Nucleophosmin mutations confer an independent favorable prognostic impact in 869 pediatric patients with acute myeloid leukemia

Lu-Hong Xu,Adrianna I. Jones,Jian-Pei Fang,Yao-Chung Liu,Li Chai

doi:10.1038/s41408-019-0268-7

Abstract

Studies on the clinical significance of Nucleophosmin (NPM1) mutations in pediatric AML in a large cohort are lacking. Moreover, the prognosis of patients with co-occurring NPM1 and FLT3/ITD mutations is controversial. Here, we analyzed the impact of NPM1 mutations on prognoses of 869 pediatric AML patients from the TAGET dataset. The frequency of NPM1 mutations was 7.6%. NPM1 mutations were significantly associated with older age (P < 0.001), normal cytogenetics (P < 0.001), FLT3/ITD mutations (P < 0.001), and high complete remission induction rates (P < 0.05). Overall, NPM1-mutated patients had a significantly better 5-year EFS (P = 0.001) and OS (P = 0.016) compared to NPM1 wild-type patients, and this favorable impact was maintained even in the presence of FLT3/ITD mutations. Stem cell transplantation had no significant effect on the survival of patients with both NPM1 and FLT3/ITD mutations. Multivariate analysis revealed that NPM1 mutations were independent predictors of better outcome in terms of EFS (P = 0.004) and OS (P = 0.012). Our findings showed that NPM1 mutations confer an independent favorable prognostic impact in pediatric AML despite of FLT3/ITD mutations. In addition, pediatric AML patients with both NPM1 and FLT3/ITD mutations appear to have favorable prognoses and may not need hematopoietic stem cell transplantations.

Highlights

Acute myeloid leukemia (AML) is a genetically heterogeneous disease that accounts for about 20% of pediatric leukemia
Our findings showed that NPM1 mutations confer an independent favorable prognostic impact in the pediatric AML patients in spite of FLT3/ITD mutations
Molecular analyses for FLT3/ ITD and NPM1 mutations were performed on genomic DNA by polymerase chain reaction (PCR)

Summary

Introduction

Acute myeloid leukemia (AML) is a genetically heterogeneous disease that accounts for about 20% of pediatric leukemia. The overall 5-year survival rate for pediatric patients with AML has increased over time and is in the range of 65–70%1. Survival rates still vary depending on the subtype of AML and genetic risk factors. Nucleophosmin (NPM1) is a widely expressed protein predominantly located in the nucleolus that continuously shuttles between nucleus and cytoplasm. NPM1 mutations cause delocalization of the protein to the cytoplasm and are involved in leukemogenesis[4,5]. The WHO classification of hematopoietic malignancies recognizes AML with mutated NPM1 as a distinct entity[6]. About 40% of NPM1-mutated AML cases have cooccurring FMS-like tyrosine kinase internal tandem duplication (FLT3/ITD) mutations[7]. The prognosis of patients with NPM1 co-occurring FLT3/ITD mutations is controversial. Numerous adult studies have shown that NPM1-mutated patients had improved

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Conclusion