Cladribine switch

C

Sorry this post was launched before I had even written it. So the idea that memory B cells may be important is getting some traction with some people but for others they don’t care. However, if people start to study these ideas them information surfaces and you then have to ask is the idea wrong.

In this study they say cladribine gets rid of memory B cells if it is working and them also say cladribine gets rid of memory B cells when it doesn’t work, In this individual the immature B cells start to appear big time. So is the memory B cell idea wrong.

First you always have to think that yep the ideas need changing or finessing.

So the idea put forward is that fingolimod is trapping cells in the lymph glands or the bone marrow and stopping cladribine working. This idea has been levelled at alemtuzumab. If this is true then surely it will do the same to some people wit ocrelizumab. I dont’ know if this happens. However what they are looking for is an explanation of why this individual failed cladribine.

It could the case, but we dont know what happens in the lymph glands….However, I thing some people do, as there are some labs that can do lymph gland biopsies and these I believe have been done after cladribine. We will have to wait for the data to surface. Then we will know.

It is evident that there is an increase of the naive B cells but what do some of these cells become….yep memory B cells. How many do you need. Probably not that many and now you can see the number of memory B cells do increase abit. Is this enough to trigger MS.

Yes it could be however, we know that some people develop attacks when they there are seemingly no B cells in the blood. If may not be the place to look and so those lymph glands studies become more important

However if the morel of this story is true then if further says that you may have to think how you will transiton off a drug when you decide which treatment to go for.

Immune phenotyping study revealing caveats regarding a switch from fingolimod to cladribine.Radlberger RF, Sakic I, Moser T, Pilz G, Harrer A, Wipfler P.Mult Scler Relat Disord. 2020 Dec 29;48:102727. doi: 10.1016/j.msard.2020.102727. Online ahead of print.PMID: 33418308BACKGROUND: Recent data support a key role of B cells in the pathogenesis of multiplesclerosis. Due to the pronounced effect of cladribine on memory B cells, we initiated an immune phenotyping study, which included monitoring of memory B cells of patients newly ass …

Background: Recent data support a key role of B cells in the pathogenesis of multiple sclerosis. Due to the pronounced effect of cladribine on memory B cells, we initiated an immune phenotyping study, which included monitoring of memory B cells of patients newly assigned to this treatment option. A patient with ongoing disease activity in the first year of cladribine after a long-standing fingolimod treatment caught our attention.

Objective: To report about differences in the immune phenotype of the case compared to patients without disease activity and to discuss possible causes for the deviations as caveats regarding treatment sequelae.

Methods: Clinical data and immune phenotyping data collected at baseline (before treatment) and after three, six and ten/twelve months after cladribine initiation were compared between our case and six patients with a stable disease course (controls).

Results: Both, the case and controls showed similar reductions of memory B cells in response to cladribine. The case however, showed an accelerated repopulation dynamic of naïve B cells with an almost 3-fold hyperrepopulation compared to baseline levels, and lower pre-treatment levels of CD4+ and CD8+ T cells and memory B cells compared to controls.

Conclusion: We propose a prolonged pre-treatment with fingolimod as possible cause for the lack of response to cladribine. Autoreactive cells sequestrated within lymph nodes may have evaded cladribine depletion on top of a delay of recirculating regulatory T cells. In addition, we want to raise awareness of the importance of monitoring T and B cells for bridging the current lack of evidence regarding sequencing therapies in the real life setting.

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MouseDoctor

2 comments

Leave a Reply to Fabio Cancel reply

  • So even small molecules cannot reach some tissues 🙁 ?
    That’s a bad news! Is it possible that cells trapped in lymph nodes are not activating the enzyme that converts cladribine to the drug thay kill them? By the time cells are released, cladribine may have been left.

  • Very helpful, thank you MD! I wonder if the same conclusion can be applied to switching from one of the immunomodulatory therapies.

    For the case above it states, “and lower pre-treatment levels of CD4+ and CD8+ T cells and memory B cells compared to controls.” Was the lower pre-treatment levels the cause of failure?

    “accelerated repopulation dynamic of naïve B cells with an almost 3-fold hyperrepopulation compared to baseline levels”……this seems similar to the issues you identified with Alem and secondary autoimmunity. I wonder if controlling the speed of naïve B cells during the immune reconstitution phase of Clad treatment would minimize risk of failure and/or severe side effects.

    This stuff is so confusion, frustrating, and scary. These neuros just hand pwms drugs and rarely provide any insights or interest in these types of issues/risks. When the first drug almost kills you, the second drug causes significant bone loss and pain, it is very difficult to get over the anxiety of what a third or forth drug may do, other than hopefully slow down progression.

    Thank you to the Barts team for giving a f#@k, means the world to patients like me!

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