title: Favorable prognostic impact of NPM1 gene mutations in childhood acute myeloid leukemia, with emphasis on cytogenetically normal AML.
abstract: Nucleophosmin (NPM1) mutations occur frequently in adult cytogenetically normal acute myeloid leukemia (CN-AML) and confer favorable outcome. We investigated the frequency and prognostic significance of NPM1 mutations in childhood AML (n=298), specifically focusing on the CN-AML subgroup (n=100). Mutations were found in 8.4%, and clustered significantly in the CN-AML subgroup (22%). No mutations were found in patients below the age of 3 years; in CN-AML, there was an increasing incidence above this age. In the overall group, NPM1 mutations conferred an independent favorable prognostic impact on event-free survival (5-year pEFS 66 vs 39%; P=0.02), which did not translate into a significantly better overall survival (5-year pOS 68 vs 56%; P=0.30). However, when the favorable cytogenetic subgroups [inv(16) and t(8;21)] were excluded from the NPM1 wild-type group, the difference in pOS was borderline statistically significant (68 vs 45%; P=0.07). In the CN-AML cohort, NPM1 mutations were an independent prognostic factor on pEFS (80 vs 39%; P=0.01), and pOS (85 vs 60%; P=0.06), which was not influenced by FLT3/ITD. However, in NPM1 wild-type CN-AML, FLT3/ITD-positive patients had a significantly worse outcome (pEFS 48 vs 18%; P<0.001). We conclude that NPM1 mutations confer a favorable prognosis in childhood AML and in CN-AML in particular.
authors.affiliation: Department of Pediatric Oncology and Hematology, Erasmus MC-Sophia Children's Hospital, Rotterdam, The Netherlands.
authors.forename: I H I M
authors.initials: IH
authors.lastname: Hollink
authors.forename: C M
authors.initials: CM
authors.lastname: Zwaan
authors.forename: M
authors.initials: M
authors.lastname: Zimmermann
authors.forename: T C J M
authors.initials: TC
authors.lastname: Arentsen-Peters
authors.forename: R
authors.initials: R
authors.lastname: Pieters
authors.forename: J
authors.initials: J
authors.lastname: Cloos
authors.forename: G J L
authors.initials: GJ
authors.lastname: Kaspers
authors.forename: S S N
authors.initials: SS
authors.lastname: de Graaf
authors.forename: J
authors.initials: J
authors.lastname: Harbott
authors.forename: U
authors.initials: U
authors.lastname: Creutzig
authors.forename: D
authors.initials: D
authors.lastname: Reinhardt
authors.forename: M M
authors.initials: MM
authors.lastname: van den Heuvel-Eibrink
authors.forename: C
authors.initials: C
authors.lastname: Thiede
mesh_terms: D000293:Adolescent; D000367:Age Factors; D002648:Child; D002675:Child, Preschool; D020732:Cytogenetic Analysis; D005260:Female; D006801:Humans; D007223:Infant; D015470:Leukemia, Myeloid, Acute / Q000175:diagnosis / Q000235:genetics*; D008297:Male; D009154:Mutation; D009687:Nuclear Proteins / Q000235:genetics*; D000090243:Nucleophosmin; D011237:Predictive Value of Tests; D011379:Prognosis; D012189:Retrospective Studies; D016019:Survival Analysis
chemical_list: C000716967:NPM1 protein, human; D009687:Nuclear Proteins; D000090243:Nucleophosmin