Thursday, 9 February 2017

HSCT and MS

High-dose immunosuppressive therapy and autologous HCT for relapsing-remitting MS.Nash RA, Hutton GJ, Racke MK, Popat U, Devine SM, Steinmiller KC, Griffith LM, Muraro PA, Openshaw H, Sayre PH, Stuve O, Arnold DL, Wener MH, Georges GE, Wundes A, Kraft GH, Bowen JD.Neurology. 2017  pii: 10.1212/WNL.0000000000003660. doi: 10.1212/WNL.0000000000003660. [Epub ahead of print]

OBJECTIVE:To evaluate the safety, efficacy, and durability of multiple sclerosis (MS) disease stabilization after high-dose immunosuppressive therapy (HDIT) and autologous haematopoietic cell transplantation (HCT).
METHODS:High-Dose Immunosuppression and Autologous Transplantation for Multiple Sclerosis (HALT-MS) is a phase II clinical trial of HDIT/HCT for patients with relapsing-remitting (RR) MS who experienced relapses with disability progression (Expanded Disability Status Scale [EDSS] 3.0-5.5) while on MS disease-modifying therapy. The primary endpoint was event-free survival (EFS), defined as survival without death or disease activity from any one of: disability progression, relapse, or new lesions on MRI. Participants were evaluated through 5 years post-transplant. Toxicities were reported using the National Cancer Institute Common Terminology Criteria for Adverse Events (AE).
RESULTS:Twenty-five participants were evaluated for transplant and 24 participants underwent HDIT/HCT. Median follow-up was 62 months (range 12-72). EFS was 69.2% (90% confidence interval [CI] 50.2-82.1). Progression-free survival, clinical relapse-free survival, and MRI activity-free survival were 91.3% (90% CI 74.7%-97.2%), 86.9% (90% CI 69.5%-94.7%), and 86.3% (90% CI 68.1%-94.5%), respectively. AE due to HDIT/HCT were consistent with expected toxicities and there were no significant late


neurologic adverse effects noted. Improvements were noted in neurologic disability with a median change in EDSS of -0.5 (interquartile range -1.5 to 0.0; p = 0.001) among participants who survived and completed the study.
CONCLUSION: HDIT/HCT without maintenance therapy was effective for inducing long-term sustained remissions of active RRMS at 5 years.



It is clear that HSCT is amongst the most effective and is probably the most effective immunotherapy. It should be it is replacing the immune system. 

The rates of control are very good, but these are selected pwMS, albeit with very active MS, and not the general population. How would this fair if we look at 500 people is a phase III study. The sucess rates of alemtuzumab were good in phase II but dropped in phase III. I would hazard a guess it would be up there. However, will this be a treatment for all...I wonder.

I rather dispare at the risk-averse neurologists that can tolerate MS brains that are battlefields full of clusterbomb holes and still support the softly, softly approach. Its not their brains that are being shredded.

Maybe it would be good to do a Freedom of Information request of prescriptions of each Hospital in UK to see what their neurologists are prescribing. A shedful of beta interferon, alemtuzumab or worse.. nothing. I am sure pharma have this info already. I know we have been FOI'd.  I'ld love to have a map of the UK to see who does what.

Would the East End of London be an injectable first line dessert, where would be the oasis of patronisation, doing nothing?

Anyway back to the HSCT, many places have haematology clinics doing cancer treatment and one wonders whether this system has any slack that could be filled by pwMS will to give this approach ago.

Importantly the MS Society have a question of what is the benefit of hard and early treatment as one of their JLA priorities and strategies. Maybe they will be supporting some studies in the UK.

P.S. HSCT depletes B memory cells;-)

28 comments:

  1. Had to Google to see what JLA is:
    http://www.jla.nihr.ac.uk/priority-setting-partnerships/multiple-sclerosis/top-10-priorities/
    Sometimes I wonder about all these kind of things, people sitting around in meetings setting goals etc etc just get on with it and do the research! I think we know that early aggressive treatment works? I see it's no 5 on the list just above whether vitamin D supplements ;-)

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    1. I think is you search on the blog profG went through these and most of them can be answered by pharma.

      I won't say what I think about it all:-(



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    2. Just do research you can only do it if you work on the jLA items and do they have the money to do them properly because the answer is trials.

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    3. Ah I understand, hence crowdfunding for Charcot as EBV is not in fashion.
      Good thing JLA wasn't around in previous centuries... Jenner, Fleming ;-)

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  2. HSCT for progressive MS, particularly PPMS? I don't think so. We go on and on waffling about this and that, but there really needs to be something for ***progression***. For those for whom DMTs are too late or would never have been much use on balance. Progression is what so many neuros just stick in the "nothing to be done / too late" pile.

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  3. Just as well that at BartsMS we don't think like that

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    1. BartsMS is a light at the end of the tunnel. How many of us are lucky enough to see a clinican at Barts/Royal London?

      I have SPMS, I finish the MS-SMART trial in 11 months Then what? I do not want to live with the definite knowledge that my brain is being shredded. I know there is no magic cure for me. I along with many other people really want something that will slow down or stop the progression of MS.

      I missed the RRMS boat and it looks like I may well miss the progressive MS boat.

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  4. lol the advices my partner received re hsct were, in hindsight, bordering on hilarious. i say that with all the bravery of something that affected us deeply but was 2 years ago and, in between the misery that was 2015, is starting to be funny in hindsight (starting to).

    neuro oyster (pet name) told her they don't know how the immune system comes back reconstituted after hsct and it could cause her cancer to come back. actual research i dug up and my partner's oncologist, haemo and breast surgeon all disagree with this. when i sent the research i dug up to neuro oyster, he replied, by letter, that it is his professional duty to warn her. again, from breast cancer point of view, my partner's haemo, oncologist and breast surgeon were as comfortable with the idea of nm hsct as they were with long term use of tysabri. i call him oyster neuro, but my partner prefers to refer to him as reconstituted orange juice neuro.

    neuro toothless gap (don't ask) warned my partner that she doesn't want to end up on a ventilator in an overseas hospital - or worse dead. i suppose that's true - she certainly wouldn't want either: but honestly, the fear of sepsis was plaguing my mind at the time and neuro toothless gap could have played on that far more effectively if she thought about it at all.

    neuro anti russian ron told us that russians are dodgy. i asked him if the germans, swedes, americans and canadians were also dodgy (mexico wasn't nkown at the time( and he refused to engage in further discussion. he also didn't offer to refund the consultation fee, though he did offer his opinion that my partner's enhancing lesion was "small"... (another neuro expressed concern about that lesion cos it was close to her grey matter lol)... i told anti russian ron that i was born in the former yugoslavia, russian's cousin, and that we weren't really consulting him for his view of russians but the science of hsct... but he was prolly too taken aback by my desperate rants by that stage to treat my partner as a human being....

    incidentally, a friend with ms was chasing lemtrada for her ms about the same time my partner was collecting opinions on hsct. anti russian ron told my friend she may not even have ms and therefore he won't give her lemtrada. he sent her to a pain specialist who wrote back her pain had no other discernable causes, and anti russian ron stopped returning her calls at that point. her next appointment at the particular ms clinic was delegated from anti russian ron to toothless gap, a far more junior neuro. i'm sure that was a complete coincidence, as was the fact that she 5 other neuro she panically consulted after anti russian ron all confirmed their unwavering belief she does indeed have ms (and 2 of them saw lesions on her MRI images the others didn't!)

    the msra neuro told us hsct was deadly - 5 to 10% mortality rate! it also turned out that msra neuro didn't know the difference between nm and myelo hsct - i asked him twice himself and finally he admitted he is a paternalistic doctor (i took that as an admission that he doesn't know the difference between the two types of hsct because he seemed to be refusing my direct question)... funnily enough, this neuro was one of the two who saw the lesions on my friend's mri that only one other neuro (out of 6 in total) saw......

    look at me ranting again. one would think i'm livid about all this dogmatic bullshit.

    i am :)

    neither of us thinks hsct is a cure or magical or anything other than a treatment which can be a bit of an overkill... still, she is doing remarkably well after the overkill and if you guys can only figure out if it the b cells or the t cells (or something entirely different lol) AND the optimal dosing without exposing her to unnecessary risks... i could even possibly agree.

    but that's a moot point :)

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    1. Dobro
      So I see you have a high opinion of neuros...We asked how many papers do some of the docs read a week...It was shocking.

      We (MDs) have a few names for people too. I guess if your neuros are reading they will remember you too.

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    2. hvala.

      everyone in the world has pet names for people that get up their nose: it's in the nature of us human beings. i would love to know that the neuros i'm referring to were reading this blog (and other things) but i suspect if that were true, they wouldn't have been giving advice 15 years out of date in 2015. pity for they are supposedly the top of their field.

      my partner's new neuro works with the majority of neuros i spoke about (though she sees him in his other private practice), and either he doesn't listen to the water cooler gossip that I'm sure is as prevalent as everywhere else, or otherwise he doesn't care cos he is treating her (and me when i need my questions answered) with all the honesty, information and compassion that every human being deserves. after 2015, i never thought i'd be in a position to say that about a neuro. it only took 3 ms patients looking for different treatments to pool their time and their resources to find him.

      incidentally, he said he is offering rituximab because nm hsct doesn't work forever, they have no biomarkers and (based on other autoimmune diseases not ms) it seems that the practice is to keep killing off those b cells before they repopulate. your article was 2 days old when we saw him, she is doing so well and is not 2 years out of hsct, she put off the continuing treatment decision for another year :), unless an mri or relapse (which she never felt) suggests otherwise in the meantime.

      i love his honesty, i love the way he treats her, i love the fact that after an incredibly difficult 2015 she is seeing him on her own and only with me when 2 heads are better than one.

      a fan of neuros.... LOL.... i love prof G and even he sometimes makes me feel like bursting into tears. still, he seems to care and he seems to try so very hard... in reality and despite the rants, that's all i ask.

      thank you for your answer to my pot/kettle comment regarding the calculations... it's friday night here in aus and i'm too tired to sit down with a pen and paper and try to work it out, but i intend to do so shortly and am grateful for your patience in going through it with me... once i've spent an hour with a pen, calculator and your answer, i will get it.

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    3. ps. i hope caroline wyatt is ok and has resurfaced.

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    4. She's apparently doing a documentary on this (surprise, surprise) that will be aired on radio 4, I think.

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    5. lol.

      it is ok. after the doco there will be a million articles warning people that hsct is experimental, needs more research and to speak to their neuro.

      do you blame her? the doco may even have negative aspects, judging by the fear in her last blog post (i googled it).

      besides, she has to recoup the cost and she has the perfect means to do it :)

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    6. Journalists rarely pass up the opportunity for a story.
      Hope HSCT works for her but by the sounds of it she's had MS for a long time and has ignored it, only acknowledging it once it seems to have entered the progressive phase so it may be too late to expect any major improvements.
      lots of love

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    7. "underwent months of tests to see if she could receive the treatment in London or Sheffield.
      But she was told in November that she was not eligible for the treatment because scans of her brain did not show any inflammation. At that point, she was crushed – and so afraid of what MS might do to her that she decided to ‘entrust [her] innards’ to Mexican doctors and pay for it herself."

      This used to be the standard policy. But in Mexico, Russia,
      and Israel they treat all stages of MS.

      http://www.dailymail.co.uk/health/article-4190148/BBC-s-Caroline-Wyatt-flies-Mexico-MS-operation.html

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    8. They do. Also, ocrelizumab is expected to be licensed for ppms shortly and we'll see what happens with spms after that.

      How many people with SPMS are on Tysabri because their doctors are unwilling to change their diagnosis from RRMS and take the treatment away?

      MS is a minefield.

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  5. Couple questions that I am wondering if you have any thoughts on the matter:

    o What would be a possible explanation for why some HSCT patients continue to have some activity but at a lower rate after the procedure from a memory B cell perspective.

    o Could you B cell table be enhanced to show the memory B cell drop and the effectiviness of the DMT? Would we likely see a correlation?

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    1. 1 there the ablative and non ablative HSCT the non ablative may not have removed enough of the bad cells.

      HSCT may not clear the CNS of the problem

      2. That is a reasonable hypothesis and indeed the data we found suggests a league table of efficacy look at the figure in the original post and the one a day later. But some of the data is a percentage .

      Some of the data I couldn't find for ms eg teriflunomide however I know of a poster from ectrims 2016 showed they go down.

      Cladribine is an unknown but I will put money on the MC dropping

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    2. Thanks for that information. I thought this article was interesting in light of your previous articles because it alludes to atacicept (shown in table 1 in the article) that drops B cells but not memory B cells that seems to have failed MS trials:

      http://journal.frontiersin.org/article/10.3389/fimmu.2015.00626/full

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    3. AnonymousThursday, February 09, 2017 11:20:00 pm

      Exactly if you read the article that we wrote you will see that we found this issue with atacicept and was one of the supportive bits of evidence we found. It helped with the Eureka moment. If you look at table 1 in the paper in the paper you saw you can see they did not make all the connections that we found in our paper

      http://multiple-sclerosis-research.blogspot.com/2017/02/ms-is-b-cell-disease-and-memory-b-cells.html

      if you don't want to read the article wait until saturday.

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    4. Sadly I read your paper before I posted that comment and missed it in there. However, now reading it a second time its totally in there :) I think in the article I linked above, what surprised me was that mature B cells seem to go down while memory B cells dont so it just really seemed like a stark contrast.

      Anyway, fascinating work you all are doing.

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    5. HaHa. There's written gold in there, spread the word:-)
      The mature B go down as do plasma cells

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  6. I participated in this trial and I feel it saved my life. I believe my EDSS improved the most of anyone in the study (could barely walk 100m to qualify, and could walk 500m for several years post transplant). Alas, my gains started slipping in year 4 and now my EDSS is back to baseline (although I am still doing well in most areas, just not walking well). I restarted therapy 5 years post transplant (Aubagio) and recently switched to Rituxan to try to keep things at bay. Would I do it all over again? Absolutely. Would I do it again now, probably not, as I am no longer an ideal candidate, as I have transitioned for all intents and purposes into secondary progressive.

    For those interested, I have detailed information on my HSCT experience on the forums at ActiveMSers, including the abstracts of most HSCT studies. There is a ton of misinformation out there on this topic, and I try to cut through the BS and hyperbole. Barts MS Blog is one of the few I trust for accuracy and I try to emulate their practical, research focus.

    My HSCT journey, unfiltered: http://forums.activemsers.org/forumdisplay.php?f=6

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    1. Thank you for your interesting comment Dave and thank you for participating in the trial and you honesty...whilst we do not normally allow links, I have decide to leave the post.

      However, your journey suggests that there needs to be more studies on HSCT and importantly we need to understand what is needed ensure that any benefit gained in maintained.

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    2. So that's it: if you've had the disease in progress for some time, even doing the HSTC, which is the most extreme measure of treatment, you can continue advancing in neurodegeneration, will you end up going to SPMS?!

      I have already talked to people here in Brazil who have done the HSTC, pwMS with the disease between 7 and 10 years since the diagnosis when they did the transplant, and they ended up losing even so, degenerate functions.

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    3. This is one persons journey. I suggest you see above in the post because there is a different view.

      I dont think we can say HSCT is one entitity because there are so many ways of doing the procedure. The agents used in the process are likely to be the key to success or failure.

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    4. dave, thank you for your comment, your blog and your participation in the ms community. my biggest fear re my partner and the nm hsct she received was continued progression post hsct (or post 6 months after hsct) without new/worsening lesions or relapses. for the time being at least my fears have not been realised, and i want to say i'm knocking on wood about that rather than having any scientific basis for the 'success'. how long will it last? i hope for long enough until there is a biomarker or something discernable, but i think i'm going to have to walk out of my bubble about this and face the hard truth that at some point she will have to face re-treatment and dosing decisions on blind faith (just like she did with nm hsct). at least her neuro is wonderful these days.

      "CinaraFriday, February 10, 2017 4:22:00 am
      So that's it: if you've had the disease in progress for some time, even doing the HSTC, which is the most extreme measure of treatment, you can continue advancing in neurodegeneration, will you end up going to SPMS?!"

      after being diagnosed with ppms, then possible spms, rpms or perhaps rrms, then finally with rrms, i deeply suspect 10 years ago, my partner would have been considered to have had spms rather thans rrms (edss of 3.5 at diagnosis mainly based on bladder function though her balance post diagnosis started to deteoriate significantly, all of which seems to have stabilised since - though the bladder function was not based on objective measures but rather her willingness to use catheters. she hasn't used a catheter since hsct, before it she was using it perhaps 5 times a year and only when she was fed up with life and too tired of trying)....

      what does all this mean? i can only hope that like in dave's circumstances, when the good news stops, there will be something to continue to treat her with... until then, i live in hope that prof g's therapeutic lag theory is true and that mousedoc will change the world with the b cell theory.

      i want to say i hope there will be something for neurodegeneration, but i've lost that hope a while ago. i think (i could be very wrong about this) mousedoc 2 mentioned something about aspirin? lol

      fingers crossed?

      lol

      in the meantime, we climbed a live volcano and went skiing. i am biased i know, but i used to be a ski instructor in a life before and she did incredibly well, better than most adults without an autoimmune disease :)

      "I dont think we can say HSCT is one entitity because there are so many ways of doing the procedure."
      Amen.

      "
      However, your journey suggests that there needs to be more studies on HSCT and importantly we need to understand what is needed ensure that any benefit gained in maintained."
      Amen 2. if only we could utilise people who have had it and collect their data, but in the beaurocracy we live in world wide, that wish seems to be as effective as wishing for world peace :(

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  7. Re Maybe it would be good to do a Freedom of Information request of prescriptions of each Hospital in UK to see what their neurologists are prescribing.
    The other way to do this is ProfG's recent suggestion of setting up a ratings site like TripAdvisor. I thought it was a great idea :-)

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