Intravenous Cyclophosphamide in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome. An Open-Label Phase II Study - 2020 - Rekeland, Mella, Fluge et al

Kalliope said:
The Kavli Trust, who has supported this research team over several years with funding, has an article today about this study.

They've written about the research team before, and provided English translations. But for now we'll have to make do with a google translation.

- Although the study alone does not provide a basis for providing cyclophosphamide outside clinical trials, it, along with an increasing number of basal studies, provides another indication that the immune system is central to the disease mechanisms of ME. Therefore, a key focus in the current phase is to better understand the role of the highly complex immune system, comments Olav Mella.

Kavlifondet: Lovende resultater fra forsøk med kreftmedisinen ved ME/CFS
google translation: Promising results from trial with cancer medicine on ME/CFS
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Translation into English of this article on the study. Published by the Kavli Trust who supports Fluge and Mella's ME research team at Haukeland University Hospital and the University in Bergen.

Promising results from trial of cancer drug in ME/CFS
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.

 
Jaybee00 said:
Also, supposes that the cyclo actually worked (not a placebo effect). If you have progressive MECFS, and you wait 5+ years for the Phase 3 study to be completed, by that time you may have progressed to severe. This study indicates that cyclo did not work for the severe patients--so it's possible you may miss your window of opportunity for treatment by waiting. This point obviously doesn't apply to people with improving-MECFS.
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Those of us who improve don't know how long an improvement lasts. I improved for about two years (with the occassional days/weeks of PEM), had one-two years of high functioning where I really had to push myself to get into PEM (so the disease wasn't really gone, but in my day to day life I didn't notice it) and if I entered PEM I would get better in about two weeks. Then I crashed, was more or less housebound for a year (except for one-two trips to university if I were able), started to improve a bit, crashed again, improved again.. All I can say is that if it's deconditioning being the problem it can happen in a days time and be reversed by next week.

My point is that the label "improving ME" is sort of meaningless when we don't know if people get better and stay better, or if they relapse. And if they relapse, will they improve later on? Will their "baseline" be permanently damage?

I've managed to continue my studies during the last few years, so by that marker I'm healthier than most. That more people in the cyclo group are back at school/work could be due to some external factor affecting many of them, like the type of work they had or study they are interested in and how easy it is to accomodate for someone with ME. I can think of a few courses at my university I would not take again as the teacher refused to help me in any way, while others are more than happy to help. If you're unlucky and get a few of the kind that doesn't help even the healthy students drop out. At lower levels of school there could be similar problems. I have no idea how the groups have been created, just throwing it out there.

I'd rather not take chemo, so I'm not that excited. My step levels can change with more than these results in a week so my situation is different to many others which make me less excited about the results. My cognitive impairment has not been that big of an issue the last few years, but it was terrible before. Now it's there sometimed with PEM but I mainly have physical symptoms.
 
Midnattsol said:
Those of us who improve don't know how long an improvement lasts. I improved for about two years (with the occassional days/weeks of PEM), had one-two years of high functioning where I really had to push myself to get into PEM (so the disease wasn't really gone, but in my day to day life I didn't notice it) and if I entered PEM I would get better in about two weeks. Then I crashed, was more or less housebound for a year (except for one-two trips to university if I were able), started to improve a bit, crashed again, improved again.. All I can say is that if it's deconditioning being the problem it can happen in a days time and be reversed by next week.

My point is that the label "improving ME" is sort of meaningless when we don't know if people get better and stay better, or if they relapse. And if they relapse, will they improve later on? Will their "baseline" be permanently damage?

I've managed to continue my studies during the last few years, so by that marker I'm healthier than most. That more people in the cyclo group are back at school/work could be due to some external factor affecting many of them, like the type of work they had or study they are interested in and how easy it is to accomodate for someone with ME. I can think of a few courses at my university I would not take again as the teacher refused to help me in any way, while others are more than happy to help. If you're unlucky and get a few of the kind that doesn't help even the healthy students drop out. At lower levels of school there could be similar problems. I have no idea how the groups have been created, just throwing it out there.

I'd rather not take chemo, so I'm not that excited. My step levels can change with more than these results in a week so my situation is different to many others which make me less excited about the results. My cognitive impairment has not been that big of an issue the last few years, but it was terrible before. Now it's there sometimed with PEM but I mainly have physical symptoms.
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You make an important Point, what does ‘improvement’ mean?
Also, what significance does it have research wise? What conclusions can we make?

We still do not have an understanding of what ME is. We do not have a biomarker. We are not absolutely certain that the cohort is homogenous. From your experience, @Midnattsol this non-specific, kill all drug is not a cure since you still experience relapses.

I question whether our next step should be more Cyclo trials, or a different next step, targeting a specific system, namely the energy metabolism for instance. Then, there would be room for many modalities, providing physicians and patients are ready to take an informed risk in getting a drug.

Of note, i am not adverse to risk myself, and look forward to the day there is a choice for the patients to make, as opposed to the most conservative kind of health care which involves patient education on how to pace and how to cope. Nothing wrong with that, but quite honestly, we can all learn this stuff online without the help of professionals worried about deconditioning and ‘getting depressed’.
 
This might add to the discussion. It's from a poster presentation of a yet unpublished study entitled "Could antiviral & chemotherapy agents have an impact in ME/CFS due to direct effects on mitochondrial function?". I've had permission to share it from Karl Morten - see attached PDF file for full poster.

My bolding.
Nucleoside reverse transcriptase inhibitor antivirals have been linked to benefit in some ME/CFS patients. This study looked to test if the antivirals acyclovir (ACV) and ganciclovir (GCV) and the chemotherapy agent cyclophosphamide (CP) had a direct effect on mitochondrial function, a factor suggested to be abnormal in ME/CFS patients. Cellular energetics has been proposed to be impaired in ME/CFS patients with both glycolysis and mitochondrial function being implicated in peripheral blood mononuclear cells (PBMC) [1] and T-cells [2].

It is well established that antiviral therapy using nucleoside reverse transcriptase inhibitors (NRTIs) has off-target effects with a significant effect on mitochondria function in many cases causing mtDNA depletion [3]. This would impact on mitochondrial energy production , mitochondrial morphology and also mitochondrial reactive oxygen species generation all of which would impact on mitochondrial function. In cells dealing with a viral infection (i.e. innate immune cells) this could have a significant effect on how the cells deal with a viral infection. Recent studies by West et al. [4] demonstrate that mitochondrial function and mtDNA release into the cell plays a critical role in the antiviral response.

We also investigated whether this could be modulated by the presence of a common variant of the mitochondrial DNA (mtDNA), in which there is a single nucleotide polymorphism (SNP) at position 16189. The mtDNA 16189 variant is a known risk factor in the development of type 2 diabetes [5] with evidence that DNA in the triple stranded D-loop from the mutant is held more tightly in the mtDNA molecule (Morten unpublished) which may hinder its release during a viral infection.
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Following exposure to a range of drugs, distinct patterns of mtDNA and MTCO1 protein expression manifested in each of the cell lines tested, indicating potential variability in the mitochondrial response to treatment within different tissues.
  • Mitochondria in the 143B wild type and mtDNA 16189 mutant cells showed contrasting responses to GCV treatment, despite originating from the same cell line, demonstrating that even single nucleotide changes in the D-loop of the mtDNA could significantly alter the mitochondrial stress response. The nuclear genomes of the two lines will likely be identical or very similar as the line was generated from a cancer cell line.

  • Cyclophosphamide treatment also revealed a distinction between the wild type and mutant cells, though only in mtDNA copy number.

  • Cyclophosphamide had the most striking effect in U87MG cells, where the levels of the mtDNA-encoded protein MTCO1 were drastically reduced, despite an apparent increase in mtDNA copy number.
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A presentation on this was given at this years CMRC conference, which can be seen here, https://www.s4me.info/threads/uk-cf...-and-11th-march-2020.11813/page-7#post-243377
 

Attachments

Andy said:
A presentation on this was given at this years CMRC conference, which can be seen here, https://www.s4me.info/threads/uk-cf...-and-11th-march-2020.11813/page-7#post-243377
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That's fascinating. Thanks for that @Andy . Great to see Karl Morten encourage others to support out of box thinking. Ron Davis and Robert Naviaux discussed drug effects on mitochondrial and metabolic function in these two posts but this is the first evidence I've seen, and how even one single common genetic mutation can change response. Very complicated subject.
https://www.omf.ngo/2016/09/09/viruses-and-cfs-statement-by-ron-davis-and-bob-naviaux/
https://www.omf.ngo/2016/09/09/upda...-fatigue-syndrome-q-a-with-robert-naviaux-md/
 
wigglethemouse said:
That's fascinating. Thanks for that @Andy . Great to see Karl Morten encourage others to support out of box thinking. Ron Davis and Robert Naviaux discussed drug effects on mitochondrial and metabolic function in these two posts but this is the first evidence I've seen, and how even one single common genetic mutation can change response. Very complicated subject.
https://www.omf.ngo/2016/09/09/viruses-and-cfs-statement-by-ron-davis-and-bob-naviaux/
https://www.omf.ngo/2016/09/09/upda...-fatigue-syndrome-q-a-with-robert-naviaux-md/
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We have this discussion thread, Impact of pharmacological agents on mitochondrial function: a growing opportunity?, 2019, Stoker et al about a paper that Karl was also an author of.
 
Forskning.no has written about the study today :https://forskning.no/sykdommer/me-pasienter-ble-bedre-av-kreftmedisin/1682544 . I liked the article except they got in a weird sentence about people being screened for ME often actually have a psychiatric disorder, and thus people in studies may be misdiagnosed (but then they never got the ME diagnosis in the first place? I don't get why this is relevant when discussing the cyclo study). Also a quote from Paul Kavli that the placebo-effect might be large with ME/CFS, which to me reads like we're more likely to experience placebo than others and I don't think that's true. Also a small quibble with the fact-box, it's not that activities that "feel" strenous causes PEM, activity causes PEM. Period.
 
Midnattsol said:
Forskning.no has written about the study today :https://forskning.no/sykdommer/me-pasienter-ble-bedre-av-kreftmedisin/1682544 . I liked the article except they got in a weird sentence about people being screened for ME often actually have a psychiatric disorder, and thus people in studies may be misdiagnosed (but then they never got the ME diagnosis in the first place? I don't get why this is relevant when discussing the cyclo study). Also a quote from Paul Kavli that the placebo-effect might be large with ME/CFS, which to me reads like we're more likely to experience placebo than others and I don't think that's true. Also a small quibble with the fact-box, it's not that activities that "feel" strenous causes PEM, activity causes PEM. Period.
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They've also interviewed main author Ingrid G. Rekeland and Øystein Fluge.

This is the first study to investigate this principle of treatment for patients with ME / CFS, and the study is thus exploratory, explains Rekeland.

Larger studies must be conducted with a control group receiving other treatment or placebo to rule out or confirm whether this is a treatment that may be effective in patients with ME / CFS, Ingrid Gurvin Rekeland emphasizes.

Therefore, it is too early to recommend treatment before further testing is done.

- But we interpret the results of the study as so positive that we plan to proceed with a study with a control group. But we know that it will be difficult for the control group to become blind, since it is a matter of chemotherapy, she explains.

google translation of article:
ME patients improved with cancer drug
 
Has anyone heard of any future papers or collaborations that may come from this study. It would be interesting to report on immune cell changes to see if there is a noticeable change for responders that is not seen in non responders. Do they have stored blood samples?
 
wigglethemouse said:
Has anyone heard of any future papers or collaborations that may come from this study. It would be interesting to report on immune cell changes to see if there is a noticeable change for responders that is not seen in non responders. Do they have stored blood samples?
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This seems to be their next step. They have a biobank and have collaborated with others before.

From the forskningno article linked above (google translated):

- Cyclophosphamide gives a broad attenuation of several immune cells, and after treatment there is a moderate decrease in various types of lymphocytes. Admittedly, Rekeland explains to research.no that this is temporary.

The group is now working on understanding how this is related to the symptom improvement in patients, in the laboratory part of the research. There they use, among other things, blood samples taken during the study.

From the Kavli Trust article linked elsewhere in this thread

“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.
 
OK, about the alleles.

10 patients had HLA-DQB1*03:03
4 patients had HLA-C*07:04
12 patients had either DQB1 and/or C
Which means that 2 patients were positive for both DQB1 and C.
And therefore only 2 patients were positive HLA-C only (i.e. positive for HLA-C but negative for DQB1)
Right?

1 Non responder for C
1 Non responder for DQB1
2 Non responders for either DQB1 and/or C
Which means the non-responders did not include the 2 patients who were positive both both alleles, i.e. the two double positives were both responders.
Right?

Which means that of the 2 patients who were positive for HLA-C but negative for DQB1, that only one of the two patients responded (50%) which is close to the response rate of the patients without the suspect alleles (43%)
Right?

Which means that it is more likely that HLA-DQB1*03:03 is the key to positive cyclo response relative to HLA-C07:04, given all the other caveats about small samples sizes, etc.
Right?

It would have been better if they broke out the subjects explicitly by these four categories--1)DQB1+C+ 2) DQB1+C- 3)DQB1-C+ 4) DQB-C-

Also, another confounding factor is that patients with the deleterious alleles skewed toward more mild/less severe MECFS compared to the patients negative for both alleles.
 
Article in Science Norway
Cancer drug helped patients with chronic fatigue syndrome (CFS/ME)
A new study now shows that half the participants with ME/CFS reported improvements after treatment with a cytotoxic (chemotherapy) drug. Their findings have been published in Frontiers in Medicine.

The group is led by the physicians Øystein Fluge and Olav Mella in collaboration with Alexander Fosså of the Oslo Radium Hospital.

Surprising ME/CFS improvements among cancer patients
A random observation years ago attracted the research group’s interest in finding a treatment that curbs the immune system’s negative processes linking to ME/CFS.

“From 2004 to 2014 we observed a number of patients with long-term ME/CFS who had also suffered from cancer reporting that their chemotherapy had decreased their ME/CFS symptoms,” says Rekeland.

These ME/CFS patients had received chemo treatment which included cyclophosphamide. This gave an inadvertent positive effect:

“Improvements of ME/CFS symptoms were surprising,” she says.

In 2014 the research group treated four ME/CFS patients, none with cancer, using the chemo drug cyclophosphamide, and two reported a long-term response, which is to say their improvement was long-lasting.
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full article here
https://sciencenorway.no/chemothera...s-with-chronic-fatigue-syndrome-cfsme/1689388
 
Dear @Jonathan Edwards,

Although I respectfully understand that you remain opposed to cyclophosphamide, I was hoping you could answer the following question about the dosing schedule for cyclo.

What is the justification for infusions every 4 weeks? Is there a biological justification for this or do they do this because that is the way that they have always done it?

For example, if patients could be infused every 6 weeks, the fifth infusion would be on week 24. The average response time in the time in study was 22 weeks. If patients were infused every six weeks, and if by week 24 if they had no response, they could forgo the week 24 infusion (and week 30) and therefore their total cyclophosphamide exposure would be roughly 3 grams less (no infusion on week 24 and week 30, so roughly 6 grams total cyclo infusions) than the patients getting infused every four weeks (including week 20).

So might lengthening the dosing intervals be a way of harm reduction, at least for non-responders?

Thanks.
 
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Kalliope said:
the immune response plays an important part in the ME/CFS disease mechanisms
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lansbergen said:
Yep. That is why I take levamisole.
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I've long wished someone would keep half an eye on ME patients who're prescribed sulfasalazine for another condition, to see whether they report changes. My N=1 response is no use to anyone, but if it's real and could improve the level of daily function for others too, it's a cheap, fairly well-tolerated drug with a good safety profile.
 
Jaybee00 said:
Dear @Jonathan Edwards,

Although I respectfully understand that you remain opposed to cyclophosphamide, I was hoping you could answer the following question about the dosing schedule for cyclo.

What is the justification for infusions every 4 weeks? Is there a biological justification for this or do they do this because that is the way that they have always done it?

For example, if patients could be infused every 6 weeks, the fifth infusion would be on week 24. The average response time in the time in study was 22 weeks. If patients were infused every six weeks, and if by week 24 if they had no response, they could forgo the week 24 infusion (and week 30) and therefore their total cyclophosphamide exposure would be roughly 3 grams less (no infusion on week 24 and week 30, so roughly 6 grams total cyclo infusions) than the patients getting infused every four weeks (including week 24).

So might lengthening the dosing intervals be a way of harm reduction, at least for non-responders?

Thanks.
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I obviously have no medical expertise or experience but I'd suggest deviating from the protocol that Fluge and Mella have used so far means that you can't assume that any results that they achieved are applicable to different dosage rates, which seems to be what you are wanting to do here.
 
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