IDH1 and IDH2 Mutations in Acute Myeloid Leukemia

Section Editor: Kamran Mirza MBBS PhD FCAP
September 7, 2026

If your bone marrow or molecular test report mentions an IDH1 or IDH2 mutation, it refers to changes in two closely related genes. Both affect how leukemia cells process energy and, as a result, how they grow and mature. Taken together, IDH1 and IDH2 mutations are found in roughly 15 to 20 percent of adults with acute myeloid leukemia.

These mutations matter mainly because they identify people who can be treated with a group of targeted drugs called IDH inhibitors. These drugs work differently from standard chemotherapy. Rather than killing leukemia cells outright, they remove a chemical block that has been stopping the cells from growing into normal blood cells. This article explains what IDH mutations are, how they cause disease, what a positive result means for treatment, and what the result does and does not tell you about outlook.

What are IDH1 and IDH2, and what do the mutations do?

The IDH1 and IDH2 genes provide instructions for making enzymes, which are proteins that carry out specific chemical reactions inside cells. The normal IDH1 and IDH2 enzymes are part of the cell’s energy-processing machinery, converting one chemical into another as cells generate energy from nutrients.

When either gene is mutated, the enzyme it makes does something it should not. Instead of carrying out its normal reaction, it produces an abnormal chemical called 2-hydroxyglutarate, usually shortened to 2-HG. Normal cells make almost none of it. In leukemia cells with an IDH mutation, 2-HG builds up to high levels.

2-HG acts like a chemical jammer. It interferes with a group of enzymes that control which genes are switched on and off, and in particular it blocks the enzymes that help blood-forming cells mature. Maturing is the process by which an immature blast gradually develops into a working red blood cell, white blood cell, or platelet. With that process blocked, the blasts stay stuck in an immature state. They keep dividing but never grow up, and over time they crowd out the healthy cells the bone marrow should be making.

This is what makes IDH mutations unusual among the changes that drive acute myeloid leukemia. Most others, such as FLT3, switch on a growth signal that tells cells to multiply too fast. IDH mutations instead jam maturation, leaving cells trapped at an early stage. That distinction explains why IDH inhibitors work the way they do.

The two genes make slightly different versions of the same enzyme, working in different parts of the cell. IDH1 works in the cytoplasm, the main fluid-filled space, and IDH2 works inside the mitochondria, the cell’s energy-generating structures. Both produce 2-HG when mutated and block maturation in the same way, but different drugs target each one, so the involved gene determines which treatments are available.

IDH1 mutations. Found in roughly 6 to 10 percent of adults with acute myeloid leukemia. Nearly all affect position 132 of the protein and are written as IDH1 R132, most often R132H or R132C.
IDH2 mutations. Found in roughly 8 to 15 percent. Two positions are affected: IDH2 R140 and IDH2 R172. R140 is more common and frequently occurs alongside an NPM1 mutation. R172 is uncommon, rarely occurs with NPM1, and its effect on outlook is less clearly established.

Both IDH1 and IDH2 mutations in acute myeloid leukemia are somatic, meaning they develop in a blood-forming cell during a person’s lifetime. They are not inherited, are not passed to children, and carry no implications for biological relatives.

Why is the test done?

IDH1 and IDH2 testing is part of the standard molecular workup for everyone newly diagnosed with acute myeloid leukemia. The main reason is treatment selection. An IDH mutation identifies patients who can receive an IDH inhibitor, and the mutated gene determines which drug applies.

Testing is repeated if the leukemia comes back. IDH status can change between diagnosis and relapse, so a mutation present at diagnosis may no longer be there, and a new one may have appeared. Retesting means treatment decisions are based on the leukemia’s current biology rather than its original profile.

How is the test performed?

IDH1 and IDH2 mutations are detected from a bone marrow sample, or occasionally from blood when large numbers of leukemia blasts are circulating. The lab extracts DNA from the leukemia cells and analyzes it.

The usual method is next-generation sequencing, which reads the genetic code across many genes at once. It detects IDH1 and IDH2, along with FLT3, NPM1, TP53, and dozens of other relevant changes, in a single test. That breadth matters because the full combination of mutations, not IDH status alone, determines the risk group and overall treatment plan. Some centers also run a faster targeted PCR test for the most common IDH changes while the full panel is still running.

How are results reported?

IDH results are reported as mutation detected or not detected, for each gene separately. When a mutation is found, the report describes the exact change, for example, IDH1 p.R132H or IDH2 p.R140Q. The notation gives the position in the protein and which building block replaced the original.

A variant allele frequency, or VAF, is usually included. This is the proportion of the tested genetic material carrying the mutation. A high VAF at diagnosis means most of the leukemia cells carry the change, which is typical. Reading a VAF measured after treatment is more complicated, as covered below.

What does an IDH1 mutation mean?

An IDH1 mutation means the leukemia cells produce 2-HG through the IDH1 enzyme, and their maturation is chemically blocked. It also means two targeted drugs are available, both of which are IDH1 inhibitors. They work by fitting into the mutated IDH1 enzyme and stopping it from making 2-HG. With the jam lifted, leukemia cells can, in many cases, finish maturing into normal blood cells, an approach known as differentiation therapy.

Ivosidenib (Tibsovo). Approved by the FDA in 2018 for relapsed or treatment-resistant IDH1-mutated acute myeloid leukemia. It was later approved for newly diagnosed disease in adults who are not fit for intensive chemotherapy, including in combination with azacitidine. In the trial supporting the first approval, 41.6 percent of people whose leukemia had returned or not responded had an overall response. About 30 percent reached complete remission, with or without partial recovery of blood counts.
Olutasidenib (Rezlidhia). Approved by the FDA in 2022 for relapsed or treatment-resistant IDH1-mutated acute myeloid leukemia. It is a more selective inhibitor than ivosidenib and offers an alternative in that setting, with a somewhat different side effect profile. Reported complete remission rates are broadly similar, though no trial has directly compared the two drugs.

Both are taken by mouth. Which one is used depends on a center’s experience, other medications being taken, and whether one has already been tried.

What does an IDH2 mutation mean?

An IDH2 mutation means leukemia cells produce 2-HG through the IDH2 enzyme, blocking maturation in the same way as an IDH1 mutation. One targeted drug is approved for IDH2-mutated acute myeloid leukemia, and it is a different drug from those used for IDH1. The two are not interchangeable because each inhibitor only fits the enzyme it was designed for.

Enasidenib (Idhifa) was approved by the FDA in 2017 for relapsed or treatment-resistant IDH2-mutated acute myeloid leukemia, and remains the only approved IDH2 inhibitor. It blocks the mutated IDH2 enzyme, lowering 2-HG and allowing leukemia cells to begin maturing. In the trial supporting its approval, roughly 40 percent of people had an overall response, and median survival was about 9.3 months, in a group with few other effective options. Complete remission was reached in roughly 1 in 5. Enasidenib works against both R140 and R172 mutations.

For newly diagnosed IDH2-mutated disease,e there is no approved IDH2 inhibitor, so initial treatment follows the standard approach for acute myeloid leukemia. Combinations pairing enasidenib with azacitidine or with intensive chemotherapy are under study, and a clinical trial may be an option worth asking about.

What does a negative IDH result mean?

A negative IDH result means the cells tested showed neither an IDH1 nor an IDH2 mutation. The other findings, including FLT3, NPM1, CEBPA, TP53, and the chromosome result, then guide risk classification and treatment.

A negative result is not, by itself, good or bad news about outlook. It means only that IDH inhibitors are not an option. As with a positive result, repeat IDH testing if the leukemia returns, because a mutation can appear that was not there at diagnosis.

IDH mutations and risk group

This is the part most often misunderstood, so it is worth stating plainly. An IDH1 or IDH2 mutation does not place acute myeloid leukemia into a risk group, and it does not define a subtype of the disease.

Neither gene appears among the changes that define acute myeloid leukemia in the current World Health Organization and International Consensus classifications. Neither appears in the favorable, intermediate, or adverse categories of the European LeukemiaNet risk system, most recently revised in 2022. That system is built from other findings: the chromosome result, NPM1, CEBPA, FLT3, TP53, and the myelodysplasia-related genes.

What this means in practice is that the outlook for a person with an IDH-mutated leukemia is set almost entirely by what else was found. An IDH mutation alongside an NPM1 mutation with no FLT3 internal tandem duplication sits in the favorable group, because of the NPM1 result. The same IDH mutation alongside a TP53 mutation sits in the adverse group, because of the TP53 result. If a source describes IDH mutations as carrying an intermediate prognosis on their own, it is describing an older understanding.

IDH status changes treatment, and that is not a small matter. Having a targeted option available, particularly for relapsed leukemia, is a meaningful advantage over having none.

Using IDH mutations to follow treatment

Because the same IDH mutation can be measured again after treatment, IDH testing is sometimes repeated to see how deeply the leukemia has responded. A falling VAF during treatment generally indicates that the leukemia is responding.

Interpreting a persistently positive result is harder, and this is an important caution. IDH1 and IDH2 mutations can arise in a pre-leukemic clone, a population of blood-forming cells that carries the mutation but is not itself leukemia. That clone can survive treatment and remain detectable in someone whose leukemia is in remission. A detectable IDH mutation after treatment therefore does not always mean residual leukemia. IDH is a less reliable marker for this purpose than an NPM1 mutation or a fusion gene.

For this reason, most centers use measurable residual disease, sometimes still called minimal residual disease, defined by flow cytometry or another molecular marker when available. The IDH result is treated as supporting information. Your hematologist will explain which method is being used in your case and how much weight a given IDH result carries.

Differentiation syndrome

IDH inhibitors work by allowing leukemia cells to mature, a process called differentiation. In some people this happens rapidly, and a large number of maturing leukemia cells are released into the bloodstream at once. This can trigger a serious reaction called differentiation syndrome, and anyone taking an IDH inhibitor should know about it.

Differentiation syndrome causes inflammation throughout the body. Symptoms include fever, difficulty breathing, fluid building up in the lungs or around the heart, low blood pressure, rapid weight gain from fluid retention, and kidney injury. It can develop within days to weeks of starting an IDH inhibitor, and sometimes later in treatment.

It can be life-threatening if it is not recognized and treated promptly. Treatment is a steroid called dexamethasone, which reduces the inflammation, and in severe cases the IDH inhibitor is stopped temporarily. The reaction is not a sign that the drug is failing. It can mean the opposite, that leukemia cells are responding and beginning to mature.

If you are taking an IDH inhibitor and develop new or worsening shortness of breath, fever, or unexplained weight gain, contact your medical team immediately. Do not wait for a scheduled appointment. Your team will watch for this closely during the first weeks of treatment. Reporting symptoms early is among the most useful things you can do while on one of these drugs.

IDH mutations in other cancers

IDH1 and IDH2 mutations are not unique to acute myeloid leukemia. They also occur in myelodysplastic syndrome, where they carry similar implications. Ivosidenib is FDA-approved for relapsed or refractory IDH1-mutated myelodysplastic syndrome, and enasidenib has been studied in IDH2-mutated disease. If your report identifies an IDH mutation and your diagnosis is myelodysplastic syndrome rather than leukemia, your hematologist will explain whether an IDH inhibitor applies.

IDH mutations are also found in some solid tumors, most notably cholangiocarcinoma, a cancer of the bile ducts, and certain brain tumors. The drugs used and the clinical situation are different there. Information written about IDH inhibitors in those settings does not transfer to acute myeloid leukemia, even though the same genes are involved.

What happens next?

For someone newly diagnosed with IDH-mutated acute myeloid leukemia who is fit for intensive treatment, standard induction chemotherapy is usually the first step. The IDH result does not change that. It matters for what follows and for the plan if the leukemia returns.

For someone not fit for intensive chemotherapy with an IDH1 mutation, ivosidenib combined with azacitidine is an approved first-line option. No equivalent approved combination exists for IDH2, so clinicians use a standard lower-intensity approach and may discuss a clinical trial.

If the leukemia returns or does not respond, an IDH inhibitor becomes a core option: ivosidenib or olutasidenib for IDH1, enasidenib for IDH2. Other salvage treatments and clinical trials are considered alongside it, and whether a stem cell transplant is possible is usually revisited at the same time.

If you have been diagnosed with acute myeloid leukemia and IDH testing has not yet been done, it is reasonable to ask when the molecular results will be available. It is also reasonable to ask how they will shape the plan.

Questions to ask your doctor

Do I have an IDH1 mutation, an IDH2 mutation, or neither?
Which specific change was found, and what is the variant allele frequency?
What other mutations were found alongside it, and what risk group do they place me in?
Given that IDH status does not itself set the risk group, what is driving my risk classification?
Is an IDH inhibitor an option for me now, or would it be used later if the leukemia returns?
Which IDH inhibitor applies to my mutation, and would it be given alone or with other treatment?
Am I being treated with intensive chemotherapy, or is a lower-intensity approach more appropriate?
What are the signs of differentiation syndrome, and who do I contact if I develop them?
Will my IDH mutation be measured again during treatment, and how will that result be used?
If my IDH mutation stays detectable in remission, what would that mean?
Is a stem cell transplant being considered, and does my IDH result affect that decision?
Will IDH testing be repeated if my leukemia comes back?
Are there clinical trials of IDH-targeted treatments that I should know about?