Cyclophosphamide

Hopefully, the Fluge/Mella cyclophosphamide trial results will be published shortly. https://clinicaltrials.gov/ct2/show/NCT02444091 (CYCLOME). This was a phase 2 unblinded study.

Jumping the gun a bit, what if the trial is positive, that is there was a response in the patients (let's say that maybe more than 20% of the patients responded significantly)?

Haukeland will invariably state that no one should try this until they complete a phase 3 (blinded) study. They will say look what happened with rituximab.

It will likely take another 5 years or so to complete a phase 3 study. Most people, myself included, do not want to wait 5 years.

Cyclophosphamide is widely available (unlike Ampligen) and relatively inexpensive (unlike Copaxone). In many countries, physicians can prescribe medications for off-label use so long as the medicine is approved for use in that country.

So, if the trial is positive, will the various NGO's and patient groups try to encourage clinicians to administer IV cyclophosphamide to treat ME/CFS? Being too cautious here is problematic as many ME/CFS patients note increasing disability with time.

If patients/physicians agree to informed consent https://www.ama-assn.org/delivering-care/ethics/informed-consent, and the patient is aware that there are serious risks associated with receiving cyclophosphamide, then then shouldn't the patient have the ability to receive it?

Sorry for jumping the gun here, but if it looks likes cyclo treats ME, I want to be first in line......

 

I am not sure you do. Cyclophosphamide causes bladder cancer, not just rarely , but in the old days in 40% of people treated. If cyclophosphamide is any use at all in ME it will need giving repeatedly, which is when the trouble starts. There will never be a blinded trial of cyclophosphamide because you cannot blind it - it makes you sick. The open trial may look positive but it will be uninterpretable like PACE. I am pretty sure this is a dead end.

 

I think that I would rather live with ME than take a chemo drug even if it was shown to work.

 

Dear Dr. Edwards,

You are correct about the blinding (you had brought this up before, but I forgot--must be the brain fog). But the 40% bladder cancer number is overstated. See here https://onlinelibrary.wiley.com/doi/full/10.1002/art.25061 There is a bladder cancer risk for high dose daily oral cyclo, but no so much for periodic IV " IV cyclophosphamide therapy, as prescribed for rheumatic diseases, carries a low risk of cystitis and probably also of bladder cancer". Also the dosage in the Fluge study is about 8 grams, which is much lower than even the control group here https://ard.bmj.com/content/63/10/1307

Fluge et al. extended the study, {{speculation here on my part}} likely because it was still working at 12 months. Which may indicate that continued dosing is not required.

@Jonathan Edwards I very much appreciate you skepticism. But if cyclo gives a year or two of normalcy before another treatment is found, I still remain first in line.

 

Hi @Jaybee00 i was a chemo nurse before i got sick. Cyclo is not a casual drug. It can cause life threatening side effects such as sepsis and bladder hemorrages. It should not be administered casually. And physicians prescribing and infusing it should have special training such as our oncologist friends in Norway.

i too eagerly await the publication, but it certainly won’t mean it will be a treatment that is ready to go as an off-label. We already know that ME patients had worse reactions to it than that of patients receiving it for other diseases.

We really need to be careful here.

Edit to add: being too cautious, well, that’s a tricky one. No physician would like to lose a patient that died from administering a drug that is not fully vetted by the appropriate authorities (FDA and such) for efficacy and safety for patients with ME.

i understand patients (and I am one) are frustrated and can’t wait. We need to understand the disease better, and we need consensus across researchers an dphysicians. We need to understand the pathology. And when that happens, there will be treatments.

The best thing we can do support our researchers, may it be financially or advocating for federal research funding, wherever you are.

 

If it is positive, it will be a shit storm as the trial was unblinded...

 

Please explain!

 

I have already had Cyclo as part of chemo treatment for cancer. It didn't cure my ME.

Either I am a nonresponder or it was the wrong dose

Chemo was miserable for me. I'd not jump in again personally until more is known.

 

The best outcome from something like cyclo is that it gives us clues for where to look next. It doesn't sound so great as a general treatment.

 

Methotrexate is an example of a "chemo drug" that many autoimmune patients take. However it is not a "chemo drug" when used for autoimmunity as the dose is way way way way smaller than what is given to cancer patients. It's not considered "chemotherapy" when used this way because the way it works in the body is different at these much smaller doses.

this article does a great job of explaining it...

https://creakyjoints.org/treatment/is-methotrexate-considered-chemotherapy-when-used-to-treat-ra/

 

No, as I said it was the rate years ago when we used daily doses. It is less with IV dosing but I have had patients with bladder cancer despite protective use of Mesna. It is used in rheumatology for life threatening conditions like lupus and Wegener's but less and less even in these.

We really have no evidence that cycle works and we will still have no evidence after these open studies are completed - as Snow Leopard indicates. I have great respect for the integrity of Oystein Fluge and Olav Mella but with the failure of rituximab to have an effect I cannot see any justification for using cycle in ME.

 

Do you know how it works biochemically? Let's say in high doses it promotes apoptosis (I'm just inventing) and in lower doses...?

 

@Jonathan Edwards

Thank you for clarifying the 40% number. But I also want to point out that some (at least one person) had a long lasting effect ~4 years from the initial infusion series. So it is possible for people to get long-term remission from one series.

Do you still think that Alemtuzumab (Campath) is a better candidate for treating ME/CFS than Cyclophosphamide?

Well in any case, if cyclophosphamide is not a promising treatment, then, unfortunately, I think it will be a long, long wait for a treatment/cure (especially if Copaxone doesn't pan out).

 

@TrixieStix

I think for cyclo, total dosage for auto-immune diseases can exceed those used for cancer, especially, if they have to retreat over a long time period. The dosages used by Fluge/Mella are similar to those used for the treatment of breast cancer, for example. http://www.just.edu.jo/DIC/ClinicGuidlines/Breast cancer regimens.pdf Assuming the body surface area is 2, then the people with cancer would receive about 5 g cyclo, and the F&M trial about 8 g cyclo total. Some of the people with rheumatic diseases were receiving over 100 g in their lifetimes.

 

Maybe. But this will take a long time ~15-20 years (including drug development/approval). Even if targeted ME/CFS drugs are developed, they are also likely to have potentially detrimental side effects. I'm guessing that the developed drugs will look something like the Disease Modifying Drugs for Multiple Sclerosis, which sometimes work and usually have serious side effects. I think that it may not be realistic to expect that there will some benign super pill that will instantly vanquish ME/CFS with no side effects. In the meantime if there is something that will reduce the time I spend as a human zombie, then I am interested...

 

I do wish we had more clinical trials.

You have to be careful in comparing chemo protocols vs single agent drug, and cancer vs ME. Cyclo is very seldom used as a single agent for breast cancer protocol. So while it may be used in lower dose, itis because it is given with another very toxic drug one after the other. Also the breast cancer protocol is used on relatively very healthy patients, in contrast to us ME patients whose disease has not been figured out yet but we do know we do present with metabolic/cellular energy issues.

 

I totally agree with you. I am certainly hoping pharma will be involved and interested and that we won’t be offered botanicals as the only clinical trials. Currently we have 2 centers that we know of that is clinical trial ready. Ok maybe 3. Bergen, Miami, and Incline Village. I agree we should have access to drug trials, in the most scientific manner, not in a cowboy, let’s-wing-it manner, because with the latter we will never learn anything, but mostly, we need safety and checks and balances (adverse events, definition of recovery or success, what is the safe dose, what are the long term side effects, etc)

The clinical trial route gives patients willing to risk it the opportunity to trial drugs they would never have access to via the regular routes. And clinical trials are usually free (unless we are talking about Ampligen)

 

Yeah for more clinical trials......(less for fecal microbiome studies?)

There are now 4 or 5 five drugs that might work for ME/CFS

Ampligen (needs another study, apparently)
Cyclophosphamide (from Fluge/Mella)--but maybe no phase 3 study possible
Suramin and Copaxone (From Ron Davis--normalized CFS blood in vitro)
Alemtuzumab (Campath) (earlier suggestion from @Jonathan Edwards --instead of cyclo)
(maybe the Nancy Klimas cocktail)

Also https://drlapp.com/research/ these guys are collecting some data on ampligen (Looks to be outside of the 2012 study--they are getting about a 25% response rate).

Merry Christmas/Mele Kalikimaka

 

@Jaybee00 Merry Christmas to you too. (What language is Mele Kalikimaka?) To hoping.

We need to build international/national/regional capacity for clinical trials.

 

The problem is that we do not know this is even an 'effect'. People get better on trials for all sorts of reasons unrelated to the drug. Cyclo at the doses used does not have a long term effect on any disease much that I can think of. It is either given as art of a combination with other toxic drugs or at much higher doses if long term remission is hoped for.