Fort Lauderdale, FL — The illness known as "chronic fatigue syndrome" isn't typically considered within the purview of oncology, but a chance finding in 2004 led two Norwegian oncologists on a career-consuming mission to shed light on the controversial condition.
Also termed "myalgic encephalomyelitis" in parts of Europe and increasingly called "ME/CFS" in the United States and elsewhere, the condition often arises after a prolonged infectious illness or environmental trigger. Its hallmark symptom is postexertional malaise, but that comes with a variety of other symptoms, including unrefreshing sleep, muscle pain/burning, orthostatic hypotension, flulike symptoms, and cognitive dysfunction, that range in severity from mild to debilitating.
Numerous diagnostic criteria have been published, the most recent being the February 2015 Institute of Medicine report, but no specific biomarker test has been developed as yet, leading some clinicians to question whether it is biologically based. Current treatments are aimed primarily at symptomatic relief.
In 2004, oncologists Øystein Fluge, MD, and Olav Mella, MD, PhD, both at Haukeland University Hospital, University of Bergen in Norway, were treating a patient with lymphoma who also had long-standing ME/CFS. When they gave her cytotoxic chemotherapy, including the B cell–depleting monoclonal antibody rituximab, her ME/CFS symptoms improved.
The observation in that patient and subsequently in two others led the pair to conduct two preliminary studies, one a small randomized trial and the other an open-label phase 2 proof-of-concept study, testing maintenance treatment with rituximab. Both trials showed significant benefit in about two thirds of patients with ME/CFS, as defined by published criteria.
Now, Dr Fluge and Dr Mella have embarked on a larger phase 3 randomized controlled trial testing rituximab in patients with ME/CFS, as well as a smaller randomized trial of the broader immune-modulating agent cyclophosphamide.
"We came into this through the back door, by seeing patients with ME responding to treatments…. We also come from a field of medicine where there is a sense of urgency. That probably has something to do with what we've been achieving during the last few years," Dr Mella said in a keynote talk given at the recent biennial meeting of the International Association of Chronic Fatigue Syndrome/Myalgic Encephalomyelitis.
However, he and Dr Fluge, who also spoke at the conference, emphasized that their work is very preliminary. Although rituximab and cyclophosphamide have long been approved for other indications — primarily in oncology and rheumatology — they don't advocate their use in patients with ME/CFS at this time.
"Until we have more evidence from the randomized phase 3 trial, we do not support treatment outside clinical trials," Dr Fluge said.
Asked to comment, Charles W. Lapp, MD, director of the Hunter-Hopkins Center in Charlotte, North Carolina, told Medscape Medical News, "We don't have an etiology so anything is up for grabs right now. If they found empirically and serendipitously that [rituximab] worked, then let's study it and see where it leads."
Dr Lapp also said it's not entirely surprising that a B cell–depleting drug may alleviate symptoms for some with ME/CFS. "[I]t just reflects that this is some sort of autoimmune disorder, and we know that. Many of our patients have autoimmune antibodies at least to thyroid, and [antinuclear antibody] positivity…. They're all subsets, but we haven't really looked at the subsets and we're still not dividing them up that way."
In all, Dr Lapp said, "I think it's very interesting research…. Not everybody responds, but I hope it will give us another option."
Evidence of Autoimmunity
Several lines of evidence support the idea that ME/CFS is an autoimmune disease in at least some patients and that it specifically involves B cells, Dr Mella explained.
A paper from the National Cancer Institute published in 2012 in the journal Cancer identified a significant association between Medicare patients diagnosed with "CFS" and the diffuse large B cell subtype of non-Hodgkin lymphoma.
"The B cell lymphoma risk is very modest, but significant. It tells us something about the disease. There's some kind of activation in the B cell system," he said.
In addition, the 40% to 50% frequency of autoimmunity in relatives of participants in the Norwegian studies, combined with the fact that 75% of patients with ME/CFS are women, similar to the proportion in many autoimmune diseases, also points to that etiology.
Moreover, the pattern of delayed responses after B cell depletion and of subsequent relapses seen in both of the small rituximab trials are similar to what is seen in some better-characterized autoimmune diseases, Dr Mella noted. Additionally, the delayed response also argues against a placebo effect.
"The pattern of response is always the same. There's always a lag time before giving the drug of at least 2 months up to 1 year before anything happens. And it can happen quite suddenly when it happens. That's one of the reasons we believe autoantibodies may be involved. In all kinds of autoimmune disease, it's not just whether you have antibodies or not, but the level of antibodies," Dr Mella told Medscape Medical News.
A Possible Mechanism
In his lecture, Dr Fluge presented new data from an amino acid analysis of samples from 153 of their patients with ME/CFS and 102 age- and sex-matched controls that suggests an underlying mechanism of the illness: a metabolic obstruction in the central energy pathway at the pyruvate dehydrogenase complex level, blocking adenosine triphosphate production and forcing the cells into less efficient compensatory anaerobic pathways.
This, he said, would explain two salient ME/CFS features: profound lack of energy and excessive lactate production from even very limited exertion, often described by patients as a "burning" sensation in their muscles.
"At present, the disturbances in metabolic patterns in ME/CFS look like a struggle for energy," he said.
"Optimistic for the Future"
In the ongoing B-lymphocyte Depletion Using Rituximab in Chronic Fatigue Syndrome/ Myalgic Encephalopathy (RituxME) trial, 152 patients with ME/CFS in five Norwegian centers are being randomly assigned to two rituximab or placebo infusions 2 weeks apart, followed by maintenance infusions at 3, 6, 9, and 12 months.
The primary outcome measure is self-reported fatigue score over 24 months. Secondary measures include the Short-Form-36, physical activity using an armband monitor, and clinical response at 24 months. Toxicity and side effects will also be recorded throughout. Early results and unblinding are expected in October 2017.
Meanwhile, the two oncologists have also launched a separate randomized phase 3 trial, Cyclophosphamide in Myalgic Encephalopathy/Chronic Fatigue Syndrome (CycloME), testing cyclophosphamide in 40 patients with ME/CFS at two Norwegian centers. Patients receive one infusion (intermediate dose) every 4 weeks for a total of six infusions, and observation thereafter.
That study is set for completion in January 2017. According to Dr Mella, "We can say already that cyclophosphamide can attenuate ME/CFS symptoms, in some patients very well," with major improvements seen after 6 months. On the other hand, he noted, "the short-term toxicity is worse than we anticipated, and worse than in cancer patients."
Nonetheless, he said, the "good message" is that a broader immune-acting drug than rituximab is active in ME/CFS, adding validity to the general approach.
"We believe the possibilities for effective treatment are rapidly increasing as we get to know more and more about the underlying disease pathomechanisms…. We have to go through the necessary phases to get drugs approved, but a lot of things are happening. I'm very optimistic for the future."
Asked to what extent ME/CFS takes up their time, Dr Mella told Medscape Medical News that both he and Dr Fluge continue to practice clinical oncology, but their entire research agenda is now devoted to ME/CFS. "We stumbled on this, and we had a problem not going into it because we knew there was so much controversy in this area…. We started, and then we got lost in it…. We work a lot on evenings and weekends."
Dr Mella and Dr Fluge's work receives support from the Kavli Foundation. Their institution, Haukeland University Hospital, has applied for a patent for the concept of B cell depletion in ME/CFS. Dr Lapp conducts research funded by Hemispherx, which manufactures rintatolimod (Ampligen), another investigational immune-modulating drug for ME/CFS.
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Cite this: Immune-Modulating Agents Eyed for 'Chronic Fatigue Syndrome' - Medscape - Nov 11, 2016.
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