New Directions in the Treatment of Imatinib Failure and/or Resistance

For the minority of chronic myeloid leukemia (CML) patients who demonstrate primary or secondary resistance or intolerance to first-line imatinib therapy, previously available treatment options were limited to cytotoxic chemotherapy, interferon alfa, or allogeneic hematopoietic stem cell transplantation. While the latter option remains a possibility for some, strong clinical efficacy data from recent phase II trials have led to the approval of two second-generation tyrosine kinase inhibitors (TKIs), nilotinib and dasatinib, for the treatment of CML following imatinib failure and/or resistance. Treatment guidelines now recommend either of these two agents as second-line therapy for most patients, although the decision of which second-generation agent to use remains subjective, and is often dependent on the agents' tolerability profiles, as comparative efficacy data from head-to-head clinical studies are not available. Sequential treatment with all three TKIs over the course of the disease is also a possibility, as both nilotinib and dasatinib have shown activity in patients with resistance to imatinib and a subsequent TKI. Novel therapeutic options are continually being developed to expand the range of treatment options, and new tyrosine kinase inhibitors or agents with other mechanisms of action, such as histone deacetylase inhibitors, may prove effective in patients with resistance or intolerance to multiple agents.