Imatinib mesylate is a small-molecule tyrosine kinase inhibitor that was initially developed as a 2-phenylaminopyrimidine derivative specific for PDGFR. Imatinib was subsequently found to be a potent inhibitor of ABL kinases, including the BCR-ABL fusion protein generated as a result of the t(9;22) chromosomal translocation (Philadelphia chromosome) found in chronic myelogenous leukemia (CML), and was also found to inhibit the receptor tyrosine kinase C-KIT. Imatinib mesylate is the canonical example of a targeted therapeutic agent, because BCR-ABL is uniquely expressed by leukemic cells and is essential for their survival.

Initial in vitro studies demonstrated that imatinib mesylate potently and specifically inhibits growth of BCR-ABL-expressing cells. Subsequent evaluation of an oral formulation in mice demonstrated
Treatment of accelerated or blast-phase CML with imatinib mesylate is less effective but associated with some responses. Imatinib mesylate is relatively well tolerated; its principal adverse effects are superficial edema, nausea, muscle cramps, skin rash, and diarrhea.

Despite impressive hematologic and cytogenetic response rates in chronic phase CML, evaluation of residual BCR-ABL transcript by reverse transcriptase PCR (RT-PCR) reveals that only 39% of patients have a complete molecular response, a much more sensitive measure of residual leukemia cells. Preliminary results suggest that, compared with the standard dose of 400 mg, initial treatment with 800 mg of imatinib mesylate may increase the frequency of molecular responses but at the expense of a higher frequency of adverse effects, and this is currently being evaluated in a randomized study. Given the relatively recent development of imatinib mesylate, longer-term follow-up is needed to determine how sustained the responses will be over time.

Mutation of C-KIT, the receptor for stem cell factor (SCF), is found frequently in gastrointestinal stromal tumors (GIST) and in the myeloproliferative disorder systemic mastocytosis. In GIST, mutations and in-frame deletions of C-KIT are typically found in the juxtamembrane domain, resulting in constitutive activation of the tyrosine kinase in the absence of ligand. In contrast, in systemic mastocytosis, the characteristic D816V activating C-KIT mutation is within the kinase domain itself. Whereas imatinib mesylate has shown significant activity in advanced gastrointestinal stromal tumors, it has proven largely ineffective in the treatment of systemic mastocytosis due to ineffective targeting of C-KIT kinases with the D816V mutation.

The idiopathic hypereosinophilic syndrome, as well as a variant of systemic mastocytosis with eosinophilia, is characterized by the expression of the FIPL1-PDGFRA fusion protein, which is generated by an interstitial chromosomal deletion and results in constitutive signaling through PDGFRA. Inhibition of PDGFRA by treatment with imatinib mesylate has been a successful therapeutic approach in both conditions.

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