There are no validated molecular biomarkers to identify newly-diagnosed individuals with chronic-phase chronic myeloid leukaemia likely to respond poorly to imatinib and who might benefit from first-line treatment with a more potent second-generation tyrosine kinase-inhibitor. Our inability to predict these 'high-risk' individuals reflects the poorly understood heterogeneity of the disease. To investigate the potential of genetic variants in epigenetic modifiers as biomarkers at diagnosis, we used Ion Torrent next-generation sequencing of 71 candidate genes for predicting response to tyrosine kinase-inhibitors and probability of disease progression. 124 subjects with newly-diagnosed chronic-phase chronic myeloid leukaemia began with imatinib (n=62) or second-generation tyrosine kinase-inhibitors (n=62) and were classified as responders or non-responders based on the BCRABL1 transcript levels within the first year and the European LeukemiaNet criteria for failure. Somatic variants affecting 21 genes (e.g. ASXL1, IKZF1, DNMT3A, CREBBP) were detected in 30% of subjects, most of whom were non-responders (41% non-responders, 18% responders to imatinib, 38% non-responders, 25% responders to second-generation tyrosine kinase-inhibitors). The presence of variants predicted the rate of achieving a major molecular response, event-free survival, progression-free survival and chronic-myeloid-leukaemia-related survival in the imatinib but not the second-generation tyrosine kinase-inhibitors cohort. Rare germline variants had no prognostic significance irrespective of treatment while some pre-leukaemia variants suggest a multi-step development of chronic myeloid leukaemia. Our data suggest that identification of somatic variants at diagnosis facilitates stratification into imatinib responders/non-responders, thereby allowing earlier use of second-generation tyrosine kinase-inhibitors, which, in turn, may overcome the negative impact of such variants on disease progression.