BACKGROUND Siltuximab is recommended by international consensus as a first-line treatment for idiopathic multicentric Castleman disease on the basis of durable efficacy and safety data. This study was done to assess the long-term safety and activity of siltuximab over up to 6 years of treatment. METHODS This study is a prespecified open-label extension analysis of a phase 1 trial (NCT00412321) and a phase 2 trial (NCT01024036), done at 26 hospitals worldwide. Patients in both studies were at least 18 years old with histologically confirmed, symptomatic Castleman disease. This extension study enrolled 60 patients who completed the previous trials without disease progression on siltuximab. Patients received siltuximab infusions of 11 mg/kg every 3 weeks (which could be extended to 6 weeks) for up to 6 years. Descriptive statistics were used to summarise the data. No formal hypothesis testing was performed. The primary endpoint was the safety of siltuximab, assessed at each dosing cycle. The study was registered with ClinicalTrials.gov, number NCT01400503 and with EudraCT, number 2010-022837-27. FINDINGS Patient enrolment into the phase 1 trial was from June 20, 2005, to Sept 15, 2009, and enrolment into the phase 2 trial was from Feb 9, 2010, to Feb 3, 2012. Patients were enrolled in this long-term extension from April 1, 2011, to Jan 15, 2014. Median follow-up was 6 years (IQR 5·11-7·76). Median treatment duration, from the beginning of the previous trials to the end of the present study, was 5·5 years (IQR 4·26-7·14). Siltuximab was well tolerated; however, adverse events of grade 3 or worse were reported in 36 (60%) of 60 patients with the most common being hypertension (eight [13%]), fatigue (five [8%]), nausea (four [7%]), neutropenia (four [7%]), and vomiting (three [5%]). 25 (42%) patients reported at least one serious adverse event, which most commonly was an infection (eight [13%]). Only two serious adverse events, polycythaemia and urinary retention, were considered related to siltuximab treatment. 18 patients discontinued before study completion, either to receive siltuximab locally (eight) or because of progressive disease (two), adverse events (two), or other reasons (six). No deaths were reported. INTERPRETATION These results show that siltuximab is well tolerated long term and provides important evidence for the feasibility of the life-long use required by patients with idiopathic multicentric Castleman disease. FUNDING Janssen R&D and EUSA Pharma.

中文翻译：

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西妥昔单抗在特发性多中心Castleman病患者中的长期安全性：两项试验的既定开放标签扩展分析。

背景技术根据持久的疗效和安全性数据，国际公认将西妥昔单抗推荐为特发性多中心Castleman病的一线治疗。进行这项研究是为了评估Siltuximab在长达6年的治疗中的长期安全性和活性。方法该研究是一项预先指定的开放标签扩展分析，用于一项在全球26家医院进行的1期试验（NCT00412321）和2期试验（NCT01024036）。两项研究中的患者均至少18岁，具有组织学证实的症状性Castleman病。这项扩展研究招募了60位完成了先前试验的西妥昔单抗无病进展的患者。患者每3周（可能延长至6周）接受11 mg / kg西妥昔单抗输注，长达6年。描述性统计用于汇总数据。没有进行正式的假设检验。主要终点是西妥昔单抗的安全性，在每个给药周期进行评估。该研究已在ClinicalTrials.gov注册，编号为NCT01400503，在EudraCT注册，编号为2010-022837-27。结果1期试验的患者入组时间为2005年6月20日至2009年9月15日，2期试验的患者入组时间为2010年2月9日至2012年2月3日。从2011年4月1日至2014年1月15日。中位随访时间为6年（IQR 5·11-7·76）。从先前试验的开始到本研究结束的中位治疗持续时间为5·5年（IQR 4·26-7·14）。西妥昔单抗耐受性良好。然而，在60例患者中，有36例（60％）发生了3级或更严重的不良事件，其中最常见的是高血压（8 [13％]），疲劳（5 [8％]），恶心（4 [7％]），中性粒细胞减少症（4 [7％]）和呕吐（3 [5％]）。25名（42％）患者报告了至少一种严重不良事件，其中最常见的是感染（8 [13％]）。只有两个严重的不良事件，即红细胞增多症和尿retention留被认为与西妥昔单抗治疗有关。18名患者在研究结束前中断治疗，要么是局部接受西妥昔单抗（8名），要么是因为进行性疾病（两次），不良事件（两次）或其他原因（六个）。没有死亡的报道。解释这些结果表明，siltuximab具有良好的长期耐受性，并为特发性多中心Castleman病患者终身使用的可行性提供了重要证据。资金Janssen研发和EUSA Pharma。