Mutations in the DNA methylation pathway and number of driver mutations predict response to azacitidine in myelodysplastic syndromes.

ABSTRACT

We evaluated the association of mutations in 34 candidate genes and response to azacitidine in 84 patients with myelodysplastic syndrome (MDS), with 217 somatic mutations identified by next-generation sequencing. Most patients (93%) had ≥1 mutation (mean=2.6/patient). The overall response rate to azacitidine was 42%. No clinical characteristic was associated with response to azacitidine. However, total number of mutations/patient was negatively associated with overall drug response (odds ratio [OR] 0.56, 95% confidence interval [CI] 0.33-0.94; p=0.028), and a positive association was found for having ≥1 mutation in a DNA methylation-related gene TET2, DNMT3A, IDH1 and/or IDH2 (OR 4.76, 95%CI 1.31-17.27; p=0.017). Mutations in TP53 (hazard ratio [HR] 3.88; 95%CI 1.94-7.75) and EZH2 (HR 2.50; 95%CI 1.23-5.09) were associated with shorter overall survival. Meta-analysis of 6 studies plus present data (n=815 patients) allowed assessment of the association of drug response with mutations in 9 candidate genes ASXL1, CBL, EZH2, SF3B1, SRSF2, TET2, DNMT3A, IDH1/2 and TP53. TET2 mutations predicted a more favorable drug response compared with 'wild-type' peers (pooled OR 1.67, 95%CI 1.14-2.44; p=0.01). In conclusion, mutations in the DNA methylation pathway, especially TET2 mutations, and low number of total mutations are associated with a better response to azacitidine.