NPM1 Mutation in AML: Prognosis, Testing, & Treatments

What is the NPM1 mutation in acute myeloid leukemia (AML)? How common is it, what is the prognosis for someone with this AML type, and how is it treated? Learn answers to these questions and more below!

Defining NPM1 Mutated AML 

The NPM1 gene provides cells with instructions for making a protein called nucleophosmin. This protein acts as a shuttle between the nucleus and cytoplasm, helping various cell processes like regulating cell replication, suppressing tumors, repairing DNA, and telling cells beyond repair to die. 

When the NPM1 gene is mutated (as seen in cancer cells like AML), the nucleophosmin protein does not work well, causing dysfunction in normal cellular processes. The NPM1 mutation in AML is commonly seen in approximately 30% of patients. 

It is also more commonly found in females (even though AML is more common in males) and in those with a higher bone marrow blast percentage.

NPM1 Mutated AML Prognosis 

You are considered to have low-risk AML if you have the NPM1 mutation without also having the FLT3 mutation. The average outcome for these patients following 7+3 induction chemotherapy and consolidation therapy is 80% of patients achieve complete remission, and about 40% of patients are still alive at the check-in point of three years after treatment. You may not need to be considered for an allogeneic stem cell transplant. 

If you have both the NPM1 mutation and the FLT3 mutation, this is a higher-risk AML type. You may experience a poor prognosis and a high relapse rate. NPM1 mutations can disappear once in remission. If you still have the NPM1 mutation and FLT3 mutation after treatment, considering a stem cell transplant is recommended.  

What Tests Evaluate the NPM1 Mutation in AML? 

Minimal residual disease (MRD) testing helps check for any remaining cancer cells after treatment and can also help identify whether AML cells contain the NPM1 mutation. 

MRD negativity means little to no cancer cells were found in a sample. For patients with the NPM1 mutation, this predicts a low risk for relapse and a good chance of survival. If you are MRD-positive, additional treatment is recommended to help manage the cancer. 

Recommendations for how often people with NPM1 mutated AML should receive an MRD test include: 

“At least at diagnosis, after 2 cycles of therapy, and at the end of treatment. MRD should be measured every 3 months for the first 2 years of follow-up. Then, timing of MRD monitoring should be personalized according to relapse risk.” - Dr. Brunangelo Falini.

Treatments for NPM1 Mutated AML 

The treatment for NPM1 mutated AML is not yet standardized; however, the treatment regimens below are recommended by specialists. 

• Venetoclax + HMAs 

  • If you are unable to receive standard intensive chemotherapy, a combination of venetoclax (Venclexta, AbbVie) and hypomethylating agents (HMAs) or low-dose cytarabine has proven to be effective. 

• Gemtuzumab ozogamicin + chemotherapy

  • AML cells with the NPM1 mutation usually express high levels of the surface protein CD33. The monoclonal antibody gemtuzumab ozogamicin (Mylotarg, Pfizer), which attaches to CD33, may be successful when added to chemotherapy. 

• FLT3 inhibitors

  • If your AML type includes an FLT3 mutation, FLT3 inhibitors like gilteritinib (Xospata, Astellas) and quizartinib (Vanflyta, Daiichi-Sankyo) are recommended.

• Engineered T-cells 

  • One study showed that engineered T-cells show promise in treating NPM1 mutated AML. 

• Menin inhibitors 

  • The menin inhibitor MI-3454 helped achieve remission in mouse models with NPM1 mutated AML. Future trials involving menin inhibitors may be a useful approach. 

Conclusion

The NPM1 mutation in AML is a genetic change found in about 30% of AML patients, mostly women. It affects how well the nucleophosmin protein works, which is important for many cell functions. The outlook for patients can change if they also have other mutations like FLT3, which can make the cancer harder to treat and affect treatment choices. These treatments can include standard chemotherapy and newer options like gemtuzumab ozogamicin, combinations of venetoclax, and possibly menin inhibitors. 

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Sources: 

• Targeted Therapy in NPM1-Mutated AML: Knowns and Unknowns

• Nucleophosmin 1 Mutations in Acute Myeloid Leukemia

• Which Gene Mutations are Categorized as Low, Intermediate, and High Risk AML? 

• NPM1-Mutated Acute Myeloid Leukemia: From Bench to Bedside 

• Mutated Nucleophosmin 1 as Immunotherapy Target in Acute Myeloid Leukemia 

• Menin Inhibitor MI-3454 Induces Remission in MLL1-Rearranged and NPM1-Mutated Models of Leukemia