Monday, 30 January 2017

Rebound? What causes the emergence of disease after alemtuzumab

#MS Research #Clinical Speak

There was a report of severe disease activity that occured within 6 months of the first infusion of alemtuzumab.This responded to B cell depletion.

http://multiple-sclerosis-research.blogspot.com/2017/01/worsening-after-alemtuzumab.html

The first suggestion was this could be a novel CNS autoimmunity, as could occur as discussed by Profg yesterday

http://multiple-sclerosis-research.blogspot.com/2017/01/clinicspeak-neurospeak-not-everything.html

However could it be disease reactivation?

This created some contradicting ideas (see post and comments) from TeamG, were we fighting online?

(a) DrK suggested neutralizing antibodies may have blunted the depletion of alemtzumab allowing disease to re-appear
(b) ProfG suggested, however that it could be a return of disease activity after rapid reconstitution.
(c) I also suggested it could be fluke occrance of natural course of alemtuzumab, on which the case reports are based.

Without knowing the depletion in the individuals, it could have been any of the above. Why?

This data from a EMA report from the phase III trials may show us why.

So it is not fighting, but independent thinking aloud.

We don't always agree, but are prepared to listen and modify our thoughts. Are you?

I have added some boxes/circles around some data from individuals to highlight some points. This shows the white blood cell level in pwMS at various times after alemtuzumab in people with (blue) and without (red) anti-drug antibodies


(1) Alemtuzumab does not deplete cells in everyone, so disease could carry on regardless, because there are non-depletors (top left dot). 


CD52 is a highly glycosylated (loads of carbohydrates) 12 amino acid long oligopeptide anchored into the membrane by a glycosylphosphatidylinositol (GPI) anchor. Two single-nucleotidepolymorphisms of CD52 were described,rs1071849 (A119G) andrs17645 (A123G).CD52 polymorphism may affect the efficiency of GPI anchor formation and thus may indirectly alter the response to anti-CD52 agents (This needs to be formally shown).

(2) ProfG hinted that as problem occurred after first infusion an influence of neutralizing antibodies, which have not been reported to occur, would be less likely to influnce treatment. 

However, following the first infusion of alemtuzmab a whopping 56% (n=486) of people injected with alemtuzumab develop neutralizing antibodies within the first month of treatment.  This is amazing given it is a humanised antibody and that alemtuzumab kills T and B cells.

Whilst the injected antibody is all but gone from the circulation within 15-20 days after first infusion, as it only takes about 6 days to produce an antibody response, at least in mice, hypothectically a neutralizing antibody response (although those found are of low titre=strength), could be generated shortly after the last infusion of the first courtse done over 5 days. This could blunt depletion and allowing rapid repopulation (e.g. see poor depleters with anti-drug antibodies above). They are unlikely to stop depletion altogether as some depletion would occur before antibodies could be formed. This could be more of a problem for the second, third, etc infusions.

(3) There are people who do not produce anti-alemtuzumab antibodies, who have high levels of cells, 2-4 months after infusion. These could be rapid repopulators (alternative was these people were poor depletors and remained poor depletors when assayed  months later. 


You have to do some detective work to find this information..Why?

27 comments:

  1. I thought alemtuzumab was a humanised antibody. Why the high NAB rate?

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    Replies
    1. We will explain this soon but it is a problem of how it works.

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  2. I assume the figure refers to the both the first and second courses of alemtuzumab. Can you split the data up into the first and second courses? Sure the issue of NABs will be more important in year 2?

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    Replies
    1. Maybe.They don't say in the report but I guess they are first and second doses. If we get access to data this can be addressed. Year 3 would be my guess.

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    2. The data is not worth much if you can't separate out 1st from 2nd course. I assume if you deplete with the first course, but not the second course the reasons will be very different to those who don't depelete after both courses. NABs vs. biology?

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    3. Re: "NABs vs. biology?"

      Yes, this is important, but the results may be the same regardless of mechanisms. What we need to find out is how alemtuzumab works, i.e. which cells is alemtuzumab targeting so we can investigate if lack of response and/or rebound is linked to lack of depletion or rebound of this population of cells.

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    4. Are there five hundred or a thousand data points. A thousand and it maybe both.
      Are we missing something

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  3. Are you guys are wrong? The Cambridge group have already shown that accelerated recovery of lymphocytes does not predict disease activity.

    https://www.ncbi.nlm.nih.gov/pubmed/24838790

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    Replies
    1. They looked at CD4 and CD8 and CD19 and you are correct this does not predict disease activity. On a population level Hans and Bans do not affect depletion but here we are talking about individuals the vast majority deplete but in a few instances you can see it is not so great so is it these or please who do badly. If you aim to show there is no influence you do the analysis that has been done, to ask if certain individuals do not do well you need to do a different type of analysis.

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    2. PS did they ask the right questions when looking for accelerated activity. I think the answer is no.

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    3. PS "Are we wrong." The raw data is in front of you,not the post analysis means. You can see forself if you think a few individuals don't deplete.

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    4. Does lack of depletion mean disease activity. Cardiff group says yes Cambridge said no, Genzyme says no.
      In all cases if you can't see the wood for the trees you get compost.

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  4. I would like to quote Professor Marc Feldmann: "Everytime you treat someone with a DMT you are performing an experiment."

    Every patient receiving alemtuzumab is an experiment; we need to learn and learn fast from the results of each experiment. I suspect we may be able to use the alemtuzumab response, and non-response, data to pin down the cause of MS. Could alemtuzumab be the Trojan Horse that contains a black swan?

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    Replies
    1. what happened to those class 1 evidence clinical trials you are so fond of :)

      snarky comment, i know :). no need to reply but the point has to be made sometime (in my humble opinion).

      thank you for the blog and the work that goes into it.

      Delete
    2. Yeah, hasn't anybody done a comparison of lymphocyte subpopulations in those who flare after alemtuzumab with those who don't? ( if the numbers themselves do not matter)

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    3. Apparently not. We have asked for this

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  5. Hahaha... in the meantime, here is convo between a friend with MS (who is having some kind of activity after switching from gilenya to lemtrada) before this entry was posted:

    My friend with MS: links "Worsening after alemtuzumab" post with the comment "Shoot me now"

    Me: "yea i saw that last night... it's the same story on the same 2 people that developed that thing where lesions started going haywire.. it's not new...if you are wanting to be shoot now because barts is having a debate about the reasons for what happened and they all have different opinions - yes shoot us both please (but don't say that too loudly cos these days you ask for it and you get it :X) LOL"


    :)

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  6. Will Ocrelizumab cannibalize Alentuzumab?

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  7. Prof G

    I'm glad the occurrence of MS activity /relapse is being discussed in the setting of Alemtuzumab. This has been my experience. MS activity resuming about 4-5 months after each Alemtuzumab infusion. The symptoms feel like a rebound and overshoot similar to when I stopped Tysabri.

    I appreciate we are breaking new frontiers constantly here.

    Where do we go once it seems that Alemtuzumab is not working for someone, either a non responder or rebound activity?

    More Alemtuzumab?
    Wait for Ocrelizumab
    Try Fingolimod ( risk of PML in a setting of low lymphocyte)?
    Go back to Tysabri (PML risk again with low lymphocytes)?
    Stem cell therapy ( but not tested against Alemtuzumab yet)?



    ReplyDelete
    Replies
    1. I'd be very interested to hear Prof G's thoughts on this also??

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    2. Sequencing post-alemtuzumab is a difficult one. Some of the cases that have been described did well on rituximab (anti-CD20). This makes sense in that it is a highly effective therapy and is unlikely to exacerbate the T-cell lymphopaenia that results post-alemtuzumab.

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  8. Depleted lymphocytes caused by Alemtuzumab which is its expected result.

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  9. This rebound of MS in alemtuzumab is not surprising in the least. What is surprising is that it does not happen more frequently with all DMD/immunotherapies. I think Dr. G. called this "field effect" previous when describing rebound effect of Tysabri.

    There is some antigen presenting cell (APC) still in play, probably in the "hot microglia" or "infected neuron", that has not been dealt with and so the immune system again recognize this still as foreign and attacks once again.

    Until the antigen & APC cell (i.e. cause of MS), like "hot microglia", is found and dealt with, then this will happen time and again. Relapses and progression of disease will continue depending on their individual immune systems. We continue to put out flames of the campfire but not the smouldering log.

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  10. From my reading, Rituximab is not licensed for MS and there have been no phase 3 studies so we are back to the practical real life question of where does one go to after Alemtuzumab.

    Any guides to this?

    This question will be asked more frequently as people increasingly face this situation.

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  11. Trying Alemtuzumab again after one course (2 infusions) hoping for a different result/effect does not sound logical.
    I know that repeat Alemtuzumab is being advised as an option for people who have not responded well.

    Didn't Einstein have a saying about this!

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  12. Maybe the proposed alemtuzumab + teriflunomide is the way to go... i really hope Genzime would try this, just maybe we can pour some water on those smouldering logs.

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