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PubMed This is a summary of 24 peer-reviewed journal articles Updated
Oncology

How Do FLT3 and NPM1 Mutations Affect AML?

At a Glance

In acute myeloid leukemia (AML), an isolated NPM1 mutation is generally favorable and responds well to standard chemotherapy. A FLT3 mutation is more aggressive and increases relapse risk, but can be effectively treated by adding targeted FLT3 inhibitor drugs to your chemotherapy plan.

In this answer

4 sections

01

What is an NPM1 Mutation?

02

What is a FLT3 Mutation?

03

How NPM1 and FLT3 Interact

04

Targeted Treatments for FLT3 Mutations

When you are diagnosed with acute myeloid leukemia (AML), your doctor will test your blood or bone marrow biopsy sample for specific genetic changes, or mutations. Two of the most common and important mutations in AML are in the FLT3 and NPM1 genes. Having one or both of these mutations tells your care team how aggressive your leukemia is likely to be, what the risk of relapse is, and which specific drugs or treatments will work best for you.

What is an NPM1 Mutation?

The NPM1 (Nucleophosmin 1) gene normally helps control cell growth and division. When this gene is mutated, it causes the leukemia cells to multiply too quickly without maturing properly.

If you have an NPM1 mutation but do not have a FLT3 mutation (often called an “isolated NPM1 mutation”), this is generally considered very good news [1][2]. AML with an isolated NPM1 mutation typically responds very well to standard chemotherapy, putting you in a “favorable-risk” category [1][3]. There is currently no approved targeted daily pill specifically for an NPM1 mutation because standard chemotherapy is already highly effective for it. Many patients with this isolated mutation can achieve a complete remission—meaning the leukemia is no longer detectable—and long-term survival with chemotherapy alone, often without needing a stem cell transplant in their first remission [3][4].

What is a FLT3 Mutation?

The FLT3 (FMS-like tyrosine kinase 3) gene acts like an “on” switch for blood cell growth. When mutated, the switch gets stuck in the “on” position, making the leukemia cells multiply rapidly. There are two main types of FLT3 mutations, and they affect the leukemia differently:

  • FLT3-ITD (Internal Tandem Duplication): This is the more common and more aggressive type [5]. If you have an isolated FLT3-ITD mutation (without an NPM1 mutation), it places the leukemia in a higher-risk category with a greater chance of relapse after standard chemotherapy [5][6]. Because of this higher relapse risk, patients with FLT3-ITD often need a stem cell transplant after they reach remission [5][7].
  • FLT3-TKD (Tyrosine Kinase Domain): This is a different type of mutation in the same gene [8]. It generally has a more favorable outcome than the ITD mutation and does not increase the risk of relapse as severely [8].

How NPM1 and FLT3 Interact

Sometimes, AML cells have both NPM1 and FLT3 mutations at the same time [9]. Because an NPM1 mutation is favorable and a FLT3-ITD mutation is aggressive, they pull your risk level in opposite directions.

Under current medical guidelines, the presence of a FLT3-ITD mutation typically overrides the favorable benefits of the NPM1 mutation [6][10]. If you have both, you are generally placed in an “intermediate-risk” category, and your doctor will likely recommend a stem cell transplant to reduce the chance of the leukemia returning [11][6][12].

Targeted Treatments for FLT3 Mutations

In the past, FLT3 mutations were very difficult to treat. Today, however, there is a class of highly effective targeted drugs called FLT3 inhibitors that specifically block the broken FLT3 “on switch” from working [13][14].

If your leukemia has a FLT3 mutation, your doctor can add these targeted drugs to your treatment plan:

  • Midostaurin and Quizartinib: These are FLT3 inhibitors that are often added to standard intensive chemotherapy for newly diagnosed patients [13][15]. Adding these drugs has become standard of care and significantly improves survival rates [16][17].
  • Gilteritinib: This is a newer, highly selective FLT3 inhibitor [18][19]. It is primarily used on its own if the leukemia comes back (relapses) or does not respond to initial treatment (refractory) [18][20]. It has also been shown to work even if you were previously treated with another inhibitor like midostaurin [21].

FLT3 inhibitors may also be used as a “maintenance” therapy (a daily pill) after a stem cell transplant to help keep the leukemia from coming back [22][23]. While these drugs are very effective, they can have side effects like low blood counts or heart rhythm changes, so your doctor will monitor you closely [20][24].

Common questions in this guide

What does an isolated NPM1 mutation mean for AML?
An isolated NPM1 mutation generally places acute myeloid leukemia in a favorable-risk category. It usually responds very well to standard chemotherapy, and many patients can achieve long-term survival without needing a stem cell transplant during their first remission.
What is the difference between FLT3-ITD and FLT3-TKD mutations?
FLT3-ITD is a more common and aggressive mutation that increases the risk of the leukemia returning after treatment. FLT3-TKD is a different mutation in the same gene that typically has a more favorable outcome and a lower risk of relapse.
How is AML treated if I have a FLT3 mutation?
If your leukemia has a FLT3 mutation, your doctor will likely add a targeted drug called a FLT3 inhibitor to your chemotherapy. These medications, such as midostaurin, quizartinib, or gilteritinib, specifically block the mutation from causing rapid cancer cell growth.
What happens if my AML has both NPM1 and FLT3-ITD mutations?
Having both mutations usually places you in an intermediate-risk category, as the aggressive nature of the FLT3-ITD mutation typically overrides the favorable benefits of the NPM1 mutation. In this situation, doctors often recommend a stem cell transplant to reduce the chance of relapse.

Questions to Ask Your Doctor

Curated prompts to bring to your next appointment.

  1. 1.Does my leukemia have a FLT3-ITD, FLT3-TKD, or NPM1 mutation, and what does this specific combination mean for my risk category?
  2. 2.Do I have an isolated NPM1 mutation, and if so, does that mean we can avoid a stem cell transplant during my first remission?
  3. 3.Which FLT3 inhibitor, such as midostaurin or quizartinib, do you recommend adding to my initial treatment plan?
  4. 4.How frequently will you monitor my heart rhythm and blood counts while I am taking a FLT3 inhibitor?
  5. 5.Should we begin searching for a stem cell donor now based on my mutation profile?

Questions For You

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References

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This page is for informational purposes only and does not replace professional medical advice. Always consult your hematologist or oncologist about your specific AML mutation profile and treatment plan.

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