Norway: A comprehensive six-year follow-up of participants from two major clinical trials investigating rituximab and cyclophosphamide for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) has yielded significant insights into the long-term efficacy and safety of these treatments. The follow-up aims to provide a clearer understanding of the sustained effects and potential benefits of these drugs in managing a condition often marked by debilitating fatigue and other challenging symptoms.

Six-year follow-up data indicate that patients with ME or CFS who received cyclophosphamide experienced more significant and enduring improvements than those treated with rituximab or a placebo.
After six years, 44.1% of patients in the cyclophosphamide group achieved an SF-36 Physical Function (PF) score of 70 or higher, with 17.6% reaching a score of 90 or above," the researchers reported in PLoS ONE. The findings suggest that cyclophosphamide may positively influence the disease course for some individuals. However, due to its potential toxicity, cyclophosphamide should be used cautiously and only within the context of clinical trials for ME/CFS patients, they warned.
Rituximab, a monoclonal antibody that targets B-cells, and cyclophosphamide, a chemotherapy agent with immunosuppressive properties, were chosen in the study due to their potential to address underlying immune system dysfunction believed to contribute to ME/CFS. Ingrid G. Rekeland, University of Bergen, Bergen, Norway, and colleagues used patient-reported outcome measures (PROMs) to compare values at baseline, at 18 months, and six-year follow-up from the RituxME and CycloME trials.
The researchers performed two clinical trials between 2014 and 2017 based on the hypothesis that ME/CFS in a subgroup of patients is a variant of an autoimmune disease.
The RituxME trial was a randomized, double-blind, placebo-controlled phase III study involving 151 patients, evaluating the effects of the B-cell-depleting antibody rituximab. In contrast, the CycloME trial was an open-label phase II study with 40 participants, assessing the use of intravenous cyclophosphamide. The present report presents the six-year follow-up results from both trials, utilizing the Short Form 36 Physical Function (SF-36 PF) and the DePaul Short Form (DSQ-SF) questionnaires.
The researchers reported the following findings:
Of the patients available after six years, 75.7% of RituxME and 94.4% of CycloME patients participated.
In the RituxME rituximab group, the mean SF-36 PF scores were 32.9 at baseline, 42.4 at 18 months, and 45.5 at six years.
In the placebo group, the mean SF-36 PF scores were 32.3 at baseline, 45.5 at 18 months, and 43.1 at six years.
In the CycloME trial, mean SF-36 PF increased from 35.4 at baseline to 54.4 at 18 months and 56.7 at six years.
At six-year follow-up, 44.1% of cyclophosphamide-, 27.6% of rituximab- and 20.4% of placebo-treated patients had an SF-36 PF ≥ 70, and further, 17.6%, 8.6%, and 7.4% of the corresponding patient groups had an SF-36 PF ≥ 90, which is within normal range.
In terms of worsening at six years, 5.9% of cyclophosphamide-treated, 10.3% of rituximab-, and 14.8% of placebo-treated patients had a drop in SF-36 PF of 20 points or more from baseline.
There were no serious unexpected adverse reactions.
The researchers advised physicians and patients not to use cyclophosphamide for ME/CFS patients outside of clinical trials before further research is available.
"The data should drive increased efforts to deepen our understanding of disease mechanisms and to explore targeted, less toxic immune-modulatory treatments for this patient population," they concluded.
Reference:
Rekeland, I. G., Sørland, K., Neteland, L. L., Fosså, A., Alme, K., Risa, K., Dahl, O., Tronstad, K. J., Mella, O., & Fluge, Ø. (2024). Six-year follow-up of participants in two clinical trials of rituximab or cyclophosphamide in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome. PLOS ONE, 19(7), e0307484. https://doi.org/10.1371/journal.pone.0307484