Resistance to imatinib in chronic myelogenous leukemia: mechanisms and clinical implications.
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.
La Rosée
Paul
P
III. Medizinische Klinik, Abteilung für Leukämieforschung, Medizinische Fakultät Mannheim der Universität Heidelberg, Wiesbadener Strasse 7-11, Mannheim, Germany.
Hochhaus
Andreas
A
D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D001549:Benzamides; D019008:Drug Resistance, Neoplasm; D016044:Fusion Proteins, bcr-abl / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D000068877:Imatinib Mesylate; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy* / Q000235:genetics; D009154:Mutation; D010879:Piperazines / Q000494:pharmacology / Q000627:therapeutic use*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D011743:Pyrimidines / Q000494:pharmacology / Q000627:therapeutic use*
D000970:Antineoplastic Agents; D001549:Benzamides; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D000068877:Imatinib Mesylate; D016044:Fusion Proteins, bcr-abl