The mutational profile of patients with acute myeloid leukemia (AML) can have profound effects on their disease progression and treatment regimens. In 2017 the World Health Organization recognized AML with nucleophosmin (NPM1) gene mutations (~30% of AML cases) as a distinct disease entity. To discuss the current state of treatment for this leukemia, Brunangelo Falini, MD, professor of hematology at the University of Perugia in Italy, and associates, presented a case study including 4 patients with NPM1-mutated AML, which was published in the journal Blood.

Treatment Plan

To determine the optimal therapeutic strategy, patients should be assessed for NPM1 mutation in marrow blasts (³20% required for diagnosis) and the specific mutation type. Assessing additional gene mutations is prudent, as NPM1 mutations have been found in combination with mutations such as Abelson murine leukemia kinase 1 (ABL1), runt-related transcription factor 1 (RUNX1), and fms-related receptor tyrosine kinase 3 (FLT3), and the expression of mutants may alter clinical progression.

“Selection of the best treatment strategy for patients with NPM1-mutated AML can be potentially refined by combining the European LeukemiaNet prognostication model with the results of minimal residual disease (MRD) evaluated by quantifying mutant NPM1 transcript copies at diagnosis and after therapy,” noted Dr Falini in an interview.


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Unlike other leukemia-associated gene mutations, NPM1 mutants do not drive clonal hematopoiesis and are good targets for MRD monitoring.

Dr Falini continued, “MRD monitoring during treatment and follow-up is essential for defining the best postremission therapy (which can include allogeneic hematopoietic stem cell transplantation) and predicts disease relapse by detecting rising levels of mutant NPM1 transcripts with the possibility of intervening early and treating patients with low burden of disease who are in better clinical condition.”

NPM1-mutated AML without co-occurring mutations

Case 1

A man aged 60 years presented with skin nodules, which, upon biopsy showed leukemic involvement. NPM1 mutation A was detected. Following “7+3” induction chemotherapy, the patient was in complete remission with a 3.9-log reduction of mutant NPM1 transcripts and MRD negativity after the second cycle.

At 6 months, NPM1 mutant transcripts began to progressively increase in his bone marrow. He was given off-label dactinomycin and received allogeneic hematopoietic stem cell transplantation (HSCT). At >3 years, he remains in complete remission.

The researchers noted that allogeneic HSCT is not recommended in the first complete remission for patients with AML who present with NPM1 mutations and not FLT3 internal tandem duplication (FLT3-ITD) mutations. In addition to chemotherapy, recent studies have suggested patients without an FLT3 mutation may have reduced risk for relapse with gemtuzumab ozogamicin.

Case 2

A man aged 76 years presented with pneumonia and fever, his bone marrow had been infiltrated by AML (40% of blasts), and NPM1 mutation A was detected. Due to his age and overall frailty, he was not a good candidate for chemotherapy. The patient was recruited for a clinical trial and given dactinomycin. He achieved clinical remission with greater than 3-log reduction of NPM1 transcripts.

At 10 months, this patient relapsed and was given off-label venetoclax with 5-azacytidine. At the publication of this case study, he was in his fifth cycle of therapy with a reduction of NPM1 mutant transcripts.

The investigators noted that in their experience, “low [white blood cell] count is still consistent with a diagnosis of NPM1-mutated AML, especially in cases with wild-type FLT3,” which was observed in the patient (white blood cell count 870/μL).

Although patients with advanced age in general have poorer clinical outcomes compared with their younger counterparts, recent studies incorporating venetoclax into the treatment plan for frail patients appears to be safe and efficacious.