Cyclophosphamide in ME/CFS Part A:an Open Label Phase-II Study With Six Intravenous Cyclophosphamide

Vegas

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For those considering such a trial, I will mention that the therapeutic effects of CTX in cancer treatment are now thought to be related in part to the induction of intestinal permeability and the attendant translocation of certain microbial organisms. This brings about a robust adaptive immune response that can be abrogated by antibiotic administration. You can read about the specific cellular responses here: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4048947/#SD1

Without getting too much into the biochemical similarities between CA and ME/CFS and the transferability of this research, I would suggest these findings certainly might say something about the pathophysiology of ME/CFS. Translocation of bacteria into the mononuclear phagocyte system is also one of the most promising developments in cancer immunotherapy. Fairly recently it was reported that administering tetanus vaccinations could triple the survival advantage in glioblastoma. They found that a simple tetanus vaccine could stimulate the migration of dendritic cells to these extraintestinal tissues.

I can't say I'm enthralled with the idea of this approach after recently witnessing the effects of this medication, but I can relate with the sentiment. In addition to the problems described above, I think the associated incidence of neutropenia is likely to require more than a handful of participants to treat secondary infections with antimicrobials, which according to the study linked above, may negate the desired cellular response.

I studied the metabolic capacities of the organisms believed to be playing a part in immunomodulation in this study some time ago, and I am interested by the finding that describes an extraintestinal proliferation of L. Johnsonii. This is a fairly unusual Firmicutes organism which is part of the lactic acidophilus group. I seem to recall that it is particularly sensitive to O2. It is effective in counterbalancing pathogenic lactic acid bacteria, i.e. reducing strep/enterococcus overgrowth. Honestly, I don't fully appreciate the significance of the accumulation of this particular organism, but it is a very unusual LAB in that lacks encoding for amino acid synthesis and purine metabolism and it acquires these resources from the environment; some of these resources are all but certainly obtained from the host since it is incapable of de novo synthesis.

I guess the take-away is don't take ABX if you choose to pursue this therapy Also, I would wonder if taurine/glycine might enhance the efficacy of this treatment because I know that this organism correlated to the therapeutic benefits is highly resistant to bile and the provision of bile acid precursors has been shown to enhance to effects of CTX, in vitro, at least.
 

BurnA

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Hello, @greeneagledown

From the study protocol:



I have no information about a phase 3 trial.
Just a thought on any potential phase 3 trial :
It would make sense imo to wait for outcome of rituxime phase 3 trial and any developments there may be in identifying responders before proceeding to phase 3 cyclophosphamide.

One of the main considerations of a phase 3 trial is to establish benefit over existing treatments. Obviously for rtx there is no existing treatment so easy just compare to placebo. But if rtx proves beneficial for some patients any cyclo trial would have to take that into consideration. The best or easiest way would be to prove efficacy in rtx non responders, or improved response duration in rtx relapsers. But for either of these scenarios I think the full results ( and maybe more ) of the rituxime trial would be needed.

All just my thoughts, not based on any in depth knowledge.

Edit : I might just add that Olav Mella mentioned that Cyclophosphamide would be much cheaper than RTX and therefore could become the drug of choice if it was proven effective. This therefore would be another reason to complete a phase 3 trial IMO.
 
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deleder2k

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Levamisole was withdrawn from the U.S. and Canadian markets in 1999 and 2003, respectively, due to the risk of serious side effects and the availability of more effective replacement medications.[1][2] The most serious side effect of levamisole is agranulocytosis, a severe depletion of white blood cells that leaves person vulnerable to infection. It belongs to the class of synthetic imidazothiazole derivatives.
Is it safe? How much will you say that it helped you?
 

lansbergen

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The most serious side effect of levamisole is agranulocytosis, a severe depletion of white blood cells that leaves person vulnerable to infection.
As I understand it. that will reverse in a few days when treatment is stopped.

I still take it every day. It haven't forgotten to take in a long time but when I did I got a huge hangover the next day.
 

BurnA

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@deleder2k -- A couple questions that you may or may not know the answers to:

Are Fluge & Mella going to wait for Part A of this phase 2 trial to be completely done (including 12-month follow-up) before they decide on the extension study for the severely ill? Or will they start the Part B trial immediately if it becomes clear during Part A that the response rate is over 40%?
This is a good question - as the trial is open label then they will know as soon as 40% response is achieved, even if they dont know to what extent the response is. Therefore I cant see any reason to wait for part B. However clinical trials never seem to be straightforward so who knows ? I would like to know the answer though, obviously it speeds things up dramatically and if we hear part B has been initiated then it is a positive indication to say the least !
 

Hip

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Levamisole helped me a lot and still does.
Do you know any ME/CFS patient other than yourself who has tried levamisole and got good results? How much improvement did it make to your ME/CFS when you first started taking it (or was it too long ago to remember)?
 

lansbergen

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Do you know any ME/CFS patient other than yourself who has tried levamisole and got good results? How much improvement did it make to your ME/CFS when you first started taking it (or was it too long ago to remember)?
I do not know anyone else and improvement was very slow.

I kept taking it because it lowered within 10 minutes the horrible pain enough to let me sleep a few hours. The pain relieve was a supprise for everybody I informed about it. It was not known before. Even the producer did not know.

I am still not cured but I have improved very much and improvement still goes on.
 

Anne

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@Jonathan Edwards

Prof Edwards, a question for you:

About the ME/CFS cyclophosphamide study: I think I read somewhere here that the effects are thought to appear much sooner with cyclophosphamide compared to Rituximab.

Why is this? Does it have a different mode of action? Why is there no time lag to the point when the possible autoantibodies are finally out of the system?

(Apologies if this has already been discussed, I am severely ill and unable to go through all the threads. Grateful for help.)
 
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@Jonathan Edwards

Prof Edwards, a question for you:

About the ME/CFS cyclophosphamide study: I think I read somewhere here that the effects are thought to appear much sooner with cyclophosphamide compared to Rituximab.

Why is this? Does it have a different mode of action? Why is there no time lag to the point when the possible autoantibodies are finally out of the system?

(Apologies if this has already been discussed, I am severely ill and unable to go through all the threads. Grateful for help.)
We have touched on this before but a long time ago. Cyclophosphamide kills a proportion of plasma cells directly so would have an immediate effect on antibody production. The downside is that unless you use very high doses it does not kill a high percentage of memory B cells. Rituximab kills a lot more memory B cells but not plasma cells so takes longer.
 

Anne

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We have touched on this before but a long time ago. Cyclophosphamide kills a proportion of plasma cells directly so would have an immediate effect on antibody production. The downside is that unless you use very high doses it does not kill a high percentage of memory B cells. Rituximab kills a lot more memory B cells but not plasma cells so takes longer.
Thank you very much! @Jonathan Edwards A follow-up question: If a patient with ME has tried Rituximab but without response, would cyclophosphamide be an option?

Or does a non-response to Rituximab mean cyclophosphamide is not likely to work either?
 
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Thank you very much! @Jonathan Edwards A follow-up question: If a patient with ME has tried Rituximab but without response, would cyclophosphamide be an option?

Or does a non-response to Rituximab mean cyclophosphamide is not likely to work either?
I don't think we know that. We are not even sure there are responses to rituximab yet, just people who have got better and have had rituximab.
 

deleder2k

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I know two persons who has responded with cyclo after being non-responders to Rituximab. I don't have any details about it though.

My question is whether a combo of full b-cell depletion + cyclophosphamide at the same time will produce even better results.
 

Kati

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I know two persons who has responded with cyclo after being non-responders to Rituximab. I don't have any details about it though.

My question is whether a combo of full b-cell depletion + cyclophosphamide at the same time will produce even better results.
This is where it is critical to have most excellent follow-up by experienced oncologists. Combination chemotherapy has more side effects and present neutropenia-associated challenges.

i wonder if Fluge and Mella are thinking about it.
 

msf

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Yep! Not a walk in the park-drug by any means, but it doesnt seem too bad either with regards to the actual chances of getting serious side effects "Myeloproliferative neoplasms, including acute leukemia, non-Hodgkin lymphoma, and multiple myeloma, occurred in 5 of 119 rheumatoid arthritis patients within the first decade after receiving cyclophosphamide, compared with one case of chronic lymphocytic leukemia in 119 rheumatoid arthritis patients without a history of cyclophosphamide use."

However - Acute leukemia, e.g, is a very very serious diagnosis indeed.
In other words - not a drug to take in a heartbeat!
Multiple myeloma doesn´t seem like much fun either. I wonder if they will find a higher rate of Non-Hodgkins Lymphoma in the ME group, aren´t we supposed to be at a higher risk of developing it?
 
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msf

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For those considering such a trial, I will mention that the therapeutic effects of CTX in cancer treatment are now thought to be related in part to the induction of intestinal permeability and the attendant translocation of certain microbial organisms. This brings about a robust adaptive immune response that can be abrogated by antibiotic administration. You can read about the specific cellular responses here: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4048947/#SD1

Without getting too much into the biochemical similarities between CA and ME/CFS and the transferability of this research, I would suggest these findings certainly might say something about the pathophysiology of ME/CFS. Translocation of bacteria into the mononuclear phagocyte system is also one of the most promising developments in cancer immunotherapy. Fairly recently it was reported that administering tetanus vaccinations could triple the survival advantage in glioblastoma. They found that a simple tetanus vaccine could stimulate the migration of dendritic cells to these extraintestinal tissues.

I can't say I'm enthralled with the idea of this approach after recently witnessing the effects of this medication, but I can relate with the sentiment. In addition to the problems described above, I think the associated incidence of neutropenia is likely to require more than a handful of participants to treat secondary infections with antimicrobials, which according to the study linked above, may negate the desired cellular response.

I studied the metabolic capacities of the organisms believed to be playing a part in immunomodulation in this study some time ago, and I am interested by the finding that describes an extraintestinal proliferation of L. Johnsonii. This is a fairly unusual Firmicutes organism which is part of the lactic acidophilus group. I seem to recall that it is particularly sensitive to O2. It is effective in counterbalancing pathogenic lactic acid bacteria, i.e. reducing strep/enterococcus overgrowth. Honestly, I don't fully appreciate the significance of the accumulation of this particular organism, but it is a very unusual LAB in that lacks encoding for amino acid synthesis and purine metabolism and it acquires these resources from the environment; some of these resources are all but certainly obtained from the host since it is incapable of de novo synthesis.

I guess the take-away is don't take ABX if you choose to pursue this therapy Also, I would wonder if taurine/glycine might enhance the efficacy of this treatment because I know that this organism correlated to the therapeutic benefits is highly resistant to bile and the provision of bile acid precursors has been shown to enhance to effects of CTX, in vitro, at least.
I haven´t read the article, but I would think the last thing ME patients need is something that increases intestinal permeability.
 

BurnA

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I know two persons who has responded with cyclo after being non-responders to Rituximab. I don't have any details about it though.

My question is whether a combo of full b-cell depletion + cyclophosphamide at the same time will produce even better results.
It's an obvious question and I think we'd all like to know. However I think it's more important to know the mechanism by which these drugs are working first. Do the rtx non responders who ( allegedly ) respond to ctx have the same underlying condition as the rtx responders ? If not then maybe combo therapy might not be so useful ?

It would be equally useful to know if All the rtx responders who relapsed also responded to ctx. This might be evidence that the underlying condition is indeed the same but the drugs work in different ways.

But I dont know enough even to speculate all I can do is ask questions
 

Kati

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It's an obvious question and I think we'd all like to know. However I think it's more important to know the mechanism by which these drugs are working first. Do the rtx non responders who ( allegedly ) respond to ctx have the same underlying condition as the rtx responders ? If not then maybe combo therapy might not be so useful ?

It would be equally useful to know if All the rtx responders who relapsed also responded to ctx. This might be evidence that the underlying condition is indeed the same but the drugs work in different ways.

But I dont know enough even to speculate all I can do is ask questions
Waiting for results and for the next steps, (and hoping the next step gets funded too) is what gets to me. Patience is what's needed here, but at the same time, in my opiniont there should be clinical trials happening on all continents, not just Norway.
 
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