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Cyclophosphamide: Phase II trials

Norwegian researchers have commenced phase II trials of the anti-cancer drug cyclophosphamide on ME/CFS patients.

Led by senior consultant Dr Øystein Fluge and Prof Olav Mella, the team is focusing on non-responders and those patients who have relapsed after treatment with rituximab, a B-cell depleting drug.

Forty patients with moderate to serious myalgic encephalomyelitis (ME) (sometimes referred to as me/cfs or chronic fatigue syndrome) are taking part in the cyclophosphamide trial, which began in March this year and is scheduled for completion by September 2016.

Twenty-five participants have not received previous treatment with rituximab, are either rituximab non-responders, or have relapsed following rituximab treatment.

Fluge and Mella’s work is bringing hope to millions of ME/CFS sufferers, worldwide. Their research into the use of rituximab to treat ME/CFS is considered a real breakthrough after the success of an earlier trial, and they are currently undertaking a large phase III trial of rituximab on 152 ME patients running over over three years.

Mella and Fluge believe that ME/CFS is a form of autoimmune illness where the body comes under attack from its own defence system.


Professor Olav Mella, national project coordinator and nurse Kari Sørland, and physician and cancer researcher Dr Øystein Fluge.
Professor Olav Mella, national project coordinator and nurse Kari Sørland, and physician and cancer researcher Dr Øystein Fluge. (Photo by Teresa Grøtan.)


Patients in the cyclophosphamide study have been selected according to the Canadian criteria (2003) from those who have had the illness for at least 2 years.

In this latest study, six intravenous infusions of cyclophosphamide will be administered at four-week intervals with the first at 600 mg/m2 and subsequent infusions at 700 mg/m2.

Side effects at these levels are expected to be minimal. Similar dosages are administered in the treatment of breast cancer and lymphoma as part of a multiple drugs regimen.

Investigations into possible large vessel endothelial dysfunction and skin microvascular dysfunction will also be performed at the start of the study and during follow-up.


Mella and Fluge's immune response hypothesis.
Mella and Fluge’s immune response hypothesis.


The Kavli Trust is contributing to funding a nursing position for 12 months and is financing laboratory work related to both the rituximab and the cyclophosphamide studies.

A chance discovery

As with many pharmaceutical developments, the possibility that cyclophosphamide might be a candidate for ME arose by chance, when two breast cancer victims with long-term ME experienced major improvements in their ME/CFS symptoms after chemotherapy.

In a subsequent small pilot study, two out of three ME/CFS patients treated with cyclophosphamide improved quite dramatically.

Before treatment, one of the pilot study participants was only able to walk an average of 326 steps per day. “After six infusions with Cyclophosphamide, she was able to take 13 000 daily paces,” Fluge explained to Teresa Grøtan.

Autoimmune response theory

Mella and Fluge believe that ME/CFS is a form of autoimmune illness where the body comes under attack from its own defence system.

“We think an autoimmune response, often after an infection, somehow disrupts the body’s ability to micro-manage the bloodstream,” said Fluge.

Øystein Fluge & Olav Mella, Haukeland University Hospital. (Photo: Barbro Eikesdalsvatnet / TV 2)
Øystein Fluge & Olav Mella, Haukeland University Hospital. (Photo: Barbro Eikesdalsvatnet / TV 2)

One indication that this might be the case is that blood vessels in ME/CFS patients do not enlarge as far as in healthy people after they have been compressed.

The researchers also believe that sufferers have a genetic predisposition to develop ME/CFS. Fluge notes that the condition tends to run in certain families.

“Members in the immediate family of 45 per cent of the participants in our first study had autoimmune illnesses. That’s a higher proportion than in the general population.”

The Nitric Oxide connection

Recent findings by Fluge and Mella have supported anecdotal evidence of ME/CFS patients receiving immediate relief after treatment with nitric oxide.

In 2014 Fluge and Mella filed a European Patent Application for the use of a nitric oxide donor in combination with a B-cell depleting agent to treat ME/CFS.

The application details a case where an ME/CFS patient experienced immediate relief from symptoms after treatment with an NO donor.

The researchers outline a strategy for the use of a B-cell depleting agent, such as rituximab, together with relatively high doses of L-Arginine 5 g twice daily and L-Citrulline 200 mg twice daily.

What is cyclophosphamide?

Cyclophosphamide dampens the immune system’s response and is used in chemotherapy to treat some forms of cancer. It is also an important treatment for serious autoimmune diseases such as systemic lupus erythematosus with severe lupus nephritis, severe rheumatoid arthritis, granulomatosis with polyangiitis and multiple sclerosis.


  • Haukeland University Hospital. Cyclophosphamide in Myalgic Encephalopathy/ Chronic Fatigue Syndrome (ME/CFS) (CycloME),, May 2015, [Trial record]
  • Fluge Ø, Bruland O, Risa K, Storstein A, Kristoffersen EK, Sapkota D, Næss H, Dahl O, Nyland H, Mella O. Benefit from B-lymphocyte depletion using the anti-CD20 antibody rituximab in chronic fatigue syndrome. A double-blind and placebo-controlled study. PLoS One. 2011;6(10):e26358. doi: 10.1371/journal.pone.0026358. Epub 2011 Oct 19. [PubMed]
  • Fluge Ø, Mella O. Clinical impact of B-cell depletion with the anti-CD20 antibody rituximab in chronic fatigue syndrome: a preliminary case series. BMC Neurol. 2009 Jul 1;9:28. doi: 10.1186/1471-2377-9-28. [PubMed]
  • Grøtan Teresa. Tackling a medical mystery, Kavlifondet, April 2015 [article]
  • Fluge Ø, Mella O. Nitric oxide donor for the treatment of chronic fatigue syndrome, European Patent Application, 26.11.2014 Bulletin 2014/48 [PDF]
  • Haukeland University Hospital. B-lymphocyte Depletion Using Rituximab in Chronic Fatigue Syndrome/ Myalgic Encephalopathy (CFS/ME). A Randomized Phase-III Study. (RituxME),, August 2014, [Trial record]


PHOTO: iv3 by Nicole Mays


Written by Russell Logan


Russell Logan worked as a magazine publisher and editor until forced into early retirement through ill health with ME. He has battled with moderate to severe ME for 25 years. He now lives in Noosaville, Australia.

87 posts


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  1. God bless you both, Pr MELLA & Dr FLUGE !!! Thanks for not let us die or auto-euthansied ourselves…Severe ME is just an horror… As a severe ME,i think too endothelial dysfunction is the root. I’m taking Rtx for that, and i will try arginine and citruline. We are a lot waiting after your works, another time : God bless you !

    • I’ve got a very significative answer to the same Rituximab protocole used in FLuge and Mella’s Rtx phase II study, during the major part of my immunodepletion in B cells. Now , im as severe as i was, before my Rituximab’s treatment……..As i can not reached to have more infusions maintenance in my country, i tried since 2 months the L-arginine and L-Citrulline Fluge & Mella’s protocole , but the dosis seems to hights for me, and as my cardio-vascular impairements are veryyyyyyy afflicted, it gave me, at the posology ” 2x 5gr of L-Arg + 2x400mg of L-Cit.”, a lot more of Cluster (Horton) headeaches ( Not sure about that, but it seems, and for me it make sens because of the vasodilatator effects of those supplements). But, at the dosis ” 2x 1.5gr of L-Arg/day + 2×500 mg of L-Cit/day”, it sufficient for me to be able to conclude with no doubts that this booster of N.O. help too( but , contrary to Rituximab, it absolutely not helped ALL symptoms, like in particulary cardio-vascular ones/ aUtonomic Nervous System’s impairements)

  2. The title is deceptive. The article states that the Canadian criteria was used for patient selection. The CCC is not an ME definition and does not select true ME patients. This is not a true ME study.

  3. I know what you are saying Jill. However since the participants are moderate to serious, I’d say most would probably meet ICC. Under these circumstances I prefer to promote ME as a disease entity, rather than me/cfs or cfs.

  4. Hi Russ,

    what a surprise. I just got a link to this blog and realize that we wrote on the same topic AND we are old acquaintance who once helped each other out. Want to get in touch ?



          • If there was EBV in the B-cells remission would come instantly. With Rituximab that takes 2-10 months. If EBV was the case then everyone should have felt an improvement instantly. We’re probably looking at some autoimmune antibodies.

          • It is not silly. If EBV was the case then patients treated with RTX would benefit immediately. B-cells are killed instantly after depletion with Rituximab.

            We’re probably looking at autoimmune antibodies. That is why remission comes after a few months with Rituximab.

  5. This study and these researchers are not about ME.
    Patients were selected by the CCC. This is ME/CFS. It is not just names.

    • I understand your point Jill, however I will take a chance that a successful treatment for ME/CFS might help ME. Or would you rather wait for 50 or so years for ME studies to be conducted using ICC? As far as I know the study authors are well aware of the political schisms of ME and CFS and are working on a genuine treatment, unlike the host of NIH-friendly researchers studying fatigue.

      I don’t tend to talk about fatigue studies and other faux studies on this site. In my mind, irrespective of whether it is labelled as ME or ME/CFS, this study, along with the Rituximab work is real science.

    • Fluge and Mella refer to CFS/ME not ME. I have changed all instances of ME to ME/CFS in the article, as CCC selects ME/CFS. Jill was quite right to pull me up on this point. I absolutely refuse to use CFS/ME, as that is the corruption introduced by Wessely.

      Not sure why I used ME. It might be that some of the source material used ME and I chose to stick with it.

      Usually, I try to use the reference that is used in the study, particularly if it is matched to a particular definition.

  6. Surely there are definitive differences between CFS and ME. I haven’t heard of deaths from CFS though many
    From ME!!
    I wish the Medical profession would take time and effort to publish the symptoms of each once and for all!!

  7. This is the second cancer treating medication now being used in treating M.E. in these new trials. Rituximab was the first. It occurs to me that if our population requires cancer treating medications to even come close to a cure, when is the CDC going to put M.E. in the same category and start publicizing just how serious M.E. really is?

    Although this is another possible hopeful medication, the article indicates that these tests will be used on some patients who did not respond to Rituximab, or had relapses with Rituximab, yet both these medications have immunosuppressant effects and can have chemo like side effects including hair loss, so I’m not sure what the article means by “minimal side effects”, since both have the same risks. Does this drug attack the B cells in the same way or are there marked differences in how it works in contrast with Rituximab and if so, what are those differences. The idea is to attack the M.E. antibodies/proteins that cause degeneration of the mitochondria. Does this medication do that in a different way than Rituximab? It will be interesting to see the level of success with this medication.

    • Rituximab is not a chemo drug. It is an antibody.

      Cyclo is chemo, but doesn’t make you lose your hair. It is a serious drug, but given alone side effects shouldn’t be a major issue. Doctors use more serious drugs in less serious diseases.

      • Yes I understand. I wasn’t saying Ritux. is a chemo drug but it does have some chemo side effects and it is an immunosuppresant, which accounts for the risk factors.

  8. Honestly plp, I just try to say. There is no and none is using ME/CFS term in Norway. ALL patients included in this trials have ME diagnosis from ME-centers in Norwegian hospitals and Hukeland have tested, pick up and accepted patients to the trials.

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