Management of tyrosine kinase inhibitors resistance

Development of tyrosine kinase inhibitors (TKIs) has led to extended life spans formany patients with chronic myelogenous leukemia (CML). However, 20 to 30% ofpatients fail to respond, respond suboptimally, or experience disease relapse followingtreatment with initial TKI. A key factor is drug resistance. The molecular mechanismsimplicated in this resistance include those that involve upregulation or mutation of BCR- ABL kinase and those that are BCR-ABL independent. The clinical consequences ofthese molecular mechanisms of resistance for disease pathogenesis remain open fordebate. This chapter summarizes the molecular mechanisms and clinical consequences ofTKI resistance and addresses the current and future treatment approaches for patients with TKI-resistant CML.