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

Abstract

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/m(2), 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.