Thesis Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS): Clinical trials, medical treatment and pathomechanisms, 2024, Rekeland

ok
1) No one is calling for high dose, life threatening cylco AT ALL. Thats HSCT which is insanely controlled in an ICU and still has a 1% death rate. It seems effective for MS yes, more data needed as per ususal = https://www.neurology.org/doi/abs/10.1212/WNL.0b013e318211c537 https://journals.sagepub.com/doi/abs/10.1177/1352458508096875 https://jamanetwork.com/journals/jama/article-abstract/2720728

2) Here is the IgG etc findings and an excellent and well thought out summary about what is unknown and where to go from here;
" In the unpublished data analysing various immunological laboratory parameters from the clinical trials, there are some interesting findings. In the following I will briefly summarise some findings from the CycloME trial.

In the CycloME trial, the mean baseline IgG and IgG1 levels were predictive for clinical response, as the levels were significantly lower in the responder group (n=21) compared to non-responders (n=16) (Figure 3). Significantly lower baseline serum IgG levels were also found in responders compared to non-responders in a previous study from our group (61), analysing serum samples from previous rituximab trials (22, 138).

In the CycloME trial there were significant but modest decreases of IgG, IgM and IgA during follow up, especially from baseline to 12 months (Figure 3). CD3 (T- cells), CD19 (B-cells) and CD16/56 (NK-cells) lymphocytes in peripheral blood showed significant trends towards ME/CFS severity, with the highest lymphocyte counts in the severe group compared to moderate and mild/moderate (Figure 4). After cyclophosphamide intervention, all subsets of lymphocytes decrease from baseline to 6 months and GLM repeated measures analyses showede significant time effects during follow-up for all subsets (Figure 4), also described by Ahlmann et al (114). CD3, CD4, CD8 T-cells and CD19 B-cells were still lower at 18 months compared to baseline, while NK cells had returned to baseline levels (Figure 4).

The broad effects of cyclophosphamide on different immune cells make it difficult to pinpoint a precise mechanism for the clinical effect observed in ME/CFS. The cytotoxic effects on proliferating cells make inhibition of activated B-cells to plasmablasts and reduction of IgG levels - including autoantibodies - a plausible possibility. The described downregulation of T cells, effects on different subsets of lymphocytes and interactions between immune cells are other possible mechanisms of cyclophosphamide in this disease."
This is the absolute correct attitude and should be leading them to consider a large phase 3. Cyclo cannot be blinded so we need a large cohort.

3) JE - you are completely right and being a good scientist by saying we dont know the efficacy of cyclo yet from this data, but to say that a clinicians good vibes is causing the remissions and improvements in this data feels like a deeply problematic and unscientific take. I am seeing patients with long COVID who have never HEARD of the norwegians nor thier data reach remission because they just so happened to be cancer patients. We cannot continue ignoring this and relying on case studies and hearsay

4) I have lost three ME Long COVID patients to suicide. I am on cyclo right now (i refuse to explain how because I dont want to help anyone else get this without doing their own due diligence via good doctors) it has a significant side effect burden that is nowhere near as bad as living with ME/LC. Frankly it would have been much more comforting to work with doctors with phase three trials and a larger data set. We need to encourage this with the same reservations of ritux, except it might be effective for unknown immune cell reasons. I am measuring immune cells as much as i can throughout this process, and will report on here but again this is a case study n-1 useless bit of data really.

5) Long COVID moonshot should consider cyclo. If there is a period where people have to choose cylco or waiting for safer drugs, they should be given the choice (if a phase three demonstrates efficacy)

Patients with such a low quality of life deserve the option if they are fully informed. I hope the ME team in Norway expand this trial to a phase three 200> people alongside the effects of daratumamab etc and plasma cell stuff, just in case it IS t cell driven.
 
There are many reasons why a phase three trial of cyclophosphamide should be pursued despite the risks and unpleasant side effects of this drug.

The original study found that cyclophosphamide responders can be predicted using HLA type 83% vs 43%. There is a 1/36 chance this is coincidence. The PHD thesis also stated that “The mean baseline IgG and IgG1 levels were predictive for clinical response to cyclophosphamide, as the levels were significantly lower in the responder group (n=21) compared to non-responders (n=16)”. Having an identifiable subgroup with a high response rate improves the risk reward balance and increases the likelihood that the treatment will be approved.

It is likely that four doses is enough to gauge if an individual is a responder. Stopping at this point and waiting for a response before continuing further improves the risk reward balance.

There are other promising treatments in the pipeline, but it is likely that several different treatments will be needed to get the majority of ME patients to at least a mild level. Some may respond to cyc but not another drug. Others may experience combined benefit from two or more. Cyc is still used for autoimmune diseases despite the fact that many safer treatments have now been approved.

Treatment with cyc is much cheaper and therefore accessible to more people than patented biological drugs. The cost difference is multiplied by the fact that some drugs may require ongoing treatment, but cyc treatment is limited. Most of the worlds population cannot afford biological drugs especially during the patent period.

Many people dismiss cyc treatment for ME without understanding how much lower the risks and side effects are for low doses and low cumulative doses compared to the high dose regimes used for cancer.

In the cyclome protocol a 70kg/1.8m2 patient would receive six monthly doses of 1280mg for a total of 7.7g. A cancer patient of the same size would receive single doses up to 3500mg. Other cancer regimes combine low doses of cyc with other chemo drugs.

Recent meta studies show that the risk of any cancer following low cumulative doses of cyclophosphamide lower than previously believed and is predominantly non melonoma skin cancer. Studies below. Early NMSC is treated by removing the mole. It has a 95% overall survival rate and 99% if caught early which is likely if patients are aware of the risk.

95% of patients in the cyclome study completed at least four infusions which shows that these doses tolerable for most ME patients. The dose could be reduced for patients who would otherwise stop treatment.

Those who claim that cyclophosphamide is too unpleasant for widespread use do not understand the suffering of many ME patients and their determination to recover. Ampligen also causes months of suffering and reduced functioning but most patients continued treatment for the chance of a better future.

The risks of cyc must be balanced against the extreme suffering and reduced life expectancy of ME patients. There are no reliable statistics on ME patient suicides, but we can infer from the frequent suicidal posts on ME support forums that it is very high. Even a modest improvement in ME symptoms will reduce suicide risk.

Evolving paradigm of cancer risk following cyclophosphamide 2015
“More recent studies, reflecting treatment periods spanning the 1990s to 2000s, have provided more reassuring findings, showing standardized incidence ratios (SIRs) (i.e. observed number of cancers divided by the expected number) of 1.6–2.1 for all cancer types [6, 7].”excess cancer risk observed was driven mainly by NMSC [6].” It is also important to note that most of the patients in the above study had much higher cumulative doses of cyc than the 7.5G used in the cyclome study. The meta study also states that it cannot control for the use of other carcinogenic immunosuppressants like Aza.

Malignancies in Wegener's granulomatosis: incidence and relation to cyclophosphamide therapy in a cohort of 293 patients
”The risk of malignancies (other than NMSC) was not increased for patients treated with cumulative CYC doses < or = 36 g.”

Malignancies in Patients with Antineutrophil Cytoplasmic Antibody-associated Vasculitis: A Population-based Cohort Study 2020
“There was no increase in incidence of cancers other than SCC for those treated with < 10 g CYC.” Squamus Cell Carcinoma is a type of NMSC.

No increase in cancer incidence detected after cyclophosphamide in a French cohort of patients with progressive multiple sclerosis
I do not know the cumulative doses in the above patient population (paywall) but I can find no MS protocols with cumulative doses less than 10G.
 
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dankeen said:
1. Average time to first response in cyc patients was five and a half months which is not typical for a placebo effect. There was no prior data that would have made anyone expect this.
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There was a delayed response in the original Rituximab trial.

"The researchers say that following two doses of the drug being given in the first two weeks of the trial, there was a lag of three to eight months before symptoms began to subside. They say this delayed response tallies with the idea that CFS is caused by autoantibodies – antibodies, made by B cells, that mistakenly attack the body’s own tissues."
https://www.newscientist.com/article/dn21065-chronic-fatigue-syndrome-eased-by-cancer-drug/
 
Another common argument against cyclophosphamide is the risk of infertility and early menopause.
Male fertility risk is significant, but can be easily be preserved by sperm freezing.

A systematic review and meta-analysis of the gonadotoxic effects of cyclophosphamide and benefits of gonadotropin releasing hormone agonists (GnRHa) in women of child-bearing age with autoimmune rheumatic disease

Risk of sustained female infertility and amenorrhea increases with age and cumulative cyc dose, but is minimised with GnRHa. There are varying results in different studies with cumulative cyc doses >5G without GnRHa. Cumulative doses of cyc below 5g are unlikely to produce sustained amenorrhoea in patients under 40 years of age who were NOT treated with GnRHa.

Average female body surface area is 1.6m2 which equates to a cumulative dose of 6.5g for the six dose cyclome protocol. Some patients may choose to reduce the number of doses to balance efficacy with amenorrhoea risk.

A return of periods does not necessarily mean fertility is unharmed. A small study found that most women (without sustained amenorrhea) who tried to get pregnant succeeded. However there is not a big enough sample with data that takes into account intention to conceive to quantify the risk.

I do not know to what extent cyc can bring forward menopause even if it does not cause it immediately.

Use of gonadotropin-releasing hormone agonists for ovarian preservation in patients receiving cyclophosphamide for systemic lupus erythematosus: A meta-analysis
56 patients of an average age of 25.6 were treated with an average cyclophosphamide dose of 8.6g with GnRHa. Sustained amenorrhoea occurred in 2 (3.6%) of patients. One of these patients was age 28 with a cumulative dose of 33g. The other was age 37, but the cumulative cyc dose is unknown.

Seven studies with 218 female patients were included. The ovarian function was preserved in 125/132 (94.6%) of women who received GnRHa concurrently with CYC compared to 50/86 (58%) of women who did not receive GnRHa (OR = 10.3, CI = 4.83–36.29).

In conclusion the risk of sustained amenorrhea is very low for women under 40 who limit cumulative cyclophosphamide dose to 5G and use GnRHa.
 
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John Mac said:
There was a delayed response in the original Rituximab trial.
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Well in fact there wasn't, it was a random blip in the data that looked a bit promising but turned out to be spurious. The real problem was my fault. I pointed out to Fluge in PlosOne that in RA full remission took around 3-6 months so the 6 month data were not as unexpected as a certain Dutch or Belgian BPS ME guy claimed! And so it became a belief that people would respond at 6 months and this showed up as a nice 6 month placebo effect in the open extension of phase II but proved to be no different from controls in phase III.

The problem with ME/CFS is that the natural history is just too unpredictable to use as a control for trials. People who are recruited to these trials are likely to be fairly atypical I suspect. They are likely to be risk takers if they agree to rite or cyclo.

Looking through all the posts above I don't see anything that would make me think a further cyclo trial justified. People get bladder cancer from cyclo fairly regularly. I had two cases in my early ritux+cyclo patients. Who knows if they were related but the medical profession has had a nasty habit of playing these things down in autoimmune disease.
 
Jonathan Edwards said:
The problem with ME/CFS is that the natural history is just too unpredictable to use as a control for trials. People who are recruited to these trials are likely to be fairly atypical I suspect. They are likely to be risk takers if they agree to rite or cyclo.

Looking through all the posts above I don't see anything that would make me think a further cyclo trial justified. People get bladder cancer from cyclo fairly regularly. I had two cases in my early ritux+cyclo patients. Who knows if they were related but the medical profession has had a nasty habit of playing these things down in autoimmune disease.
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Please could you clarify your first point. If the natural history of ME is too unpredictable for researchers to use ME patients as controls, then who should they use? Trials are conducted on many other conditions with randomly fluctuating symptoms.

I agree that trial participants are in general likely to be risk takers, but I don’t understand how this is relevant especially since it applies to the participants of both studies.

“Overall, the chance that men will develop bladder cancer during their lifetime is about 1 in 28. For women, the chance is about 1 in 89“. So two is not statistically significant, especially without knowing their cumulative cyclophosphamide dose and whether mesna was used. The meta-study I posted stated that many autoimmune patients have a history of other immunosuppressive drugs that also increase cancer risk which is not the case for most ME patients.
 
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Jonathan Edwards said:
Well in fact there wasn't, it was a random blip in the data that looked a bit promising but turned out to be spurious. The real problem was my fault. I pointed out to Fluge in PlosOne that in RA full remission took around 3-6 months so the 6 month data were not as unexpected as a certain Dutch or Belgian BPS ME guy claimed! And so it became a belief that people would respond at 6 months and this showed up as a nice 6 month placebo effect in the open extension of phase II but proved to be no different from controls in phase III.

The problem with ME/CFS is that the natural history is just too unpredictable to use as a control for trials. People who are recruited to these trials are likely to be fairly atypical I suspect. They are likely to be risk takers if they agree to rite or cyclo.

Looking through all the posts above I don't see anything that would make me think a further cyclo trial justified. People get bladder cancer from cyclo fairly regularly. I had two cases in my early ritux+cyclo patients. Who knows if they were related but the medical profession has had a nasty habit of playing these things down in autoimmune disease.
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why is further evidence not required? because of the risk? in a patient population where suicide is a HUGE risk? https://www.tandfonline.com/doi/abs/10.1080/07481187.2020.1776789 . Its very dispiriting to hear a medical professional say no to more information that could help patients, that does factor in the possible side effects. Do you have a say in any NHS trials at the moment for long COVID?

The norwegians are right to be very cautious with this, but there is absolutely a case for more studies with fully informed consent.
 
dankeen said:
Please could you clarify your first point. If the natural history of ME is too unpredictable for researchers to use ME patients as controls, then who should they use? Trials are conducted on many other conditions with randomly fluctuating symptoms.

I agree that trial participants are in general likely to be risk takers, but I don’t understand how this is relevant especially since it applies to the participants of both studies.

“Overall, the chance that men will develop bladder cancer during their lifetime is about 1 in 28. For women, the chance is about 1 in 89“. So two is not statistically significant, especially without knowing their cumulative cyclophosphamide dose and whether mesna was used. The meta-study I posted stated that many autoimmune patients have a history of other immunosuppressive drugs that also increase cancer risk which is not the case for most ME patients.
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well apparently we should just do nothing risky because we are too difficult a population group, I understand being conservative and risk adverse but apparently it doesnt matter that ME and LC patients are at risk of suicide because the quality of life is atrocious
 
dankeen said:
I agree that trial participants are in general likely to be risk takers, but I don’t understand how this is relevant especially since it applies to the participants of both studies.
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Again it emphasises the problem with historical controls from population data.
ME/CFS has a huge impact on cognition but variable. People ready to enter trials with risk are likely to be different from those who don't and maybe significantly different in natural history.

I am personally not very happy about any of these trials drawing on volunteers recruited via the internet. I think it highly likely that these will be an atypical subset in one way or another. That problem exists for all trials but if patients are recruited from a pre0established diagnosed population attending a specialist centre I think there is les chance of bias.
 
siobhanfirestone said:
why is further evidence not required?
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Because the evidence to date is almost impossible to interpret and really not very convincingly positive even if taken at face value and the drug is seriously toxic.

Lower dose cyclophosphamide has needed to be used chronically to have any real impact on those diseases it does help - rheumatoid is perhaps as good an example as any. But the bladder cancer rate from the original chronic usage studies was something like 40%. IV courses in lupus may have had better risk benefit ratio but lupus is very much an episodic problem for many.

If anyone genuinely thinks that ME/CFS is driven by an adaptive immune response, which it might be, then it makes much more sense to use a highly targeted therapy rather than a very old very toxic drug with little or no specificity. If T cells are suspected then why not use Campath-1H which seemed pretty safe long term if I remember rightly.
 
Jonathan Edwards said:
Yes it was. It was two out of ten, and within ten years, not a lifetime.
Despite full mesna cover.
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If your own clinic had a 20% rate I can at least understand this level of conservativsm.
Studies, an the information I was given, show in general a much more complex picture than this figure and was presented to me as a issue of accumulative dose and a non negligible but low risk and this was the info i was given:
https://boris.unibe.ch/64147/
A total of 168 patients were included. Cumulative CYC dose was 7.45 g (range 0.5-205 g). Gastro-intestinal side effects were seen in 68 events, hair loss occurred in 38 events. A total of 58 infections were diagnosed in 44/168 patients (26.2%) with 9/44 suffering multiple infections. Severity grading of infections was low in 37/58 cases (63.8%). One CYC-related infection-induced death (0.6%) was registered. Amenorrhoea occurred in 7/92 females (7.6%) with 5/7 remaining irreversible. In females with reversible amenorrhoea, prophylaxis with nafarelin had been administered. Malignancy was registered in 19 patients after 4.7 years (median, range 0.25-22.25) presenting as 4 premalignancies and 18 malignancies, 3 patients suffered 2 premalignancies/malignancies each. Patients with malignancies were older with a higher cumulative CYC dose. Death was registered in 28 patients (16.6%) with 2/28 probably related to CYC.
https://journals.sagepub.com/doi/abs/10.1177/1078155220920690

Can you please explain to me if you have a scientifically oriented issue with either the actual study and its findings? As in, there is X issue with the hypothesis that means cyclo is not worth this risk because of Z issue specifically, or is it that you have an issue with the associated risk which in itself for you mean ME patients should not be given access to this purly on the basis of risk, wether it is a valid treatment or not (which we dont know yet)
 
siobhanfirestone said:
Can you please explain to me if you have a scientifically oriented issue with either the actual study and its findings? As in, there is X issue with the hypothesis that means cyclo is not worth this risk because of Z issue specifically, or is it that you have an issue with the associated risk which in itself for you mean ME patients should not be given access to this purly on the basis of risk, wether it is a valid treatment or not (which we dont know yet)
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I have explained. I don't think we have data from studies that are reliable enough to mean much. The toxicity is considerable. The reality probably only becomes clear after watching people for twenty years. There are all sort of other practical issues likely to be weighting my view but in the end one has to come to some sort of judgment. Doing a robust trial would be difficult and you would need to expose a hundred or so people to toxicity. As soon as a trial is set up corners get cut and patients who probably shouldn't be recruited do get recruited.
 
Jonathan Edwards said:
am personally not very happy about any of these trials drawing on volunteers recruited via the internet. I think it highly likely that these will be an atypical subset in one way or another. That problem exists for all trials but if patients are recruited from a pre0established diagnosed population attending a specialist centre I think there is les chance of bias.
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I think your hitting the “sweet spot”.

ME-patients are in the desert of drug trials, treatments and specialist centers.

Unfortunately, there is no pre-established diagnosed ME-population attending specialist centres.
There are no specialist centers. There is no money and medical/scientific interest.
It is a utopia maybe 10–20 years away from now - if things progress with the same speed as they are doing now.

Very different from RA or other auto immune.

Therefore scientists like Fluge & Mella (and any other ME-scientist or other post infectious illnesses) have to work & plough through under complicated circumstances.

At the moment I cannot even think of 2-3 ME-drug trials that are being rolled out.

We should applaud and fight for every drug trial - with a minimum of methodological standards oc - despite the strong limitations it has.

As there’s no choice. As the alternative of nót trialing is worse.
- even with higher risk treatments, considering very low quality of life and lack of alternative treatments
- íf patients are well informed
 
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Arvijansen said:
I think your hitting the “sweet spot”.

ME-patients are in the desert of drug trials, treatments and specialist centers.

Unfortunately, there is no pre-established diagnosed ME-population attending specialist centres.
There are no specialist centers. There is no money and medical/scientific interest.
It is a utopia maybe 10–20 years away from now - if thing progress with the same speed as they are doing now.

Very different from RA or other auto immune.

Therefore scientists like Fluge & Mella (and any other ME-scientist or other post infectious illnesses) have to work & plough through under complicated circumstances.

At the moment I cannot even think of 4 ME-drug trials that are being being rolled out.

We should applaud and fight for every drug trial - within a minimum of methodological standards oc - despite the strong limitations it has.
As there’s no choice. As the alternative of not trialing is worse.
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exactly
with all due respect JE and i do mean this as having the weight of a drug toxicity that can cause a horrific deadly cancer is not a light thing for a clinician and i understand and do respect this, i just think there is no alternative at the moment. I am not sure about campath1 but i believe, i may be wrong, that it has a large side effect profile and has been linked to causing other autoimmune diseases? If thats the case is it not about degrees of care, starting with patients for the least risk to the most and them having informed concent.

Fluge etc have said they feel very conflicted about this an i believe are trying daratumamab first for this reason. I begrugingly accept that this is the most logical option given the toxicity.

Im also really trying to understand the direct issues with the study that indicate all studies should stop VS we need more information?
 
sorry just on that note of alemtuzmab toxicity/implcations
https://academic.oup.com/brain/article/145/5/1711/6590581
Alemtuzumab is a monoclonal antibody that causes rapid depletion of CD52-expressing immune cells. It has proven to be highly efficacious in active relapsing–remitting multiple sclerosis; however, the high risk of secondary autoimmune disorders has greatly complicated its use. Thus, deeper insight into the pathophysiology of secondary autoimmunity and potential biomarkers is urgently needed. The most critical time points in the decision-making process for alemtuzumab therapy are before or at Month 12, where the ability to identify secondary autoimmunity risk would be instrumental. Therefore, we investigated components of blood and CSF of up to 106 multiple sclerosis patients before and after alemtuzumab treatment focusing on those critical time points.

Consistent with previous reports, deep flow cytometric immune-cell profiling (n = 30) demonstrated major effects on adaptive rather than innate immunity, which favoured regulatory immune cell subsets within the repopulation. The longitudinally studied CSF compartment (n = 18) mainly mirrored the immunological effects observed in the periphery. Alemtuzumab-induced changes including increased numbers of naïve CD4+ T cells and B cells as well as a clonal renewal of CD4+ T- and B-cell repertoires were partly reminiscent of haematopoietic stem cell transplantation; in contrast, thymopoiesis was reduced and clonal renewal of T-cell repertoires after alemtuzumab was incomplete. Stratification for secondary autoimmunity did not show clear immununological cellular or proteomic traits or signatures associated with secondary autoimmunity. However, a restricted T-cell repertoire with hyperexpanded T-cell clones at baseline, which persisted and demonstrated further expansion at Month 12 by homeostatic proliferation, identified patients developing secondary autoimmune disorders (n = 7 without secondary autoimmunity versus n = 5 with secondary autoimmunity). Those processes were followed by an expansion of memory B-cell clones irrespective of persistence, which we detected shortly after the diagnosis of secondary autoimmune disease.

In conclusion, our data demonstrate that (i) peripheral immunological alterations following alemtuzumab are mirrored by longitudinal changes in the CSF; (ii) incomplete T-cell repertoire renewal and reduced thymopoiesis contribute to a proautoimmune state after alemtuzumab; (iii) proteomics and surface immunological phenotyping do not identify patients at risk for secondary autoimmune disorders; (iv) homeostatic proliferation with disparate dynamics of clonal T- and B-cell expansions are associated with secondary autoimmunity; and (v) hyperexpanded T-cell clones at baseline and Month 12 may be used as a biomarker for the risk of alemtuzumab-induced autoimmunity.
 
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@dankeen, what are the error bars on these charts please? I note that there was an adjustment for age, sex and ME/CFS severity, but I'm not sure why that was done when the chart says 'SF-36 raw score'.
 
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FWIW, in my case, I’m not a big fan of SPF PF, because at baseline I score pretty high—pretty close to normal. I hope they present additional data like their fatigue index, vitality index, etc.
 
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