, Volume 3, Issue 2, pp 72-79

Resistance to imatinib in chronic myelogenous leukemia: Mechanisms and clinical implications

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The introduction of imatinib represented a breakthrough in the treatment of chronic myelogenous leukemia (CML). However, about 20% of patients treated in early chronic-phase CML are off therapy after 6 years because of resistance or intolerance, and most patients taking imatinib remain BCR-ABL-positive at the molecular level, indicating primary refractoriness of a leukemic subpopulation. Patients with advanced disease often do not respond, or they eventually relapse. Resistance frequently is associated with mutations in the kinase domain of BCR-ABL. Other mechanisms leading to reactivation of BCR-ABL or preventing sufficient BCR-ABL inhibition also exist. Resistance of patients with continued BCR-ABL inhibition despite leukemic progression indicates clonal evolution triggered by BCR-ABL-independent mechanisms. Current efforts to optimize BCR-ABL-targeted treatment focus on the difficulty in reaching CML stem cells. Success will most likely depend on integration of combined treatment algorithms—whether they be a combination of molecules interfering with signaling pathways or additional immune-based treatment adjuncts.