Tyrosine kinase inhibitors in the treatment of chronic myeloid leukaemia: so far so good?

Chronic myeloid leukaemia (CML) is characterized by marked expansion of the myeloid series, and is thought to arise as a direct result of the bcr-abl fusion-gene. The BCR-ABL oncoprotein is a constitutively active protein tyr osine kinase (PTK), which results in altered cell signalling and is respons ible for the changes that characterize the malignant cells of CML. It has b een shown that the increased tyrosine kinase activity of BCR-ABL is a requi rement for transformation and is, therefore, a legitimate target for pharma cological inhibition. Several compounds have now been identified as relativ ely selective inhibitors of BCR-ABL, including members of the tyrphostin fa mily, herbimycin A and most importantly the 2-phenylaminopyrimidine ST1571. Having established the efficacy of this agent in vitro, phase I trials usi ng an oral formulation were commenced in the USA in mid 1998. Early data fr om an interferon-cx (IFN) resistant/refractory or intolerant cohort demonst rated good patient tolerance and effective haematological control at doses above 300 mg. More promising was its ability to induce cytogenetic response s in this pretreated group of patients. Phase II data, albeit far from comp lete, appear to confirm its efficacy even in the context of advanced diseas e and phase III clinical trials are currently underway in many countries. R ecent laboratory evidence, however, suggests that the development of drug r esistance is a possibility (via amplification of the bcr-abl fusion gene, o verexpression of P-glycoprotein or binding of ST1571 to cc I acid glycoprot ein) and that combination therapy including ST1571 should be considered. (C ) 2001 Harcourt Publishers Ltd.