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.”