The first FDA-approved and best known TKI, imatinib mesylate, has been shown to be potent for the inhibition of the BCR/ABL tyrosine kinase in chronic myeloid leukemia (CML). Like other RTKIs, imatinib also inhibits two other tyrosine kinases, PDGFR and c-kit, at similar concentrations. A small percentage of CMMOL patients express PDGFR fusion genes involving four partner genes. This is now a distinct phenotype classified by the World Health Organization (WHO) as CMMoL-Eos, with reciprocal translocations on chromosome 5q33. Imatinib interacts with the ATP-binding pocket of PDGFRp kinase associated with the translocation [e.g., t(5;12)(q33;p13)], much like its interaction with BCR/ABL in CML.
Four patients with CMMoL harboring a t(5;12), three of whom had the associated fusion gene ETV6/PDGFRQ, were treated with imatinib.25 Hematologic responses were achieved within 4 weeks of starting treatment, and normal counts were maintained for up to 1 year. Even more impressive was the disappearance of the translocation t(5;12) by 12 weeks in three patients and by 36 weeks in the fourth patient.
Raza et al. treated 16 CMMoL patients lacking translocations of the PDGFRfi gene with imatinib. No responses were seen,26 further confirming the specificity of the drug for this target. Another phase II study of 18 MDS, CMMoL, and AML patients, all lacking the fusion gene, showed no responses.27 Although c-kit is expressed in over 80% of AML and MDS patients and imatinib is thought to inhibit c-kit, in this study no responses were achieved. These results were also seen in some solid tumors, where ima-tinib has failed to show any significant responses as monotherapy, despite the expression of c-kit.
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