Advertisement

High NPM1-mutant allele burden at diagnosis predicts unfavorable outcomes in de novo AML

Sanjay S. Patel, Frank C. Kuo, Christopher J. Gibson, David P. Steensma, Robert J. Soiffer, Edwin P. Alyea III, Yi-Bin A. Chen, Amir T. Fathi, Timothy A. Graubert, Andrew M. Brunner, Martha Wadleigh, Richard M. Stone, Daniel J. DeAngelo, Valentina Nardi, Robert P. Hasserjian and Olga K. Weinberg

Key Points

  • High NPM1-mutant allele burden at diagnosis is associated with poor clinical outcome in de novo AML.

  • The adverse effect of high NPM1-mutant allele burden is independent of comutations and clinical variables.

Abstract

Acute myeloid leukemia (AML) with mutated NPM1 is a newly recognized separate entity in the revised 2016 World Health Organization classification and is associated with a favorable prognosis. Although previous studies have evaluated NPM1 in a binary fashion, little is known about the significance of its mutant allele burden at diagnosis, nor has the effect of comutations (other than FLT3) been extensively evaluated. We retrospectively used targeted sequencing data from 109 patients with de novo AML with mutated NPM1 to evaluate the potential significance of NPM1 variant allele frequency (VAF), comutations, and clinical parameters with regard to patient outcomes. We observed that high NPM1 VAF (uppermost quartile) correlated with shortened overall survival (median, 12.1 months vs not reached; P < .0001) as well as event-free survival (median, 7.5 vs 65.44 months; P < .0001) compared with the other NPM1-mutated cases. In both univariate and multivariable analyses, high NPM1 VAF had a particularly adverse prognostic effect in the subset of patients treated with stem-cell transplantation in first remission (P = .0004) and in patients with mutated DNMT3A (P < .0001). Our findings indicate that the prognostic effect of NPM1 mutation in de novo AML may be influenced by the relative abundance of the mutated allele.

  • Submitted January 19, 2018.
  • Accepted May 1, 2018.
View Full Text