Department of Leukemia, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
Curr Hematol Malig Rep. 2010 Apr;5(2):70-80. doi: 10.1007/s11899-010-0045-y.
The treatment of chronic myeloid leukemia (CML) drastically changed with the introduction of imatinib mesylate, a Bcr-Abl1 tyrosine kinase inhibitor (TKI), in 1998. By directly targeting this leukemogenic protein kinase, imatinib affords patients with CML sustained chromosomal remissions, which translate into prolonged survival. However, there has been concern over the emergence of resistance to imatinib, and some patients fail to respond or are intolerant of imatinib therapy because of untoward toxicity. This has spurred interest in developing novel TKIs to overcome the mechanisms of resistance that lead to treatment failure-most importantly, Bcr-Abl1 kinase domain mutations. Two of these second-generation TKIs, nilotinib and dasatinib, are approved worldwide for the treatment of CML after imatinib failure or intolerance. Although these agents are active, they fail in many patients because of the development of highly resistant mutations such as the T315I, against which several novel agents are currently being tested in clinical trials. This review provides an account of the progress made in the field of TKI therapy for CML over the past decade.
1998 年，甲磺酸伊马替尼（一种 Bcr-Abl1 酪氨酸激酶抑制剂[TKI]）的问世，使慢性髓性白血病（CML）的治疗发生了重大变化。通过直接靶向这种致白血病蛋白激酶，伊马替尼使 CML 患者获得持续的染色体缓解，从而延长了生存时间。然而，人们一直担心伊马替尼会出现耐药性，并且由于不良反应毒性，一些患者对伊马替尼治疗无反应或不耐受。这激发了人们开发新型 TKI 的兴趣，以克服导致治疗失败的耐药机制——最重要的是，Bcr-Abl1 激酶结构域突变。其中两种第二代 TKI，尼洛替尼和达沙替尼，在伊马替尼失败或不耐受后，已在全球范围内获得批准用于 CML 的治疗。尽管这些药物具有活性，但由于高度耐药突变的发展，如 T315I，许多患者仍然无法获益，目前正在临床试验中测试几种新型药物。本文回顾了过去十年中 CML 的 TKI 治疗领域取得的进展。
