Chronic myeloid leukemia: current therapies and the potential role of farnesyltransferase inhibitors

The treatment of patients with chronic myeloid leukemia (CML) is evolving rapidly. With conventional chemotherapy the clinical course is characterized by a chronic phase (median duration, 4 to 5 years), followed by an accelerated phase with transition to a terminal blast crisis. Treatment with busulfan or hydroxyurea does not alter the natural history. Interferon alfa (IFN-alpha) prolongs life expectancy by approximately 20 months but is associated with significant toxicity. Evidence indicates that bone marrow transplantation from a related human leukocyte antigen (HLA)-identical donor can be curative in younger patients. However, transplantation is available to only a minority of patients and entails severe toxicity and transplant-related mortality. Dramatic advances in the understanding of the molecular pathophysiology of CML have led to a new era of targeted therapy. The specific tyrosine kinase inhibitor imatinib mesylate demonstrates a high level of efficacy in CML with acceptable toxicity. Farnesyltransferase inhibitors (FTIs) are another important class of targeted agents with the potential to act at multiple sites within dysregulated signal transduction networks. ZARNESTRA (formerly R115777, Ortho Biotech Oncology, Raritan, NJ), an oral FTI, has shown activity and is well tolerated in both chronic- and accelerated-phase patients. With their mechanistic specificity, the new modalities offer the promise of increased antileukemic activity and an improved therapeutic index.