BCR-ABL tyrosine kinase inhibitors in the treatment of Philadelphia chromosome positive chronic myeloid leukemia: A review

An, Xin; Tiwari, Amit K.; Sun, Yibo; Ding, Pei-Rong; Ashby, Charles R.; Chen, Zhe-Sheng

doi:10.1016/j.leukres.2010.04.016

« Previous Next »Leukemia Research
Volume 34, Issue 10 , Pages 1255-1268, October 2010

BCR-ABL tyrosine kinase inhibitors in the treatment of Philadelphia chromosome positive chronic myeloid leukemia: A review

Xin An
- Department of Pharmaceutical Sciences, College of Pharmacy and Allied Health Professions, St. John's University, 8000 Utopia Parkway, Jamaica, NY 11439, USA
- Department of Medical Oncology, Cancer Center, Sun Yat-Sen University, Guangzhou, China
- State Key Laboratory of Oncology in South China, Sun Yat-Sen University, Guangzhou, China
- These authors contributed equally to this work.
Amit K. Tiwari
- Department of Pharmaceutical Sciences, College of Pharmacy and Allied Health Professions, St. John's University, 8000 Utopia Parkway, Jamaica, NY 11439, USA
- These authors contributed equally to this work.
Yibo Sun
- Department of Pharmaceutical Sciences, College of Pharmacy and Allied Health Professions, St. John's University, 8000 Utopia Parkway, Jamaica, NY 11439, USA
- These authors contributed equally to this work.
Pei-Rong Ding
- Department of Pharmaceutical Sciences, College of Pharmacy and Allied Health Professions, St. John's University, 8000 Utopia Parkway, Jamaica, NY 11439, USA
- Department of Medical Oncology, Cancer Center, Sun Yat-Sen University, Guangzhou, China
- State Key Laboratory of Oncology in South China, Sun Yat-Sen University, Guangzhou, China
- These authors contributed equally to this work.
Charles R. Ashby Jr.
- Department of Pharmaceutical Sciences, College of Pharmacy and Allied Health Professions, St. John's University, 8000 Utopia Parkway, Jamaica, NY 11439, USA
Zhe-Sheng Chen
- Department of Pharmaceutical Sciences, College of Pharmacy and Allied Health Professions, St. John's University, 8000 Utopia Parkway, Jamaica, NY 11439, USA
- Corresponding author. Tel.: +1 718 990 1432; fax: +1 718 990 1877.

Received 21 January 2010; received in revised form 25 April 2010; accepted 25 April 2010. published online 07 March 2011.

Abstract

Chronic Myeloid Leukemia (CML) is a clonal disease characterized by the presence of the Philadelphia (Ph+) chromosome and its oncogenic product, BCR-ABL, a constitutively active tyrosine kinase, that is present in >90% of the patients. Epidemiologic data indicates that almost 5000 new cases are reported every year and 10% of these patients eventually succumb to the disease. The treatment of CML was revolutionized by the introduction of imatinib mesylate (IM, Gleevec^®), a BCR-ABL tyrosine kinase inhibitor (TKI). The clinical use of specific BCR-ABL inhibitors has resulted in a significantly improved prognosis, response rate, overall survival, and patient outcome in CML patients compared to previous therapeutic regimens. However, the complete eradication of CML in patients receiving imatinib was limited by the emergence of resistance mostly due to mutations in the ABL kinase domain and to a lesser extent by molecular residual disease after treatment. The second-generation BCR-ABL TKIs nilotinib (Tasigna^®) and dasatinib (Sprycel^®), showed significant activity in clinical trials in patients intolerant or resistant to imatinib therapy, except in those patients with the T315I BCR-ABL mutation. Identifying key components involved in the CML pathogenesis may lead to the exploration of new approaches that might eventually overcome resistance mediated to the BCR-ABL TKIs. Here, we present an overview about the current treatment of Ph+ CML patients with the TKIs and the obstacles to successful treatment with these drugs.

Keywords: CML, Philadelphia chromosome, TKI, BCR-ABL