Monday, 14 December 2015

ResearchSpeak: can we prevent autoimmunity post-alemtuzumab?

The PAPA Study: an attempt to prevent secondary autoimmunity post-alemtuzumab. #ResearchSpeak #MSBlog #MSResearch

"Alemtuzumab is one of the most effective licensed treatments we have for relapsing MS. The majority of people with MS (pwMS) only require two courses of alemtuzumab to go into long-term, and possibly life-long remission (cure). The main long-term side effect of alemtuzumab treatment is secondary autoimmunity; the study below indicates that the accumulative incidence of  secondary autoimmunity is just shy of 50% (higher than we previously thought)."

"Secondary autoimmunity may also occur in pwMS treated with BMT/HSCT, but is generally not seen with other induction therapies that have been used to treat MS, i.e. cyclophosphamide, mitoxantrone and cladribine. The risk of secondary autoimmunity, and the monitoring requirements (monthly blood and urine tests) that are bundled with the use of alemtuzumab, are the main reason for its slow adoption as a DMT in MS and may yet prove to be its achilles heel when safer high-efficacy therapies are licensed."

"We hypothesise that the secondary autoimmunity that occurs with alemtuzumab in pwMS is due to the repopulation kinetics of the peripheral T and B cell pools; the B-cell pool repopulates rapidly with and overshoot above normal. The latter does not occur with cladribine and we have therefore hypothesised that it is the repopulation of the peripheral B-cell compartment in the absence of regulatory T cells that is responsible for the high incidence of secondary autoimmunity. We have therefore proposed a study whereby we give alemtuzumab-treated pwMS a low dose of rituximab, after each cycle of alemtuzumab, to blunt and delay the recovery of the peripheral B-cell compartment until regulatory T-cells are back to control autoimmune T & B-cells. This is a high-risk trial, but if it works it would change the risk:benefit profile of alemtuzumab and make it more appealing to many more pwMS and possibly their neurologists. What do you think? Would you volunteer to participate in this study if you had already decided to be treated with alemtuzumab? Our preliminary power calculations suggest we will need 30 pwMS in each arm."


"We have proposed an adaptive design study so that sequential arms could be added to test other strategies, by using the same control arm. This is a novel way of maximising the potential of the study design."

Epub: Willis et al. Alemtuzumab for multiple sclerosis: Long term follow-up in a multi-centre cohort. Mult Scler. 2015 Oct 29. pii: 1352458515614092.

BACKGROUND: Alemtuzumab has recently been approved for treatment of relapsing MS, but concerns remain about its use since long-term studies of adverse events remain limited. Furthermore, a clear understanding of its application and durability of effect in clinical practice has yet to evolve.

OBJECTIVES: To investigate long-term efficacy and safety outcomes in a multicentre cohort of patients treated with alemtuzumab.

METHODS: Patients treated from 2000 and followed-up at three regional centres were identified. Baseline and prospective data were obtained and validated by clinical record review.

RESULTS: One hundred patients were identified with a mean follow-up of 6.1 years (range 1-13). Forty patients were retreated with at least one further treatment cycle. Annualized relapse rates fell from 2.1 to 0.2 (p<0.0001) post-treatment and were sustained for up to eight years of follow-up. Mean change in EDSS score was +0.14. Forty-seven patients developed secondary autoimmunity.

CONCLUSION: Observed reduction in relapse rates reflected those reported in clinical trials, but we were unable to corroborate previous observations of disability reversal. 40% of patients required additional treatment cycles. Autoimmune adverse events were common, occurring at a higher rate than previously reported, but were largely predictable, and could be managed effectively within a rigorous monitoring regime.

CoI: multiple

19 comments:

  1. As it uses a relatively small sample how do the confidence limits of this and previous studies compare?

    Re. would I take part in the trial? How risky is it?

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  2. What would be the risks of adding rituximab?

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    1. You do not know as the trial is pioneering, infection risk may be higher

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    2. Do you know what the risk is if you already have Graves disease?

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    3. Can profG comment on it?

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    4. Re: "Do you know what the risk is if you already have Graves disease?"

      We will be powering the study based on the incidence of Grave's disease post-alemtuzumab. Therefore anyone who already has autoimmune thyroid disease will be excluded from the trial.

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    5. Bummer I'm too late, 8 months post first infusion and a tsh of 70. Rather sporting I thought.

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  3. I have my second round of lemtrada next summer. I'd be happy to do the trial but would want to know the potential risks involved.

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  4. Dear Prof G./ Team G

    I recently had my second round of alemtuzumab infusions abroad. My neurologist there does not want to give me rituximab. Since you are the only one I found who does this low dose rituximab treatment, I wanted to ask if it would be possible to have that at your hospital under the NHS or is there another possibilty to get that here in the UK?
    Just to clarify, at the moment I am a student living in the UK.

    Please let me know how to get in touch, if there is a chance that I can get that here. Thank you!

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    1. This is not our standard practise yet and can only be done if it is decided
      to do the study

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    2. I remember Prof G posting about this some time ago, pretty sure that he has already done it. I would also be willing to take part in the study, but since my second round is already done, I would need the rituximab infusion rather timely if its to have any effect.
      Do you know about any other place, where this can be done (in Europe)? Thanks!

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    3. You need to speak to someone who does private practise and have a discussion about the approriateness of this. ProfG does not do private practise, neuros like Dr Ben Turner at QMUL does private practise.

      I am pretty sure he has not does this. He would want to do this as part of a trial so that it gets done and an answer comes form the experiment

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  5. Is there anything coming out of the Cambridge trial on this point yet? Or do you just disagree on the potential solution?

    If I were going to take alemtuzumab, I'd be very happy to add on something that might help protect from secondary autoimmunities.

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    Replies
    1. Cambridge have a trial on their solution. You will have to wait to see if it is the right or wrong one. I am pretty sure that Cambridge are not doing this type of study yet

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  6. I'd do it to get alemtuzumab as the gate keeper at my clinic is the lets see if you can fail on another treatment type before we give you something effective but more risky. Sounds like a good idea in the theory.

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  7. I am just getting set up for first round of lemtrada in late jan, early feb. Happy to have a chat about adding on rituximab as a possibility?

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  8. If I want to take part in this trial, how would I go about it?

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    Replies
    1. The trial profG is talking about needs to be supported first....probably by Genzyme, otherwise profG would need to get funding to do this and funders would ask why is genzyme not doing this

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