Leukemia Insights - Fall 2008
Approximately 80% to 85% of patients with CML in early chronic phase achieve a complete cytogenetic response with standard-dose imatinib mesylate therapy (Gleevec). With a median follow up of 7 years, the overall survival is 90%.1 The estimated 5-year survival considering only CML-related deaths is 95%. However, resistance to imatinib occurs in up to 4% to 7% per year, at least for the first 3-4 years. The most common mechanism of resistance is point mutations of the Bcr-Abl kinase domain (40% to 60% of resistant cases).
Over 50 different mutations have been reported which vary in their extent of resistance to imatinib.2 Other mechanisms of resistance include BCR-ABL-dependent (e.g., overexpression and amplification) and BCR-ABL-independent mechanisms (e.g., overexpression of Src-related kinases).3 This led to developing new agents/strategies which may overcome or prevent resistance. Targeted approaches such as second generation tyrosine kinase inhibitors (TKIs) have been favored, e.g. dasatinib (Sprycel), nilotinib (Tasigna) and bosutinib (SKI606). Dasatinib and nilotinib are now FDA approved for the treatment of CML post imatinib failure. Other non-TKIs are in development. T315I mutations are emerging with increasing frequency, and patients with this mutation do not respond to current TKIs. Several studies with tyrosine kinase inhibitors with activity against T315I are ongoing with positive results. Homoharringtonine is also under investigation for patients with T315I inhibitors and those whose CML is resistant to 2 or more TKIs. These will be discussed in this update.