Siltuximab for multicentric Castleman's disease: a randomised, double-blind, placebo-controlled trial
Siltuximab for multicentric Castleman's disease: a randomised, double-blind, placebo-controlled trial
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DOI：
10.1016/s1470-2045(14)70319-5
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发表时间：
2014-08-01
期刊：
影响因子：
51.1
通讯作者：
Casper, Corey
中科院分区：
文献类型：
--
作者：
van Rhee, Frits;Wong, Raymond S.;Casper, Corey
背景多中心Castleman病是一种罕见的由白细胞介素6分泌失调引起的淋巴细胞增生性疾病。目前还没有进行随机试验来确定这种疾病的最佳治疗方法。我们评估了西妥昔单抗（一种抗白细胞介素6的嵌合单克隆抗体）在hiv阴性多中心Castleman病患者中的安全性和有效性。方法：我们在全球19个国家的38家医院进行了这项随机、双盲、安慰剂对照研究。我们招募了有症状的多中心Castleman病的hiv阴性和人类疱疹病毒-8血清阴性患者。使用计算机生成的列表随机分配治疗，分组大小为6，并根据基线皮质类固醇使用情况分层。患者和调查人员对治疗分配不知情。患者被随机分配（1:1）至西妥昔单抗组（每3周静脉输注11mg /kg）或安慰剂组；所有患者均接受了最佳支持性护理。患者继续治疗直至治疗失败。主要终点是意图治疗人群的持续肿瘤和症状缓解至少18周。报名已完成。该研究已在ClinicalTrials.gov注册，编号NCT01024036。我们筛选了140例患者，其中79例随机分配到西妥昔单抗组（n=53）或安慰剂组（n=26）。西妥昔单抗组53例患者中有18例（34%）出现持续的肿瘤和症状反应，而安慰剂组26例患者中无持久的肿瘤和症状反应（差异为34%，95% CI为11.1-54.8,p=0.0012）。尽管西妥昔单抗的中位治疗时间比安慰剂更长（375天[范围1-1031]比152天[23-666]），但两组中3级或以上不良事件（25例[47%]比14例[54%]）和严重不良事件（12例[23%]比5例[19%]）的发生率相似。最常见的3级或更高级别是疲劳（5比1）、盗汗（4比1）和贫血（1比3）。53例患者中有3例（6%）发生与西妥昔单抗相关的严重不良事件（下呼吸道感染、过敏反应、败血症）。解释对于有症状的多中心Castleman病患者，西妥昔单抗加最佳支持治疗优于单用最佳支持治疗，且长期暴露耐受性良好。西妥昔单抗是治疗此病的重要新选择。
Background Multicentric Castleman's disease is a rare lymphoproliferative disorder driven by dysregulated production of interleukin 6. No randomised trials have been done to establish the best treatment for the disease. We assessed the safety and efficacy of siltuximab-a chimeric monoclonal antibody against interleukin 6-in HIV-negative patients with multicentric Castleman's disease.Methods We did this randomised, double-blind, placebo-controlled study at 38 hospitals in 19 countries worldwide. We enrolled HIV-negative and human herpesvirus-8-seronegative patients with symptomatic multicentric Castleman's disease. Treatment allocation was randomised with a computer-generated list, with block size six, and stratification by baseline corticosteroid use. Patients and investigators were masked to treatment allocation. Patients were randomly assigned (2: 1) to siltuximab (11 mg/kg intravenous infusion every 3 weeks) or placebo; all patients also received best supportive care. Patients continued treatment until treatment failure. The primary endpoint was durable tumour and symptomatic response for at least 18 weeks for the intention-to-treat population. Enrolment has been completed. The study is registered with ClinicalTrials.gov, number NCT01024036.Findings We screened 140 patients, 79 of whom were randomly assigned to siltuximab (n=53) or placebo (n=26). Durable tumour and symptomatic responses occurred in 18 (34%) of 53 patients in the siltuximab group and none of 26 in the placebo group (difference 34 0%, 95% CI 11.1-54.8, p=0.0012). The incidence of grade 3 or more adverse events (25 [47%]vs 14 [54%]) and serious adverse events (12 [23%] vs five [19%]) was similar in each group despite longer median treatment duration with siltuximab than with placebo (375 days [range 1-1031] vs 152 days [23-666]). The most common grade 3 or higher were fatigue (five vs one), night sweats (four vs one), and anaemia (one vs three). Three (6%) of 53 patients had serious adverse events judged reasonably related to siltuximab (lower respiratory tract infection, anaphylactic reaction, sepsis).Interpretation Siltuximab plus best supportive care was superior to best supportive care alone for patients with symptomatic multicentric Castleman's disease and well tolerated with prolonged exposure. Siltuximab is an important new treatment option for this disease.