Road to Impact, By Delaying B cell treatment

R

In our science jobs we have to justify our use and assess what impact our work has on Society.

For Prof G is is easy. He is lead on a clinical trial of drug X and it works and is licensed and so it has impact on people with MS, but maybe drug X gets used in other autoimmunities and the impact gets bigger and it works in Cancer too a bit impact etc. Then there is impact on Society. Manufacturer of Drug X makes at load of cash and Manufacturer opens up a factory in Tyne and Weirdside employing 8,000 people and the impact gets bigger and bigger

But for a humble scientist it is much more different..Yep we were the first group to underpin the science of cannabis for use in spasticity and yes cannabis became a licensed drug and yes it has helped a certain company make loads of cash for UK PLC but as there is a time limit from the discovery to the Impact so we can’t use it so as a scientist you are stuffed:-).

Yes it is all a load of boll***cks for example Prof Brian Cox made the point for Manchester University that he made more people do physics A level and the Impact Comittee bought it,

We have to play this game, So if we are making stuff up, Do you think we could try this one?

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

What did it say?….It would be safe to delay dosing ocrelizumab when the COVID-19 pandemic.

Now you say it has a september 2021 date and the pandemic hit in feb/march….but I say I foresaw the problem and that is why I put it online at MedrXiv in Jan 2020 https://www.medrxiv.org/content/10.1101/2020.01.09.20016774v2

Did it have impact? Yes it did as it changed clinical practice

In the Netherlands

van Lierop ZY, Toorop AA, van Ballegoij WJ, Olde Dubbelink TB, Strijbis EM, de Jong BA, van Oosten BW, Moraal B, Teunissen CE, Uitdehaag BM, Killestein J, Kempen ZLV. Personalized B-cell tailored dosing of ocrelizumab in patients with multiple sclerosis during the COVID-19 pandemic. Mult Scler. 2021 Jul 9:13524585211028833. doi: 10.1177/13524585211028833.

But also is Germany


Ocrelizumab Extended Interval Dosing in Multiple Sclerosis in Times of COVID-19.Rolfes L, Pawlitzki M, Pfeuffer S, Nelke C, Lux A, Pul R, Kleinschnitz C, Kleinschnitz K, Rogall R, Pape K, Bittner S, Zipp F, Warnke C, Goereci Y, Schroeter M, Ingwersen J, Aktas O, Klotz L, Ruck T, Wiendl H, Meuth SG.Neurol Neuroimmunol Neuroinflamm. 2021 Jul 14;8(5):e1035. doi: 10.1212/NXI.0000000000001035.

Objective: To evaluate the clinical consequences of extended interval dosing (EID) of ocrelizumab in relapsing-remitting multiple sclerosis (RRMS) during the coronavirus disease 2019 (COVID-19) pandemic.

Methods: In our retrospective, multicenter cohort study, we compared patients with RRMS on EID (defined as ≥4-week delay of dose interval) with a control group on standard interval dosing (SID) at the same period (January to December 2020).

Results: Three hundred eighteen patients with RRMS were longitudinally evaluated in 5 German centers. One hundred sixteen patients received ocrelizumab on EID (median delay [interquartile range 8.68 [5.09-13.07] weeks). Three months after the last ocrelizumab infusion, 182 (90.1%) patients following SID and 105 (90.5%) EID patients remained relapse free (p = 0.903). Three-month confirmed progression of disability was observed in 18 SID patients (8.9%) and 11 EID patients (9.5%, p = 0.433). MRI progression was documented in 9 SID patients (4.5%) and 8 EID patients (6.9%) at 3-month follow-up (p = 0.232). Multivariate logistic regression showed no association between treatment regimen and no evidence of disease activity status at follow-up (OR: 1.266 [95% CI: 0.695-2.305]; p = 0.441). Clinical stability was accompanied by persistent peripheral CD19+ B-cell depletion in both groups (SID vs EID: 82.6% vs 83.3%, p = 0.463). Disease activity in our cohort was not associated with CD19+ B-cell repopulation.

Conclusion: Our data support EID of ocrelizumab as potential risk mitigation strategy in times of the COVID-19 pandemic.

Using standard 6 monthly dosing the people with more ten cells or more per microlitre were 26/176 (17.6%) at six months and 17/102 (15.7%) if it was delayed by more than a month. So if we say that people with B cells can make a COVID-19 vaccine responses it suggests that at least 1/5 people will make an antibody response after COVID vaccination and delaying by a month would make much difference.

It also shows you can relapse whilst you have no peripheral B cells

B cell numbers with standard interval (5 monthly) or extended interval (EID) dosing, B cell numbers verses relapse (red dot)

So if we delayed by 3 months (I can’t answer this) or 6 months (I can answer this) how many more people would have B cell counts above 10 cells/microlitre and could make an antibody response following COVID-19. However, would this work? and would it be safe? and importantly would it matter? We need data for this.

Did this cause this change? Well it is reference number 13…..So why not claim it….now that’s Impact Isn’t it:-(

Yep what a pile:-)

Next issue covid19 vaccination

About the author

MouseDoctor

30 comments

  • What markers did the original studies use to determine a six month dosing schedule and why?
    Plus isn’t this a premature conclusion of no harm given all the increasing thoughts that there is more to progression in the long term than relapses?
    Definite impact in U.K. also though as have heard of more than one unit now extending dosing schedules based on CD19 levels.

    • Yeah, didn’t Prof G just recently mention that in Sweden they are finding that rituximab is worse than interferon beta at slowing brain atrophy? Rituximab is six times less potent than ocrelizumab in terms of B-cell depletion. It seems pretty likely that the higher the dose of anti-CD20 the better. This should probably be made clear to patients considering EID for ocrelizumab.

      • “Rituximab is six times less potent than ocrelizumab in terms of B-cell depletion. It seems pretty likely that the higher the dose of anti-CD20 the better.”

        You’d think but there’s plenty of people saying they went downhill fast on
        ocrevus. AIMs FB site has video where Dr. Burt says…”I don’t believe in
        hidden inflammation…so maybe I shouldn’t mention this to you…But
        recently I was looking at scans of people who declined on ocrevus and
        that’s what I thought of”

        Basically he was saying people had no mri lesions…but their edss
        was going through the roof.

        • > You’d think but there’s plenty of people saying they went downhill fast on ocrevus.

          Actually this was my experience, too. I did terribly after my first round of Ocrevus. My neurologist was sceptical about Ocrevus being the cause but respected my desire to switch to a different DMT (now on Lemtrada).

        • “lets see the published data”

          Why wait…might never be published or take years…time is our brain…

          Why not just call..Frederik Piehl in Sweden and
          invite him to do a guest post..?.

          This is the post from July Q’s

          “PROF G
          July 4, 2021 at 3:13 pmny
          We just heard from Frederik Piehl at our MS meeting that in their Swedish cohort the brain volume loss on rituximab was greater than the interferon-beta treated comparator group. The BVL data in general on anti-CD20 therapies is very disappointing. Anti-CD20 may be good at stopping relapses and MRI activity but is not that effective at stopping smouldering pathology or the real MS.”

          • You need a good brain to follow most of this, but at least I am intrigued by the reference to Interferon Beta, as that’s what I was on for about 25 years, and I am currently wrestling with the question of whether I am progressing or if my almost flat foot eventually gave under the influence of 25 years of mild gate change due to MS (back then).

            But my hat is off to all you smart guys & gals!

    • The idea was that CD19 B cells are the problem so redose when they come back i.e. 6 months.
      However if a CD19 subset is important it means you are overdosing

  • Good work MD & Team,

    Any predictors of patients relapsing with no peripheral B cells? Longer disease duration/higher disease burden prior to B-cell depletion? Gene?

    Thanks.

    • I would appreciate input on this as well.

      Assuming the disease process is in a different stage, as from what I recall the B cells are more involved with the initiation of activity- as in new WM lesions.

      Would an alternative drug be better suited for this type of pwMS? When it would seem that the CD20+ bcells aren’t primarily responsible for this individuals disease activity. Someone who continues to clinically relapse after B cell depletion?

      I anticipate that part of the answer to my question involves a sigh along with the reminder that this could be smouldering MS, well as the hard reality that these interventions have yet to be developed.

      But what about someone with relatively short disease duration? (<5 years) And only mild disease burden and activity radiologically?

      • “Someone who continues to clinically relapse after B cell depletion?”

        If the b cells are already in the brain i.e. b cell follicles…then they can
        function as antigen to t cell attack.

        “Autoimmunity is postulated to evolve in the following steps: (1) CD8+ T-cell deficiency, (2) primary EBV infection, (3) decreased CD8+ T-cell control of EBV, (4) increased EBV load and increased anti-EBV antibodies, (5) EBV infection in the target organ, (6) clonal expansion of EBV-infected autoreactive B cells in the target organ, (7) infiltration of autoreactive T cells into the target organ, and (8) development of ectopic lymphoid follicles in the target organ. ”

        https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3270541/

    • blood is probably not the place where the action is but As i have said imagine the problem is a red ford mustang and you are standing on a bridge overlooking the Motorway…..at 3pm you stand on u see no cars and then a 3.55 one red mustang goes past

      • Nice analogy, so a higher dose would still have a higher chance of catching sneaky red Mustangs for those needed (fast b-cell repopulating individuals), but unlikely needed for those with slow b-cell repopulating individuals (enough patrols).

        • Yes probably with more antibody you have more stingers tyre deflation devices on the road and it stops them

          • As someone who’s partner owns a black Ford Mustang, I am not sure whether to laugh or cry at this analogy. 😄😢😂

  • After reading about the ongoing work on EID of ocrelizumab on here myself during the pandemic, I decided to take the risk and delayed my redosing. I then became evidence myself by remaining relapse-free and developing covid antibodies after the vaccine.

    So it has had an impact on a personal basis as well!

    • I agree with you if you delay dosing you are more likely to get antibody response. however not everyone will. This is because the range fo repopulating the B cell response is 25-175 weeks. So if you wait for 9months to vaccinate there will still be people that have no B cells and so will not respond. I am going to look to see how many this would be if we waited 12 months we dont have the three month data. If we could say when you get to X% B cells you give a response

      • About 32 weeks since last OCR infusion. Zero B cells. Being offered a booster. Just spinning my wheels? In face of Delta and in light of very recent Israeli data on MRNA it is persuasive.

  • When discussing OCR, we should remember that OCR targets a specific subset of b-cells.

    Unfortunately, OCR does not have much of an impact on memory b-cell, evidenced by some pwms having breakthrough disease active, despite zero circulating CD-19/20 B-cells.

    • OCR does not have much of an impact on memory b-cell, wrong it has a massive impact on memory cell number as evidenced by studies looking at memory B cells and in many people this last for over 18months

      Relapse despite zero circulating CD-19/20 B-cells….there is always the odd one…how many do you need

      • You do not have mean in your response. Not everybody is a doctor or scientist, so excuse my ignorance. Let me clarify…..OCR does not target memory b-cells.

        “B cells are formed in the bone marrow. They then enter the blood and go through several steps before becoming mature B cells. Partially mature B cells are the ones that present targets to the T cells. Fully mature B cells make antibodies. CD20 is not found on the surface of B cell precursors in the bone marrow, and it is not on the fully mature cells that make antibodies. It is only found on the partially mature cells.”

        https://www.swedish.org/~/media/Images/Swedish/Multiple%20Sclerosis/Ocrevus%20page.pdf

        • ocrelizumab kills memory B cells because memory B cells express CD20.

          It was shown by the swedish Docotrs that memory B cells are the ones that present antigen to T cells.
          Mature B cells also known as naive B cells (CD20+, CD38+, CD27-) do not make antibodies it is the plasma cell that does this

          I suggest you rip-up the informaton source you are reading because it is misleading you because they are using language (the plasma cells are older and so more mature) that confuses with the B cell terminology

          • Thanks MD. Brain fog is pretty bad these days. Sorry for upsetting you and providing a flawed assessment. Please excuse my ignorance.

      • How were relapses distributed in time in the ocrelizumab clinical trials? When did they happen most frequently? I think that most of them happened in the first 6 maybe 12 months from first dose and then nothing. Maybe the odd ones fall in this case? This is also relevant with the paper you posted from Germany: it does not say so much information about the treatment background of those who relapsed.

        • You are correct if you were detined for a relapse it may have been too late for ocrelizumab to stop it, but we know it work fast as it can stop natalizumab rebound when stopping natalizumab. I am looking at the phase II data now

  • “Someone who continues to clinically relapse after B cell depletion?”

    If the b cells are already in the brain i.e. b cell follicles…then they can
    function as antigen to t cell attack.

    “Autoimmunity is postulated to evolve in the following steps: (1) CD8+ T-cell deficiency, (2) primary EBV infection, (3) decreased CD8+ T-cell control of EBV, (4) increased EBV load and increased anti-EBV antibodies, (5) EBV infection in the target organ, (6) clonal expansion of EBV-infected autoreactive B cells in the target organ, (7) infiltration of autoreactive T cells into the target organ, and (8) development of ectopic lymphoid follicles in the target organ. ”

    https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3270541/

By MouseDoctor

Translate

Categories

Recent Posts

Recent Comments

Archives