Howard Hughes Medical Institute, Oregon Health and Science University Cancer Institute,
L592, 3181 SW Sam Jackson Park Road, Portland, OR 97239, USA
1 Introduction 391
2 Clinical Features of CML 392
3 BCR-ABL as a Therapeutic Target 393
4 Clinical Trials in CML 394
4.1 Phase I and Pharmacokinetic Studies 394
4.2 Phase II Studies 395
4.3 Phase III Comparison of Imatinib to Interferon in Newly Diagnosed Chronic Phase Patients 398
5 Mechanisms of Relapse/Resistance to Imatinib 398
6 Safety and Tolerability 400
7 Gastrointestinal Stromal Tumors and KIT 401
8 PDGFR as a Therapeutic Target 403
9 Conclusions 405
Abstract Imatinib is an inhibitor of the ABL, platelet-derived growth factor receptors, and KIT tyrosine kinases. Given the pathogenetic role of the BCR-ABL tyrosine kinase in chronic myeloid leukemia, this was the first disease selected for clinical trials with ima-tinib. In the clinical trials, patients in all phases of the disease responded to imatinib and experienced minimal toxicity. Responses in patients with chronic phase disease have been durable, thus far. Clinical trials with imatinib were expanded and there are now examples of malignancies driven by each of the targets of imatinib where remarkable results have been seen. The rationale for the use of imatinib in these various diseases and the clinical trial results will be reviewed.
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