New pilot study in the loop from the researchers at Haukeland

[Avena]

The price listed in the description is < NOK 200/injection. This might give an indication on the dosage? The price of an ampoule of 1000 mg is NOK 186.
http://www.felleskatalogen.no/t/medisin/sendoxan-baxter-563813

 

[Sherlock]

Here's a nice exposition of using low dose Cytoxan in vasculitis, including discussion of side effects:
http://www.hopkinsvasculitis.org/vasculitis-treatments/cyclophosphamide-cytoxan/

• Infection
• Bone marrow suppression
• Cancer
• Bladder problems
• Infertility

They don't give the actual dose, though.

 

[NK17]

Note that cyclophosphamide has different effects at low and high doses: At high doses it has an immuno-suppressant effect, and at low doses it has an immuno-stimulant effect.

At low doses, and when being carefully monitored, I imaging that it's not nearly as harmful as the full list of side-effects suggest.

But I've no idea what dose Fluge and Mella are using. My guess is that it's a fairly high dose, as they're administering it monthly, and the wiki quote below suggests that a low dose would be given 'continuously', which perhaps mean more frequently. But I'm guessing.




Also of interest:

"The dose makes the poison."
- Paracelsus

 

[Forbin]

I'm sure it's been said before, but I just would like to express my gratitude to the brave patients everywhere who participate in trials like these despite the possible risks. Their intrepidness reflects well on the courage of the ME community as a whole.

People who volunteer for things like spinal taps and infusions of cancer drugs in an effort to push the science forward... people with courage like that do not have a "fear" of exercise.

 

[Kati]

I'm sure it's been done before, but I just would like to express my gratitude to the brave patients everywhere who participate in trials like these despite the possible risks. Their intrepidness reflects well on the courage of the ME community as a whole.

People who volunteer for things like spinal taps and infusions of cancer drugs in an effort to push the science forward... people with courage like that do not have a "fear" of exercise.

@Forbin for having done it and still going to do it again, I think the toughest part is to convince the physicians to do something, anything. I am not talking about our very few experts who are walking the walk with us, I am talking about the thousands other who just look at us like we are crazy or something and that tell us they can't do anything. Bullshit!

 

[Sherlock]

for having done it and still going to do it again

Kati, are you the one who tried RTX with Kogelnick and had a blog about it? That was the same time as Jacque.

 

[Kati]

Kati, are you the one who tried RTX with Kogelnick and had a blog about it? That was the same time as Jacque.

Yes Sherlock that was me.

 

[Jonathan Edwards]

Wow it is really cheap, almost free of charge. The biggest dose (1000 mg) is $10 US here in Turkey and I can buy it without a doctor prescription. Now, the question is should I.

There is also a tablet form. 50 mg 50 tablets $8 US.

No, you shouldn't. Cyclophosphamide used in the wrong frequency is fairly reliably lethal. Long term tablet usage produced an odds on chance of bladder cancer. The study the Haukeland are setting up will be safe and good science but lease 'do not try this at home'!

 

[Jonathan Edwards]

I can't read the translation but Cyclophosphamide is an interesting choice.

From my cancer nursing perspective, here is what I know about 'Cyclo.
This is a 'real' chemo drug. It means that it is kills the cells in the body that reproduce fast, including the blood cells, white and red blood cells, and hair cells (it makes you lose your hair), although it is dose dependant. Small dose means less side effects.

Losing the protection of the white blood cells results in neutropenia for a period of time, making the patient prone to potentially dangerous infections. Of course it would be dose dependant, and the dosage here is not specified. I would love to hear Dr Fluge and Mella's feedback, and also Dr @Jonathan Edwards's thoughts, since I believe Cyclo is also being used in rheumatology.

There is also significant bladder toxicity to be considered but this is also dose dependant-high dose means much increased risks. Usually for small doses, patient is hydrated and instructed to drink plenty and to empty the bladder often on chemo day so the Cyclo is not allowed to sit in the bladder for very long.

Certainly this is not a drug to be considered outside clinical trials and competent physicians This is not something you can just try at home.

In simple terms, cyclophosphamide kills all dividing cells to an extent. It's main therapeutic value is in killing B cells which are more sensitive that almost all other cells (hence the pay off for B cell disease). It has a paradoxical stimulatory effect on T cells (which you almost certainly do not want) and stem cells, which come out of the bone marrow into the blood after cyclo.

It is used in rheumatology chiefly in diseases with a high mortality like lupus or dermatomyositis. It works in RA but the benefits do not justify the side effects. Low dose oral cyclo is probably the most carcinogenic, for reasons that are unclear.

I used cyclo as an additive in my first RA trial for specific reasons relating to drug synergy. I think it is justified to do a small trial in ME if only because it may tell us something about the mechanism. It would only really be worth having it as a standard therapy for severe cases and only if it produced long term remission with a short course, in my view.

 

[Jonathan Edwards]

I wonder if this means that cytoxan doesn't literally kill cells. Rather, it would reduce the numbers of short lived cells by inhibiting their replication. Not that this would make much difference, I guess - except that it wouldn't involve a die off of cells that was any more rapid than would normally happen - they just wouldn't be replaced - i.e. no massive, sudden die off.

I don't know, though.

It kills cells trying to divide. It also kills B cells through another mechanism. So after cyclophosphamide B cell counts tend to plummet to near zero. But then they plummet to 50% just with a medium dose of steroid.

There are really three dose levels.

50mg daily orally I would not give to anyone because of the risk of cancer.

750-1000mg infusions kill off a lot of B cells and increase the benefit of rituximab in RA, for instance. But they d not kill all B cells. They cause nasty nausea but not usually neutropenia.

10gm infusions ablate bone marrow - on purpose - so you have a guaranteed period of neutropenia. This is used for conditioning prior to bone marrow transplantation. Since it is usually only done once long term complications are not that great but in the past the mortality of the acute procedure was as high as 5%. It is now less but it is no picnic. Ablation of bone marrow has been tried in RA and lupus but only at a coupe of centres. In RA the long term benefit is not more than rituximab. In lupus it may be life-saving but we do not know.

 

[deleder2k]

Could cyclo+rituximab be a viable treatment scheme in the future if the trials turn out good? Would that combination be likely to kill off more b-cells, including memory b-cells?

@Jonathan Edwards, I have read your thoughts on different ME groups with great interest. Do you still believe that a major group do not have an autoimmune type of ME? Or could it be that we all have a type of AI disease that requires a specialised treatment scheme for each patient with immunosuppressive medication?

 

[Kati]

It kills cells trying to divide. It also kills B cells through another mechanism. So after cyclophosphamide B cell counts tend to plummet to near zero. But then they plummet to 50% just with a medium dose of steroid.

There are really three dose levels.

50mg daily orally I would not give to anyone because of the risk of cancer.

750-1000mg infusions kill off a lot of B cells and increase the benefit of rituximab in RA, for instance. But they d not kill all B cells. They cause nasty nausea but not usually neutropenia.

10gm infusions ablate bone marrow - on purpose - so you have a guaranteed period of neutropenia. This is used for conditioning prior to bone marrow transplantation. Since it is usually only done once long term complications are not that great but in the past the mortality of the acute procedure was as high as 5%. It is now less but it is no picnic. Ablation of bone marrow has been tried in RA and lupus but only at a coupe of centres. In RA the long term benefit is not more than rituximab. In lupus it may be life-saving but we do not know.

There are more doses schedules than that since it is used in combination with different chemotherapeutic protocols (breast, lymphomas, sarcomas).

I agree that it is not to be taken lightly, and needs to be used only under close and experienced supervision.

However Dr @Jonathan Edwards patients are desperate. They wonder, why is it happening in Norway but not in their country. Why are patients forbidden access to drug options such as ampligen, Rituxan, and in this case cyclophosphamide and instead offered meditation, exercise therapy or CBT or vitamin b-12?

In the light of our most recent fatality in our community, Vanessa Li who just died on Tuesday at the tender age of 34, we are in a hurry. We are tired of the BS. Things are getting urgent.

And you probably know clinical trials do not happen within 2 months. It takes time and careful planning, careful resource allocation.

We need help today.

 

[Bob]

So after cyclophosphamide B cell counts tend to plummet to near zero. But then they plummet to 50% just with a medium dose of steroid.

Jonathan, did i read that correctly? Are you saying that a small dose of steroids reduce B cell counts by half?

And if that's the case, could steroids potentally be a helpful treatment for a subset of ME patients?

I'm not aware that there have been any trials using steroids. Does anyone else know of any studies?

I know an ME patient who was given steroids for another chronic condition, and every time he comes off the steroids, his ME symptoms flare up.

Edit: ah, as gingergrrl points out, in the next post, you probably mean that steroids bring the B-cell levels back up from zero to 50%.

 

[Gingergrrl]

I read it as they go to zero but then they give you steroid which brings it back up to 50% (but I may be reading it wrong and am the last person to grasp these things!)

I actually have a separate question for @Jonathan Edwards which may be better in a different thread but does relate. Here it is: several months ago, you took a poll of how many of us on PR also have Hashimotos (an autoimmune condition) but never told us your findings.

Do you think the group with Hashimotos would respond better to Rituxan or is there no connection? I was just curious.

 

[DanME]

In simple terms, cyclophosphamide kills all dividing cells to an extent. It's main therapeutic value is in killing B cells which are more sensitive that almost all other cells (hence the pay off for B cell disease). It has a paradoxical stimulatory effect on T cells (which you almost certainly do not want) and stem cells, which come out of the bone marrow into the blood after cyclo.

It is used in rheumatology chiefly in diseases with a high mortality like lupus or dermatomyositis. It works in RA but the benefits do not justify the side effects. Low dose oral cyclo is probably the most carcinogenic, for reasons that are unclear.

I used cyclo as an additive in my first RA trial for specific reasons relating to drug synergy. I think it is justified to do a small trial in ME if only because it may tell us something about the mechanism. It would only really be worth having it as a standard therapy for severe cases and only if it produced long term remission with a short course, in my view.

@Jonathan Edwards Thank you for your additional information! Is long term remission after a short course of cyclophosmaide a real possibility? Have you seen such cases in other autoimmune diseases, like RA or Lupus? Or do the symptoms almost certainly come back after awhile? I have read, that the drug is used in severe cases of Lupus, MS and RA, especially for a fast symptom control. Why does is work so fast? Does it slow down the whole immune response in addition of killing almost all B Cells?

 

[Snow Leopard]

I'm not aware that there have been any trials using steroids. Does anyone else know of any studies?.

Studies using steroids such as hydrocortisone have shown some benefit in CFS patients:
http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(98)04074-4/abstract
http://jama.jamanetwork.com/article.aspx?articleid=188004

 

[beaker]

No, you shouldn't. Cyclophosphamide used in the wrong frequency is fairly reliably lethal. Long term tablet usage produced an odds on chance of bladder cancer. The study the Haukeland are setting up will be safe and good science but lease 'do not try this at home'!

I am wondering about the alternative use of LEUKERAN (chlorambucil). It is in the same drug category as Cytoxan, and many of the same actions but in a milder form. It is known as "baby chemo". I used in on a cat w/ severe IBD.
Would this be a comparable less toxic alternative. Is this every used for RA and other autoimmune disorders in people ? Thanks.

 

[Jonathan Edwards]

Could cyclo+rituximab be a viable treatment scheme in the future if the trials turn out good? Would that combination be likely to kill off more b-cells, including memory b-cells?

@Jonathan Edwards, I have read your thoughts on different ME groups with great interest. Do you still believe that a major group do not have an autoimmune type of ME? Or could it be that we all have a type of AI disease that requires a specialised treatment scheme for each patient with immunosuppressive medication?

Cyclophosphamide and rituximab might be useful for some severe cases but my decision after treating a number of patients with RA was that if something was to be added to rituximab cyclophosphamide would probably not be the best option. It is all a matter of weighing in the balance. The combination almost certainly does kill more B cells but maybe not enough more to justify.

I still think that there are people who could be classified as having ME who do not having an antibody mediated autoimmune disease. What I continue to be puzzled about is the most common mechanism for PEM type ME.

 

[Jonathan Edwards]

Jonathan, did i read that correctly? Are you saying that a small dose of steroids reduce B cell counts by half?

And if that's the case, could steroids potentally be a helpful treatment for a subset of ME patients?

I'm not aware that there have been any trials using steroids. Does anyone else know of any studies?

I know an ME patient who was given steroids for another chronic condition, and every time he comes off the steroids, his ME symptoms flare up.

Edit: ah, as gingergrrl points out, in the next post, you probably mean that steroids bring the B-cell levels back up from zero to 50%.

No, you were right first time. The steroid injection we gave with rituximab in the large phase II trial produced a 50% fall in B cell counts in the placebo group with no rituximab. B cells are normally short lived and if they find nothing of interest around they die very readily. Steroids accelerate that. It probably has no significance to useful treatment though, because it is the B cells with nothing to do that die. The autoimmune ones, if there are some, are likely to survive. Steroids produce temporary benefit in lots of conditions and have been tried in ME (Charles Shepherd knows about this) but they do not have useful long term benefit at safe doses in general.

 

[Jonathan Edwards]

I read it as they go to zero but then they give you steroid which brings it back up to 50% (but I may be reading it wrong and am the last person to grasp these things!)

I actually have a separate question for @Jonathan Edwards which may be better in a different thread but does relate. Here it is: several months ago, you took a poll of how many of us on PR also have Hashimotos (an autoimmune condition) but never told us your findings.

Do you think the group with Hashimotos would respond better to Rituxan or is there no connection? I was just curious.

Yes, I suspect I never gave a clear answer. The feedback I got suggested that having either abnormal thyroid function levels or thyroid antibodies looked to be a bit more common than one would expect from normal but the difficulty in interpreting is the likelihood of answering bias. The people with positive answers would be more likely to answer. I thought the level was high enough to deserve further study but it would have to be done on a rigorous population based cohort, which so far we do not have. It is one of the things that makes me feel that setting up population based cohorts is so important.

I guess one would expect people with thyroid antibodies to be more likely to respond to rituximab than others, although I do not think the Haukeland researchers found any particular association.