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

If we are revisiting the 2020 study, then have a look at some of the other metrics like fatigue score, steps, function level, etc. Like I said above I’m not a fan of the PF questions.

 

Thanks for clarifying. As you said, your patients had much more than six doses. It is also likely they had a history of other immunosuppressive treatments.

I accept that suppression of adverse events does happen, but the second and third cancer studies that I posted used data from Danish and Sweden registries of cancer patients which I think we can trust.

The 40% bladder cancer rate is for the (almost obsolete) long term oral protocol. 100mg a day for years results in huge cumulative doses. For pulsed IV doses bladder toxicity is reduced by consuming lots of fluids and urinating every hour to reduce contact time. This is difficult to sustain for long term oral dosing which also increases the risk for a given cumulative dose.

Bladder and kidney cancer following cyclophosphamide therapy for non-Hodgkin's lymphoma
“Within a cohort of 6171 two-year survivors of non-Hodgkin's lymphoma (NHL), 48 patients with secondary cancer of the urinary tract were identified and matched to 136 control subjects with NHL who did not develop a second malignancy.”

“Among patients who received a total amount of cyclophosphamide of less than 20 g, a nonsignificant 2.4-fold risk of bladder cancer was apparent. Significantly elevated sixfold and 14.5-fold risks of bladder malignancy followed cumulative doses of 20–49 g and 50 g or more. For patients given cumulative doses between 20 and 49 g, the absolute risk of bladder cancer is on the order of three excess cancers per 100 NHL patients” This is at 15 year follow-up and no doubt a few more have been diagnosed since.

For arguments sake I will make a linear extrapolation from the above data assuming a mean cumulative dose of (20+49)/2 =34.5g. 34.5/7.5= 4.5 fold dose reduction. 3(excess cancers)/4.5= 0.65 excess cancers per hundred patients for a 7.5g cumulative dose.

However the real number is much lower because the risk is exponential not linear. This is another study using data from the Swedish cancer registry. “The risk of bladder cancer doubled for every 10 g increment in cyclophosphamide”.

The risk of bladder cancer at 7.5G is not zero, but it is so low that it is unlikely there will ever be a study big enough to reach statistical significance.

 

No they only had two doses in fact, as IV pulses with fluids and meson. I am not saying that this is a statistically useful finding but the reality of supporting people who gradually become more and more incapacitated and then die from a complication of treatment is not easy.

Another part of the problem is the question as to whether risk is increased in people with certain conditions that you might treat.

I agree that the survey data make it look as if the risk is low but there are lots of unknowns and in my field of medicine cyclophosphamide has been steadily disappearing from the treatment options with time, mostly because of toxicity. And even in the conditions where it helps it tends not to be that dramatic, except perhaps sin the context of lupus or Wegener's crisis.

 

I guess if the CAR T-cell therapies work out for a big enough proportion of the patients where it's still used, it might disappear altogether?

 

But cyclo dosage for AI disease is typically 200 mg/kg, correct?

 

No, doses are usually around 750mg total. 200mg/kg would be about 10grams which is more like the dosage for immunoablation with stem cell rescue, which nobody uses routinely although Ann Trainor tried it for lupus about twenty years ago.

 

you mean doses are around 6-800mg per m2 over 6 infusions? Do you mean the specific Lupus low dose type stuff: https://www.jrheum.org/content/jrheum/49/6/607.full.pdf
thats a bit different, The EuroLupus regimen consists of a fixed dose of CYC (500 mg) administered every 2 weeks for a total of 6 doses.

It seems to vary a lot but i dont quite know what the pulse is:
https://www.researchsquare.com/article/rs-504049/v1

what do you mean by people only responding a little and then relapsing, was that from your clinic/work for jus RA or within wider literature?: "
i. In their 10 years follow up, they found that low dose of CTX is beneficial in the long term as 70% of patients that took this regimen did not require any pulse of CTX following their initial therapy. However, they reported that there was no significant difference in mortality between the two groups treated with low dose and high dose of CTX respectively [10]/" https://assets.researchsquare.com/f...-3f2c-45ea-a4b8-d1fe7ee3cdb3.pdf?c=1631883195

Seems to differ but the Norwegians protocol seems in line with a diversity of immune related disorders:
https://secure.library.leicestersho... (Intravenous) UHL Rheumatology Guideline.pdf