Döhner K et al. (2005) Mutant nucleophosmin (NPM1) predicts favorable prognosis in younger adults with acute myeloid leukemia and normal cytogenetics—interaction with other gene mutations. Blood [doi: 10.1182/blood-2005-05-2164]

Around 50% of patients with acute myeloid leukemia (AML) do not show chromosomal aberrations on conventional analysis. A study has shown that NPM1 mutations in the absence of FLT3 internal tandem duplications (ITDs) define a distinct molecular and prognostic subclass of young adult AML patients with normal cytogenetics.

The nucleophosmin (NPM1) gene is known to be involved in a number of chromosome translocations associated with leukemia and lymphoma, and mutations in this gene are the most frequent events identified in adult AML with normal karyotype. This trial examined the incidence and prognostic relevance of NPM1 mutations in a series of 300 homogenously treated adults (16–60 years old) with AML and normal cytogenetics. Treatment regimens included double-induction therapy and consolidation therapy with high cumulative doses of cytarabine. Mutations in NPM1 were seen in 48% of patients and were associated with specific clinical, phenotypic and genetic features. The potential association of these mutations with FLT3 and CEBPA mutations was also examined, showing a significant interaction of NPM1 and FLT3 ITDs. The presence of NPM1 mutations predicted better response to induction therapy and multivariate analysis showed that NPM1-mutated/FLT3 ITD-negative status and mutated CEBPA were predictive of favorable overall survival (P <0.0001 and P = 0.05, respectively).

Comprehensive molecular screening can allow for the classification of subclasses within young adult AML patients. It could lead to improved risk stratification and better treatment outcome, while minimizing toxicity.