The answer was clear: the cancer drug rituximab does not relieve chronic fatigue syndrome. (Photo: Stokkete / Shutterstock / NTB scanpix)

Cancer drug doesn’t work for chronic fatigue

Cancer drug rituximab has no effect on chronic fatigue syndrome (ME/CFS), according to a Norwegian study.

“Now we can put this to rest,” says researcher Øystein Fluge.

He is referring to the idea that the cancer drug rituximab, which affects certain cells of the immune system, was thought to be helpful in treating chronic fatigue syndrome (ME/CFS).

Recently, Fluge and his colleagues published the results of the latest study of this drug in Annals of Internal Medicine. It marked the end of a nearly 15-year-long research story that began with great hope and enthusiasm, but ended in disappointment.

Now, the researchers have to look for other possibilities.

“You have to respect the results you get and adjust course,” says Fluge, who still believes it would be interesting to do more research on the immune system's role in ME/CFS.

Random discovery

It all began in 2004 when Fluge and his colleague Olav Mella stumbled upon an interesting coincidence.

Both are oncologists and at that time they were treating a patient with lymphoma. The treatment included a type of chemotherapy (Ifosfamide) that also suppresses immune cells.

The patient also had ME/CFS. And, surprisingly, it seemed that the treatment relieved the chronic fatigue. A while after the treatment ended, the ME/CFS symptoms returned.

In 2008, Fluge and Mella saw another lymphoma patient with long-standing ME/CFS. The patient received chemotherapy (cyclophosphamide) combined with the drug rituximab, which specifically inhibits B-lymphocytes, a type of immune cell.

She also experienced clear improvement of her ME/CFS symptoms.

This effect was certainly not expected. But it was also not completely improbable. Other indicators suggest that the immune system is involved in the disease mechanisms of ME/CFS. Could Fluge and Mella have stumbled upon a new medicine to treat this serious chronic disease?

Promising study

The researchers decided to test both the drug cyclophosphamide and the antibody rituximab in separate clinical studies.

They initiated a small pilot study with rituximab to see if more ME/CFS patients experienced a positive effect. The results were promising. Some of the participants seemed to be getting better with the medication.

This created great expectations in a patient group that lacked good treatment options. The researchers conducted several studies, but the studies were small or had too many weaknesses to draw fast conclusions.

In 2014, Fluge and his colleagues started the RituxME/CFS study, which they aimed to make both big and good enough to determine the medication’s efficacy.

Blind study

The study included 151 patients who all met the relatively strict Canadian criteria. No tests exist that can definitively isolate ME/CFS from other types of long-term fatigue. However, the rigorous diagnostic requirements increase the chances of excluding other causes of fatigue, although they do not provide any guarantee.

The study was a randomized double-blind placebo-controlled trial. The patients were randomly divided into two groups, who either received rituximab or a placebo. Neither the researchers nor the participants knew who got what.

The treatment lasted a year, but the researchers used both a questionnaire and the physical activity level measurements to follow up on the patients for a total of two years.

When the results came back, the conclusion was clear and unambiguous. But disappointing.

Rituximab had no effect.

No difference

The disease remained stable in most patients throughout the period, with 30% experiencing improvement and 10% experiencing deteriorating health. But the two groups showed no difference in results.

Patients receiving rituximab were on average neither better nor worse than those who received a placebo.

Could it be that the medicine nevertheless had an effect on a particular subgroup of patients? The researchers examined different subgroups among the patients. But even that showed no difference.

"The study was successful in the sense that it was carried out completely according to plan," says Fluge.

“And it has yielded a clear answer: completely negative. There is no need for any more studies. For that, there would need to be laboratory data that could unambiguously identify a subset of ME/CFS patients who might have a positive effect, but we didn’t find that,” he says.

Already in 2017, Fluge and his colleagues published preliminary results that indicated the medicine was not having positive effects.

We can’t deny that individual patients may have benefitted from the medication, but at the group level there was no trace of any effect, he adds.

Solid study

“This is a very solid and well conducted study. The data is complete and the conclusions clear,” says Karl Johan Tronstad, who also researches ME/CFS. He did not participate in the study, but works with Fluge and his colleagues in Bergen.

Ingrid B. Helland at the Norwegian National Advisory Unit on ME/CFS has no connection to the study. She also finds the research to be solid.

“This is a good and important study,” she says.

One weakness in the study is that it is based on self-reporting from the patients.

But Helland and Tronstad believe there is no reason to doubt the negative results.

Knowledge is all to the good

So what does the study mean for our understanding of ME/CFS?

Fluge, Tronstad and Helland all believe the result suggests that B-lymphocytes are not that central to the disease mechanism behind ME/CFS.

“That fork in the road is now closed,” says Tronstad.

Helland, on the other hand, points out that several patients in each group actually experienced improvement.

“The patients’ improvement confirms what we’ve seen before – that being part of a study has a positive effect in itself. The fact that someone cares and having a fixed routine help most people. Positive expectations are also significant,” she says.

“It would be going too far to say that ME/CFS is a mental disorder. But we know that a person’s psychological condition affects the body and the immune system, and vice versa,” Helland adds.

Helland would like to see broad research on ME/CFS. “Whatever knowledge we can gain is all to the good. Patient organizations request studies on treatments that some patients benefit from, but that are lacking documentation, like immunoglobulins or vitamin B12. We need more studies of this sort."

More studies on psychological treatment approaches should also be made on patients, as defined by the Canadian criteria.

More research on blood

Tronstad agrees that we should keep the doors open.

“It’s important to research a wide spectrum of approaches,” he says.

Tronstad is particularly interested in mechanisms that overlap between the body’s immune system and metabolism.

He used blood samples from the RituxME/CFS study to look for biochemical differences in the blood of patients who experienced improvement and those who did not. The data can also be used to compare blood samples between healthy and sick people.

30 years behind in understanding

Fluge is all for pursuing varied avenues of research, because so much is still lacking.

He views ME/CFS research from his point of view as a cancer researcher. The contrast between the cancer and ME/CFS research fields could hardly be greater, he believes.

“Major cancer conferences in the US have 40 000 participants attending and an almost infinite amount of resources and research impetus. Within the treatment realm, hospitals have protocols and departments for cancer,” says Fluge.

“But in the ME/CFS field there’s almost nothing. You’ll find about 50 researchers at the conferences. The understanding of the disease is 30 years behind and many patients have to deal with the illness on their own,” he says. “It’s thought provoking to see patients who’ve been bedridden for several years – resourceful people who are no longer able to eat or talk.”

“Yet, some ME/CFS patients eventually get better. Some recover completely. And this indicates that the illness is reversible. Then I think: we have to figure something out.”

He wants to join the effort and do just that.

“Patients deserve to have us try a little harder,” he says.

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Read the Norwegian version of this article at forskning.no

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