Wednesday, 7 May 2014

Clinic Speak: switching from fingolimod to alemtuzumab

Switching from fingolimod to alemtuzumab #ClinicSpeak #MSBlog #MSResearch

"My post on switching from natalizumab to alemtuzumab has generated a lot of interest and comments; some have come to me via email. This post addresses some of the questions raised."


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"One question needs more explanation and I don't have an answer; i.e. '.... surely alemtuzumab is safe after Gilenya? Gilenya is not meant to delete lymphocytes but to only trap them in lymph nodes'." Yes,  that is the current dogma and in all the short-term studies of fingolimod treatment the lymphocyte counts rebound rapidly after about 6-8 weeks post-withdrawal of the drug. However, what concerns me is the report below that describes two MSers who had sustained lymphopenia (low lymphocyte counts) 9 & 34 months after stopping fingolimod. What would happen if these MSers had been given alemtuzumab that blows away your immune system and relies on stem cells and memory cells to reconstitute the immune system? I suspect alemtuzumab would have made matters worse in this situation. Therefore bridging from natalizumab to alemtuzumab via fingolimod or switching from prolonged use of fingolimod to alemtuzumab needs to come with a health warning to your immune system. I suspect that the cause of prolonged lymphopenia post-fingolimod is related to duration of fingolimod treatment and if you bridge for a short period of time it is unlikely to be a problem. A simpler solution would be not to use fingolimod as the bridging agent, but rather teriflunomide of dimethyl fumarate that have a less effect on peripheral lymphocyte counts. I hope you are beginning to realise the importance of post-marketing studies to look at these options. We need evidence."

"This discussion raises questions about using alemtuzumab post-fingolimod when the MSer have been on fingolimod for a long period of time and are at risk of persistent lymphopenia. Based on the observations below I think a fingolimod wash-out with a period of observation would be appropriate. You would not want to treat someone with with alemtuzumab who had a persistent lymphopenia post-fingolimod. The problem is that a fingolimod washout has problems of its own. Not too dissimilar to a natalizumab washout, a fingolimod wash-out is associated with rebound of MS disease activity. I have pulled together a few of the papers below that describe this phenomenon. The implications of this are not minor and if you are risk averse and don't want to take a chance of rebound MS disease activity you may want to bridge with another agent when switching from fingolimod to alemtuzumab."
"It is becoming increasingly clear that sequencing of MS DMTs will become more complicated with time. This is why we are going to need real-life data from registries to inform clinical practice. A good example of this is the evidence that has emerged when switching from natalizumab to fingolimod; we have confidence in making recommendations."

"Does the information presented above and the infographic below make sense?" 

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Johnson et al. Reconstitution of circulating lymphocyte counts in FTY720-treated MS patients. Clin Immunol. 2010 Oct;137(1):15-20.

Background: FTY720 (Fingolimod) reduces multiple sclerosis disease activity by inducing lymphopenia and inhibiting lymphocyte re-entry from lymph nodes. Peripheral lymphocyte reconstitution following drug discontinuation has been considered relatively rapid (2-4 weeks), based on short-term studies. 


Objective: We investigated the kinetics of lymphocyte reconstitution in MSers in open label extension phases of FTY720 clinical trials who discontinued therapy after prolonged use (>1-5 years), and examined histological features of a mediastinal lymph node obtained from a lymphopenic FTY720 MSer. 

Results: Although three MSers showed reconstitution of peripheral lymphocytes within the predicted timeline, two MSers continued to be lymphopenic 9 and 34 months after therapy cessation. Lymph nodes from the latter MSer showed preserved architecture. 

Conclusion: Notwithstanding preserved lymph node integrity, time for lymphocyte reconstitution after prolonged FTY720 therapy can be significantly greater than predicted by shorter-term studies. This is relevant for clinical decisions regarding management of MSer using this therapy and for introducing alternate therapies.

Rebound post fingolimod:

Rebound MS disease activity post-fingolimod. From: Neurology. 2012 Nov 6;79(19):2006-7.

Hakiki et al.Withdrawal of fingolimod treatment for relapsing-remitting multiple sclerosis: report of six cases. Mult Scler. 2012 Nov;18(11):1636-9.

Objective: To report our experience on fingolimod suspension in MSers. Methods: We evaluated clinical and magnetic resonance (MR) outcomes in 6 MSers after fingolimod discontinuation. Results: Within 3 months from fingolimod suspension, 5 subjects returned to pre-treatment disease activity; one MSers, however, exhibited a clear rebound of clinical and MR activity. Conclusion: Our findings suggest that clinical and MR outcomes after fingolimod suspension can vary among MSers. Systematic collection of clinical, laboratory and imaging data is highly advisable to identify subjects who are at higher risk of rebound and to define effective management strategies in these subjects.

Sempere et al. Rebound of disease activity during pregnancy after withdrawal of fingolimod. Eur J Neurol. 2013 Aug;20(8):e109-10.


Gross et al. Multiple sclerosis rebound following herpes zoster infection and suspension of fingolimod. Neurology. 2012 Nov 6;79(19):2006-7.

CoI: multiple

3 comments:

  1. This post is very clear. Thanks for taking the time to try and explain this complex topic. I agree with you that MS is going to become increasingly specialised as more DMTs appear on the market.

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  2. Does rebound occur in patients with persistent lymphopenia after fingolimod discontinuation? One might (naively) expect that maintaining low lymphocyte counts would still protect from autoimmune attack. If rebound still occurs, does it imply additional mechanisms of fingolimod efficiency (beyond trapping the lymphocytes in the lymph nodes)?

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    Replies
    1. Re: "Does rebound occur in patients with persistent lymphopenia after fingolimod discontinuation?"

      I don't know. I agree if that is the mode of action is linked to lymphopaenia then rebound should not happen. But in autoimmunity only a very small number of cells can trigger the disease.

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