Introduction

Imatinib mesylate (Gleevec, Glivec, formerly STI571) is an inhibitor of the ABL, platelet-derived growth factor receptor (PDGFR), and KIT tyrosine ki-

nases. Preclinical data with this compound demonstrated specific killing of cells expressing the constitutively activated BCR-ABL tyrosine kinase. As BCR-ABL is the causative molecular abnormality of chronic myeloid leukemia (CML), this was the first disease selected for clinical trials with imatinib. In these clinical trials, rapid responses to imatinib were observed with durable responses in patients with CML in the chronic phase. A randomized study comparing imatinib to standard therapy with interferon-a for newly diagnosed patients with CML in the chronic phase demonstrated significantly improved outcomes for patients randomized to imatinib as initial therapy. Thus, imatinib has rapidly become the standard therapy for patients with newly diagnosed CML.

Other disease indications for which imatinib has shown clinical activity are based on the KIT and PDGFR inhibitory activities of this drug. Specifically, the majority of gastrointestinal stromal tumors (GISTs) have activating KIT mutations that drive the growth of these tumors, and imatinib has shown remarkable single agent activity in this disease. Interestingly, a subset of patients with GIST and wild-type KIT expression have activating mutations of the PDGFRA that are imatinib-sensitive, and patients with these tumors also respond to imatinib. Similarly, the subset of patients with chronic myelomonocytic leukemia (CMML) with EVT6-PDGFRB rearrangements have responded well to imatinib, as have patients with dermatofibrosarcoma protuberans (DFSP), due to the activation of the PDGFRB by constitutive production of the ligand for this receptor. Lastly, patients with hypere-osinophilic syndrome (HES) have recently been shown to have an intrachro-mosomal deletion that results in the production of an activated PDGFRA, and these patients respond extremely well to imatinib. Whether additional uses for imatinib will be found is less clear, but at a minimum, the concept of effective and selective therapies arising by targeting pathogenetic events in tumors has been validated.

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