Monday, 4 September 2017

#ThinkSpeak: we need to make sure science happens the way it is meant to happen

Has HSCT become the new CCSVI? #ThinkSpeak

Summary: This post summarises the current scientific perspective of HSCT and attempts to put it as a treatment for MS into perspective. 

Like most modern treatments that get adopted prematurely in MS, i.e. before the necessary science is done to convince the wider community, they are driven by social media. We have a lot of experience on this blog with CCSVI; in fact, CCSVI is one of the main reasons why I started this blog. 

The question I now find myself asking has HSCT become the new CCSVI? Could the current support for HSCT as a treatment for MS getting ahead of the curve? Is the HSCT movement in MS becoming an anti-science movement, i.e. adopted against the predominant scientific opinion of the time? The wider MS community, pwMS, neurologists, scientists, charities, healthcare systems, etc. have agreed that there is a place for HSCT in the treatment of MS, but until we have better evidence of its relative benefits and risks compared to licensed DMTs we should be limiting HSCT to patients with more active MS who have failed at least one (high-efficacy), or two, established DMTs. In direct opposition, there are a group of HSCT-supporters who disagree and want everyone with MS to have the option of being treated with HSCT first-line. The latter recommendation is not supported by the science/data.

Sociological studies have identified 4 main social drivers of anti-science movements: 
  1. The ‘dissident scientists’ who lends credibility to the theory. 
  2. The ‘cultropreneurs’ who peddle the therapy. 
  3. The ‘living icons’ and ‘miraculous responders’ who have been treated. 
  4. The ‘praise-singers’, ‘journalists’ and ‘politicians’ who promote the theory 
I agree that HSCT looks like a very effective treatment for MS. Does it cure MS? No, we can't make that claim yet. Cohorts of HSCT-treated pwMS have not been followed long enough to justify this claim. Is it better than established or licensed DMTs? Possibly, indirect comparisons suggest it might be, but until we have head-2-head studies we can't make that claim. Is it safer than established DMTs? It depends on what you are comparing it with and the specific outcome. For example, when it comes to the risk of neutropenic sepsis it is riskier than licensed therapies. Similarly, it has a much higher risk of ovarian toxicity (premature menopause) than established treatments. Safety, or relative safety, is another reason why we need large head-2-head studies to define the risks better in well-controlled randomised trials of sufficient size.  

What should we tell pwMS? My message is simple. HSCT is a very effective therapy for treating MS. It has substantial risks associated with its use. We only offer HSCT to our patients who have active MS and have failed at least one high-efficacy DMT. We are however in the process of trying to obtain the necessary funding to compare the benefits and risk of HSCT to alemtuzumab. The latter is part of our scientific due diligence. 

It is, however, reassuring to note that in the UK the costs of HSCT under the NHS appear very reasonable compared to licensed treatments. This could potentially make it a very cost-effective option for treating MS in the future. There are well established local and regional guidelines for HSCT and NICE is trying to establish national guidelines. 

From a scientific perspective, we need to ask ourselves how HSCT is working? We think it is working via a B-cell mechanism, similar to other DMTs. If this is the case then do we need HSCT to achieve our therapeutic aims? Could we not get away with a more selective IRT (immune reconstitution therapy) that has a better safety profile? Clearly the latter would be much safer. The difference between scientists and anti-scientists is that we put forward testable hypotheses and they put forward beliefs. Unfortunately, it is difficult to challenge beliefs and you can't test them in a scientific experiment.

I would urge anyone in England considering to travel abroad for HSCT to discuss your decision with your neurologist and MS clinical nurse specialist. If you are eligible for it under your local guidelines I would recommend having the treatment in England. The following are three relevant documents you may wish to read that we have published on the blog in the past.

1. London MS-AHSCT Collaborative Group eligibility criteria
2. The Bristol guidance document for pwMS considering HSCT abroad
3. NICE draft technology appraisal for HSCT as a treatment for MS in England.

CoI: multiple


  1. "we should be limiting HSCT to patients with more active MS who have failed at least one (high-efficacy), or two, established DMTs"

    ...why? I think there was a blog about flipping the pyramid and hitting ms hard and early. I can't remember the site now. Barts something....

    Failing DMDs and starting hsct are unrelated. Actually only related in so much that hsct is more effective and better tolerated if no DMDs have been administered.

    1. Can't you read? The Barts-MS team can't offer HSCT first-line; they have to follow current NHS/London-AHSCT guidelines. At least they offering the treatment.

    2. Re: "Actually only related in so much that hsct is more effective and better tolerated if no DMDs have been administered."

      Do you have class 1 evidence to support this statement? I not aware of it. This actually applies to most high DMTs; e.g. if you get onto natalizumab or alemtuzumab first-line you do better than when you use them second-line. The only exception to this rule is teriflunomide. The latter is an interesting phenomenon and needs to be explained; what is different about the biology of Teriflunomide in MS? Could it be telling us something about the cause of MS?

    3. Yes you are correct we don't have access to HSCT as a first-line treatment for MS. At the moment people have to have failed natalizumab or alemtuzumab. When I offer HSCT to pwMS in this category most choose other treatment options. In my experience it is the minority of pwMS who actually want to be treated with HSCT. We need to keep remember this and keep HSCT in perspective.

    4. HSCT is not even first-line for cancer treatment.

    5. The efficacy of autologous HSCT is now established for AD and the future is about fine tuning
      to maximise safety and efficacy. Health economic considerations and implementation science
      are also essential to define how best to deliver HSCT in the context of biological and other
      modern therapies.

      John Snowden
      Autoimmune Diseases Working Party (ADWP)

  2. Please consider the question is the comment constructive. Just as the blog became unpleasant with CCSVI trolls causing comments to be moderated, HSCT Trolls may cause comments to turned off.


  3. Prof G thanks for the post. For a lot of us with MS HSCT is simply too dangerous. I am holding out for Mavenclad or Ocrevus, both these drugs have a better safety profile than HSCT.

  4. What about progressive MS? Do you propose excluding these people from accessing HSCT?

    1. According to the above guidelines, only PPMS patients with active lesions would be eligible for HSCT treatment.

      In virtually all of longitudinal studies that have been done, people with active MS (relapses and/or enhancing lesions) do much, much better than those without. One recent study found 73% of RRMS patients progression free at five years, compared to 33% of SPMS patients. One might suspect that the SPMS patients who were "successes" still had active disease.

      That said, I'd love to see some trial results that included PPMS and SPMS patients with strictly progressive disease (no relapses/no enhancing lesions). Would be wonderful if HSCT actually worked for them. I am aware of the anecdotal accounts on FB/the Internet, but I'm also aware that negative reports are either disparaged or deleted outright on these sites, thus presenting a very one-sided view of what can reasonably be expected.

  5. I am happy this is being addressed in a level-headed manner by this blog. There are certain individuals, some with vested commercial interests in the procedure (I will not name names here, but suffice it to say, this "expert" on FB convinces every MS patient, whether progressive or with a 9.o EDSS can benefit from HSCT), that give false hopes to many pwms. It is a shame that this person is seen as almost a god-like figure by patients who feel like there is a pharma conspiracy to keep us all on lifetime meds. I agree, HSCT has become the new CCSVI, with patients jumping over each other to drink the Kool Aid . Most, especially, progressive patients without active lesions, will soon find out the hard way and with a lighter wallet that no, HSCT is only indicated in a small subset of early RRMS patients. I had HSCT done with Dr Saccardi, one of the early pioneers of BEAM and was early SPMS. He warned me that it would likely not work for me but accepted me due to a lower EDSS (3.5). As of the time of this writing, it is at least a point worse. I'm happy this has been addressed here and the recognition of how science works apparently eludes most of the desparate MS patients who just want a chance .

    1. The word 'Charlatan' or 'Quack' comes to mind.

  6. Thank you for this blog post. It is nice to see a balanced and well laid out (albeit short) scientific opinion on this subject.

    HSCT feels very polarised at the moment - on the one hand you have those advising caution (or dismissing it outright) and then there are others who push HSCT as a miracle that everyone should undertake regardless of if it is right for them. Sadly social media is not the best place to find balanced information yet this is where most people turn for advice. A lot of newcomers to forums on HSCT are bombarded with emotional appeals, anecdotes of why they should get it done, and as mentioned above, comments about some "pharma" conspiracy which keeps us all from getting it. There are few voices from those for whom HSCT didn't work, so the outward appareance of effectiveness is biased. This is clearly not healthy or helpful. There isn't a whole host of information online regarding HSCT which is easily understood by the layman and that hasn't got a hidden agenda (websites which are glorified ads for a HSCT clinic somewhere). Add to this the neurologists whom we trust with being up to date with current technology for the disease just seem to be, on the whole, lacking in knowledge.
    So these two things - lack of credible sources, and groups using emotive reasoning are coming together to create a dangerous environment for interested patients.

    I personally think the technology is very exciting - it is still in its infancy and there is obviously a lot more work that needs to be done, but I don't think it is quite on a par with CCSVI. What does worry me is the fact that from a scientific standpoint it is still considered experimental and has not undergone full testing yet - and this is just the protocol outlined by Dr. Burt et. al. not the protocols used by some of the other facilities which have had next to no rigorous scientific investigation into efficacy - yet a lot of people see it as a holy grail of sorts, without substantial evidence to show this. It doesn't help that in the short term people often see improvements and think that it's worked, but we know very little about how long these positive effects will last in the majority of patients.
    I also think that in future HSCT will be seen more as a possible first line option, since most of the studies on the subject so far indicate that early RRMS patients with relatively mild disease will benefit the most - it is often stated that by the time a person gets to SPMS it is too late for this treatment. It is a catch 22 for clinicians - HSCT is viewed as a last resort, a method with many risks that should only be used for patients who fail to respond elsewhere. Hopefully this will change after the clinical trials have been completed.

  7. If hsct is the new ccsvi, then why do barts and nhs offer it?

    1. Re: "If hsct is the new ccsvi..."

      This refers to the social phenomenon of rapid adoption ahead of the science. We offer it as a back-up option for people with active MS who have have failed conventional DMTs. I have no problem accepting that HSCT is effective, but I am not convinced yet that its a treatment for everyone and whether its risk:benefit profile justifies it being used first-line. The latter position may change in the future when controlled trial data emerges.

    2. "We offer it as a back-up option for people with active MS".

      These will come back to haunt you (or maybe not give your dogmatism towards DMDs).

      I still have trouble reconciling the obvious logic surrounding hsct. Suppression v ablation. It's undeniable.

    3. We are neurologists we don't run BMT-HSCT units, the haematologists do. In the UK the haematologists have about 10% of their capacity to allocate to autoimmune and other disorders. They have a capacity issue, hence them signing up to the guidelines as well. The NHS has systems in place, audit, etc. to make sure we are using resource appropriately. We can't ignore the NHS systems. In the private sector it is fee for service and if you are prepared to pay you will always find someone who is prepared to take your money.

    4. The problem with Hsct is that steal market share from Bayer-Schering Healthcare, Biogen-Idec, Genzyme, GW Pharma, Ironwood, Merck, Merck-Serono...etc

      Over the last 20 years we have developed the largest database worldwide for HSCT in
      autoimmune diseases with around 2,300 cases reported. Since 2013, the yearly number of
      HSCT procedures registered has increased by over 25%, and is now hitting 200 registrations
      annually, reflecting a significant change in transplant practice and the active role of many EBMT

      So its 25% less drugs from Pharma drugs to profit from those patients every year ,Yes because most of them(especialy pwms)
      Dont need to inject or take any ms pill hopefully for manny years and thats why pharma has no interest in hsct ...Meaning less money also for neurologists to go around the world doing drugs presentation studies

    5. A 5th factor that should be highlighted as a social driver of anti-science movements is an underlying 'conspiracy theory'. This is what the CCSVI lobby did as well. We have a lot of conflicts at Barts-MS, but trying to protect Pharma's market share is not one of them. We have actively been promoting a 'Essential Off-label' list of DMTs that includes HSCT. So I think you are on thin ice with your claims.

      At the end of the day adoption of any treatment is a slow process and is data driven. The data has to be good quality. The reality at the moment is the quality of HSCT data as a broad treatment for MS is simply not good enough, in particular its relative efficacy and risk-benefit profile relative to other DMTs, to result in high adoption rates. This is why we are trying to get funding to do a comparative clinical trial.

      I am now going to draw a line under this discussion because you have a evangelical belief that HSCT is the only option for treating MS. This is clearly not the case. Can you please let science do its job and we will see how things play out in the future as and when the data emerges.