Alemtuzumab rescue therapy for rebound after stopping natalizumab

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Natalizumab is an effective strategy for achieving disease control in those with highly-active MS, but owing to the risk of progressive multifocal leucoencephalopathy (PML), often needs to be de-escalated. However, discontinuation of natalizumab therapy is not without its own risks; the biggest risk being rebound activity, which rarely may be a flare beyond that of pre-treatment disease activity.

The RESTORE study showed much to the surprise of all that rebound may begin as early as 4-8 weeks after natalizumab discontinuation, this despite switching to either glatiramer acetate (Copaxone), interferon beta therapy or pulsed methylprednisolone.

Early switch (less than 3 months after stopping natalizumab) to fingolimod , however, seems to be superior to both interferon beta and glatiramer acetate in reducing the risk of rebound. Whilst, in a smaller study rituximab was found to be superior to fingolimod and dimethylfumerate, in terms reducing radiological activity based on number of enhancing lesions on MRI.

Little is know about how the other highly active therapies fare on preventing rebound. Alemtuzumab notably seems to be like rituximab, better than fingolimod; in one study after one year of treatment the fingolimod group had fewer without a relapse (54% fingolimod vs. 77% alemtuzumab) and MRI activity (50% fingolimod vs. 74% alemtuzumab) than alemtuzumab. And recently this week, in a case report Federle et al., following a particularly severe rebound after natalizumab discontinuation (12 new brain and spinal cord lesions, and an increase in disability scores from EDSS 1.5 to 6.5; see figure below), alemtuzumab stopped the development of new lesions and led to an improvement in the EDSS score to 4.

The authors suggest that alemtuzumab should be considered as an immediate rescue strategy for cases where rebound is catastrophic. Moreover, the JCV index, in this particular case was high at 3.63. Recommencing natalizumab or using maintenance strategies that lead to chronic lymphodepletion, are therefore not valid long-term strategies. When commencing natalizumab, sequencing of treatments post-natalizumab based on risk-minimization is important to consider at the very start.

Figure summarizes the clinical and therapeutic course. Flashes indicate relapses. Grey box indicates the post-natalizumab period, which was characterized by
both EDSS worsening and accumulation of white matter lesions (see MRI at top)

ABSTRACT
Mult Scler Relat Disord. 2019 Mar 5;30:262-264. doi: 10.1016/j.msard.2019.03.002. [Epub ahead of print]
Alemtuzumab as rescue therapy in case of multiple sclerosis rebound following Natalizumab break: Clinical case and literature review.
Federle L1, Puthenparampil M2, Stenta G1, Paolo G1, Francesco P1.

Introduction: Natalizumab break exposes multiple sclerosis (MS) patients to a high risk of disease reactivation or rebound, whose prevention and treatment constitute a clinical challenge.

Case Presentation: We describe a dramatic case of MS rebound, characterized by the development of severe neurological and psychiatric symptoms, following natalizumab break. Alemtuzumab rapidly and completely suppressed brain inflammation as demonstrated by clinical and radiological findings.

Conclusions: Our case further adds to the available literature evidence on Alemtuzumab as first-choice rescue therapy following Natalizumab discontinuation.

About the author

Neuro Doc Gnanapavan

16 comments

  • After 11 years on natalizumab (last infusion in 27 December 2018), started Alemtuzumab in 18/feveruary, hope it works.

    • I am assuming that you were JCV- and NEDA3 on tysabri?

      If so, why switching if I may ask?

      And how did you switch? (washout period, transitional medication, etc…)

  • Is there a working model for a JCV- patient migrate from tysabri to Lemtrada or HSCT without a clinical or radiological spike in disease activity?

    • Hi Tony, in ECTRIMS 2018 there was a study saying that you can do a direct swap without incidence of PML. However, there has been a carryover PML although in retrospect the PML was evident on the MRI head scan prior to starting alemtuzumab. We check for presence of JCV DNA in the CSF prior to switching and this has worked to date.

      • That is why I specified JCV- patient in this case (PML risk close to 0).

        It is the immune reconstitution syndrome I am most concerned about. It can be as fatal as PML.

        • So the findings from ANSWER MS study presented at ECTRIMS 2018 showed a shorter bridging period is important. Their finding was less than 3mth washout was more favourable in terms of ARR. We do a switch in 8weeks, JCV DNA is checked regardless of if you’re serum positive or negative for the antibody.

      • This article certainly doesn’t encourage me to consider Natalizumab as my next treatment but I find the side effect profile of Alemtuzumab rather worrying. Is anything being done at the moment to try and make it a far less risky DMT? I have heard too many reports of serious side effects and further worsening for some unfortunate patients following Alemtuzumab yet hear much praise for it on this blog. Just how much of a problem are the neutralising antibodies that MouseDoctor has mentioned in the past? Is there any way of knowing who will fare best from taking such a potent drug?

        • Who fares best?

          I don’t know…there are many that do very well, there are some that dont do anything at all.

          How much of a problem for antibodies….I dont know yet as Genzyme have not given us the data. We have asked over and over again and they have fobbed us off, over and over again. They know the answer, but have probably hidden the data…so it is they who have made a mountain out of a mole hill.

          In the population-based data, it says they are not important. The third dose works…works for most people. We know this from the Cambrdige data. But are they hiding the fact that thhese will be important for certain individuals. I guess it is not too many. Based on the tiral data it only affected 1 person in the second cycle only 5 had post dose neutralizing antibodies (0.6%), The problem was there for about 30% prior to third potential dose. They know how many people do not deplete well after first, second, third or forth dose.

          It is they that have made a mountain out of a mole hill…if they had acknowledged that neutralising antibodies exist, there would no need to be a thorn in their side. They have changed the European label to acknowledge this issue.

          Cambridge did a trial to get rid of them and so they know too….you wouldn’t do a trial for no reason.

          Maybe it is time to go back to the EMA with another freedom of information request….However, they have also created a ferret..A ferret locks its jaws when it bites and does let go…..Actually they have created lots of student projects a month here and a month there… so thanks for that. They will be very happy to get a publication or two, as it will help their career and important it will be able to help people with MS

        • With highly active disease, the evidence is to go in with natalizumab as first-line. It works fast. I believe with the information that we currently have, it’s not going to be a problem to de-escalate. We now know which drugs not to use.

          Alemtuzumab’s secondary autoimmunity and rarer side effect profiles have been reported in the blog in the past, as well as the Nabs issue. My clinical experience of these have been, in particular the thyroid issues is that they’re manageable. Having some one who improves by two EDSS points is something to see. I’ve always said that with alemtuzumab the best outcomes are if you use it early (is EDSS 2), but have with experience noted that it works even at higher EDSS scores as well. My secondary option ocrelizumab, I avoid in young women because of the potential breast cancer issue – or I inform them of this when I discuss. I’m waiting to see how the ocrelizumab 5y data compares to that of alemtuzumab.

          • Anon 6:42am: Thank you for your contribution to this blog!

            Have you ever considered HSCT for your patients?

            Tony

          • Yes, I have one patient who has met the Pan-London Stem cell guidelines and has had it done!

  • Interesting article. I have been on Tysabri for 13 years. Converted to JCV+ after 9. I have been on extended dosing for the last 4. So my confusion is that if many show rebound as early as 6 weeks, how does the extended dosing seem to work for so many??? When I first converted I took a 3 month break from Tysabri and from there I have been every 8 weeks with no symptoms that I can see. My MRI have been stable as well. Although after reading the blog I now realize is only one part of the picture. Would love brain volume loss and NfL levels checked!
    Thanks for any clarification

    • Yes, so rebound on natalizumab is based on pre-natalizumab MS characteristics. If you had lots of relapses and many enhancing lesions beforehand, it puts you at higher risk. All highly-active patients are on a spectrum from this. I have patients whom I know I simply wouldn’t be able to shift to extended formulation.

      NEDA-NFL is probably as close to a disease remission that we’ll get to!

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