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 Rekeland et al. Intravenous Cyclophosphamide in ME/CFS 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.

Reduced Endothelial Function in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome–Results From Open-Label Cyclophosphamide Intervention Study

“…Although 22 of the 40 patients reported clinical response after cyclophosphamide treatment (29), our data did not reveal any statistically significant changes in endothelial function (FMD or PORH) from baseline to 12 months (Only patients with values for both timepoints included, and analyzed by Wilcoxon signed ranks test) ( Table 3, Figures 2A,B). Furthermore, GLM repeated measures analyses showed no significant differences in changes of endothelial function (FMD or PORH) from baseline to 12 months, between responders and non-responders after cyclophosphamide treatment, i.e., there were no significant differences assessed by the interaction term response group-bytime (Figures 2C,D).…”

“…This study was performed as a substudy to the open-label phase II trial “Cyclophosphamide in myalgic encephalomyelitis/chronic fatigue syndrome” ( 29 ). The study has a cross-sectional design, comparing endothelial function in patients at baseline with healthy individuals.…”

“…After a preliminary assessment of eligibility based on records of medical history and current disease severity, we performed a random selection among candidates who met the inclusion criteria. Candidates were invited to receive further information on the trial and this substudy, and subject to informed consent, they were screened according to protocol ( 29 ). Fifteen patients were recruited among previous rituximab trial participants (non-responders or responders with full or partial relapse) ( 30 , 31 ).…”

“…The variable Fatigue Score was calculated as the mean change score for four fatigue-related items: "Fatigue, " "Postexertional malaise, " "Need for rest" and "Daily functioning." Clinical response was defined as Fatigue Score ≥4.5 for at least 6 consecutive weeks (29).…”

“…In 2014, we performed a small pilot study at Haukeland University Hospital and found very low values of FMD in ME/CFS patients (unpublished). Following the pilot experience, studies of endothelial function were performed as substudies to two intervention drug trials for patients with ME/CFS at Haukeland University Hospital: a phase III trial of rituximab vs. placebo ( 28 ) and a phase II trial of cyclophosphamide ( 29 ). This article reports the results from the endothelial function substudy of the cyclophosphamide trial.…”