Data_Sheet_1_Intravenous Cyclophosphamide in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome. An Open-Label Phase II Study.PDF

Introduction: Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a disease with high symptom burden, of unknown etiology, with no established treatment. We observed patients with long-standing ME/CFS who got cancer, and who reported improvement of ME/CFS symptoms after chemotherapy including cyclophosphamide, forming the basis for this prospective trial.Materials and methods: This open-label phase II trial included 40 patients with ME/CFS diagnosed by Canadian criteria. Treatment consisted of six intravenous infusions of cyclophosphamide, 600–700 mg/m2, given at four-week intervals with follow-up for 18 months, extended to 4 years. Response was defined by self-reported improvements in symptoms by Fatigue score, supported by Short Form 36 (SF-36) scores, physical activity measures and other instruments. Repeated measures of outcome variables were assessed by General linear models. Responses were correlated with specific Human Leukocyte Antigen (HLA) alleles.Results: The overall response rate by Fatigue score was 55.0% (22 of 40 patients). Fatigue score and other outcome variables showed significant improvements compared to baseline. The SF-36 Physical Function score increased from mean 33.0 at baseline to 51.5 at 18 months (all patients), and from mean 35.0 to 69.5 among responders. Mean steps per 24 h increased from mean 3,199 at baseline to 4,347 at 18 months (all patients), and from 3,622 to 5,589 among responders. At extended follow-up to 4 years 68% (15 of 22 responders) were still in remission. Patients positive for HLA-DQB1*03:03 and/or HLA-C*07:04 (n = 12) had significantly higher response rate compared to patients negative for these alleles (n = 28), 83 vs. 43%, respectively. Nausea and constipation were common grade 1–2 adverse events. There were one suspected unexpected serious adverse reaction (aggravated POTS) and 11 serious adverse events in eight patients.Conclusion: Intravenous cyclophosphamide treatment was feasible for ME/CFS patients and associated with an acceptable toxicity profile. More than half of the patients responded and with prolonged follow-up, a considerable proportion of patients reported ongoing remission. Without a placebo group, clinical response data must be interpreted with caution. We nevertheless believe a future randomized trial is warranted.Clinical Trial Registration:www.ClinicalTrials.gov, identifier: NCT02444091.

引言：慢性疲劳综合症/肌痛性脑脊髓炎（ME/CFS）是一种症状负担沉重的疾病，其病因尚不明确，且缺乏公认的治疗方法。我们观察到长期患有ME/CFS的病人在罹患癌症后，化疗（包括环磷酰胺）治疗后报告了ME/CFS症状的改善，这构成了本前瞻性试验的基础。材料与方法：本开放标签的II期临床试验纳入了40名符合加拿大标准的ME/CFS患者。治疗方案包括每四周一次，共六次静脉注射环磷酰胺，剂量为600-700 mg/m²，随访时间为18个月，后延长至4年。响应定义为通过疲劳评分自我报告的症状改善，并得到简明健康调查问卷（SF-36）评分、体力活动测量和其他工具的支持。通过广义线性模型对结果变量进行重复测量。响应与特定的人类白细胞抗原（HLA）等位基因相关。结果：根据疲劳评分的整体响应率为55.0%（40名患者中的22名）。与基线相比，疲劳评分和其他结果变量显示出显著的改善。SF-36身体功能评分从基线的平均33.0分增加到18个月时的51.5分（所有患者），以及响应者的平均35.0分增加到69.5分。平均每24小时的步数从基线的平均3,199步增加到18个月时的4,347步（所有患者），以及响应者的3,622步增加到5,589步。在延长的4年随访中，68%（22名响应者中的15名）仍然处于缓解状态。HLA-DQB1*03:03和/或HLA-C*07:04阳性（n = 12）的患者与这些等位基因阴性（n = 28）的患者相比，响应率显著更高，分别为83%和43%。恶心和便秘是常见的一级至二级不良事件。八名患者中有一起疑似意外严重不良事件（加重的POTS）和11起严重不良事件。结论：静脉注射环磷酰胺治疗对ME/CFS患者来说是可行的，并伴有可接受的毒性谱。超过一半的患者有响应，并且随着随访时间的延长，相当一部分患者报告了持续的缓解。由于没有安慰剂组，临床响应数据必须谨慎解读。尽管如此，我们认为进行一项随机试验是必要的。临床试验注册：www.ClinicalTrials.gov，标识符：NCT02444091。