A no-brainer?

A

Barts-MS rose-tinted-odometer: ★★★★★ (aquamarine on a very rainy Friday in London, #00FFBF) 

I recently had a patient of mine who has been desperate to be treated with alemtuzumab actually ask if he can change his mind and rather be referred for AHSCT (autologous hematopoietic stem cell transplantation). Why? Because the chances of being put into long term remission, and hence potentially being cured of having MS, seems to be much higher with AHSCT. This particular patient has no concerns about the risks associated with alemtuzumab or AHSCT. The most important concern on his radar is his long term outcome. He wants a healthy brain when he gets older.

This is why this most recent paper on the long term outcome of Italian patients who received AHSCT adds to the mounting evidence base of the effectiveness of AHSCT. In patients with relapsing-remitting treated with AHSCT, MS 86% and 71% were free of disability worsening at 5 and 10 years, respectively. These figures for patients with progressive MS were 71% and 57% at 5 and 10 years, respectively. 

The results are less impressive when using NEDA-3 status, i.e. no relapses, MRI activity or disability progression. For patients with RRMS, probabilities of achieving NEDA3 status were 62% at 5 years and 41% at 10 years, respectively. However, and importantly, in the subgroup of patients with RRMS who underwent AHSCT with the BEAM+ATG conditioning protocol, which is more aggressive, NEDA-3 status was achieved in 68% and 55% of subjects at 5 and 10 years, respectively. 

In subjects with progressive MS, NEDA-3 status was only achieved 51% and 37% of subjects at 5 and 10 years, respectively. 

On average, disability scores improved in relapsing-remitting subjects and got worse in subjects with progressive disease, which implies that AHSCT does not stop smouldering disease. However, almost all subjects had failed one or more DMTs prior to AHSCT. The latter is important. The average EDSS was ~6.0 and most patients had a disease duration of longer than 10 years. This makes me wonder how better the results would be if AHSCT was done earlier in the course of MS, i.e. before too much damage to the brain and spinal cord had accumulated. This is why we really need to test AHSCT as first-line therapy in MS. Could AHSCT done early stop/reverse or prevent the establishment of smouldering disease? In other words, does AHSCT cure people from having MS? This is why a trial of AHSCT in very early MS, i.e. as a first-line treatment, is a no-brainer to me.

Please note that three deaths occurred due to AHSCT, which was 1.4% of the entire study population. 

The take home messages are: 

  1. AHSCT is the most effective DMT we have for treating MS. 
  2. RRMS responds better to AHSCT than progressive MS.
  3. BEAM+ATG conditioning protocol is superior to cyclophosphamide-based protocols.
  4. Mortality remains relatively high with AHSCT.
  5. The results would be much better than this if patients had had AHSCT earlier in the course of their disease. 

I was criticised yesterday for suggesting lifestyle changes to pwMS when I had no idea what it was like to have MS. It was implied that unless you have lived with MS, i.e. the lived experience, I shouldn’t be making any lifestyle recommendations to pwMS particularly around weight loss and diet. What I can say is that I have treated and followed thousands of people with MS and I know enough that if I had MS I would have no hesitation in wanting to be treated first-line with AHSCT or alemtuzumab and to manage all the lifestyle issues I referred to in my post ‘ASK NOT‘. 

What underpins my decision to be treated with alemtuzumab and AHSCT first-line is the data missing from this paper on the end-organ; both of these treatments will on average normalise brain volume loss in treated subjects. In other words, these treatments are on top of the ladder when it comes to preventing end-organ damage. The downside of AHSCT is that the brain takes a significant neurotoxicity hit from the chemotherapy with accelerated brain volume loss in year one. In addition, there is also the high, but delayed secondary malignancy risk and high mortality risk associated with AHSCT that needs to be taken into account. Therefore, alemtuzumab probably wins out on safety as a potential first-line therapy. Please remember being treated with alemtuzumab does not exclude you from being treated with AHSCT at a later stage. 

Boffa et al. Long-Term Clinical Outcomes of Hematopoietic Stem Cell Transplantation in Multiple Sclerosis. Neurology. 2021 Jan 20;10.1212/WNL.0000000000011461. doi: 10.1212/WNL.0000000000011461. 

Objective: To determine whether autologous hematopoietic stem cell transplantation (aHSCT) is able to induce durable disease remission in people with multiple sclerosis (MS), we analyzed the long-term outcomes after transplant in a large cohort of MS patients.

Methods: To be included, a minimum data set (consisting of age, MS phenotype, EDSS at baseline, information on transplant technology and at least 1 follow-up visit after transplant) was required.

Results: 210 patients were included [relapsing-remitting (RR)MS=122(58%)]. Median baseline EDSS was 6(1-9), mean follow-up was 6.2(±5.0) years. Among RRMS patients, disability worsening-free survival (95%CI) was 85.5%(76.9-94.1%) at 5 years and 71.3%(57.8-84.8%) at 10 years. In patients with progressive MS, disability worsening-free survival was 71.0%(59.4-82.6%) and 57.2%(41.8-72.7%) at 5 and 10 years, respectively. In RRMS patients, EDSS significantly reduced after aHSCT [p=0.001; mean EDSS change per year -0.09 (95%CI=-0.15 to -0.04%)]. In RRMS patients, the use of the BEAM+ATG conditioning protocol was independently associated with a reduced risk of NEDA-3 failure [HR=0.27(0.14-0.50), p<0.001]. Three patients died within 100-days from aHSCT (1.4%); no deaths occurred in patients transplanted after 2007.

Conclusions: aHSCT prevents disability worsening in the majority of patients and induces durable improvement in disability in patients with RRMS. The BEAM+ATG conditioning protocol is associated with a more pronounced suppression of clinical relapses and MRI inflammatory activity.

Classification of evidence: This study provides Class IV evidence that for people with MS, aHSCT induces durable disease remission in most patients.

Conflicts of Interest

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General Disclaimer: Please note that the opinions expressed here are those of Professor Giovannoni and do not necessarily reflect the positions of the Barts and The London School of Medicine and Dentistry nor Barts Health NHS Trust and are not meant to be interpreted as personal clinical advice. 

About the author

Prof G

Professor of Neurology, Barts & The London. MS & Preventive Neurology thinker, blogger, runner, vegetable gardener, husband, father, cook and wine & food lover.

66 comments

  • How does this: “On average, disability scores improved in relapsing-remitting subjects and got worse in subjects with progressive disease, which implies that AHSCT does not stop smouldering disease”

    isn’t equal to this: “What underpins my decision to be treated with alemtuzumab and AHSCT first-line is the data missing from this paper on the end-organ; both of these treatments will on average normalise brain volume loss in treated subjects. In other words, these treatments are on top of the ladder when it comes to preventing end-organ damage. ”

    Isn’t the main and leading component of the smouldering MS the brain atrophy?

    Also “Therefore, alemtuzumab probably wins out on safety as a potential first-line therapy. Please remember being treated with alemtuzumab does not exclude you from being treated with AHSCT at a later stage. “, does it go the other way around? Does being treated with aHSCT exclude pwMS from being treated with alemtuzumab at a later stage?

    • The problem is that the progressive patients in this cohort were treated too late; i.e. too much damage had accumulated hence they got worse. Even with AHSCT earlier is better. The message is loud and clear to maximise MS outcomes you have to treat as early and as effectively as possible.

      • Thank you for answering, fully agree on the “treat early, treat effectively”.

        Isn’t it believed that both aHSCT and Alemtuzumab have “permanent” effect on brain atrophy, therefore using both of these DMT’s in order to focus mainly on end organ damage isn’t necessarily, as there are more efficacious drugs in terms of stopping relapses/new lesions?

        • Not sure I would use the word permanent to describe the effects. Brain volume loss is a normal phenomenon and happens in all of us after about the age of 35. All that Alemtuzumab and AHSCT do is take the accelerated BVL seen in MS and ‘normalise’ it. The latter is an average effect; is some people who have a lot of pre-existing damage (longstanding MS with a high lesion load) will probably continue to lose volume at an accelerated rate, whilst others with less damage and a healthier brain will do better.

          • How to define lesion load then? There is probably no top-down value at which we can talk about a high lesion load or a low lesion load. How would you describe it, Professor? Directly on the basis of the number of lesions, their total volume or maybe the ratio of the volume of lesions to the volume of the brain? How pwMS is to decide whether or not a given therapy will be effective in the context of smouldering disease.

            And won’t the recurrence of disease activity after Alemtuzumab or aHSCT use, result in a slow rebound in annual BVL? If the hypothesis that demyelinating plaques are a derivative of an autoimmune response of the body to the ongoing inflammatory “smouldering MS” process, then is the emergence of new resonance lesions not synonymous with the re-activation of this long-term process?

      • When you say the damage had accumulated what do you mean? Are you referring to a persons physical presentation or EDDS score, or are you referring to the person who has many lesions, but not much (yet) in the way of disability?

        • When I refer to the damage I mean loss of neurons, axons and synapses; the functional units of the nervous system.

    • “Does being treated with aHSCT exclude pwMS from being treated with alemtuzumab at a later stage?”

      Pretty much as all -mab drugs do not get in the brain…and so must be used very early in rr..

      • Re: “Pretty much as all -mab drugs”

        This is not true. All monoclonal antibodies get into the brain in proportion to the circulating concentration. CSF levels of antibody concentrations are roughly 1/200th or 0.5% of blood levels.

  • Prof G,

    Thanks for your post.

    “Could AHSCT done early stop/reverse or prevent the establishment of smouldering disease?”

    My neuro told me that he doesn’t support the idea of “smouldering MS” (I’m not clear as to what he thinks drives progressive disease). What evidence is there that smouldering MS exists – MRI? Biomarkers? BVL measurements?

    Given that in many cases, even after Alemtuzumab or HSCT, smouldering MS continues, are there any promising looking therapies in trial which are seeking to address smouldering MS?

    • The underlying hypothesis/question is if you treat MS early enough do you prevent or reverse the processes driving smouldering MS? I think this is highly likely with alemtuzumab and AHSCT, but again this is not all or nothing. Only a proportion of patients treated with alemtuzumab remain NEDA-3 or NEIDA (no evident inflammatory disease activity) and I have no idea how many of these are also NEO-EOD (no evident ongoing end-organ damage). I suspect with AHSCT, particularly with BEAM-ATG AHSCT, this proportion will be higher.

      • Smouldering as a term incorporates the concept of PIRA, but also takes into account processes that aren’t necessarily detected in routine clinical practice, for example, brain volume loss.

  • I would love to be treated with AHSCT but without £££ it’s not available……. My neuro won’t even talk with me about it!

    • “I would love to be treated with AHSCT but without £££ it’s not available….”

      Blame Prof G..10 years ago he had a chance to start a hsct unit in U.K. but
      he didn’t do it…so now everyone has to pay $$$ and go to Russia/Mexico
      all because of that clueless decision.

  • Would love to have been treated with AHSCT until I found out about the fertility problems risk. Otherwise, to get one round of treatment and be cured without worrying about my future with MS would be great.

    • “Would love to have been treated with AHSCT until I found out about the fertility problems risk.”

      Unless you stop ms in it’s tracks first…will be hard to raise a child over 20 years.

      • Yes, the infertility risk is the number one reason why people with MS don’t want to be referred for AHSCT. The good thing is that alemtuzumab does not affect fertility.

  • Hi Prof G.

    A family member has SPMS (secondary progressive). Since their initial diagnosis of RRMS almost 14 years ago, the course of their treatment has spanned everything from monthly infusions of Tysabri, to the more experimental balloon stent in the neck artery, and most recently, HSCT chemo-stemcell-reboot. Suffice it to say that none of these treatments have reversed the progress of their disease, which is now SPMS. In fact, in the case of HSCT, it has caused additional problems such as Reynaud’s disease in the hands. To say that we are exasperated and despairing, is an understatement. Why are these treatments having such a poor effect on this misery causing disease? Are we all looking in the wrong direction as to the cause?

    I have come across an MS survivor from Canada, Pam Bartha, who has made me think that this is the case. She was diagnosed at aged 28. Today, (I believe she is now 60), she shares her research and findings into her disease, and more importantly, the highly positive testimonies of those who follow her treatment program (dietary, herbal and anti-parasite medication). Her findings are fascinating and highly plausible, specifically that MS is an infectious disease caused by tiny parasites, happily growing and reproducing in various parts of the body, but wreaking havoc by their very presence. She references the studies of a Dr Alan B MacDonald, who in 2016, found, for the first time ever, Borrelia endosymbionts inside parasitic nematode worms in the autopsy cerebrospinal fluid of patients who had died of multiple sclerosis. Pam gives a weekly live on Youtube/Facebook “Live Disease Free” channel with updates of current studies. I would be interested in your thoughts on her line of treatment of MS. Thank you and kind regards.

    • I’m sorry but my cynicism meter just tripped out. This sounds like a typical site of someone promoting theories and products of dubious value for potential financial gain of which there truly is an infestation on the web.

    • >Borrelia
      As soon as you see this word you can safely dismiss whoever is using it as a quack. Please do not fall for the naturopathic quacks who attribute every single neurological condition to Lyme disease and coinfections, heavy metal poisoning, or “mold.” Experimental treatments that might actually help your relative: subcutaneous cladribine, HAART.

    • There is a section in the medical canon called ‘Causation Theory’. When you apply it to parasites and infections, apart from EBV, they fall down and hence are not the cause of MS. Please be aware that the cause of a disease doesn’t just happen, it takes decades to prove causation and the final proof is usually in the treatment of the cause or the prevention of the cause.

    • There are some people w/ms who never decline…close to 80% maybe..???
      writer Joan Didion..diagnosed in 1972 is 86 and still walking around but she has no
      infectious theory…just good fortune.

      • Not sure where you get 80% from. In the pre-DMT era after 50 years of follow-up, >95% of pwMS in the Gothenborg natural history study had declined. This is what the concept of so-called benign MS is so fraught. Give untreated MS sufficient time and the majority of pwMS develop MS-related disability. Saying this however in the DMT era this has improved dramatically.

    • She’s only had ms 32 years…she can still turn progressive..One man posted here it took him
      50 years…another woman 40 years before they became progressive.

        • It’s also why Burt and Mark Freeman are so wrong saying
          hsct is only for the minority of patients who can’t control disease with DMT. They clearly are unaware how
          effective DMT really are. Wishfull thinking on their parts..

    • “Why are these treatments having such a poor effect on this misery causing disease? Are we all looking in the wrong direction as to the cause?”

      Yes..all the drugs just focused on stopping relapses…and making money for companies..
      instead of stopping the relentless brain damage that causes progression/disability.

      Still nothing effective for ppms…although hsct seems to stop progression in a minority.

      • Not sure I agree. Ocrelizumab is licensed for PPMS. I agree it is not a miracle treatment, but it is the beginning of what it to come. What we now need to do is test add-on treatments to see if we can add anything on top of ocrelizumab to tackle smouldering MS.

        • “but it is the beginning of what it to come. ”

          No..it’s a dead end. Ocrevus II isn’t going to do any better.

  • Could smouldering MS just be age related?

    The damaged areas of myelin cells just become less able to naturally repair over time? Leading to overall thinner myelin in the brain

    How long do you think until be get a definitive answer over exactly what ‘smouldering MS’ is?

    • Re: “Could smouldering MS just be age-related?”

      Yes, part of it is which is why antiageing therapies are the flavour of the month.

          • You could argue we’ve already cracked part of it. – people live longer now than ever before thanks in part to medical interventions

            But maybe not on a cellular level yet. I suppose the aim in MS is to normalise and slow down the ageing process aswell as control immune systems attacks obviously.

          • ” people live longer now than ever before thanks in part to medical interventions”

            No.. mostly from clean water and clean wounds to avoid infection.

          • I think the longevity gains are due to multiple reasons not only social determinants.

    • “Could smouldering MS just be age related?”

      Pender says control of EBV fails w/age just as ms progresses over time as anti-EBV t cells
      suffer t cell exhaustion.

      “These results are consistent with progressive T-cell exhaustion of EBV-specific CD4+ T cells and CD8+ T cells during the course of MS although they could also be due to other factors, for example an age-related decline in the tendency of EBV to reactivate.”

      https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5292561/

      • ‘No.. mostly from clean water and clean wounds to avoid infection’

        Yes isn’t wound cleaning a medical intervention?

        Killing harmful pathogens in drinking water, is that not a medical intervention? Stopping the pathogens before it reaches humans? That’s the best form of treatment?

        Basically I suppose the answer is education.

  • I am a sample set of 1 in this idea. I had first line AHSCT 2 months after diagnosis, if you can call it that. (200mg/kg Cy + 1000mg Rx) Though the odds may be lower than BEAM I’m hopeful as I did it very early on I may have a good outcome. If it doesn’t work I’m not sure what my backup would be – Cladribine, Ocrelizumab, Alemtuzumab, or maybe even higher intensity HSCT. Seems like a very unanswered question?

    • If you have breakthrough disease activity, doing HSCT again is a perfectly reasonable option, much like they do two or sometimes even three courses of alemtuzumab.

    • Most of the breakthrough cases are people w/highly active and numerous relapses say 2 or 3 a year…But you didn’t have ms long enough to know….Numerous relapses isn’t the norm though so the odds are way in your favor.

    • ” If it doesn’t work ”

      The chemo doesn’t seem to factor as much in results..as do levels of memory cd4/8 t cells…Get academic lab to measure this and you have better idea.

      “While we did not see a correlation between treatment success or other patient parameters and cellular repopulation, we found that patients who remained healthy throughout the 5‐year study had significantly higher absolute numbers of memory CD4 and CD8 T cells in the periphery prior to HDIT/HSCT treatment.”

      https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5543487/

      • This is interesting, but you mention “prior” to HSCT. At this point such labs are temporally out out my reach. Do you still believe they may have value afterwards to gauge treatment success in the absence of inflammatory activity? I was thinking of checking BVL once I have a year or two worth of MRIs and perhaps a spinal tap after a few years if I can get it… thanks for the reference! In retrospect that would have been an interesting lab to ask for 🙂

  • Apparently the mirror are publishing an article/ interviews on HSCT this Sunday. I had it done in Mexico and for me the decision was a no-brainer.

  • 62% NEDA 3 at year 5 seems lower than I thought. What is the equivalent for Alemtuzumab? Can I ask what your patient is on now Prof? Presumably they have failed a high efficacy treatment? All things being equal, I would probably choose HSCT too but the referral process is slow and the chances slim. For a patient failing treatment such a wait could have dire consequences

    • The cumulative NEDA rates on alemtuzumab will be lower than this; ~25% in subjects getting alemtuzumab 2nd or third-line and ~40-45% in subjects getting alemtuzumab first-line within 2 years of disease onset. The treatment response with IRTs and for that matter, all DMTs is about timing.

      • “~40-45% in subjects getting alemtuzumab first-line within 2 years of disease onset.”

        This isn’t so good..you need to stop leaving impression that alemtuzumab is
        comparable to hsct.

  • I’m entirely persuaded by the arguments for HSCT in general but are there any groups of people (in terms of MS disease course to date, age, time since diagnosis, EDSS, etc) where the evidence does not support HSCT?

    • ” but are there any groups of people (in terms of MS disease course to date, age, time since diagnosis, EDSS, etc) where the evidence does not support HSCT?”

      No…read of Australian w/ppms reverse disability edss and have no progression for 10 years.

      Read of a rr patient who had hsct after only 2 years of ms fail treatment. In general
      of course rr and recent diagnosis does better than progressive patient.

    • Re: “…. are there any groups of people (in terms of MS disease course to date, age, time since diagnosis, EDSS, etc) where the evidence does not support HSCT?”

      Yes, people with advanced progressive disease, people with inactive MS, people who are risk-averse (not prepared to sign-up for a 0.3% to 2% mortality risk, infertility, chemobrain, sepsis, mucositis, hair loss, infertility, etc.).

      • Thanks for the reply. In this context, what constitutes inactive? No new lesions, no relapses, no/slow deterioration?

        I know you can’t give personal advice but I’ll describe my own situation to help illustrate the dilemma in case a general answer helps others.

        I’m in my late 40’s, 13yrs post-diagnosis (caught early), recently started on Ocrevus as a first DMT after years of watchful-waiting (I wanted Lemtrada but just got caught by the EMA decision in 2019), EDSS 2, look after myself & fortunate enough to be mostly well so far. So what I wonder is, should I find the money to pay for HSCT now or does the risk/benefit not stack up for me?

        In a general sense if you were fortunate enough that you could raise the money for HSCT, didn’t have advanced disease & were not risk averse how would you decide if you should?

        • Absolutely…preserve your current condition before it worsens.
          It would be crazy not to. Ocrevus and all DMT are band aids and don’t protect you from ms brain loss…so you need to do it.

        • “In this context, what constitutes inactive? ”

          They mean progression but without any lesions showing.
          Hsct for you it’s a no-brainer.

        • I had HSCT less than a month after diagnosis. I believe I am one of the quickest to be treated. I am almost a year post treatment and I have zero limitations. I fully support HSCT as a first line treatment.

        • “I’m in my late 40’s,”

          Say no more. Do it before you start to progress.
          MS progression is based on your biological age and how long
          your system has had disease. It usually starts to show in the ’50s.

  • “This is why a trial of AHSCT in very early MS, i.e. as a first-line treatment, is a no-brainer to me.”

    You could have done such a study yourself…over 10 years ago..if you had opened the hsct clinic when you had the chance. “No brainer”…yeah you can say that again.

    You need to read the blog more..cause it’s been done in Sweden..https://multiple-sclerosis-research.org/2019/07/hsct-is-it-remission-or-is-it-a-cure-for-ms/

    Sweden does early hsct..20% fail…50% remission..30% cure. It was BEAM ATG
    with one non-myelo thrown in.

    What is cure..?..”the disappearance of oligoclonal bands (antibody synthesis) in the cerebrospinal fluid (CSF) is a good indicator of this. They have also included into this definition stabilization of CSF neurofilament levels into this (i.e. no further ongoing neuronal injury).”..So hsct is not a miracle..it has it’s limits.

  • If AHSCT does not stop smouldering MS after treatment. Doesn’t that imply smouldering ms is immune mediated disease? Given after you have AHSTC, the immune memory is wiped clean and therefore smouldering MS should stop if its was immune mediated.

    • “If AHSCT does not stop smouldering MS after treatment.”

      If you define smouldering as progression..it does stop it.
      Burt says if chemo removes inflammation and t cells…then
      the t cells repopulate in non-inflammatory environment..
      “Regeneration in the absence of inflammation induces
      tolerance”.

    • “If AHSCT does not stop smouldering MS”

      Video at 5:15……..”In most cases it stops disease in it’s tracks…no relapses…no progression”

      • “However, and importantly, in the subgroup of patients with RRMS who underwent AHSCT with the BEAM+ATG conditioning protocol, which is more aggressive, NEDA-3 status was achieved in 68% and 55% of subjects at 5 and 10 years, respectively.”

        Barely 70% at 5 years and only 55% at 10 years…clearly not a cure..better
        treatments are needed. It’s just a remission…people on FB post they are cured
        because they feel better and are amazed not to be worsening weekly/daily.
        But some days there are multiple people posting they feel progression..all of them posting at the 4 year mark.

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