Hypomethylating agents (HMAs) are widely used in the treatment of myelodysplastic syndromes (MDSs), yet identifying those patients unlikely to benefit remains challenging. We assessed response and overall survival (OS) in 247 patients molecularly profiled by next-generation sequencing (NGS) before first-line HMA therapy, and a subset of 108 patients were sequenced serially during treatment. The most common mutations included TP53 (33.1%), ASXL1 (19%), TET2 (16.5%), DNMT3A (14.1%), and SRSF2 (12.1%). The overall response rate was 42.1%, with the composite TET2-mutant/ASXL1 wild-type genotype representing the strongest predictor of response (overall response rate, 62.1%; complete remission rate, 34.5%). The median OS for the cohort was 15 months, and the number of mutations detected by NGS (hazard ratio [HR], 1.22; P = .02), as well as mutations in TP53 (HR, 2.33; P = .001) and EZH2 (HR, 2.41; P = .04) were identified as independent covariates associated with inferior OS in multivariable analysis. Serial molecular profiling revealed that clearance of TP53 mutations during HMA therapy was associated with superior OS (HR, 0.28; P = .001) and improved outcome in patients proceeding to allogeneic hematopoietic cell transplantation. These data support baseline molecular profiling by NGS in MDS patients treated with HMAs and provide novel observations of sequential profiling during therapy that provide particular value in TP53-mutated disease.
