ClinicSpeak: DMF fails to stop post-natalizumab rebound

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

"At Barts-MS we continue to de-risk natalizumab-treated MSers at high risk of PML as much as possible. With other treatment options for MSers why would anyone want to stay on natalizumab who is JCV seropositive? There are also more treatments coming, for example, ocrelizumab and daclizumab that will offer efficacy and relative safety from PML. In Sweden, for example, the drug of choice is rituximab that is being used off-label."

"The case study below is a reminder that the lower efficacy drugs, on this occasion DMF (Tecfidera) is not up to the task of preventing rebound post-natalizumab."

"Our biggest problem is switching from natalizumab to alemtuzumab. The switch is relatively straightforward if you are JC virus seronegative and are switching because of lack of efficacy, or for a lifestyle 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 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 within in 6-8 weeks. This early switching strategy also prevents rebound activity when natalizumab wears after approximately 3-4 months."

"With alemtuzumab, an induction agent, 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. I am aware of one person already who has died under these circumstances. 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. Please note that at present only fingolimod has robust enough data to be confident that it prevents rebound. There have been several poster presentations at meetings showing that DMF is not up to the task. I also have personal experience with one of my patients who transferred to me from the USA that had a devastating spinal cord relapse 4 months after stopping natalizumab despite being started on DMF without a washout."

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."

Patti et al. Clinical and radiologic rebound after discontinuation of natalizumab therapy in a highly active multiple sclerosis patient was not halted by dimethyl-fumarate: a case report. BMC Neurol. 2015 Dec 7;15(1):252.

BACKGROUND: The evidence on the use of the oral dimethyl-fumarate after the discontinuation of treatment with natalizumab in people with Multiple Sclerosis is still little. Natalizumab discontinuation may induce the recurrence or rebound of the clinical and neuroradiological disease activity. Currently no therapeutic approach has been established to abolish disease reactivation and rebound after natalizumab interruption.

CASE PRESENTATION: We describe a case of a 21-year-old woman affected from a highly active relapsing-remitting Multiple Sclerosis who developed a clinical and radiological rebound 5 months after the last infusion of natalizumab, while she was being treated with dimethyl-fumarate 240 mg twice daily. She had received a bridge "therapy" with Cyclophosphamide before staring dimethyl-fumarate.

CONCLUSION: We report on this case to stimulate further research to establish whether new current and future drugs available for multiple sclerosis are able to halt the disease rebound after the natalizumab interruption.


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