David Frame1. 1. Department of Pharmacy, University of Michigan, 1500 Medical Center Drive, Ann Arbor, MI 48109, USA. dframe@med.umich.edu
Abstract
PURPOSE: Imatinib has been quite effective in maintaining patients with CML in the chronic phase (CP); however, some patients develop imatinib resistance. This review addresses the mechanisms underlying imatinib resistance and the strategies currently being used to overcome that resistance. SUMMARY: Chronic myeloid leukemia (CML) is a stem cell cancer caused by BCR-ABL. Imatinib, a BCR-ABL inhibitor, has significantly decreased CML mortality by stopping disease progression in CP. This success has been tempered by the appearance of imatinib-resistant clones. These clones allow CML to progress to advanced stages of disease where the prognosis is poor. Mechanisms of imatinib resistance include plasma protein binding, drug efflux, mutation of BCR-ABL, gene amplification of BCR-ABL, and activation of BCR-ABL independent proliferative pathways. The first four of these mechanisms could potentially be addressed by increasing the imatinib dose and recent clinical trials have shown this to be the case. Pharmacokinetic analysis demonstrated that patients with low imatinib plasma concentrations fared more poorly then patients with high plasma concentrations. Doubling the standard dose of 400 mg per day increased patient responses while decreasing the time to response. Toxicity was also increased resulting in approximately 50% of patients decreasing the dose. The strategy of waiting to see who failed imatinib at 400 mg per day and then increasing the dose of that subpopulation was unsuccessful. The interpretation of these data is that it is beneficial to treat CML as aggressively as possible as early as possible. Dasatinib is the second BCR-ABL inhibitor to become available. It binds with a 350-fold greater affinity to BCR-ABL and shows efficacy against a number of imatinib-resistant mutations. Dasatinib also inhibits SRC kinase, which may play a role in both maintaining BCR-ABL activity and in BCR-ABL independent signaling pathways. Clinical trials with dasatinib have had favorable results and are comparable with high-dose imatinib. Imatinib also compares favorably with stem cell transplant (SCT). Economic analysis shows imatinib and dasatinib therapies, while quite expensive, are on par with dialysis in terms of cost of quality adjusted life years. CONCLUSION: A better understanding of imatinib resistance mechanisms has resulted in the development of useful strategies both to predict responders and nonresponders and to minimize imatinib resistance and prolong the life of the patient.
PURPOSE:Imatinib has been quite effective in maintaining patients with CML in the chronic phase (CP); however, some patients develop imatinib resistance. This review addresses the mechanisms underlying imatinib resistance and the strategies currently being used to overcome that resistance. SUMMARY:Chronic myeloid leukemia (CML) is a stem cell cancer caused by BCR-ABL. Imatinib, a BCR-ABL inhibitor, has significantly decreased CML mortality by stopping disease progression in CP. This success has been tempered by the appearance of imatinib-resistant clones. These clones allow CML to progress to advanced stages of disease where the prognosis is poor. Mechanisms of imatinib resistance include plasma protein binding, drug efflux, mutation of BCR-ABL, gene amplification of BCR-ABL, and activation of BCR-ABL independent proliferative pathways. The first four of these mechanisms could potentially be addressed by increasing the imatinib dose and recent clinical trials have shown this to be the case. Pharmacokinetic analysis demonstrated that patients with low imatinib plasma concentrations fared more poorly then patients with high plasma concentrations. Doubling the standard dose of 400 mg per day increased patient responses while decreasing the time to response. Toxicity was also increased resulting in approximately 50% of patients decreasing the dose. The strategy of waiting to see who failed imatinib at 400 mg per day and then increasing the dose of that subpopulation was unsuccessful. The interpretation of these data is that it is beneficial to treat CML as aggressively as possible as early as possible. Dasatinib is the second BCR-ABL inhibitor to become available. It binds with a 350-fold greater affinity to BCR-ABL and shows efficacy against a number of imatinib-resistant mutations. Dasatinib also inhibits SRC kinase, which may play a role in both maintaining BCR-ABL activity and in BCR-ABL independent signaling pathways. Clinical trials with dasatinib have had favorable results and are comparable with high-dose imatinib. Imatinib also compares favorably with stem cell transplant (SCT). Economic analysis shows imatinib and dasatinib therapies, while quite expensive, are on par with dialysis in terms of cost of quality adjusted life years. CONCLUSION: A better understanding of imatinib resistance mechanisms has resulted in the development of useful strategies both to predict responders and nonresponders and to minimize imatinib resistance and prolong the life of the patient.