Monday, 8 February 2016

ClinicSpeak: reflections on HSCT after the fallout of the BBC Panorama programme

Should we create the equivalent of the Ig Nobel prize for irresponsible journalism? #ClinicSpeak #MSBlog #MSResearch

“It is clear from our analytics (page views and comments) that HSCT (hematopoietic stem cell transplant) is a hot topic at the moment. The BBC Panorama programme and subsequent news coverage only told half the story and was in some respects misleading. I was at a meeting this weekend and Fred Lublin (Mount Sinai, New York) took me to task about how much clinic time the BBC story had cost him and did we not have some influence over how the media reported MS stories? He was particularly upset about claims of a cure with no mention of the real risks of the procedure. As with all good storytelling the BBC got the soft touches right, but as Fred pointed out they failed to discuss the risks of HSCT and more importantly alternatives treatments available to neurologists to treat MS."


"Where do I begin?”

“HSCT is in fact a rebranding of bone marrow transplantation or BMT. BMT was used when the stem cells had to be harvested from doing bone marrow aspirates; thick needles were inserted into the bone and the marrow sucked out under pressure. This procedure was very painful and had to be done under sedation. I remember it very well, when I was a houseman and junior medical registrar, or trainee, I worked on a haem-oncology unit, and had to help do this procedure. Fortunately, the haematologists now have a very effective way of mobilising and harvesting stem cells from the blood without having to tap the bone marrow. This is done by giving a small dose of chemotherapy followed by growth factors so that the stem cells spillover from the bone marrow into the blood. These stem cells are harvested and frozen down to be given after immunoablation therapy. All that these stem cells do is allow you to receive more potent chemotherapy and work by stimulating your bone marrow to recover more quickly. There is nothing magic about this; HSCT in the treatment of MS is simply used to speed up bone marrow recovery, nothing more and nothing less.”

“What was not told in the BBC programme is that there are different intensities of bone marrow ablation therapy. So called myeloablative therapy is aimed at wiping out your immune system completely and replacing it with a new immune system. Non-myeloablative therapy is less intense in that it simply depletes your immune system partially and allows it be rebooted (partially). The non-myeloablative therapy is clearly less risky than the myeloablative therapy, but less effective. In other words more pwMS have recurrence of their disease activity after non-myeloablative HSCT, when compared to ablative-HSCT (A-HSCT). The treatment in the BBC programme was non-myeloablative HSCT (NM-HSCT). This is why the treated MSers didn’t look too bad. The chemotherapy that is used for NM-HSCT is less toxic. Many in the field believe that if you are going to treat MS with HSCT you need to go the more aggressive route and use the more toxic and risky A-HSCT. They argue that NM-HSCT is not really better than the current high-efficacy drugs we are currently using to manage MS, i.e. alemtuzumab and/or natalizumab and/or ocrelizumab (still to be launched). This is why we are proposing to do a ZEUS-type trial comparing alemtuzumab with NM-HSCT to see if NM-HSCT is more efficacious than alemtuzumab and to see of the benefits warrant the risks.”

“What are the risks of NM-HSCT? The chances of dying from the NM-HSCT is in the order of 0.5%-2%; 1-in-200 to a 1-in-50 chance of dying. Then there is the toxicity associated with the chemotherapy; nausea, vomiting, diarrhea, hair loss, bleeding, infections, infertility and neurotoxicity to name a few. It seems that the more disabled your are the worse the neurotoxicity. If you have lost a lot of nerve fibres already and have reduced brain reserve you handle chemotherapy poorly. The chemotherapy worsens neurological function. This is why a large number of BMT units stopped using this therapy in people with progressive MS. Once your immune system recovers it does not mean it is back to normal. There is evidence that HSCT causes premature immune senescence, or ageing of the immune system. This may not be important in young people but may be important later in life when you need your immune system to fight new and persistent infections and keep malignancies at bay. The premature ageing of the immune system has been linked to an increased incidence of secondary, or delayed, malignancies; this is a theoretical risk with all immunosuppressive therapies. None of this was explained in the BBC documentary. What about secondary autoimmunity? There is data in the literature that pwMS treated with HSCT are at risk of developing secondary autoimmune diseases similar to that which occurs after alemtuzumab treatment. If this is the case I would find it hard to recommend NM-HSCT, over alemtuzumab, unless it was part of a controlled trial, or the person had already failed alemtuzumab.”

“What about A-HSCT? This now is a different beast compared to NM-HSCT in that the short term risks associated with the intense chemotherapy needed to ablate the immune system are so much worse. Everything is worse; the diarrhoea tends to be bloody and protracted, mucositis is the norm (the lining of your mouth, throat and intestine slough), infections are more severe, and are likely to be life threatening, there is solid organ toxicity (liver, lungs, kidneys and heart), your bone marrow takes longer to recover and a result you are more likely to need platelet and blood transfusions. I could go on but I will stop, the picture is not a pretty one. A-HSCT is not for the faint hearted. Nothing was mentioned about the A-HSCT vs. NM-HSCT debate in the BBC programme. Why not? A large number of HSCT enthusiasts in the autoimmune field are of the opinion A-HSCT is the way to go; the failure rate from NM-HSCT is too high. If you are going to take the risk, you might as well go for maximum efficacy.”

“The seemingly miracle treatment effects of somebody in a wheelchair getting up and walking is not unique to HSCT. We see it with other highly-effective DMTs. Provided you have sufficient reserve capacity in the brain and spinal cord you will see spontaneous recovery from relapse-related disability once inflammation is switched off and recovery mechanisms are allowed to proceed. Tragically these Lazarus-like examples create unrealistic expectations for pwMS with more advanced disease. Once you have fixed or progressive disability it is likely that you have lost your neurological reserve and hence even if you switch off inflammation with HSCT, or any other anti-inflammatory DMT for that matter, it is unlikely that there will be significant recovery. This is one reason why so many progressive MS trials have failed in the past. Therefore the benefit:risk ratio changes with more advanced disease and its the reason why most HSC trials will have age and disability cut-offs.”

“So would I refer pwMS for HSCT? No, not as part of routine clinical practice. I would however be prepared to refer my patients to participate in a well-designed clinical trial to compare current treatments with HSCT. As part of the trial I would not expect my patients to pay for their treatment. The situation where HSCT is indicated as part of routine clinical care is the rare patient with MS with malignant disease that has failed all licensed treatment options. In this patient the benefits of HSCT outway the risks of the disease.”

“Please remember the human brain is hard-wired to be optimistic. I like to use the gambler’s dilemma as an analogy. No gambler places a bet, or goes into a casino, to lose money; they alway believe they are going to be the one that wins the jackpot. No person will sign-up to HSCT believing that they are going to die or develop complications. However, there will always be the unlucky ones who have the serious complications and occasionally die from the procedure, or develops serious delayed adverse complications. If you decide to go into an HSCT trial, or receive HSCT as part of routine care, you need to ask yourself the question what if I am the unlucky one? Am I am ready to leave my family and loved ones prematurely? If you answer yes, and yes, then you are ready to take the risks. In the same way I always tell my patients who sign-up for alemtuzumab treatment that they should expect to develop a secondary autoimmune complication; if they don’t they should count themselves lucky. if they are not prepared to develop a second autoimmune disease then shouldn’t be treated with alemtuzumab.”

“If we have the equivalent of the Ig Nobel prize for bad and irresponsible journalism the BBC Panorama will get my vote in 2016. Biased reporting with a catchy title that has created false expectations and driven up medical tourism. What is happening to the BBC? I promised Fred on Saturday that I would do this post for him.”




CoI: multiple

78 comments:

  1. Ideally for patients it would help tremendously if MS experts would sit with hematologists and others with expertise in A-HSCT and NM-HSCT and come to an internationally accepted consensus on current stem cell therapies in MS. I realize there would still be unscrupulous clinics offering bogus treatments but such a consensus would be of great benefit. Until this is done patients will be traveling to institutions in Russia and Israel ( for example) to receive SCT.The ball is in your court.

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    1. Re: "Ideally for patients it would help tremendously if MS experts would sit with hematologists and others with expertise in A-HSCT and NM-HSCT and come to an internationally accepted consensus on current stem cell therapies in MS."

      We have done that already. MD posted on it several weeks ago. What we really need is a clinical trial to show how HSCT does against alemtuzumab/natalizumab/ocrelizumab and a cost-effectiveness analysis. HSCT may be more effective, more risky, but cheaper and this will then need to be taken into account.

      Please note that these treatments are not for everyone; you have to have active MS with a poor prognostic profile to justify the risks. We don't treat people with inactive MS and we try not to expose pwMS with active MS with a good prognostic profile to unnecessary/unjustified risks. However, sometimes pwMS choose their own poison and if they do we are here to support them.

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    2. Great post. Please define 'active' disease? What about the appearance of new lesions/s on MRI without gad enhancement & in the absence of any relapses related to the new lesion/s?

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    3. from a haemotological viewpoint, why is lemtrada so much better than the chemo protocols used in NM HSCT? in particular, cyclosphomide and Rituximab, which I believe are subject of the BBC program?

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  2. Thanks for the clear explanation. I hope other blog readers will take note and not take undue risks. Shame on the BBC!

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  3. Thank you for this post.

    I switched off in the middle of the BBC programme. It was like televised bits of an article from a magazine someone found in a hairdresser.

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  4. Nice commentary. You won't hear this type of input on the HSCT Facebook pages because they are of one mind and if you don't agree or question this procedure you will be quickly removed.

    Unfortunately you are going to be labeled as a lacky for big pharma by the HSCT chearleaders.

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    1. You can't win, I am in the dog house with Big Pharma already about our off-label prescribing and high-cost drug initiative. The bottom line if you stick your head above the parapet and take a stand you are going to upset someone; c'est la vie!

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    2. As we've long realised on the blog, you're damned if you do and damned if you don't ;-)

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    3. lol woe is me. you at least get as many accolades (from me included) as you get unhappiness thrown at you.

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  5. Your explanation of the proceedures and risks are very good but not the material for a TV program. How many of the blog readers get their news from The Sun, The Daily Mail or Daily Express.

    Panorama has 30 minutes of airtime, this is not long enough to go into the risks and problems of this treatment but it did make people aware of this treatment and therefore possibly raise false hopes. Red tops sell by the van load and do not tell the full story either.

    I am not a qualified medical expert but a small amount of research told me that there is a lot more to this treatment than aired on the TV program.

    I'm sure other Panorama programs create false impressions. I would rather be told that the opportunity might exist than remain in ignorance

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  6. This is where I wish Dr Dre still commented on this blog.

    I believe you are perhaps right in your cautionary stance on HSCT, Prof G, but I am wary when you as someone highly vested in Big Pharma's steering committee on alemtuzumab, and therefore may have received commission, takes a very provocative line on a therapy that is off-patent and cheaper to administer. Why can't you just agree to disagree?

    Progressive MSers are the most hard done by. Neurologists ignore them, Big Pharma isn't interested in them, and the NHS views them as too hard to deal with. The Panorama documentary filled them with false hope, but what is the alternative?

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  7. what about prof gold's bbc piece???

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    1. RE: "what about prof gold's bbc piece???"

      He was simply interviewed in relation to a piece done by the BBC, nothing more nothing less. Have you watched it? If you had you wouldn't be referring to it a his piece.

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  8. I'm not a fan of the BBC programme. I don't think, journalistically, it really did the topic justice, and to try to tackle it in 30 mins was a mistake in my view.

    Equally, I don't think a good solution to tackling sensationalism/bias is to present an article of equal or greater sensationalism and bias in the opposite direction - which is what this post is.

    No centre in the world is running a 1-in-50 mortality rate in non-myelo HSCT for MS, so this is just silliness.

    Let us hope this Nobel Prize for biased/tabloid-like reporting doesn't take off, or you may well be dusting off your tux. But, all sides entitled to their opinion. :)

    On a serious note, I think MD1 did a much better job a couple of weeks ago in summarising the treatment, risks, etc. in a very informative post that was fair, factually correct, balanced and unemotional.

    Still, I'm sure your old chum Fred is over the moon.

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    1. It is about risks and benefits. We know the risks of HSCT, but we don't know the relative benefits. Until we have head-to-head data with a licensed MS treatment we can't say HSCT is superior. This is why we have been calling for the ZEUS trial. I won't stop one of my patients having HSCT; in fact one of my patients is having it this week. They are well informed, intelligent and have come to the conclusion that HSCT is the most efficacious option and that the risks are worth taking.

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    2. Re: "No centre in the world is running a 1-in-50 mortality rate in non-myelo HSCT for MS, so this is just silliness."

      Not true the patient who I described above signed a consent form at a London centre that has quoted at 2% mortality risk. I am just quoting the consent forms; some units state 0.5% other 2%. These are not my figures.

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    3. The centre in Sheffiled cites a 1% risk, but also states that they haven't had this level of mortality.

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    4. Likewise Prof M from Imperial also stated this figure when I asked this specific question and he and the London consortium vetted the post before it was aired.

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    5. From the Phase II MIST trial:
      - 151 patients, treatment-related mortality was 0%.

      From the Phase II Swedish experience:
      - 48 patients, treatment-related mortality rate 0%.

      From the Phase II Russian experience:
      - 99 patients, treatment-related mortality rate 0%.

      I am just quoting the published studies; These are not my figures.
      I could go on, but suggest I leave it there to avoid being hammered by for "promoting health tourism".

      I'm not suggesting the rate is 0 by the way. Clearly there is a mortality risk here. The point I am making is that 1-in-50 being quoted here is over-stating the TRM risk for non-myelo HSCT in MS patients (at experienced centres).

      I highly doubt the UK is any different in 2016.

      If, on the other hand, London truly do lose 1-in-50 of their NM-HSCT for MS patients (which I highly doubt), it’s probably worth thinking about going somewhere else.

      e.g. Sheffield, which MD says above is quoting half the mortality rate, and in reality coming in well beneath that.

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    6. UK cohort (Sheffield and London) published a conference paper in for Haemtology Istanbul meeting in 2015 reporting one death in 21 patients due to MS related progression - not the treatment as such. Who knows what that really means...

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  9. Prof G can you tell us more about immune senescence and cancer risk? This is clearly something that has never been communicated to me in relation to HSCT.

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    1. Re: "...can you tell us more about immune senescence and cancer risk?"

      Will do, but this is generic problem to all therapies that target the stem cells in the thymus, in the MS space this includes HSCT, alemtuzumab, cladribine and other T-cell depleting agents. It simply means that post T cell depletion and repopulation your immune repertoire shrinks and becomes dominated by anti-CMV and anti-EBV T cell clones. There is less space in your T cell memory/effector cell pool for other infections and cancers. In short your immune system ages prematurely and your become susceptible to opportunistic infections and cancer. The complications of immunosenescence will only manifest decades later.

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    2. This not something you will hear from the HSCT chearleaders. They are only concerned about the immediate mortality rate during the procedure. If you make it through it's all good in their minds but the issues of immunosenescence won't become a problem until a long time after the procedure.

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    3. No chemo treatment I'm aware of, including Lemtrada, comes without the risk of secondary malignancy. Anyone claiming otherwise is just being silly. How much secondary malignancy is an issue for an individual person with MS will depend on too many factors to name - age, health status, life experience etc. Professor Giovannoni said his patients are free to choose their own poison. When my partner was diagnosed last year, we described her choices between the 3 options before her the 'celebrity get me out of here' tucker trial options - choose your nightmare.

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  10. Thank you for this explanation. Very helpful

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  11. Media really needs to be disciplined on how they report medical news stories. I have lost count on how many times I have read headlines like "Scientists discover possible cure for MS". It sends my heart racing and then get disappointed when I read that the research has only been done on mouse models :(

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  12. Matt you seem to be so pro-HSCT. Is this because you came through unscathed? How ablative was your HSCT? Do you consider yourself lucky or just the norm for HSCT? You may have a different opinion if you had a different result. Ever since you starting posting on this blog you have sounded like a car salesman for HSCT. You need to step back and ask yourself how biased you are when you comment on this issue.

    In my opinion you are too biased and conflicted by your own experience to comment on this issue. I would prefer to listen to neurologists who work on the coalface; it is quite clear that Prof G treats MS aggressively, but even he has limits to what risks he is prepared to expose his patients to. You should take heed of his advice.

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    1. Re: ".... it is quite clear that Prof G treats MS aggressively, but even he has limits to what risks he is prepared to expose his patients to....."

      Treatment is about choice and prescribing within the NHS England guidelines. I prescribe within the guidelines; i.e. we only treat active MS and then there are a further two categories to consider highly-active and rapidly evolving severe MS. I also only prescribe off-label if there are special circumstances to justify it; I would classify HSCT in the latter category.

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    2. Anon.

      My treatment experience is irrelevant here. Even if I answered – good or bad - you’d (quite rightly) say it is just anecdotal evidence so I’m not even going to bother.

      I defend HSCT on here because – entirely regardless of my experience - there’s a lot of poorly researched crap spouted about the treatment, the patients who have undergone the procedure, and (occasionally) the docs who offer it.

      Of course, some posts are fair/well intentioned and I respect that. But some of it is the nonsensical rambling of muppets (like your namesake above, with their daily trolling about “HSCT cheerleaders”). I've zero respect for that.

      You may think a one-sided debate is healthy. I don’t. And contrary to your view, I’d say I’m pretty well placed to comment on it, having personally experienced it, with not an inconsequential amount of research prior and since.

      The joy of the internet is that, if you don’t want to read my comment, you can skip on. It is unlikely to keep me up at night, though obviously I’ll miss your intelligent and constructive input on the matter (I jest of course). Car salesman, right? Yawn.

      Thanks for all the advice though. It really means a lot (no, really!).

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  13. If I was in my 20s with RRMS with no disability I would go Lemtrada. I am in my 50s and about to be diagnosed with MS. If I have PPMS then I would go HSCT to catch the immune system before the damage is done. no time to wait and i would take the risk as I dont like the obvious result if i do nothing.

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    1. I think this is part of the propoganda being spread by the HSCT chearleaders. They think progressive MS is nothing more than an epitope spread (the immune target becomes the nerves instead of the myelin sheath over time). This is why they think that if you wipe out your immune system the damage is halted, even in proressive disease.

      But it is clear that science has evolved past this which is why in any established trial for HSCT the inclusion criteria is active white matter inflamation.

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    2. Nobody thinks this. Rubbish.

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  14. Prof G - you have been very negative about people using anidoctal evidence to support HSCT, yet you yourself quote 'there is evidence that HSCT causes premature immune senescence' I've done a lot of reading on published papers for HSCT FOR MS, and not seen this as a risk in one of them. Can you elaborate?

    The problem is that no one will follow up patients (a decent cohort) for 15+ years to see if SPMS onset is delayed or stopped from either HSCT or a MAB drug. The patients are there but not followed up on.

    The one thing that isn't mentioned above is stats. If HSCT is basically as effective as Alemtuzumab, why not show a comparison between the trial in Chicago and one of the Alemtuzumab trials?

    Also I'd similar why is one of the criteria for the fragment in London failing a MAB drug? Surely if similar efficiency you would not fail one to move onto another treatment that is no better?

    But I agree - the pro HSCT camp are very single minded in their approach, which is also very disconcerting. The problem is trying to get a balanced view, and people can do that by researching.

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  15. I'll be blunt... Fred Lublin is one of those big guys who sign trial papers for the industry - and thus his opinions may be a tad biased? Just a hypothesis :-)
    And I am just so sick and tired of wonderful pharma products that cost a bomb and don't work...

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  16. This blog is hands down the best resource for patients of any disease online... Some would say cynical, just balanced. Every newly diagnosed person should be told to read this.

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    1. This is a fantastic blog for patients and health professionals. I only wish my hospital had told me about it earlier (ie that their NHS colleagues were publishing all this fantastic information on MS in the first place) - however they don't share this info with patients as afraid we will 'know too much'. How condescending!

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  17. I have a problem with your views on brain senescence post-HSCT. HSCT might not be good for CNS, but active MS certainly makes the brain age faster!

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  18. It's absolutely astonishing how laypersons feel so very qualified to contradict both an experienced, highly trained physician who specializes in this disease AND written documentation which they've never laid eyes on and couldn't begin to comprehend if they did. Ah, but then, much like American Tom Cruise, they have "read articles," which of course qualifies them as experts equal to the aforementioned physicians, scientists, etc. Here's a thought - push forward full steam with this and every other new idea touted as the "cure" for MS by giving the treatment first to these people who believe they know more than the doctors, scientists, researchers, and drug developers. Let THEM be the test subjects. This will accomplish two aims: it will prove whether or not said treatments are in fact efficacious, and if not, it will put a stop to their ridiculous conspiracy allegations - and all by their own demand. Brilliant, eh?

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    1. Houston, we have a sheep!

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    2. The HSCT cheerleaders are coming out of the woodwork, or should I say venturing beyond their Facebook pages. It's really not a good idea. Please go back to your caves.

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    3. Not really helpful, really disrespectful of both the health professionals who work in the area and patients who suffer this terrible disease. I am a scientist and from a haematology medical background. It is now 2016 and not 1956, patients are more informed (or misinformed) of trials and drugs. What they need is balance and options. HSCT is aggressive, and does age the immune system. However, when a patient goes from an active productive life to a total transformation where they feel they have no life, it becomes a balance between quality of life verses a potential increase in the quality of life. Yes, Panorama has been irresponsible in not giving the full picture of the treatments harm to the immune system, but every MS patient watching that program will be now asking themselves the question, why have I not been offered this? Some of the medical profession are somewhat to blame by not talking to patients (patients by the way are the ones paying to government or charities to pay our salaries) about the effectiveness of drug therapy as against aggressive HSCT treatment. Maybe, a little more openness and a little less of a condescending attitude by some health care professionals is what is needed here. Also, more comparisons with best drugs and HSCT trails to effectiveness.

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  19. "The one thing that isn't mentioned above is stats. If HSCT is basically as effective as Alemtuzumab, why not show a comparison between the trial in Chicago and one of the Alemtuzumab trials"

    They are different demographics

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    1. 'Every MS patient is different'
      ' no 2 MS patients are the same'
      'don't compare your progression to anyone else's as everyone is individual'

      As long as you are comparing the same disease type (RRMS, SPMS) is that not a comparison? I mean any trial where you are picking patients, you honestly have no idea if they have/will have the same/similar disease progression. You can have active MS that can goes in normal remission, you have inactive MS that suddenly can kick into overdrive. So no matter what you say, all trials are only guessing if the demographic is the same/similar as you have no conclusive way of defining progression, just some trends that are washy at best.

      For comparison purposes it's as good as any, but for some reason you don't see it.

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  20. I am beginning to doubt my judgement about doing this post. Fred I hope you have read it. HSCT is obviously a very polarising subject. The bottom line is that HSCT is an unlicensed procedure for the treatment of MS and to become part of mainstream clinical practice we need more data; comparative head-2-head data. It is data (evidence) that will change practice. At the moment I am prepared to use HSCT for a small group of patients who have failed other treatments. Why because we have licensed alternative that have passed muster with the regulatory authorities. Some of you will say that the regulators are simply an extension of big pharma and do their bidding for them. I don’t buy that. The regulators are a part of our democracy; we can’t simply cherry-pick which part of government regulations we like and which part we don’t like. So we have to have very good reasons for prescribing off-label; in this case using HSCT in routine and regular clinical practice. You need to understand that our license to practice as clinicians is based on acting responsibly. That is why the London MS-AHSCT collaborative group have formulated guidelines and eligibility criteria; they are acting responsibly and setting boundaries.

    However, the real issue underlying this post is the BBC. The BBC is probably the most trusted and respected media brands in the world. When the BCC reports on a 'cure for MS' and 'Lazarus-like treatment-effect’ the world takes notice. If the BBC says it like this then it must be true. What do you know you are only a jobbing neurologist the BBC knows more than you do? As they say in America 'time is money'; how many hours have been used up by neurologists and healthcare professionals across the world talking to their patients about the BBC Panorama programme, putting it into perspective, discussing risk and undefined relative benefits, etc.? Irresponsible, unbiased reporting, creating false hopes and expectations is quite simply a nightmare for healthcare professionals looking after people with MS. That is the story people should be focusing on; the BBC and not whether or not we should offering HSCT as part of routine clinical practice. The HSCT vs. alemtuzumab vs. natalizumab vs. ocrelizumab debate will be answered in time and with data; it won’t be answered by discussing the pros and cons of HSCT on a blog. Can I urge you all to be patient science takes time and please think carefully before you spend large sums of money on medical tourism.

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    1. Well this little bunny appreciates the post and others on the same topic. I also like that the blog is broadening discussion, and not just sticking to its own NHS backyard - although that is a bit inevitable in many posts with home base of the blog and the Barts crew being the UK.

      At least the discussion is robust, and I just ignore the trolls - they clearly don't have a life (and some probably don't have MS either but just need to rant a bit to make themselves feel important)

      It's now about a year and a half since I found this blog and I've learnt more from this site than any other - nearly all of the MS Society sites around the world are good for the basics but they certainly don't have much more than the basics. They're also rather fond of rose coloured glasses in many instances, or skirt round the real issues PwMS need to know about like risks, options, outcomes etc.

      So, Prof G and the rest of the Barts crew - you just keep right on doing what you've been doing.

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    2. I suggest contacting the BBC over this. I'm sure they are completely unaware of the storm this programme has caused (and not only in the UK).

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    3. In the UK, we are not living in the world of my childhood with just BB1, BB2, ITV and Channel 4 any more. We have all kinds of trash via Freeview, Sky etc. I don't even take the BBC programmes seriously now, unless they have David Attenborough in them. Do some people really think the BBC are the last word on everything nowadays? They really shouldn't. Panorama is not cutting edge or well researched any more, particularly not in comparison to "Die Story" on Germany's WDR, for example.

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    4. The trouble is the BBC is still viewed in many countries as a beacon of integrity and truth in comparison to their domestic media. So whilst many in the UK might share your view, an awful lot more in other countries don't, which is part of the problem here.

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  23. Very good piece - thank you. Sets it in context and also explains why my neuro looked to the heavens when I saw him last week and uttered the words 'stem cells'!!
    What is your view on the use of mesenchymal stem cells - can these help repair myelin in PPMS and SPMS lacking active inflammation?

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  24. Team G... It would of been good if they had this 'other side of the story' (even a very watered down version) on the BBC Points of View TV programme.

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  25. Why would you do a trial vs alemtuzumab or nataluzimab? Orceliuzmab isn't, you do what both these drugs did and do a test vs Beta interferon to get approved.

    Are you prepared to put Clabribine up against alemtuzumab? No, but interferon you would. That ZEUS trial is the way all drugs should be tested against the best on market, but that is not how it is done.

    Would you say there is relevant long term data on alemtuzumab? I am sure that HSCT was first done for MS in the 90's, same as alemtuzumab, so there should be data out there for both drugs.

    On this blog it's often talked about options, why should pharma drugs be the only option? HSCT should be another option for people to choose from.

    There are a lot of contradictions on this subject, which is why it is so provocative, but when challenged they are sadly never answered by the md's or neuros on this blog.

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    1. Re: "Why would you do a trial vs alemtuzumab or nataluzimab?"

      HSCT is not a drug it is a procedure and you won't be making a decision between IFNbeta vs. HSCT will you? Considering HSCT's risk (up to 2% chance of dying) you will need to show its better than alemtuzumab, arguably the most risky of the high-efficacy therapies we have. If HSCT can't beat alemtuzumab it is going nowhere as a treatment for MS.

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    2. Interesting,

      Alemtuzumab is the depletion of T-Cells and B-Cells using one chemo agent.

      HSCT is the depletion of T-Cells and B-Cells using 2 agents (cyclophosphamide and another looking at various protocols)

      The only procedural bit of the treatment is the harvesting and re introduction of stem cells, which you yourself has said isn't where the risk lies, as its your own stem cells that are taken from your blood after a drug is given to stimulate cel production, and then reintroduced.

      So effectively (the less risky piece of the treatment (and procedural part is the harvesting and reintroduction of stem cells) but fundamentally the aims of the treatment aren't that diferent. It is claimed that HSCT IS more effective at depleting damaged t/b cells than Alemtuzumab.

      Is the stem cell but the reason why one is a procedure and the other is just a treatment? .

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    3. procedurr treatment it is all the same

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    4. I can't speak for the original poster, but I think the underlying point has been missed here. It is a question of critical bias.

      Interferon Beta is at one end of the risk and efficacy scale, whilst Lemtrada is at the other. Really, Lemtrada should have been trialled against Natalizumab, or at least one of the medium efficacy drugs. But instead, it was tested against the weakest possible comparator, in IF-b, presumably to make it look better to the markets.

      Arguably, Tysabri may be statistically safer, and equally effective for some patients (we've no head-to-head trial data to know). Yet still, you prescribe Lemtrada (even to JCV negative patients who are at a lower risk of complications via Tysabri), and are not campaigning that it has no place in the market until such a head-to-head trial is done with Tysabri.

      Similarly, you support the off-label use of Cladribine, suggesting the regulator made a mistake in not approving it due to a statistical anomaly (i.e. abnormally low malignancy rate in the control group). I agree with you. But, nevertheless, Cladribine is a chemo agent induction therapy - not entirely dissimilar to the agents used in HSCT (e.g. Israel use Fludabarine as one of their HSCT conditioning agents). Was Cladribine tested head-to-head with Lemtrada? Nope. Are you campaigning against it on that basis? Nope. In fact, you're campaigning strongly for it.

      So we have a double standard here. Because, for HSCT, which is being tested predominantly versus 2nd line treatments including Tysabri (a far more worthy comparator than the IF-B used in the Lemtrada trial), you are suggesting it cannot be licensed unless trialled head to head with Lemtrada. This seems to be a clear double standard, and is really medical idealism on your part since you fully appreciate such a trial is highly unlikely to be funded without pharma backing, due to the cost of Lemtrada (and why on earth would pharma back a non-patentable treatment trial aiming to replace their own drug); a fact you've alluded to in the past re the difficulty in getting ZEUS off the ground.

      So, surely, if the safety/efficacy in the NM-HSCT trial (once Phase III is complete) shows the treatment related mortality (TRM) to be close to 0 - 0.5% in experienced centres (as it is to date), and it shows a substantially higher efficacy (tbc in Phase III MIST trial) than reported for Alemtuzumab, that would give you the data you need to make an informed comparison, with or without a head-to-head trial?

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    5. Prof G.

      I can’t speak for the original poster, but I think the point here is that you appear to be applying different standards to one treatment versus the other, which (whether intentional or not) results in bias.

      1. MORTALITY DATA

      You base the Lemtrada risk profile on the published studies (rightly so). If one of your patients had a "consent form" from another hospital stating the risks associated with Lemtrada to be double or triple those shown in the trial data, I highly suspect you would not post that on your blog as though it were fact, to scare them off; Rather, you'd continue to base your view on the clinical/trial data, as is the scientific way.

      If we take NM-HSCT, on the other hand, where no study in MS patients has ever shown a 2% mortality rate in MS patients, you wilfully ignore the entirety of the international Phase I/II data and base your assessment solely upon a 'consent form' from one hospital - which, as far as I'm aware, is not even part of the trial and has treated only a handful of MS patients.

      This is not an inconsequential discrepancy. The rate you’re quoting is double (i.e. 100% higher) than the risk reported by the centre running the trial (Sheffield state 1% potential risk, though actual TRM is currently at 0%), and roughly quadruple the risk widely suggested elsewhere around the world (0.5%) - which is itself higher than the actual rate of TRM seen so far in any of the trials for MS patients. You make no mention of these facts. Put simply, 2% is not consistent with the data, and basing your facts on an administrative form, over the huge body of evidence available via published clinical trial data, seems uncharacteristically irresponsible, and most unlike the standards you apply to reporting on pharma therapies.

      Also, you've posted a very emotional post here re how you advise HSCT patients "are you prepared to leave your loved ones and die", and that they should expect to be the unlucky ones. Yet, for Lemtrada (which lost more patients to TRM in CARE-MS trials than NM-HSCT has to date), you only warn them of secondary AI. Do you not tell them also to assume they'll be the unlucky one who will leave their family and die from infection, ITP, etc.? You may say this risk is reduced through careful monitoring in follow up, which I'd say applies equally to HSCT. Similarly, presumably you don't tell patients on Tysabri they should be "prepared to be the unlucky ones" and "leave their friends and loved ones" to die of PML. Or at least, if you do, it was conspicuously left out of your post above where it is positioned as though HSCT is the only treatment where patients are rolling the dice on associated mortality.

      I would absolutely agree that HSCT has a higher risk of mortality than Lemtrada – and I think it’s important that this is highlighted (as it should’ve been by the BBC). But trumping up the risk versus other therapies is not helping anybody. This just leads to mistrust.

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    6. RE-BASELINING

      Now, you may say we should take into account rebaselining post Lemtrada (ie, retreating with further induction / immunosuppression upon treatment failure). But if you do so, you have to allow the same for HSCT otherwise this is not comparable.

      I expect you'll say "But HSCT is a procedure, not a drug". To which I'd say, you can't have it both ways. You've said yourself that the treatment effect of HSCT is entirely down to the conditioning agents, and that stem cells are used only as a support product to aid/speed recovery (I agree by the way).

      So what we're saying is that, in terms of treatment effect, HSCT is essentially a combination drug therapy (Cy/Rituximab, in my case, or Cy/ATG in the MIST trial).

      So, the question is, what do HSCT centres recommend if you relapse post HSCT? The answer is... additional induction therapy with the conditioning agents (e.g. Rituximab, Cy, etc.). And, when that is included, NEDA rates (just like for Lemtrada) shoot up. For example, in Dr Burt's earlier paper, the 20% who failed HSCT had additional immune suppression and all (100%) went back into remission. This is exactly the same principle as Lemtrada. So why would you exclude rebaselining post HSCT, but allow for Lemtrada? This is again suggests a degree of bias.


      SUMMARY
      The BBC aired a skewed story, to draw in viewers and tell the story they wanted to tell. I agree that the flippant use of the word "cure" in their programme title was sensationalism and irresponsibility at its worst, as was the one-sided reporting. However, I think you're partially guilty of a similar crime, in the opposite direction, to paint the picture ol' Fred lynched you into telling - rather than necessarily a balanced view of the facts. This approach may dissuade some, but will equally frustrate/lose the trust of others who may feel they're not getting the full story from you. This is a shame. As a (very highly respected) doctor in the field, I think you have exactly the same obligation to provide a fair and balanced report as do the BBC.

      Thanks again for the blog - it remains the best out there, and I do appreciate the work of Team G (especially the Charcot project!) - but also the time you put into answering questions on this blog. Without it, we'd all be stuffed!

      Hope this is constructive feedback. :)

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    7. Matt. I was the origanal poster, and I agree with what you said about. I post annomusly due to google searches for my very uncommon first name search thi blog and bring back my name.

      I think saying that HSCT is a treatment and the MABs are drugs is an odd statement, and MD2 seems to agree with me on that, effectively they are the same thing.

      Also agree that when posting about nataluzimab, you don;t quote the 1-2% chance you have of getting PML when JCV positive, and though it is not death, I can't imagine that those who have survived Nataluzimab induced PML are sadly in a severely disabled situation.

      I just want the biased removed, and balanced opinion. I am not pro HSCT but want balanced opinion!

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    8. I am disappointed to see that no response has been provided by Barts here, but not surprised as some tough questions/points in the above..

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    9. Barts here....I have not had alot of time today to bother with the blog but I am not getting into this one, ProfG digs his own grave :-0

      However on the whole you are not going to offered HSCT on the NHS, so off you go on a bit of health tourism...we tow the party line that this not ideal. There's the answer dammed if you do dammmed if you don't :-)

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    10. lol damned if you do damned if you don't - perhaps that's the problem that inevitably arises when professionals toe the party line instead of treating the people in front of them :P

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    11. Matt, I posed the same arguments to my partner's neuro some 6 months ago. In return for my questions, my partner received the neuro's support but not answers to my questions. I suspect part of the answer lies in neuro's disinterest in HSCT and lack of objective thinking on the subject. The other part, I suspect, has to do with legal liability (or as MouseDoctor keeps repeating, damned if you do and damned if you don't).

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    12. PS I posted a comment efficacy comparing the MIST and CARE-MS1 results - facts only, from two peer reviewed published studies.

      Did it not come through, or has it been censored (and, if so, why)?

      Happy to play by the blog rules, but don't see how showing the factual results of the two seminal studies is unreasonable...

      Thanks

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    13. @MouseDoctor - There are about 50 now in UK who have done HSCT on the NHS between London and Sheffield - if one meets the criteria is can happen rather easily. And I know a LOT of people who meet the criteria. It's certainly a topic worth discussing - and thank you for your keeping up the blog we do all really appreciate it.

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  26. Prof G,

    Could you please define 'active' disease? What about the appearance of new lesions/s on MRI without gad enhancement & in the absence of any relapses related to the new lesion/s?

    If a new lesion appears between two MRIs performed a year apart but does not show had enhancement, does this mean the patient has active disease? They are not achieving NEDA on their current treatment.

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    Replies
    1. I'm not a doc, but I can chip in on this. Active disease, from an MRI perspective, is generally any new or enhancing T2 lesions.

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  27. Thank you for this post - interesting reading. I am glad to learn some more science behind HSCT because it helps reach an informed position. Please can you explain a little more about senescence? When the cell telomeres get too short over time, is that when apoptosis occurs? What is the impact on the patient when the T cells/killer T cells etc get too old?

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    Replies
    1. All I know about telomeres is you can lengthen them through meditation etc - very interesting research from Harvard folk.

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  28. To anonymous 9:57:00 pm
    Define active disease...
    http://multiple-sclerosis-research.blogspot.com/2014/11/clinicspeak-do-you-have-active-ms.html

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  29. Prognostic profile -I thought this was hard to predict so why make a decision based on a view of poor vs good? What is good and how do you measure it and what data is there to support judgements of good with hindsight? Don't used wrongs to justify another judgement

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  30. Thank you so much for this post - I have PPMS, and was in despair at the dreadful quality of reportage on the Panorama programme, and the 'wow, it's a miracle' effect it had on so many. The whole thing smacked of populist nonsense, and the science was poorly handled . Shame on Panorama and shame on the BBC for spreading false hope and misunderstanding of what is a very complex and tragic condition for which there is NO CURE.

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