stein-blood-2017/)
- drugs: [Azacitidine](https://onco.cc/drugs/azacitidine/), [Cytarabine + anthracycline ('7+3')](https://onco.cc/drugs/cytarabine-7-3/), [Enasidenib](https://onco.cc/drugs/enasidenib/), [Ivosidenib](https://onco.cc/drugs/ivosidenib/), [Olutasidenib](https://onco.cc/drugs/olutasidenib/), [Venetoclax](https://onco.cc/drugs/venetoclax/)
- biomarkers: [IDH1 R132 mutation](https://onco.cc/biomarkers/idh1-r132/), [IDH2 mutation (R140 and R172)](https://onco.cc/biomarkers/idh2-mutation/)

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