Switch of the mutation type of the NPM1 gene in acute myeloid leukemia (AML): relapse or secondary AML?

Mutations in exon 12 of the nucleophosmin (NPM1) gene have been described as primary leukemogenic event in up to 35% of adult acute myelogenous leukemia (AML) cases, mainly those with normal karyotype. This type of AML is listed as provisional entity in the World Health Organization classification of tumors of the hematopoietic and lymphoid tissues 2008. NPM1 mutation status has improved risk stratification and therapy choice of the AML intermediate-risk group with normal karyotype, as NPM1-mutated cases without fms-related tyrosine kinase 3 (FLT3) gene internal tandem duplications have a favorable outcome and no need for bone marrow transplantation first line. Furthermore, mutations in other genes—for example, isocitrate dehydrogenase (IDH1 and IDH2 genes)—seem to influence prognosis as patients with both NPM1 and IDH mutations show improved overall 3-year survival, whereas NPM1-positive cases without IDH mutations have a much less favorable outcome. In addition to diagnosis and risk stratification, NPM1 mutation analysis can be used to monitor therapy response. However, although NPM1 mutations are regarded to be an early event in leukemogenesis, serial analysis of 245 initially NPM1-mutated AML cases revealed a loss of the mutation at relapse in 9% of the cases. This phenomenon is well known for genetic events occurring late in AML evolution, for example, FLT3 mutations. For FLT3, also switches of the mutation type at progression of AML (initial diagnosis with D835 tyrosine kinase mutation, relapse with internal tandem duplication) but stable NPM1 mutation at both time points are documented. Here, we describe for the first time a switch of a NPM1 mutation type at relapse having profound impact on AML monitoring strategies.