Dr Bieger and Dr Mikovits discuss treating ME patients with Rituximab

[Marky90]

Well what we can say is that cases like Bodden is probably extremely rare, based on the sole fact that something likewise has not occured in the norwegian ritux-studies.

It would be great if the treatment differences between the norwegians and germans could be explained somehow. It might just be chance, or it might be due to dosage. Or disease severity etc etc

 

[deleder2k]

That's what I was thinking. But many CFS patients with low NK function AND reduced antibodies don't seem to be prone to infections at all - more the opposite.

What about the Norwegian RTX trial(s) - were low NK function and/or hypogammaglobulinemia exclusion criteria? @deleder2k, do you know?

I know hypogammaglobulinemia is.

• Known immunodeficiency with risk from therapeutic B-cell depletion, such as hypogammaglobulinemia

You can read more about the exclusion criterias here: https://clinicaltrials.gov/ct2/show/NCT02229942

 

[DanME]

Well what we can say is that cases like Bodden is probably extremely rare, based on the sole fact that something likewise has not occured in the norwegian ritux-studies.

It would be great if the treatment differences between the norwegians and germans could be explained somehow. It might just be chance, or it might be due to dosage. Or disease severity etc etc

Yes, I agree! It seems to be a rare phenomenon. And we still don't know, what really happened to Bodden in the physiological sense. It is hard to explain until we don't know the underlying pathophysiology of ME.

As far as I know, nothing similar happened during the Norwegian studies and I am sure Fluge and Mella wouldn't go on with their RTX treatment, if cases of worsening were not the rare exception.

Also I want to point out, that most drugs for serious diseases are not without risks. The doctor's job is to decide, if the potential benefits outweigh the potential risks. That's why, it is so important, that Norway is currently conducting the Phase III study with over 150 patients.

 

[deleder2k]

I got the impression these cases were treated by other doctor(s) in Germany. I understand that Dr K has also been using rituximab for some patients in the States. I think if this treatment worked for ME/CFS (in the real world outside of clinical trial mysteries) we'd have heard about all these remissions if there were any. The problem is we don't know what this disease is and until we find out more about it and its possible subsets, jumping to radical treatments is bound to lead to some tragic outcomes like the German patient.

I know several people that have or are being treated by Kogelnik. Many of them got their life back. Kogelnik says that 2/3 of his patients have an effect - the same proportion of patients that got better in the Double-blind placebo-controlled study at Haukeland ( http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0026358 ). A study like this is not a myth. Myths like this don't happen in good blinded RCT's. Remember that they have treated more patients with RTX. After a successful pilot study on Cyclophosphamide has lead them to start a phase 2 study. These guys don't joke around. Too bad it takes years to do this in a proper way.

 

[Jonathan Edwards]

It may be useful for people to know that there is a good reason for not giving rituximab in a low dose. Rituximab is chimaeric antibody, part mouse part human, which is what the (xi) stands for. Most chimaeric antibodies lose effectiveness fairly soon becuase of an immune or allergic response to the drug (HACA response). Rituximab is unique in that its mode of action involves killing all the B cells that might create a HACA antibody response - it is sort of self protecting. Probably because of this we have been able to use rituximab for at least 12 years repeatedly when needed with virtually no problems from HACA reactions.

If a low dose is given then not all B cells will be killed and a HACA response would be expected to be common. Moreover, since the ida is to block the formation of any new disease antibodies there is no particular logic in giving a dose that dose not achieve this. For this reason rituximab is one of the few drugs for which a reduced dose does not seem to have any justification.

 

[deleder2k]

What about other drugs as the humanised version of Rituximab, Ofatumumab. Could a small dose be beneficial since it is 100% human?


But do Roche and others really know how much one need to use? I recall you said that one "just used what was left in the freezer" if I am not mistaken. I have heard stories from India where they use 100mg/m2, instead of 500mg/m2. Apparently with good results.

 

[wastwater]

I'm still more interested in whether there are retroviruses involved,and would high levels of reverse transcriptase be a good indicator? I felt the science moved on to thinking around HERVs

 

[DanME]

Isn't the main goal to destroy as many B cells as possible to avoid them becoming plasma cells, which then go on with producing problematic auto antibodies? So the moment the "bad" plasma cells die, they cannot be replaced by younger B Cells and the auto antibody cycle is stopped?

Maybe 100mg/m2 is enough to achieve that. But if I understood Mikovits correctly, she just wants to lower the B Cell amount, which makes no sense in relation to antibody production.

 

[Jonathan Edwards]

What about other drugs as the humanised version of Rituximab, Ofatumumab. Could a small dose be beneficial since it is 100% human?

But do Roche and others really know how much one need to use? I recall you said that one "just used what was left in the freezer" if I am not mistaken. I have heard stories from India where they use 100mg/m2, instead of 500mg/m2. Apparently with good results.

In fact fully humanised monoclonals have not proved to be necessarily much freer of immune responses than chimaerics. You get a HAHA or human antihuman antibody response which is to the antigen binding part of the monoclonal that is a unique (and therefore 'foreign') sequence for all monoclonals. Adalimumab produces reactions although maybe not quite as much as infliximab. So probably the argument for not giving low doses of anti-B cell antibodies is more general.

You are right that we do not really know what a 'low' dose is - which I guess makes the suggestion of using a low dose even more peculiar. But where we have information it seems that to get a good clinical response you want to see >98% B cell clearance from circulation. There are data from Birmingham suggesting that benefit correlates with even more stringent depletion. A half dose (500mg x 2) trial arm in RA seemed to slightly less effective. When I used half or quarter doses in pilot studies results were poor but numbers were small. I have a feeling that it may be possible to get reasonably comparable results to Igm x2 (standard) with half dose or even less in some conditions but all the signs we have seem to suggest going down to a sub-depleting dose is unwise. In lupus inadequate depletion is common and so are HACA responses.

So you are right, it is all uncertain, but I do not see any logic in deliberately going for a low dose. Most of the adverse reactions are seen with the first 100mg of the first infusion anyway.

 

[Jonathan Edwards]

Isn't the main goal to destroy as many B cells as possible to avoid them becoming plasma cells, which then go on with producing problematic auto antibodies? So the moment the "bad" plasma cells die, they cannot be replaced by younger B Cells and the auto antibody cycle is stopped?

Maybe 100mg/m2 is enough to achieve that. But if I understood Mikovits correctly, she just wants to lower the B Cell amount, which makes no sense in relation to antibody production.

Precisely.

 

[Sidereal]

A study like this is not a myth. Myths like this don't happen in good blinded RCT's.

If that statement were true, then you would never need to replicate a well-designed RCT because the first one would tell you The Truth and all subsequent trials would yield the same result. But they don't. Read any meta-analysis of treatments for conditions that are heterogeneous. A normal looking forest plot will show you that RCTs give results all over the place (unless the evidence base is contaminated by publication bias) and in many cases you can't explain the heterogeneity by factoring in things like study design or patient characteristics.

Well what we can say is that cases like Bodden is probably extremely rare, based on the sole fact that something likewise has not occured in the norwegian ritux-studies

Quite the opposite. If severe adverse events are rare, then studies of the sort that have been published to date are no good for detecting them. An N=3 case series of patients with ME/CFS + lymphoma and a 30 person RCT in which 15 persons received the drug is the extent of the published literature to date. The statistical probability of capturing a rare severe negative reaction like Mr Bodden's (if the rate of such an event is low in the population) in such small samples is minuscule. The current evidence base thus tells you absolutely nothing about the incidence of adverse events in the population of ME/CFS patients. Even a well-designed phase III trial will tell you little.

You generally don't find out how often a drug is harmful or kills people until it's unleashed on the general population after regulatory approval. Think black box warnings on antidepressants etc.

 

[deleder2k]

If that statement were true, then you would never need to replicate a well-designed RCT because the first one would tell you The Truth and all subsequent trials would yield the same result. But they don't. Read any meta-analysis of treatments for conditions that are heterogeneous. A normal looking forest plot will show you that RCTs give results all over the place (unless the evidence base is contaminated by publication bias) and in many cases you can't explain the heterogeneity by factoring in things like study design or patient characteristics.

I am not an expert in this field, but one can't compare a double blinded RCT to studies on say Cytokines. The study from Haukeland can and will (partly have actually) been replicated. Some information from their next study have been posted on this forum, and in general they are even more promising than before.

 

[Gijs]

Variations in FcR3A just alter the potential killing efficiency of the drug and might alter the dose required. However, it seems that the dose response curve is pretty flat and is not affected much by FcR3 variation. We looked at that right at the beginning.

I cannot see what NK function has to do with using rituximab to be honest. I am not even convinced that people are agreed on what NK defect there may be in ME/CFS. I am afraid that to me as an immunologist most of this stuff is fairy tales. Real immunology does not work like that.

She said -correct me if i am wrong- that CD20 cells are replicated in ME/CFS al the time (slowly) because NK cells don't klill them and slow them down. That is why they get cancer (lymphoma). Something like that. Mikovits must stop with ME/CFS and be quite untill she got real evidence of retroinfection. She makes things more worse. I don't take her seriously anymore. She made a very big mistake with XMRV. I think she is a very nice and good person but she must stop and get on with her life.

 

[Marky90]

If that statement were true, then you would never need to replicate a well-designed RCT because the first one would tell you The Truth and all subsequent trials would yield the same result. But they don't. Read any meta-analysis of treatments for conditions that are heterogeneous. A normal looking forest plot will show you that RCTs give results all over the place (unless the evidence base is contaminated by publication bias) and in many cases you can't explain the heterogeneity by factoring in things like study design or patient characteristics.



Quite the opposite. If severe adverse events are rare, then studies of the sort that have been published to date are no good for detecting them. An N=3 case series of patients with ME/CFS + lymphoma and a 30 person RCT in which 15 persons received the drug is the extent of the published literature to date. The statistical probability of capturing a rare severe negative reaction like Mr Bodden's (if the rate of such an event is low in the population) in such small samples is minuscule. The current evidence base thus tells you absolutely nothing about the incidence of adverse events in the population of ME/CFS patients. Even a well-designed phase III trial will tell you little.

You generally don't find out how often a drug is harmful or kills people until it's unleashed on the general population after regulatory approval. Think black box warnings on antidepressants etc.

I agree, but at least there is nothing that indicates severe effects to happen imo, based on what the drug does. Can we even be sure that Bodden got worse due to rituximab?

 

[heapsreal]

I would like to know how the 2 doctors are going, that started arv's because of xmrv, although unproven, the imune markers were changing with treatment. I wonder if the doctors think arvs work by some other mechanism?

Someone mentioned her main goal was to prove her theory was a retrovirus, i think that was down the track. I think the main goal was to try and theorize who was most likely a good fit for rituximab.

I know there were 2 Dr K patients on here who got very ill from rituxan, would be interesting to look back at their nk function etc.

I know her xmrv was withdrawan but im sure there are papers on cfsme immune dysfunction etc that were published. All her work isnt a total right off just the xmrv virus. Other than the xmrv, her resume is pretty good with her background in cancer research and HIV. Im not sure its wise to just right her off so fast. She may have made some mistakes while in the interview but gee she was jumping around like a jack rabbit, maybe nerves or just excitement, it happens, everyone doesnt it, especially so since she has come back from all the rot that went on.

I want to make sure its the right drug as its not as safe as everyone is making out. Need to nail out the sub groups and maybe find treatments to get people to be rituximab responders, just maybe improving nk function is an option?

Bone marrow stem cell transplant with chemo sound very interesting as eastern europeans have been getting good result with certain MS patient and other autoimmune diseases, maybe stem cell transplant is an option for full recovery so regular rituximab treatment isnt needed??

 

[Sherlock]

I know there were 2 Dr K patients on here who got very ill from rituxan, would be interesting to look back at their nk function etc.

They were @Jacque and @Kati

I want to make sure its the right drug as its not as safe as everyone is making out. Need to nail out the sub groups and maybe find treatments to get people to be rituximab responders, just maybe improving nk function is an option?

Bone marrow stem cell transplant with chemo sound very interesting as eastern europeans have been getting good result with certain MS patient and other autoimmune diseases, maybe stem cell transplant is an option for full recovery so regular rituximab treatment isnt needed??

In the larger world, a bone marrow transplant is far more dangerous than RTX,

 

[Sherlock]

One oddity is that Mikovits seems to say repeatedly that B cells are part of innate immunity. She seems to have a way of speaking which comes off as somewhat disordered (to me anyway), so I think she is creating some misconceptions overall about what she means.

Even so, her own slide (labeled as 'innate') seemingly says the same thing. B and T cells are in the 3rd row down, at the left.

 

[Kati]

They were @Jacque and @Kati

In the larger world, a bone marrow transplant is far more dangerous than RTX,

To be clear, I did not get very ill (or ill at all for that matter) with Rituximab. Unfortunately for whatever reasons, it didn't work on me. I really wish it worked


Absolutely agree. (Bone marrow transplant RN here)- the drugs given are near lethal. It clears the bone marrow of all stem cells. No stem cells, no immunity whatsoever. No production of white and red blood cells, or platelets.
Then the chemo given is very toxic and causes the mucosa membrane, from mouth to anus to slough off causing diarrhea, horrible mouth sores. Patients get all kinds of infections and are prone to C-diff. Not for the faint at heart. When the stem cells are infused (either autologous (your own) or someone else's, then the stemcell migrate in the bone marrow and start producint cells again. There is usually a window of 3 weeks where the patient is quite vulnerable to all kinds of dangerous events not limited to what I mentioned above.

 

[Sherlock]

This is what I think she's saying as her main contention:

Some CD20+ cells become deranged from DNA changes due to a retrovirus. The deranged CD20+ cells then begin producing and emitting autoantibodies, even though the deranged CD20+ cells have not differentiated into plasma cells as is usual.


At this point I'd ask @Jonathan Edwards: ITP can occur as secondary to lymphoma (I've seen exactly that). When such humoral autoimmunity develops, is that the way it happens? Do deranged CD20+ B cells produce antibodies while staying CD20+ (and not differentiating in the normal way into plasma cells)? The 2ndary ITP case that I'd seen did resolve after ~8 weeks of RTX.


Further guessing about her contentions: the deranged CD20+ cells proliferate because of other DNA derangements, crowding out production of normal CD20+ cells (in the marrow). So, while the total number of CD20+ cells does not increase, the deranged CD20+ cells become a greater and greater percentage of the total CD20+ population, as the normal CD20+ cells become a lesser percentage of the total CD20+ population.

Those are the CFS cases that she thinks should be treated with RTX. But why does she think that low dose RTX will help kill off the deranged CD20+ cells but not the normal CD20+ cells?

I also don't recall that she addressed proliferation of B cells in lymph nodes or lymphoid tissue, which is where lymphoma usually develops. That's also where you'd expect the humoral response to develop in the short period after RTX dosing anyway - not the marrow.

 

[DanME]

If that statement were true, then you would never need to replicate a well-designed RCT because the first one would tell you The Truth and all subsequent trials would yield the same result. But they don't. Read any meta-analysis of treatments for conditions that are heterogeneous. A normal looking forest plot will show you that RCTs give results all over the place (unless the evidence base is contaminated by publication bias) and in many cases you can't explain the heterogeneity by factoring in things like study design or patient characteristics.



Quite the opposite. If severe adverse events are rare, then studies of the sort that have been published to date are no good for detecting them. An N=3 case series of patients with ME/CFS + lymphoma and a 30 person RCT in which 15 persons received the drug is the extent of the published literature to date. The statistical probability of capturing a rare severe negative reaction like Mr Bodden's (if the rate of such an event is low in the population) in such small samples is minuscule. The current evidence base thus tells you absolutely nothing about the incidence of adverse events in the population of ME/CFS patients. Even a well-designed phase III trial will tell you little.

You generally don't find out how often a drug is harmful or kills people until it's unleashed on the general population after regulatory approval. Think black box warnings on antidepressants etc.

Generally I agree. One small blinded RCT is not enough. But replication is under way. An open Phase II study, a blinded Phase III study and sooner or later another blinded RCT in the UK. Also we don't know, if ME is really that heterogenous. Maybe we have a large subset, which is comparable in its autoimmunity.

You are right, that we need much bigger studies and a much bigger use of RTX to see the true incidence of adverse effects. But as others have already said, we don't really know, what caused the reaction, Bodden had and if it's truly a consequence of RTX used with a ME patient. We just don't have the data. Also even if there were the risk of some severe adverse effects, we would still have to see if the potential benefits outweighs the potential risks.,