Loss of response to imatinib: mechanisms and management.
Loss of response to imatinib: mechanisms and management.
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DOI：
10.1182/asheducation-2005.1.183
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发表时间：
2005
期刊：
影响因子：
--
通讯作者：
N. Shah
中科院分区：
文献类型：
--
作者：
N. Shah
小分子 BCR-ABL 选择性激酶抑制剂伊马替尼彻底改变了慢性粒细胞白血病 (CML) 的治疗。尽管伊马替尼最初非常有效并且通常耐受性良好，但临床上越来越多地遇到复发的情况。直到最近，对于大多数对伊马替尼不再有反应的 CML 患者以及伊马替尼不耐受的患者，几乎没有有效的治疗选择。我们对伊马替尼耐药主要机制的了解导致了两种新型 BCR-ABL 抑制剂的临床开发，它们在早期临床试验经验中具有显着的治疗前景。这些药物达沙替尼 (BMS-354825) 和 AMN107 是比伊马替尼更有效的 BCR-ABL 抑制剂，此外，对体外测试的几乎所有伊马替尼耐药的 BCR-ABL 激酶结构域突变形式均具有活性。值得注意的是，这些化合物都不能有效对抗伊马替尼耐药的 BCR-ABL/T315I 突变。治疗伊马替尼耐药和不耐受的 CML 病例的高效药物的潜在可用性预计将使其他有效疗法（例如同种异体干细胞移植）的时机进一步复杂化。此外，定期对 BCR-ABL 激酶结构域进行基因分型以筛选耐药突变可能在 CML 病例的未来管理中发挥越来越重要的作用。
The treatment of chronic myeloid leukemia (CML) has been revolutionized by the small molecule BCR-ABL-selective kinase inhibitor imatinib. Although imatinib is highly effective initially and generally well-tolerated, relapse is increasingly encountered clinically. Until recently, for the majority of CML patients with disease no longer responsive to imatinib, as well as for patients with imatinib intolerance, few effective therapeutic options existed. Our understanding of the major mechanisms of imatinib resistance has led to the clinical development of two novel BCR-ABL inhibitors that harbor significant therapeutic promise in early clinical trial experience. These agents, dasatinib (BMS-354825) and AMN107, are more potent inhibitors of BCR-ABL than imatinib, and moreover, harbor activity against nearly all imatinib-resistant BCR-ABL kinase domain mutant forms tested in vitro. Notably, neither of these compounds is effective against the imatinib-resistant BCR-ABL/T315I mutation. The potential availability of highly effective medications for the treatment of imatinib-resistant and intolerant cases of CML is expected to further complicate the timing of other effective therapies, such as allogeneic stem cell transplantation. Additionally, periodic genotyping of the BCR-ABL kinase domain to screen for drug-resistant mutations may play an increasingly important role in the future management of CML cases.