NPM1 Mutations in Acute Myeloid Leukemia

Section Editor: Kamran Mirza MBBS PhD FCAP
September 6, 2026

If your bone marrow or molecular test results mention an NPM1 mutation, this refers to a change in the NPM1 gene. It is found in roughly 30 percent of adults with acute myeloid leukemia, making it the single most commonly mutated gene in this disease.

An NPM1 mutation matters in three ways. It defines a subtype of acute myeloid leukemia. It is one of the more favorable findings when certain other mutations are absent. And it provides the most reliable marker available for tracking very small amounts of leukemia after treatment. Since 2025, it has also become a drug target, which is a change this article describes in detail.

What is NPM1, and what does the mutation do?

The NPM1 gene provides instructions for a protein called nucleophosmin. In a healthy cell, nucleophosmin works mainly inside the nucleus, the compartment at the center of the cell that holds the DNA. There, it helps assemble the machinery cells use to make proteins, helps repair damaged DNA, and helps control how and when cells divide.

Nucleophosmin shuttles between the nucleus and the surrounding cytoplasm, and a short signal sequence in the protein keeps pulling it back into the nucleus. When NPM1 is mutated, that return signal is disrupted. The protein becomes stranded in the cytoplasm, outside the compartment where it works, and the cell loses control over growth and division.

This mislocalization is the defining feature of NPM1-mutated leukemia. It is consistent enough that pathologists can detect it by staining cells with a dye that shows where the NPM1 protein sits. In a mutated cell, the stain lights up the cytoplasm rather than the nucleus, a pattern visible directly under the microscope. Nearly all NPM1 mutations in acute myeloid leukemia are small insertions into the same region of the gene, exon 12. Dozens of variants exist, and all produce the same effect, with the most common, type A, accounting for roughly 75 to 80 percent.

Why is the test done?

NPM1 testing is part of the standard molecular workup for everyone newly diagnosed with acute myeloid leukemia. The result serves three purposes: it helps define the diagnosis, it contributes to the risk group, and it establishes the marker used to follow the leukemia during and after treatment.

The role in defining the diagnosis is easy to miss. Under the current classifications, an NPM1 mutation is one of the genetic changes that establishes a diagnosis of acute myeloid leukemia on its own. The usual requirement for 20 percent or more blasts in the bone marrow does not apply. The diagnosis can therefore be made at a lower blast count than otherwise required.

How is the test performed?

NPM1 testing is performed on a bone marrow sample, or on blood when large numbers of leukemia blasts are circulating at diagnosis. Next-generation sequencing is the main method used at diagnosis, because it detects NPM1 alongside FLT3, IDH1, IDH2, TP53, and dozens of other relevant genes in a single test.

For post-treatment monitoring, clinicians use a more sensitive method called PCR. PCR can detect NPM1 mutation sequences at levels as low as one leukemia cell among 100,000 to 1,000,000 normal cells. This sensitivity makes NPM1 a valuable marker for follow-up because it finds traces of leukemia far below what any microscope can see.

How are results reported?

An NPM1 result at diagnosis is reported as mutation detected or not detected. When a mutation is found, the report identifies the specific variant, for example, NPM1 exon 12 insertion, type A. It usually also gives the variant allele frequency, meaning the proportion of the tested genetic material carrying the mutation. A high frequency at diagnosis means most of the leukemia cells carry it, which is typical.

Results measured after treatment are reported differently. They are given as the number of NPM1 mutation copies relative to a fixed number of copies of a reference gene, for example, 50 copies per 100,000 ABL1 copies. Some laboratories instead report the reduction from the level measured at diagnosis, expressed in logs. The units look technical, but what matters is whether the number is falling, stable, or rising.

What does an NPM1 mutation mean for risk group?

An NPM1 mutation is one of the more favorable molecular findings in acute myeloid leukemia. What it means for your risk group depends entirely on what else was found alongside it. The European LeukemiaNet system, most recently revised in 2022, is the international standard, and it changed its treatment of NPM1 in that revision.

NPM1 mutation with no FLT3-ITD. Favorable risk. Complete remission is achieved in roughly 80 to 90 percent of people with standard induction chemotherapy, and long-term survival is substantially better than in intermediate- or adverse-risk disease. Many people in this group are cured with chemotherapy alone.
NPM1 mutation with any FLT3-ITD. Intermediate risk. This change was made in 2022. The previous system divided FLT3-ITD results into high- and low-burden using a measure called the allelic ratio, and classified NPM1 with low-burden FLT3-ITD as favorable. The allelic ratio was removed because laboratories could not measure it consistently, so any FLT3-ITD now places this combination in the intermediate group.
NPM1 mutation with adverse-risk chromosome changes—adverse risk. Where the chromosome result includes a finding such as a complex karyotype or loss of chromosome 7, that finding takes precedence over the NPM1 mutation.

A report or a website from before 2022 may therefore describe the same combination of results more optimistically than your team does now. If the two accounts differ, the current classification is what your team uses to plan your treatment.

What does an NPM1 mutation mean for treatment?

For people with NPM1-mutated acute myeloid leukemia who are fit for intensive treatment, standard induction chemotherapy remains the backbone of initial care. This is usually cytarabine combined with an anthracycline such as daunorubicin. The NPM1 result does not change that first step, but it shapes what follows.

For older or less fit adults who cannot tolerate intensive chemotherapy, the combination of venetoclax with azacitidine is the standard approach. It has shown particularly strong activity in NPM1-mutated leukemia. Response rates in this group were among the highest seen in the trials that established the combination. This makes it a well-supported option for older adults whose leukemia carries an NPM1 mutation.

Menin inhibitors: NPM1 as a drug target

Until recently, no drug targeted NPM1-mutated leukemia specifically. That changed with a class of drugs called menin inhibitors, and this is the most important development in NPM1-mutated acute myeloid leukemia in many years.

The connection is biological. An NPM1 mutation disrupts a group of genes called HOX genes, keeping leukemia cells in an immature, dividing state. Menin is a protein those cells depend on to maintain that state. Blocking menin allows the cells to mature and die.

Two menin inhibitors are approved, both taken by mouth. Revumenib was approved in November 2024 for relapsed or treatment-resistant acute leukemia with a KMT2A translocation, and in October 2025 for relapsed or treatment-resistant NPM1-mutated acute myeloid leukemia. Ziftomenib was approved in November 2025 for adults with relapsed or treatment-resistant NPM1-mutated acute myeloid leukemia.

Both approvals are for leukemia that has come back or has not responded to earlier treatment, so a menin inhibitor is not part of first treatment outside a clinical trial. Trials combining these drugs with chemotherapy at diagnosis are underway. The class has a characteristic side effect called differentiation syndrome, in which maturing leukemia cells cause fever, breathlessness, and fluid retention, and it needs prompt treatment.

NPM1 and stem cell transplantation

For favorable-risk NPM1-mutated leukemia, meaning an NPM1 mutation with no FLT3-ITD, a stem cell transplant in first remission is generally not recommended when the leukemia clears completely after chemotherapy. The risks of transplantation outweigh the benefit when the disease has responded that well. This is worth knowing, because many people expect a transplant to be part of any leukemia plan.

For intermediate-risk NPM1-mutated leukemia, including cases with a FLT3-ITD and cases where residual leukemia remains detectable after induction, transplant is more likely to be recommended. The residual disease result after treatment is one of the main factors in that decision, sometimes more influential than the genetics measured at diagnosis.

Measurable residual disease monitoring

For NPM1-mutated acute myeloid leukemia, molecular monitoring is one of the most important parts of post-treatment care. It looks for measurable residual disease (MRD), meaning very small amounts of leukemia below what a microscope can detect. Older reports may call the same thing minimal residual disease.

Results fall into three patterns.

MRD negative. No NPM1 mutation copies detected. This is the deepest measurable response and the treatment target. Reaching it, particularly in the bone marrow after induction chemotherapy, is strongly associated with long-term remission.
MRD positive. Copies remain detectable, even at very low levels. A result that stays positive after chemotherapy, or that fails to fall far enough, is associated with a higher risk of relapse. The trend matters as much as the number.
MRD rising. An increase across two or more consecutive tests after a period of negativity or very low positivity. This is called molecular relapse, and it is often detectable weeks to months before the leukemia reappears in the blood count or bone marrow.

Bone marrow is preferred for the assessments that drive decisions, because blood is roughly ten times less sensitive for this test. Blood is often used for the routine checks in between, which avoids a bone marrow procedure at every visit. Testing is typically every one to three months in the first year, then less often. A single raised result does not mean the leukemia is returning, and your hematologist will look at the trend over time rather than any one number.

What does a negative NPM1 result mean?

A negative NPM1 result means the mutation was not found in the leukemia cells tested. The other findings, including FLT3, CEBPA, IDH1 and IDH2, TP53, and the chromosome result, then guide risk classification and treatment.

A negative result also means NPM1-based PCR cannot be used to follow the leukemia after treatment. Monitoring will use another method instead, usually flow cytometry, or PCR for a different marker if the leukemia carries one.

Are NPM1 mutations inherited?

NPM1 mutations in acute myeloid leukemia are almost always somatic. They develop in a blood-forming cell during a person’s lifetime and are not present in any other cells in the body. They are not passed to children, and a positive NPM1 result carries no implications for your biological relatives.

This is different from several other genes tested on the same panel. CEBPA, DDX41, RUNX1, and GATA2 mutations can be inherited, and finding one may lead to testing normal tissue and testing relatives. You can read more in our article, What is a hereditary cancer syndrome?

What happens next?

For most people newly diagnosed with NPM1-mutated acute myeloid leukemia who are fit for intensive treatment, induction chemotherapy begins within days of diagnosis. The NPM1 result, along with the FLT3 result and the chromosome findings, determines the risk group and shapes decisions about how intensive treatment after remission should be.

Once treatment begins, regular NPM1 PCR monitoring becomes part of routine follow-up. Your hematologist will explain how often testing will happen and what level of response is being aimed for. The goal is to reach and maintain MRD negativity, and the monitoring schedule adjusts as results change.

If the leukemia comes back, options include a menin inhibitor, salvage chemotherapy, venetoclax-based combinations, and clinical trials. A stem cell transplant may also be discussed at that point if it wasn’t part of the initial plan.

Questions to ask your doctor

Do I have an NPM1 mutation, and which specific variant is it?
Do I also have a FLT3-ITD, and what risk group do the two results together place me in?
My report gives a FLT3 allelic ratio. Does your team use that number, given that it was removed from the risk classification in 2022?
Were any adverse chromosome changes found that would override the favorable effect of the NPM1 mutation?
Based on my risk group, is a stem cell transplant being planned, or is chemotherapy alone the approach?
Will NPM1 PCR be used to monitor residual disease, and how often will testing happen?
Will monitoring use bone marrow, blood, or both, and at which points?
What would a persistently positive result after induction mean for my treatment plan?
If the level rises during follow-up, when would that change management?
Is venetoclax-based treatment being considered for me?
If my leukemia comes back, would a menin inhibitor be an option?
Are there clinical trials involving menin inhibitors or other NPM1-directed treatments that I should know about?