#COVIDMS COVID-19 case study 2

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I hope you enjoyed the first COVID-19 case study. The following is another case study that has just arisen in our unit.

Case study: The patient has highly-active DMT having failed a trial of dimethyl fumarate (DMF). She had a brain-stem relapse and her MRI had shown several new lesions. She was switched to oral cladribine and had her first-cycle of 5 days of treatment two weeks ago. She is due for her second cycle of oral cladribine in 2 weeks time. She is very concerned about COVID-19 infection. She works in London and communtes daily to work on the overground.

The COVID-19 ABN guidelines advise us not to do give her her second cycle of oral cladribine.

How are you going to manage this patient?

Postscript – 18 March 2020

Please note I am going to curate these case studies on a dedicated COVID-19 microsite to allow readers to access them in one place.

There is no right or wrong answer her only an opinion and an informed choice. 

This patient has highly-active MS and needs it treated. As she has committed herself to treatment with oral cladribine she will likely be mildly lymphopaenic already from the first cycle of cladribine. 

If we stick to the SIN or ABN guidelines we would have to suspend dosing. However, we may not have given her sufficient cladribine to have an effect on her MS. We do know that one course of cladribine does work and there is published data from Australia that shows this quite convincingly (see MS-Base data below). 

If we don’t complete her course of cladribine could we use an alternate DMT? I would not recommend platform therapies as she has failed on DMF, although teriflunomide may be a holding strategy. Why teriflunomide? It works better second or third-line and has broad antiviral properties that may make it an ideal DMT in this situation. 

Natalizumab would also be an option, but as she does not fulfil the current guidance for being treated with natalizumab under the NHSE DMT treatment algorithm this is not an option at present. Fingolimod will leave her immunosuppressed and starting her on fingolimod when she has a cladribine-induced lymphopaenia is unknown territory and likely to increase her level of immunosuppression. 

My recommendation would be for her to complete her first course of cladribine and to be extra-vigilant about hygiene and social distancing and avoiding high-risk travel. I also want to remind you that the level of immunosuppression after one course of cladribine is relatively moderate. Cladribine only drops T-cell counts by about 40-50% and the levels usually don’t fall into the range that is associated with opportunistic infections. When you analyse the safety profile of those subjects in the CLARITY and CLARITY EXTENSION studies, even those that develop grade 3 or 4 lymphopaenia (lymphocyte counts less than 500/mm3), there really is no obvious viral or severe viral, infection signal apart from herpes zoster. Therefore, I suspect the risk to this patient from severe COVID-19 infection is low. 

Based on the lymphocyte pharmacodynamics and the integrated safety analysis I would classify cladribine as an intermediate risk DMT in relation to severe COVID-19 infection in the same class as ocrelizumab. I really don’t know why it is being put in the same risk category as HSCT and alemtuzumab. 

MS-BASE single course of oral cladribine data

Kalincik et al. Cladribine Versus Fingolimod, Natalizumab and Interferon β for Multiple Sclerosis. Mult Scler, 24 (12), 1617-1626 Oct 2018. 

Objective: This propensity score-matched analysis from MSBase compared the effectiveness of cladribine with interferon β, fingolimod or natalizumab.

Methods: We identified all patients with relapse-onset multiple sclerosis, exposure to the study therapies and ⩾1-year on-treatment follow-up from MSBase. Three pairwise propensity score-matched analyses compared treatment outcomes over 1 year. The outcomes were hazards of first relapse, disability accumulation and disability improvement events. Sensitivity analyses were completed.

Results: The cohorts consisted of 37 (cladribine), 1940 (interferon), 1892 (fingolimod) and 1410 patients (natalizumab). The probability of experiencing a relapse on cladribine was lower than on interferon ( p = 0.05), similar to fingolimod ( p = 0.31) and higher than on natalizumab ( p = 0.042). The probability of disability accumulation on cladribine was similar to interferon ( p = 0.37) and fingolimod ( p = 0.089) but greater than natalizumab ( p = 0.021). The probability of disability improvement was higher on cladribine than interferon ( p = 0.00017), fingolimod ( p = 0.0025) or natalizumab ( p = 0.00099). Sensitivity analyses largely confirmed the above results.

Conclusion: Cladribine is an effective therapy for relapse-onset multiple sclerosis. Its effect on relapses is comparable to fingolimod and its effect on disability accrual is comparable to interferon β and fingolimod. Cladribine may potentially associate with superior recovery from disability relative to interferon, fingolimod and natalizumab.

Lymphocyte depletion kinetics and impact on subsets post cladribine

Stuve et al. Effects of Cladribine Tablets on Lymphocyte Subsets in Patients With Multiple Sclerosis: An Extended Analysis of Surface Markers. Ther Adv Neurol Disord, 12, 1756286419854986 2019 Jun 18 eCollection 2019

Background: Cladribine tablets 3.5 mg/kg cumulative over 2 years (CT3.5) had significant clinical/imaging effects in patients with clinically isolated syndrome (CIS; ORACLE-MS) or relapsing-remitting MS (RRMS; CLARITY and CLARITY Extension). 

Objective: This analysis compared the effect of cladribine tablets on the dynamics of immune cell reduction and reconstitution in ORACLE-MS, CLARITY, and CLARITY Extension during the first year of treatment (i.e. the first course of CT1.75) in patients randomized to CT3.5.

Methods: Lymphocyte subtypes were analyzed using multiparameter flow cytometry. Changes in cell counts and relative proportions of lymphocytes were evaluated at weeks 5, 13, 24, and 48.

Results: Across studies, consistent and comparable selective kinetics of immune cell populations occurred following the first treatment year with CT. A rapid reduction in CD16+/CD56+ cells (week 5 nadir), a more marked reduction in CD19+ B cells (week 13 nadir), and a less-pronounced effect on CD4+ (week 13 nadir) and CD8+ T cells (week 24 nadir) was shown. There was little effect on neutrophils or monocytes. Lymphocyte recovery began after treatment with CT3.5. Regarding relative proportions of naïve and memory T-cell subtypes in ORACLE-MS, the proportion of naïve-like naturally occurring T-regulatory cells (nTregs) decreased, and the proportion of memory-like nTregs increased, relative to total CD4+ T cells.

Conclusions: CT3.5 has comparable effects on the immune systems of patients with CIS or RRMS. The pronounced reduction and recovery dynamics of CD19+ B cells and relative changes in the proportion of some immune cell subtypes may underlie the clinical effects of CT3.5.

The safety profile of cladribine showing that severe viral infections are not a clinical problem

Cook et al.  Safety of Cladribine Tablets in the Treatment of Patients With Multiple Sclerosis: An Integrated Analysis. Mult Scler Relat Disord, 29, 157-167 Apr 2019.

Background: Treating patients with relapsing multiple sclerosis (MS) with cladribine tablets (two times 4 or 5 days of treatment each year for 2 years) results in long-lasting efficacy, with continued stability in many patients for 4 or more years. Safety and tolerability outcomes from individual clinical studies with cladribine tablets have been reported previously.

Objective: Report safety data from an integrated analysis of clinical trials and follow-up in patients with MS to further characterize the safety profile of cladribine tablets.

Methods: Data for patients treated with cladribine tablets 10 mg (MAVENCLAD®; 3.5 mg/kg cumulative dose over 2 years, referred to as cladribine tablets 3.5 mg/kg) as monotherapy (n = 923) or placebo (n = 641) in Phase III clinical trials (CLARITY, CLARITY Extension and ORACLE-MS) and followed up in the PREMIERE registry were aggregated (Monotherapy Oral cohort). To better characterize rare events, additional data from earlier studies which involved the use of parenteral cladribine in patients with MS, and the ONWARD study, in which patients were given cladribine tablets in addition to interferon (IFN)-β or placebo plus IFN-β were included in an All Exposed cohort (cladribine, n = 1926; placebo, n = 802). Adjusted adverse events incidences per 100 patient-years (Adj-AE per 100 PY) were calculated for the integrated analyses.

Results: The incidence rate of treatment-emergent adverse events (TEAEs) in the Monotherapy Oral cohort was 103.29 vs. 94.26 Adj-AEs per 100 PY for placebo. TEAEs that occurred more frequently with cladribine tablets were mainly driven by the TEAEs of lymphopenia (Adj-AE per 100 PY 7.94 vs. 1.06 for placebo) and lymphocyte count decreased (Adj-AE per 100 PY 0.78 vs. 0.10 for placebo) as anticipated due to the mode of action of cladribine. An increase in TEAE incidence rate was also observed in the cladribine tablets 3.5 mg/kg group vs. placebo for herpes zoster (Adj-AE per 100 PY 0.83 vs. 0.20, respectively). There were no cases of systemic, serious disseminated herpes zoster attributed to treatment with cladribine tablets. In general there was no increase in the risk of infections including opportunistic infections with cladribine tablets versus placebo, except for herpes zoster. Periods of severe lymphopenia (< 0.5 × 109 cells/L) were associated with an increased frequency of infections, but the nature of these was not different to that observed in the overall patient group treated with cladribine tablets 3.5 mg/kg. Within the constraints of a limited sample size, malignancy rates in the overall clinical program for cladribine in MS did not show evidence of an increase compared to placebo-treated patients and there was no increase in the incidence of malignancies over time in cladribine-treated patients.

Conclusion: The AE profile for cladribine tablets 3.5 mg/kg as a monotherapy has been well-characterized in a pooled population of patients from early to more advanced relapsing MS. There was no increased risk for infections in general except for a higher incidence of herpes zoster. Lymphopenia was amongst the most frequently observed TEAEs that occurred at a higher incidence with cladribine relative to placebo. There was also no increase in malignancy rates for cladribine relative to placebo.

Disclaimer: Please note this post, as with all of my blog posts, represents my personal opinions and not the views of my colleagues at Barts-MS.

CoI: multiple

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.

35 comments

  • Would it be an option for you to test B lymphocyte subsets and look for memory B cell count if maybe the first mavenclad cycle was enough?

      • Thanks for your response. I’m wondering do we have any data on when memory B cells repopulate after a cladribin dose? I’m only aware of 48week data which show still depletion. Thanks

        • can you tell me where the data is please? We have just got ethics to re look at people in our cohort who will be three years out now. The data with alemtuzumab suggests about two and a half years, but I suspect this population will be filled by anti-viral cells

          • Thanks for your response. Sorry if it was ambiguous I meant 48week after the first dose (unpublished data from a colleague). I’m really curious if disease activity will be associated with repopulation of memory b cells and if those are the people which need retreatment. I will be awaiting eagerly your results.

          • Our published data with the subcutaneous variant is out to a year and the same level of deplteion is there after a few weeks and this is in line with meeting reports published.

            As for disease reactivation and memory B cells. We will also be doing some of this. I would have though the Italians would be on the case, but sadly their minds are understandably thinking about other issues. There is also a larger study of looking at blood frequently and they are looking at memory B cells. This is called MAGNIFY. This must have been going for about a year and I am godsmacked that this infomration has not surface yet as it would confirm what we have shown, it would also make the memory B cell hypothesis is worth exploring. Importantly it makes it very easy to explain how cladribine is working. People are very unsure about this drug and not understanding how it does things makes an easy sell a hard sell. Why the radio silence. I bet a load of die hard T cell immunologists are in control, with massive T cell labs don’t want that known, until the T cell lab becomes a B cell lab. God forbid the idea that there may be something simple, not all this complicated regulated network that allows us to waste time looking in the wrong place. This is the current thinking I have seen it presented over and over again.

            As there people who will need retreatment, absolutely likely. Remember 50% of alemtuzumab treated people require a third cycle and 50% of those need a four cycle or switching to something else. Even some people on HSCT have break through. I heard of a story of someone having two rounds of autologous HSCT and then switched to allogeneic HSCT (cells from someone else and their MS went away. It is probably the case that the new stem cells could recognise the old immune system and get rid of it, they would be able to go into the brain and scrub it clean.

            Cladribine will be the same as alemtuzumab and some people will need a retreat, I think from the original cladribine trial our first person did alright for six years, but it should a signal to retreat not switch if there is disease breakthrough. There is a case of NMO in a patent they did alright for about 2.5-3 years and was then switched. Why not retreat. Sadly because of the way that cladribne was removed from the market we dont have the long term data.

  • Depends on overall heatlh pf course, but I would say go for the second course and monitor closely. Possibly put the patient on a sick leave.

  • I started my second week of year 1 Thursday. My neurologist wouldn’t advise me.

    I felt the delay required would be longer than 6 weeks (to get me past the worst of the virus hitting our area), and was concerned I would waste a treatment year since there is no real data for delaying year 1 week 2 past six weeks. I would have delayed if I were year 2.

    Our province is shutting down, and I am able to isolate easily in a rural community. We have no cases yet, and if we delay spread to tourist season my immunity may start to recover by that time.

    I will have more information middle of March when I have first bloodwork. I requested blood work before week 2 and neuro refused.

    As long as my husband stays virus free, I should be good. Any recommendations for others in same household?

    That’s the only missing piece in my management plan.

  • Is her employer sympathetic to her current condition and therefore agreeable to home working to avoid public transport and contact with general public? Hopefully then allowing her to then start phase two of the treatment

  • In that case, wouldn’t the second 5 days of therapy be a part of the first cycle? At least that is how I understand the recomendations. Doesnt the “second” cycle refer to the one occuring 1 year after they second one? In this case I would recommend the patient to complete the first cycle and probable to confine herself.

  • Don’t the guidelines suggest the year 2 round should/can be delayed by up to 6 months -possibly longer?
    It does not seem to specify the second cycle at week 5 unless I am missing?
    So I would suggest she complete all round 1 ie cycle 1 and 2
    Then delay round 2 due to start February 2021 depending on circs then

    I have completed cycle 2 year 1 at December 2019 and so am worried as in 3 -6 month danger period but lucky not to use public transport but my kids at school in UK do
    Can she isolate?

  • No further Cladribine in this patient until the pandemic ends. Here in the USA , I would try to authorize ASAP Aubagio ( Teriflunomide ) on this patient, as Teriflunomide is cytostatic and immunomodulatory and not cytotoxic and immunosuppressant. Recent data on Teriflunomide shows broad antiviral effects . Teriflunomide, as an MS disease modifying medication has been under appreciated, until the recent past, when repeated emerging data on it have been a smorgasbord of positive results. Teriflunomide is beneficial for the progressive-degenerative-smoldering inflammatory slow burn ( Dr. G’s ‘right on’ terminology and analysis of the real MS ), beginning years before an MS patient even gets diagnosed with the 10-15 years of the big burn, which is only a heightened transient immunologic response to the underlying disease, and continues to work on the slow burn to the end of that patients life. If Teriflunomide is not available, perhaps the mother drug Leflunomide is available, as an affordable and accessible generic version, and could have a positive MS class effect like its slightly more pristine daughter drug Teriflunomide?

    • Doesn’t it block DNA formation so would it not be immunosuppressive on an expanding immune response? I guess what is the effect on vaccination.

      • I appreciate Mouse Doctor questioning my post on the consideration of transitioning from mavenclad to teriflunomide based on my arguments. Don’t get me wrong, I am a huge fan of mavenclad. By the end of 2019 I had the 3rd largest population of mavenclad patients in the United States. Unfortunately, we are now in unchartered territory with this new pandemic and obviously no easy answers regarding MS patients and the more powerful immunologic MS DMT’s.
        As far as teriflunomide, and questions of immunomodulation versus immunosuppression, along with concern about vaccination, whether it be recall antigen or neoantigen, I would defer to the fairly short, but very concise, review article, with lead author Amit Bar-Or, along with Heinz Wiendl, et al., as follows:

        Drugs (2014) 74:659-674
        Teriflunomide and Its Mechanism of Action in Multiple Sclerosis

        • Thanks for your resonse I have now had a look about vaccination and teriflunomide does not seem to interfer I will do a post

  • I believe the patient should make an informed decision, understanding the risks both short and long term. I am not aware of any data on what happens if you delay the 2nd round of cladribine in year 1 and I think it is bonkers to consider switching tx in the first year of clad if you have had one round, but I’m no medical professional. As such, I would proceed with the second round for Year 1. This pandemic will eventually cessate (will it be 6 months or longer?), but MS and its progression won’t. I did previously read Prof G’s points about people who are even more immunosuppressed (organ transplants) and there being no plans to stop Rx to waste precious organs, and I’d put damage to the brain and spinal cord on an even keel. Maybe we can say that waiting a few months for ‘herd immunity’ to develop in the population will insulate us against the risk of infection if we are taking powerful immunodepletory drugs, but who knows? It’s most likely to stay like many viruses are and is now another risk factor, but what do you do? These are unprecedented times.

  • Treat if she has no simptoms for covid19 or test for it. Consult epidemiologist about selfisolation procedure (14 days) during cladribine treatment.

  • This is a general comment regarding COVID 19 and MS patient treatment. So many are being forced to stop treatment and not given a choice! In most cases there are no clear cut answers. Inform the patient of the possible risks, make a recommendation but then let the patient make the choice if they have a sound informed opinion on the matter. Just like they are capable of deciding what level of risk they are comfortable with on treatment options.

  • Would you care to comment on the MS recommendations just provided by the Swedish Neuroscience Institute, Seattle, Washington, USA?

    https://s3-us-west-2.amazonaws.com/images.provhealth.org/Swedish-Images/DMTs_and_COVID19.pdf

    Multiple Sclerosis Medications and Coronavirus

    Having multiple sclerosis would not increase the risk of coronavirus disease (COVID19)
    in most patients. People with MS generally have more robust immune systems, so robust
    that the immune system attacks their nervous system, causing the MS. The disease, MS,
    does not cause suppression of the immune system.
    Some people with disabilities may be at increased risk of complications of COVID19.
    This includes people with weakness of their breathing muscles, or decreased ability to
    cough. Very few people with MS are affected in this way.
    In general, people on disease-modifying therapies should continue these therapies.
    Specific information about each medication follows:

      • The information from the Swedish Neuroscience Institute in Seattle was emailed to MS patients by: Erin Carper
        Program Coordinator
        MS Center at Swedish
        erin.carper@swedish.org

        Her email included information directed toward local patients primarily and concluded as follows… “MS DMTs and COVID-19: We know there are a lot of questions about MS DMTs and this virus. Our MS Center providers have put together a document that we hope will answer some of your questions and concerns. Please click here to view: MS DMTs and COVID-19.

        The MS Society has also put together some resources about COVID-19 & MS

        As a reminder, symptoms can include fever, cough and difficulty breathing (shortness of breath). If you develop symptoms or have been in close contact with a person known to have COVID-19, please contact your primary care provider immediately.” End Quote
        Of course, Seattle is one of the COVID-19 outbreak areas in the US and they are doubtless quite busy.

  • Hi Gavin.
    I would treat her as I would consider benefits to outweigh risks in a patient with such highly active disease . Also, as she already completed week1 of year 1 she is already immune suppressed and to the current knowledge suggest the completion of week2 should not increase risk further significantly. I would do wbc and lymp count with differentials pre week 2 to get more info to look back at and recommend strongly to work remotely as feasible for at least 2 weeks (and make a note to the employer if needed). I hope people in her position would be eligible to receive paid sick leave for 14 days at least- as the government is saying to be implementing.

  • I feel all advice in place from Health & Government is fair but doesn’t seem to confirm about immune-suppressed people – other than to take more care! I work in the public sector with over 1800 people within my job world. I’m immune suppressed – do I now call in & stay at home – the worry element isn’t helping my condition (I have to say) or do I continue as normal – but wear gloves & continually wash & wipe down! If I were the person in your post – like me, I would think seriously about staying home now until things settle down. If extremely active MS I would as a patient want to continue with the treatment but self isolate (ish if you have a family/partner) but not go out in public places unless really necessary. If you delay the treatment for say 6 months – the dose so far could be helping, although not fully. Also, how are folk catching the virus if they’ve not been in contact with anyone who has it – I guess, so they might say, as who knows if you have it before symptoms start to show!?! Take care Prof G & all medical staff – it is worrying & sad times. Wear protective gloves & keep your distance from us patients – we will not take offence, on the contrary, just be pleased to see measures in place. I agree there should be sanitising of all surfaces regularly throughout day but not with the same piece of cloth, please (saw this at my local Costco – who were sanitising the trollies!).

    All the best & keep safe,

  • 1. How much FURTHER does the 2nd week of pills in year 1 actually suppress the immune system once week 1 has been taken? I think I have read somewhere (?) that taking the 2nd week of pills does not cause that much more of an immune suppression anyway? In which case, that ship has sailed.

    2. And secondly, would NOT taking the 2nd week of pills in yr 1 reduce the length of time of significant immune suppression?

    (From a v selfish point of view, this case study is me, bar perhaps having quite as highly-active disease. Due 2nd wk tomorrow, so v interesting reading the responses. Answer to my question is the key to my decision at this point. Something I can talk with my MS team about if they manage to contact me in the next week or so).

  • There is no vaccine for the corona virus but what do we advise patients during and just before the flu season? We advise to get the vaccine yet I’m sure not all MS patients follow that advice. Do unvaccinated MS patients stop their DMT because they are fearful of contracting influenza? I would think not.

  • Agreed. Self-isolation to avoid Social contact and self hygiene measures. It looks Like Innate immune system matters more than aquired

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