Department of Pharmaceutical Sciences, College of Pharmacy and Allied Health Professions, St John's University, 8000 Utopia Parkway, Jamaica, NY 11439, USA.
Leuk Res. 2010 Oct;34(10):1255-68. doi: 10.1016/j.leukres.2010.04.016.
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.
慢性髓性白血病（CML）是一种克隆性疾病，其特征是存在费城（Ph+）染色体及其致癌产物 BCR-ABL，这是一种组成性激活的酪氨酸激酶，存在于>90%的患者中。流行病学数据表明，每年报告近 5000 例新病例，其中 10%的患者最终死于该疾病。甲磺酸伊马替尼（IM，格列卫）的引入彻底改变了 CML 的治疗方法，它是一种 BCR-ABL 酪氨酸激酶抑制剂（TKI）。与以前的治疗方案相比，特定的 BCR-ABL 抑制剂的临床应用导致 CML 患者的预后、反应率、总生存率和患者结局得到了显著改善。然而，由于 ABL 激酶结构域的突变以及治疗后分子残留疾病在接受伊马替尼治疗的患者中，CML 的完全根除受到限制。第二代 BCR-ABL TKI 尼洛替尼（Tasigna）和达沙替尼（Sprycel）在对伊马替尼治疗不耐受或耐药的患者的临床试验中显示出显著的活性，但 T315I BCR-ABL 突变的患者除外。确定参与 CML 发病机制的关键成分可能会导致探索新的方法，最终可能克服对 BCR-ABL TKI 的耐药性。在这里，我们概述了目前用 TKI 治疗 Ph+CML 患者的情况以及这些药物成功治疗的障碍。
