ME and PEM recovery via Cyclophosphamide (personal story)

I am thinking if its useful to be able to post things like the actual data, including IgG and other values and timelines and stuff but in a write up, but then again if i do that i feel it needs a researcher to do so and could potentially be published as a case study, not sure how to go bout that as the doctor wont be interested in that.

 

Was she getting worse before that though
That’s what people seem to miss here ….

 

the treatments just before cyclo also hypothetically worked by reducing IgG, so if that was the case I believe it’s just more evidence for the theory. All I can say is it took to <4 IgG for me to get that therapeutic effect but after all treatments and before cyclo it was a healthy 8.

I don’t think say paxlovid in early 2023 had any role at all though.

I don’t think case studies can like prove a causal role that’s for more comprehensive studies, but it certainly suggests that there is something to the plasma cell and IgG theory. I see my case as a small contribution to a larger set of data that demonstrates a correlation between the two. It’s not definitive proof nor are we near that, but I’m certainly glad I didn’t dismiss the data found in the IgG focused studies.

I think people need to think of it this way, what is more likely;
1) I magically got better four months into chemo hell from a disease that I was experiencing a reductionin capacity and QoL from, that just so happened to take place at the exact time that my IgG dropped to levels used to treat autoimmune diseases.
2) The correlation between very low IgG and remission, remission = full health not just a bit better, indicated a pathological role in the IgG.

 

If Siobhan was the only case I would also be skeptical, but her case needs to be viewed within the larger body of evidence. 22/40 trial participants reported some degree of improvement (some temporary) and cyclophosphamide significantly outperformed rituximab and placebo at six years. This is far better than the results for any psychological study.

I am sure there are patients who experienced just as dramatic as fast remissions as Siobhan after the lightning process, but they are probably just outliers of the many thousands of ME patients that have done psychological therapies over the years.

Fluge is quoted in the Norwegian press as saying he has seen 15 cancer patients with ME improve after cyclophosphamide. There have been a few more on twitter who report the same thing. I think we can safely assume the majority of cancer patients were not expecting this.

It is plausible that a subset of ME is immune mediated (even if it is not a conventional autoimmune disease). The evidence for this is
-A lot of patients report disease onset following infection or a vaccine and many report temporary or permanent worsening following subsequent infections
-A higher frequency of autoimmune disease amongst close relatives of ME patients than the general population
-A high rate of allergies and intolerances
-The gender ratio of ME is similar to the gender ratio for some autoimmune diseases

It is therefore plausible that a strong, broad spectrum immunosuppressant could help a subset.

 

Thanks, @Hutan . You outlined the reasons why I think the data are still relevant really well – you saved me a post!

I think what’s difficult, @siobhanfirestone , is that you’re posting your story – which is fabulous; on a personal level it is so wonderful to hear of someone going from sick to apparently healthy and I and others are delighted for you – on a science forum, so people are responding in sciencey ways. I think all that cautious people are saying on here is that we are not comfortable saying anyone's remission is likely due to cyclo until a randomised, placebo-controlled trial is positive. [Editing to add: or a trial that looks for a dose response, as in @Jonathan Edwards ' post #83 below https://s4me.info/threads/me-and-pe...amide-personal-story.40009/page-5#post-556926]

I think it’s worth looking at the last few publications from Rekeland et al. – i.e. the Norwegian Fluge and Mella group.

In 2020, Rekeland et al. published the results of the cyclophosphamide study. https://pubmed.ncbi.nlm.nih.gov/32411717/ They concluded:

Another paper by the same group, Rekeland et al. 2022, is also very interesting in this regard. This was not a treatment study. They just followed people with ME/CFS for 6 months using Fitbits and questionnaires. Their data are publicly available. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9484698/

Out of 14 patients who were moderate at baseline (SF36PF 30-59 in weeks 1-4):

• 3 reported SF36PF scores that were ≥20 points higher in the final month (weeks 21-24). The biggest jump was 45 points.
• The step count of 4 patients (i.e. 29%) increased by more than 2000 steps in this time period.
• One patient who started at 3900 steps per day finished at 10219 steps per day.
• Another started at 4453 and finished at 8661, all in 6 months of no intervention.

They conclude:

Then Rekeland et al. 2024 present promising data from a 6 year follow-up, and conclude https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11265720/:

What people are doing on here is just heeding the warnings of these excellent scientists, and learning from long experience of our own remissions and relapses, improvements and deteriorations, treatments tried, and the rituximab rollercoaster.

Edited formatting

 

In the original study they stated.

“This study shows that cyclophosphamide intervention is feasible for ME/CFS patients. The growing evidence for immune alterations in ME/CFS and the high symptom burden with very low quality of life, we believe can justify use of an immune modulating drug with possible side effects. The treatment period was demanding for most patients, but in total the toxicity was interpreted as acceptable.”

“We nevertheless believe a future randomized trial is warranted.”

They backed down on the idea of widespread use of cyclophosphamide presumably due to backlash from people who don’t understand that this disease causes people to kill themselves and should be treated as seriously as a disease which directly kills people.

One of the Norwegian cancer patients who recovered also endured radiotherapy, surgery and two other chemo drugs all of which left her with new problems. She still said “Thank god I got cancer” because her net quality of life is much better.

 

Rekeland et al. did not condone widespread use of cyclophosphamide in the 2020 paper. Here's the unedited context of the part you quoted, including the text that preceded and followed it:

 

I meant widespread use after a randomised trial has been conducted. I thought I made that clear by quoting the part in which they advocate a randomised trial, but maybe I should have quoted the other part.

@Trish I stated my experience with cyclophosphamide earlier in the thread. I am happy to answer any additional questions.

I am adamant it should be used more because I have done a 100+ of hours of research into the risks and I believe that the risk/reward/evidence ratio is strongly favourable. I posted more about the risks and made a case for cyclophosphamide in other threads for anyone who is interested.

 

Thanks for clarifying. In that case, I don't understand why you say

How can you back down on something you might have advocated if a trial that has not yet happened were positive? I don't follow.

 

Are we sure about that?

I thought the problem always had to do with the feasibility of a cyclo trial. From what I've understood you cannot meaningfully placebo-control cyclo. So the only answers you'll get will be from some form of randomised controlled trial, with likely insufficient control and possibly relying on somewhat subjective outcome measures, i.e. you'll be dealing with some of the same problems that occured in the PACE trial.

I always thought that if anybody would discover some ME/CFS pathology that could be tracked as part of trials, something like a cyclo trial would become much more feasible even if you cannot placebo control it. That is to say we can't advocate for widespread use without a well conducted phase 2/3 study and one currently cannot meaningfully trial cyclo in a larger trial, i.e. it has nothing to do with not taking ME/CFS seriously.

 

Thanks so much for explaining that, @EndME , and for doing it so clearly. I did not know that, and now I do.

Rekeland et al. give a nice list of possible mechanisms of action for cyclo in ME/CFS in the 2024 paper. Maybe there are less toxic drugs that could test some of them:

 

I'm not sure about any of the things I've said. This was just how I've read the room, which might be very incorrect.

Regarding less toxic drugs to target some of the possible mechanisms above and which is also what the case report here is about:
From what I've vaguely understood Efgartigimod doesn't have too many toxicity concerns and causes an effective reduction in IgG levels. Of course it was trialled in Post-Covid POTS without success, so any trials for ME/CFS seem unlikely (especially because they would be very expensive). I suspect that trial might have included a small handful of ME/CFS patients as well. Maybe someone is interested in retrospective case reports.

Regarding some of the other possible mechanisms (but for drugs that to me appear very toxic): I think one should at some point get case reports of pwME that additionally have developed cancer or an autoimmune disease and are part of a bispecific mAb or CAR-T study. So sort of similar to the original Rituximab case reports or the stories one hears about with cyclo in ME patients with cancer. A problem currently might be they would likely be living in China and I have no idea how recognised or widespread ME/CFS and ME/CFS diagnostic criteria are in China...

Overall I wouldn't be suprised if one can only have really successful trials if one actually has a much better idea about the pathology one is trying to address.

 

I may have got this wrong but I thought that Siobhan's experience was that improvement came with hypogammaglobulinemia. That is quite plausible. Jo Cambridge and I have spent some time considering the idea that in ME the problem is that IgG is 'generally badly made' in some way rather than auto reactive in a typical sense. I imagine that in the Fluge/Mella trials patients did not become hypogammaglobulinemic, so the data are if anything inconsistent.

But that is all very underwhelming. As Trish says, by six years everyone knew rituximab was a flash in the pan. Cyclo patients would still be hoping. Psychological studies are irrelevant, since we don't think psychology works

No, but maybe Dr Fluge was. Oystein Fluge is a fantastic scientist and totally honest about what he is doing but he was following a lead.

Absolutely. That is why Jo Cambridge and I are here and she is looking at antibodies on a broad front. Nobody is denying that. The issue is whether or not a single case of improvement linked to low IgG tells us much. You can't combine it with the other different data on cyclo, apart from anything because that would be post hoc. I think it is of interest. My surprise was your suggestion that it was good evidence of 'response'.

Like who was that? Who is it who didn't understand that people kill themselves? This seems a bit of a stretch.

OK, but I have spent thousands of hours over a period of forty years engaged in the problem of cyclo toxicity, including having to handle my own patients developing and dying of cancers, and designing trials that used cyclo. As far as I can see we have no reliable evidence for cyclo being a good option here and we have the very strongest evidence of serious harm.

The key point for me is that if Siobhan is right that low IgG is what matters cyclo is not an obvious choice. The lowest IgG levels I have seen with anti-B cell agents in trials were with a biologic (either rite or belimumab I think) and mycophenylate.

 

scepticism is fine and expected, but you cant have a randomsied placebo controlled trial with chemo, at all. trust me on this, when you spend days vomiting after. they use the ritux failed data to do the same thing

that 36 questionnarire thing doesnt capture my sickness at all that was 100% PEM and brain fog driven, so in all honetsy im not sure how useful it is, i think they should develop a seperate questionnaire for it tbh

 

Is there a reasonable less toxic alternative to cyclo with same moa? Could also be a combination of other drugs that effectively do the same thing?

 

As said before i am invisioning a future where i get this again, so a non-cyclo drug is essential for me in the future. I hope dara passes, but regardless I eill find a way. If patients can get something as safe as dara and it has good efficacy....to have the remission I have now witohut having had to deal with chemo and getting my bladder checked yearly would be great. We will have to wait and see. I just was not going to wait because MAID was the only other option for me to be blunt.

 

yes hopefully, there are a bunch of drugs but 1) IgG lowering is hard and dangerous for reasons said in this forum. 2) The norwegians are trialing dara for this very reason 3) There are up coming things like CAR-T that are much better for classic autoimmune conditions but they often focus on b cell depletion not IgG as in other studies, and its very expensive and still isnt 100% success.
I dont know if anyone has any indication when the case studies from dara will be released but we are aware some responded to remission level, or at least 1 from a presentation about a year ago.