Molecular studies in chronic myeloid leukemia patients treated with tyrosine kinase inhibitors.

The tyrosine kinase inhibitor imatinib mesylate (Gleevec, Novartis Pharmaceuticals Corp, East Hanover, NJ) (formerly STI571) blocks the constitutively activated Bcr-Abl tyrosine kinase that is characteristic of chronic myeloid leukemia (CML). Molecular analysis for the presence of residual Bcr-Abl-positive cells in patients with a cytogenetic response following treatment with imatinib mesylate reveals that some patients have undetectable disease using quantitative reverse-transcriptase polymerase chain reaction (RT-PCR) assays capable of detecting 1 in 10(5) Philadelphia chromosome-positive (Ph(+)) cells. To examine whether the leukemia is still Bcr-Abl-dependent in patients who have responded to imatinib mesylate but have relapsed, a quantitative assay that directly measures enzymatic activity of Bcr-Abl toward one of its major signaling substrates has been developed. This assay allows monitoring both of the imatinib mesylate sensitivity of patient cells in vitro, and of the endogenous inhibition of Bcr-Abl kinase activity during imatinib mesylate treatment and relapse. Studies show that imatinib mesylate resistance is associated with restored activation of the Bcr-Abl signal transduction pathway in the majority of cases, indicating that Bcr-Abl remains a valid target for therapeutic intervention. Understanding resistance mechanisms of Ph(+) leukemia to imatinib mesylate will allow design of therapies to overcome such barriers to efficacy.