Agents targeting fusion RTKs

Discovery of unique chromosomal abnormalities and underlying molecular changes of RTKs causatively associated with CMML or atypical chronic myelogenous leukemia (aCML)5-8 suggested potential therapeutic agents targeting the molecular basis of these disorders. The proof of principle was provided by documentation of activity of imatinib mesylate in the management of MPD, including CMML, characterized by activation of the PDGFRfi gene by its fusion to tel oncogene, a process rendering the PDGFRp TK permanently activated and responsible for the dysregulated cell growth.7 After the publication of encouraging results on the in vitro inhibitory activity of imatinib mesylate on PDGFRp TK,28 four patients with t(5;12)(q33;q13) and PDGFR(3 fused with either TEL(ETV6) (three patients) or an unknown partner (one patient), all with elevated WBC counts and eosinophilia, were treated with 400 mg of imatinib orally, daily. All four patients achieved a CR and the levels of fusion transcripts decreased significantly, even becoming negative in one patient.5 Responses occurred as early as 1 month, but could be delayed up to 9 months, suggesting disease heterogeneity and the need for prolonged treatment in some cases. Similar responses to imatinib were reported for a CMML patient with the RAB5EP/PDGFRfi fusion gene underlying a t(5;17)(q33;p13.3) who achieved a molecular CR 6 weeks after the start of imatinib therapy.6 Further CRs were reported for a CMML patient with t(5;12)(q33;p13)29 and for a patient with aCML and a t(5;10)(q33;q22).30 This concept supported a trial in which imatinib was given to patients with CMML in the expectation of potential activity through as-yet-undetected imatinib-sensitive pathways. So far, the results have been uniformly negative in 19 patients with CMML,3132 seven with aCML,31 and eight with MDS.32 Thus, imatinib continues to be indicated for trial use in patients with documented rare karyotypic abnormalities that lead to production of imatinib-sensi-tive fusion TKs. Most patients achieved response within 6 weeks of the initiation of treatment with 400 mg ima-tinib mesylate daily and continued the treatment in remission. With only preliminary experience, duration of the responses and the optimal treatment schedule are unknown. Although data on the association between the progression of CMML and aCML into more aggressive disease and decreased effectiveness or loss of response to imatinib have been restricted to those from single-case observations (M. Beran, personal observation), this association is analogous to the limited activity of imatinib in advanced BCR-ABL-positive CML.33

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