Somewhere to go after alemtuzumab

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Autologous hematopoietic stem cell transplantation following alemtuzumab therapy in aggressive multiple sclerosis: A report of three cases.Boffa G, Sbragia E, Raiola AM, Varaldo R, Capello E, Gallo P, Granella F, Mancardi G, Inglese M.Mult Scler. 2020 Aug 25:1352458520914818

The management of multiple sclerosis patients with persistent disease activity under alemtuzumab treatment is not established yet. Concerns have been raised on the safety of autologous haematopoietic stem cell transplantation (aHSCT) after alemtuzumab treatment because of the risk of serious infectious adverse events. We report short-term safety and efficacy data from three patients treated with aHSCT following alemtuzumab treatment. Early adverse events were consistent with expected transplant toxicities. All patients were free of disease activity at the last follow-up. Our data suggest that aHSCT can be considered as a rescue treatment strategy for MS patients with persistent disease activity during alemtuzumab treatment.

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  • I met a person that had alemtuzumab with no benefit at all. Actually, she is on Ocrelizumab and doing good. She had quite relevant infusion related symptoms and got no secondary autoimmunity. I think that she developed ADA immediately after first infusion. How much time does it take for antibody drugs to get the target cells killed? Is it possible that the immune system is so fast that it could neutralize the antibody drug before it starts working? This would be very frightening.

    How long ADA against alemtuzumab last after last dose? I think I will talk to my neuro to inform about the globody test.

    • So people dont respond to alemtuzumab, just like there will be people who dont respond to ocrelizumab and cladribine, this may be a genetic thing. Most people make ADA after first infusion. The ADA appear within the first month of infusion and generally take about 9-10 months to wane and so this allows the next infusion to go ahead but with time they can become quite persistent and we have a case of positive antibodies about 4-5 years after last infusion. The alemtuzumab kills its target within a day or two, it generally takes at least 6 days for an antibody to form alemtuzumab hangs arond for about 2 weeks and is gone by a month.

      If the concentration of ADA is high enough it will neutralize immediately

      • Thank you for taking time to reply!
        I think I am missing something based on the timings you reported.
        If alemtuzumab kills its target in just two days, including the b cells that end up making ADA, how can we have ADA? To me this means that some b cells are capable of evading alemtuzumab depletion. Maybe they do it quickly downregulating CD52 or migrating somewhere alemtuzumab can’t go?
        This would add sense in giving anti-CD20 after (and maybe even before alemtuzumab). We have already written about this but now there is also the study on varicella immunity loss after vaccination followed by ocrelizumab that may support the loss/avoidance of ADA after CD20 depletion. What do you think about that, could it work to make repeated alemtuzumab dosing safe and effective? It would be a relevant improvement of the pulsed IRT treatment strategy.

        • Alemtuzumab kills B cells in the blood, but I would suggest that it does not clear out the lymph glands and the bone marrow as well because a low dose is used and to destroy B cells not only does the antibody have to get into and bind to the B cells but cells such as natural killer cells have to get into the tissues to mediate the killing, however you are correct CD52 negative cells also appear. This may explain how fingolimod treatment may stop alemtuzumab form working. The B cells causing ADA appear quickly and I would argue that this is why alemtuzumab causes autoimmuntity.

          Yes it is possible that the block of antibody response and hypogamma globulinemia blocks ADA, they are low with ocrelizumab, however the same problems of vaccination block and hypogammaglobulinemia occur with rituxumab yet about 25% of people get ADA. Now ocrelizumab may be better here, but after ocrelizumab the antibody will be present for month and at some point it becomes limiting allowing B cells to return at that point ADA could be generated

  • When I had my 2nd Infusion. Wednesday Thursday Friday, Saturday. I was told by my care provider that there were very limited staff on Saturday and to come back on Monday for my final infusion. I argued religiously saying the trials were for alemtuzumab were done with continuous daily infusions and by changing the timing they would invalidate the trial conditions and therefore potentially reduce the efficacy of the drug. The doctors looked at me as something they stepped on and this made me angrier and I sent email to the head neurologist arguing my point. But it took a kind hearted nurse to say if your OK with no doctors around for the last infusion. There’s a bed available. I’m now 3 years Neda. Ps got all my info from this blog to present the facts to them.

    • I suspect the delay of a two days may not have made a big difference as the alemtuzumab hangs around for at least 12 days after infusion, but for second cycle of infusion with alemtuzumab there is normally only three infusions, five on the first cycle. Happy you are NEDA for 3years long may it continue.

  • How about oposite? I got aHSCT and relapsed 4 years after the procedure, with new, active lessions. Considering alemtuzumab as a follow up treatment.

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