FLT3 Mutations in Acute Myeloid Leukemia

by Kamran Mirza MBBS PhD FCAP
April 4, 2026

If your bone marrow or blood test results mention a FLT3 mutation, this refers to a change in a gene that controls how blood-forming cells grow and divide. FLT3 mutations are among the most common molecular findings in acute myeloid leukemia (AML), found in roughly 30% of adult cases. There are two distinct types — FLT3-ITD and FLT3-TKD —, and they behave differently, carry different prognostic implications, and are both targets for a group of drugs called FLT3 inhibitors. This article explains what type you have, what it means alongside other findings in your report, and how it shapes treatment decisions.

What the test looks for

The FLT3 gene provides instructions for making a protein — also called FLT3 — that sits on the surface of blood-forming cells in the bone marrow. FLT3 acts like a receiver. When the right signal arrives from outside the cell, it briefly activates and tells the cell to grow and divide. When the signal passes, it switches off again.

In AML, two different types of mutation can break this off switch in different ways:

FLT3-ITD (internal tandem duplication)

An internal tandem duplication — ITD — is a type of mutation where a short stretch of the gene’s code is copied and inserted twice, back to back, like a word accidentally typed twice in a row. This extra copied section sits inside a part of the FLT3 protein that normally keeps the receiver in the off position when no signal is present.

With this extra insertion in place, the off switch no longer works. The FLT3 protein stays permanently switched on, continuously telling leukemia cells to grow and divide — even when no signal is present. This constant, uncontrolled growth is one of the things that makes FLT3-ITD AML particularly aggressive.

FLT3-ITD is found in about 25% of all AML cases. It is one of the most important findings in AML because it significantly affects prognosis and predicts which patients are most likely to benefit from FLT3-targeted drugs.

FLT3-TKD (tyrosine kinase domain mutation)

A TKD mutation is a different kind of change — a single letter in the gene’s code is altered at a specific location inside the part of the FLT3 protein responsible for sending the growth signal. The most common TKD mutation is called D835.

This change also keeps the FLT3 protein switched on when it should be off, but through a slightly different mechanism than ITD. The protein’s signal-sending machinery is directly altered, rather than the off switch being disabled. FLT3-TKD mutations are found in about 5–10% of AML cases and generally carry a less severe impact on prognosis than FLT3-ITD, though they are still clinically relevant — particularly because some FLT3 inhibitor drugs work better against TKD mutations than others.

Why is the test done

FLT3 testing is performed as part of the standard molecular workup for all newly diagnosed AML cases. It serves three purposes: determining how aggressively the leukemia is likely to behave, deciding whether to add an FLT3 inhibitor to treatment, and assessing whether a stem cell transplant should be considered.

Because FLT3-ITD in particular is associated with a higher risk of relapse after chemotherapy, identifying it at diagnosis allows the treatment team to plan a more intensive approach from the start — rather than discovering the risk only after an initial treatment fails.

FLT3 testing is also performed at relapse, because the FLT3 mutation status can change between diagnosis and relapse. A patient whose AML was FLT3-negative at diagnosis can acquire a FLT3 mutation at relapse, and vice versa. Testing at relapse ensures treatment decisions are based on the current biology of the leukemia rather than its original profile.

How the test is performed

FLT3 mutations are detected from a bone marrow sample or, in some cases, a blood sample when the leukemia is circulating in high numbers. The DNA extracted from leukemia cells is analyzed in the laboratory using one of two approaches.

The most common method is fragment analysis combined with sequencing — a targeted test that examines the regions of the FLT3 gene where ITD and TKD mutations occur. This test is fast and reliable and is used at most specialist centers.

Next-generation sequencing (NGS) — a technology that reads the genetic code of the leukemia cells across many genes at once — is increasingly used as the primary diagnostic platform. NGS can detect FLT3-ITD and FLT3-TKD alongside dozens of other clinically relevant mutations in a single test. This comprehensive approach is particularly valuable in AML because the full combination of mutations present, not just FLT3 alone, is what most accurately predicts how the disease will behave.

One important limitation of standard NGS is that it can sometimes miss very small FLT3-ITD insertions or report them inaccurately. For this reason, dedicated fragment analysis is still often performed alongside NGS when FLT3-ITD is specifically in question.

How results are reported

Positive or negative

The basic result is reported as FLT3-ITD detected or not detected, and FLT3-TKD detected or not detected. The specific mutation is described — for example, the size of the inserted sequence in an ITD mutation, or “FLT3 D835Y” for a TKD mutation.

The allelic ratio — a number that matters

For FLT3-ITD, the report also includes an allelic ratio. This measures the proportion of FLT3 gene copies in leukemia cells carrying the ITD mutation relative to normal copies.

Think of it this way: most of your cells contain two copies of every gene — one inherited from each parent. In a leukemia cell, an FLT3-ITD mutation affects one or both copies of the FLT3 gene. The allelic ratio compares the amount of mutated FLT3 to the amount of normal FLT3 in the sample. A ratio of 0.5 means the mutated version is half as abundant as the normal version — suggesting that roughly one copy is mutated. A ratio above 0.5 means there is more mutated FLT3 than normal FLT3, which can happen when leukemia cells duplicate the mutated copy, amplifying the signal further.

A high allelic ratio — generally defined as 0.5 or above — is associated with a worse outlook than a low allelic ratio. Leukemia cells with more mutated FLT3 relative to normal FLT3 receive a stronger, more persistent growth signal. This is why the allelic ratio is reported alongside the basic positive or negative result and why your treatment team will consider it when making decisions about treatment intensity and stem cell transplantation.

What the result means

FLT3-ITD detected

A positive FLT3-ITD result means the leukemia cells carry this mutation and are being driven to grow by a permanently switched-on FLT3 receptor. FLT3-ITD is associated with a higher white blood cell count at diagnosis, a higher rate of early relapse after chemotherapy, and — without targeted treatment — a poorer long-term outlook than FLT3-negative AML.

However, the impact of a FLT3-ITD result depends heavily on two other factors: the allelic ratio and the presence or absence of an NPM1 mutation.

When FLT3-ITD is present alongside a NPM1 mutation and the allelic ratio is low, the prognosis is considerably better than when FLT3-ITD occurs alone or with a high allelic ratio. This is because NPM1 mutations generally confer a favorable influence in AML and partially offset the negative impact of FLT3-ITD when the ITD burden is not too high. Risk classification systems used by hematologists, including the European LeukemiaNet (ELN) guidelines, take this combination into account when assigning patients to risk categories.

Patients with FLT3-ITD in the absence of NPM1 mutation, or with a high allelic ratio, are generally classified as intermediate to high risk and are typically offered more intensive treatment — including stem cell transplantation in first remission — than lower-risk patients.

FLT3-TKD detected

A positive FLT3-TKD result indicates the leukemia harbors a point mutation in the signal-sending domain of the FLT3 protein. FLT3-TKD mutations generally carry a less severe effect on prognosis than FLT3-ITD. In the current ELN classification, FLT3-TKD alone does not automatically place a patient in a higher-risk group, unlike FLT3-ITD.

FLT3-TKD mutations are still clinically important, however, because some FLT3 inhibitor drugs — particularly gilteritinib — are active against both ITD and TKD mutations. Identifying a TKD mutation at relapse, in particular, may open the door to targeted treatment.

FLT3 not detected

A negative FLT3 result means neither ITD nor TKD mutations were found in the leukemia cells tested. Risk classification and treatment decisions will be guided by the other molecular findings in the report — such as NPM1, CEBPA, IDH1, IDH2, and others — as well as the overall chromosomal picture.

It is worth knowing that FLT3-ITD mutations can appear or disappear between diagnosis and relapse. A negative result at diagnosis does not permanently rule out FLT3 involvement if the leukemia returns, which is why testing is repeated at relapse.

FLT3 inhibitors: the drugs that target FLT3

FLT3 inhibitors are drugs that bind to the FLT3 protein and block its ability to send growth signals. With the signal blocked, the leukemia cells that depend on constant FLT3 activity lose a key driver of their growth.

Three FLT3 inhibitors are currently approved for AML:

Midostaurin (Rydapt). The first FLT3 inhibitor approved for AML. It is added to standard chemotherapy — specifically the combination of cytarabine and daunorubicin, often called “7+3” — for newly diagnosed FLT3-positive AML in patients fit for intensive treatment. In the RATIFY trial, adding midostaurin to chemotherapy improved overall survival compared to chemotherapy alone, with five-year survival of approximately 51% in the midostaurin group versus 44% in the chemotherapy-only group. Midostaurin is active against both FLT3-ITD and FLT3-TKD mutations.
Gilteritinib (Xospata). A more powerful and more selective FLT3 inhibitor, approved for relapsed or treatment-resistant FLT3-positive AML — meaning AML that has come back or stopped responding to prior treatment. In the ADMIRAL trial, gilteritinib achieved an overall survival of approximately 9.3 months compared to approximately 5.6 months with standard salvage chemotherapy — a meaningful improvement in a setting where effective options are limited. Gilteritinib is active against both FLT3-ITD and FLT3-TKD mutations, including some that confer resistance to other FLT3 inhibitors.
Quizartinib (Vanflyta). A highly selective FLT3-ITD inhibitor, approved for newly diagnosed FLT3-ITD-positive AML in combination with chemotherapy, and in some settings for relapsed disease. In the QuANTUM-First trial, adding quizartinib to standard chemotherapy and continuing it as maintenance therapy after remission improved overall survival compared to chemotherapy alone, with a three-year survival rate of approximately 33% versus 26%. Quizartinib is specific to FLT3-ITD and is not active against FLT3-TKD mutations.

The choice of which FLT3 inhibitor to use, and when, depends on your mutation type (ITD versus TKD), whether you are newly diagnosed or have relapsed, and your overall health. Your hematologist will discuss which option applies to your situation.

FLT3 mutations and stem cell transplantation

For many patients with FLT3-ITD AML — particularly those with a high allelic ratio or without an NPM1 co-mutation — allogeneic stem cell transplantation is recommended in first remission. A stem cell transplant uses healthy blood-forming cells from a donor to replace the patient’s own bone marrow after it has been treated with high-dose chemotherapy. It offers the best chance of long-term disease control in high-risk AML by allowing the donor’s immune system to seek out and destroy any remaining leukemia cells.

The decision about transplantation depends on many factors beyond FLT3 status alone — including age, overall health, the availability of a suitable donor, and how the leukemia responds to initial chemotherapy. Your hematologist will discuss whether transplantation is appropriate for you and what it would involve.

Monitoring FLT3 after treatment

After treatment, FLT3-ITD can be used as a marker to check whether any leukemia remains — a concept called minimal residual disease (MRD) testing. MRD testing looks for very small traces of leukemia that are too few to be seen on a routine bone marrow examination. Finding residual FLT3-ITD signal after chemotherapy — even at very low levels — is associated with a higher risk of relapse, and this information can influence decisions about whether to proceed to stem cell transplantation or to continue maintenance therapy.

MRD monitoring using FLT3-ITD is more challenging than MRD monitoring for some other AML markers — such as NPM1 — because FLT3-ITD mutations can change between diagnosis and relapse, and because very sensitive detection of ITD mutations is technically more difficult. Your treatment team will explain how and whether MRD monitoring will be used to guide decisions in your case.

What happens next

For most patients with newly diagnosed FLT3-positive AML who are fit for intensive treatment, the next step is chemotherapy combined with a FLT3 inhibitor — typically midostaurin or quizartinib, depending on mutation type and local availability. Treatment usually begins quickly, given how rapidly AML can progress.

After the first round of chemotherapy — called induction — a bone marrow test is performed to check whether the leukemia has gone into remission. If remission is achieved, further treatment — called consolidation — follows. For FLT3-ITD-positive patients, particularly those at higher risk, this is when the discussion about stem cell transplantation typically takes place.

If your AML has relapsed or stopped responding to initial treatment, gilteritinib is the most commonly used FLT3-targeted option, and your hematologist will discuss it alongside other treatment possibilities, including clinical trials.

For patients who are not fit for intensive chemotherapy — due to age or other health conditions — gentler treatment combinations are available. These may include lower-intensity chemotherapy agents combined with a FLT3 inhibitor, or regimens specifically designed for older or less fit patients. Your hematologist will recommend the approach that best balances effectiveness with your ability to tolerate treatment.

Questions to ask your doctor

Do I have a FLT3-ITD mutation, a FLT3-TKD mutation, or both — and what does each mean for my treatment?
If I have FLT3-ITD, what is my allelic ratio, and how does it affect my risk classification?
Do I also have an NPM1 mutation, and how does the combination of FLT3 and NPM1 result change my outlook?
Which FLT3 inhibitor are you recommending, and will it be given alongside chemotherapy or on its own?
Based on my FLT3 result and overall risk category, is stem cell transplantation being considered for me?
Will my FLT3 status be tested again after treatment to check for remaining leukemia?
If my leukemia comes back, will FLT3 testing be repeated to guide the next treatment decision?
Are there clinical trials involving FLT3-targeted treatments that I should know about?