HSCT vs. Alemtuzumab: is it time for a head-2-head study?

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“In view of the current interest in HSCT I have made a first attempt at designing a trial to ascertain whether or not HSCT (hematopoietic stem cell transplantation) is non-inferior to alemtuzumab. The latter is the only realistic way of powering the study. For this to be developed into a protocol each section needs work. Any volunteers? It also needs a name; I have come up with ZEUS, but as with all community-designed trials I think we should have a competition with a vote to name the trial. Therefore suggestions are welcome.”

“I assume a lot of of you will still disagree with the need for a comparator trial; I think it is essential. Without data from at least one, and preferably two,  well-designed phase 3 studies the MS community, the regulators and the payers won’t accept HSCT as a treatment for MS.”

“Some of you will say that HSCT is too risky and that this proposal is crazy? I would have said so myself, until a week  ago; the recent poll on this site about risk and HSCT has made me reassess my position. It is clear that MSers are much more willing to take risks than I realised. There is one caveat; MSers who follow this blog are unlikely to be representative of the wider MS community.”

“Finally, at some point in time we will need to assess the wider communities appetite for a trial of this nature; without buy in from a larger group of people this study even as a fledgling concept is going nowhere. We can do some quantitative and qualitative work once we have a workable trial protocol in place.”

CoI: multiple

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.


  • Why is there a need for head to head trials? When I buy a car I identify 3-4 makes and then look at fuel efficiency, top speed, depreciation figures. These are facts available in car magazines etc. We have a wealth of data on the efficacy of Alemtuzumab e.g. reduction in annual relapse rate, impact on disability progression….. I'm guessing that we have simialr data for HSCT (although the protocols for undertaking the studies may be different). So we could have a comparator table – including adverse incidents etc. I'm assuming these facts are accurate as they are compiled by scientists / academics like yourselves. Why then do you need a head to head trial?

    • Re: "Why then do you need a head to head trial?"

      You need a head-2-head trial to assess the risk benefit ratio and to get HSCT licensed. Without a license we will not be able to offer MSers HSCT, payers won't pay for it and the community won't adopt HSCT as a treatment for MS. Generating class 1 evidence is the way we do science. Open-label observational studies provide some evidence that a drug works, but is simply not good enough in the modern era. Please take a look at what it took to get alemtuzumab to market. Alemtuzumab started off as an open-label treatment trial and then went into a fully fledged phase 2 and 3 development programme. Why would we accept a lower standard for HSCT? I won't.

    • Is there an issue with the ongoing trial design (MIST Study) , and will it meet the "Gold standard" once its complete ?

    • I've had Alemtuzumab so don't have any interest in HSCT. My question was why the need for head to head trials. Usain Bolt is the fastest runner in the world – you can get him to run 10 100m races on his own and time them, or time him in ten races against others. If the starting pistol and timing system are the same it will still show him as the fastest man. If you have accurate data on his speed from him racing on his own and accurate data of another runenr racing on his own, you can wokr out who is best. I'm jsut curious what head to head races (trials ) add.

  • The question is whose monies for the trial…. and what would be the adoption,

    We have had this anti-alemtuzumab wave of sentiment and now we are going gung ho for HSCT. Is the buzz being whipped up by a vocal few…..creating CCSVI2. There are clearly a number of centres charging for this service (no publications) around the global and as interest rises so will the scammers. The MS Societies will have to think if and how they respond.

    If anything is to be done surely it needs to be a co-ordinated and consistent study so it gets done properly and duplication avoided and that adoption is ensured should the trials work.

    I suspect if the question posted by ProfG were put to MS register/NARCOMS there would be less enthusiasm

    Also should HSCT to be a first line or a third line. Importantly who do you treat. It seems from the comments of the post by ProfG there are PPMSers and SPMSers doing health tourism and I understand why. However, the trials however exclude PPMSers and SPMSers notably those who are non-relapsing because this group do not show the best of responses. Who are shouting the loudest?, because if this becomes a regulated procedure in the NHS, I suspect the PP/SPMSers will miss out again.

  • Estimated cost Drug costs for the alemtuzumab year 0 £7045 x 5 x 200, year 1 7045 x 3 x 200, year 3 + 7045 x 3 x 100 (50% retreats) = £13.400,000 costs of dealing with autoimmunity, so easily £15,000,000. (In UK this would be a standard of card cost to NHS), plus cost of the HSCT. I don't know what the NHS cost (procedure and post transplant care) is at £40,000 this is £8,000,000 at £20,000 it is still £4,000,000 which is a big grant so a £20,000,000 study.

  • Re "trials however exclude PPMSers and SPMSers notably those who are non-relapsing because this group do not show the best of responses"

    The HSCT trial being run in Australia includes SPMSers and patients who do not have relapses, but not PPMSers. The MS criteria for inclusion are as follows (taken directly from Aus & New Zealand Clinical Trials Register (complete with misspelling of glatiramer). The trial is also including patients with other types of auto-immune diseases such as Crohns etc.

    "3. Multiple Sclerosis (MS):
    MS clinically defined and supported by laboratory tests (eg:MRI). Patients should have an EDSS between 3.5 and 6.5 at screening evaluation and the presence of one or more enhancing lesion on MRI. Previous Treatment with Nataluzimab is allowed but a minimum of 3 months MUST have elapsed since completion of treatment.

    The forms of MS eligible for the Australian HSCT trial include:
    a) Secondary Progressive form of MS with or without relapses, with recent worsening of disease in the previous year despite immunomodulating therapy (interferon beta or glatimer acetate) and/or immunosuppressive therapy
    b) Relapsing remitting form of MS with recent worsening of disease or accumulation of disability in the previous year despite immunomodulating therapy (interferon beta or glatimer acetate) and/or immunosuppressive therapy.
    c) Relapsing-remitting forms of MS who do not accumulate disability but who have at least two relapses per year, in spite of immunomodulating therapy (interferon beta or glatiramer acetate, where approved) or immunomodulating and immunosuppressive therapy and presence of one or more enhancing areas at MRI (possible repetition of MRI within three months).
    d) Secondary progressive form of MS with or without relapses or relapsing-remitting MS form who accumulate disability between relapses (relapsing-progressive) with a worsening documented by EDSS during the last year in spite of the immunomodulating therapy (interferon beta or glatiramer acetate, where approved) or immunomodulating and immunosuppressive therapy, even in the absence of contrast enhancing areas at MRI."

    See full details on:

    If a trial in the Colonial Outposts can include such patients there is no real reason why other trials cannot do so. At least then there may be some more definitive answers about HSCT for SPMS and non-relapsing MS, whether the news be good or bad.

    For a list of other MS trials being run see

    • If you load your trials with potential non-responders you reduce the power needing more people in a trial to see an effect. The reason why SPMS are excluded for some studies is because of the history of poor response in other trials ..please read the post by Dr Burt, which started this all off.

  • Why you can not include PPMSers in a HSCT trial?
    I saw few post in this blog assuming that the Ocrelizumab trial for PPMS could be positive.
    So, if you assume Ocrelizumab could work with PPMSers why you can not assume the same with HSCT? HSCT is more agressive than Ocrelizumab so chances are better for a good outcome.

    • Based on ritizuimab the gadolinium enhancing PPMSers should respond I would not be so sure it will be good for everyone. I am sure relapsing PPMSers would respond to HSCT also

  • Yeah, these MSers may be risk-averse, but what about if the develop catastrophic secondary side-effects? Are we then expected to pay for additional treatments for them? Hell, no!

    You roll the dice and pay the price. Take the risk if you wish but then live with the outcomes. They should be made to sign contracts that consequential damage from the treatment is their responsibility.

    Dr Dre, back me up on this, brother

    • "They should be made to sign contracts that consequential damage from the treatment is their responsibility."

      That would swiftly ensure that any drug development for MS by pharma would be immediately terminated.
      Is that what you want?

    • If you have the courage of your convictions then you've got nothing to fear, MD2 If these DMTs do the job then it's all great. Therefore, you must underwrite any detrimental consequences.

    • Which again is the quickest way to ensure that no new drugs would ever be developed. No company lawyer would go anywhere near what you suggest except in some non-existent Utopia.

    • I'd be much more in favour of Pharma reducing the prices for their products, rather than appearing to behave as a cartel.

    • So, Anonymous at 1:08 pm – can we take it that if you develop some other condition where HSCT could be used to treat it, you would happily sign a contract in relation to "consequential damage" and "catastrophic secondary side effects"? Yes – for HSCT the highest risk is infection and death, but don't forget that all of the existing MS treatments are not without side effects and risks, and PML can easily be fatal or turn you into a vegetable in a bed (which MS has the potential to do anyway). And the others – liver damage, thyroid problems, risk from opportunistic infections due to suppressed immune function, depression (up to and including suicide) – should we all be signing waiver of rights contracts for these as well??? I don't think so……….

    • RE Anon12:44pm – Yes, you need to take full responsibility for the medicine you choose to be on, including bad outcomes.

      If someone is into a forced marriage in a foreign land and needs the British embassy to recue them, they are still responsible for the costs of repatriation despite it not being their fault. Therefore, I find it alarming that we as tax payers subsidise DMTs that may cause devastating side-effects and then pay for those consequences while Big Pharma just shrugs it away.

      We cannot afford dangerous DMTs and nor should we. MSers need to take responsibility and contribute economically as does Big Pharma.

    • Good bye NHS, it seems then. Bevin must be spinning in his grave at these kind of remarks. Not everyone with MS is in a position to pay for treatment, possibly with these 'dangerous' drugs they may get their lives back and continue to contribute economically. But with comments like this, I guess there are people who'd prefer to see people with MS shoved away and forgotten. Stop all research, as we're really not worth it. Thanks for your compassion and humanity.

    • Reading these comments makes me genuinely think that the NHS dying. It's inevitable, it seems.

      We've underappreciated the NHS and all that it has done for us. You watch the news and the reports outline an institution begging to be put out of its misery. No-one's defending it. Even this blog doesn't speak up for it enough.

      Prof G, tell your readers how much the NHS means to you.

    • To Anon at 12.16pm
      You cannot have it both ways – those "dangerous DMT's" can be the difference between an MSer being able to contribute economically or not. All MSers and MS clinicians would much prefer it if the DMTs were less "dangerous", but they are pretty much all we have available at the moment, and the "bad outcomes" cannot be reliably predicted for any particular individual. All of us except for Big Pharma would also like to see them much cheaper as well.

      Clearly you are one of the people who would much "prefer to see people with MS shoved away and forgotten". How about you direct your venom elsewhere – like sorting out the obesity epidemic which is causing even more health issues (but then I suspect that you wouldn't want any of the health problems caused by obesity treated either – a sort of perverse caveat emptor perspective). We MSers did not ask to get MS and did not do anything which brought it down upon us. I can guarantee that every single one of us would like to shove it in a box marked "Return to Sender"!

      However, I suspect that comments such as yours and others of a similar ilk which have recently been posted on this blog are somewhat akin to a nasty little boy poking something with a sharp stick to see if they get response. As far as I'm concerned, you should go and find another "something" to poke at – preferably one of your fellow nasty little boys. After posting this comment of mine, I shall in the future do my best to refrain from rising to the bait, and I sincerely hope that other contributors to this blog will take the same approach.

  • Hi Prof G,

    Probably not the type of volunteer you are looking for at this point in time, but it's worth a try.

    I would like to volunteer myself for inclusion in the HSCT side of this study, ideally following the myelo protocol.

    Based on the suggested projected cost by MouseDoctor, I am even willing to cover part/all of the cost to the NHS for this treatment!

    Anticipatively yours, a progressive MS SUFFERER ( and a UK citizen).

    • I have also seen prices mentioned like £250,000/ I dont know the real cost it would depend on how you do the ablation. In a trial you volunteer and then you are randomly assigned it is not your choice once you volunteer. However you mention yourself as a person with progressive MS and one has to accept that at present the data would suggest that it would not be money well spent I am sorry to say.

  • As I understand it, this is the basic formats of clinical trials. You test it by itself, once you get something effective and safe, you test it against something else. That trial has people on each side that match as closely as possible, age, disability, and so on. Those people are randomly assigned. After that, the NHS through NICE decide whether it is cost effective in comparison to treatments they have already approved – is the amount of improvement worth it. I can't see how HSCT will get NICE approval without a head to head, the same as everything else.

    Any head to head trial will only be RRMS because that's where the money is to be made and spent. Only after all this will a trial include either SPMS or PPMS.

    As I see it, if you don't support what was posted here, your only option is to travel somewhere and pay for it yourself. That's not an option I personally would consider.

  • There is a very good article in Pediatric Research vol 71 Issue 4-2 produced by nature discussing complications of autologous HSCT's for patients with auto immune diseases (not just children). Everyone seems to be discarding alemtuzumab and rushing head first into HSCT's without looking at the risks. Yes, there have been 10s of thousands of HSCTs carried out, but pubMed 2006 June 27(3)297-309 in an article 'major complictions following HSCT' says that between 15-40% of patients undergoing HSCT end up in intensive care

    • The problem with brain atrophy is so called pseudoatrophy,so if you have any immunosuppressive drug or treatment then the brain appears to shrink, possibly because it is getting rid of swelling.

  • If you are really serious about this study you may want to contact the European Bone Marrow Transplant society (EBMT) as they have a group for autoimmune disease:


    To me this organization seems legitimate along with the group involved in the Mist trial at Northwestern University as wewell as those working on the Halt MS trial at the Fred Hutchinson Cancer Institute.

    To in any way equate HSCT as an equivalent phenomenon as Zamboni's theories/followers shows a complete lack of knowledge as to what is going on in this field.

  • Prof G, how do you get a study like this off the ground? I am guessing that to securing funding and go though all the NHS bureaucracy you are looking at 18 months minimum maybe more like 36? Is there not a case to say that published data already out there has all the results you need to present to NICE as a treatment option? I know you talk about controlled vs open label studies but didn't the FDA (America I know) reject alemtuzumab in Dec 2013 calling for more controlled studies yet hey presto a year later the drug was approved? I don 't those controlled stuides happened in the 10 months between rejection and approval. Just better presented data…

    • Hi Matt,
      How long ago did you have the procedure and what have been the outcomes so far? Did you have any disability and has this improved?

    • Hey Matt,

      Can you help me with one thing? If the HSCT "fails" initially in that there is a relapse down the line, can you do HSCT again? Or is this ill-advised or becomes life threathening? Thanks dude.

    • Hey Matt,

      Thanks so much for your replies. I'll definitely be very curious to hear about your experiences and feelings going forward. Maybe you should start a blog and write about what you are going through – I am sure many MSers (and not only) would be interested!! Stay strong and keep up the great work!!

      You too MD, MD2 and GG!!

    • My response to Matt's 'quoting stats and splicing contexts' seems to have gone astray in the ether. I don't think it was abusive or troll like! What I said was that it's important for MSers to look at the articles themselves and judge for themselves, and not just take mine or Matt's interpretation of them eg he fails to mention the possibility of further autoimmune diseases developing (as happens with alemtuzumab). I know Matt has done his homework, but even on the replies an MSer was willing to undergo myelo procedure, and I feel that the dangers of HSCT need to be considered as well as the potential benefits. Also I did try to back up my points by referring to sources, which then can be read and critiqued by anyone reading the blog (as has been done) rather than just assertions that the statistics for this are such and such with no source quoted.
      I do believe a non myelo HSCT or alemtuzumab is the way forward- nataluzimab being too dangerous until they can remove the risk of PML. However, waiting for the NHS to ok HSCT for MS maybe several years away whilst alemtuzumab is available now, and as we all know, time is brain. Also MS-UK has a section on HSCT diaries of patients who have had the procedure

    • It is ether there is nothing in spam I have checked.

      Well said, there are clear issues with HSCT its side effects and its relative efficacy and its failure rate and I suggest that we do not use the blog as a soap box and I do not want to see a deluge of references as I don't have the time to read them.

      For the person in the UK who is newly diagnoses there is one highly effective treatment available as a first line and that is alemtuzumab, if your disease has certain level of activity you can have natalizumab and if you fail first line you can have fingolimod, Based on comments by some neuros I would put tecfidera in the moderately effective. HSCT is experimental

      This will change with time but this is the present situtation

  • Re "the recent poll on this site about risk and HSCT has made me reassess my position" (in the actual post from Prof G). Good on you Prof G, for being open-minded enough to be prepared to reassess your position (I must note that this is not being said in sarcasm). While followers of this site may be "unlikely to be representative of the wider MS community", and apart from a few sh-t stirring trolls who should be buried at the bottom of the garden (preferably with a few cloves of garlic), I have no doubt that blog followers are, whether clinicians or MSers, people who are genuinely interested in the latest research and in finding ways to combat this horrible disease.

    In anything there is a continuum of uptake, from the early adopters to the laggards, and I actually salute those MSers who are willing and financially able to take the risk of having HSCT, even if the Gold Standard clinical trials are lagging far behind. Despite the risks and costs of Health Tourism, both you and the clinicians offering HSCT are in some ways the pioneers of the MS version of the Wild West. Yes – the trials and the science do need to be done and the evidence produced, but without people willing to push the boundaries we'd all be going backwards fast. And at least what may come out of this is far more valuable to society as a whole than having a boob job or a face lift in Thailand. (As far as cost goes – it's around $A50,000 for an Australian MSer to undergo HSCT in Russia with Dr F – but don't ask me what a Thai boob job costs, because I haven't a clue)

    Personally, I think that the many recent posts and comments about HSCT on this blog are some of the best and most interesting discussion I have seen here.

  • Mouse Doctor ,You said "Based on ritizuimab the gadolinium enhancing PPMSers should respond I would not be so sure it will be good for everyone. I am sure relapsing PPMSers would respond to HSCT also"
    Most of PPMSers are not relapsing and do not show gadolinium enhancing lesions but I am sure there must still be some low-grade inflammation occurring in PPMS without showing as gross Gd lesions on MRI.
    In many MS Hospitals they are treating PPMSers ( even with no enhancing lesions) with Rituximab (off label ,as I do) , and results seems to be positive ,so would also be interesting to offer PPMSers to be treated with HSCT off- trials.
    I understand that you need to select the best candidates for a trial ( Highly active RRMS) but why to not give a chance to PPMSers with low EDSS, even with no enhancing lesions ?
    You could offer them to be treated off trial .You always ignore PPMSers is a shame!

    • You are absolutely wrong that I ignore PPMSers, it was because of PPMS that I switched focus from immunotherapy however you are right PPMSers will have inflammation. However the inflammation driving progression verses that driving relapses are probably different. The results published suggest a subset a PPMSers benefit, so it would be good if you have enough good evidence to to show otherwise. I suspect immunotherapy is good for all MSers however progressive MSers need to have treatments that deal with nerve damage/loss

  • Prof g, mouse Dr 1 or 2, any one who can answer this question I would be most appreciative if you could answer this question I have been offered alemtuzumab on the nhs for rrms. But feel this is inferior to rituximab as I believe in your and penders theory that ms is more to do with ebv B cells etc first question do you agree that anti cd20 eg rituximab is more efficient than alemutuzab with less side effects? Question 2, can I get rituximab off label and pay privately if so what would the cost be? Question 3, pender suggested that rituximab with effective anti viral eg hopefully raltegravir could be effective at reducing disease activity. So if I can get rituximab off label with an effective anti viral do you feel this would be a sensible approach? I had high ebv tiltre when diagnosed! If this approach doesn't work then it's abroad for hsct for me!

    • Here knowledge comes to bite ProfG.

      I suspect he cannot answer your question as he should give personal advice on the blog. Therapeutically alemtuzumab is pretty good,but at present I am not aware that studies can prove it is therapeutically better, however it will have less capacity to induce autoimmunities than alemtuzumab and it is typically administered ver
      . Q2 Whilst ProfG has done this in relapsing PPMS I am not sure we should answer this and the European rules are that if there is a licensed drug it should be used rather than the unlicenced treatment. Rituximab is not licenced and is not likely to be licenced as ocreluzimab is being developed Q3 Is there evidence for real that this is useful. No one way or the other

    • Dear MD
      Re "Therapeutically alemtuzumab is pretty good, but at present I am not aware that studies can prove it is therapeutically better, however it will have less capacity to induce autoimmunities than alemtuzumab and it is typically administered ver……."

      The cyber-gremlins seem to have attacked your post – this sentence does not make sense and has been chopped off at the end. You appear to be comparing alemtuzumab with alemtuzumab – please could you clarify…….

    • I suspect he cannot answer your question as he should give personal advice on the blog.

      Therapeutically alemtuzumab is pretty good in RRMS at present I am not aware that studies can prove rituximab is therapeutically better from and efficacy standpoint in RRMS. Alemtuzumab is licensed for treatment Rituzimab is not. However rituzimab will have less capacity to induce autoimmunities than alemtuzumab and it is typically administered every 6 months verse and induction treatment with alemtuzumab.I dont think alemtuzumab has been treated in PPMS

      Q2 Whilst ProfG has looked in to prescription of rituximab in relapsing PPMS I am not sure we should answer this and the European rules are that if there is a licensed drug it should be used rather than the unlicenced treatment. Rituximab is not licenced and is not likely to be licensed as ocreluzimab is being developed

      Q3 Is there evidence a real effect that anti-virals are useful.. No not yet, so one could not be recommending this.

  • "MSers who follow this blog are unlikely to be representative of the wider MS community." I would agree with this. This is the only place which says it as it is. Other sites including charities put a much more positive spin on things, you've noted this yourself with charities wanting to take out the palliative care part of your holistic map. If all MSers were told the hard truth about the disease I'm confident the statistics would reflect the wider population.

    What can MSers do to help this research get of the ground?

    • Find a champion with the expertise and the enthusiasm to drive change. The CCSVI lobby was powerful in many places to get studies done, the MS Soceities will need to respond

    • They may feel they have already as studies are being done…however there is therapy gap and the question is how do we get positive trial data translated into available treatments.

  • A trial with rituximab would be beneficial . However it is off patent and financing such a trial may be problematic. Ocrelizumab is probably going to be approved for RRMS and SPMS. Would lead one to think that rituximab would be similar with a long history of use in oncology, transplant, and other autoimmune diseases.

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