Experience with Rituximab

[Gingergrrl]

That's not a formula to calculate body surface area; it's just tells you what dose to give once you have calculated the area.

For example, if someone has a body surface area of say 1.7 square meters, then the dose to be given is 1.7 x 375 mg = 638 mg.

I am so sorry to still not understand this and hoping I can phrase my question well. I'm not even trying to understand the math formula vs. I am trying to understand if the two outcomes (re: Rituximab dose) would be the same or different?

My question is: If the BSA formula (for Patient #1 who has a BSA of 1.7 as you chose) was plugged into the 375 mg formula (1.7 x 375 mg) and then the SAME Patient #1 was plugged into the 500 mg formula that Fluge and Mella used in the Phase 2 Study (1.7 x 500 mg) wouldn't they come up with two different doses in the end?

Or is there something about this particular formula in which you end up with the same dose regardless if you use 375 mg or 500 mg? This is part of what I am trying to understand re: the study.

That's right, all doses were individually tailored according to body surface area.

This is the second thing I am trying very hard to understand. If Fluge & Mella did individual dosing for ALL Rituximab infusions in Phase 2 (tailored to body surface area) but in Phase 3 they gave all patients a dose of 500 mg for infusions #3, 4, 5 & 6... then how is this the same study and how is it not a confounding variable? I am not even talking about ME/CFS but just in general for a trial. How can you make a major change in the middle of the trial but not count it as a factor that affects the results?

Talking of misdiagnosis, if the person the original poster is asking about had been ill for less than five years with suspected ME/CFS when they were found to have a cancer too, a differential diagnosis to explain responding to rituximab could be that it was a paraneoplastic syndrome occuring with Lambert Eaton's Myasthenic Syndrome instead.

@kangaSue This is an excellent point and I can't believe that I did not think of it considering that I was in the exact same situation except that no cancer has ever been found in my case... as least so far... and my illness started in Jan 2013 so I am well past the 5 year mark although the LEMS autoantibody was not found until early 2016. I have no idea if I had it prior to that b/c I had never been tested before. I suspect that a very high percentage of people with LEMS (who have the autoimmune version without cancer) are initially given a "CFS" diagnosis. Although in the groups I belong to, many are not responders to Rituximab and many take 3,4 DAP or Firdapse vs. I was a responder to Rituximab.

 

[Hip]

My question is: If the BSA formula (for Patient #1 who has a BSA of 1.7 as you chose) was plugged into the 375 mg formula (1.7 x 375 mg) and then the SAME Patient #1 was plugged into the 500 mg formula that Fluge and Mella used in the Phase 2 Study (1.7 x 500 mg) wouldn't they come up with two different doses in the end?

Or is there something about this particular formula in which you end up with the same dose regardless if you use 375 mg or 500 mg? This is part of what I am trying to understand re: the study.

Yes, they would come up with two different doses. But I don't see where the 375 mg figure comes into it. This figure does not come from the F&M studies.


The 2015 phase II study that you read, and the phase III study used almost identical rituximab dosing protocols, with very little difference between them.

So if you are looking at dosing to explain the difference between these studies, it's a non starter.


EDIT: oops, my mistake: in fact the 2015 phase II study did have higher rituximab doses during the maintenance stage, compared the phase III study.

 

[Gingergrrl]

Yes, they would come up with two different doses. But I don't see where the 375 mg figure comes into it. This figure does not come from the F&M studies.

The 375 mg is in the BSA formula that my own doctor used to calculate my dose and it is also in the (US) package insert for Rituxan (for autoimmune dosing, I do not know about cancer dosing).

I am mentioning it b/c it would mean that the doses used in the study would be even higher with the BSA formula of 500 mg (than of 375 mg) which means that most subjects did get a higher initial dose and then in Phase 3 it was cut to 500 mg for four of the infusions.

The 2015 phase II study that you read, and the phase III study used almost identical rituximab dosing protocols, with very little difference between them. So if you are looking at dosing to explain the difference between these studies, it's a non starter.

It's not a non-starter and I am actually shocked that no one else gets this and am wanting someone to explain to me where I am going wrong?!!!

I am not talking about whether or not Rituximab is effective specifically for ME/CFS (which is a different issue that we do not yet know the answer to). I am talking about that in a trial if you give a dose in Phase 2 for ALL infusions based on the BSA formula (which per your calculations of the average person was around 865 mg) but then for Phase 3, you cut the dose to 500 mg, it means that many patients did not receive a dose to effectively kill all B cells AND more importantly, the dosing regimen is no longer consistent!

It the trial was to see if Tylenol (Acetominophen) helped headaches and every patient got 1000 mg of Tylenol but then suddenly in the Phase 3 of the trial, for the last four doses, every patient only got 500 mg of Tylenol and it affected the results... how would you know if it was because Tylenol simply does not help headaches or b/c the dose was significantly reduced?

I will drop the issue here but if 600 mg is my dose of Ritux (using the BSA formula) and I am not a large person and my doctor felt that going lower than that risked NOT killing all B cells, how does this make sense? If I suddenly found out that my next Ritux infusion (on 5/3) was going to be 500 mg versus 600 mg (which is the dose I have done for seven infusions), I would be terrified and if my remission stopped, I would never know if it was b/c we lowered the dose or b/c of some other factor? But logically, I would assume it was b/c of the dose versus another random factor.

Does this make sense?

 

[Hip]

@Gingergrrl, sorry, what I said above about the dosing was wrong. I was getting confused, as I was quite tired yesterday.

Yes, the 2015 phase II study used higher rituximab maintenance doses than the phase III study.



Here are the doses used in the Fluge and Mella rituximab studies:

2011 phase II study:
Two initial rituximab infusions at 500 mg/m2 given two weeks apart.
No further follow-up infusions.

2015 phase II study:
Two initial rituximab infusions at 500 mg/m2 given two weeks apart.
Followed by 4 maintenance rituximab infusions of 500 mg/m2 at 3, 6, 10 and 15 months.

2019 phase III study:
Two initial rituximab infusions at 500 mg/m2 given two weeks apart.
Followed by 4 maintenance infusions with a fixed dose of 500 mg at 3, 6, 9 and 12 months.

 

[Gingergrrl]

EDIT: oops, my mistake: in fact the 2015 phase II study did have higher rituximab doses during the maintenance stage, compared the phase III study.

@Gingergrrl, sorry, what I said above about the dosing was wrong. I was getting confused, as I was quite tired yesterday. Yes, the 2015 phase II study used higher rituximab maintenance doses than the phase III study.

Hi @Hip, No worries and thanks for clarifying and confirming what I was seeing re: the doses. I was really starting to question myself b/c you are much more knowledgeable at math and science than I am!

This is my take on the three studies and I would love someone to prove me wrong, or just explain to me, re: the dose change between (the second) Phase 2 Study and the Phase 3 Study but so far, I haven't found anyone who has been able to. I wanted to believe this study was solid but no longer do due to the dose change (and this is just in general and not about ME/CFS). If this study were about LEMS, or any autoimmune disease, I would be questioning the results identically as I am now b/c of the dose change.

2011 phase II study:
Two initial rituximab infusions at 500 mg/m2 given two weeks apart.
No further follow-up infusions.

This first study, in my opinion, is not conclusive b/c subjects only received the loading dose (first two infusions given two weeks apart on Day 0 and Day 14) but did not receive a series of six infusions (per autoimmune protocol).

2015 phase II study:
Two initial rituximab infusions at 500 mg/m2 given two weeks apart.
Followed by 4 maintenance rituximab infusions of 500 mg/m2 at 3, 6, 10 and 15 months.

This second study, in my opinion, is solid b/c subjects not only received the series of six infusions BUT every single subject received the ideal dose for their own individual BSA (body surface area) for all six infusions. And in this study, there were some patients who had significant improvements.

2019 phase III study:
Two initial rituximab infusions at 500 mg/m2 given two weeks apart.
Followed by 4 maintenance infusions with a fixed dose of 500 mg at 3, 6, 9 and 12 months.

This third study, I have to reject b/c the dosing was reduced to only 500 mg for FOUR of the infusions, and this dose would be too low for many of the subjects (even for myself who has a BSA dose of 600 mg). So for me the results are inconclusive b/c of the dosing factor. We can say the results are a failure but the dosing is so different from the prior study (which was a success) that for me, this make it null and void.

 

[Hip]

By your argument, @Gingergrrl, the study that should get the worst results would be the 2011 phase II study, which only gave 2 initial infusions — the least amount of rituximab of all the 3 studies. But the 2011 study in fact had the highest response rate of 67%.

Response rates:

2011 phase II study response rate: 67% in the rituximab group, and 13% in the placebo group.
2015 phase II study response rate: 64% in the rituximab group.
2019 phase III study response rate: 26% in the rituximab group, and 35% in the placebo group.

 

[Gingergrrl]

By your argument, @Gingergrrl, the study that should get the worst results would be the 2011 phase II study, which only gave 2 initial infusions — the least amount of rituximab of all the 3 studies. But the 2011 study in fact had the highest response rate of 67%.

On the surface I would agree with this but if I am reading the three phases of the study correctly, the 2011 study only followed the subjects for three months and had no long term data (on that particular group of subjects). So the fact that there were only two infusions given and there was no long-term monitoring makes it inconclusive (to me).

Versus in the 2015 Study, they followed the subjects for 36 months and in the 2019 Study they followed the subjects for 24 months (if I am understanding it correctly). In my opinion, 24 months is adequate to see if the remission lasted (and on July 18th, it will be exactly 24 months for me). But at the three month mark, it would not have been adequate to tell much of anything.

 

[Hip]

I think it is all very complicated, @Gingergrrl, and it would require a lot of time reading the studies in depth to come up with any conclusions.

The response rate was not the only measure they used in these studies, so you would also have to look at the other measurements they used. I am not really inclined at the moment to read through all these papers, because I generally find reading large amounts of text difficult.

(After my viral brain infection in 2005, I developed severe ADHD, making reading near impossible sometimes; my brain has healed a bit over the last decade, and the ADHD has improved, but is still there, along with the ME/CFS brain fog in addition, giving me double trouble. So I only tend to read in-depth articles or studies when I feel they are really necessary, and even then it's a struggle to get the info into my brain).


In the first 2011 study, they actually say:

The primary end-point, defined as effect on self-reported Fatigue score 3 months after intervention, was negative.

So the first study was actually negative by the primary end-point (the self-reported fatigue). So I am not to clear why that first phase II study was considered positive enough to continue the rituximab research, when it really was a failure by its own primary end-point.


Another issue you would have to consider if looking into these studies is the measurement of B-cell levels. I believe F&M measured the B-cells levels in the patients, to ensure that the rituximab had killed off the B-cells.

I am not sure if they did this for all the studies, but that would be the thing to compare: if B-cells were equally depleted in these studies, then that I believe is the bottom line, rather than the dosing level.


I do remain open to the possibility that rituximab might work for some specific subset of ME/CFS patients, but the negative phase III result suggests that if it does, then that subset will be a very small one. Because if it were a large one, then the phase III result would have been positive.

 

[Gingergrrl]

I think it is all very complicated, @Gingergrrl, and it would require a lot of time reading the studies in depth to come up with any conclusions.

I absolutely agree.

(After my viral brain infection in 2005, I developed severe ADHD, making reading near impossible sometimes; my brain has healed a bit over the last decade, and the ADHD has improved, but is still there, along with the ME/CFS brain fog in addition, giving me double trouble. So I only tend to read in-depth articles or studies when I feel they are really necessary, and even then it's a struggle to get the info into my brain).

I don't have ADHD or brain fog and I find reading scientific material incredibly challenging b/c I have no background in the subject to draw from. I understand only reading the studies that are of intense interest to you and even in those studies (for me), it is still challenging! I have extreme personal interest in Rituximab which is why I cannot figure out why F & M reduced the dose of the Phase 3 studies for infusions #4-6.

I completely understand that it is very possible that ME/CFS is NOT going to prove to be an autoimmune disease, even in a sub-set. But it seemed that F & M were trying to decipher if there was an autoimmune subset who were responders, so I assumed that they would therefore use the autoimmune protocol (which at minimum is giving a dose at the BSA formula per patient). They could certainly choose to give a higher dose but I still can't figure out why they would give a lower dose.

So the first study was actually negative by the primary end-point (the self-reported fatigue). So I am not to clear why that first phase II study was considered positive enough to continue the rituximab research, when it really was a failure by its own primary end-point.

I am so glad you also interpreted it that way and I had the same question! If the first study was considered negative at the 3-month point, why did they continue? There are definitely factors that I am not able to understand.

Another issue you would have to consider if looking into these studies is the measurement of B-cell levels. I believe F&M measured the B-cells levels in the patients, to ensure that the rituximab had killed off the B-cells. I am not sure if they did this for all the studies, but that would be the thing to compare: if B-cells were equally depleted in these studies, then that I believe is the bottom line, rather than the dosing level.

I absolutely agree with this, too, and have not been able to figure out if F & M did the lymphocyte subset panel (or some other measurement of B cells) to verify that each subject in the study was maintaining a B cell level of zero for the duration of the six infusions. If they did, and if all subjects had B cells at zero (even once they lowered the dose to 500 mg), this would be very important to know.

Of course having B cells at zero only means that the Rituximab did it's job and it does not mean that the person will be a responder. BUT, if some people received too low of a dose that their B cells were not at zero, then you cannot really say why they were not a responder. Was it b/c the dose was too low or b/c of another reason?

I do remain open to the possibility that rituximab might work for some specific subset of ME/CFS patients, but the negative phase III result suggests that if it does, then that subset will be a very small one. Because if it were a large one, then the phase III result would have been positive.

I agree that the subset would be very small, which is why it seemed even more crucial that that subset received the autoimmune protocol dosing (at minimum) using the BSA formula for all six infusions. If the BSA formula was not important, it would not be in the package insert for Rituxan in the US and used by infusion center doctors, nurses, and pharmacists. My doctor used it to calculate my dose and he wanted to go with the lowest dose that he felt could be effective for me which was 600 mg per infusion.

I also wanted to clarify something I'd written in a post above. When I said that mid July (2019) would be 24 months for me, my case is actually very different than the study. In the study, patients stopped Rituximab at either month 12 or month 15 but then were monitored to month 24 or month 36 to see how long they maintained remission.

But In my case, I am still getting Rituximab (my next infusion is on 5/3) and I got my test results back and my B cells (Absolute and % CD19) are still at zero. So I cannot compare myself to the study b/c it would be like if I did one year of Ritux and then stayed in remission vs. continuing to do Ritux and continuing to keep B cells at zero. If I had stopped Ritux and then maintained the remission, I would feel confident that my new B cells grew back healthy. But in my case, we are continuing treatment, and keeping my B cells at zero, so it is a very different situation and we do not yet know if my new B cells will grow back healthy or pathogenic.

 

[Wonkmonk]

I just got aware of this interesting discussion. It's great to see this exchange of ideas happen so openly and respectfully.

Couldn't one summarize the state of research regarding Rituximab in the following way?

(1) A small fraction of patients diagnosed with ME/CFS responded positively to Rituximab (both in studies and forum reports), and some of these responses were long-term successful and life-altering.

(2) Some of these patients have tried so much before with no success at all, so in these cases it is very unlikely that all those patients only had a placebo effect. For some it was most certainly a real, specific effect of the drug.

(3) So, if you have been diagnosed with ME/CFS there is a small chance that you will have a real therapeutic effect and major benefits from Rituximab. Based on the data and forum reports, it may perhaps be 3% or 5%, but it is rather unlikely to be above 10%.

(4) So, it is rather unlikely that you will benefit from Rituximab, but it is also impossible to rule out that you would be among the responders if you try it.

(5) For (3) and (4), It doesn't really matter if you were misdiagnosed with ME/CFS or if you have the "real" ME/CFS (whatever it may be). Some of the responders later have their ME/CFS diagnosis corrected, others have not. It doesn't really matter if Rituximab only works in misdiagnosed cases (because it actually treats something else) or if it (also) works in a subset of "real" ME/CFS patients. The bottom line remains the same: If you are diagnosed with ME/CFS, you have a small chance of responding.

(6) Rituximab has many known side effects, some of which can be very severe.

(7) In ME/CFS patients, Rituximab might have additional risks compared to other patient populations. According to F&M's trials, there is a substantial chance that patients worsen moderately (at least for some time). There is also a small chance of worsening terribly after Rituximab, going as far as permanently slipping into a "very severe" state of CFS.

(8) Rituximab is expensive and trying to get it can take long and be stressful.

As far as I'm concerned, these are the facts and everyone who thinks about trying Rituximab (and has access) should have a hard and sober look at those facts and then take a rational decision if it makes sense to try it.

 

[Hip]

I think that's an excellent summary of rituximab, @Wonkmonk.

 

[Gingergrrl]

I also appreciate your summary @Wonkmonk and it is great to see you (and hope you are doing okay)!

I want to add that I also think it is very important to know if the individual patient (regardless if their ME/CFS diagnosis ultimately proves to be correct or incorrect) has auto-antibodies or B-Cell driven autoimmunity (or something that clinically leads their doctor in the direction that they could be a responder to Rituximab) vs. someone with active infections on a PCR test, immune deficiency like CVID, or has active Lyme/tick borne infections, etc (where Ritux should be avoided and could be very dangerous).

I don’t think Ritux is ever something to be tried at random vs. having a doctor(s) determine if they feel it is the right path in any individual case. (And this of course does not guarantee that any individual person will be a responder -- even if they have an FDA approved diagnosis like RA). But in the lack of having ANY autoimmunity, I would be very hesitant for someone to try it at random, just my personal opinion.

I also feel that dosing is important (in autoimmunity which I believe is the mechanism why it works in certain patients) and at minimum the BSA formula should be followed for each patient but it was not for four of the doses in Phase 3 of F & M Study.

Also, I wanted to add that in the US, if not covered by insurance, you can apply to get Ritux for free through Genentech (if your doctor does the application after 2-3 insurance denials). I got it covered by insurance and never had to go to Genentech but just wanted to mention that (at least in autoimmunity), there is a decent chance at getting the treatment.

Also wanted to add that I do not think ANYONE should ever try this treatment without the full support and supervision of a doctor.