Targeting BTK with ibrutinib in relapsed or refractory mantle-cell lymphoma.
Targeting BTK with ibrutinib in relapsed or refractory mantle-cell lymphoma.
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DOI：
10.1056/nejmoa1306220
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发表时间：
2013-08-08
期刊：
影响因子：
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通讯作者：
Blum KA
中科院分区：
文献类型：
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作者：
Wang ML;Rule S;Martin P;Goy A;Auer R;Kahl BS;Jurczak W;Advani RH;Romaguera JE;Williams ME;Barrientos JC;Chmielowska E;Radford J;Stilgenbauer S;Dreyling M;Jedrzejczak WW;Johnson P;Spurgeon SE;Li L;Zhang L;Newberry K;Ou Z;Cheng N;Fang B;McGreivy J;Clow F;Buggy JJ;Chang BY;Beaupre DM;Kunkel LA;Blum KA
布鲁顿酪氨酸激酶 (BTK) 是 B 细胞受体信号通路的介质，与 B 细胞癌症的发病机制有关。在一项 1 期研究中，BTK 抑制剂 ibrutinib 对多种类型的非霍奇金淋巴瘤（包括套细胞淋巴瘤）显示出抗肿瘤活性。在这项 2 期研究中，我们对 111 名复发或难治性套细胞淋巴瘤患者进行了每日 560 毫克口服依鲁替尼的研究。患者被分为两组：之前接受过至少 2 个周期硼替佐米治疗的患者和接受过少于 2 个完整周期硼替佐米治疗或之前未接受过硼替佐米治疗的患者。主要终点是总体缓解率。次要终点是缓解持续时间、无进展生存期、总生存期和安全性。中位年龄为68岁，根据临床预后因素，86%的患者患有中危或高危套细胞淋巴瘤。患者之前平均接受过三种治疗。最常见的治疗相关不良事件是轻度或中度腹泻、疲劳和恶心。 3 级或以上血液学事件并不常见，包括中性粒细胞减少症（16% 的患者）、血小板减少症（11%）和贫血（10%）。观察到的缓解率为 68%（75 名患者），其中完全缓解率为 21%，部分缓解率为 47%；先前使用硼替佐米治疗对缓解率没有影响。预计中位随访时间为 15.3 个月，预计中位缓解持续时间为 17.5 个月（95% 置信区间 [CI]，15.8 未达到），预计中位无进展生存期为 13.9 个月（95% CI，7.0 未达到），中位总生存期未达到。 18 个月时估计总生存率为 58%。依鲁替尼在复发或难治性套细胞淋巴瘤中显示出持久的单药疗效。 （由 Pharmacyclos 和其他机构资助；ClinicalTrials.gov 编号，NCT01236391。）
Bruton's tyrosine kinase (BTK) is a mediator of the B-cell–receptor signaling pathway implicated in the pathogenesis of B-cell cancers. In a phase 1 study, ibrutinib, a BTK inhibitor, showed antitumor activity in several types of non-Hodgkin's lymphoma, including mantle-cell lymphoma. In this phase 2 study, we investigated oral ibrutinib, at a daily dose of 560 mg, in 111 patients with relapsed or refractory mantle-cell lymphoma. Patients were enrolled into two groups: those who had previously received at least 2 cycles of bortezomib therapy and those who had received less than 2 complete cycles of bortezomib or had received no prior bortezomib therapy. The primary end point was the overall response rate. Secondary end points were duration of response, progression-free survival, overall survival, and safety. The median age was 68 years, and 86% of patients had intermediate-risk or high-risk mantle-cell lymphoma according to clinical prognostic factors. Patients had received a median of three prior therapies. The most common treatment-related adverse events were mild or moderate diarrhea, fatigue, and nausea. Grade 3 or higher hematologic events were infrequent and included neutropenia (in 16% of patients), thrombocytopenia (in 11%), and anemia (in 10%). A response rate of 68% (75 patients) was observed, with a complete response rate of 21% and a partial response rate of 47%; prior treatment with bortezomib had no effect on the response rate. With an estimated median follow-up of 15.3 months, the estimated median response duration was 17.5 months (95% confidence interval [CI], 15.8 to not reached), the estimated median progression-free survival was 13.9 months (95% CI, 7.0 to not reached), and the median overall survival was not reached. The estimated rate of overall survival was 58% at 18 months. Ibrutinib shows durable single-agent efficacy in relapsed or refractory mantle-cell lymphoma. (Funded by Pharmacyclics and others; ClinicalTrials.gov number, NCT01236391.)