Baran Yusuf, Saydam Guray
Department of Molecular Biology and Genetics, Izmir Institute of Technology, Izmir, Turkey.
J Blood Med. 2012;3:139-50. doi: 10.2147/JBM.S29132. Epub 2012 Nov 16.
Chronic myeloid leukemia (CML) is a malignant disease that originates in the bone marrow and is designated by the presence of the Philadelphia (Ph+) chromosome, a translocation between chromosomes 9 and 22. Targeted therapy against CML commenced with the development of small-molecule tyrosine kinase inhibitors (TKIs) exerting their effect against the oncogenic breakpoint cluster region (BCR)-ABL fusion protein. Imatinib emerged as the first successful example of a TKI used for the treatment of chronic-phase CML patients and resulted in significant improvements in response rate and overall survival compared with previous treatments. However, a significant portion of patients failed to respond to the therapy and developed resistance against imatinib. Second-generation TKIs nilotinib and dasatinib were to have higher efficiency in clinical trials in imatinib- resistant or intolerant CML patients compared with imatinib. Identification of novel strategies such as dose escalation, drug combination therapy, and use of novel BCR-ABL inhibitors may eventually overcome resistance against BCR-ABL TKIs. This article reviews the history of CML, including the treatment strategies used prediscovery of TKIs and the preclinical and clinical data obtained after the use of imatinib, and the second-generation TKIs developed for the treatment of CML.
慢性粒细胞白血病（CML）是一种起源于骨髓的恶性疾病，其特征是存在费城（Ph+）染色体，即9号和22号染色体之间的易位。针对CML的靶向治疗始于小分子酪氨酸激酶抑制剂（TKIs）的开发，这些抑制剂对致癌性断裂点簇区域（BCR）-ABL融合蛋白发挥作用。伊马替尼成为用于治疗慢性期CML患者的TKI的首个成功范例，与先前的治疗相比，其缓解率和总生存率有显著提高。然而，很大一部分患者对该疗法无反应，并对伊马替尼产生耐药性。与伊马替尼相比，第二代TKIs尼罗替尼和达沙替尼在伊马替尼耐药或不耐受的CML患者的临床试验中具有更高的疗效。确定诸如剂量递增、联合药物治疗以及使用新型BCR-ABL抑制剂等新策略最终可能克服对BCR-ABL TKIs的耐药性。本文回顾了CML的历史，包括在TKIs发现之前使用的治疗策略以及使用伊马替尼后获得的临床前和临床数据，以及为治疗CML而开发的第二代TKIs。
