Rituximab Serum Concentrations and Anti-Rituximab Antibodies During B-Cell Depletion Therapy for ME

[Murph]

Clin Ther. 2018 Nov 28. pii: S0149-2918(18)30514-9. doi: 10.1016/j.clinthera.2018.10.019. [Epub ahead of print]
Rituximab Serum Concentrations and Anti-Rituximab Antibodies During B-Cell Depletion Therapy for Myalgic Encephalopathy/Chronic Fatigue Syndrome.
Rekeland IG1, Fluge Ø2, Alme K2, Risa K2, Sørland K2, Mella O3, de Vries A4, Schjøtt J5.
Author information
Abstract
PURPOSE:
Previous Phase II trials indicated clinical benefit from B-cell depletion using the monoclonal anti-CD20 antibody rituximab in patients with myalgic encephalopathy/chronic fatigue syndrome (ME/CFS). The association between rituximab serum concentrations and the effect and clinical relevance of antidrug antibodies (ADAs) against rituximab in ME/CFS is unknown. We retrospectively measured rituximab concentrations and ADAs in serum samples from patients included in an open-label Phase II trial with maintenance rituximab treatment (KTS-2-2010) to investigate possible associations with clinical improvement and clinical and biochemical data.

METHODS:
Patients with ME/CFS fulfilling the Canadian criteria received rituximab (500 mg/m2) infusions: 2 infusions 2 weeks apart (induction), followed by maintenance treatment at 3, 6, 10, and 15 months. The measured rituximab concentrations and ADAs in serum samples included 23 of 28 patients from the trial.

FINDINGS:
There were no significant differences in mean serum rituximab concentrations between 14 patients experiencing clinical improvement versus 9 patients with no improvement. Female patients had higher mean serum rituximab concentrations than male patients at 3 months (P = 0.05). There was a significant negative correlation between B-cell numbers in peripheral blood at baseline and rituximab serum concentration at 3 months (r = -0.47; P = 0.03). None of the patients had ADAs at any time point.

IMPLICATIONS:
Clinical improvement of patients with ME/CFS in the KTS-2-2010 trial was not related to rituximab serum concentrations or ADAs. This finding is also in line with a recent randomized trial questioning the efficacy of rituximab in ME/CFS. Rituximab concentrations and ADAs still offer supplemental information when interpreting the results of these trials.

Copyright © 2018. Published by Elsevier Inc.

KEYWORDS:
B-cell depletion; antidrug antibodies; chronic fatigue syndrome; myalgic encephalopathy; rituximab; rituximab concentrations

PMID:
30502905
DOI:
10.1016/j.clinthera.2018.10.019

 

[Gingergrrl]

The association between rituximab serum concentrations and the effect and clinical relevance of antidrug antibodies (ADAs)

What do they mean by “anti drug antibodies” or ADA’s? I am not familiar with this term?!

There were no significant differences in mean serum rituximab concentrations between 14 patients experiencing clinical improvement versus 9 patients with no improvement

Even though there were no significant differences in mean serum Ritux concentrations, are Fluge & Mella saying that 14 patients experienced clinical improvement and only nine did not?! This seems very significant (if I understand it correctly)?

 

[Hufsamor]

Even though there were no significant differences in mean serum Ritux concentrations, are Fluge & Mella saying that 14 patients experienced clinical improvement and only nine did not?! This seems very significant (if I understand it correctly)?

I was wondering about this myself...

 

[Murph]

Are Fluge & Mella saying that 14 patients experienced clinical improvement and only nine did not?! This seems very significant (if I understand it correctly)?

This refers to the Phase 2 trials that we know about already.

 

[Gingergrrl]

I apologize in advance if any of my questions are stupid but I really want to understand this topic as Rituximab has been life-changing for me.

@Murph Do you understand what they mean by “anti drug antibodies” or ADA’s? Is this an autoantibody that literally attacks the Rituximab itself or does it attack the B-cells (or something different)? My doctor has never mentioned to me that this autoantibody even exists!

This refers to the Phase 2 trials that we know about already.

This also confused me. Is the article that you linked in this thread something new (meaning it is new info that is being published for the first time) or was it all already known as part of the Phase 2 trials?

Even if it was already known as part of the Phase 2 trials, it seems very significant to me that 14 people experienced clinical improvement and only nine people didn't? I know it is a small sample size overall but wouldn't it still be relevant or significant?! I don't get why this would be dismissed? (in general, I don't mean by you).

 

[Murph]

I apologize in advance if any of my questions are stupid but I really want to understand this topic as Rituximab has been life-changing for me.

@Murph Do you understand what they mean by “anti drug antibodies” or ADA’s?

You always ask smart questions!

I'd never heard the term anti drug antibodies before but apparently our bodies can inactivate some drugs with their immune system: https://en.wikipedia.org/wiki/Immunogenicity

Is the article that you linked in this thread something new (meaning it is new info that is being published for the first time) or was it all already known as part of the Phase 2 trials?

I believe they're doing new analysis on old blood they had stored from those trials. So this finding - that there was no Anti-drug antibody - is new.

Even if it was already known as part of the Phase 2 trials, it seems very significant to me that 14 people experienced clinical improvement and only nine people didn't? I know it is a small sample size overall but wouldn't it still be relevant or significant?! I don't get why this would be dismissed? (in general, I don't mean by you).

Absolutely yes it *seems* significant! It's the exact kind of result that would inspire you to set up a Phase 3 trial, which is exactly what they did.

Obviously the Phase 3 trial was better quality trial: larger sample, controlled and multi-centre. And it failed. But until they actually report on it we won't know if it failed only narrowly and we should keep a small ember of hope alive for Rituximab in ME/CFS more generally, or if it failed so completely that the Phase 2 trial results can be dismissed confidently. (I believe the practice in medicine is to ignore a Phase 2 trial success if a Phase 3 trial fails, but I believe good statistical practice is to assess all the available evidence.)


I'm really impatient for their paper. Perhaps the emergence of this one suggests it is coming soon!?!

 

[Gingergrrl]

You always ask smart questions!

Thank you and it never feels this way!

I'd never heard the term anti drug antibodies before but apparently our bodies can inactivate some drugs with their immune system: https://en.wikipedia.org/wiki/Immunogenicity

Thank you for this link and it was very interesting, especially this part:

• Unwanted immunogenicity is an immune response by an organism against a therapeutic antigen (ex. recombinant protein, or monoclonal antibody). This reaction leads to production of anti-drug-antibodies (ADAs) inactivating the therapeutic effects of the treatment and, in rare cases, inducing adverse effects.[2] The prediction of the immunogenic potential of novel protein therapeutics is thus a challenge in biotherapy.[3]

I bolded the part that says "monoclonal antibody" since this is exactly what Rituximab is. I guess "MAB" drugs can cause these ADA's in certain people? I can only assume that they did not occur in my case and it is not something that my doctor tested me for or ever mentioned.

Do you know if these are only measured as part of a research study vs. in real life?

I believe they're doing new analysis on old blood they had stored from those trials. So this finding - that there was no Anti-drug antibody - is new.

Thank you for confirming and I had thought it was something new but I miss a lot of posts (or I read something like a research study and don't fully understand it so I don't retain all of the details). If I understood this one correctly, it seemed that no one in the study had ADA's to Rituximab (which I can only assume is a good thing)?!

Absolutely yes it *seems* significant! It's the exact kind of result that would inspire you to set up a Phase 3 trial, which is exactly what they did.

That's what I thought but thank you for clarifying.

Obviously the Phase 3 trial was better quality trial: larger sample, controlled and multi-centre. And it failed. But until they actually report on it we won't know if it failed only narrowly and we should keep a small ember of hope alive for Rituximab in ME/CFS more generally, or if it failed so completely that the Phase 2 trial results can be dismissed confidently. (I believe the practice in medicine is to ignore a Phase 2 trial success if a Phase 3 trial fails, but I believe good statistical practice is to assess all the available evidence.)

Were the subjects in the Phase 3 trial the EXACT same subjects from the Phase 2 trial (meaning the 14 responders) or were they an entirely new group of people?

Why is is considered standard practice to ignore the results of a Phase 2 trial if a Phase 3 trial fails? I know this must seem like an odd question but how do researchers rule out that Phase 2 results were inherently false and Phase 3 were inherently correct? Why were the 14 people responders in Phase 2? Are they now saying that those 14 people were either (A) Not really responders (B) Misdiagnosed and really had a different autoimmune disease or (C) Something else?

I'm really impatient for their paper. Perhaps the emergence of this one suggests it is coming soon!?!

I would LOVE to see this paper, too, and if it should come out and I am clueless, can you please tag me so I don't miss it? Thank you again @Murph!