New pilot study in the loop from the researchers at Haukeland

[Jonathan Edwards]

@Jonathan Edwards: Thanks for your reply!

I doubt that Fluge/Mella would start a study with a drug like cyclo - that has relatively serious potential side effects - if the pilot patients had only seen 1-3 months of improvement. But we don't know, of course.

But cyclo also affects T cells, right, in contrast to rituximab? Yeah this is getting advanced...
Since some patients don't respond to rituximab: could it be that B cells are not the only problem - at least for a subset of patients? Wasn't that one of the possible theories?

One would think that they could try cyclo on a group of rituximab-non-responders and cyclo+rituximab on a group of patients who haven't received treatment before? I know that this is not what the study protocol is saying, but: why not?

Yes, it is complicated. I suspect that previous cases receiving cyclo may have had other drugs as well for lymphoma. A limited course of IV cyclo might help in ME and is worth exploring at least on a small scale. I am a bit doubtful it would have long term benefit on its own but since we know so little about mechanism that may turn out to be wrong.

Cyclo affects T cells but in a rather odd way - it actually stimulates some T cell activities. B cells are much more sensitive to cyclo at low to medium doses.

 

[lansbergen]

Cyclo affects T cells but in a rather odd way - it actually stimulates some T cell activities.

Can you say which ones?

 

[Jonathan Edwards]

Can you say which ones?

This goes back to work John Turk did in the 1980s and is all pretty difficult to interpret because what you measure as stimulated is some in vitro response or an in vivo 'hypersensitivity' response like the Jones Mote reaction in an animal and I am not sure anybody knows quite what these things mean in terms of affecting relevant immunological processes in the face of specific diseases. The one thing that does seem of practical relevance which again is odd about cyclo is that it induces stem cells to pass into the blood so that you can harvest them for re-infusion later.

 

[deleder2k]

Yes, it is complicated. I suspect that previous cases receiving cyclo may have had other drugs as well for lymphoma. A limited course of IV cyclo might help in ME and is worth exploring at least on a small scale. I am a bit doubtful it would have long term benefit on its own but since we know so little about mechanism that may turn out to be wrong.

Cyclo affects T cells but in a rather odd way - it actually stimulates some T cell activities. B cells are much more sensitive to cyclo at low to medium doses.

Thank you so much for you answer.

I think two had cyclo with other drugs. From my understanding they then did a pilot study with 3 subjects. I think two of them considers themselves at "100%", and the last subject reported a significant effect.

What about Mycophenolate mofetil. Could that be a drug one could use in the "mix"? Apparently Mycophenolate mofetil is used in several diseases because it inhibits an enzyme needed for the growth of T cells and B cells.

 

[Jonathan Edwards]

Thank you so much for you answer.

I think two had cyclo with other drugs. From my understanding they then did a pilot study with 3 subjects. I think two of them considers themselves at "100%", and the last subject reported a significant effect.

What about Mycophenolate mofetil. Could that be a drug one could use in the "mix"? Apparently Mycophenolate mofetil is used in several diseases because it inhibits an enzyme needed for the growth of T cells and B cells.

Mycophenolate is very interesting because it has been tried in combination with rituximab and if I remember rightly there were major falls in total antibody levels - which you do not get with rituximab alone. The implication is that the combination may lead to die off of long term plasma cells - which is of course what Radbruch and colleagues were hinting at being worthwhile. My information at the time was that because of the fall in total antibody the scientists running the study got worried and decided not to pursue it - assuming that it would cause infection problems. There may even have been some increase in infection.

What I think this demonstrates is that we need to devise a clever protocol that gets rid of just the right amount of plasma cells in a way that can allow background immunity to be 'topped up' afterwards if necessary. Treatment of leukaemias suggests that if you are brave you can clear the whole system out and get it to recover, but it can be hard work for patients. Anyway, I do think mycophenolate could be a key ingredient in a successful protocol in due course. The other drugs that may be useful are the BAFF antagonist biologicals like the anti-BAFF antibody Belimumab and the receptor construct TACI-Ig. Trouble is getting drug companies to work together to plan intelligent combination protocols - even in diseases like lupus or RA.

 

[deleder2k]

Very interesting! I like that we now have several drugs that we can combine. If you would clear the entire "system", would that mean that one would be vulnerable to literally "everything"? Would it mean that one could get diseases like chicken pox again? And that one would need new vaccines? Would a "wipe" of the entire immune system mean a prolonged hospital stay in isolation?

 

[lansbergen]

The one thing that does seem of practical relevance which again is odd about cyclo is that it induces stem cells to pass into the blood so that you can harvest them for re-infusion later

What happens when they are not harvested? Do they differentate to T lymphocites?

 

[Joolz]

I suspect that previous cases receiving cyclo may have had other drugs as well for lymphoma. A limited course of IV cyclo might help in ME and is worth exploring at least on a small scale.

I really hope that they'll provide cyclo-responders with some kind of follow-up/maintenance therapy (RTX? Oral MTX?). Given the nasty potential side effects, only three months of remission with a subsequent relapse to the previous level of symptom severity would be disappointing, to put it mildly. And cyclo doesn't exactly seem to be a drug that you want to be on for years, since the total dose predicts the probability for side effects.. right?

I am a bit doubtful it would have long term benefit on its own but since we know so little about mechanism that may turn out to be wrong.

I sure hope you're wrong!

 

[SaraEngland]

The Swedish friend who told me about Cyclo says that she spoke to one of the three in the pilot study. She says that the effect for all 3 have lasted for 6 months without symptoms of relapse. It will be interesting how long the effect will last. Maybe some of them will go into a complete remission!

 

[Kati]

The thing is so little is known about SEID. It is with people's experiences, physicians' willingness to be curious that we can move forward in this field, until we can have substantial funding for research from governments.

I am very thankful for these 3 pioneers, and I am hoping for many more brave doctors.

 

[Jonathan Edwards]

What happens when they are not harvested? Do they differentate to T lymphocites?

I suspect they either die or go back into bone marrow and do what they would have done anyway.

 

[Joolz]

@deleder2k: Out of pure curiosity: If you had been given the choice between the placebo-controlled RTX-study and the open phase II cyclo study, what would have been your choice?

 

[Adele]

@Joolz and everyone else - that is a question we can all play around with I guess We could all make a "choice" the same way deleder can (or can't actually… )

From what the rumors say, both drugs gave equal results for the pilot patients. Rtx has proven good results also in the next round, but in the trial one only stands 50% chance of receiving it. Which means about 30% chance of having a good effect. Maybe the odds for results are better in the cyclo trial - but then there are the possible side effects... I really dint know what I would have chosen. Anyone else who has a clear choice on this? Anyone want to make a poll?

 

[deleder2k]

@deleder2k: Out of pure curiosity: If you had been given the choice between the placebo-controlled RTX-study and the open phase II cyclo study, what would have been your choice?

I guess the fact that all the subjects in the cyclo study gets the drug makes that an interesting choice. On the other hand: we have only a few patients who got better with it. We don't know if anyone will experience a full remission with it. I don't know if 6 months is enough to say they are "cured". Probably not.

I really don't know. If one get placebo in the RTX study, one is guaranteed to get the "real deal" after the study is completed.

 

[Joolz]

Thank you for your opinions!

Rtx has proven good results also in the next round, but in the trial one only stands 50% chance of receiving it. Which means about 30% chance of having a good effect.

I agree on that one..
And of course there is always a small but existing chance for a "natural" improvement, as the Nyland study on EBV-onset patients shows.

Maybe the odds for results are better in the cyclo trial -

Not sure if I'd talk about "odds" with only a handful of patients... That's the problem. It's more a psychological factor - we hear the success histories (more rumors than histories!) and think "wow, that could be me".. and start dreaming about a better future. There is no 60% or 100% chance of getting better from cyclo (I've heard rumors about 2/3 having a significant effect) - we simply don't know. Also, as I mentioned above, there was apparently another cancer patient who was treated with the BEACOPP protocol - and didn't get better. (I have no clue what dose of cyclo was used in that protocol. Could also be that he/she would have needed more cyclo infusions.)

@deleder2k: When was your first RTX infusion? Sorry for the OT.

 

[Freddy]

Hi,
I have a maybe stupid question. @deleder2k : did you mention, that the Bergen researchers saw their frist success using Methotrexat? If so, does anybody know (maybe @Jonathan Edwards), why there isn't a Methotrexat study?
To many adverse effects? No long-lasting effects?
If I just missed an older discussion, sry for bothering...

 

[Jonathan Edwards]

I don't know the answer but MTX produces a lot of minor nuisance side effects, it has no clear cut mode of action so is scientifically less helpful and on its own it has relatively modest effects at tolerable doses. I think like azathioprine it may have been tried before without much effect, but all of this is speculation.

 

[deleder2k]

I think it was a "chemo-combo" that included Methotrexat that gave them the idea of trying Rituximab, @Freddy. I know there are positive stories which include Cyclo, MTX, and RTX. Also know a patient had a major improvement after IVIG, but I don't think they aren't going that road. Not sure if they have tried anything else.

 

[drob31]

Allot are using this drug for autoimmune. It makes me think more and more CFS is autoimmune.

 

[Freddy]

Thank you, @Jonathan Edwards and @deleder2k !
So MTX was only effective in combination with other drugs, not stand allone.