Imatinib Resistance: Obstacles and Opportunities

Abstract Objective.—To review the current status of resistance to imatinib mesylate (IM) in patients with chronic myelogenous leukemia, and the obstacles and opportunities presented by the development of this resistance. Data Sources and Study Selection.—Review of selected studies obtained from a MEDLINE search encompassing the years 1950 to 2004. Data Extraction and Data Synthesis.—Relevant information from the selected studies was abstracted and summarized. Conclusions.—The identification of the Philadelphia chromosome and the subsequent discovery that it represents a translocation between the long arms of chromosomes 9 and 22 producing an aberrant tyrosine kinase, known as BCR-ABL1, has catalyzed our understanding and treatment of this hematologic malignancy. An extensive search for molecules to block the aberrant BCR-ABL1 protein resulted in the development of IM as an orally bioavailable agent with remarkable efficacy in producing hematologic, cytogenetic, and molecular remissions. However, follow-up...