Chronic myeloid leukaemia: the evolution of gene-targeted therapy.
Chronic myeloid leukaemia (CML) was the first human cancer linked to an acquired chromosomal abnormality, subsequently shown to be a reciprocal translocation between chromosomes 9 and 22. The resulting fusion gene product, BCR-ABL, was shown to be the causative agent of the disease. CML has an incidence of around 1-2 cases per 100,000; in Australia, there are probably more than 200 new cases per year and more than 1300 prevalent cases. Treatment of CML with imatinib has been a powerful vindication of the concept of rational, gene-targeted drug design. Five-year published experience with imatinib at 400 mg orally daily demonstrates 89% overall survival and an estimated 93% freedom from disease progression. Adverse effects are mostly mild and transient. Higher doses of imatinib may be more efficacious and will be studied in upcoming clinical trials in Australia; however, imatinib is almost certainly not curative. Up to 28% of patients may have to stop imatinib because of intolerance or disease resistance, mostly due to point mutations of BCR-ABL. In this situation, many patients will respond to second- and third-generation tyrosine kinase inhibitors. Management of CML patients should involve close monitoring, especially in the first 2 years, with regular cytogenetics and quantitative polymerase chain reaction to optimise response and identify suboptimal responders as early as possible. Bone marrow transplantation remains the only known cure, but is reserved for patients whose kinase inhibitor therapy has failed, or who have advanced disease (accelerated phase or blastic transformation).
Joske
David J L
DJ
Department of Haematology, Sir Charles Gairdner Hospital, Perth, WA, Australia. david.joske@health.wa.gov.au