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首页 » 白血病 » N Engl J Med.:临床二期试验表明Ibrutinib 对慢性白血病和套细胞淋巴瘤两种疾病有效

N Engl J Med.:临床二期试验表明Ibrutinib 对慢性白血病和套细胞淋巴瘤两种疾病有效

来源:生物谷 2013-06-20 13:11

2013年6月20日讯 /生物谷BIOON/--发表在New England Journal of Medicine杂志上的两项临床试验结果表明,新药ibrutinib能够安全,有效的治疗成人慢性淋巴细胞性白血病(chronic lymphocytic leukemia ,CLL)和套细胞淋巴瘤(mantle cell lymphoma ,MCL)两种疾病。

两项研究都是由俄亥俄州立大学癌症研究中心,Arthur G. James癌症医院,Richard J. Solove研究中心和MD Anderson研究中心的科学家完成的。

慢性淋巴细胞性白血病和ibrutinib

临床二期实验结果表明该药物的整体反应率为71%,依据26周结果估计生存率为75%整体生存率为83%。

该研究的领导者John C. Byrd博士称,从本质上来说所有的CLL病人都对ibrutinib有反应,而该药物没有化疗的副作用,对具有基因缺陷的病人来说也有极大的缓解作用。

CLL是最常见的白细胞。该病是由于B细胞癌变造成的。研究发现Bruton酪氨酸激酶对CLL细胞生存和扩增有重要作用。科学家设计Ibrutinib针对Bruton酪氨酸激酶抑制其活性。Ibrutinib能够杀死恶性B细胞而对健康T细胞副作用很小。这样使得机体免疫系统功能不受到很大影响,保持病人健康状态。

该临床试验包括了85位复发性CLL病人(平均年龄为66岁),这些病人每天服用Ibrutinib一次。51位病人每天接受420mg剂量,34位病人接受每天840mg剂量。长期服用会造成轻微副作用,包括腹泻,疲劳和感染等。

套细胞淋巴瘤和Ibrutinib

该临床二期实验显示整体反应率为68%,其中21%病人达到完全反应水平,47%达到部分反应。预计18个月的生存率为58%。

Kristie Blum博士表示,该结果意义重大,因为上一个FDA认证的治疗MCL的药物只有30%的反应率。本实验表明ibrutinib能够明显提高MCL的治疗效果。

MCL是一种非霍奇金淋巴瘤,该病也是B细胞癌变造成的,该病占白血病比例为7%。目前治疗MCL的方法是干细胞移植结合化疗和免疫疗法。

本次实验包括111位复发性或重症MCL病人,病人接受1到5轮治疗,也包括了bortezomib治疗,bortezomib有时会用于治疗MCL。估计平均反应周期为17.5月,平均生存率为14月。(生物谷Bioon.com)

Targeting BTK with Ibrutinib in Relapsed or Refractory Mantle-Cell Lymphoma

Michael L. Wang, Simon Rule, Peter Martin, Andre Goy, Rebecca Auer, Brad S. Kahl, Wojciech Jurczak, Ranjana H. Advani, Jorge E. Romaguera, Michael E. Williams, Jacqueline C. Barrientos, Ewa Chmielowska, John Radford, Stephan Stilgenbauer, Martin Dreyling, Wieslaw Wiktor Jedrzejczak, Peter Johnson, Stephen E. Spurgeon, Lei Li, Liang Zhang, Kate Newberry, Zhishuo Ou, Nancy Cheng, Bingliang Fang, Jesse McGreivy, Fong Clow, Sc.D., Joseph J. Buggy, Betty Y. Chang, Darrin M. Beaupre, Lori A. Kunkel, and Kristie A. Blum

Background 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. Methods 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. Results 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. Conclusions Ibrutinib shows durable single-agent efficacy in relapsed or refractory mantle-cell lymphoma. (Funded by Pharmacyclics and others; ClinicalTrials.gov number

Targeting BTK with Ibrutinib in Relapsed Chronic Lymphocytic Leukemia

John C. Byrd, Richard R. Furman, Steven E. Coutre, Ian W. Flinn, Jan A. Burger, Kristie A. Blum, Barbara Grant,Jeff P. Sharman, Morton Coleman, William G. Wierda, Jeffrey A. Jones, Weiqiang Zhao, Nyla A. Heerema, Amy J. Johnson, Juthamas Sukbuntherng, Betty Y. Chang, Fong Clow, Sc.D., Eric Hedrick, Joseph J. Buggy, Danelle F. James, and Susan O'Brien

Background 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. Methods 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. Results 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%. Conclusions 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

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