Efficacy and safety of a specific inhibitor of the BCR-ABL tyrosine kinase in chronic myeloid leukemia.
Efficacy and safety of a specific inhibitor of the BCR-ABL tyrosine kinase in chronic myeloid leukemia.
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DOI：
10.1056/nejm200104053441401
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发表时间：
2001-04-05
影响因子：
158.5
通讯作者：
Sawyers, CL
中科院分区：
文献类型：
--
作者：
Druker, BJ;Talpaz, M;Sawyers, CL
背景：BCR-ABL 是一种组成型激活的酪氨酸激酶，可导致慢性粒细胞白血病 (CML)。由于酪氨酸激酶活性对于 BCR-ABL 的转化功能至关重要，因此该激酶的抑制剂可能是 CML 的有效治疗方法。 方法：我们对 BCR-ABL 酪氨酸激酶的特异性抑制剂 STI571（以前称为 CGP 57148B）进行了 1 期剂量递增试验。 83 名慢性期 CML 患者口服 STI571，这些患者用干扰素 α 治疗失败。患者被连续分配接受 14 个剂量中的一个，剂量范围为每天 25 至 1000 mg。 结果：STI571 的副作用很小；最常见的是恶心、肌痛、水肿和腹泻。尚未确定最大耐受剂量。每日剂量 300 mg 或以上的 54 名患者中有 53 名观察到完全血液学反应，通常发生在治疗的前 4 周。在接受 300 mg 或以上剂量治疗的 54 名患者中，29 名患者出现细胞遗传学反应，其中 17 名患者（接受该剂量的 54 名患者中的 31%）出现了主要反应（费城染色体中期细胞呈 0% 至 35% 阳性）；其中 7 名患者获得完全细胞遗传学缓解。结论：STI571 耐受性良好，并且对于干扰素 α 治疗失败的 CML 患者具有显着的抗白血病活性。我们的结果提供了 BCR-ABL 酪氨酸激酶活性在 CML 中的重要作用的证据，并证明了基于人类癌症中存在的特定分子异常开发抗癌药物的潜力。 （N Engl J Med 2001；344：1031-7。）版权所有 (C) 2001 马萨诸塞州医学会。
Background: BCR-ABL is a constitutively activated tyrosine kinase that causes chronic myeloid leukemia (CML). Since tyrosine kinase activity is essential to the transforming function of BCR-ABL, an inhibitor of the kinase could be an effective treatment for CML.Methods: We conducted a phase 1, dose-escalating trial of STI571 (formerly known as CGP 57148B), a specific inhibitor of the BCR-ABL tyrosine kinase. STI571 was administered orally to 83 patients with CML in the chronic phase in whom treatment with interferon alfa had failed. Patients were successively assigned to 1 of 14 doses ranging from 25 to 1000 mg per day.Results: Adverse effects of STI571 were minimal; the most common were nausea, myalgias, edema, and diarrhea. A maximal tolerated dose was not identified. Complete hematologic responses were observed in 53 of 54 patients treated with daily doses of 300 mg or more and typically occurred in the first four weeks of therapy. Of the 54 patients treated with doses of 300 mg or more, cytogenetic responses occurred in 29, including 17 (31 percent of the 54 patients who received this dose) with major responses (0 to 35 percent of cells in metaphase positive for the Philadelphia chromosome); 7 of these patients had complete cytogenetic remissions.Conclusions: STI571 is well tolerated and has significant antileukemic activity in patients with CML in whom treatment with interferon alfa had failed. Our results provide evidence of the essential role of BCR-ABL tyrosine kinase activity in CML and demonstrate the potential for the development of anticancer drugs based on the specific molecular abnormality present in a human cancer. (N Engl J Med 2001;344:1031-7.) Copyright (C) 2001 Massachusetts Medical Society.