#MSCOVID19: cladribine is being unfairly tarnished with alemtuzumab’s brush


Barts-MS rose-tinted-odometer: ★★★★★

I think the North American MS community have made some mistakes with their COVID-19 vaccine recommendations, in particular, the NMSS COVID-19 vaccine guidelines for cladribine. In view of the immunology of cladribine’s mode of action and new data that is emerging, I would suggest the NMSS considers updating its guidelines. 

Lemtrada and Mavenclad

If you are about to start Lemtrada or Mavenclad, consider getting the Pfizer BioNTech or Moderna COVID-19 vaccine so that the second vaccine injection is done 4 weeks or more prior to starting Lemtrada or Mavenclad. If you are already taking Lemtrada or Mavenclad, consider administering the vaccine injections starting 12 weeks or more after the last Lemtrada or Mavenclad dose, with the optimal timing of the vaccine 24 weeks or more after the last DMT dose2. When possible, resume Lemtrada or Mavenclad 4 weeks or more following the second vaccine injection. This suggested scheduling is not always possible and getting the vaccine when it becomes available to you may be more important than timing the vaccine with your DMT. Work with your MS healthcare provider to determine the best schedule for you.

Lumping cladribine and alemtuzumab together as being immune-depleters of the same ilk is simply wrong. Alemtuzumab is more of a sledgehammer and is relatively non-selective in depleting both T-cells and B-cells and it also hits innate immunity, in particular monocytes. This is why there is a major infection signal (e.g. listeriosis) with alemtuzumab in the 4-6 weeks after each course of treatment. The latter does not occur with the doses of cladribine we use to treat people with MS.

In comparison, the mode of action of cladribine is very subtle and more in keeping with a selective B-cell depleting agent. Cladribine depletes B-cells by about 85-90% and hits mainly memory B-cells, in other words, large numbers of naive B-cell persist in the peripheral blood. We think as memory B-cells are being killed fresh naive B-cells are being released from the bone marrow. This is important because it is the naive B-cell population that is required to make new antibody responses to vaccines. 

Cladribine only depletes T-cells by about 50% a level that in general is not sufficient to put patients at risk of opportunistic infections or even viral infections. When we recently reanalysed all of the cladribine safety data there was no novel or new exogenous (from outside the body) viral infection signal. The only viral infection signal we saw was zoster or shingles, i.e. a reactivation of a latent virus, which is common and occurs with all immunosuppressive therapies. 

Another very big difference between cladribine and alemtuzumab is the fact that cladribine leaves the innate immune system intact, which is important for fighting infections and for processing vaccine antigens and presenting them to the immune system. 

Another factor that is different is the temporal profile of immunodepletion that occurs with alemtuzumab and cladribine. Alemtuzumab causes rapid cell lysis with its effect noticeable in hours to days; in other words, peripheral blood lymphocyte and monocyte counts are depleted to very low levels (nadir) very quickly. In comparison, cladribine works by triggering apoptosis of cells and lymphocytes die slowly over weeks to months reaching a nadir at about 3 to 4 months after each course. Therefore for the NMSS guidance to say “consider administering the vaccine injections starting 12 weeks or more after the last Mavenclad dose, with the optimal timing of the vaccine 24 weeks or more after the last DMT dose” is actually recommending giving the vaccine from the start of the nadir. 

Unlike alemtuzumab, I think the timing of vaccination in patients treated with cladribine is unlikely to make much of a difference because both the afferent (antigen processing and presentation) and efferent (B-cells/antibodies and T-cells) limbs of the immune system is intact, i.e. there is enough hardware or cells at all times post cladribine to make an immune response. Saying this the summary of product characteristics of cladribine clearly states that live vaccines should be avoided until the immune system has reconstituted and the cells counts have returned to normal. Please note this refers to live vaccines and doesn’t apply to the currently licensed COVID-19 vaccines, which are not live attenuated vaccines or LAVs.

The good news is that the above predictions are being borne out by some real-life flu and VZV vaccine data in cladribine-treated patients that have been presented at ACTRIMS this week. My interpretation of this data is that regardless of when a vaccine is administered in patients on cladribine the appear to mount a good antibody response. I agree the number of subjects studied is small and no subject has had grade 4 lymphopaenia (<200/mm3), but these data at least confirm what you would expect to happen based on immunological principles. 

My advice, therefore, remains the same for pwMS on DMTs; during the height of the pandemic having some immunity to SARS-CoV-2 is better than having no immunity. This is why you should get vaccinated ASAP. If you live in an environment where the background risk of COVID-19 is low then you may want to optimise the timing of your vaccine, when you are next dosed with an immunodepleting therapy or when you start or switch therapies.

Roy & Boschert. Analysis of Influenza and Varicella-Zoster Virus Vaccine Antibody Titers in Patients with Relapsing Multiple Sclerosis Treated with Cladribine Tablets. P059 – ACTRIMS 2021

Background: There is a lack of data available to determine the effect of cladribine tablets (CladT) on the antibody response to vaccination in patients with relapsing multiple sclerosis (MS).

Objectives: To investigate the immunoprotective response to seasonal influenza and varicella-zoster virus (VZV) vaccination in patients treated with CladT (3.5mg/kg over 2 years) for relapsing MS.

Methods: Blood samples collected during the MAGNIFY-MS study (NCT03364036) from 9 patients with relapsing MS treated with CladT who received seasonal influenza (n=8) or VZV vaccinations (n=1; Shingrix) as a standard of care were retrospectively analyzed. Two control blood samples (baseline sample before starting CladT and closest sample available just before vaccination) and two post-vaccination blood samples (closest sample available after vaccination) were examined. Quantitative antibody titers in response to the seasonal influenza and VZV vaccine were measured by hemagglutination inhibition (HAI) assay and Enzyme-Linked Immunosorbent Assay (ELISA), respectively. The seroprotection titer level for the seasonal influenza vaccine is considered ≥40, and was ≥100 IU/L for the VZV vaccine.

Results: Influenza: All patients vaccinated against influenza A and B during year 1 or 2 of CladT treatment retained seroprotection titers of ≥40 in post-vaccination samples across all strains present in the vaccine administered. The number of seropositive patients (HAI ≥40) with a ≥4-fold and ≥2-fold increase against at least 1 strain in post-vaccination titers were 3/8 and 7/8, respectively. VZV: Post-vaccination antibody titers were 40-fold increased over the protective titer at all time points (titers >4748 IU/L).

Conclusions: In this small retrospective investigation, post-vaccination antibody titers in patients treated with CladT for relapsing MS remained at levels that offer protective immunity against seasonal influenza and VZV.

Wu et al.  Evaluating the Impact of Cladribine Tablets on the Development of Antibody Titers: Interim Results from The CLOCK-MS Influenza Vaccine Substudy. P071 ACTRIMS 2021

Background: Cladribine tablets have been approved in more than 80 countries for the treatment of relapsing forms of multiple sclerosis (RMS), and are hypothesized to function as an immune reconstitution therapy with potential to cross the blood-brain barrier. The CLOCK-MS study (cladribine tablets: collaborative study to evaluate impact on central nervous system biomarkers in multiple sclerosis), is a 24-month, open-label, randomized, multicenter, collaborative Phase IV biomarker research study. The COVID-19 pandemic, and pending vaccine availability, have raised important questions around the impact of MS disease modifying therapies on vaccine efficacy.

Objectives: To evaluate the potential impact of prior treatment with cladribine tablets on the development of antibody titres post-influenza vaccination via a sub-study of CLOCK-MS.

Methods: The CLOCK-MS main study will enroll approximately 50 subjects age 18-65, diagnosed with relapsing-remitting MS or active secondary progressive MS, who had inadequate response to, or were unable to tolerate, an alternate drug indicated for the treatment of RMS. Study participants who have taken at least one dose of cladribine tablets and are planning to obtain one standard-of-care influenza vaccine are eligible to take part in the sub-study if they consent to blood draws. Blood sampling will occur 1) 3 Weeks Pre-Vaccine (within 21 days prior to obtaining a standard of care vaccine), 2) 4 Weeks Post-Vaccine (+/- 7 days), and 3) 6 Months Post-Vaccine (+/- 7 days). Measurements of antibody responses will be performed.

Results: So far 5 patients have been enrolled in this sub-study and had initial titers drawn. All patients fulfilled the per-label requirements for vaccination after cladribine tablets treatment. Initial results at Week 4 post-vaccination will be presented.

Conclusions: The impact of cladribine tablets, a lymphocyte-lowering agent, on the immune system’s ability to develop antibodies in response to a vaccine has not yet been studied. These results are expected to provide preliminary observations around the impact of cladribine tablets on influenza vaccine efficacy in patients with RMS.

CoI: multiple

Twitter: @gavinGiovannoni                                      Medium: @gavin_24211

About the author

Prof G

Professor of Neurology, Barts & The London. MS & Preventive Neurology thinker, blogger, runner, vegetable gardener, husband, father, cook and wine & food lover.


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    • Our data won’t be available for some months. I am hoping the Israeli MSologists will publish their data soon. I am told that cladribine-treated patients seroconvert very well.

    • It wish!. ProfK hs some insight. I think disease activity after cladribine treatment should be an option to re treat not switch after all with alemtuzumab people fail the first two cyles and get more. I found out recently that there is a risk sharing scheme in the UK that the makers of the drug pay the UK government back for everyone that switches from cladribine within the first 4 years. I hope the manufactureres with give us the result soon

    • My advice is in the guide:

      Starting treating? If you can, delay starting alemtuzumab until 3-4 weeks after completing COVID-19 vaccine
      On treatment already? If you can, consider delaying second or subsequent courses of alemtuzumab until 3-4 weeks after completing COVID-19 vaccine. If your immune system has recovered from previous courses of alemtuzumab there are no concerns about the timing and receipt of the vaccine.
      Which vaccine? Whichever COVID-19 vaccine is offered

    • It is only if you have had alemtuzumab in the last few months and you are severely lymphopaenic that there are concerns about a suboptimal response, which is why the NMSS and others are saying delay vaccination for 24 weeks. I say yes and no. Yes, if you are prepared to continue self-isolating etc. No, if you want a chance of some immunity now. You also have to realise that immunity is not guaranteed. None of the vaccines is 100% effective, but they very close to that in terms of preventing severe COVID-19.

  • Potential mechanisms of action related to the efficacy and safety of cladribine David Baker , Gareth Pryce , Samuel S Herrod, Klaus Schmierer . Mult scelr rel disor 2020; DOI: 10.1016/j.msard.2019.02.018

    Read this paper and it predicts what may happen…so far nothing dissuades me that we are wrong…reassuringly simple

  • Have to agree with ProfG…Cladribine is reassurringly simple to explain and it is very different from alemtuzumab but I think it is similar in terms of efficacy and perhaps evenn better

      • No Cladribine is a small molecule and not a biological (protein) so neutralising anti-drug antibodies are not a problem. Saying this a small number of people develop skin hypersensitivity reactions to cladribine; the latter is a form of an allergic reaction. This is thought to be by a process called a hapten effect; i.e. cladribine bound to a protein becomes immunogenic and triggers an allergic reaction. Hapten-induced allergic reactions are uncommon but are how small molecules induce allergic reactions, some of these hypersensitivity reactions antibody-mediated.

  • Just been contacted by a journalist to comment on this post. This is what I said:

    I am told the NMSS advisory committee wanted to keep things simple, which they have a right to do. But the MS community is very knowledgeable and have shown many times that they can deal with complexity. In my experience, the informed patient with MS is often more knowledgeable about their disease than their neurologist. I have learnt that trying to dumb things down for the sake of simplicity, is not only patronising but is bound to backfire. It is sloppy and lazy to lump cladribine and alemtuzumab together. These two drugs may have similar modes of action in terms of targeting memory B-cells in MS, but how they get there is very different. The advice on DMT dosing during COVID-19 has safety implications. I can imagine the scenario of someone not being vaccinated when they should have been and then getting severe COVID-19 and dying. Who is responsible? 

  • This vaccine view was given to the the US neurologists by Prof Bar-Or at ACTRIMS, so you know where it comes from

  • “Alemtuzumab is more of a sledgehammer and is relatively non-selective in depleting both T-cells and B-cells and it also hits innate immunity, in particular monocytes.”

    What about the situation where year 1 Mavenclad reduced monocytes by 80%, even though it’s not supposed to? (Documented).

    This is innate immune system. I also had thyroid effects from Mavenclad which is also not supposed to happen.

    I would like to know why – overtreatment? The dose-by-weight did concern me because I am both heavy, and overly sensitive to medications.

    Is there another reason Mav would remove such a large chunk of monocytes? They did recover eventually.

    Should someone in this situation follow Lemtrada guidelines for Covid vax rather than your suggestions for Mavenclad?

    How could one remove the possibility of monocytes being decimated again for year 2? (Hypothetical question since you don’t speak to specific situations here.)

    I would love some insight for those of us at the extremities of the bell curve.

  • Good Evening.
    First thank you for your data and knowledge. Second, I was hoping to ask a question. I am scheduled to start year 1, dose 2 of cladribine on March 15th. I have read your blog and it was very informative. My question is, I want to get the covid vaccine asap and can however I keep pushing it to the side because my biggest concern is the vaccine affecting the efficacy of the cladribine meaning if I take the covid vaccine either a few days before or even during treatment, the vaccine will not allow the cladribine to do its job. Please know that I have done my research and have even called the manufacturer without any success. I know the covid vaccine is something new that most MS pharmaceutical companies have not dealt with but the manufacturer for cladribine could not even tell me if I could take a non-live vaccines either before or during treatment. Please know I am not scared of the covid vaccine I am more concerned of it affecting the efficacy of the cladribine.

  • Summary: it doesn’t matter when I am vaccinated with Mavenclad.

    I’m year 2 week 1. I will be able to be vaccinated between weeks 1 and 2 according to the vax schedule but could delay a month .

    I’m being told to wait for months.

    The article suggests there is no ideal time and that I should go ahead.

    Would it depend on monocyte level? Mine was substantially reduced year 1.

    No vax hesistancy here! Medical hesitancy.

    • ProfK has just finished updating vaccine advice and that will be uploaded very soon, ProfG is keen you start quickly but to optimize response maybe some waiting. ProfK specifically addresses mavenclad. Based on the MAGNIFY you should respond to vaccination…we are aware that there is data in israel, the person will present it

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