Dosing to CD19 repopulation. Is this a no brainer?

D

Punching neurologists. Why are they like drummers?

There are a lot of drummer jokes out there. I guess they can be used…..before drummers become an ethnic minoritity and it becomes un-PC to do so:-).

Here is one:

Q. What’s the difference between a drummer and a drum machine?

A. You only have to punch the information into a drum machine once!

OK …For the drummers out there, I apologise to you, before I get a kicking from the Drummer’s Union. Likewise, I hope the Association of Neurologists don’t get too upset. However, I can see for a number of people that dosing every 6 months with anti-CD20 is more than is needed.

How many times do we have to punch neurologist so they get this information?.

There is another right-hook (below)!

In 2012 (only 9 years ago:-) the data from the ocrelizumab phase II extension study was reported at ECTRIMS/AAN. It suggested that fixed dosing of ocrelizumab every 6 months may be overkill for some…actually many people. This was never published!

(So shame on the opinion-leading neuros doing the company study for allowing for this to go unreported). Therefore, your neurologist may not be aware of the information. We published alot of it in 2020.

Baker D, Pryce G, James LK, Marta M, Schmierer K. The ocrelizumab phase II extension trial suggests the potential to improve the risk: Benefit balance in multiple sclerosis. Mult Scler Relat Disord. 2020 Sep;44:102279. doi: 10.1016/j.msard.2020.102279.

However, if it is not a company report is it going to make any difference?

I have to say we know have access to the full data set.

The suggestions are that CD20 depletion results in lots of B cell subsets disappearing. The B cells that are going to form new antibody responses are depleted for some time but and it takes 60-70 weeks after 3-4 ocrelizumab treatment cycles for 50% of the people to repopulate (CD19) B cells. This ranged from about 27 weeks (5 months) to 175 weeks (3.25 years). The memory B cells disappear for a lot longer. So why are we dosing every one at 6 months?

This is because what Neurologists are told to do by the regulators and the label. This is clearly overkill for many, many people as there is not a B cell in sight to deplete….so it is not surprising that there are few infusion reactions as there are no B cells to Smash. You dose every 6 months because that is what you are told to do.

Dare we change the dosing scedule?…I suspect not. Not without data.

However, how much data do you want?

The six month dosing shedule was created when the idea was to just kill all B cells and as some B cells reappeared at 5-6 months, this is the reason to keep dosing. However, COVID-19 has shown us this view can be challenged.

When COVID-19 hit the scene…..the Neurology Associations said “Schtop (Stop with a Dutch Grolsch Accent:-)”. So neurologists stopped and delayed dosing of ocrelizumab and guess what happened…Yep…no (essentially no) relapses appeared.

Today (below) we get an Italian Experience, but I know other places had the same experience. They stopped dosing. Indeed in the study below, they stopped by an average of more than 100 days (3months). So do we need a trial to check this? Rather than dose every 6 months, one could dose when the CD19+ B cells begin to result.

Would this work? I think sure it will work. To me this is rather a NSS (No **** Sherlock) moment. However, some people will say we need proof. So a few million dollars and a few years later.

But why would a company do this, if cuts their profits. Once patent protection is lost, again why would this happen.?

The idea is that we are supposed to think about personalised medicine….the mass one size fits all for MS does not support this aim. If we look at the MS drugs only one is dosed based on weight. So I would get half the amount of drug compared to DrM&M So would it work for as long? However, if you have dose to weight would mistakes be made? Maybe but surely it is not that difficult and the society advantags may outweigh the disadvantages. However, I think we could personalise anti-CD20 further.

I have agrued that there something within the memory B cell population that is important. This view is still largely ignored by many immunologists, who want to suggest that MS is so complicated and we should look elsewhere. Therefore, they support the Status Quo. These people people will need to be told over and over again.

However, some of our Italian Friends do not need to be punched over and over again and sort of get it. They say we dont need to dose when the CD19 B cells return but we can go further and treat to when memory (CD19+, CD27+) B cells return. This is important because memory B cells return much slower that CD19 immature/naive B cells. They get smashed for at least 12-18months.

Novi G, Bovis F, Fabbri S, Tazza F, Gazzola P, Maietta I, Currò D, Bruschi N, Roccatagliata L, Boffa G, Lapucci C, Pesce G, Cellerino M, Solaro C, Laroni A, Capello E, Mancardi G, Sormani M, Inglese M, Uccelli A. Tailoring B cell depletion therapy in MS according to memory B cell monitoring. Neurol Neuroimmunol Neuroinflamm. 2020 Aug 4;7(5):e845

So rather than dosing ever 6 months (rate = 2) within 3 years they were dosing at a rate of 0.78 (6 months- 2.2 years)

They said “One hundred two patients were included in the analysis. The annualized relapse rate (ARR) was 0.67 in the year before rituximab start and decreased to 0.01 in the 3 years after rituximab initiation. The proportion of patient with MS activity (i.e., relapse or MRI activity) was 63.16% in the year before rituximab and decreased to 8.7% (0–6 months), 1.3% (6–12 months), 0% (12–24 months), and 0% (24–36 months). Annualized rituximab infusion rates were 1.67 (95% confidence interval [CI]: 1.43–1.94), 0.76 (95% CI: 0.58–0.98), and 0.78 (95% CI: 0.52–1.12) for the first 3 years after rituximab initiation, respectively. Patients were reinfused with a mean infusion interval of 367 days (range 181–839 days).”

The 4 years data has been presented and it is better than that seen after 3 years (Novi et al. ECTRIMS Abstract: P971).

So in the COVID-19 study (below), delays occurred and relapses were not a majot problem. This further supports the idea that cells within the memory B cell population inhibit MS

Tazza F, Lapucci C, Cellerino M, Boffa G, Novi G, Poire I, Mancuso E, Bruschi N, Sbragia E, Laroni A, Capello E, Inglese M. Personalizing ocrelizumab treatment in Multiple Sclerosis: What can we learn from Sars-Cov2 pandemic? J Neurol Sci. 2021 May 20;427:117501. doi: 10.1016/j.jns.2021.117501.

Abstract: During SARS-CoV-2 pandemic, we adopted a personalized delayed protocol for ocrelizumab infusions in Relapsing Remitting Multiple Sclerosis (RRMS) patients according to the national recommendations. Out of the 83 RRMS patients whose infusion was scheduled between March and December 2020, 56 patients experienced a delay in treatment based on MS severity and SARS-CoV2 infection risk profile. In most cases, the immunophenotype was performed monthly to guide re-infusions. Specifically, B CD19 + cells repopulation rate was monitored. Mean infusion delay was 103.1 [SD 40.6] days, and none of the patients presented relapses or active disease at MRI at the end of the observation period. Treatment naïve status and the interval between immunophenotyping and the last ocrelizumab infusion were predictors of earlier B CD19 + cells repopulation…..Definitive data about Sars-Cov2 vaccine efficacy in patients treated with ocrelizumab are still lacking (No I think there is enough data out ther to say the efficacy for creating antibody responses is not going to b be great). Our findings suggest that a personalized treatment with a delayed infusion schedule does not compromise ocrelizumab short-term efficacy and may help to lengthen the therapeutic window for an effective response to SARS-CoV2 vaccine.

This idea is what the “Margaret Keenan of MS” (The first person to get a COVID-19 vaccine after approval) thought….as a delay in their ocrelizumab paid off and they made an anti-SAR-COV2 vaccine response, based on their and our data. What should we recommend? We need to have a global colection of reponses as each centre may not have enough people.

However, maybe rituxiland will have the answe or have enough people in their care to get the answer. I am really looking forward to Prof Piehl from Sweden coming to give us a seminar. Maybe they have enough info to convince people towardds a more personalised approach

COI: Multiple

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

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MouseDoctor

17 comments

  • But aren’t you focusing on the wrong target? Even low dose anti-CD20 therapy flattens relapses and MRI activity. Don’t you need high-dose anti-CD20 to maximise its impact on disability progression?

    • These are attempts to find out how much/how often to dose, you can’t simply just say “I want low dose CD20”.

      Prof G is doing the Dodo study so attempt at finding how to do the high-dose part.

      You should go to Prof G’s post and asking him how much dose he was planning to test for the Adios study.

    • On seeing this question I penned the following blog post for you.

      https://multiple-sclerosis-research.org/2021/06/do-you-want-to-be-treated-with-low-dose-anti-cd20-therapy/

      It is clear MD doesn’t accept the real MS is smouldering MS and is happy to accept that MS is under control if you are relapse and MRI activity free. Sadly, the accelerated brain volume loss and disability progression in these ‘adequately treated’ patients continue regardless.

      I have little doubt that we are undertreating MS with anti-CD20 therapies. Because they are so effective at switching off relapses and MRI activity, that is not MS, we have been lulled into a false sense of security that we have cracked MS when the real MS or smouldering disease continues to shred the brain albeit at a slower rate.

      • Please be more supportive of Prof G’s efforts. You’re beginning to sound like Kier ‘Captain Hindsight’ Starmer. You wait for the results of a trial and say “I knew it wouldn’t pan out… I wouldn’t have done it like that”. More collaboration at the start of these trials is needed e.g. get in early with your suggestions on trial design so that lessons from earlier trials can be learned.

        • As you continually fail to appreciate Sid, clinicians and/or pharma will go their own sweet way.

          • As an MSer I see a structure (researchers, pharma, neuros) which has succeeded in not addressing the one aspect this disease which all patients fear – continuously worsening disability. Anti CD 20 drugs were the big breakthrough, but we now learn that they don’t address progressive MS. My interest is in my children. I’d hate to think that in 10 or 15 years time, we’ll still be going round the same circles.

          • It’s only relatively recently that neurodegeneration was identified as the major cause for concern in MS.
            As it is, hit it hard and as early as possible remains the way to go with things as they are at the moment.
            Until this is the default for all MS clinicians we will continue to go round in circles until we disappear up our own fundament.

          • “(researchers, pharma, neuros) which has succeeded in not addressing the one aspect this disease which all patients fear – continuously worsening disability.”

            It’s the reason why there’s no real treatment for ppms. If you want to stop worsening progression you have to ask…how likely is this to work in ppms..?

  • As I told before. My (Dutch) neurologist keeps postponing until cd19/cd20 is almost at normal level. 41 weeks last cycle.

    • My neurologist does this too (also Dutch) since the pandemic.
      After 33 weeks a fairly normal lymphocyte flow again, 1st Covid Pfizer vaccination at 36 weeks, 2nd vaccination 41 weeks. Next Ocrelizumab course planned at 47 weeks.

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