New Rituximab ME/CFS open-label phase II study with rituximab maintenance treatment

[girlinthesnow]

Anecdotal, but a friend aged mid 50's was given Rituximab along with other treatment for his non-Hodgkins Lymphoma. I asked him about symptoms and he felt it was benign, compared to the other drugs he was given. He is now very well, has taken early retirement and spends his days kite surfing. He has the energy of a 20 year old.

 

[alex3619]

The reason I ask is if the problems with post cancer fatigue and ME are similar than Rituximab might treat both.

 

[Kati]

Something that occurred to me just a few minutes ago, what do we know about rates of post cancer fatigue after Rituximab for lymphoma?

Answering as a former chemo nurse

Alex, the thing is Rituximab is very seldom used as a single agent for lymphoma unless it is used for remission maintenance following 4-5 chemo agents for an intensive 6 months. One could not be able to single out which agent causes fatigue but my best guess would be the most caustic agents, on top of the compounding effect of all the drugs hitting the system at the same time as being the culprit.

Many reasons could cause fatigue following chemo therapy. It would be safe to say the higher doses of chemo regimens causing higher rates of post chemo fatigue, for instance with high dose chemo required for bone marrow transplants. It could also signify in some cases that the cancer has not been eradicated and it will usually clue the oncologist to perform follow-up imaging as needed.

Eta it is not everyone who expericence lingering debilitating fatigue following chemotherapy. Some manage quite well while others remain debilitated.

 

[Simon]

From the minutes of the July CMRC Board meeting:

Rituximab: Reference was made to the Phase II open label observational trial publication led by Norwegian researchers. Phase III multi-centre trial is underway and they have almost finished recruiting although the trial won’t conclude and publication until 2017/8. B cell status function study being undertaken in the UK, funded by Invest in M.E. and it is anticipated that there will be a small trial following this. The Board felt that a large, randomised controlled trial is needed in the UK and there is mainstream funding which could be applied for; a good quality application would be an attractive proposition for one or two of them.

I'm assuming that @charles shepherd raised this: thank you, Charles. I hope that the Board actively pursues this.

 

[Sasha]

From the minutes of the July CMRC Board meeting:

I'm assuming that @charles shepherd raised this: thank you, Charles. I hope that the board actively pursue this.

Yes, me too - hard to overstate the importance of this.

 

[Battery Muncher]

From the minutes of the July CMRC Board meeting:

I'm assuming that @charles shepherd raised this: thank you, Charles. I hope that the board actively pursue this.

Outstanding work @charles shepherd , I too hope that the board will pursue this.

 

[JamBob]

Thanks @charles shepherd - great work!

 

[cigana]

From the minutes of the July CMRC Board meeting:

I'm assuming that @charles shepherd raised this: thank you, Charles. I hope that the Board actively pursues this.

Excellent news, thank you indeed Charles Shepherd!
Do we know which people are on this board? I am wondering how many of them are pyschiatrists, it would be interesting to know how many of them supported this motion...

 

[Scarecrow]

@cigana

The minutes listing those involved are here.

http://forums.phoenixrising.me/inde...ard-incl-peter-white.37888/page-2#post-620437

AFAIK, the only psychiatrist is Carmine Pariante, who has just joined the board. If you look at the list pages of this document you will see research he has recently been involved in. Trouble is, they used Hep C patients treated with interferon-alpha, which is known to induce fatigue, as a model for CFS.

We're waiting for confirmation about Mark Edwards, another new member, but he is is believed to be a neurologist with a particular interest in functional disorders. Make of that what you will.

@charles shepherd will be able to confirm the executive board members. IIRC some people are there in the capacity of observers and don't have voting rights.

 

[greeneagledown]

Hate to over-analyze this study, but it's so encouraging that I keep coming back to it and digging into the data.

I'd previously noticed that 3 of the 7 "mega-responders" got ME/CFS following a mono infection as a teen. Now I've noticed that leaving aside the mono observation, 6 of the 7 mega-responders first got ME/CFS between ages 13 and 18 -- a pretty small age range. So while the rest of the treated patients (21 of them) were fairly heterogeneous age-wise, the mega-responder group was entirely composed of people who got ME in the same tiny age range, except for 1 patient who got it at age 33.

Again, we are talking about a very small sample size and an uncontrolled study, so this could easily be a quirk that is the result of mere randomness.

 

[leokitten]

I know everyone is very excited about this study and possibly extrapolating which types of PWME are most likely to benefit from rituximab - I don't know if I'm the first person in this thread to say this but I've read quite a few posts similar to the one above and I don't want to disappoint people but you absolutely cannot draw any reliable conclusions from a study with such a tiny sample size, there is just no statistical power and therefore no correlations like this can be made. If they could with any statistical significance the authors would've have done so themselves.

 

[greeneagledown]

I know everyone is very excited about this study and possibly extrapolating which types of PWME are most likely to benefit from rituximab - I don't know if I'm the first person in this thread to say this but I've read quite a few posts similar to the one above and I don't want to disappoint people but you absolutely cannot draw any reliable conclusions from a study with such a tiny sample size, there is just no statistical power and therefore no correlations like this can be made. If they could with any statistical significance the authors would've have done so themselves.

Certainly there are limitations, which I already pointed out. And I'm definitely not saying we can "draw conclusions." I will say that simply as a statistical matter, small sample sizes can be overcome by large effect sizes. For example, the p-value on the 3 mono teens versus all the rest of the patients who were not mono teens was very impressive despite the sample size being so tiny (see Simon's earlier post). But, of course, there's more to drawing conclusions than p-values.

I don't think it's unreasonable, even at this early juncture, to start thinking out loud about which groups might be more likely to benefit.

 

[user9876]

I know everyone is very excited about this study and possibly extrapolating which types of PWME are most likely to benefit from rituximab - I don't know if I'm the first person in this thread to say this but I've read quite a few posts similar to the one above and I don't want to disappoint people but you absolutely cannot draw any reliable conclusions from a study with such a tiny sample size, there is just no statistical power and therefore no correlations like this can be made. If they could with any statistical significance the authors would've have done so themselves.

Sometimes we shouldn't take stats too seriously. They are a tool for investigating rather than an end in their own right. The nice thing about the Rituximab work is it has large effects with some people and seems to follow the dynamics associated with auto-immune disease. From the sample size I would argue that it says its likely to work with a proportion of patients. I don't see how small samples can give a great quantitative proportion.

Stats can help us understand and gain a glimpse on a mechanism but we shouldn't substitute trying to understand why and how for significance testing or more esoteric stats.

 

[leokitten]

Sometimes we shouldn't take stats too seriously. They are a tool for investigating rather than an end in their own right. The nice thing about the Rituximab work is it has large effects with some people and seems to follow the dynamics associated with auto-immune disease. From the sample size I would argue that it says its likely to work with a proportion of patients. I don't see how small samples can give a great quantitative proportion.

Stats can help us understand and gain a glimpse on a mechanism but we shouldn't substitute trying to understand why and how for significance testing or more esoteric stats.

Totally agree, sorry I wrote my post very quickly I think it got misunderstood - I should have clarified that I meant we absolutely cannot draw any conclusions as to the types of PWME that are most likely to benefit from this study. But yes we can reliably say that from this study and the previous phase II RCT that a significant proportion of PWME will likely get benefit from rituximab.

 

[bel canto]

@JamBob, have you seen the thread?
Autoantibodies research in POTS: promising or not? (sorry, don't know how to link)

eg

http://www.dysautonomiainternational.org/page.php?ID=200

Dysautonomia International Announces $200,000 Research Grant
to Study Often Misdiagnosed Neurological Condition

EAST MORICHES, NEW YORK (February 12, 2015) - Dysautonomia International, a not-for-profit patient advocacy organization focused on disorders of the autonomic nervous system, has awarded a three-year $200,000 grant to Dr. David C. Kem at the University of Oklahoma to support innovative new research on postural orthostatic tachycardia syndrome (POTS). The $200,000 grant is the largest private grant ever awarded for POTS research.

POTS is a debilitating neurological condition that impacts an estimated 1-3 million Americans; 85% are young women between the ages of 12 and 40. POTS is often misdiagnosed, resulting in an average six-year diagnostic delay. There is currently no cure for POTS, and few effective treatments, but Dysautonomia International is seeking to change that.

Dr. Kem is a George Lynn Cross Research Professor of Medicine at the University of Oklahoma Health Sciences Center and Oklahoma VA Medical Center. Last year Dr. Kem's research team, working with researchers at Vanderbilt University, identified adrenergic receptor antibodies that they believe may be contributing to symptoms in some POTS patients, providing evidence that POTS may be an autoimmune disease (when your immune system attacks your own body). This grant will allow Dr. Kem's team to continue their pursuit to develop a blood test for these antibodies that could potentially be used to help diagnose POTS, and to develop new treatment options targeting these antibodies. "We're researching potential drug therapies that may be used to block and inhibit production of these autoantibodies, and thereby lesson their burden on the patient," says Dr. Kem.

The grant was made possible by a donor family that wishes to remain anonymous, whose daughter has POTS and an inherited connective tissue disorder known as Ehlers-Danlos syndrome, which is found in approximately 30% of POTS patients. She has also tested positive for some of the antibodies involved in this research. The three-year post-doctoral fellowship position created with the funding will be named the "Meghan's Hope POTS Research Fellowship" in honor of their daughter.
​

In my experience, POTS and NMH blur into one another - my heart rate and blood pressure are just generally not working right.

This statistic re: POTS occurence has always interested me. If the incidence is disproportionately younger women - what does that mean? A couple of ideas: for some reason diagnostic procedures are more likely to be done in younger women than older or the incidence is rising significantly in the younger population, or women with POTS have shorter lifespans. Anyone have any ideas?

 

[user9876]

Totally agree, sorry I wrote my post very quickly I think it got misunderstood - I should have clarified that I meant we absolutely cannot draw any conclusions as to the types of PWME that are most likely to benefit from this study. But yes we can reliably say that from this study and the previous phase II RCT that a significant proportion of PWME will likely get benefit from rituximab.

Probably me not following the thread.

I worry about the notion of defining types of PWME without a better understanding of the disease. We could cluster people by symptoms, triggers etc but we don't really know if they have any meaning. Even with distinct clusters subgrouping is speculation and if clusters merge into each other is would feel not well founded.

Maybe the type of PWME that rituximab would work on are those that it works on. Ok thats a tautology but if the way it works implies a mechanism but its the only way we have to look at that mechanism that is all we are left with.

Detailed blood work and brain scan info would be interesting to look at since something like the brain scans suggests Microglia activation which could also imply mechanism.

 

[dannybex]

...I base this assumption on a scenario whereby we wait for the (hopefully positive) results of the phase 3 Norwegian trial in 2017/2018, then set about organising a phase 3 clinical trial here, and hope that others may follow suit.

This will take another 2 to 3 years to plan, set up, carry out, and analyse the results.

Which takes us up to 2021 or 2022...…

A long time to wait!

I went to a talk given by Dr. David Bell, whom I'm sure you're familiar with, and while he too was excited by the results so far from the Rituximab studies, he thought it might take '20-30' years before it's approved by the FDA here in America.

Maybe he was exaggerating, or just speaking from 30 years experience w/fighting to get ME/CFS taken seriously. I can't imagine it would take that long, but wouldn't be surprised if it takes at least 10-15. Time will tell...

 

[Seanko]

Going back to the Fluge & Mella hypothesis on how Rituimab could work with ME/CFS...

New Scientist Summary of Paper

"The researchers think the body’s own antibodies are to blame...An infection may trigger the body to produce antibodies that then turn against a person’s own tissues,...His team suspect that these antibodies may stop blood from circulating properly...preventing people from getting enough oxygen, explaining their extreme fatigue...We think the antibodies target the blood vessel system, because patients have very low anaerobic pressure, and produce waste lactate earlier, which stops muscles working"

Assuming the hypothesis is correct

Could there be other ways of

i) wiping out the rogue antibodies?

ii) increasing anaerobic pressure

iii) reducing lactate?

Apologies if these questions have been asked before...it is difficult to search through 12 pages of comments with brain fog. Thank you for understanding!

 

[Sasha]

What is anaerobic pressure?

 

[Seanko]

Anaerobic threshold/ lactate threshold = anaerobic pressure?

The lactate threshold (LT) or anaerobic threshold (AT) is the exercise intensity at which lactate (more specifically, lactic acid) starts to accumulate in the blood stream.