Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA.
Leuk Lymphoma. 2010 Mar;51(3):363-75. doi: 10.3109/10428190903518295.
The BCR-ABL inhibitor imatinib revolutionized the treatment of chronic myeloid leukemia (CML). However, resistance and intolerance to imatinib have emerged as substantial clinical issues. The mechanisms underlying resistance are multifactorial and may include mutations in the kinase domain of BCR-ABL, increased production of BCR-ABL, or activation of BCR-ABL-independent pathways. Two second-line BCR-ABL inhibitors are now approved for treatment of patients with resistance or intolerance to imatinib. Dasatinib is a dual BCR-ABL/Src-family kinase (SFK) inhibitor approved for patients with imatinib-resistant and -intolerant CML in any phase and Ph+ ALL. Nilotinib, an analogue of imatinib, is approved for the treatment of imatinib-resistant or -intolerant patients with chronic or accelerated phase CML. Both agents have shown significant clinical activity in patients with imatinib-resistant or -intolerant CML, and their approval represents a major advancement in the treatment options available. Choosing the most appropriate treatment after imatinib failure may be critical in attaining the best possible long-term prognosis. The presence of certain disease characteristics (e.g. specific BCR-ABL mutations) or patient comorbidities may facilitate more effective treatment. In this review, we discuss mechanisms of imatinib resistance and preclinical and clinical data with dasatinib and nilotinib which may have potential use for guiding second-line treatment decisions.
BCR-ABL 抑制剂伊马替尼彻底改变了慢性髓性白血病（CML）的治疗方法。然而，对伊马替尼的耐药性和不耐受性已成为重大的临床问题。耐药性的机制是多因素的，可能包括 BCR-ABL 激酶结构域的突变、BCR-ABL 的产量增加，或 BCR-ABL 非依赖性途径的激活。目前有两种二线 BCR-ABL 抑制剂被批准用于治疗对伊马替尼耐药或不耐受的患者。达沙替尼是一种双重 BCR-ABL/Src 家族激酶（SFK）抑制剂，适用于任何阶段和 Ph+ALL 的对伊马替尼耐药和不耐受的 CML 患者。尼洛替尼是伊马替尼的类似物，被批准用于治疗对伊马替尼耐药或不耐受的慢性或加速期 CML 患者。这两种药物在对伊马替尼耐药或不耐受的 CML 患者中均显示出显著的临床疗效，其批准代表了治疗选择方面的重大进展。在伊马替尼治疗失败后选择最合适的治疗方法可能对获得最佳长期预后至关重要。某些疾病特征（例如特定的 BCR-ABL 突变）或患者合并症的存在可能有助于更有效的治疗。在这篇综述中，我们讨论了伊马替尼耐药的机制以及达沙替尼和尼洛替尼的临床前和临床数据，这些数据可能有助于指导二线治疗决策。
