Friday, 23 January 2015

ClinicSpeak: are we being too conservative?

Is Prof G a laggard? Is he being too conservative by not embracing HSCT as an MS treatment? #ClinicSpeak #MSReserch #MSBlog

"It is clear from reading comments on several recent posts, including yesterday's post, that a large number of you would prefer the option of non-myeloablative, or ablative, hematopoietic stem transplantation (HSCT) to alemtuzumab treatment. Is that correct? HSCT looks to have the same or higher efficacy than alemtuzumab treatment and seems to come with a lower risk of secondary autoimmunity. HSCT is clearly more expensive initially, but may prove more cost-effective over time, particularly if a larger proportion of MSers treated with HSCT go into long-term remission compared to alemtuzumab. The problem we have as an MS treatment centre is that HSCT is not a licensed treatment for MS and hence our hospital, or Trust (Barts Health), would have to cover the costs of the treatment. In comparison, the costs of alemtuzumab, a licensed MS treatment, is covered by NHS England and not our own hospital. Under the current financial constraints in the NHS our managers would, almost certainly, prevent us offering HSCT to MSers as part of routine care. However, if we did this as part of a clinical trial and got the NIHR (National Institute for Health Research) to fund the treatment we would be able to offer this as a treatment for MS. However, this would have to be under a research protocol hence there is no guarantee that you would be randomised to the HSCT arm. Do you think the NIHR should a trial of this kind? It would have to be a pragmatic non-inferiority, or safety, study; trying to show that HSCT is superior to Alemtuzumab using our current outcomes would be very difficult and prohibitively large."

"Back in 1998, when I had moved to the Royal Free Hospital, for a short period of time, I did due diligence on bone marrow transplantation in MS and other autoimmune conditions. At the time there was a very active group at the RFH doing BMT to treat a host of other autoimmune diseases, in particular systemic sclerosis and SLE. When I saw that the mortality from having a BMT in autoimmunity was between 2-5% I decided back then that the risks outweighed the benefits in relation to MS. However, since then the risks associated with BMT and HSCT have plummeted and the mortality in good units is well below 0.5% from the procedure (less than 1 in 200). The question is are these risks worth it? I suspect yes. On my recent visit to Canada I discovered that several Canadian centres are now offering HSCT as part of their routine service to MSers with highly-active MS. On the spectrum of neurological conservatism the Canadian neurologists are very similar to UK neurologists; I would therefore expect that some UK neurologists and MSers with opt for this treatment option if it was available. Therefore it may be time for neurologists in the UK to join the Canadians, Americans and other countries (and the handful of centres in the UK) and start offering HSCT to our MSers with highly-active MS, who prefer the risks associated with HSCT over the risks of alemtuzumab treatment."


"I find it very interesting that a large number of you have criticised me for being so gung-ho over my attitude to using highly-effective treatments early in the course of MS and yet others of you are saying that I am too conservative, and a laggard (non-adopter), over my attitude to HSCT. The reason I have been slow to adopt HSCT and remain conservative is because anti-CD20 treatment may change things. Anti-CD20 as a class of therapies may prove to be so good at controlling MS disease activity, with a much better safety profile compared to alemtuzumab, natalizumab and HSCT that it would be hard to justify more risky therapies outside of the small group of MSers who breakthrough on an anti-CD20 therapy. Ocrelizumab, and the other anti-CD20 and anti-CD19 monoclonals (also a B cell therapy), may change the treatment paradigm and the risk-benefit of highly-effective treatments to such an extent that some of these arguments above would be academic. I think the arrival of ocrelizumab as a treatment for relapsing-MS, and possibly PPMS, will be the real game-changer in relation to risk:benefit. I sincerely hope Roche have a heart and don't price the drug too high taking it out of the reach of most MSers. What I am most interested in knowing is how ocrelizumab and the other anti-CD20 therapies work? Therein lies the clue to what causes MS."



CoI: multiple

40 comments:

  1. "I sincerely hope Roche have a heart and don't price the drug too high taking it out of the reach of most MSers."

    Sadly I think we all know what the expected outcome of this will be and the bean-counters will insist it is priced around the level of the other new DMTs but I would be delighted to be proved wrong.

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    1. You guys are always talking about repurposing drugs and I'm curious that since Rituximab is used for arthritis and it is in phase 2 for ms why it can't be repatented for MS when the current RA patent expires this year?

      Isn't this the point of repurposing drugs?

      I would consider Rituximab over HSCT if it were available.

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    2. Yes that is the point of repurposing.

      However as we have said there is the pharma way of repurposing and the way academic neuros think of repurposing, but the position seems that it is not possible to repurpose a drug when there is already an available drug for the indication e.g. ocreluzimab..

      So the pathway for rituzimab would be two phase III and then licencing who is going to pay for this? Do neuros have the guts/balls/knowledge to take on pharma? Can the MS Societies prove me wrong?

      However, you are getting repurposing the pharma way. It was clear that rituzimab was not going to be developed when ocreluzimab came on the radar. They knew ritiuximab worked, it had no patent life so they repurposed to come up with ocreluzimab. Let's not delude ourselves they will price it as high as possible

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  2. I know I keep harping on about this, but there is an FDA Phase III trial currently in progress (MIST), which is comparing HSCT against current 2nd line treatments. It's partially blinded (doctor, not patient), and the control arm are predominantly on Tysabri. The UK are already taking part in it, at Hallamshire hospital, under Dr Basil Sharrack (neuro) and Dr John Snowden (haemo). The patient selection criteria is stricter than for the paper you commented on eariler this week (RRMS only, EDSS <6, failed 2 first line treatments, evidence of active disease).

    The issue for some of us is that we don't want to wait until 2022 for the trial to complete and all the red tape to go through to get it approved. Rationale (for me) was three-fold;

    1) From the evidence already out there, it's already clear that it is more effective than the current treatments available and has, so far, the best chance of achieving durable remission and the best chance at EDSS improvement.

    2) Long term risks of HSCT are already well understood. It's been used for decades for other haemotological conditions.

    3) if I wait until 2022, I will no longer be in the group who respond best to the treatment (early, active RRMS).

    The data is pretty consistent across multiple studies from unlinked, highly respectable international centres for over a decade, and it's been proven across a number of AI diseases. So, despite the picture painted by many UK neuros, it's not some snake oil being sold by a crazed lunatic overseas.

    For those reasons, I think it should be a choice open to patients who want to take it. The fact that I had to travel to Moscow to get it done (even on a private basis), is pretty ridiculous given the mountain of evidence out there that it works.

    That's my view anyway. Others may disagree.

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  3. Dear Professor!

    Surely you are not too conservative, in general, your effort is really appreciated, and this is clearly the best blog/information page out there!

    The truth about HSCT is that it is highly effective but not patentable, hence it lacks behind studies of the monoclonal antibodies. It is probably more effective than the monoclonal antibodies since they target a wider range of the auto aggressive immune components.

    The question however, is not so much about how patients should be treated since you cannot control that, see your points regarding hospital policy, this is mostly market driven, and you will burn your fingers if you try to change this.

    The question is rather, what you would do as an individual if you were just starting with an active form of that disease or if it was your child? This is really the only thing that matters, and you would probably want to have the chance of a normal life and go through the BMT, am I right?

    So what does speak against HSCT? I think only the chemotherapeutic substances being used which are damaging the genome...

    What should be done in the UK? Well, balls, kick ass and the disease out of your patients, that's all!

    Here is one suggestion you could do in the Barts hospital and it wouldn't be that expensive since all drugs used are cheap, it is only a one-phase treatment and patients would have to stay only for 2-3 weeks in the hospital:

    day 1: High-Cy (4g/m2) and Carmustine
    day 2: High-Cy (4g/m2) and Carmustine
    day 3: ATG
    day 4: Rituximab
    day 5: Rituximab
    day 6: ATG
    No stem cell collection or reinfusion!

    Explanation: This protocol is similar to the non-myeloblative one pioneered by Burt (cy/ATG). However, the cy/ATG regimen had a high relapse rate (1 in 4 of treated patients) when compared to a protocol like BEAM/ATG. The BEAM/ATG is good but too strong to get it into the mainstream MS treatment for aggressive cases. The addition of rituximab and carmustine to the substances used by Burt will most likely quench the around 20% relapse rate, hopefully to under 10 or 5%. The infusion of stem cells is not necessary since cyclophosphamide spares the stemmies and the amount of carmustine should be adjusted to that logic.

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    1. Medicine is evidence based....one needs to get the evidence for the treatment

      As to ProfG being too conservative...I often hear you say he is a Thatcherite:-)

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    2. what do you mean? everything is evidence based, or would you buy a car without knowing the details?

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  4. I think the last 2 posts on HSCT really highlight a gap between neurologists and MS patients,
    1) If I take a drug like nataluzumab . I run this risk of getting PML, that risk increases the longer I am on the drug. PML is likely to significantly effect my brain or kill me. (I know you say "if" captured early it can be controlled) that is a high risk treatment, that you yourself have caused a "sticky plaster" not a cure. This is where neuros seem to look at the black and white of "living or dying" and don't seem to accept that quality of life to some MS'ers is as important. "some" would say that being physically disabled/bed ridden and having neurological function seriously impacted is no quality of life, and your blog tells me that is what is going to happen. So HSCT is high risk, high reward, and you can't see why some people would take that risk?

    2) You mention these new treatments that can control MS. Does that mean that my EDSS will go up slower as I get older, where as Dr Burt's latest paper says HSCT treated patients see an improvement of over 1 point on EDSS. So a slower decline or improvement? Again, you can't see the attraction?

    3) The lack of interest by the neuro community I find amazing. Here is a treatment that has a better prognosis than anything you can offer me, but you are not going to push NICE or NHS England to offer it because you feel it is too risky. Don't you always say that a patient should be able to make their own decisions with relevant un-biased advice? If I want the highest risk/highest reward treatment shouldn't that be my choice? At the moment it looks like places like Canada, US, Norway etc are on the front foot yet people in England are just not worthy of the most effective treatment, and the people who could change that (neuros) aren't wiling to as they prefer less effective drugs? As a doctor don't you want to see the best for your patients, and the best means the most options/best treatment??

    4) Cost - well this one I will leave to you. If I have a DMT, + MRI scans + numerous neuro/GP visits + other drugs to help with MS symptoms + as I get older walking assistance + nursing home costs VS HSCT treatment + post treatment drugs and follow up.
    Even if HSCT gives 10 years progression free + improvement so I don't need to go to the hospital, you could work out that cost now. (on avg)
    I emphasize this is not or all MS'ers. some don't want to take the risk that is their choice, but to take the risk should be their choice also!

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    1. "The problem we have as an MS treatment centre is that HSCT is not a licensed treatment for MS and hence our hospital, or Trust (Barts Health), would have to cover the costs of the treatment. In comparison, the costs of alemtuzumab, a licensed MS treatment, is covered by NHS England and not our own hospital. Under the current financial constraints in the NHS our managers would, almost certainly, prevent us offering HSCT to MSers as part of routine care."
      No-one is saying that Prof G doesn't want the best for his patients as any regular reader of this blog or his patients would know. As regards HSCT, his and other MS specialists in the UK hands are tied. The NHS is strapped for cash as we all know. If HSCT is truly the answer then there will be pressure applied to get the procedure approved but there needs to be a properly controlled trial for this to happen.

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    2. These ("my hands are tied") are just excuses!

      if a trial is needed, who do you think has a chance to get one going, you or me?

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    3. First of all you need to get funding (several million at the very least, probably more) to do the trial in the UK. No charity can afford that amount of money, nor can the NHS at the moment and pharma wouldn't go near it for obvious reasons. So, what to do because the procedure is by no means trivial?

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    4. MouseDoctor2.- You care so much about your patients but yet are willing to do nothing to offer them the best treatment than present the challenges. Sorry, that doesn't add up. Besides, most of the HSCT treatments use (ATG, Alemtuzumab, Rituzmab etc) as part of the treatment. Proposal to the drug company - your drug could be used in conjunction with Chemo to halt and even improve the disability levels of people with MS, you don't think the drug companies would see the potential in that??

      Caring for your patients is giving them all the options, not talking about why you can't. Do I think neurologists could do more, absolutely, and it is such a shame they won't. Do you think that a suffer of MS should be given the option of the most efficient MS treatment regardless of the blockers or the politics) If the answer is yes, then do something about it, if the answer is no, then tell me how that is caring for your patients?

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    5. If I had a haemotological malignancy, this is the standard treatment. How did the oncologists get it approved? Presumably they faced the same problems...

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    6. Yeah well, the funding issue like usually...Dr. Burt managed to set-up a Phase-III trial, even in the US, so it is possible!

      You could start with an observational trial, Dr Saccardi has already published in 2005 the results of his BEAM/ATG protocol, 95% of the patients did not have anymore inflammatory disease activity within 5 years. This is already 10 years ago with 19 patients:
      http://www.ncbi.nlm.nih.gov/pubmed/15546956

      I mean just let the patients pay by themselves for the treatment, they will do if there is a real chance of them getting their life back. A protocol like the one above shouldnt be very aggressive and neither expensive.

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    7. Doing phase III is one thing getting treatments to people is another thing

      The regulators are making pharma do trials with a few hundred people doing a trial with thirty people and they will crying foul. Or will the FDA only give a licence for highly active MS failing other treatments.

      I suspect the results could be even better, because remember these are impressive results in people with MS that has failed other tretments

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    8. It is important that you as a doctor make a decent contribution to the medical field, it does not need to be a revolution, but it needs to be more than enjoying nice dinners paid by Big Pharma...

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    9. Dr Slavin in Israel pioneered the non-myelo protocol for autoimmune diseases, with Dr Burt. He was kind enough to speak with me on the phone last year, and at the time the Israeli Ministry of Health was blocking him from performing HSCT for MS due to some sense of injustice that it was unfair to pharma. He went to court over it, I believe, and they ruled in his favour.

      His view was that HSCT is not a drug, and should not be subject to drug trials. Chemotherapy is well understood, he's using already licensed drugs for the purpose they were licensed for (ie depleting lymphocytes). The principle of immune ablation as a therapy for MS is well established. And from cancer they already know the merits of the different chemo agents versus the mabs (including Lemtrada, or campath as it was formerly known). The safety of HSCT is well understood also from cancer. So what exactly is on trial?

      He said the drug trial/approval system is designed for drugs. Not for medical procedures, where no single party stands to gain from profit or patent.

      Why is HSCT being treated as a drug?

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    10. Nice post,

      CAMPATH-1H is used to deplete cells in cancer so maybe it too should have had a free ride using your logic

      HSCT is a procedure and you need to access the risk benefit and efficacy, in some cases the stem cell conditioning was what appeared to be mediating the effect and with a significant mortality risk it is right that this needs to becomes an approved treatment,
      HSCT is used in people who have cancer but it is easier to perform in cancer where it can be a life or death issue and there is no alternative,

      Maybe be one of the neuros can have a look at what the NHS cost is for this procedure.

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    11. "It is important that you as a doctor make a decent contribution to the medical field, it does not need to be a revolution, but it needs to be more than enjoying nice dinners paid by Big Pharma..."

      Maybe whilst enjoying some food with Big Pharma maybe have a thought that this maybe making a contributing to the medical field.

      What about those neuros who never have any involvement with pharma? They are followers not leaders, without pharma there is nothing atpresent and this includes HSCT as they procedure needs pharma drugs as part of the procedure.

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    12. yes, it is a sad system. One could try to be optimistic and say neurologists are now better than one generation ago. I think the only neurologist to win the nobel price was the one that developed lobotomy. What does this tell? Nothing, right?

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  5. How far along the development process are we with ocrelizumab? Phase 2? Phase 3? When would/is it likely to go to the regulators for a decision?

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  6. Do you think ocrelizumab can be as good as HSCT?

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    1. Re: "Do you think ocrelizumab can be as good as HSCT?"

      We need to wait for phase 3 data. But based on the phase 2 results it looks very promising. The reason why I discussed ocrelizumab and anti-CD20 is that all the highly effective therapies deplete B cells. The exception is daclizumab. Could HSCT simply be working in the same way as anti-CD20 and working via B-cells. If that is the case we don't need a sledgehammer; an anti-CD20 therapy will suffice. It is more targeted and much safer.

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    2. Is it not true though that the mabs can't get into the CNS (unless there's a BBB breach)? One of thebenefits of the chemo protocols in HSCT is that it also hits Ts & Bs in the CNS as it can permeate the BBB with ease.

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  7. I am interested to know if being treated with alemtuzumab now would prevent being treated with anti CD20s in the future (if they were required)?

    Would appreciate an opinion on this as I am anticipating starting on alem mid year.

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    1. You could have Lemtrada now and anything you want afterwards. It leaves your system quickly and doesn't stop you have another treatment (Lemtrada, cd20+, HSCT or otherwise) down the line.

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  8. And what about CCSVI........:-)

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  9. Why is it not my choice to get the best treatment? Are Neuros better at analyzing statistical data than me? Or is the relationship with big Pharma the issue here?

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  10. HSCT works! CCSVI is away with the fairies�� The Charcot project hopefully the way forward!

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  11. I think neurologists are too conservative full stop. I worry re-branding MS as dementia may reinforce a paternalistic culture and lead to doubts re capacity of MSers to make informed decisions. Brain shredding or not the majority of MSers are quite able to make decisions about their body and life.

    I would risk HSCT and looking at the current poll results the majority of people would.

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    Replies
    1. I bet neurologists are more conservative than MS patients (such as myself) partly because it's harder to make life-or-death decisions about someone under your care. Risking our own lives is different from risking other people's lives. Prof.G keeps talking on this blog about his worst nightmares about one of his patients on Tysabri contracting PML, surely all his patients are fully aware of the risks and made unformed decisions to go on this treatment - and still the doctor cannot distance himself from the risks.
      Another potential issue is liability - recommending risky, unapproved (for MS) procedure may lead to devastating legal consequences. And not just legal - a cardiac surgeon was recently fatally shot in Boston by the son of his patient who died after surgery.
      Perhaps neurologists should remain conservative, but the patients should be able to advocate for themselves, and have access to high risk-high reward treatments. Will hematologists or oncologists help?

      Delete
  12. In my opinion NIHR should fund a trial comparing HSCT to alemtuzumab, but not a randomized one. There are enough-patients who themselves would choose alemtuzumab because of the lower short term risk, and there certainly are many enough who wants HSCT. Therefore the trial hasn't at all have to be randomized (make a protocol with suitable inclusion and exclusion criteria). It is mandatory that besides using NEDA (number of relapses after treatment, EDSS after treatment and plaques and contrast enhancements on MRI) you also have to use quality of life (QoL) as an endpoint, for instance SF-36. For all ms-patients quality of life is greatly decreased each day because of fatigue, pain, cog fog, bad sleep etc., and it is incredible that studies on DMDs - practiacally all of them - haven't applied QoL as an endpoint (but then, practically all the DMDs reduces QoL even more in addition). Therefore in a non-inferiority trial when you define a noninferiority margin and include a noninferiority hypothesis, you obviously have to also include QoL as an endpoint!!!
    Besides, the NIHR should fund the same type of study for patients who have not had ms for a long time, and without highly-active ms (frequent relapses). The absolute majority of ms-patients are in this category, and their quality of life is low (it is mandatory for you to apply quality of life in all studies on DMDs and HSCT, and as Burt points out you haven't because DMDs don't improve QoL), and most of them have a dismal prognosis ending up out of work and in the long term with a high EDSS.

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  13. In my opinion NIHR should fund a trial comparing HSCT to alemtuzumab, but not a randomized one. There are enough patients who themselves would choose alemtuzumab because of the lower short term risk, and there certainly are many enough who wants HSCT. Therefore the trial hasn't at all have to be randomized (make a protocol with suitable inclusion and exclusion criteria). It is mandatory that besides using NEDA (number of relapses after treatment, EDSS after treatment and plaques and contrast enhancements on MRI) you also have to use quality of life (QoL) as an endpoint, for instance SF-36. For all ms-patients quality of life is greatly decreased each day because of fatigue, pain, cog fog, bad sleep etc., and it is incredible that studies on DMDs - practically all of them - haven't applied QoL as an endpoint (but then, practically all the DMDs reduces QoL even more in addition). Therefore in a non-inferiority trial when you define a noninferiority margin and include a noninferiority hypothesis, you obviously have to also include QoL as an endpoint!!!
    Besides, the NIHR should fund the same type of study for patients who have not had ms for a long time, and without highly-active ms (frequent relapses). The absolute majority of ms-patients are in this category, and their quality of life is low (it is mandatory for you to apply quality of life in all studies on DMDs and HSCT, and as Burt points out you haven't because DMDs don't improve QoL), and most of them have a dismal prognosis ending up out of work and in the long term with a high EDSS.

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  14. Prof G do you think raltegravir will be better than lemtrada and HSCT?

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  15. Do you think Lemtrada and raltegravir together would work as a belt and braces approach?

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  16. For the survey, perhaps add MS type and/or if a person is a caretaker.

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