van Rhee Frits, Casper Corey, Voorhees Peter M, Fayad Luis E, Gibson Damilola, Kanhai Karan, Kurzrock Razelle
Myeloma Center, University of Arkansas for Medical Sciences, Little Rock, AR, USA.
Infectious Disease Research Institute, Seattle, WA, USA; Departments of Medicine and Global Health, University of Washington, Seattle, WA, USA.
Lancet Haematol. 2020 Mar;7(3):e209-e217. doi: 10.1016/S2352-3026(19)30257-1. Epub 2020 Feb 3.
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.
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.
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.
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.
Janssen R&D and EUSA Pharma.
基于持久的疗效和安全性数据，国际共识推荐西妥昔单抗作为特发性多中心Castleman病的一线治疗药物。本研究旨在评估西妥昔单抗长达6年治疗期的长期安全性和活性。
本研究是一项预先设定的开放性标签扩展分析，基于一项1期试验（NCT00412321）和一项2期试验（NCT01024036）开展，这两项试验在全球26家医院进行。两项研究中的患者均为年龄至少18岁、经组织学确诊的有症状Castleman病患者。这项扩展研究纳入了60名在前述试验中完成治疗且疾病未因西妥昔单抗发生进展的患者。患者每3周接受一次11 mg/kg的西妥昔单抗静脉输注（可延长至6周），最长持续6年。采用描述性统计对数据进行总结。未进行正式的假设检验。主要终点是每个给药周期评估的西妥昔单抗安全性。本研究已在ClinicalTrials.gov注册，注册号为NCT01400503，并在欧洲临床试验数据库（EudraCT）注册，编号为2010-022837-27。
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。本长期扩展研究的患者入组时间为2011年4月1日至2014年1月15日。中位随访时间为6年（四分位间距5.11 - 7.76）。从之前试验开始至本研究结束的中位治疗持续时间为5.5年（四分位间距4.26 - 7.14）。西妥昔单抗耐受性良好；然而，60名患者中有36名（60%）报告了3级或更严重的不良事件，最常见的是高血压（8例[13%]）、疲劳（5例[8%]）、恶心（4例[7%]）、中性粒细胞减少（4例[7%]）和呕吐（3例[5%]）。25名（42%）患者报告了至少一项严重不良事件，最常见的是感染（8例[1
