Clinic Speak: switching from natalizumab to alemtuzumab

Yes, we have used all three strategies to switch JC+ve MSers from natalizumab to alemtuzumab. #ClinicSpeak #MSBlog #MSResearch

How do you switch from natalizumab to alemtuzumab? #ClinicSpeak #MSBlog #MSResearch

“The interested generated at the CME meeting, last week, and via several recent emails from MSers regard to switching therapies has prompted me to repost this post.”

“Yes, we have several MSers go through all three options outlined below. One MSers chose option one,  the high risk option, she had previously switched to DMF and had a major relapse at 4 months with rebound. She did want to take a chance of rebound on fingolimod. Fortunately, there has been no carry-over PML and she is alive and well post receiving alemtuzumab. One of my colleagues has taken several patients through option two; the problem he has has has been separating out rebound from potential IRIS (immune reconstitution inflammatory syndrome). When you do the MRI at 3-6 months and see enhancing lesions are these MS lesions or is it IRIS in response to asymptomatic PML? In the one case the lesions looked very atypical for MS, but he went ahead and treated with alemtuzumab and the patient concerned is alive and well. If it was PML he would not be alive. Finally, we have several MSers on option 3; they are all bridging at present on fingolimod with the plan to switch them to alemtuzumab at 6-12 months.”

“I have had several MSers ask me recently about switching from natalizumab to alemtuzumab. The switch should be relatively straight forward if you are JC virus seronegative and are switching because of lack of  efficacy, or for a life-style choice, for example if you are tired of monthly infusions, or you want to an induction therapy that offers you the freedom to fall pregnant without worrying about rebound activity, or you simply prefer the long-term potential that an induction therapy offers. In this situation switching without a wash-out period to prevent rebound makes sense and should be relatively safe (option 1 below).”

“The situation if you are JC virus seropositive is much more problematic because of the risk of carry-over PML. With a maintenance agent such as fingolimod we simply exclude asymptomatic PML by doing a lumbar puncture to look for JCV DNA in the spinal fluid and an MRI; if these tests are clear we now start fingolimod as soon as possible after the last natalizumab infusion with the knowledge that if PML should develop we can always stop fingolimod and it will be cleared from the body withing in 6-8 weeks. This early switching strategy also prevents rebound activity when natalizumab wears after approximately 3-4 months.” 

“With an induction agent, such as alemtuzumab, things are more complicated because we can’t reverse its action hence we have to be confident that there is no carry-over PML. Why am I so concerned? Simple, if you develop carry-over PML post-alemtuzumab before reconstitution of your immune system your are likely to succumb to the PML. The reason for this is that we have to rely on a functioning immune system to clear the virus, in particular a population of cells called CD8+ cytotoxic T-lymphocytes (CTLs). As you can see from the graph below CD8+ lymphocytes take many months to reconstitute and even at 12 months, the time you would be due your second course of alemtuzumab, they are not back to normal.”

From Coles et al. Multiple Sclerosis 1998; 4:232-238.

“The pivotal questions are: (1) how long is the period of asymptomatic PML and (2) can we be confident in excluding asymptomatic PML by simply doing a lumbar puncture for spinal fluid JCV DNA detection and an MRI for suspicious lesions? I suspect not. The process that underlies the development of PML is long and complicated. The JC virus has to acquire several mutations to be able to cause PML; acquiring mutations takes time typically more than 12-24 months. Once the virus has acquired the mutations it must then infect the glial cells within the brain and start dividing and spreading. This initial infection must start microscopically below the threshold of detection by MRI and spinal fluid analysis. So simply switching to alemtuzumab without a break from natalizumab is risky; how risky is difficult to say at present.”

“I envisage 3 scenarios: 

(1) The most risky one is the immediate switch from natalizumab to alemtuzumab without a wash-out; the risk being a small chance of carrying over asymptomatic PML.

(2) A switch after a 3-6 month wash-out of natalizumab; this will allow time for asymptomatic PML to declare itself and it will also allow immune surveillance to of the nervous system to find any mutant JC virus. This strategy was initially proposed with fingolimod and had to be stopped because of the risk of rebound MS activity. Because of rebound, I don’t think this is a strategy that most MSers will be prepared to take. 

(3) A bridging strategy in which you switch to a maintenance oral agent, such as teriflunomide, dimethyl fumarate or fingolimod. The bridging agent will hopefully prevent rebound MS activity and give you a sufficient period of time to observe for the development of PML. I suggest this period of observation would need to be for a 6-12 months. Once this period of observation is over and PML has not emerged you could probably transition to alemtuzumab without too many concerns. The one proviso is we don’t have data in using alemtuzumab after these new oral agents and hence can’t be confident that the kinetics of immune system reconstitution will be the same as when using alemtuzumab as a 1st-line therapy or following interferon-beta or glatiramer acetate.”

Click on picture to see large image.

“Please note that this advice is not evidence-based and is my opinion backed-up by clinical experience and a theoretical knowledge. Hopefully, Genzyme will do a formal clinical study to test these different options. I think it is very important to know what happens when using alemtuzumab after the oral bridging agents; in particular we need data on safety. Another factor that I have not discussed is availability and local guidelines; firstly you may not have access to the agents outlined above and you may be restricted by local guidelines on how you to use these agents. Finally, a lot of you may disagree with the above proposal; If you are considering switching from natalizumab to alemtuzumab I suggest you have a discussion about these issues with your neurologist. At present I favour option 3; but as with all treatment decisions in MS this should be personalised to the individual concerned and hopefully it will become evidence-based in the future.”

CoI: multiple

23 thoughts on “Clinic Speak: switching from natalizumab to alemtuzumab”

    1. The more I read about alemtuzumab, the more I want it 😉 And I'm getting it in 2 weeks (was on Tysabri, JCV+)

  1. Prof G surely alemtuzumab is safe after Gilenya? Gilenya is not meant to delete lymphocytes but to only trap them in lymph nodes.

    1. This could be interesting looking at the alemtuzumab data in humanised CD52, ALEM got rid of blood B cells but was less effective on cells in lymph glands. I wonder if this will affect autoimmunities appearing

  2. Re anonymous at 2:15, the more I read about later stage ms the less I want it. If alemtuzumab is effective, it is worth the risk.

  3. I agree 2:56, I am also terrified about later stage MS. Thank you for this post Prof G.

  4. My doc warned me that Alemtuzumab is a one way street, but so is MS. (He meant if I were to go on it, would I lose any chance of getting on to new treatments like Ofatumumab at a later stage? Think mouse doc said it would be ok, so is my doc wrong?)Thanks for this brilliant site, btw.

    1. It may well be that the anti-CD20s will knock Alemtuzumab of its perch and there is ocreluzimab and ofatumab. However remember how many years away these drugs are from the finish post. It may well be that a combination of alemtuzumab plus rixtuximab, ocreluzimab or ofatumab. A quick look at ofatumab on clinical trials gov and the phase II finishes in 2016 and then you have 5-6 years for the phase III. By redoing trials infavour of subcutaneous route suggests they are abandoning the induction therapy route to go for repeat dosing and profits. Anti-CD20 as an induction therapy looks attractive on available data and clearly lacks many of the problems of alemtuzumab. However if you are getting on a trial then prior treatment with alemtuzumab may well be excluded and so your neuro may well be rightOcreluzuimab is nearest a phase III finishes december 2015, so 2016 for results to appear for licencig 2017 and NICE 2018. So may be 3-4 years away.ProfG may have more knowledge and it may be quicker. There is always going to be something better round the corner but the question you have to answer is how long do you have to wait. In UK maybe if Novartis can get a first line, given that alemtuzumab has it then it may give more options.However agents like ofatumab on top of alemtuzumab may be the solution to getting rid of the side-effects of alemtuzumab. The antibody is very good at getting rid of T cells perhaps too good, but the B cells are only transiently affected and as they regenerate rapidly within a few moths of treatment and do above starting levels, this may be why you get B cell autoimmunities because there is no T cell control of a rampant B cell response. One solution may be use B cell depleting antibody to stop the autoimmunities. I

    2. Thanks a lot for this, MD. Am weighing up alem, etc, vs poss Laquinimod, both in diff trials. But finding it hard to know which wins..?

    3. Laquinimod about 25% inhibition of relapse, alemtuzumab about 55-75% inhibition, influence on brain shrinkage both I believe, risk of autoimmunity on laquinimod very low, alemtuzumab is high, Risk of getting nothing on laquinimod trial 1 in 3. Talk to your neuro and MS Nurse and read as only you can make the decision. Sorry I can't advise.

    4. Thanks again, am getting as much info as poss, appreciate you not here to advise, but thanks anyway.

  5. I was previously on Natalizumab, Last dose was in 2013. I have a titer count for JC Virus of 3.56. Will this effect me if I take the course of Alemtuzumab ? I recently stopped Tecfidera awaiting wash out period to possibly begin Alemtuzumab. Is there a risk of PML ?

  6. I am on Tysabri and looking to change to either Alemtuzumab or Orcelizumab. As I am JC negative and titer of only 0.18 is it necessary to have a 3 month washout or can I adopt Option 1 above, ie: no washout at all? Does my low titer level reduce the chances of carry over PML?

    1. My titre is 0.216 and I'm classified as JC positive. So my doctor would recommend a spinal tap if I was to transfer to Alemtuzumab. That was more than enough to put me off 😉

  7. I've got a couple of questions on this:1) I've never quite understood why HSCT has lower risk of autoimmunity than Alemtuzumab, though it looks from all the data so far that it does. The conditioning in HSCT (cyclophosphamide & ATG/rituximab) drops your PB leukocyte count close to zero (undetectable) – to the point that you're neutro/lympho/leukopenic and require isolation and prophylaxis – so it must wipe out more T & B lymphocytes than Alemtuzumab… And they even purge lymphocytes from the graft in most protocols (CliniMacs magnetic purging, and/or Rituximab/ATG post transplant), so it's not like the stemmy graft is reloading you with pre-grown lymphocytes.So why does this imbalance of Bs & Ts not happen in HSCT at such a high rate? Appreciate in HSCT you have CD34 stemmies infused to speed up the production of new lymphocytes, but presumably an Alemtuzumab patient hasn't had these knocked out of their bone marrow at all, so they have these in place already. Can you explain what you think is happening differently between the two therapies?2) Feels like there's a huge elephant in the room if Ocrelizumab and Ofatumamab work as well as the data so far suggests. As these anti-CD20's are almost exclusively B cell agents (bar a tiny subset of T cells that it also knocks out), does the data published so far (Ocrelizumab, Rituximab, Ofatumumab) not already punch a big gaping hole in the current understanding that T-Cells are the main culprit? Is it back to the drawing board in that case, and who is doing something about this (appreciate it circumstantially supports the EBV hypothesis Dr G is working on in Charcot)?3) If the anti-CD20s work (and I think everyone will fall over in shock if they don't, based on the current data), why are neurologists not petitioning the regulator about Rituximab – a highly effective anti-CD20 that is already here today, is relatively cheap, and relatively safe (far safer than Ocrelizumab it would seem from the experience in other conditions), and which is very much a known quantity that has been used for decades in other conditions?Is it just me, or is the world going absolutely mad???! If knocking out CD20 is highly effective, and is safer than alemtuzumab, and we can do it today, and people are losing their livelihoods in the meantime to disability and/or PML whilst being asked to wait until 2019…. Whhhhhyyyyyyyyy?!??Surely someone at the top needs to say something? We can all rant on here but have zero sway with the powers that be. Why are neurologists not banding together to do something about this? What are they waiting for? Are they the new FIFA (getting their pockets lined by pharma to shut up) – or do they just not care for their patients? I don't get it.You guys do a great (and very honest) job on the blog of explaining this all to us – for which I am really grateful, but why are the respected experts in the field not kicking someone's door down at NICE and slapping them (very publically) around the face with some of this science fact? Or "accidentally" leaking it to the press?

    1. Point 1IF secondary autoimmunites were going to appear on a par with alemtuzumab then this should have happened by not but it doesnt with other depleting drugs and so i think the problem lies with the MOA of alem and i have a plausible hypothesis based on our work with .mouse CD52 which we will present at MS frontiers and we are writing up the study..

    2. Point 2. Yep the T cellers have a problem with this one. I will accept so of the blame is with the animal modellers for this one….but immune responses even B cell responses rely on T cells. T cell immunotherapy can inhibit all sorts of autoimmunities except human ones…. So is it that the human conditions are not T cell mediated and dogma is wrong. Maybe.Animal modellers are desperately trying to get B cell depletion to do something….but in most studies the influence is not very good. Yep we have tried itHow do anti-CD20 work the modellers will have us believe that it is the few T cells that express CD20…. the other set of people will argue that the antibody is removing antigen presenting cells. However you are right this needs to be brought into the world view, virtually all effective MS drugs target B cell, daclizumab is sort of the odd on one.

    3. Point 3. Read the post linked by Steve S, but as to banding neuros together…it may be easier to heard cats…when taking on pharma is the name of the game.It is easier for Neuros to wait until Ocreluzimab and the others to arrive rather than trying, probably in gain to get rituzimab resurrected so maybe laziness and the amphioxus effect. It boils down to the repurposing effect or the lack of it and the difficulties of doing this. Solve this issue, which is bigger than MS, and then you can get rituximab on the agenda. It makes my blood boil too but having spent three years trying and failing I know there is no easy solution and needs some bigger fish to kick some a**e:-)

    4. Sorry to say what happens at MS frontiers stays at MS frontiers…its not a place frequented by the media types and no public abstracts….we have to wait until the papers arrive.

  8. I'm doing very well on Tysabri. I was diagnosed in 2008. My doctor talked to me yesterday about switching to Lemtrada for multiple reasons:1) I've been on Tysabri since 2010 and just had my 73rd infusion.2) I am JCV positive with an index greater than 1.5 (I think it was 3.47 a few months ago)3) My MS is highly inflammatoryPrior to being on Tysabri, I was taking Copaxone daily. This resulted in active lesions, slurred speech, and vertigo. Within weeks, if not days, after taking Tysabri, I was great. My MRIs have been very stable for the couple of years.Bottomline, I don't want change a good thing. To me the benefits of taking Tysabri out weighed the risk of PML. I'm aware of the symptoms to watch for regarding PML. Lemtrada truly alarms me in terms of treatment (30 hours in one week with drip & wait time), potential side effects and reactions.Please give me your thoughts.

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