Favorable prognostic impact of NPM1 mutations in older patients with cytogenetically normal de novo acute myeloid leukemia and associated gene- and microRNA-expression signatures: a Cancer and Leukemia Group B study

Abstract

Purpose: To analyze the prognostic significance of NPM1 mutations, and the associated gene- and microRNA-expression signatures in older patients with de novo, cytogenetically normal acute myeloid leukemia (CN-AML) treated with intensive chemotherapy.

Patients and methods: One hundred forty-eight adults age >or= 60 years with de novo CN-AML, enrolled onto Cancer and Leukemia Group B protocols 9720 and 10201, were studied at diagnosis for NPM1, FLT3, CEBPA, and WT1 mutations, and gene- and microRNA-expression profiles.

Results: Patients with NPM1 mutations (56%) had higher complete remission (CR) rates (84% v 48%; P < .001) and longer disease-free survival (DFS; P = .047; 3-year rates, 23% v 10%) and overall survival (OS; P < .001; 3-year rates, 35% v 8%) than NPM1 wild-type patients. In multivariable analyses, NPM1 mutations remained independent predictors for higher CR rates (P < .001) and longer DFS (P = .004) and OS (P < .001), after adjustment for other prognostic clinical and molecular variables. Unexpectedly, the prognostic impact of NPM1 mutations was mainly observed in patients >or= 70 years. Gene- and microRNA-expression profiles associated with NPM1 mutations were similar across older patient age groups and similar to those in younger (< 60 years) patients with CN-AML. These profiles were characterized by upregulation of HOX genes and their embedded microRNAs and downregulation of the prognostically adverse MN1, BAALC, and ERG genes.

Conclusion: NPM1 mutations have favorable prognostic impact in older patients with CN-AML, especially those age >or= 70 years. The gene- and microRNA-expression profiles suggest that NPM1 mutations constitute a marker defining a biologically homogeneous entity in CN-AML that might be treated with specific and/or targeted therapies across age groups.

Fig 1.

(A) Disease-free survival and (B) overall survival of patients age ≥ 60 years with cytogenetically normal de novo acute myeloid leukemia according to NPM1 mutation status. (C) Disease-free survival and (D) overall survival of patients age ≥ 70 years with cytogenetically normal de novo acute myeloid leukemia according to NPM1 mutation status. NPM1mut, NPM1 mutated; NPM1wt, NPM1 wild-type.

Fig 2.

Heat maps of the (A) gene- and (C) microRNA-expression signatures associated with NPM1 mutations in older patients with cytogenetically normal de novo acute myeloid leukemia. Rows represent probe sets (A) or microRNA probes (C), and columns represent patients. Patients are grouped by NPM1 mutational status and ordered by age within these groups. Expression values of the probe sets and microRNA probes are represented by color, with green indicating expression less than, and red indicating expression greater than, the median value for the given probe set or microRNA probe. (B) Fold-changes for selected genes of the signature. Genes are sorted by fold-change in expression between the NPM1mut and NPM1wt groups (MUT/WT). For genes with more than one corresponding probe set in the signature, the geometric mean of the fold-changes of these probe sets is displayed. (D) Fold-changes for selected microRNAs in the signature. MicroRNAs are sorted by fold-change in expression between the NPM1mut and NPM1wt groups (MUT/WT). Fold-change is displayed for those probes hybridizing with the respective mature microRNA. For microRNAs with more than one corresponding probe in the signature, the geometric mean of the fold-changes of these probes is given. Selection of genes and microRNAs is based on the fold-change and previous reports of these genes and microRNAs associated with NPM1 mutations, leukemia, or other malignancies.

Fig. A1.

Comparison of the gene-expression signatures associated with NPM1 mutations in younger (< 60 years) and older (≥ 60 years) patients with cytogenetically normal de novo acute myeloid leukemia. The heat map is derived using the 3,577 probe sets that formed the signature in the older cohort. Rows represent probe sets, and columns represent patients. Patients are grouped by NPM1 mutational status and ordered by age within these groups. Expression values of the probe sets are represented by color, with green indicating expression less than, and red indicating expression greater than, the median value for the given probe set.