Christmas comes early from Rituxiland…

C

Today I give thanks…

Many Americans will sit down to watch the football today… Not realising the football is really on tomorrow (friday =World Cup:-)

As the Americans tuck into their turkey,  nut roast or what-ever floats their boat, for Thanksgiving, where thanks is given for natural things that they can kill and eat:-). I can only dream of tucking into Christmas pud…a bit of cheese, a slice of  turkey and some festive cheer.

However, Christmas has arrived and I have been sent a present from Sweden.

Sometimes you have an idea, you open your big gob and then get a good intellectual kicking as people rush off to prove you and your idea are wrong.

Now one should not think that people proving you wrong is a bad thing, because this is a scientific process.  You don’t try to prove stuff you try to disprove it….if you succeed the idea is wrong, but if you fail you try again to disprove it. So far I don’t think the idea has been disproved and this is why I am happy

So a few years ago we made the comment that all MS drugs inhibit the memory B cell response and importantly alemtuzumab and cladribine do the same thing as CD20 depleting antibodies. Therefore, do you need to dose CD20 B cell depleting antibodies  every 6 months? Alternatively can you dose for a year (like alemtuzumab and cladribine) and then do a “watch and wait” like alemtuzumab and cladribine as MS is inhibited..

I got the phase II extension data and suggested that you could dose less frequently and still get benefit from ocrelizumab and we also reported that when memory cells are depleted they stay depleted for a long, long time suggesting that you may not have to dose as frequently thus potentially avoiding risk of serious infections and perhaps allowing a drug-free pregnancy. This was retrospective evidence from looking at past studies, but can we do a study looking forward to see we can do the same thing. This is what we call a prospective study.

We planned it with other groups around the UK and then came along COVID-19 and some people started extended dosing intervals (dosing interval longer than 6 months) to increase vaccination potential and avoid COVID-19 risks, meaning it was going to difficult to get people to recruit to studies loking at standard or extened dosingintervals. It is not in the interest of pharma to do these studies after all turkeys don’t vote for Thanksgiving/Christmas. But remember sooner or later you are going to have agents that inhibit progressive MS and pharma will charge top dollar. Anti-inflammatory drugs will come out of patent and you will want them in addition to the protection repair agents. So having an immunomodulator that you dont have to take all the time has merits.  So having IRTs (Immune reconstitution therapy) would be useful and I think anti-CD20 depleters are IRTS. The data isn’t clear cut but today we have more evidence.

In Sweden they use a lot of rituximab and here they examine the effect of extending the dosing interval from the standard 6 months to 18 months, in people who were showing a response to rituximab. They looked at people treated at less than 8 month intervals, 8-12 month intervals, 12-18month intervals and more than 18 months intervals and did not find significant differences, so an 18 month delay still gives disease control. B cells repopulated by 12 months, telling me that ocrelizumab is probably a bit more effective and  at the dose used as it takes about 14-16 months for ocrelizumab. Memory B cells were depleted for 16 months so again further supporting the data we had teased out from data we had obtained from ocrelizumab trials. This study goes further an indicates that the class switched memory B cells, take 24 months to repopulate

There was no indication that when cells come back, disease comes back and again this doesn’t surprise me there as the cells that come back are not the same as was there before. Imaging also did not show marked differences from extending the interval between  doses. Remember there may be some disease breakthrough with treatment with alemtuzumab (~40-50%) so you may expect a few people to relapse.

The study suggests that ” relapse risk remains low with extended infusion intervals of rituximab, so maybe it is as much or an IRT as alemtuzumab and cladribine..

Love it!!!

Starvaggi Cucuzza C, Longinetti E, Ruffin N, Evertsson B, Kockum I, Jagodic M, Al Nimer F, Frisell T, Piehl F. Sustained Low Relapse Rate With Highly Variable B-Cell Repopulation Dynamics With Extended Rituximab Dosing Intervals in Multiple Sclerosis. Neurol Neuroimmunol Neuroinflamm. 2022 Nov 21;10(1):e200056.

Background and Objectives B cell–depleting therapies are highly effective in relapsing-remitting multiple sclerosis (RRMS) but are associated with increased infection risk and blunted humoral vaccination responses. Extension of dosing intervals may mitigate such negative effects, but its consequences on MS disease activity are yet to be ascertained. The objective of this study was to determine clinical and neuroradiologic disease activity, as well as B-cell repopulation dynamics, after implementation of extended rituximab dosing in RRMS.

Methods We conducted a prospective observational study in a specialized-care, single-center setting, including patients with RRMS participating in the COMBAT-MS and MultipleMS observational drug trials, who had received at least 2 courses of rituximab (median follow-up 4.2 years, range 0.1–8.9 years). Using Cox regression, hazard ratios (HRs) of clinical relapse and/or contrast-enhancing lesions on MRI were calculated in relation to time since last dose of rituximab.

Results A total of 3,904 dose intervals were accumulated in 718 patients and stratified into 4 intervals: <8, ≥8 to 12, ≥12 to 18, and ≥18 months. We identified 24 relapses of which 20 occurred within 8 months since previous infusion and 4 with intervals over 8 months. HRs for relapse when comparing ≥8 to 12, ≥12 to 18, and ≥18 months with <8 months since last dose were 0.28 (95% CI 0.04–2.10), 0.38 (95% CI 0.05–2.94), and 0.89 (95% CI 0.20–4.04), respectively, and thus nonsignificant. Neuroradiologic outcomes mirrored relapse rates. Dynamics of total B-cell reconstitution varied considerably, but median total B-cell counts reached lower level of normal after 12 months and median memory B-cell counts after 16 months.

Discussion In this prospective cohort of rituximab-treated patients with RRMS exposed to extended dosing intervals, we could not detect a relation between clinical or neuroradiologic disease activity and time since last infusion. Total B- and memory B-cell repopulation kinetics varied considerably. These findings, relevant for assessing risk-mitigation strategies with anti-CD20 therapies in RRMS, suggest that relapse risk remains low with extended infusion intervals. Further studies are needed to investigate the relation between B-cell repopulation dynamics and adverse event risks associated with B-cell depletion.

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MouseDoctor

12 comments

  • In other words, why take the risk of nuclear chemo immunodepleting when you can do it gently with Cladribine.

    Message sent from 11D, typed by a guy hooked up to Lemtrada (year 2)

    • It depends on whether you agree with the idea that T cell depletion is needed for optimal effect…to help with the protection against atrophy. The way to see this is to see what happens when you use cladribine at onset to compare with CARE-MS data. Cladribine doesnt have all the monitoring associated with alemtuzumab, but we know it is a very good drug and would be even better if the side effects were dealt with

      • The way to see this is to see what happens when you use cladribine at onset to compare with CARE-MS data

        Yes
        But you would have convice the neuro and the patient

        Nice post

        Thanks

        • Yes I agree and probably alemtuzumab has had its day as it has too much negative baggage, notably in the US where is it viewed as third line, however cladribine has its own baggage too…Can you sell the view of using HSCT first line….some neuros will find it a hard concept but it is not their risk….In answer I think you can

          • Well i can answer for myself
            Next saturday 26 of november marks 5 years hsct for me

            5 years ago my neuro doc said that i would be dead
            I had hsct first line

            No ms drugs until today 24/11/2022

            Obrigado

  • I am not sure if MS is the only field of medicine/science where such drug schedules go unchallenged. Of course, the REPLETION of B cell subpopulations, by their OWN data (i.e., provided by the drug companies themselves) in the form of graphs/graphics and whatever else clearly show that B cells do NOT repopulate as early as 180 days or 4 wks (ofatumumab) and yet we flog a dead horse.

    Prof G himself commented about my article years ago on this very blog and you can research it, It is amazing we just do not do Q 8 wkly CD19 counts as a surrogate of CD20, and replenish as needed. Besides, giving anti CD20 drugs to patients is NOT like giving tPA and if the drug is not given within the next blah blah blah, the sky is not going to fall and the patient is NOT going to perish and yet we all seem to be jumping up and down about q6 monthly dosing(s) or q 28 days dosing (for ofatumumab). When will the MS world ask very simple Qs of the drug companies or is the cause lost even before we begin ?

    Multiple Scler Relat Disord
    2021 Nov;56:103250. doi: 10.1016/j.msard.2021.103250. Epub 2021 Sep 4.
    Dosing schedules for Ofatumumab in multiple sclerosis: Overegging the pudding
    Jagannadha Avasarala, Patricia Olson

    Drug Target Insights
    2017 Oct 25;11:1177392817737515. doi: 10.1177/1177392817737515. eCollection 2017.
    Anti-CD20 Cell Therapies in Multiple Sclerosis-A Fixed Dosing Schedule for Ocrelizumab is Overkill

    Jagannadha Avasarala

    The article on Ocrelizumab was published in 2017, a few months after the drug was FDA approved. Even back then I thought that it was ludicrous that we were allowing patients to be dosed excessively.

    • “I am not sure if MS is the only field of medicine/science”…..I suspect not as people follow protocols and the protocols are set by pharma for many conditions…will it change..probably not until pharma do a study:-(

    • Thanks for your comments you paper was ahead of its time, but its interesting the study developed by pharma was double dosing

  • The paper is very nice. I think that the relation with the number of previous doses and BMI through the study should be considered as well.
    If we look at lupus, recently, a group of patients was given CD19 CAR-T. After recovery of B-cells (I don’t know how this can be possible if CAR-T should stay forever…) all patients had no disease recurrence. This tells that an IRT that targets B-cells and completely clear the B cell pool can stop autoimmune disease. For their mechanism of action CAR-T should be less impacted by BMI than antibodies.
    So, with Anti-CD20 “how much courses should one have to reduce disease activity risk to virtually zero?”
    And this relates with the point of double dosing: one can double dose and reduce the number of courses to achieve the same long-term effect reaching a more complete depletion sooner.
    For cladribine, I think that when given early the cells to kill are not as many as after some years and this could explain why it could work better than given later. The same for alemtuzumab and Anti-CD20. I bet that if one gives cladribine for note than 2-3-4-5 courses it will work well as Anti-CD20. I think I have read a paper here maybe from Rejdak.

  • The point has been driven home over and over again that relapses and radiological activity are not (the whole of) MS. I want to see brain atrophy data for the extended interval dosing vs. standard dosing before agreeing that it is ethical to adopt EID. And I want proof that peripheral CD19 counts are an appropriate proxy for control of brain atrophy in addition to control of relapses. Very thankful that Prof. G’s DoDo study is going ahead, because it should answer these questions. In the meantime I am not comfortable with a neuro wanting to put me on EID (one of the reasons I pushed for alemtuzumab for myself actually–my neurologist does EID for his anti-CD20 patients).

    • Suspect that the brain atrophy of regular
      and EID doses will both be lacking for
      anti-CD20 unless dealing with very recent
      dx young patients.

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