NPM1 is the most frequent mutation found in AML. It interacts with other proteins to block cell growth and stops DNA from repairing any cell damage. NPM1 mutations occur in 30% of all adult AML cases, but has a favorable diagnosis if there is an absence of the FLT3 mutation. “The overall survival rate is about 40% and complete remission (CR) rate is about 80%.”

The NPM1 mutation is only involved in cancerous cells and is not inherited. It is an abundant protein that moves between the nucleus (which contains the chromosomes) and the cytoplasm (the fluid where most cell interactions occur). It is more commonly found in females (even though AML is more common in males) and in those with a higher bone marrow blast percentage.

The prognosis is often dependent on other co-occurring mutations. The combination of the FLT3 mutation causes severe side effects, a worse prognosis and high relapse rates. “NPM1 mutations are persistent throughout the course of AML and disappear with remission.” If they are present after completing treatment, a stem cell transplant may be necessary.

The standard therapy for NPM1 is 7+3 induction chemotherapy (the first treatment given) and consolidation therapy (treatment given after relapse). MRD (measurable residual disease) monitoring is essential to establish a risk for relapse. MRD negativity after treatment predicts a low risk for relapse and a good chance for survival. MRD-positive patients require additional treatment.

According to recommendations, patients undergoing standard treatment should be tested “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.”

Targeting NPM1

Patients with the NPM1 mutation usually express high levels of CD33. This combination may be successfully treated when gemtuzumab ozogamicin is added to the chemotherapy regimen. And, “combining venetoclax with hypomethylating agents or low-dose cytarabine is emerging as the standard of care” for older, unfit patients.

Venetoclax regimens are also recommended for an alternative to standard chemotherapy. It is a potent and effective small-molecule inhibitor that has shown promising results when combined with hypomethylating agents (HMAs) or low-dose cytarabine (LDAC). FLT3 inhibitors should be used if this mutation is present. And, using engineered T cells against the NPM1 mutation has been shown to be successful. 

Studies have indicated that menin inhibitors can reverse leukemic activity. “Targeting menin could be a therapeutic strategy in NPM1-mutated AML.” Treatment success has been shown when combining menin inhibitors with FLT3 inhibtors. XPO1 inhibitors (selinexor and venetoclax) may be a promising approach.