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：肌痛性脑脊髓炎/慢性疲劳综合征（Myalgic Encephalomyelitis/Chronic Fatigue Syndrome, ME/CFS）是一种症状负荷高、病因不明且尚无公认治疗方案的疾病。我们观察到罹患长期ME/CFS的癌症患者，在接受包括环磷酰胺在内的化疗后，其ME/CFS症状有所改善，这为本项前瞻性试验奠定了研究基础。

材料与方法：本项开放标签II期试验共纳入40名符合加拿大诊断标准的ME/CFS患者。治疗方案为每4周静脉输注环磷酰胺600~700 mg/m²，共6次，随访时长为18个月，后续延长至4年。疗效判定以患者自我报告的疲劳量表评分改善为核心依据，并辅以简明健康调查问卷36项版（Short Form 36, SF-36）评分、体力活动测量结果及其他评估工具进行验证。采用广义线性模型（General linear models）对结局变量的重复测量数据进行统计分析，并探究疗效与特定人类白细胞抗原（Human Leukocyte Antigen, HLA）等位基因的相关性。

结果：基于疲劳量表评分的总体应答率为55.0%（40例患者中22例达标）。与基线水平相比，患者的疲劳量表评分及其他结局变量均得到显著改善。所有患者的SF-36躯体功能评分从基线的平均33.0分提升至18个月时的51.5分；应答者的该评分则从基线平均35.0分提升至69.5分。所有患者的24小时平均步数从基线的3199步提升至18个月时的4347步；应答者的该指标则从3622步提升至5589步。在延长至4年的随访中，68%的应答者（22例中15例）仍处于症状缓解状态。携带HLA-DQB1*03:03和/或HLA-C*07:04等位基因的患者（n=12）应答率显著高于未携带上述等位基因的患者（n=28），分别为83%和43%。恶心与便秘为常见的1~2级不良事件。8例患者共计发生11起严重不良事件，另有1起疑似意外严重不良反应（加重的体位性直立性心动过速综合征，POTS）。

结论：静脉输注环磷酰胺用于ME/CFS患者具有可行性，且毒性谱可接受。超过半数的患者实现应答，且在延长随访后，仍有相当比例的患者维持持续症状缓解。由于本试验未设置安慰剂对照组，对临床应答数据的解读需谨慎。尽管如此，我们仍认为未来有必要开展随机对照试验。

临床试验注册：www.ClinicalTrials.gov，注册号：NCT02444091。