6. May 2020

Promising results from trial of cancer drug in ME/CFS

- But results should be interpreted with caution, according to researchers from Haukeland University Hospital.

By Kari Sørland/Hanne Eide Andersen 

With support from Kavli Trust, the ME/CFS research group at Haukeland University Hospital led by doctors Øystein Fluge and Olav Mella, in collaboration with Alexander Fosså at the Oslo Radium Hospital, have completed a trial investigating treatment with the cytotoxic drug cyclophosphamide in ME/CFS.

The trial was carried out from 2015 to 2017, and after long-term follow-up for up to 4 years the results are now published in Frontiers in Medicine.

“The main conclusion is that treatment with cyclophosphamide was feasible for ME/CFS patients,” says lead author Ingrid Gurvin Rekeland.

“22 out of 40 patients who commenced study treatment, reported clinical response, and there were few unexpected side-effects.”

Larger studies are needed

According to Dr. Rekeland, the results must nevertheless be interpreted with caution: 

“In this trial, all participants received the study drug cyclophosphamide, and we have no control group for comparison,” she says.

“In order to confirm – or disprove – whether this is a good treatment for patients with ME/CFS, there is a need for larger studies with a control group receiving alternative intervention or placebo treatment. We cannot recommend treatment with cyclophosphamide until further studies have been performed,” says Rekeland.

Ingrid Gurvin Rekeland. Photo: Haukeland University Hospital

How the trial was conducted

The participants met the Canadian diagnostic criteria and suffered from mild-to-moderate, moderate, moderate-to-severe or severe ME/CFS.

Patients with mild or very severe disease were excluded from the trial. Mean age was 41.7 years, and half the participants had been ill for at least ten years.

The treatment consisted of six intravenous infusions of cyclophosphamide, which is a cytotoxic drug also used in the treatment of cancer and certain autoimmune diseases.

Cyclophosphamide affects the cells of the immune system in particular, although the exact mechanism for its effect on the various diseases is as yet unknown,” says professor Olav Mella, who leads the ME/CFS research group at Haukeland University Hospital along with professor Øystein Fluge.

After the six-month treatment period, the participants attended regular checkups for one year, followed by extended follow-up in 2018 and 2019. During the trial the participants were required to take blood samples regularly, they completed forms for self-assessment of function level and symptom change, and their physical activity level (steps per 24h) was recorded using an activity monitor.


  • 22 of 40 patients (55 per cent) reported slight-to-moderate, moderate or major improvement of typical ME/CFS associated symptoms for at least six consecutive weeks, thereby meeting the criteria for clinical response.
  • By means of the SF-36 questionnaire, which is a common tool to measure health-related quality of life in clinical studies, the patients as a group reported a mean increase from 33 to 52 points on a scale from 1 to 100, where the population mean is approx. 84 points.
  • For the 22 patients who experienced a clinical improvement of their ME/CFS symptoms, the mean change was from 35 to 70 points.
  • Physical activity monitoring showed that after 18 months, the 22 responders had increased their mean steps per 24 hours from approx. 3600 to approx. 5600 steps.
  • Out of six patients with severe ME/CFS, none registered clinical response according to study criteria.
  • Of the 22 responders, 15 reported continued clinical improvement four years after study start date.

Acceptable toxicity profile

The most common side effects reported in the trial were nausea and general malaise for days or weeks after each treatment.

“In general, the patients reported more nausea and discomfort than cancer patients typically do at similar doses,” says Rekeland.

“This could be due to a general sensitivity to both drugs and physical stress, as reported by many ME/CFS patients.”

Another expected side effect from cyclophosphamide is a detrimental effect on women’s menstrual cycle. Two female patients in their 40s experienced premature menopause, and another two reported irregular menstruation at end of follow-up.

There were few serious side effects. The authors conclude that the toxicity profile was acceptable, although the treatment period was challenging for the patients.

Association between gene variants and response? In a recent study, Asgeir Lande and colleagues investigated a group of genes called HLA genes, which play a pivotal part in the regulation of the immune system, in patients with ME/CFS.

Read also: Human Leukocyte Antigen alleles associated with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS)

Lande found that two specific HLA gene variants, or alleles, occurred more often in ME/CFS patients than in healthy controls. In the cyclophosphamide trial, 30 per cent of the participants had one of these “risk” alleles.

Furthermore, the results showed that 83 per cent (10 of 12) patients who had a risk allele, reported a clinical improvement during the trial, compared to 43 per cent (12 of 28) who did not possess either of these HLA variants.

“This could indicate a possible association between these HLA alleles and treatment effect from cyclophosphamide. Associations between HLA gene variants and treatment effect have been reported in other autoimmune diseases,” says Rekeland.

“Even though the numbers are too small to draw any firm conclusions, these data warrant further investigation in future studies.”

Øystein Fluge. Photo: Kristin Risa

What do the results mean?

“We cannot draw firm conclusions on the effect of cyclophosphamide based on this trial, Øystein Fluge concurs.

“The results are interesting, but must be interpreted cautiously. Cyclophosphamide is a drug that can cause side effects,” he stresses.

“At present, we are working to further elucidate the symptom mechanisms and identify patients with a probable immunological basis for the disease, as well as developing better methods to characterize the clinical course and changes following treatment of the individual patient.”

The goal is to conduct further medical intervention studies in ME/CFS.

“Although the results of this trial alone do not justify treatment with cyclophosphamide outside clinical trials, the CycloME study, along with a growing body of basic research, provides another indication that the immune response plays an important part in the ME/CFS disease mechanisms. Therefore, a main focus at the present stage is to increase our understanding of the role played by the very complex immune system,” comments Olav Mella.

BACKGROUND – Support from Kavli Trust

Kavli Trust has contributed to the CycloME trial through part-time funding of a medical consultant and research nurse for treatment and follow-up of study patients.

As part of a long-term collaboration with the ME/CFS research group at Haukeland University Hospital, Kavli Trust has also funded biochemical and genetic analyses of blood samples from patients participating in the trial.

Top photo: Pål Schaathun

Read more: All articles on ME/CFS research funded by Kavli Trust

The ME/CFS research group at Haukeland University Hospital. Karl Johan Tronstad, Ina Pettersen, Kine Alme, Sissel Dyrstad, Ove Bruland, Kari Sørland and Olav Mella. Photo: Kristin Risa