Targeting BTK with ibrutinib in relapsed chronic lymphocytic leukemia.
Targeting BTK with ibrutinib in relapsed chronic lymphocytic leukemia.
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DOI：
10.1056/nejmoa1215637
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发表时间：
2013-07-04
期刊：
影响因子：
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通讯作者：
O'Brien S
中科院分区：
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作者：
Byrd JC;Furman RR;Coutre SE;Flinn IW;Burger JA;Blum KA;Grant B;Sharman JP;Coleman M;Wierda WG;Jones JA;Zhao W;Heerema NA;Johnson AJ;Sukbuntherng J;Chang BY;Clow F;Hedrick E;Buggy JJ;James DF;O'Brien S
复发性慢性淋巴细胞白血病（CLL）的治疗几乎没有持久的缓解。布鲁顿酪氨酸激酶（Bruton’s tyrosine kinase， BTK）是b细胞受体信号传导的重要组成部分，介导与肿瘤微环境的相互作用，促进CLL细胞的存活和增殖。我们进行了一项1b-2期多中心研究，以评估ibrutinib （PCI-32765）的安全性、有效性、药代动力学和药效学，ibrutinib是一种首屈一指的口服BTK共价抑制剂，设计用于治疗复发或难治性CLL或小淋巴细胞淋巴瘤患者的b细胞癌。共有85名患者，其中大多数被认为患有高风险疾病，每天口服一次伊鲁替尼；51人摄入420毫克，34人摄入840毫克。毒性作用主要为1级或2级，包括短暂性腹泻、疲劳和上呼吸道感染；因此，患者可以在最小的血液学毒性作用下接受延长治疗。420mg组和840mg组的总有效率相同（71%），另外20%和15%的患者出现淋巴细胞增多的部分反应。该反应独立于治疗前存在的临床和基因组危险因素，包括晚期疾病、先前治疗的次数和17p13.1缺失。26个月时，估计无进展生存率为75%，总生存率为83%。伊鲁替尼与复发或难治性CLL和小淋巴细胞淋巴瘤患者（包括高风险遗传病变患者）的持久缓解的高频率相关。（由pharmacyics等资助；ClinicalTrials.gov编号：NCT01105247）
The treatment of relapsed chronic lymphocytic leukemia (CLL) has resulted in few durable remissions. Bruton's tyrosine kinase (BTK), an essential component of B-cell–receptor signaling, mediates interactions with the tumor microenvironment and promotes the survival and proliferation of CLL cells. We conducted a phase 1b–2 multicenter study to assess the safety, efficacy, pharmacokinetics, and pharmacodynamics of ibrutinib (PCI-32765), a first-in-class, oral covalent inhibitor of BTK designed for treatment of B-cell cancers, in patients with relapsed or refractory CLL or small lymphocytic lymphoma. A total of 85 patients, the majority of whom were considered to have high-risk disease, received ibrutinib orally once daily; 51 received 420 mg, and 34 received 840 mg. Toxic effects were predominantly grade 1 or 2 and included transient diarrhea, fatigue, and upper respiratory tract infection; thus, patients could receive extended treatment with minimal hematologic toxic effects. The overall response rate was the same in the group that received 420 mg and the group that received 840 mg (71%), and an additional 20% and 15% of patients in the respective groups had a partial response with lymphocytosis. The response was independent of clinical and genomic risk factors present before treatment, including advanced-stage disease, the number of previous therapies, and the 17p13.1 deletion. At 26 months, the estimated progression-free survival rate was 75% and the rate of overall survival was 83%. Ibrutinib was associated with a high frequency of durable remissions in patients with relapsed or refractory CLL and small lymphocytic lymphoma, including patients with high-risk genetic lesions. (Funded by Pharmacyclics and others; ClinicalTrials.gov number, NCT01105247.)