New Strategies in Controlling Drug Resistance

BACKGROUND: Chronic myeloid leukemia (CML) is most often caused by the translocation of chromosomes 9 and 22 to create the fusion protein, BCR-ABL. This constitutively active tyrosine kinase promotes cell division and blocks apoptosis, leading to unregulated growth of hematopoietic stem cells. Imatinib is a small molecule that binds to BCR-ABL at the site in which adenosine triphosphate (ATP) binds and blocks BCR-ABL function by blocking its ability to use ATP. As a front-line therapy, imatinib has been tremendously successful, with 80% to 90% of patients with chronic phase (CP) CML remaining progression free for more than 5 years. Increasingly, however, imatinib-resistant clones are appearing that allow the disease to progress. Dealing with the rise of these resistant clones has presented an important challenge to health care providers. OBJECTIVES: To review the mechanisms by which CML becomes resistant to imatinib and to discuss the new therapeutic alternatives to imatinib and when they should be considered. SUMMARY: Managed care weighs advances and associated costs to determine the introduction of imatinib has indefinitely lengthened the survival time of patients with CML, transforming this into a chronic disease condition. However, care must be taken to avoid the appearance of imatinib-resistant clones. Resistance can manifest through 1 of several mechanisms, including increased plasma protein binding, increased drug efflux, the appearance of BCR-ABL mutants that have low affinity for imatinib, the appearance of BCR-ABL independent proliferation signals, and the amplification of the BCR-ABL gene. Subtherapeutic dosing is highly likely to result in the selection of a resistant clone; thus, it is of paramount importance to ensure the imatinib dose is sufficient. Measurements of plasma levels of imatinib are proving to be predictive of outcomes, suggesting that the monitoring of imatinib levels will be an important and necessary aspect of monitoring disease. Several clinical trials have shown that high-dose imatinib provides greater and faster response rates. This also may lead to better long-term blockade of disease progression. Waiting until disease progression begins appears to lead to greater resistance to high-dose imatinib and should be avoided. Dasatinib is a next-generation kinase inhibitor that binds to both SrC and to multiple conformations of BCR-ABL. It is capable of blocking several BCR-ABL mutants that are resistant to imatinib. Clinical trials have shown dasatinib is effective in maintaining patients in CP and can return a percentage of patients with advanced CML to CP. Economic analysis indicates that the cost-efficacy ratio for imatinib is approximately $40,000 per year and compares favorably with the costs of accepted procedures, such as dialysis. Data have shown that tyrosine kinases also have better mortality rates than allogeneic bone marrow transplant for the first 8 years and appear to also be more cost-effective than transplantation for this time frame. CONCLUSIONS: new clinical data are beginning to supply us with effective dosing and monitoring parameters for imatinib and dasatinib treatment of CML. economic analysis indicates that these therapies are acceptable in cost and effective in providing good quality of life to patients.