Alemtuzumab and B cells. Snooze and you may lose

A

About 5 or more years ago Prof G and I went to see Genzyme to propose a study on doing B cell depletion after alemtuzumab to try and limit, ideally prevent, secondary autooimmunity that occurred in about 50% of people with MS who were treated with MS.

At the time there was no ocrelizumab, cladribine in the picture and they simply were not interested in B cells. They thought T regs increased after alemtuzumab and they were not interested in doing the study.

We would have had an answer by now and maybe just maybe, this would still be the go-to treatment rather than having it at the bottom of the pile, certainily if the EMA continue with their current view.

(Update). Now this idea was a trial to prevent secondary autoimmunity by zapping the B cells as they emerge after alemtuzumab. But if you dont do this you have to treat the fall out of the alemtzumab treatment

In OZ they don’t say wait until pharma fund it, they just get on and do it. This work is by the Brother of the Ex-Blackburn Footballer of the same surname, for those interested in football. Irrelevant for those not interested.

B cell depletion therapy resulting in sustained remission of severe autoimmune complications following Alemtuzumab treatment of Multiple Sclerosis. Massey J, Barnett Y, Curnow J, Sutton I. Mult Scler Relat Disord. 2019 Jul 20;35:100-103

Secondary autoimmune disorders (AID) are a recognised complication of alemtuzumab treatment for multiple sclerosis. We have previously reported two female multiple sclerosis patients treated with alemtuzumab who developed rare but severe secondary AID; acquired haemophilia A and autoimmune encephalitis with seizures. Both cases proved to be refractory to treatment with conventional immuno-therapy. However, treatment of the patients with anti-CD20 therapy resulted in sustained remission. This observation validates anti-CD20 therapy as a potential treatment option in patients with autoimmune complications of alemtuzumab that are postulated to arise as a result of B cell hyperpopulation.

This is treatig the autoimmunity not preventing it

However, you need foresight, because now, it is rather late to try answer the question we posed all those years ago, most people will say give me ocrelizumab, cladribine etc, etc and so you will find it hard to recruit to such a study.

Will Roche take the plunge and see if they need to dose as frequently as every six months to try limit infection risk?

Do we say what risk? You are too theoretical, after all it is indeed well tolerated by most people.

Snooze and you lose for what is otherwise a useful treatment.

Are they sleeping? You heard about OXO this week…We need to do ADIOS

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MouseDoctor

18 comments

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  • Okay I’m going to ask the obvious question. Why not just give people Ocrelizumab after 2nd dose of Alemtuzumab? Both are licencesed for MS. Then present you clinical data to pharma.

    • I think that if you have had alemtuzumab, there may be an issue of getting ocrelizumab from the NHS. If you fail alemtuzumab will you fail

      • If ocrelizumab is used to treat secondary autoimmune problems post alemtuzumab, it’s use would surely be off-label anyway. You are no longer using it to treat the MS. Or, can neurologists mount a different arguement?

  • I’m not sure that characterisation of these cases is accurate. It doesn’t sound an effort was made to avoid secondary autoimmunity, rather the anti-CD20 were used to try and treat them after they had already appeared. I’m from Oz as well and am in the same boat, with multiple severe autoimmunities post alemtuzumab that have been treated with multiple courses of rituximab. Surely the same thing is occurring in the UK right now as the more severe adverse effects start to pile up?

    My point is, this unfortunately doesn’t get us any closer to knowing what would happen with some preventative b-cell depletion during to prevent the b-cell overpopulation in the first place. The horse has already bolted and the autoimmune problems can unfortunately be very recurrent.

    • Yes you are correct, we would have given the anti-CD20 post CD52 to treat the B cell surge so our idea was preventative rather than dealing with the problem after it has happened so it is different I will correct the post too clarify this.

      As to the severe autoimmunites, maybe profG can say, we are/were one of the largest prescribers in the UK, and I am aware of unusual secondary autoimmunites that have appeared, but I cannot comment on how the neuros eal with these.

    • May I ask which sever autoimmunities you have? I was diagnosed with Acquired Haemophilia about 2 months ago and I am currently undergoing rituximab therapy. This happened about 4 weeks after having a baby so it’s not clear whether it was triggered by alemtuzumab or having a baby. I am hoping that this treatment will be effective.

      • Sure thing – I’ve had Graves’ disease, ITP (multiple times), and haemolytic anaemia. I’m definitely an unusual case. Steroids didn’t seem to do much for me, but rituximab does the job really well (albeit slowly). It’s a bit rubbish watching your B cell numbers come back and waiting to see what’s next tho! Fingers crossed I’ll be out of the risk period soon. Good luck with it all, and hope you are well and able to fully enjoy your little one soon 🙂

    • Treated with rituximab, not ocrelizumab. That makes a big difference concerning indication and PBS reimbursement.

      To avoid secondary autoimmune problems, why not alemtuzumab > 6 months > ritxuximab > 6 months > alemtuzumab > 6 months > rituximab….????

      Or instead of rituximab every 6 months, treat to target (b cells exceed x).

      Or use ocrelizumab. Shit, it could result in a distinct label indication (for the treatment of secondary autoimmune conditions post alemtuzumab treatment).

      On a side note, the blood watch service in Australia don’t look at B cell vs T cell repopulation rates. I asked for that data today and they don’t have it. Just the differentials.

      • Why not?…. probably because it is no based on the biology of what happens to the B cell compartment, if it is B cells in absence of regulation alternative regimes would have more logic. Is B just CD19?

      • I was offered ocrelizumab to use instead of rituximab, but my haematology team were not keen on using it so I ended up paying for rituximab myself ($$$). Not ideal and am considering asking genzyme to contribute. Any future DMT will probably be ocrelizumab.

        As for Bloodwatch they would be a hell of a lot more useful if they tracked b vs T cells or even things like reticulocytes that could guide clinical decisions if there is a problem.

        These all feel like problems that could be worked around with a little thought!

        • ocelizumab is super rituximab and so one would ask on what basis did not like ocrelizumab? It is licenced for MS, rituximab is not. I not would ask Genzyme to contribute, as the don’t make rituximab or ocrelizumab (both Roche/Genetech) and your descision has cost them money.

          Reticulocytes are immature red blood cells.

          • I think familiarity is the reason they preferred rituximab to treat post alemtuzumab autoimmunity, particularly given the mess that my immune system has been in. Perhaps it is just super rituximab but there’s enough uncertainty there to make them think twice.

            Also not sure how my decision cost them money? Cumulatively I’ve spent months in hospital from side effects of their drug (alemtuzumab) and treating these has cost our health system dearly (surgery, hospital stays, ivig, and other even more expensive treatments), not to mention the out of pocket costs I’ve borne. They still got paid and have had somebody else deal with the fallout.

            In my experience reticulocytes are the difference between getting a low platelet or haemoglobin count and knowing that your body is responding appropriately, or knowing that you are heading towards a life threatening crash. Waiting to see what the count is next month is just irresponsible. This stuff plays out in days not months.

          • OK I did not understand the nuansance and if you you are post alemtuzumab I guess I understand the reason for the choice of charging them (genzyme), now/ In terms of costing them it was costing roche money chose ocrelizumab and they make 4 tmes as much. .My misunderstanding

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