Rebound after switching with fingolimod

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Rebound in MS disease activity occurs when coming off highly-active drugs. It refers to a return in MS activity that is more than before. The drugs most likely to demonstrate this are the highly-active treatments that are given on a regular basis (i.e. maintenance treatments, such as natalizumab and fingolimod – it is too early to say with ocrelizumab) that create a gating system for the immune system and once released from the hold result in an inflated rebound phenomenon. But, this is not to say that it doesn’t occur with induction strategies, and I have witnessed this with alemtuzumab.

See the source image
Figure: Severe rebound after withdrawal of fingolimod – arrowed with enhancement on the far right images (source: Severe rebound after withdrawal of fingolimod treatment in patients with multiple sclerosis – Multiple Sclerosis and Related Disorders (msard-journal.com)

The strategy then is to step down/up or switch individuals to an equivalent or more highly active preferably induction treatment, especially one that is a immune cell depleter. An example, is to switch fingolimod to alemtuzumab, ocrelizumab or cladribine, or natalizumab to alemtuzumab, fingolimod or cladribine. My preference over the years, however, has been to rely exclusively on switching to an induction strategy as this gives room for the body’s own homeostatic/regulatory aspects to act in between the induction courses to prevent that sudden alteration that comes with directly switching to another maintenance strategy.

I learnt this observing the haem-oncology patients receiving bone marrow transplant and various induction courses of immune cell treatments and use the term ‘de-escalation’ when referring to this type of protocol, as you are by in large de-escalating the rebound risk or another risk perceived with the parent compound.

The drug you choose to de-escalate with is critical and should be of similar or better efficacy than the parent compound. So, no use de-escalating fingolimod to interferons, or dimethyl fumarate for that matter as they’re not highly active enough to smooth over the rebound that will occur once the gate is re-opened.

In this modestly sized study reported below the authors talk about how best to de-escalate fingolimod, whether cladribine or rituximab would be better. It is no surprise that this study has come out now, it most likely stems from the lack of COVID-19 antibody response to vaccines with fingolimod and clinicians are trying to see how best to withdraw out fingolimod.

And, much as I do champion cladribine, it is to be expected that rituximab would fare better in the outcomes (See Figure below). It is important to note that the baseline make-up of the individuals undergoing either switch were very similar and therefore this result is due to the drugs that they switched to.

Figure: Proportion of patients treated with cladribine or rituximab experiencing rebound disease activity, relapse or MRI activity after switching from fingolimod.

I might also add that using a pure B-cell depleter in the context of an MS rebound phenomenon doesn’t make much sense. If this is a B-cell lymphoma then I would say certainly, but really I would have used a higher efficacy global agent (both T and B-cell depleter), such as alemtuzumab – although I agree with the authors that the data on alemtuzumab for this purpose is conflicting. Another point to make is that age matters and this is because of senescence of immune system over time, and being young when making these switches may be one of the most important factors in rebound. Moreover, the more highly active in terms of Gad enhancing lesions at the start of your MS the more likely that you will experience rebound when switching treataments.

Abstract

Mult Scler Relat Disord. 2022 Apr 17;62:103812. doi: 10.1016/j.msard.2022.103812. Online ahead of print.

Risk of fingolimod rebound after switching to cladribine or rituximab in multiple sclerosis

Gro Owren Nygaard Hilde Torgauten Lars Skattebøl Einar August Høgestøl Piotr Sowa Kjell-Morten Myhr Øivind Torkildsen Elisabeth Gulowsen Celius 

Background: A sudden onset of extensive disease activity, including severe clinical relapse and extensive brain or spinal magnetic resonance imaging (MRI) lesions, termed “rebound” disease activity has been reported after withdrawal of fingolimod in patients with multiple sclerosis (MS).

Objective: To compare the risk of rebound after switching from fingolimod to cladribine or rituximab in MS.

Methods: All patients switching from fingolimod to cladribine or rituximab were included in a retrospective cohort study utilizing prospectively collected data from two university hospitals with different treatment strategies.

Results: A total of 73 patients with at least 6 months follow-up after switching were identified, 33 patients had switched from fingolimod to cladribine and 40 patients to rituximab. No patients in the rituximab group and seven (21.1%) in the cladribine group qualified for rebound disease activity. Ten (30.3%) of the patients using cladribine and five (12.5%) of the patients using rituximab experienced a relapse. MRI disease activity was seen in 18 (54.5%) and eight (20.0%) of the patients using cladribine and rituximab, respectively. Younger age and previous high relapse rate were associated with increased risk of rebound in the cladribine group.

Conclusions: We identify a lower risk of rebound during the first year after switching from fingolimod to rituximab compared to cladribine, indicating a better initial clinical outcome with the former treatment strategy.

About the author

Neuro Doc Gnanapavan

19 comments

  • Hello, are there any studies on which is the best DMT to avoid rebound after Natalizumab discontinuation? Thanks.

    • Hi Aileen, the link is to another article on this topic published in the MSARDs journal which is why I’ve put the figure details in there for those who don’t have a subscription.

  • Thanks

    Are there any researchers looking at the reasons for rebound activity? The answer as to why it occurs should tell us something fundamental about MS.

    I’m not a scientist, but the rebound phenomenon suggests that:

    (i) the immune cells in the peripheral immune system can’t get in to the CNS so start building up. Once the gate is opened to the CNS eg patient stops taking Natalizumab, the immune cells rush in in numbers causing lots of damage; or

    (ii) when the patient starts on a drug such as Natalizumab which stops immune cells from the peripheral immune system entering the CNS, the cause of MS (?virus, ?plasma cells) increases to a much higher level than before ie when the immune cells kept it in check. Thus, when the gates are opened (patient stops taking Natalizumab) the immune system piles in as the cause / damaging processes have got out of control.

    Perhaps the Sizomus trial will provide some insights ie if plasma cells in the CNS are destroyed one might expect to see less immune cells entering the CNS from the peripheral immune system as the targets are no longer there / are reduced. I assume this can be measured ie analysis of CSF.

    • The timing of the rebound suggests it’s more likely to be (i) rather than (ii), particularly as it takes a certain amount of time before residual natiluzimab is cleared from the body.

    • the migration inhibitors natalizumab are associated with rebound…I think the others are largely just relapses coming back….if you take the breaks off thedamaging cells are waiting to pour into the CNS, with others they have to be generated and this occurs at variable rates

  • Thanks for the post!
    Considering the high risk of rebound disease activity after fingolimod, and the fact that it is also a moderately efficacious DMT makes me really question what the appeal of this type of treatment is. I mean, how many people stay on fingolimod for extended periods of time to compensate for this risk? And is the side-effect profile really that much better than the more potent therapies? (save alemtuzumab, which obviously comes with a greater risk than the other infusions)

      • Induction treatments do but upfront and then your own body’s immune homeostatic mechanisms kick in. With sustained immunosuppression the deficit becomes larger over time.

        • what about Fingolimod and Siponimod? How does it compare to antiCD20’s and does it become worse overtime? Thank you!

  • “And, much as I do champion cladribine, it is to be expected that rituximab would fare better in the outcomes… It is important to note that the baseline make-up of the individuals undergoing either switch were very similar and therefore this result is due to the drugs that they switched to.”

    First, I didn’t know you’re a champion of cladribine, but welcome to the club🙂

    Second, this study is inconclusive to say the very least – in reality I believe it is flawed. Why? Because we know that rebound disease after Fingolimod can occur with total lymphocyte counts as low as 0.6/0.7. However, the mean count at treatment start was around 1.0. If you wait that long, and remember that cladribine develops its full effect within 4-6 weeks, you are opening a large ‘window of opportunity’ for breakthrough disease to happen. This is particularly true in pwMS who have breakthrough disease on an – in most cases – very effective DMT.
    So, your statement that the difference in rebound activity “is due to the drugs that they switched to” cannot be supported by this study. The difference is far more likely explained by the time neurologists were prepared to wait before starting follow-on treatment. The lack of an association between Tx delay and rebound does nothing to refute this given both the degree of lymphocyte depletion on Fingolimod and the speed of recovery after stopping it are highly variable. IMO this study does nothing to help clarifying rebound disease or to decide whether one or another DMT is more effective in preventing it.

    • I take your point and the switch would have been better if it had happened sooner. But, I don’t think total lymphocyte counts (i.e. peripheral blood counts) are a good marker of disease activity in MS and too many people faff around talking about waiting for lymphocyte counts to recover.

      The definition used in the study for rebound is as follows: ‘Rebound was defined as new clinical neurological symptoms and extensive MRI lesions exceeding pre-fingolimod treat
      ment disease activity within the first year after switch.’

      They found also the following: ‘Risk of rebound was associated with a younger age (t = 2.54, p =0.016) and a higher pre-fingolimod treatment annual relapse rate (t= 2.10, p = 0.044). Patients who experienced rebound were on average 10 years younger. Neither gender, disability level, number of previous DMTs, lymphocyte counts, switch interval, bridging therapy with steroids or duration of fingolimod treatment before withdrawal were associated with risk of rebound’

    • As someone who has been researching stopping fingolimod for several months now, it seemed immediately suspicious me that 20-30% of patients switching to cladribine had new disease activity. It seems to me that with the mitigation methods available, the baseline rebound rate is lower than this?

      • This figure varies from publication to publication, from 10%-40%. Not surprisingly those using shorter MRI interval after stopping quote a higher figure Ten percent is still a high figure though.

  • When I went off of fingolimod I had to wait just over 5 months for my lymphocytes to return to a high enough level to start Ocrevus. The study you mentioned did not say what the time periods were for people on no treatment before the switch to either Rituximab or Cladribine. I do hope that neurologists are very clear now before putting folks on Fingolimod about the risks of rebound and the lack of response to Covid vaccines. It seems to me that those two strikes are enough to opt for a different DMT.

    • RA – Hope this information is helpful. Manuscript on Cladribine, which includes recommendations for switching from DMT x to CLAD. The only information missing in the below paper are guidelines for switching from an Anti CD-20 to CLAD. Nevertheless, a good reference for anyone taking of thinking about taking CLAD.

      AlJumah M, Alkhawajah MM, Qureshi S, et al. Cladribine Tablets and Relapsing-Remitting Multiple Sclerosis: A Pragmatic, Narrative Review of What Physicians Need to Know. Neurol Ther. 2020;9(1):11-23. doi:10.1007/s40120-020-00177-5 (Feb. 13, 2020):
      https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7229040/#CR26

    • The gap between switch was 44days (standard deviation 31days) for cladribine and 42 days (standard deviation 33days) from stopping fingolimod so a fairly large gap.

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