NPM1-mutated AML with co-occurring mutations

Case 3

A man aged 58 years presented with fatigue, gingival hyperplasia, and bleeding. He had cytoplasmic expression of NPM1 and bone marrow examination confirmed NPM1 mutation A and FLT3-ITD. His ratio of mutant to wild-type FLT3 transcripts was 0.9, putting him at higher risk for poorer clinical outcomes. He was given a 7+3 chemotherapy induction and achieved clinical remission with a 1.7-log reduction of NPM1 mutant transcripts and an FLT3-ITD ratio of 0.01. He received a bone marrow transplant and remains in remission at 5 years.

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The investigators noted that patients with NPM1-mutated AML who also have an FLT3 mutation should receive an FLT3 inhibitor in addition to their chemotherapy. At the time of treatment, FLT3 inhibitors were not yet approved for NPM1-mutated AML.

Case 4

A woman aged 68 years presented with fatigue, dyspnea, and chest pain. She exhibited cytoplasmic expression of NPM1, had NPM1 mutation A, co-expressed myeloperoxidase and macrophage-restricted CD68, and was CD34 negative. She received a 7+3 chemotherapy induction which resulted in a 4-log reduction of NPM1 mutated transcripts, entering remission.

At 14 months, she developed a fever and thrombocytopenia. Her bone marrow examination showed myelodysplastic syndrome without NPM1 mutations. Karyotyping uncovered a deletion of tumor protein p53 (TP53). She was administered 2 cycles of 5-azacytidine. Although her platelet count recovered, the TP53 deletion remained in 90% of nuclei. She underwent haploidentical HSCT and remains in cytogenetic complete remission after 2.5 years.

Relapse of AML with no NPM1 mutation is observed in approximately 10% of patients. Such a case can occur by either a secondary independent AML diagnosis or a therapy-related event. For this patient, her recurrence without an NPM1 mutation was determined to be therapy related.

Future Directions

Although great progress over the last decade has been made for the diagnosis and treatment of NPM1-mutated AML, several aspects of the disease warrant further research, including diagnostic criteria (requiring ³20% of blasts), implications from individual NPM1 mutations (rare vs commonly observed mutations), and new therapeutics (combinatorial therapies such as gene inhibitors and venetoclax).

When asked about the future of therapies for this disease, Dr Falini stated “promising future new agents in NPM1-mutated AML include exportin 1 (XPO1) and MLL-Menin inhibitors, alone or in combination with FLT3 inhibitors, and the results from ongoing phase 1/2 studies combining venetoclax with gilteritinib ( Identifier: NCT03625505) or quizartinib ( Identifier: NCT03735875).”

Disclosure: Multiple authors declared affiliations with industry. Please refer to the original article for a full list of disclosures.


Falini B, Brunetti L, Martelli MP. How I diagnose and treat NPM1-mutated AML. Blood. Published online November 20, 20202. doi:10.1182/blood.2020008211