The quantitative level of T315I mutated BCR-ABL predicts for major molecular response to second-line nilotinib or dasatinib treatment in patients with chronic myeloid leukemia

Abstract

The BCR-ABL T315I mutation causes resistance to imatinib, nilotinib and dasatinib in chronic myeloid leukemia. Forty BCR-ABL positive patients with imatinib resistance were analyzed for T315I mutated clones after six months on nilotinib or dasatinib treatment by quantitative allele-specific ligation polymerase chain reaction with a sensitivity of 0.05%. Ligation polymerase chain reaction revealed 10 patients with more than 10⁻⁵ BCR-ABL^T315I%/GUS (high levels), none of whom achieved major molecular response after 12 months, and a further 8 patients with 10⁻⁵ or below BCR-ABL^T315I%/GUS (low levels) who all achieved major molecular response (<i>P</i><0.001). A second independent group showed molecular response in one of 12 patients with high levels and 5 of 8 patients with low levels (<i>P</i>=0.018). Combining the groups resulted in a sensitivity and specificity of 92.9% and 87.5%, respectively. We conclude that the quantitative level of mutant T315I allele is predictive of major molecular response at 12 months on second-line nilotinib or dasatinib treatment.