Monday, 29 January 2018

Disease activation after alemtuzumab. Was it the B cells? or the fingolimod?

Rebound disease activity in people taking alemtuzumab.

Whats it the B cell surge or

Because they had taken fingolimid


Activation of disease during therapy with alemtuzumab in 3 patients with multiple sclerosis.
Wehrum T, Beume LA, Stich O, Mader I, Mäurer M, Czaplinski A, Weiller C, Rauer S.

Neurology. 2018 Jan 19. pii: 10.1212/WNL.0000000000004950. doi: 10.1212/WNL.0000000000004950. [Epub ahead of print]




OBJECTIVE:To report 3 patients with multiple sclerosis showing severe activation of disease during immunotherapy with alemtuzumab.

METHODS:

Retrospective case series.

RESULTS:

Patient 1, a 21-year-old woman, developed severe cognitive impairment, sight deterioration, severe gait ataxia, urinary retention, and extensive progression of cerebral lesion load, including new lesions that exhibited gadolinium ring enhancement and dominance of CD19/20-positive B lymphocytes, 6 months after induction of alemtuzumab. 
Patient 2, a 28-year-old man, developed left-sided hemihypesthesia and ∼60 new cerebral and spinal lesions including lesions with gadolinium ring enhancement 6 months after induction of alemtuzumab. 
Patient 3, a 37-year-old woman, developed ataxia and numbness of the left thigh, 16 new gadolinium-positive supratentorial lesions, and partly ring-enhancing and dominance of CD19/20-positive B lymphocytes 6 months after induction of alemtuzumab.

CONCLUSION:

This is a case series reporting severe activation of disease during immunotherapy with alemtuzumab. All patients showed onset of symptoms 6 months after induction of alemtuzumab, strikingly similar MRI lesion morphology, and unexpected high total B cell count, which may suggest a B-cell-mediated activation of disease. 

This study reports on the development of highly active disease after alemtuzumab treatment and they suggest that it may be due to B cells, hence I have decided to report it as it keeps up the B cell momentum. 

But importantly was the reactivation really due to B cells. previously it has been reported that repopulation of CD19 B cells was not associated with relapse activity in alemtuzumab studies. We also reported that this was the case with cladribine too. But are we looking at the right B cells. In these studies the B cells had repopulated to over 250% of their starting value after 6 months and so this is high compared to what you might expect. We have said previously that alemtuzumab may not clear the bone marrow well and so immature and then mature B cells rapidly repopulate the blood. However, what happened to the memory B cell subset. Did they repopulate. studies to properly interrogate the repopulating B cell subsets 

However importantly all three of these individuals were switched from fingolimod. So is the real interest from these three individuals. In a study from a group in Wales 25% of those switching to alemtuzumab  after fingolimod. So it is important to think how you switch from one treatment to another. In this case people were switched from alemtuzumab to rituximab. It will be interesting to know if these people will develop secondary autoimmunity due to alemtuzumab. It would help us know if it is the B cell hyperproliferation in the absence of T cell regulation that is the key...Time will tell. 

17 comments:

  1. Beginning to wonder if it would actually be wise not to take a DMT at all. Do you have any data on how people with MS fare who choose never to have any of these drug therapies? Do they really do much worse and live considerably shorter lives?

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    1. yes...new example
      The long-term impact of early treatment of multiple sclerosis on the risk of disability pension.

      Landfeldt E, Castelo-Branco A, Svedbom A, Löfroth E, Kavaliunas A, Hillert J. J Neurol. 2018 Feb 1. doi: 10.1007/s00415-018-8764-4. [Epub ahead of print]

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  2. What was the washout period after fingolimod before starting the alemtuzumab?

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  3. Am currently in the ~22 month post R2 lemtrada, (previously did naive) where I have slid from neutropenia to pancytopenia. Current dx is to suppress antibodies with steroid, with some recovery observed at this point. I had thought rituximab might be the right approach to adjust the B cells at this reconstitution stage. Do I have my game plan mistaken? Trying to interpret your last statement with great interest...and trying to get it right! Thoughts?

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    1. "I had thought rituximab might be the right approach to adjust the B cells at this reconstitution stage. Do I have my game plan mistaken".
      No, you're not, that is our thinking too.

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    2. Someone should initiate a trial on Alem+RTX :/

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  4. My sister gonna be start the washout from Fingo to Alem (cause her possible pregnancy plans) in the middle of March so not only the couple of weeks, but this year gonna be stressing. I told the washout is risky so Clad might be a better option but the EMA regulation demand a lower rate of normal Lymphcounts. Gilenya not only trapped the Lymphs but also a f***in trap. Her neuro dont permit to switch to Nat in spite of she was JC negative. Her edss 3,5 and very stable with Fingo.

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  5. Isn't there just the same danger when switching from fingolimod to cladribine?

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    1. Simple answer is we dont really know we dont have the experience but we have switched fingolimod rebound to cladribine. This case report is published

      However, cladribine being a small molecule can more easily enter the lymphoid tissue and bone marrow and so would mean that cells can't hide.

      For alemtuzumab the antibody has to enter the tissue and likewise the killing mechanism (Natural killer cells) has to enter too. We know that antibodies clear the bone marrow out less well than the blood, whether this is the case for cladribine I dont know. Maybe there is literature on people with cancer in the marrow and if they respond to cladribine it gets in.

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  6. Are you saying that fingolimod may sequester B cells in bone marrow as well as lymph glands?

    How long a wash out would one need to safely switch? As I understand it the length of washout is mediated by blood testing to monitor lymphocyte count and lemtrada is only given once lymphocytes return to within normal range? Wouldn’t this ensure that lemtrada is effective?

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    1. But waiting until lymphocytes return to "normal range" will increase the chances of a rebound and also if there are sequestered lymphocytes in the bone marrow, then lemtrada is unlikely to touch these due to poor penetrance. As MD says, cladribine may be more effective here but the data needs to be collected before any judgements can be made.

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    2. A lymphocyte is loads of different cell types so normal lymphocyte numbers does not mean all the lymphocytes are normal

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  7. It does increase the chance of relapse I agree but I believe that is clinical practice?

    How long would it take for lymphocytes in the bone marrow to return to circulation do you think?

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    1. with alemtuzumab they are coming out within a month and this increases with time

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  8. As someone with ppms who has noticed progression (possibly only) in association with viral infections (colds), I find it incredible that partially destroying the immune system, leaving one less able to fend off infections helps MS at all. Okay, I can see how it would help with relapses, but I can only think that it potentially makes progression worse. Given my experience.

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  9. https://www.thelancet.com/journals/laneur/article/PIIS1474-4422(16)30382-9/fulltext
    Case1 had DMF treatment before Alem (Case2 had fingo)

    http://nn.neurology.org/content/5/1/e420
    This case: Natalizumab - Pregnancy - Alemtuzumab - (Bcell CNS disease)

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