The Star-MS trial: to be HSCTed or not

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Barts-MS rose-tinted-odometer: ★★★

There is little doubt in my mind that HSCT is the most effective DMT we have for treating MS. The latter is based on NEDA (no evident disease activity) rates post-HSCT and brain volume loss data after year one. HSCT appears to put the majority of treated patients into long-term remission and normalises end-organ damage as measured by brain volume loss. In addition, a not insignificant proportion of HSCT-treated patients may be cured depending on how you want to define an MS cure. Despite these data most MSologists however, consider HSCT too risky to refer patients for treatment and hence prefer to go with the more acceptable risk profile of licensed DMTs. This is why HSCT hasn’t taken off as a mainstream treatment for MS and remains a niche treatment. 

What is not known is that HSCT may yet prove to be one of the most cost-effective DMTs we have. Although quite expensive, with most of the costs front-loaded, HSCT does lead to significant cost savings in the long-term (see study below). I wonder if healthcare systems will clock this and take the bold step of underwriting more HSCT treatments for MS with the promise of long term cost savings? The problem we have in medicine is that healthcare budgets typically run on an annual cycle and so costs savings unless made the same year often don’t influence treatment decisions. 

“Why should I spend more money today to only save money in the 5 years time? My responsibility is to this year’s or maybe next year’s budget not the budget in 5 years time.”

The counter-argument to this is should be if I don’t save my brain volume this year or next year, by the time I get to year 5 in my disease course it will be too late. At the moment MS brain and spinal cord damage are irreversible. Yes, time really is brain.

What do you do as a person with MS who has decided to be treated with HSCT, but your neurologist says no? Do you find a neurologist who will say yes? Do you travel abroad and take the private route? Or do you accept your neurologist’s advice and go for the safer, but ultimately more expensive, licensed but less effective DMT? 

The good news is that we in the UK will soon be starting the StartMS trial, which will compare autologous stem cell transplantation (AHSCT) versus alemtuzumab or ocrelizumab in relapsing-remitting MS. This means at least some of you will be offered the opportunity to be randomised to AHSCT or ocrelizumab/alemtuzumab. A major outcome of this study will be a cost-comparison to see how much money it will save the NHS. Exciting or not? Some people are arguing that we don’t need this study as the information is already available. Not sure I agree. Sometimes doing your own research and generating your own data is what is required to change behaviour, i.e. the wide adoption of HSCT as a treatment for MS. 

Orlewska et al. Impact of Immunoablation and Autologous Hematopoietic Stem Cell Transplantation (AHSCT) on Treatment Cost of Multiple Sclerosis: Real-World Nationwide Study. Value Health Reg Issues. 2021 Apr 14;25:104-107.

Objectives: To provide real-world data on the impact of autologous hematopoietic stem cell transplantation (AHSCT) on treatment costs of patients with multiple sclerosis (MS) in Poland.

Methods: Medical data of 105 patients who underwent AHSCT in the years 2011 to 2016 were obtained from the National Health Fund (NHF) database. Treatment costs were calculated from the public payer’s perspective per patient-year for the total available period as well as 12 months before and after AHSCT. The statistical analysis was performed using MATLAB 2016b.

Results: Mean treatment-related costs covered by the NHF per patient-year before and after the transplantation were €4314.9 and €1188.8 , respectively. The average cost of disease-modifying drugs per patient was reduced from €2497.9/year before to €65.3/year after AHSCT.

Conclusions: Although the initial cost of AHSCT is high, the costs involving AHSCT and post-AHSCT treatment could, according to our analysis, pay off in 3.9 years, when compared to the costs of disease-modifying drug therapy in aggressive MS. The study provides evidence that the AHSCT can lead to significant savings in treatment costs of aggressive MS from the public payer’s perspective.

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Disclaimer: Please note that the opinions expressed here are those of Professor Giovannoni and do not necessarily reflect the position of the Barts and The London School of Medicine and Dentistry nor Barts Health NHS Trust.

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.

40 comments

  • “however, consider HSCT too risky to refer patients for treatment and hence prefer to go with the more acceptable risk profile of licensed DMTs. This is why HSCT hasn’t taken off as a mainstream treatment for MS and remains a niche treatment. ”

    thats not the problem though is it ? the problem is the guidlines put in place that the neurologists have to follow. i got myself under one of the most forward thinking neurologists in the country who completely agreed lemtrada or hsct would be perfect in my situation, however he could not treat me with it due to the guidlines he had to follow. so again choice of treatment taken out of the hands of the specialist/ patient due to what the nhs and nice who have no idea of any individual situation deem as the right safety to efficacy balance. its a joke, the entire trial should be forgotten about and just monitor the amount of patients that decide with their specialist to go for hsct first line! it would stop so many having to go abroad and paying out their life savings to get treatment that they should be entitled to in the uk.

    its bad enough losing your future with ms but when your educated you tend to lose your future financial stability as well.

      • as a pwms who’s first attack has been life altering i appreciate your advocacy but this post was two years ago. nothings changed, people are still going abroad or being stuck on the same dead end dmt. its not the patients that need convincing that change is required, its the people that write the guidelines which for some of us means a life or worsening pain and symptoms and less want to live the next day.

        pretty much all people newly diagnosed now educate themselves about hsct and there is a fantastic online community that shares the research and anecdotal stories. my mission within the first six months was to self advocate to the neurologist that i knew had the best chance of getting me the potential “cure”. what we really need is someone who knows who to speak to and what would need to be done to change the treatment guidlines and actually help us do it rather than it all being spoken about for two years with countless trials. i dont understand why substantiated evidence is not used from these treating hospitals all over the world to say to nice and the nhs THIS WORKS LETS HELP PEOPLE.

        i have just followed the story of a young lady diagnosed recently on social media who gave an update today with all of her symptoms reverting after being treated first line in mexico. why did she have to fly half way round the world and leave her two young children at home to get the best treatment? instead of now draining more and more cash from the nhs she can get on with her life rather than a lifetime of hospital trips and different drugs. they need to just change the guidlines and stop using pwms finance with new drugs.

        • I suggested setting up a Citizen’s jury two years ago to break this catch-22 or HSCT deadlock but only go a lukewarm response. Life is too short for me to take this on, which is why I am now focusing on MS prevention and not curing MS. Too many hurdles regarding the latter. We went out on a limb with alemtuzumab and all I got was pushback and now alemtuzumab is now 2nd- or 3rd-line. Making the case for alemtuzumab and/or HSCT to be a 1st-line MS treatment is like banging your head against a brick wall.

          https://multiple-sclerosis-research.org/2019/02/hsct-citizens-jury/

          • people are alot more educated today than even one year ago about hsct prof G, but i also give up sometimes when things get to complicated or take too long. i don’t blame my neurological deficit but then im not someone who can make a real difference or contact the right people for the good of all pwms.

          • This brick wall underscores the need for another view and initiative which we try to stimulate via the Start2Cure foundation. We hope to reach those scientists who dare to think big and different than the overall consensus. We hope to be the sledgehammer to break this wall and inspire scientists to explore other novel avenues than for instance remyelination to improve the quality of life of progressive MS patients. Improving or even reversing longstanding accumulated neurological disability is the biggest unmet need in the underserved Advanced (progressive) MS community.

            It should, therefore, be abundantly clear to the Advanced (progressive) MS community that remyelination therapies will have no to limited effect due to the inflammatory penumbra. Only new acute inflammatory lesions are suitable for remyelination and neuroprotection. Again, like with current DMT’s mainly (Early) Relapsing MS is addressed with remyelination and neuroprotection Research and research to create adequate treatments for non-inflammatory and/or smouldering Progressive MS are still lacking.

            I therefor do wonder why for instance the progressive MS Alliance and other national ms societies and foundations so strongly focus on remyelination therapies for Progressive MS. Cumulative neurological disability via axonal degeneration and CNS atrophy due to neurodegeneration and/or inflammation will not be addressed with remyelination therapies. In best case scenario it will limited and prevent progression in Progressive MS.

            At present PwMS, especially people with progressive MS, have unrealistically high expectations for potential remyelination therapies while those living with advanced levels of disability are likely to not benefit from them. Therefore, we must manage the expectations to the underserved progressive MS patient community and explain the complexities and challenges posed by remyelination and neurorestorative therapies.

            The way we see it, in 5 to 10 years’ time there will arguably be roughly 2 types of MS patients.

            1. Early diagnosis with a hit hard induction therapy with possible remyelination therapy resulting in low EDSS and stable MS. (cure?)
            2. MS Patients with cumulative acquired disability with hopefully CNS penetrable medical interventions to keep them stable and stop progression.

            For those PwMS in the second group Start2Cure wants to develop novel medical interventions than remyelination alone to improve or even reverse longstanding accumulated neurological disability and improve quality of life. Ultimately, we hope to enable those scientists who are prepared to not follow the overall consensus and views in MS Research to actually find a cure. As an independent Foundation we have the means and freedom to actually do so.

            We are always open to new ideas and are looking to connect with those scientists and KOL’s pursuing novel translational research.

      • . I have always advocated for alemtuzumab and HSCT to be 1st-line options for treating MS

        Really?

        A large number of the HSCT zealots seem to ignore the fact that HSCT does not result in a cure in many pwMS treated with HSCT and that there is an issue of HSCT-related mortality. The latter is often conveniently ignored

        The main message from this post is that HSCT is not that safe; HSCT has many short-term complications including a relatively high mortality and although its efficacy is high it is not necessarily higher than currently licensed DMTs. So don’t believe everything the HSCT zealots tell you or ask them to show you the data.

        https://multiple-sclerosis-research.org/2016/02/clinicspeak-reflections-on-hsct-after-the-fallout-of-the-bbc-panorama-programme/

        https://multiple-sclerosis-research.org/2018/01/is-hsct-for-everyone-or-not/

        • Maybe I should have separated my comments about alemtuzumab and HSCT. Being a scientist does allow you to change your mind 😉 I did due diligence on setting up an HSCT unit for MS at the Royal Free Hospital back in 1999 but was discouraged by my colleagues (pity I listened to them).

        • I don’t know if you have MS or not. I do. The spectre of it hanging over you means that discussions about safety are really about risk tolerance. If it is honestly explained to me then it is for me to overlay a filter of my risk tolerance onto it. The whole patrician ‘Dr knows best’ attitude doesn’t sit well with me. I am the one with MS and provided I can satisfy one or more independent doctors (other than my own clinician) that I fully understand the risks then who is anyone else to stop me?

          I have the MS, I know what it will do to me, I can see the others affected, I can read, I can contextualise risk so I ought to be able to access HSCT.

  • As a recipient of Alemtuzumab some 15 years ago (and who has done well so far), if I was recently diagnosed, I’d be jumping at the chance to be part of this study.

    As HSCT has, for many, shown to be highly effective, what is it telling us about what causes and drives MS?

    I do wonder (given the time to complete the study) if the game may have moved on. BTK inhibitors look promising and are in late trials.

    Dr Fauci told an AAN meeting at the weekend that “mRNA vaccines are a “home run out of the park” and agrees with the neurology panel that similar technology could be used to eradicate EBV, acute flaccid myelitis, west nile, eastern equine encephalitis, and other illnesses.” Perhaps anti-ebv treatments will negate the need for the big guns such as Alemtuzumab or HSCT?

    • Re: ” Perhaps anti-ebv treatments will negate the need for the big guns such as Alemtuzumab or HSCT?”

      Yes, but this is a hypothesis that needs testing.

  • Hi Prof, this is a very relevant topic which will no doubt generate a lot of responses. The trial is a step forward, i agree. One of the access issues is that you cant enter the trial if already on a highly efficacious agent. I understand the reasons but it does take out a huge chunk of the receptive audience for HSCT and creates a dilemma for this group. In many cases, they have fought for an effective agent first line or their MS is agressive enough to merit it. The treatment gets focal inflammation under wraps. Good news. However, this in turn prevents them from accessing HSCT via the NHS as the criteria requires active inflammation. This leaves some patients actually hoping for new activity – a crazy situation. If they cannot show it then even the option of being treated privately in the UK is out of reach so the next step in a search for ‘the best DMT’ is to travel abroad, mainly to Russia or Mexico. Barts doesn’t encourage this but presumably doesnt encourage avoidable damage to the brain or spinal cord either. So its catch 22. Out of interest, there are many HSCT advocates on the forums that claim Russia and Mexico are more experienced in performing this procedure. I am sure that this is true for MS patients but presumably in the UK the HSCT procedure is undertaken for cancers etc all of the time? Sounds to me like HSCT followed by a vaccine for EBV is 5 yearsish is not a bad approach

  • How do you see the death risk and cancer risk considering that a minimal small increase in cancer risk for cladribine was enough to make its story so troubled?
    Results should also be compared with beatms and there should be concordance or data could be pooled to get a stronger conclusion

  • I went abroad, I really could not reconcile the evidence emerging my situation at diagnosis, and going down any other route.
    The staff and hospital were absolutely wonderful, but going abroad for such a massive procedure is def not ideal, not to mention not being able to access haematology follow up locally, how does that help matters at all. The system here is broken

  • Professor G, a few weeks ago you wrote that General anaesthetic often causes irreversible multiple sclerosis relapses in those with progressive/ advanced MS. Why is this?

    You say that the patient often can never return to their baseline and symptoms may become intrenched. That sounds very serious and I cannot find any blog posts on this subject.

    Can you please elucidate on this subject because as elective surgery will gradually resume, and backlogs of patients will be rushed through, information on this subject is essential.

    • Re: “General anaesthetic often causes irreversible multiple sclerosis relapses in those with progressive/ advanced MS. Why is this?”

      No, I didn’t say this. All I said is that people with MS who are disabled may not handle a general anaesthetic very well, i.e. they may find worsening of symptoms after the GA that may not get back to baseline. Whether this is the GA itself, the surgery or other factors (infections, low blood pressure, mini-strokes, etc.) is not known. This observation is not unique to MS but also occurs in patients with other neurodegenerative disorders such as Parkinson’s or Alzheimer’s disease. The message is to only have GAs if absolutely necessary.

    • HSCT and alemtuzumab are pretty good anti-EBV drugs. Some people become EBV negative after HSCT. Interesting? You bet it is!

      • “HSCT and alemtuzumab are pretty good anti-EBV drugs. Some people become EBV negative after HSCT. Interesting? You bet it is!”

        Yes.. but don’t around 50% fail Alemtuz and about 30% fail hsct at 5 years…so not cures by any means for MS or EBV.

        Chemo kills B and T cells…it’s not meant to get rid of EBV..and in fact the reason people relapse after hsct is most likely uncontrolled EBV
        caused by genetic lack of cd8 and cd4 tcells .
        “In general, the repopulation of immune cell subsets progressed similarly to 2 years for all patients studied, regardless of clinical outcome. ”
        “Although none of the observed treatment effects correlated with clinical success, patients who remained healthy (remission)
        throughout the 5‐year study had significantly higher absolute numbers of memory CD4 and CD8 T cells in the periphery prior to HSCT..”

        In other words there were no immune changes from therapy that directly affected EBV…those who stayed in remission simply started with higher CD4 and CD8 t cells to control EBV. This was HALT MS study 2010-2015.

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

        But this is old news Pender told us 10 years ago….

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

        Why was there threat to ban Luis for mentioning/advertising hsct years ago ?…a really sad look…Neuro lashing out at treatment that comes out of hematology and not pharma. Patients advocated HSCT,,,not CCSVI

        https://multiple-sclerosis-research.org/2020/01/premature-ageing/

        Reason this patient can’t lift her leg is not “premature ageing”…it’s spms spasticity that pushes her leg down…spasticity not foot drop is her problem. see video @6:30

      • It’s not interesting to me to destroy my immune system. Particularly if all that’s actually needed is an antiviral for EBV.

        • “not interesting to me to destroy my immune system.”

          Just temporary depletion of b and t cells…the real danger is to your brain as chemo is neurotoxic..depending on how long you’ve had ms it can take up to one year to just get back to baseline and then you improve out to year 2. Diagnosed in last
          10 years probable one year total recovery.

          This is why they develop non-myelo…more so as to use less chemo and save brain. Safety is still risk as you go into neutropenia…just not as deep neutropenia as with myeloablative…and efficacy is similar.

      • “HSCT and alemtuzumab are pretty good anti-EBV drugs. Some people become EBV negative after HSCT. Interesting? You bet it is!”

        And yet the U.K. has the worst record for EBV flare-ups after HSCT! 80% of those treated will have an EBV flare-up. Most of those cases will self-rectified without intervention, but those who reach dangerous levels will have rituximab infusions to eradicate it. One patient very nearly died 5 years ago.

        It seems that this is due to the use of rATG – other countries (Russia, Mexico) don’t use this old drug anymore, they favour rituximab over rATG in the first place. The EBV flare up is also something that seems to be specific to the U.K. – Dr Burt, for example, didn’t experience this is his patients although he also used rATG. So the U.K. must be doing something slightly differently.

        Incidentally, one of the reasons that British people with MS flock to Russia and Mexico for HSCT (Russia and Mexico have a much lower mortality rate than the U.K. does at around 0.3% v around 2% in the U.K.) is because the criteria in the U.K. are so restrictive. The insistence of one active lesion or two T2 lesions rules a lot of people out. The U.K. is definitely following Burt’s lead in terms of HSCT and needs to be more progressive than that. Burt himself freely admitted that, for him, a reversal of symptoms/a lowering of the EDSS is what he considers a success with HSCT. For many, many progressive MS patients, a halting of their progression is sufficient for them.

        My husband had HSCT 5 years ago in London. He was (and still is) EDSS 6.5. He had rapidly progressing secondary progressive MS. His mobility is the same as it was, perhaps even a little worse (likely as a result of the permanent damage) but he’s still on his feet and not in a wheelchair. Without HSCT we are certain he’d have been in a wheelchair (or worse) within a year. For him, for us, HSCT has been a resounding success. He’s seen many symptomatic improvements (a bonus), and his quality of life has improved massively. But here’s the thing – he was only the 17th person to have HSCT in London, and he didn’t fit the criteria. He had no active lesions or T2 lesions. He slipped through under the radar because HSCT wasn’t as widely known about in those days (our own neurologist even asked us to spell haematopoietic when we first brought it up). There’s no way he’d be accepted today, and yet it has improved his life immeasurably. And he is just one of many.

        We are very grateful for the fact that he received HSCT in this country and his care was exceptional. EBV did flare up for him post-treatment and he had 4 infusions of rituximab to bring it back under control.

        It was because of our gratitude that we set up the charity AIMS (Auto Immune & Multiple Sclerosis) which is the first charity in the world with a focus on HSCT that offers financial support to those undergoing HSCT. We would be delighted to be involved in the setting up of a citizens’ jury, Gavin. You can contact me at alison@aimscharity.org

        HSCT should be an option for all from the outset.

  • My local hospital seem to have an excuse against anything I mention: cannabis, response was ‘well it makes you a bit ga ga’; stem cell response was ‘it’s a chemotherapy drug so you will need to stay in hospital overnight’. Never has my neurologist or MS nurse made suggestions about drugs for actually treating or slowing the progression of MS.

  • Is there a chance that the upper age limit for the trial might be increased if they are not able to recruit enough suitable candidates?

  • Prof G you took the words out of my mouth. I have thought for a long time that it’s more cost effective for everyone with MS to be offered aHSCT as a frontline treatment. I also wonder whether the pandemic may speed this up? Will aHSCT be offered to those with Long Covid-19 to save the NHS millions in the future? I have no medical training but it occurs to me Long Covid-19 mimics MS. I really want to take part in this trial . Does anyone in this forum have contact details for STAR MS trial?

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