Friday, 1 September 2017

#ResearchSpeak: does HSCT have a chance?

Alemtuzumab 5-year extension data supports flipping the pyramid and hitting MS early and hard. #ResearchSpeak

Summary: The following post summarises the very good 5-year extension data of people with MS treated with alemtuzumab in the pivotal phase 3 trials. In short, the result of very good with most subjects only requiring 2 courses of treatment with a very good outcome. Particularly impressive is the observation of 'normalised' brain volume loss in years 3, 4 and 5. 

The following are the 5-year extension study results of the alemtuzumab trial subjects. If you have MS these results are simply the best long-term data we have on any DMT including HSCT (hematopoietic stem cell therapy). 

We have been pushing the treatment paradigm of flipping the pyramid (high-efficacy first-line) for some time now. The CARE-MS 1 study is just this, i.e. these subjects were DMT naive before being treated with alemtuzumab; 68.5% only needed two cycles of treatment in year 1 and 2 with the majority being NEDA in years 3, 4 and 5. The important metric is brain volume loss, a measure of end-organ damage, which was less than or equal to 0.2% per year. This level of brain volume loss is what you see in normal people. 

The results in the CARE-MS 2 extension study are no less impressive. These subjects had all failed prior DMTs and hence had a longer disease duration and went onto alemtuzumab with greater underlying damage and/or loss of brain reserve; 60% only needed two cycles of treatment (year 1 and 2), the majority were NEDA and brain volume loss in years 3, 4 and 5 were well under 0.2% per year. Please note brain volume loss in year 1 and 2 are high, this is because of therapeutic lag. Brain volume loss in the next 2 years of your disease is primed by previous inflammatory disease activity hence we would not expect alemtuzumab to impact on this previous damage. 

The cons of alemtuzumab are well rehearsed; ~45-50% of subjects will develop secondary autoimmunity over time. The commonest is autoimmune thyroid disease. Alemtuzumab comes with strict monitoring requirements, i.e. monthly blood and urine monitoring for at least 48 months after the last course of treatment. There is also a not so insignificant infection risk in the first few weeks after alemtuzumab infusions. The studies below quote epoch NEDA rates, i.e. NEDA rates per annum. The accumulative rates are lower than this and at 5 years the NEDA rates are less than 50% for both the CARE-MS 1 and 2 studies. The latter is important as this will be the metric we use if and when we do our trial comparing AHSCT to alemtuzumab in the NHS. 

Despite these negatives, there is little doubt that alemtuzumab is the most effective DMT we have available to treat people with active MS. Alemtuzumab is also the most cost effective therapy we have licensed to use under the NHS. NHS England would prefer us to use alemtuzumab to all other licensed DMTs because of this. NICE is not the only HTA (health technology appraisal) to come to this conclusion, the Norwegian HTA has drawn the same conclusion. At an NHS service level, alemtuzumab is causing a pharmacovigilance nightmare for us. To see the scale of the problem imagine you treat 100 patient per year with alemtuzumab and you have to do monthly blood and urine monitoring. After 5 years you will have 500 patients requiring monthly monitoring and 500 patients requiring annual MRI scans. This is an industrial-scale logistics problem; it is something we have to gear up for. This is why other emerging DMTs such as oral cladribine and ocrelizumab will have an advantage over alemtuzumab. The monitoring requirements are so much less with these agents that the incentives for MS services to shift to a less arduous mix of DMTs are obvious. For the individual person with MS I would ask your neurologist what the long-term brain atrophy data is for cladribine and ocrelizumab and how they interpret the results. Then you should ask them if they, or one of their close family members, had MS which agent would they choose? I think you may find their answer quite surprising. 


Havrdova et al. Alemtuzumab CARE-MS I 5-year follow-up: Durable efficacy in the absence of continuous MS therapy. Neurology. 2017 Aug 23.

OBJECTIVE: To evaluate 5-year efficacy and safety of alemtuzumab in treatment-naive patients with active relapsing-remitting MS (RRMS) (CARE-MS I; NCT00530348).


METHODS: Alemtuzumab-treated patients received treatment courses at baseline and 12 months later; after the core study, they could enter an extension (NCT00930553) with as-needed alemtuzumab retreatment for relapse or MRI activity. Assessments included annualized relapse rate (ARR), 6-month confirmed disability worsening (CDW; ≥1-point Expanded Disability Status Scale [EDSS] score increase [≥1.5 if baseline EDSS = 0]), 6-month confirmed disability improvement (CDI; ≥1-point EDSS decrease [baseline score ≥2.0]), no evidence of disease activity (NEDA), brain volume loss (BVL), and adverse events (AEs).

RESULTS: Most alemtuzumab-treated patients (95.1%) completing CARE-MS I enrolled in the extension; 68.5% received no additional alemtuzumab treatment. ARR remained low in years 3, 4, and 5 (0.19, 0.14, and 0.15). Over years 0-5, 79.7% were free of 6-month CDW; 33.4% achieved 6-month CDI. Most patients (61.7%, 60.2%, and 62.4%) had NEDA in years 3, 4, and 5. Median yearly BVL improved over years 2-4, remaining low in year 5 (years 1-5: -0.59%, -0.25%, -0.19%, -0.15%, and -0.20%). Exposure-adjusted incidence rates of most AEs declined in the extension relative to the core study. Thyroid disorder incidences peaked at year 3 and subsequently declined.

CONCLUSIONS: Based on these data, alemtuzumab provides durable efficacy through 5 years in the absence of continuous treatment, with most patients not receiving additional courses.

Coles et al. Alemtuzumab CARE-MS II 5-year follow-up: Efficacy and safety findings. Neurology. 2017 Aug 23.

OBJECTIVE: To evaluate 5-year efficacy and safety of alemtuzumab in patients with active relapsing-remitting multiple sclerosis and inadequate response to prior therapy.

METHODS: In the 2-year Comparison of Alemtuzumab and Rebif Efficacy in Multiple Sclerosis (CARE-MS) II study (NCT00548405), alemtuzumab-treated patients received 2 courses (baseline and 12 months later). Patients could enter an extension (NCT00930553), with as-needed alemtuzumab retreatment for relapse or MRI activity. Annualized relapse rate (ARR), 6-month confirmed disability worsening (CDW; ≥1-point Expanded Disability Status Scale [EDSS] score increase [≥1.5 if baseline EDSS = 0]), 6-month confirmed disability improvement (CDI; ≥1-point EDSS decrease [baseline score ≥2.0]), no evidence of disease activity (NEDA), brain volume loss (BVL), and adverse events (AEs) were assessed.

RESULTS: Most alemtuzumab-treated patients (92.9%) who completed CARE-MS II entered the extension; 59.8% received no alemtuzumab retreatment. ARR was low in each extension year (years 3-5: 0.22, 0.23, 0.18). Through 5 years, 75.1% of patients were free of 6-month CDW; 42.9% achieved 6-month CDI. In years 3, 4, and 5, proportions with NEDA were 52.9%, 54.2%, and 58.2%, respectively. Median yearly BVL remained low in the extension (years 1-5: -0.48%, -0.22%, -0.10%, -0.19%, -0.07%). AE exposure-adjusted incidence rates in the extension were lower than in the core study. Thyroid disorders peaked at year 3, declining thereafter.

CONCLUSIONS: Alemtuzumab provides durable efficacy through 5 years in patients with an inadequate response to prior therapy in the absence of continuous treatment.


Alemtuzumab vs. HSCT: who will come out on top?

CoI: multiple, I am a co-author on these papers

40 comments:

  1. We have been pushing the treatment paradigm of flipping the pyramid (high-efficacy first-line) for some time now.

    ...yes. It's called HSCT.

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    1. Aah, but is HSCT more effective and safer than Alemtuzumab or Ocrelizumab or Natalizumab? I don't think we know the answer to this question.

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    2. This seems like spin, Prof G. You're too involved with this med to be balanced.

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    3. I don't know how you can seriously ask that. You've answered it in the study / article. "In years 3, 4, and 5, proportions with NEDA were 52.9%, 54.2%, and 58.2%," HSCT is up in 80+% for RRM. As far a side-effects, again... I can only say, re-read your own article. Stop trying to insinuate you've found a 'DMD version of HSCT". Are you seriously suggesting something that suppresses the immune system is more powerful than something that ablates it? What is it with the strange determination to fight the logical? Where does this come from?

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    4. Until you do a head-2-head study nobody can claim treatment strategy x is better than treatment strategy y. I agree that based on the published data HSCT looks likely to be more effective, but we can't make that a definitive statement without class 1 evidence.

      I have several patients from the pivotal phase 3 trial who have been on natalizumab for over 15 years, who are NEDA and functioning normally. Will HSCT give the same results?

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    5. I agree that I may not have a balanced view, but I do offer HSCT to my patients under our London HSCT guidelines. I also have to disclose that I am a co-applicant on a grant to the NIHR to do a head-2-head study of alemtuzumab vs. HSCT. At least I am walking the talk and trying to generate the class 1 evidence to answer the question I have proposed above. If I was so convinced that alemtuzumab was the most effective treatment available I would not have the necessary equipoise to offer screening for this trial to my patients.

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    6. Aah, but is HSCT more effective and safer than Alemtuzumab or Ocrelizumab or Natalizumab? I don't think we know the answer to this question.
      I am doing Hsct in november have talked to hematologish where i live she does 60 Ahsct a year ...She says that Alemtuzumab its no good for cancer patient or any other disease

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    7. I have several patients from the pivotal phase 3 trial who have been on natalizumab for over 15 years, who are NEDA and functioning normally. Will HSCT give the same results?

      Relapsing-remitting MS patients (n = 22)

      Patient and year
      of AHSCT
      Gender Age at
      AHSCT
      MS duration
      (year)
      Relapses
      before AHSCT
      Baseline
      EDSS
      Hsct Age at
      year Hsct
      #1, 1999 M 44 16.83 Years post hsct
      #2, 2004 F 37 10.83 Years post hsct
      #3, 2005 F 30 10.75 Years post hsct
      #4, 2005 F 36 10.08
      #5, 2007 M 27 7.6

      https://www.ncbi.nlm.nih.gov/pubmed/28396953

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    8. Dear Prof.,

      I have a question relating HSCT/Campath, as as you say these might become obsolete once the real cause has been found:

      The HSCT conditioning regimen, and I assume also the Campath treatment, contains a lot of antibiotics that needs to be taken for months. Could it be that MS is caused by a low intensity bacterial infection of the gut, so weak that blood levels are not rised significantly? We do know that the gut contains a lot of neurons. Possibly some of the lymphocytes involved in battling the gut infection might, through simply following the blood circulation and having as antigens MBPs or other neural peptides, end up in the brain where they could cause an even less intense immune attack on brain cells.

      My question are:

      i) Has there been a conclusive clinical study in MS showing that strong antibiotics have no effect on the disease?
      ii) Has there been a thorough autopsy of somebody suffering from an acute MS relapse apart from the reason of death?

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  2. Lets trundle along, playing with DMD's and people's misery for another decade or so (in my opinion, genuinely coming close to breaking the Hippocratic oath that Drs take).

    If as much time, effort and money was put in to HSCT, as it DMDs, a lot of pain and suffering would be saved.

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    1. DMDs generate billions of $$$. They will not be threatened by HSCT without a fight. These head to head studies will drag on for years and ensure continuing cash flow. I agree that in the end ablation and reconstitution will be the optimal strategy over targeted immune suppression.

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    2. May be you don't need a sledgehammer to target the cause of MS, for example EBV. Maybe a small molecule anti-viral, or anti-EBV cytotoxic T-cells, will do the trick. I would suggest taking your HSCT-blinkers off and thinking a bitter broader about the treatment of MS. I predict that once we definitively know what causes MS HSCT will become obsolete as a treatment for the disease.

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    3. #Facepalm.

      For all of your many undoubted merits, Prof G, you clearly have no idea what it is like to have MS. Nobody has HSCT because they like the idea of a sledgehammer/chemotherapy. But all this idealistic bullsh*t about a small molecule anti-viral doing the trick is just nonsense. I REALLY REALLY hope it materialises - and I elieve it surely will, in time.

      I've had HSCT, and nothing would make me happier than knowing that - should MS ever rear it's ugly head again, I can pop a couple of pills and be rid of it forever. But this is currently nothing more than a wet dream.

      You, as a non-MS-er, can wait 20 years for that to get ideated, funded, trialled, repeated, and regulated - and I hope you and your colleagues make it over the line and claim all of the deserved plaudits for doing so.

      But anyone with MS has no such luxury and can't wait indefinitely for years and years for your moonshot to come off - or we'll end up disabled, jobless and broken - facing a grim and lonely life, whilst you're jetting around the world enjoying your pharma-funded lunch!

      What you are proposing here is to "take our blinkers off", and not have the current most-effective treatment, in the blind hope that a better option MIGHT materialise in a decade.

      Imagine it was your daughter facing life in pain/a wheelchair/unemployment/divorce, etc.... Would you ask her to go all in with her life on a blind bet..... REALLY?!

      Take your pharma blinkers off, and ask yourself what would you do if you were a patient, rather than a well-meaning (but somewhat conflicted) researcher.

      Matt

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    4. Lot of maybes but in the meantime HSCT is available.. Hopefully HSCT will be obsolete once the cause is known.

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    5. "May be you don't need a sledgehammer to target the cause of MS".

      No, you're right of course. Forgive me, who was it who said "Alemtuzumab 5-year extension data supports flipping the pyramid and hitting MS early and hard."?

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    6. "Gavin GiovannoniFriday, September 01, 2017 6:31:00 pm
      May be you don't need a sledgehammer to target the cause of MS, for example EBV. Maybe a small molecule anti-viral, or anti-EBV cytotoxic T-cells, will do the trick. I would suggest taking your HSCT-blinkers off and thinking a bitter broader about the treatment of MS. I predict that once we definitively know what causes MS HSCT will become obsolete as a treatment for the disease."

      YES please!!!! - to all the quoted comments.... but until then all MS patients are a 20 year experiment. use them more and implore your colleagues to collect more data (not just the basics).

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  3. Agreed that the only way the HSCT versus Alemtuzumab question to rest is a head-to-head trial, but based on longitudinal studies as well as anecdotal evidence – I know, anecdotal evidence shouldn't hold much weight – it seems that HSCT offers higher efficacy with a higher safety profile as long as the protocol is administered by experienced practitioners.

    Also, patient selection is extremely important, as I personally know several patients who have undergone HSCT or Lemtrada therapy who don't fit the optimal profile (patients with active inflammatory disease as marked by active relapses and/or evidence of inflammatory activity in the CNS) who haven't received benefit. In the case of some of the Lemtrada patients, some have suffered terrible side effects and actually saw their disease progression speed up. One Lemtrada patient in particular has suffered some sort of Mast Cell reaction that has sent her to the hospital several times in an anaphylactic state. Again, yes, anecdotal evidence…

    I also know several progressive MS patients who underwent HSCT and saw no benefit. Let's not forget, going through HSCT is no picnic. Unfortunately, the voices of these patients have generally been shut out of HSCT forums and Facebook pages, where negative reports are discouraged or even banned outright. The amount of misinformation one encounters on MS Facebook sites is startling.

    What bothers me most, though, is the thought that if a fraction of the money being spent exploring newer and better ways to manipulate/suppress/ablate the immune system was instead spent on discovering the underlying cause of the disease, we might actually see progress towards a cure rather than extensions of the current treatment status quo. The very success of the DMDs has, I fear, impeded the search for a cure. Too much money being made treating, and since the vast majority of mid to late stage research is funded by Pharma, the hunt for a cure has taken a backseat to the wonders of immunosuppression.

    Seems that with recent advances in the understanding of the workings of the immune system and the underlying genetics of autoimmunity, a well-funded push to find a cure might now yield results that have been elusive for decades. A concentrated effort to explore the interaction between smoldering infections and genetic predisposition might just produce, if not a cure, then much less toxic and more effective treatments.

    But there I go, dreaming again. If you don't have dreams, you have nightmares…

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    1. if it wasn't for the 50% secondary autoimmunity my partner would have prolly chosen lemtrada over hsct...

      i know a couple of people on this forum who would have liked to have received b depletion shortly after lemtrada but didn't end up being able to talk their neuro into it...

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  4. Not one MS drug has cured MS its all about making profits, shares and commissions you get also by this its all about making money from every vunerable patient . I look forward to you being named and shamed .

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    1. "Not one MS drug has cured MS its all about making profits" No there is no cure for MS because one has not been found. Science like engineering is difficult. We have come a long way in a short time, but until any disease is understood fully in detail, then the treatments are difficult to find, like looking for a black cat in a dark room. Disclaimer I have nothing to do with MS treatments or medicine, I am just fed up of those who 'cannot' telling those who are trying that they are hiding something miraculous.

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    2. Sorry this comment from Leicester (if not from leicester it is their MO) slipped through there are a hundred of them or more in spam.

      However dear anon 7:49 thanks for sensible words

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  5. As of my last comment wasn't long enough, I forgot one last point.

    Dr. G, on the topic of therapeutic lag, how to explain the long-term differences in efficacy between relapsing MS and progressive MS patients seen in longitudinal studies of HSCT? One recent longitudinal study of HSCT treated patients across Europe showed far greater efficacy at the five year mark for relapsing MS patients (73% progression free) when compared to SPMS patients (33% progression freight). Shouldn't five years be long enough to see a narrowing of this gap?

    Here's the abstract to this study, which doesn't include the above numbers. I managed to get hold of the full study which does breakdown the numbers by MS subtype:

    http://jamanetwork.com/journals/jamaneurology/article-abstract/2604135


    Not trying to be overly critical, just wondering your thoughts on these numbers?

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    Replies
    1. if you judge by ocrelizumab results in ppms... the suggestion would be that hsct could slow down the progression not stop it altogether

      also, they don't re-baseline with hsct... i understood they did with ocrelizumab and lemtrada

      so to answer the question, you'd need to know what and how the patients progressed, not just that they did or didn't...

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  6. Does Alemtuzimab have a chance? Less than 50% 5 year NEDA vs HSCT is poor. A head to head trial would be like a one sided boxing match.
    What is the 5 year NEDA of Tysabri, Tecfidera, Gileyna, Aubagio and the interferons? Surely this must be being measured by the NHS or the manufacturers? (basic business to know how effective one's product is).

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  7. Hi Professor Giovannoni,

    I'm a bit confused about how we interpret NEDA percentages. The article says:

    "Most patients (61.7%, 60.2%, and 62.4%) had NEDA in years 3, 4, and 5."

    I see that NEDA increases from year 4 to 5, so presumably this means that each year's NEDA rate is measured independently of previous years, and therefore a patient in the lucky 60% on year 5 may have actually experienced disease activity in every preceding year, which looks good for the statistics but isn't much use for that particular patient.

    So, if about 40% of alemtuzumab patients in any given year continue to experience disease activity, doesn't that mean that over the 5 years the great majority of patients will end up experiencing disease activity?

    Purely mathematically, all things being equal, the probability of a patient being in the 60% NEDA group 5 years in a row must be pretty small, something like a 7% chance (if we flip a 60/40 probability coin each year - 0.6*0.6*0.6*0.6*0.6). Of course, not all other things are equal, and for all I know a large chunk of that 60% of patients could be the same people year after year remaining NEDA, with only a small minority of each year's 60% cohort being new entrants.

    Do we have any breakdown on the composition of the NEDA group from year to year? Is it the same people? Is it a different bunch of people each year? How many patients were NEDA from treatment to endpoint?

    In other words if I was given alemtuzumab tomorrow, what would be my chance of being continuously disease free for the next five years?

    I really do want to believe that Alem puts the large majority of RRMS patients into long-term remission but I'm concerned that the statistics aren't as flattering as they look. I fear the percentage chance of being continuously NEDA for year after year after year is more like 6% rather than 60%.

    Am I interpreting the data wrong? I really am a big fan of the blog so I don't want to seem harshly critical. But the sceptical part of my mind thinks these figures are just too good to be true.

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    Replies
    1. I really really hope Prof G answers this question!! I also see no point in reporting NEDA rates 'per year'. Is the cumulative 5 year NEDA value really that bad that can't be printed and released?

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    2. Page 5 of the full article reports "Cumulatively over years 3–5, most patients showed no clinical (65.3%) or MRI lesion (53.8%) activity, and 39.5% attained sustained NEDA."

      Looks like 39.5% is the statistic of interest.

      Mind you, the starting point here is year 3, not the beginning of the study. So you need to reach Year 3 NEDA to even have the chance to be in this lucky cohort. From memory and from the original trial results, only 39% made it to the end of year 2 with NEDA.

      So, we want to be in the 39.5% of the 39%!

      Please comment on these figures Prof G.

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    3. Warmly agree with you both. Another (strange)use of statistics is the mean number of relapses. When it is written (the mean diminishes of X%) I always wonder is it because they were some 'cured' people without relapse and some 'non-cured' with a normal rate of relapsess or is it because the number/probability of relapses diminishes for everybody and nobody is cured.

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    4. This type of analysis was presented at ECTRIMS, it is clearly hiding efficacy failure. I have yet to read the full documents but suspect there is no mention of neutralizing antibodies and treatment failure either

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    5. This must be saying cumulative NEDA othwrwise this is a mockery if year by year. I am 44 and don't hope or expect to die in the 5 years (fingers crossed) so if annual NEDA then this drug should almost be removed now.
      Please clarify Prof G.
      Thank you

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    6. On the plus side only 40% of those in the extension received a third dose, hopefully this was to due to need and not to people dropping out and switching to something else.

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  8. "The important metric is brain volume loss"

    What about brain integrity? The following study found that fingolimod "...did not affect the widespread, diffuse microglial activation in the NAWM and GM."

    Are microglia in NAWM and GM going to stay activated forever because of previous damage in lesion sites, or constant NEDA may lead to their de-activation?

    Why don't you use microglial activation in NAWM and GM as a measure of MS activity?

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    1. Probably too complicated for routine use, but happy to be proved wrong

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    2. Neda its "nice" for the doctor not so much for the patient

      For the patient the best measure should be Pfs

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  9. Forgot the link:
    http://jnm.snmjournals.org/content/early/2017/03/22/jnumed.116.183020.abstract

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  10. You say flip the pyramid. But you do not plan to use less effective treatment like interferons if alemtuzumab does not work. This flipping the pyramid story is more a figure of speech, no?

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  11. multiple, I am a co-author on these papers

    So basicaly you are judging your onw work

    Own about that for a good end result

    Sure you would not say bad things about your onw work

    Luis

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  12. aHSCT for MS may be more efficacious in children than in
    adults. PFS in the present study was 100% in comparison with
    66–91% at 3–5 years after aHSCT in adults.10–14 EDSS improvement
    was also seen to a substantially higher degree than the 50%
    reported from one study.14 aHSCT also compares somewhat
    where 46% of patients improved at least 1 point in the EDSS
    and disease-free survival was 58% in one large case series.21 In a
    smaller case series of rituximab-treated children with low-grade
    disability, median EDSS improved with 0.5 points and disease-free
    survival was 57%.22
    About half of the patients included in this study were diagnosed
    with SPMS, which is considered rare in children. This may
    be a classification error but could also be due to an enrichment
    of the most severe cases considered for this procedure.
    Nevertheless, most of the patients diagnosed with SPMS
    had gadolinium-enhancing lesions and relapses, suggesting an
    inflammatory phenotype, consistent with active SPMS in the
    Lublin classification.

    https://www.ncbi.nlm.nih.gov/pubmed/28319075

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  13. As someone with MS and not due to see my consultant for another six months,am I allowed to ask via this blog the actual long term brain atrophy data for cladribine and ocrelizumab compared with alemtuzimab? Am I right in thinking that your own personal choice of the three at this moment in time would favour Alemtuzimab? Thank you so much for your help.

    ReplyDelete

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