BCR-ABL mutational studies for predicting the response of patients with chronic myeloid leukaemia to second-generation tyrosine kinase inhibitors after imatinib failure

Abstract

Imatinib is the standard treatment for chronic myeloid leukaemia. BCR-ABL kinase domain mutation is the commonest mechanism implicated in imatinib resistance. In in-vitro studies, kinase domain mutations are variably resistant to second-line agents. We performed BCR-ABL kinase domain mutational studies in 25 patients in five institutions who failed imatinib and were treated with either nilotinib or dasatinib, to see if their mutational status would predict their clinical responses. Kinase domain mutations involving 11 amino acid substitutions were found in 12 (48%) patients. Most patients showed single kinase domain mutations. There was some concordance between reported drug sensitivity patterns and patient responses. Discordant responses could be related to drug dosage variations and unknown BCR-ABL independent mechanisms. The response prediction for patients with multiple kinase domain mutations was challenging and their mutational patterns could change after tyrosine kinase inhibitor therapy. Although BCR-ABL kinase domain mutational analysis has limitations as a means of predicting the clinical response to second-line tyrosine kinase inhibitors, it helps inform therapy decisions in the management of chronic myeloid leukaemia after imatinib failure.