Thinking about switching.


Switching from fingolimod has an impact on ocrelizumab

Signoriello E, Lus G, Bonavita S, Lanzillo R, Saccà F, Landi D, Frau J, Baroncini D, Zaffaroni M, Maniscalco GT, Curti E, Sartori A, Cepparulo S, Marfia GA, Nicoletti CG, Carotenuto A, Nociti V, Caleri F, Sormani MP, Signori A. Switch from sequestering to anti-CD20 depleting treatment: disease activity outcomes during wash-out and in the first 6 months of ocrelizumab therapy. Mult Scler. 2021 Apr 15:13524585211005657. doi: 10.1177/13524585211005657. 

Last week NDG posted on “stuck in the Loop” and suggested you need to think about how you exit from a treatment before you start it. There have been a few papers on alemtuzumab and cladribine about whether fingolimod treatment may influence the efficacy of the subsequent treatment and here is another example with ocrelizumab

Objectives: Switching between treatments is an opportunity for patients with multiple sclerosis (MS) to ameliorate disease control or safety. The aim of this study was to investigate the impact of switching from fingolimod (FTY) or natalizumab (NTZ) to ocrelizumab (OCR) on disease activity.

Methods: We retrospectively enrolled 165 patients treated with OCR from 11 MS centres. We assessed the association of demographic and clinical characteristics on relapse rate (RR) and activity on magnetic resonance imaging (MRI) during wash-out and after 6 months of treatment with OCR through univariable and multivariable negative binomial regression models.

Results: We registered a total of 35 relapses during the wash-out period. Previous treatment with FTY, relapses in the previous year, and relapsing-remitting course were associated with higher RR. In the first 6 months of OCR, 12 patients had clinical or MRI disease activity. Higher Expanded Disability Status Scale (EDSS) and higher lymphocyte count at OCR start were associated with a reduced probability of relapse.

Discussion and conclusion: This study confirms that withdrawal from sequestering agents as FTY increases the risk of relapses in the wash-out period. Nevertheless, starting OCR before achieving complete immune reconstitution could limit its effectiveness in the first 6 months probably because trapped lymphocytes escape the CD20-mediated depletion.

Switching from Fingolimod to Alemtuzumab runs the risk of failure and secondary autoimmunity

Alemtuzumab used to have a first line (use straight from diagnosis) use in Europe and it was relatively well tolerated, based on UK data, but the US thought it was more problematic and had it third line (you had to fail two other MS drugs before you can use it) and now because of vascular issues Europe is more likely to use it third line. So if you fail second line, this real life data is of interest. This data suggests that if you are failing fingolimod the risk of alemtuzumab not working is increased as is the risk of secondary autoimmunity. This data would not occur in the trials as the drug was used after a CRAB drug (beta interferon of glatirmer acetate) and not fingolimod. It was first suggested that fingolimod may limit the activity of alemtuzumab possibly because it traps cells in the lymph glands or bone marrow and so they aren’t effectively killed by alemtuzumab.

So again, I say when you think about going onto a disease modifying treatment you need to give consideration to “where next?” in case it fails. This perhaps makes alemtuzumab a less exciting third choice or perhaps makes fingolimod as a less obvious second choice. Is this a problem of fingolimod or sphingosine-one-phosphate receptor modulators (Siponimod, ozaniod, ponesimod)?

Other people had taken interferon beta, dimethyl fumarate or were natalizumab failers or natalizumab switchers due to PML risk mitigation (avoidence of PML a viral brain disease). Natalizumab prior use was also risk factor for relapse (Hazrd Ratio 1.460, 95% CI 1.098 to 1.940; p=0.009). This could be drug-related although the people taking natalizumab and fingolimod, may have had an underlying high-disease activity.

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Impact of previous diseasemodifying treatment on effectiveness and safety outcomes, among patients with multiple sclerosis treated with alemtuzumab.Pfeuffer S, Ruck T, Pul R, Rolfes L, Korsukewitz C, Pawlitzki M, Wildemann B, Klotz L, Kleinschnitz C, Scalfari A, Wiendl H, Meuth SG.J Neurol Neurosurg Psychiatry. 2021 Mar 12:jnnp-2020-325304.

Objectives Alemtuzumab is effective in patients with active multiple sclerosis but has a complex safety profile, including the development of secondary autoimmunity. Most of patients enrolled in randomised clinical trials with alemtuzumab were either treatment naïve or pretreated with injectable substances. Other previous disease-modifying treatments (DMTs) were not used in the study cohorts, and therefore, associated risks might yet remain unidentified

Methods We retrospectively evaluated a prospective dual-centre alemtuzumab cohort of 170 patients. We examined the baseline characteristics as well as safety and effectiveness outcomes, including the time to first relapse, the time to 3 months confirmed disability worsening and the time to secondary autoimmunity

Results The analysis showed that, among all previously used DMTs, the pretreatment with fingolimod (n=33 HRs for the time to first relapse (HR 5.420, 95% CI 2.520 to 11.660; p<0.001)) and for the time to worsening of disability (HR 7.676, 95% CI 2.870 to 20.534; p<0.001). Additionally, patients pretreated with fingolimod were more likely to experience spinal relapses (55% vs 10% among previously naïve patients; p<0.001) and had an increased risk of secondary autoimmunity (HR 5.875, 95% CI 2.126 to 16.27; p<0.001).

Conclusion In the real-world setting, we demonstrated suboptimal disease control and increased risk of secondary autoimmunity following alemtuzumab, among patients previously treated with fingolimod. These data can provide guidance for improving MS therapeutic management.

If fingolimod increases risk of autoimmunities, what does it do to anti-drug antibody responses…Dr Angry Can you help?COI Multiple

Disclaimer: Please note that the opinions expressed here are those of the author and do not reflect the positions of the Barts and The London School of Medicine and Dentistry nor Barts Health NHS Trust or Queen Mary Univeristy of London.

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  • Is there any downside in transitioning from fingolimod to another S1 modulator with a shorter washout period?

    • Very good question. We dont have the evidence I suspect, siponimod in Europe is a a secondard progressive agent, so there is nothing to switch to…the others haven’t been around long enough. As you say fingolimod has a long wash out period and it will be interesting to know. Also we need to know how you switch from the new S1P1 agents

  • “increased risk of secondary autoimmunity following alemtuzumab”

    But this happens with hsct..and can happen naturally with no treatment.

  • Shouldn’t ocrelizumab stay around for months and kill lymphocytes as soon as they are released from lymph nodes if given immediately after the decision is taken?

    • Replapes in the first 3 months of switching is likely due to a limited number of antibody getting into CNS. What are the risks of switching to Ocrelizumab as soon as stopping FTY?

  • Should Ocrevus users be exercising extra care re Covid?

    According to MS Trust : Your risk of severe Covid-19 infection is likely to be increased for many months after treatment with Ocrevus. People on Ocrevus should therefore take extra precautions to prevent infection.

    Such as what do you think?

  • Mouse Doctor, I am in full decision to switch: alemtuzumab or ocrelizumab?
    I try to explain myself, but I’m Italian so forgive my English.
    I am a woman and had my diagnosis in 2018 with norb (largely resolved vision problem). Negative rachicentesis (CSF and serum oligloclonal bands absent) and some small lesions, no spinal cord but “only” at the level of the brain. My EDSS was, and still is, equal to 1.

    I started with Tecfidera, but after a year and a half my 3 MRIs showed new lesions, some active. So I switch with Fingolimod.
    After a year of Fingolimod and 2 still not clean resonances, with 3 new lesions, one of which is active. (My lesions are localized on the left periventricular region, the new active lesion is in the right periventricular area and dull lesions are at the level of the corpus callosum in the right frontal site.)

    So here I am now, at 34, with a new therapy change.
    My neurologist first proposed Lemtrada to me as the most effective therapy in my case and considering the change from Fingolimod. Then, given my fear of serious side effects and my doubts (will they be right?), She proposed me as a safer alternative (but will it be just as effective?).
    From this article I read that switching from Fingolimod can have problems for both Alemtuzumab and Ocrelizumab.

    Beyond the switching problems, I struggle to choose … I wouldn’t want to miss the opportunity to make a super effective drug like Lemtrada now that I’m fine, but I don’t know if the risks actually exist.

    I am reading your articles to get an idea but it is not easy.
    I don’t know if you can give me information that will help me clarify my ideas.

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