Impact of PPM1D mutations in patients with myelodysplastic syndrome and deletion of chromosome 5q.

Abstract

PPM1D is a serine/threonine phosphatase that inactivates the p53 pathway. PPM1D mutations have been described in myelodysplastic syndromes (MDS), but their prognostic impact in del(5q) MDS is less well defined. We analyzed 234 patients with del(5q) MDS or secondary AML and correlated PPM1D and TP53 mutation status by Sanger and/or next-generation sequencing (NGS) at baseline with clinical outcome. At diagnosis, PPM1D and TP53 mutations were detected in 13 of 234 (5.6%) and 35 of 234 (15%) patients with del(5q) MDS, respectively. PPM1D and TP53 mutations had no impact on the risk of progression to acute myeloid leukemia (AML) or overall survival (OS) in 164 patients with WHO 2016 defined del(5q) MDS. Of the 65 WHO 2016 defined del(5q) MDS patients known to be treated with lenalidomide (LEN), 83% of the patients achieved hematological response, while 38.5% became refractory to LEN or progressed to AML after a median follow-up of 3.1 years, independent of PPM1D and TP53 mutation status. 22 LEN treated patients underwent sequential monitoring of molecular kinetics at the time of response, resistance and disease progression. Compared to baseline, median variant allele frequency (VAF) increased from 10.2% to 23.3% and from 5.9% to 23.2% at the time of LEN resistance or AML progression for PPM1D and TP53 mutations, respectively. Sequential analysis of TP53 and PPM1D mutation burden may help to identify patients at risk of disease progression during LEN treatment. This article is protected by copyright. All rights reserved.