What are the other mechanisms by which RTX might be working?

[Kati]

Given its risk profile, it seems like cyclophosphamide isn't going to be worth using at all in CFS if it's not going to produce long remissions. Even if it leads to remissions lasting for a year or two, it seems like it would be exceedingly dangerous for someone to do a 6-month, 6-infusion cycle every one or two years -- so dangerous that it's not really an option.

That's your opinion, but you will find out there are people desperate for relief of their symptoms out there. In the oncology world and in rheumatology both drugs are given on a very regular basis for both patient groups.

Many people out here opt for lighter and more natural treatments, which is fine, however I would not discount the very important work that Dr Fluge and Mella are doing in running these trials to truly find out whether both these treatments are valuable for patients with ME. It sounds like so far the answer is yes.

Thanks for their willingness and curiosity, these drugs might well be the first in line for FDA approved treatments, because Ampligen is sadly still being stalled. Getting FDA approved treatments is a huge deal for a disease, it's like giving big pharma permission to do drug development.

 

[nandixon]

Just thinking out loud here.

In their ME/CFS cyclophosphamide study, the Norwegians appear to be using standard cancer therapy-type intermittent IV dosing of 600-700mg/m2.

If I understand correctly, for the more risky* continuous daily oral dosing regimen, the amount of cyclo might be as little as about 1/10 to 1/5 that amount. [*Due to bladder cystitis and cancer concerns from the cyclo metabolite acrolein.]

However, if we got (really) "lucky," and it turns out that Tregs are somehow contributing substantially to the underlying problem in ME/CFS, then based on the selective susceptibility that Tregs have to cyclo, the IV or oral dose might be able to be greatly reduced, possibly even to 1/100 the usual amount for cancer.

So a daily oral dose of cyclo on the order of less than 5mg per day for treatment might not be out of the question, in theory. And that small an amount might have very little toxicity concerns, even if taken indefinitely.

Again, this is just hypothetical.

 

[Jonathan Edwards]

Just thinking out loud here.

In their ME/CFS cyclophosphamide study, the Norwegians appear to be using standard cancer therapy-type intermittent IV dosing of 600-700mg/m2.

If I understand correctly, for the more risky* continuous daily oral dosing regimen, the amount of cyclo might be as little as about 1/10 to 1/5 that amount. [*Due to bladder cystitis and cancer concerns from the cyclo metabolite acrolein.]

However, if we got (really) "lucky," and it turns out that Tregs are somehow contributing substantially to the underlying problem in ME/CFS, then based on the selective susceptibility that Tregs have to cyclo, the IV or oral dose might be able to be greatly reduced, possibly even to 1/100 the usual amount for cancer.

So a daily oral dose of cyclo on the order of less than 5mg per day for treatment might not be out of the question, in theory. And that small an amount might have very little toxicity concerns, even if taken indefinitely.

Again, this is just hypothetical.

I am a bit sceptical about cyclo having a preferential effect on Treg. Everyone wants to find something that makes Treg important now because they are trendy and you get grants for them. Generally speaking Tregs are supposed to be good guys in autoimmune or autoinflammatory responses anyway.

Treg may be more sensitive from not having a transporter but they may be less sensitive for other reasons. My understanding has always been that cyclo kills a lot more B cells than T cells. However, the number of cells dying may be a red herring. Cyclo, like steroids, is good at inducing death in cells that may be likely to die by apoptosis pretty soon anyway. So much of the cell death may be just clearing out the garbage a bit earlier. Also, these cells vary in susceptibility to dying according to which compartment they are in. They use molecules like bcl2 to regulate their death susceptibility. Sometimes they sit tight and protect themselves. Sometimes they go and play Russian roulette in a follicle centre.

I think the problem with reducing the dose below the rheumatological dose is that you would end up just killing all the cells that were going to die anyway. The total dose of cyclo with an oral regimen is not so very different from the IV regimen because you give it more often - maybe 100-150mg per dose. Hardly anybody uses oral dosing except for maybe myeloma these days I think.

 

[deleder2k]

Ann Rheum Dis.

2015 Jun;74(6):1195-201. doi: 10.1136/annrheumdis-2013-204544. Epub 2014 Jan 17.
An extra dose of rituximab improves clinical response in rheumatoid arthritis patients with initial incomplete B cell depletion: a randomised controlled trial.
Vital EM1, Dass S1, Buch MH1, Rawstron AC2, Emery P1.
Author information

Abstract
OBJECTIVES:
Since clinical non-response to 2×1000 mg rituximab has previously been found to be associated with incomplete B cell depletion, we determined, in a randomised controlled proof of concept study, whether patients with initial incomplete B cell depletion would benefit from an additional infusion of rituximab at week 4.

METHODS:
Patients with active rheumatoid arthritis despite methotrexate received a first infusion of rituximab 1000 mg and were tested for persistent B cells using highly sensitive flow cytometry on day 15. All received a second infusion of 1 g (according to license), but patients with persistent B cells were subsequently randomised double-blind to receive, 2 weeks later, either a third infusion of 1000 mg rituximab or placebo. Clinical response was determined by European League Against Rheumatism (EULAR) and American College of Rheumatology (ACR) criteria.

RESULTS:
Baseline characteristics were balanced between groups. Treatment with 3×1000 mg rituximab resulted in significantly greater depletion (lower B cell and plasmablast numbers between 8 and 28 weeks) paralleled by significantly better EULAR and ACR20 response rates at 40 weeks (p=0.035 and p=0.027, respectively) and 52 weeks (p=0.021 and p=0.043, respectively) compared with 2×1000 mg. Immunoglobulin titres remained stable in both arms, and adverse event rates were balanced.

CONCLUSIONS:
In rituximab-treated patients with incomplete B cell depletion (predictive of poor response), an extra 1000 mg infusion of rituximab at 4 weeks produced both better depletion and clinical responses than placebo with no worsening of safety. Degree of depletion is an important, but modifiable, determinant of response.

Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.

http://www.ncbi.nlm.nih.gov/pubmed/24443001


@Jonathan Edwards, what do you think of this study? Could this be related to Fluge and Mella's studies on RTX in ME? They give 500 mg/m^2 in the first to rounds, i.e max of 2g during the two first rounds. Could an extra round of Roche's Rituximab help improve the outcome of patients that do not undergo a complete B-cell depletion? I am not sure what they mean by "predictive of poor response" - could it be the count of CD27+ cells?

 

[Jonathan Edwards]

http://www.ncbi.nlm.nih.gov/pubmed/24443001


@Jonathan Edwards, what do you think of this study? Could this be related to Fluge and Mella's studies on RTX in ME? They give 500 mg/m^2 in the first to rounds, i.e max of 2g during the two first rounds. Could an extra round of Roche's Rituximab help improve the outcome of patients that do not undergo a complete B-cell depletion? I am not sure what they mean by "predictive of poor response" - could it be the count of CD27+ cells?

This group showed that some patients have slightly more B cells left than others after standard dosages. Giving a third 1000mg dose at 4 weeks seems to have improved responses a bit (they give rather feeble p values and no actual data in the abstract). This suggests that the standard dose is not right at the top of the dose response curve, but we already knew the curve was likely to have a rather gradual slope. The question is whether it is good value for money giving more at 4 weeks or whether it might be even better to save that up for a 3 month maintenance shot like F and M are doing. I don't think the data were strong enough here to persuade anyone to change the standard dosing regimen.

Giving a bit more than F and M in ME might be useful but I think we want to get confirmation of primary efficacy first before playing around with higher doses. The budget has a limit and I think it would be better to use the drug for studying more patients in other ways rather than trying to push the response rate up marginally when it is a bit difficult to measure anyway.

 

[deleder2k]

Thank you for your answer.

(figure 2)



Figure 2 Proportion of patients with detectable B cells of any lineage. Brackets with p values indicate results of univariate binary logistic regression comparing B cell status for each group.

p=0.009

I hope Fluge and Mella have an idea to kill memory b-cells better than Rituximab does. They believe that the elimination of B-cells plays a role in which patients are likely to be responders/non responders.

 

[Jonathan Edwards]

Thank you for your answer.

I hope Fluge and Mella have an idea to kill memory b-cells better than Rituximab does. They believe that the elimination of B-cells plays a role in which patients are likely to be responders/non responders.

I get the impression from the graphs that what they are showing is that three doses instead of two leads to a further gradual wipe out of B cells over about three months. So it looks as if the effect may have more to do with the longer time rituximab is in the circulation with the higher dose. That makes me think that if keeping levels up over several months is the key then F and M are doing the more sensible thing with topping up at 3 months and 6 months. I find the Vital study quite hard to interpret - as I did when it first appeared.

It is very likely that killing more memory B cells in lymphoid follicles would be good. The new antibodies may do that. But the impression from other diseases is that if B cell depletion is a good strategy at least rituximab does a reasonable job in the medium term.

 

[deleder2k]

That is particularly interesting. It looks like the result from Fluge and Mella's new study with 6 infusions compared to two in their first study shows that patients stay in remission for a longer time. It will be interesting to have a look at how many patients that are still in remission at 3 years follow-up.

The new antibodies look very interesting, but it seems to me that we are years before they get approved by EMA/FDA(?). In the meantime I think they are looking into if some drugs that are available now are better at killing B-memory cells (Obinutuzumab for instance).

I think we have also discussed mycophenolate mofetil (MMF). This is from a study called "Mycophenolic acid counteracts B cell proliferation and plasmablast formation in patients with systemic lupus erythematosus."

Absolute numbers of CD27+IgD+ pre-switched memory B cells (C) were significantly lower in patients taking AZA compared to patients without IS. However, absolute numbers of CD27+IgD- post-switched memory B cells did not differ significantly (D). Patients taking AZA had the highest, and patients taking MMF the lowest frequency of CD27+IgD- post-switched memory B cells (D). Median values are shown: statistically significant differences were detected comparing patients on AZA and MMF (*P < 0.05, **P < 0.01, ***P < 0.001) or patients on AZA (§P < 0.5, §§P < 0.01, §§§P < 0.001) or patients on MMF (#P < 0.05, ##P < 0.01, ###P < 0.001) to patients without immunosuppressive therapy (Dunn's multiple comparison test).

Could this mean that we can drop MMF into the mix?

 

[Jonathan Edwards]

That is particularly interesting. It looks like the result from Fluge and Mella's new study with 6 infusions compared to two in their first study shows that patients stay in remission for a longer time. It will be interesting to have a look at how many patients that are still in remission at 3 years follow-up.

The new antibodies look very interesting, but it seems to me that we are years before they get approved by EMA/FDA(?). In the meantime I think they are looking into if some drugs that are available now are better at killing B-memory cells (Obinutuzumab for instance).

I think we have also discussed mycophenolate mofetil (MMF). This is from a study called "Mycophenolic acid counteracts B cell proliferation and plasmablast formation in patients with systemic lupus erythematosus."

Could this mean that we can drop MMF into the mix?

In those plots MMF does not look very different from controls. I think MMF could have important potential because in combination with one of the antibodies (?belimumab) it produced profound hypogammaglobulinaemia, suggesting a way of clearing out plasma cells that otherwise seem to be immovable. The trouble is that clinicians don;t like to see hypogammaglobulinemia and I suspect the combination was not pursued.

All interesting possibilities.

 

[greeneagledown]

That's your opinion, but you will find out there are people desperate for relief of their symptoms out there. In the oncology world and in rheumatology both drugs are given on a very regular basis for both patient groups.

I don't think cyclophosphamide infusions are given yearly in either cancer or rheumatology. I think those patients are given one infusion regimen that is similar to what F&M are doing in CFS and then hopefully they go into long-term remission. Fluge & Mella are probably hoping to use it the same way in CFS -- hopefully one 6-infusion regimen sends some patients into long-term remission. I don't think they envision putting patients on a regimen where they get 6 infusions over 6 months every year or two, except maybe for very severely ill, bed-bound patients. Even one cycle of this drug is highly carcinogenic, so taking 6 infusions every year or two seems incredibly dangerous, and like I said, I don't think it's used that way in other diseases.

@deleder2k, what are your thoughts on the above?

Rituximab is a different story. It's much safer than cyclo.

 

[deleder2k]

I have no clue. All that I know is that I heard some of the patients stayed in remission for at least 6 months after their last cyclo infusion. I think they hope that they won't have a relapse. I don't know how likely that is.

 

[Kati]

I don't think cyclophosphamide infusions are given yearly in either cancer or rheumatology. I think those patients are given one infusion regimen that is similar to what F&M are doing in CFS and then hopefully they go into long-term remission. Fluge & Mella are probably hoping to use it the same way in CFS -- hopefully one 6-infusion regimen sends some patients into long-term remission. I don't think they envision putting patients on a regimen where they get 6 infusions over 6 months every year or two, except maybe for very severely ill, bed-bound patients. Even one cycle of this drug is highly carcinogenic, so taking 6 infusions every year or two seems incredibly dangerous, and like I said, I don't think it's used that way in other diseases.

@deleder2k, what are your thoughts on the above?

Rituximab is a different story. It's much safer than cyclo.

You misunderstood what I said. I meant that these doctors were very experienced in prescribing these chemo drugs for their respective patient population.

 

[Snow Leopard]

The justification for strong drugs like cyclo depends on the severity of the illness. Eg if the person is stuck in bed all day, then the risk of not doing anything at all is large, hence greater justification.

 

[BurnA]

I don't think cyclophosphamide infusions are given yearly in either cancer or rheumatology. I think those patients are given one infusion regimen that is similar to what F&M are doing in CFS and then hopefully they go into long-term remission. Fluge & Mella are probably hoping to use it the same way in CFS -- hopefully one 6-infusion regimen sends some patients into long-term remission. I don't think they envision putting patients on a regimen where they get 6 infusions over 6 months every year or two, except maybe for very severely ill, bed-bound patients. Even one cycle of this drug is highly carcinogenic, so taking 6 infusions every year or two seems incredibly dangerous, and like I said, I don't think it's used that way in other diseases.

@deleder2k, what are your thoughts on the above?

Rituximab is a different story. It's much safer than cyclo.

Do we have any information on the original cancer patients who received cyclo and how long their remissions lasted ?

At the IIME conference Olav Mella spoke about Cyclo potentially becoming the prefferred treatment option due to cost - ( after he joked about potentially ruining the RTX phase III trial with the cyclo trial )
Would he have said these if the remission rates were poor or if he didn't expect significant responses or am I trying to read too much ?

 

[MeSci]

like @cigna and others, I find this hypotheses very intriguing. i've always been struck by the "hypersensitivity" aspect of ME/CFS. Off the top of my head I can think of hypersensitivities to mold, various types of food, sound, light, temperature, odors, exertion, and a few more....

Apologies if this has already been mentioned but I am behind on this thread. It has occurred to me that at least some of the hypersensitivities may be due to a slowness of our autonomic (corrective) responses. For example, with temperature - or at least perceived temperature, I go from feeling too cold from feeling too hot. It's not just feeling cold and hot in fact, but the autonomic responses, so within minutes I go from having goosebumps to sweating. I 'overshoot' the ideal perceived temperature. We often have a slowness in other areas too, such as thinking and moving.

With chemical sensitivity, which many of us have, could this be due to us being too slow to excrete the offending substances, or to turn down our responses? With light sensitivity, is this due to a failure to adjust the pupils quickly enough or sufficiently? With exertion, it feels to me as though I am failing to cool myself down adequately so quickly become overheated. Just speeding up slightly and briefly trying to pay for goods at the till in a shop often brings me out in profuse sweat, which is quite embarrassing as well as debilitating.

This may not be directly relevant to the subject of this thread, so apologies for that.

 

[MeSci]

Apologies if this has already been mentioned but I am behind on this thread. It has occurred to me that at least some of the hypersensitivities may be due to a slowness of our autonomic (corrective) responses. For example, with temperature - or at least perceived temperature, I go from feeling too cold from feeling too hot. It's not just feeling cold and hot in fact, but the autonomic responses, so within minutes I go from having goosebumps to sweating. I 'overshoot' the ideal perceived temperature. We often have a slowness in other areas too, such as thinking and moving.

With chemical sensitivity, which many of us have, could this be due to us being too slow to excrete the offending substances, or to turn down our responses? With light sensitivity, is this due to a failure to adjust the pupils quickly enough or sufficiently? With exertion, it feels to me as though I am failing to cool myself down adequately so quickly become overheated. Just speeding up slightly and briefly trying to pay for goods at the till in a shop often brings me out in profuse sweat, which is quite embarrassing as well as debilitating.

This may not be directly relevant to the subject of this thread, so apologies for that.

Answering myself here - maybe I should refrain from posting until my brain has woken up properly. I think I grasp that the hypersensitivities are being posited to result from stimuli like those I have mentioned above causing a surge in 'rough-and-ready' antibodies, and we are reacting to those. How does that fit in with a failure of autonomic corrective processes, or doesn't it?

 

[MeSci]

I am now thinking about connections with other theories, notably the gating theories which posit that the cells which normally keep (sensory) input to a manageable level are defective in ME, so that we get overwhelmed by stimuli.

Perhaps it is more that the actual stimuli are greatly increased (such as these 'rough-and-ready' antibodies and their consequences - inflammation?), so that our cells, etc. are in fact forced to be hyperactive trying to combat them. Maybe there is so much of this detrimental activity/stimulation going on that even a healthy person would struggle to cope with it.

I have a new slogan coming to mind...something like "I may seem inactive, but on a molecular level I am incredibly busy!"

Or has that one been done?

 

[lansbergen]

With light sensitivity, is this due to a failure to adjust the pupils quickly enough or sufficiently?

Mine certainly is a pupilreflex problem.

 

[lansbergen]

I have a new slogan coming to mind...something like "I may seem inactive, but on a molecular level I am incredibly busy!"

Or has that one been done?

I think a member has it in the signature.

 

[lansbergen]

With light sensitivity, is this due to a failure to adjust the pupils quickly enough or sufficiently?

Mine certainly is a pupilreflex problem