Safety and efficacy of thalidomide in patients with POEMS syndrome: a multicentre, randomised, double-blind, placebo-controlled trial
Safety and efficacy of thalidomide in patients with POEMS syndrome: a multicentre, randomised, double-blind, placebo-controlled trial
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DOI：
10.1016/s1474-4422(16)30157-0
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发表时间：
2016-10-01
期刊：
影响因子：
48
通讯作者：
Kuwabara, Satoshi
中科院分区：
文献类型：
--
作者：
Misawa, Sonoko;Sato, Yasunori;Kuwabara, Satoshi
多发性神经病、器官肥大、内分泌病、M蛋白和皮肤改变（POEMS）综合征是脱髓鞘神经病的一种罕见病因，其特征为多器官受累，浆细胞恶液质和VEGF过度产生。对于不适合干细胞移植的POEMS综合征患者，尚未建立治疗方法。沙利度胺抑制VEGF和浆细胞增殖。我们的目的是评估沙利度胺治疗POEMS syndrome.Methods的安全性和有效性，我们做了一个随机，双盲，安慰剂对照，在日本的12家医院2/3期试验。POEMS综合征成人患者（年龄≥ 20岁），不适合进行自体移植，按最小化方法随机（1：1）分配至口服地塞米松（12 mg/m2/d，每28天为1周期，前4天为1周期）联合口服沙利度胺（200 mg/d）或安慰剂治疗6个周期。所有研究人员和患者均对治疗分配设盲。主要终点是24周时血清VEGF浓度的降低率。研究结果在2010年11月11日至2014年7月3日期间，我们将25例患者随机分配接受沙利度胺（n=13）或安慰剂（n=12）;安慰剂组中的1例患者因违反方案而被排除在分析之外。沙利度胺组第24周时校正的平均VEGF浓度降低率为0.39（SD 0.34），而安慰剂组为-0.02（0.54）（校正的平均差异0.41，95% CI 0.02-0.80; p=0.04）。沙利度胺组轻度窦性心动过缓的发生率高于安慰剂组（7例[54%] vs 0例; p=0.006）。5名患者出现严重不良事件：沙利度胺组3名（短暂性心脏骤停、心力衰竭和脱水），安慰剂组2名（肠梗阻和发热）。随机化研究期间未发生死亡。在48周开放标签研究期间（n=22），新发生的不良事件为窦性心动过缓（n=4）、便秘（n=5）和轻度感觉神经病变（n=5）。两名患者在开放标签研究中死亡;这两名患者最初都在安慰剂组，死亡原因是疾病的进展。解释沙利度胺降低血清VEGF浓度，代表了POEMS综合征患者不适合干细胞移植的新治疗方法。沙利度胺治疗有心动过缓的风险;然而，获益可能超过风险。
Background Polyneuropathy, organomegaly, endocrinopathy, M-protein, and skin changes (POEMS) syndrome is a rare cause of demyelinating neuropathy, with multi-organ involvement characterised by plasma cell dyscrasia and VEGF overproduction. No treatments have been established for patients with POEMS syndrome who are not eligible for stem-cell transplantation. Thalidomide suppresses VEGF and plasma cell proliferation. We aimed to assess the safety and efficacy of thalidomide for the treatment of POEMS syndrome.Methods We did a randomised, double-blind, placebo-controlled, phase 2/3 trial at 12 hospitals in Japan. Adults (age >= 20 years) with POEMS syndrome who were ineligible for autotransplantation were randomly assigned (1:1) by a minimisation method to treatment with oral dexamethasone (12 mg/m(2) per day on the first 4 days of every 28-day cycle) plus either oral thalidomide (200 mg daily) or placebo for six cycles. All study personnel and patients were masked to treatment allocation. The primary endpoint was the reduction rate of serum VEGF concentrations at 24 weeks. Analysis was by intention to treat. This study is registered with the UMIN Clinical Trials Registry, UMIN000004179.Findings Between Nov 11, 2010, and July 3, 2014, we randomly assigned 25 patients to receive either thalidomide (n=13) or placebo (n=12); one patient in the placebo group was excluded from analyses because of a protocol violation. The adjusted mean VEGF concentration reduction rate at 24 weeks was 0.39 (SD 0.34) in the thalidomide group compared with -0.02 (0.54) in the placebo group (adjusted mean difference 0.41, 95% CI 0.02-0.80; p=0.04). Mild sinus bradycardia was more frequent in the thalidomide group than in the placebo group (seven [54%] vs zero; p=0.006). Five patients had serious adverse events: three in the thalidomide group (transient cardiac arrest, heart failure, and dehydration) and two in the placebo group (ileus and fever). No deaths occurred during the randomised study. In the 48-week open-label study period (n=22), newly developed adverse events were sinus bradycardia (n=4), constipation (n=5), and mild sensory neuropathy (n=5). Two patients died in the open-label study; both patients were initially in the placebo group, and the cause of death was progression of the disease.Interpretation Thalidomide reduces serum VEGF concentrations and represents a new treatment for patients with POEMS syndrome who are not eligible for stem-cell transplantation. Thalidomide treatment poses a risk of bradycardia; however, the benefits are likely to exceed the risk.