AML: Understanding FLT3 and NPM1 Mutations

When you are diagnosed with acute myeloid leukemia, your blood or bone marrow goes for molecular testing. That is a test that checks for certain genes, proteins, or other molecules in a sample. Two gene names come up often in AML: FLT3 and NPM1. This page explains what each one is and why it is tested. It also covers what the National Cancer Institute's patient information does and does not say about it.

There are two reasons. First, a gene change can help define the disease. For newly diagnosed AML, at least 20% of the cells in the bone marrow are blasts (leukemia cells) or there are certain gene changes. So molecular results can be part of the diagnosis itself.

Second, and more immediately, one of these results can change which drugs you are offered. That is true of FLT3.

Genetic changes in FLT3 are common in people diagnosed with AML. Roughly 25% to 30% of AML cases carry a FLT3 mutation. These mutations go with a particularly aggressive form of the disease.

There are two main types. Your report will usually name which one you have:

• ITD (internal tandem duplication) is present in about one-quarter of people diagnosed with AML.
• TKD (tyrosine kinase domain) is the other. When people with the ITD mutation relapse, it is often because a TKD mutation has developed.

What it means for outlook. Certain genetic changes in FLT3 make AML more troublesome. They raise the chance that the cancer will come back after the first round of treatment, and they make it less likely to respond to other treatments. This is why the result is not simply filed away. It shapes how intensively your team plans to treat.

What it means for treatment. Combination chemotherapy with targeted therapy — midostaurin or quizartinib — is a treatment option for people whose AML has a mutation in the FLT3 gene. The drugs are not interchangeable. Quizartinib was designed specifically to target AML cells with the ITD mutation. Midostaurin and gilteritinib target both ITD and TKD mutations. Gilteritinib also appears among the targeted therapy options for AML that has come back after treatment. People with a FLT3 ITD mutation typically receive a stem cell transplant as standard consolidation therapy, meaning treatment that follows the first round, when they are healthy enough for one.

How it is tested. These drugs are paired with approved tests that confirm the mutation, called companion diagnostics. Midostaurin's approval requires the use of the LeukoStrat CDx FLT3 Mutation Assay. A blood test to identify patients with the FLT3 ITD mutation was approved alongside quizartinib. If your team is considering one of these drugs, the specific test used matters. It is reasonable to ask which one was run.

NPM1 mutations are one of the two most common gene changes in AML, along with KMT2A rearrangements. NCI describes what these changes do to a cell. They cause blood cells to regress, or dedifferentiate, and behave like the stem cells they came from. The result is that leukemia cells form instead of working blood cells.

Together, the genes that depend on a protein called menin are involved in roughly 40% to 50% of all acute myeloid leukemias. That is the basis for a newer class of drug called a menin inhibitor. Revumenib, a menin inhibitor, is listed among the targeted therapies for AML that has come back.

There is also one point where the two genes on this page meet. The negative impact of the FLT3 ITD mutation is strongest in people whose AML also has NPM1 mutations. If your report names both, that combination is worth raising specifically.

Be aware of a gap. NCI's patient summary on adult AML treatment does not discuss NPM1 at all. It does not state what an NPM1 mutation on its own means for your outlook. It does not list a treatment that is chosen because of an NPM1 result in newly diagnosed disease. More detail exists in NCI's version written for health professionals. That version is not written for you and can be easy to misread.

So if NPM1 appears on your report, ask your team directly:

• Is my NPM1 mutation being counted as a favorable finding, and what does that mean in my case?
• Does it change whether you recommend a stem cell transplant?
• Does it change how you will monitor me for relapse?
• Is a menin inhibitor or a clinical trial relevant to me now or later?

• Which molecular tests were run on my sample, and which are still pending?
• Do I have a FLT3 mutation, and is it ITD or TKD?
• If I have a FLT3 mutation, is midostaurin, quizartinib, or gilteritinib part of my plan?
• How do my FLT3 and NPM1 results together affect the transplant decision?
• Will these genes be retested if the leukemia comes back?

• National Cancer Institute — Acute Myeloid Leukemia Treatment (PDQ) Patient Version
• National Cancer Institute — FDA Approves Vanflyta for FLT3-Mutated AML
• National Cancer Institute — Midostaurin Approved by FDA for Acute Myeloid Leukemia
• National Cancer Institute — Revumenib Shows Promise for Advanced Acute Myeloid Leukemia