Yamauchi Takahiro, Ueda Takanori
Division of Hematology and Oncology, University of Fukui Hospital.
Gan To Kagaku Ryoho. 2011 Jun;38(6):911-5.
Chronic myeloid leukemia(CML)is a clonal disease of the hematopoietic stem cells that is characterized by excessive proliferation, but retains of the capacity for differentiation duringthe chronic phase of the disease. This phase is followed after 4-6 years by rapid progression, an accelerated phase, and consequently a fatal acute leukemia a blast crisis. The hallmark abnormality of CML is the Philadelphia chromosome that generates a BCR-ABL fusion gene, resulting in the expression of a leukemia-specific oncoprotein, Bcr-Abl. Bcr-Abl is a potent tyrosine kinase and plays a central role in CML pathogenesis. Recently, the treatment of CML has been revolutionized by the introduction of imatinib mesylate(IM). With daily IM treatment, more than 80% of chronic-phase CML patients achieve a complete cytogenetic response. Nevertheless, a small percentage of CML patients are primarily refractory or acquire secondary resistance against IM. Nilotinib is a highly selective Abl kinase inhibitor that possesses greater potency and selectivity for Abl kinase than IM. In addition to being more potent than IM against wild-type BCR-ABL, nilotinib is significantly active against many IM-resistant BCR-ABL mutants. In preclinical studies, nilotinib has produced hematologic and cytogenetic responses in CML patients, with either IM resistance or IM intolerance. As second-line treatment, both nilotinib and dasatinib may be used in case of suboptimal response or failure, which is defined in the efficacy criteria of the European Leukemia Net Consensus. The choice of second-generation tyrosine kinase inhibitors may be made after the mutation analyses of the kinase domain. It is recommended that nilotinib or dasatinib whichever was shown to be active against the specific mutation, should be chosen for treatment. For patients with no mutations or patients with IM intolerance, it is recommended that either second-generation tyrosine kinase inhibitor be chosen, based on the patient's disease history.
慢性髓性白血病（CML）是一种造血干细胞的克隆性疾病，其特征是过度增殖，但在疾病的慢性期仍保留分化能力。在4 - 6年后，这个阶段会迅速进展为加速期，进而发展为致命的急性白血病即急变期。CML的标志性异常是费城染色体，它产生BCR-ABL融合基因，导致白血病特异性癌蛋白Bcr-Abl的表达。Bcr-Abl是一种强效酪氨酸激酶，在CML发病机制中起核心作用。最近，甲磺酸伊马替尼（IM）的引入彻底改变了CML的治疗方法。每日服用IM治疗，超过80%的慢性期CML患者可实现完全细胞遗传学缓解。然而，一小部分CML患者对IM原发性耐药或获得继发性耐药。尼罗替尼是一种高度选择性的Abl激酶抑制剂，对Abl激酶具有比IM更高的效力和选择性。除了对野生型BCR-ABL比IM更有效外，尼罗替尼对许多IM耐药的BCR-ABL突变体也具有显著活性。在临床前研究中，尼罗替尼在对IM耐药或不耐受的CML患者中产生了血液学和细胞遗传学反应。作为二线治疗，在反应欠佳或失败的情况下（欧洲白血病网络共识疗效标准中定义），尼罗替尼和达沙替尼均可使用。第二代酪氨酸激酶抑制剂的选择可在激酶结构域突变分析后进行。建议选择对特定突变显示有活性的尼罗替尼或达沙替尼进行治疗。对于无突变或对IM不耐受的患者，建议根据患者的病史选择任何一种第二代酪氨酸激酶抑制剂。
