Friday, 10 June 2016

GuestSpeak: Prof Mark Freedman on their new HSCT results

How close are we getting to a potential cure for MS? #GuestSpeak #MSResearch #MSBlog


Professor Mark Freedman

Dr. Freedman is currently professor of medicine in the field of neurology at the University of Ottawa, as well as director of the Multiple Sclerosis Research Unit at the Ottawa Hospital, General Campus and a Senior Scientist at the Ottawa Hospital Research Institute. A graduate of the University of Toronto, Dr. Freedman holds his Masters Degree in Molecular Neurochemistry and continued his postgraduate work specializing in neurology and neuroimmunology. His specialized training took him to the Weizmann Institute of Science, Israel; The National Hospital, Queen Square, London UK, as well as the Montreal Neurological Institute, where he subsequently joined the clinical staff at McGill as an Assistant Professor. He holds his specialist certification in Quebec CSPQ and all of Canada FRCP(C) and is a Fellow of both the American Neurological Association (FANA) and the American Academy of Neurology (FAAN).

Dr. Freedman has published nearly 300 pieces, including articles, books, book chapters and abstracts and has been invited to give hundreds of lectures and presentations nationally and internationally. His extensive research includes the area of molecular neurochemistry, cellular immunology, neuroimmunology and clinical research studies in MS. He is currently holding peer reviewed and industry related funding for clinical and translational research investigating potential MS treatments with a particular interest in cell based therapies. He is was the lead investigator in the Canadian Bone Marrow Transplant Study in MS and co-leader of the International Mesenchymal Stem Cell Transplantation for MS (MESEMS) Study Group.


Dr. Freedman has nearly 30 years of experience in the management of patients with multiple sclerosis and has been the principal investigator on numerous clinical trials with new therapeutic agents for MS. He has experience from serving on several research study steering committees as well as data safety monitoring boards. He serves on the editorial boards for several journals including the Multiple Sclerosis Journal. He has also served on several national and international committees and is currently the Treasurer of the Americas Committee for Treatment and Research in MS (ACTRIMS).

Immunoablation and autologous haemopoietic stem-cell transplantation for aggressive multiple sclerosis: a multicenter single-group phase 2 trial

Why do this?
Without knowing what immune mechanism is operating to cause harm in any given MS individual, it might make sense simply to replace the entire system and re-build it using new bone marrow derived stem cells that, once they mature will not attack the CNS.

How is this accomplished?
Bone marrow transplantation procedures have been developed using many different recipes depending on the expertise in any given centres. They all involve 3 basic steps:

1. Mobilization: This is where the stem cells are chased from the bone marrow and collected and frozen for future use.

2. Conditioning:
This is the most risky and worrisome part where high doses of potent chemotherapy drugs are used to essentially wipe out the immune system.

3. Stem cell transplantation: Following the conditioning step, without stem cell support the immune system is incapable of growing back and the person would die if not for the ability to generate a new immune system from special bone marrow derived stem cells which are obtained in step 1, are thawed and given intravenously.

What do we do differently from others?
Many other groups have reported on their results using various recipes, but none have eradicated all measures of inflammation going out long-term. We believe it was because they did not go far enough with step 2 above and failed to completely wipe out the old immune system; i.e. there are still remnants of the old system that eventually return to re-attack the CNS. Unless all “memory” is erased, the immune system remembers and can return to its old ways. Our technique is aggressive in insuring that all immunological “memory” is erased; not only memory for the disease, but also from all childhood immunizations and previous infections. As such, patients will need to be re-immunized following the procedure.

How do we do it?

1. Mobilization: We use a potent chemotherapy drug called cyclophosphamide as a single intravenous dose followed by a series of daily injections of a drug called filgrastim which helps to mobilize the stem cells from the bone marrow into the blood. After about a week, patients are hooked up to a machine to collect the stem cells from their blood and then, using a specialized set of magnetic beads to select out the specific cells capable of re-growing the immune system, the stem cells are separated from the rest of the blood and are frozen away.

2. Conditioning
: Here we again use cyclophosphamide, not in very high doses for several days along with another very toxic drug called busulfan. These 2 were chosen, not only because they are capable of completely removing an immune system, but because both can penetrate the CNS and potentially remove cells that have already made their way in to attack.

3. Stem cell transplantation: Frozen cells from step 1 above are thawed and after a week or so following the conditioning step, these cells are given to the patient intravenously followed by another powerful anti-T cell drug called ATG (anti-thymocyte globulin) which will kill any mature T cell that might still be left in the frozen graft. Patients then re-inject with the filgrastim for several days to help the newly maturing immune cells to “engraft” or set up home again in the bone marrow and start churning out mature immune cells.

What are our results?
We planned on treating 24 patients with aggressive MS (early multiple relapses, EDSS progression to 3.0 or more within the first 5 years of disease, age up to 50, and evidence of ongoing inflammatory disease activity in the way of relapses or MRI or relentless recent disease progression) and having 8 “controls”, who were patients otherwise meeting inclusion criteria but who chose not to have the procedure. (We could only find 2 such individuals: 1 relapsed twice within months of completing a 2 year course of mitoxantrone chemotherapy and eventually went into the study and had a full transplant; the other, also getting mitoxantrone, started to progress again within 5 years.) All patients were meticulously followed regularly with clinical exams, MRI studies and numerous immunological tests.

Despite the very high activity prior to doing the transplant procedure not a single recorded relapse or new MRI lesion was noted in any patient followed for up to 13 years. Additionally, some 30% of patients continued to progress a bit, but all did so immediately within the first 2 years, indicating to us that whatever started this progression was not altered by removing further inflammation. More importantly 70% of patients did not progress and 35% of patients enjoyed some remarkable recovery with return of several functions they had lost for a long time such as sight, walking or balance. The rate of brain loss, as measured by MRI, leveled off and within 5 years was no different than age-matched healthy controls. Most importantly, these results were accomplished in the complete absence of any disease modifying therapies.

These results were not without cost in terms of side effects

One patient died early on, a tragic consequence of one of the drugs, busulfan, that was only available as an oral formulation, making it difficult to control blood levels. Soon thereafter, an intravenous formulation became available and we no longer saw any of the same toxicity noted with the oral drug. There were many other typical post-transplant complications such as infections, but none were serious as all patients took preventative medicines against bacteria, fungus and viruses. A few people developed problems with their thyroid. There were no long term complications noted within the span of 13 years.

What are the implications of this research?
This work indicates that the immune system is clearly at fault for causing the damage leading to disability in MS, since if it was due to simply genes or environment, then we would have expected that the disease would return in the time we followed these patients. It also presents a new option for patients at the extreme of disease that are not adequately controlled with today’s ever growing array of powerful drugs. 

It cannot be stressed more that this is very complicated and risky procedure and as such, should only be undertaken in centres with expertise in the technique as well as having the MS expertise at being able to choose the best patient.

Atkins et al. Immunoablation and autologous haemopoietic stem-cell transplantation for aggressive multiple sclerosis: a multicentre single-group phase 2 trial. Lancet 2016; S0140-6736(16)30169-6.

Background: Strong immunosuppression, including chemotherapy and immune-depleting antibodies followed by autologous haemopoietic stem-cell transplantation (aHSCT), has been used to treat patients with multiple sclerosis, improving control of relapsing disease. We addressed whether near-complete immunoablation followed by immune cell depleted aHSCT would result in long-term control of multiple sclerosis.

Methods: We did this phase 2 single-arm trial at three hospitals in Canada. We enrolled patients with multiple sclerosis, aged 18–50 years with poor prognosis, ongoing disease activity, and an Expanded Disability Status Scale of 3·0–6·0. Autologous CD34 selected haemopoietic stem-cell grafts were collected after mobilisation with cyclophosphamide and filgrastim. Immunoablation with busulfan, cyclophosphamide, and rabbit anti-thymocyte globulin was followed by aHSCT. The primary outcome was multiple sclerosis activity-free survival (events were clinical relapse, appearance of a new or Gd-enhancing lesion on MRI, and sustained progression of Expanded Disability Status Scale score). This study was registered at ClinicalTrials.gov, NCT01099930.

Findings: Between diagnosis and aHSCT, 24 patients had 167 clinical relapses over 140 patient-years with 188 Gd-enhancing lesions on 48 pre-aHSCT MRI scans. Median follow-up was 6·7 years (range 3·9–12·7). The primary outcome, multiple sclerosis activity-free survival at 3 years after transplantation was 69·6% (95% CI 46·6–84·2). With up to 13 years of follow-up after aHSCT, no relapses occurred and no Gd enhancing lesions or new T2 lesions were seen on 314 MRI sequential scans. The rate of brain atrophy decreased to that expected for healthy controls. One of 24 patients died of transplantation-related complications. 35% of patients had a sustained improvement in their Expanded Disability Status Scale score.

Interpretation: We describe the first treatment to fully halt all detectable CNS inflammatory activity in patients with multiple sclerosis for a prolonged period in the absence of any ongoing disease-modifying drugs. Furthermore, many of the patients had substantial recovery of neurological function despite their disease's aggressive nature.

Funding: Multiple Sclerosis Scientific Research Foundation.

45 comments:

  1. These are some of the best long-term efficacy results ever published, albeit it an open-label study, and support MS being an 'autoimmune' disease with inflammation being the main driver of disease progression.

    Please note it is not possible to do a blinded HSCT/BMT trial.

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    2. It would also work if the driver for MS was rogue B cells immortalised by Epstein Barr as you would also be killing these cells. Such cells do very strange things to the immune system in the early stages of Hodgkin's Lymphoma.

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    3. It's what I was intrigued as well.

      "There Were many other typical post-transplant complications such as infections, but none serious Were the all pacientes redbourn preventative medicines against bacteria, fungus and viruses. A few people developed problems with Their thyroid. There Were the long term complications Noted Within the span of 13 years".

      During these 13 years of follow-up of these patients none of them infected with Epnstein Barr? If so, how was the reaction of this new immune system to infection by EBV, asymptomatic or symptomatic?

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    4. doesnt alemtuzumab do the same thing? reset the immune system? and it doesnt have a 1 in 10 mortality!

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    5. It may not be that you are infected by Epstein Barr but that you get a specific mutation in the B cells that matters, you would then see reoccurrence of MS in a very small subset of these people. It cannot simply be infection with Epstein Barr and a particular set of genes otherwise twins who get Epstein Barr would both get MS and they don't. In Hodgkin's the chemo does not clear the Epstein Barr but very few people re undergo the damage that gives them another cancer ( not the old one relapsing).

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    6. Alemtuxumab doesn't completely wipe out the immune system like this. 1/24 patients died unfortunately and Prof Freedman says due to the old version of busulfan - which is no longer widely used in most HSCT centres these days....not sure why, perhaps the risk profile. European Bone Marrow Transplantation fatality rates now hover between 0.5-2% depending on disease / age group / source.

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  2. It's on the BBC news website today.
    http://www.bbc.co.uk/news/health-36490315
    New treatment can 'halt' multiple sclerosis, says study

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  3. Thanks so much for this! I was reading about this at a few sites today.

    Then I ran across a recent document published by UC Riverside California about Toxoplasma Gondii parasite. Did some research on that. Nasty lil' buggers.

    You might want look at this Prof G. & Mouser: https://ucrtoday.ucr.edu/37754

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  4. This is a cure, as long as you are prepared to assume the risk. Now how much time will people need to wait for this to be an approved treatment option?

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    1. I'd asked this same question in respect to such treatment approved in the USA. One can of course have the procedure done but do not expect insurers to be paying for it anytime soon and how the governmental establishment handles it is completely up in the air.

      In the USA they want facilities capable to performing the procedure and being able to provide proper care especially directly in weeks after these procedures. The FDA has issued several warnings on this. People go to "Bob's Stem Cell Clinic and Dent Repair..." pay $45,000. Released. Then BAM sitting in care systems hammered. Some worse than when they began and $45,000+ the less. Others, $45,000+ no results. Others, $130,000+ out of pocket only to relapse at a good facility.

      Standards need get into place, assessment towards efficacy given a patients current disease state for example.

      With insurers going, "Oh my gosh is chronic illness causing us to think McDonalds Coffee .vs. Starbucks" something is going to give. Just a question of what.

      The Pharma economy also is at play in all this. Since intravenous infusion of money plays a role in the US political system... well... who knows?

      Some things are pretty clear that MS'ers in the USA need to consider.

      We have two main candidates now.

      One is a billionaire who clearly is not exactly sympathetic to the end person and has "played" the political money game towards his billionaire pursuits.

      I am pretty certain that his "fix" to chronic care will be risk pool based and for MS'ers in particular given the long duration of chronic care could be downright devastating.

      In the USA you may well see Stem Cell restorative therapy (coming from Stroke research) before you see stem cell therapy towards prospect cure.

      This may actually make some sense. Restoration and then ablation which would perhaps open aHSCT to a wider demographic?

      Doc Freedman?

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    2. Dr Freedman's study is on 24 patients. It will be interesting to see what comes out of it - but I doubt it will be opening hstc to a wider demographic. In any event, I think I read some reports about Professor Freedman startig MSC trials soon.

      You have Dr Burt in America who preforms non myelo HSCT trials and Dr Nash who performs the US myelo HSCT trials. The Tisch centre is doing MSC trials. My understanding is that some insurers are covering Dr Burt's HSCT trial, though not all are. Many have had the procedure done with insurance.

      Places like Bob's Stem Cell Clinic and Dent Repair don't usually sell "hsct", they sell "stem cells". stem cells have nothing to do with hsct, other than keeping you alive with myelo protocol and speeding up recovery in non myelo protocol.

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  5. Dr. Freedman uses an atomic bomb to kill a wasp, well I have highly active MS and no matter how good the efficacy was I would never ever consider HSCT as a treatment.

    Keep up the good work prof G the most positive thing from this research is that it shows youre on the right track.

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    1. I can totally understand and respect your position, you can have that choice, probably your Neuro will feel safer putting you on CRABS. On the other side when I was diagnosed I pushed for that with most efficacy, at the end i got it, but not without a fight. I just feel the most choices we have the better. The reward for the risk is no small thing, a life without MS as it seems.

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  6. Although finding a treatment in search of a drastic solution for MS, and it seems is getting it (even if very aggressively), for me the answer of what causes MS has not yet come, the interview with Dr. Freedman and the research still not responds.

    "What are the implications of this research?
    This work indicates that the immune system is clearly at fault for causing the damage leading to disability in MS, since if it was due to simply genes or environment, then we would have expected that the disease would return in the time we followed these patients".

    So why, "spontaneously", your immune system turn against you, preferably choosing your Central Nervous System ?!
    As far as I know there is no "abiogenesis" in diseases, they don't originate "from nothing" and "for nothing", or have a genetic cause, or environmental, or interaction between the two...

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    1. Few days back I went to a local MS function and for the FIRST time ever (been to alot of functions past year) I heard, "Right here lay the highest density rates of MS in the world."

      That statement by two clinical folks and a pharma entity. Some 17,000+ active cases in less than a 150 mile radius around lake Ontario.

      I knew that the US National MS Society has considered this a hot spot nearly since the patient associations inception. My fiance's mother was an MS Nurse when nothing existed for treatment and hospitals were racked with people destroyed by MS.

      Back then when she was a nurse (she's 91 now) she said the train of thought was environmental. To be more specific, a highly industrialized region for many years. Chemicals resulting in genetic damage / alteration. From where? Well... Interestingly Western NY not only having been very industrialized also would get what later was deemed "acid rain" from industrialization to the west (Detroit etc). Essentially chemicals airborne from vent stacks, smoke stacks, smelting on and on... Go into the air, over the lakes, end up in rain water.

      Here in Rochester which again, the US National MS Society declared a hot spot way back when (one of only three) we'd had many a industry in the day including Eastman Kodak / Eastman Chemical, many many people worked there.

      Lead also was cited back then. Lots of lead pipes, lead paint etc. Still a problem to this day in fact.

      I am not aware of any specific studies. Aka: Trying see if via family history into current generations had MS / other neurological disorders. Nor am I aware of any mentions of rates of Lupus, Alz's, etc. in the area. Though, even in my small circle of friends / their families past/present neurological/immune issues seem to be pretty common.

      What I am very aware of is a TON of people here have MS. The number of 17,000+ in the near region would mean the 400,000 figure in the USA (which is now thought a low estimate) would have nearly 20% of all MS in the USA pretty much right here.

      -----

      Many folks immune systems turn against them, Lupus, Systemic Sclerosis etc.

      You are SPOT ON (IMHO) of WHY the CNS?

      Something is flipping the Active Immune System towards seeing myelin as an antigen. Immune system ablation followed by the reboot with the efficacy being witnessed anecdotally supports this. Can it flip on again? Probably.

      Are genetics involved? Probably and just recently (literally) science seems support that. Albeit science often finding it was wrong perhaps more often than right.

      A ton of people I question often say they were under high stress prior to symptoms resulting in diagnosis and that is also my story and most relapses I have had seem circle around high mental stress.

      That all said one might think that studies here might take place in respect to finding both historical and current clues to MS. Especially given the fact we have research facilities both here in Rochester and Buffalo NY (60 miles west). But... nothing that I am aware of.

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    2. Autologous HSCT essentially resets the immune system by reseeding the bone marrow with primordial stem cells. The idea that MS is not caused by genes or the environment is not proven by disease free patients after 13 years following HSCT. MS occurs in the majority of patients between 20-40 years of age. If it was strictly an immune system disease without a genetic or environmental component then why are there not more cases of pediatric and juvenile MS?

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    3. i don't think the statement that "his work indicates that the immune system is clearly at fault for causing the damage leading to disability in MS, since if it was due to simply genes or environment, then we would have expected that the disease would return in the time we followed these patients." argues that MS is strictly an immune system disease without a genetic or environmental component - it just says that immune system is the driving force behind disability.

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    4. There are many cases here under the age of 20. A MS Nurse at the same function I noted above last week noted a 3 year old here who was DX'd with MS scant weeks back.

      Perhaps children are less susceptible or it lay dormant. I personally believe for what its worth which is not much is that MS has numerous triggers or entry points. Why should it be different than countless other diseases?

      The concept of MS in ages 20-40 strays along the samelines as the 400,000 or 2.3 million number globally. These are estimates and apparently not good ones. The largest insurer in the USA made statement not a month or so back that given their records they statistically believe in the USA the number is greater than 400,000 and that is not even taking into account government insurers. The number may well be as much as double that. Globally MS is now being reported from places that did no reporting.

      Here at MS Central (Rochester) I can tell you the age range is all over the roads. I was DX'd at 44. At same function was at earlier this week, one person just DX'd at 65 and another at 57. The fact is reporting has and still is haphazard.

      Here, from what the discussion stated. The Neuro who spoke at the event stated, "If presentation is CIS now we move towards a DMT immediately".

      Numbers of patients are growing, not slowing.

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  7. I've started to receive emails from family members about this news. I hope I don't get any newspaper clippings about it in the post.

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    1. I saw the newspaper headline on the Press preview and I thought oh no I'll get the calls and emails. I saw my sister and she mentioned it to me and said "it's not for you". It's a shame everything is sensationalised. After all these years my friends and family know to read between the lines.

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  8. I wish I could afford HSCTFriday, June 10, 2016 7:13:00 pm

    I've heard its now available in the UK for the sum of 65k, good news I guess but a figure out of reach for many. I can understand why people choose to go abroad for the treatment. You cant really put a price on hope.

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    1. It's available off trial in London hospitals if you meet the criteria: http://multiple-sclerosis-research.blogspot.com/2016/01/london-ms-ahsct-collaborative-group.html

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  9. i wish that the myelo camp and the non myelo camp would have an open debate one of these days. each supports their own treatment and each believes the other treatment is too toxic or not toxic enough while the success rate is just wonderful: put them in a room by satellite please and record the debate :)

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  10. Thanks for this post. In how many more decades is this going to be approved for any MS patient? This study started in Ottawa, Canada well over a decade ago. Why just aggressive RRMS in the trial and not a parallel study not been done in PPMS, SPMS, non aggressive-RRMS or 10+ year RRMS? If progression of MS disease, regardless of type, is mainly immune based, then it should work on every type of MS correct? Why has Dr. Burt's trial failed to halt the disease in progressive MS patients with immunoablation/stem cells? It would be interesting to see an arm of their trial being Alemtuzumab vs immunoablation/HSCT vs placebo.

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    1. You're unlikely to see a placebo arm in a trial now, let alone against a highly effective treatment.

      HSCT has been trialled for progressive ms... Saccardi et al, 2005, is just one published paper that comes to mind.

      http://m.bloodjournal.org/content/105/6/2601.full.pdf

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  11. Thanks for the interview and for delving further into the study - media coverage has been wide but not in depth - so always appreciate this blog. Thank you!

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  12. I wonder what Dr. Friedman thinks of the medical tourism going on for those seeking HSCT? He is stressing this is to be restricted to aggressive cases but the HSCT gangsters are promoting it for all cases, even mild MS.

    The gangsters also suggest that this treatment is not gaining widespread investigation because pharma an neurologists are in bed together. But it isn't as simple as that and the medical professionals should be concerned about this.

    If you delete your immune system, you no longer have the capacity to generate a new one because your thymus involutes with age (fewer T cells can be generated).

    This is why cancer becomes more prevalent with age (see for yourself) because the immune system is vital for cancer surveillance.

    http://www.cancerresearchuk.org/health-professional/cancer-statistics/incidence/age#heading-Zero

    So all is good for the HSCTers now but I suspect they are in for a tough road as they age.

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    1. Lol. there is a theoretical cancer risk with high efficacy DMTs too and a known risk with lemtrada.

      There is a cancer risk associated with leaving your house in summer without putting on sunscreen (and apparently if you do put on sunscreen you're risking not getting enough vit D). There may be increased cancer risks with ocrelizumab and there are cancer risks with claradbine. But thank you for reminding me that my partner, who was diagnosed with cancer at the age of 30, can get it again. I suppose you'll want to remind me or warn me that the radiation she received as part of the cancer treatment will increase her future risk of cancer as well? I wish you were there when she was receiving her cancer treatment as part of a clinical trial to warn her that tamoxifen may or may not have an association with demylienation and that induced menopause as a treatment for estrogen based cancer (then in clinical trials, now approved as treatment) may or may not worsen the MS which she may or may not have had at the time she was receiving her chosen cancer treatment.

      By the way, she spoke to her oncologist and cancer surgeon at length prior to receiving any MS therapy (she has received 2 treatments since diagnosis). She then spoke to her heamo about the same issues. So did her neuro.

      Prof Freedman performed a highly toxic myelo hsct on 24 patients over 13 years. Dr Burt has and continues to perform a less toxic non myelo ms on far more patients with less stringent criteria than Prof Freedman's study. Is Dr Burt more reckless than Prof Freedman? Or does he use a different type of hsct and believes that the lesser toxicity makes it appropriate for more people, though not everyone?

      What would either of them think of medical tourism? The same as Barts i suspect - don't do it outside a clinical trial and don't travel for it.
      But of course, comments that seek to put others down for choices they've made are often more about the commenter's own defences and biases, then the people they are seeking to judge and remind of foolish cancer risks.

      As far as mild ms is concerned- I've heard this phrase reported a lot by Australian patients who say their neuros are telling them their ms is mild when they are talking them into having gilenya (neuro's choice) instead of lemtrada (patient's choice). I've looked up "mild" MS in scientific studies and I even asked Barts what this mild MS business is - and I'm still waiting for an answer. Perhaps it means MS without a lot of worrying prognostic factors, or perhaps it means MS which is not highly inflammatory or perhaps it means that the level of disability people are experiencing or fearing does not justify the treatment choice – but as I have not found a scientific explanation of “mild MS” I have no idea what that means.

      We all die from our own poisons, MS or otherwise. Why be so

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    2. Has there been any information on Professor Freedman proceeding with phase 3? If not, why not? All I've seen recently is news about Prof Freedman's upcoming MSC trial nothing about phase 3 of his myelo hsct trial.

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    3. It's really not a foolish cosiderattion and won't show its face for many, many years down the road:

      http://www.sciencedirect.com/science/article/pii/S1044532307000802

      But I suspect your glib response is indicative of why you are a Bozo.

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    4. Isn't the increased cancer risk with Lemtrada and Cladribibe theoretical? I've read that the incidence of melanoma and thyroid cancer are 0.3% each with Lemtrada. Cladribine on review was shown the have an initially falsely perceived risk but only because the placebo arm of the trial had 0 cancers.

      As you state Bozo Forgot, any DMT that alters the immune system creates a cancer risk. And since its cumulative, one has to weigh up the risk of lifelong DMTs against a large but one time treatment with HSCT.

      The cyclophosphamide is the backbone of most HSCT protocols. This is *known* to be incredibly toxic and is a reason why Cytoxan isn't used routinely as a treatment in Australia, despite the fact it is more effective than many DMTs.

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    5. Yes, all immunosupressants can conceivably increase your risk of cancer over long time scales and this risk doesn't show up in two year trials or follow up observational data that Bozo mentioned by Dr Burt.

      The truth is nobody knows what will happen in their old age (will the cancer rate be 100%?) but this is of no concern at this specific moment.

      This is analogous to what happened in the development of Natalizumab (Tysabari) in which there were no cases of PML in the 2 year trial but only started to occur years after.

      So by the time the effects of pre-mature immunosesence (witch HSCT and immunosupressants cause) becomes an issue, there is nothing that regulators would be able to do except maybe black box the label. At this point hopefully actual treatments to address the disease will have been developed and the immunosupressants will have been delegated to the dust bin.

      So if you want to understand what immunosesence is here is a good article that describes it:

      http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1931833/

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    6. Snoop Dog - I have to admit that in my 36 years I have been called many things bug insincere or shallow has never been one of them. Thank you for broadening my resume lol, I feel quite smug about it.

      I'm quite fond of Bozo Forgot, I've used the name for very long time now. I'm glad you like it.

      Anonymous save for skin cancer associated with Lemtrada, I don't necessarily disagree with you. My point wasn't that cancer risks are equal across the spectrum of treatments but that decisions are a bit more complicated than a linear measure of risk. My partner's perception of risk and value was changed by the cancer experience - whether 'for better or for worse' or rational or otherwise is besides the point. it's been a long 12 years that started well before cancer and ms and she is where she is as a result of decisions she made along the way (and she likes where she is). i can say that she ultimately received non myelo hsct with her neuro's support, that she thought long and hard about the decision and that we played with whether she (and we, but we is really she) felt ready to face whatever scenario came after it. she consulted with no less than 8 specialist doctors about her decision, including 4 neuros. she knows it's all guesswork at this stage and she's rolling the dice: but at this stage, with everything she's been through in the last 12 years i'm confident it's her dice to roll.

      playing the 'mysterious' cancer risk as the biggest unknown associated with hsct just irks me. there is a definitive risk, some of which is quantified as much as is possible to quantify such things. but suggestions that my partner rushed into hsct gangster like without taking seriously or considering the cancer risk is just insulting to her experience. she also doesn't disparage anyone else's choices, even if she doesn't make the same choices herself.

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    7. Yes there is a risk of getting cancer in the general population as we age, but immunosuppression and in particular HSCT will in many people's view shifts the odds.

      You say you have weighed the cancer risks but that is a baseless analysis because you don't know what these risks are in the longterm after HSCT treatment.

      So the alternative is to try to understand mechanistically how the immune system functions and how defects in this system such as immunosenescence effects this in terms of cancer surveillance.

      This is what researchers on this spearhead are looking at now and they are beginning to understand this interaction.

      So it really comes down to being fully up to speed on the possible consequences of a given therapy, nor just restricted to what is available to clinicians. After all, going back to my Tysabri analogy, the so called experts had no issues doling out this drug, but I'm sure there were those who predicted the PML fiasco just by looking at it from a practical point of view.

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    8. Snoop Dog, I'm beginning to wonder if you can read because I've answered all the points you've raised, (including that decisions are often more complicated than a linear risk).

      How can we possibly not be aware that chemo involved in HSCT protocols, whatever the protocol, (or radiation or 5 years of early menopause) will age her central nervous system or indeed the body? She is 40. She had cancer when she was 30 and treatment which lasted 5 years, each aspect of which increased her future cancer risks in addition to the genetic and environmental components that already increased her particular risk relative to general population?

      We had read and discussed the issues raised in http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1931833/ with her haemo and her oncologist, both in the context of myelo HSCT and non myelo HSCT, and before that with her oncologist and breast surgeon in the context of her contemplated treatment during cancer. Bozo Forgot is touched by your trolling concern though lol.

      While non myelo HSCT has definitive risks and things to be concerned about, and premature aging of the immune system due to agents used is just one of the many things to be concerned about, it does spare the actual bone marrow from damage. The immune system is not "literally" reset - instead of waxing you are shaving and just repopulating in an incredibly short time. What kind of effects will this show relative to a 5+ year course of Tysabri or relative to myelo HSCT? - I don't know, hopefully we'll find out in about 15-20 years.

      I do know that my partner is happy and able today and that she has led an incredible life, particularly over the last 10 years. About 5 years ago, we were sitting on top of the Florence hill, on the second bottle of red wine and a thought popped in my head that if I was to die now I would die happy with the life I lived, despite losing sight of the incredible view in front of me. I was really content. I had a similar experience climbing a volcano in May this year, about 5/6 years later. It made me happy: instead of feeling the mortality pinch and hurriedly comparing it with the list bucket list of life we didn't want to miss out on if we had to leave early, I was content. Our life list keeps shortening and growing and changing, but it's no longer a bucket list, there are so very few items left that 'must' be done. There is really only one: live the next 10 years as well as we have lived the last 10, enjoy the next 10 years as much as the 10 before and regret nothing. I so can't wait for the next 10 years, with everything we have planned, it should be an incredible ride. Feel free to ask me again in 10 years how it's all going - unless they've found the cure to MS, I should still be around these types of forums.

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    9. We dont know the long term risk of HSCT, alemtuzumab, claribidine and many other DMTs... but we DO know the risk of having MS for a long time thats for sure, as a patient you have to put that on the balance, we cant just wait and lose brain in the process.

      ¨He who is not corageus enought to take risk will acomplis nothing in life¨ Ali.

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    10. Hey Bozo,

      I have no issue with your partner's choice of HSCT. That is your partners decision. I could not give a damn one way or the other.


      But what I have said before that raised my initial comment is there is a faction of the of the HSCT gang that is promoting this treatment for all forms of MS (from mild to progressive). And some are promoting it as a cure for the disease. But clearly in any of the legitimate trials it is restricted to aggresive MS with signs of inflamation. Why is this? Why are researchers hesitant to support this when their patients come to them with this? The ganstas believe it is a conspiracy.

      Sure, if the Bozos of the world have the money and have weighed the risks to travel overseas for treatment, more power to the Bozos. But everytime these questions are brought up about what long term effects this might have, the HSCT Bozos don't want to hear about it, even if it is just a theory. So maybe the HSCT Bozo movement is nothing more than a fanatical cult much like the CCSVI hype was a few years ago. But if I was considering this treatment I would want to hear all sides and decide for myself.

      Good luck to you and your partner in the future Bozo.

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    11. You wouldn't be Dr Dre under a new (old school rapper)name by any chance?

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  13. https://en.wikipedia.org/wiki/Name_calling

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  14. Hey Snoop.

    New name, same old trolling! Frankly, you can stick your unjustified condescension right up your crimper – in the nicest possible way, of course. 

    HSCT, and the other high efficacy induction therapies offer MS patients - particularly those with early disease - a *chance* at getting their lives back, after diagnosis with this horrible disease. It’s not right for everyone, nobody is forcing it on anyone, but certainly nobody should consider you an authority on this topic, sufficient to tolerate you calling THEM a “bozo”!

    For any chemo, there is going to be an increased risk of malignancy. However, this has to be weighed against a very decent prospect (for RRMS patients) that you can live a normal life without relapses, lesions, detectable progression or (perhaps) accelerated BVL - for the foreseeable future (i.e. 10-15 years, and counting, NEDA status for many post-induction patients).

    Noting that such induction therapies generally select for those patients at the most aggressive end of the MS spectrum.

    Even if this lasts for “only” 10 years, who knows what advancements will be available by then. Moreover, advancements aside, induction therapies offer some hope (not definitive - but hope, for sure) of at least a functional (if not biologically complete) "cure".

    Unless you have MS yourself – which, from your comments, I highly doubt - I'm afraid you are incapable of fully grasping the psychological, societal and financial value of such a gift - in terms of both hope itself, the ability to “forget” about MS day-to-day, and a second chance to really live out the prime of your life, without the daily symptomatic burden of this disease.

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  15. All of that aside, if we look at this plainly and simply; RRMS typically emerges in the early 30s, and transition to SPMS takes an average of ~10 years. So the choice here, for most of us, is regretfully not one of “induction therapy vs perfect health”.

    The risk we’re all weighing is of a long and despairing life of (statistically probable) relentless progressive cognitive and physical disability - and all of the societal/family/empoloyment/psychological impacts that come with that – VERSUS - a relatively high probability of avoiding that fate in the prime of your life, and living a healthy, enjoyable, productive and full life – potentially indefinitely - but with a theoretical/unquantified increased risk of malignancy in your latter years due to premature immune senescence.

    You also need to factor in to this calculation that the baseline risk of both cancer and malignancy – even if you steer clear of any immunotherapy whatsoever – is circa 50% (lifetime cancer risk for anyone born after 1960 in the UK), and a near-certain risk that they will, at some point, also suffer the effects of immune senescence.

    Nobody would wish to increase their risk of cancer, but if the price of living into my 90s is one of enduring misery due to the onset of progressive MS and relentless decline into disability and destitution from my early 40s - that's a pretty shit deal!

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  16. Re thymic involution, this is a complex topic which you spout relentlessly without doing justice. Many studies indicate that the thymus is somewhat plastic, and that thymic involution can– to a degree – be reversed. Indeed, in Muraro’s paper on immune reconstitution post-HSCT, he notes not only thymic rebound (i.e. hypertrophy – the opposite of involution), but also that a MORE DIVERSE T-Cell repertoire emerges post-HSCT than before treatment!

    In a similar study of immune reconstitution post-HSCT in Lupus patients, they concluded that T-cell reconstitution post-HSCT saw continued generation of new naive CD4+ T cells for up to 8 years post treatment.

    In the regenerated patients, absolute naive CD4+ T-cell counts continuously increased to levels twice as high as those in age-matched controls, resembling those in young children.

    All of which collectively supports the notion that, after immunoablation, the naive CD4+ T-cell compartment is regenerated by thymic reactivation rather than by lymphopenic expansion of surviving naive T cells. I fully appreciate more studies are needed on this, and that CD8+ recovery (at 1 year) is skewed far more towards clonal expansion than CD4+.

    But, I think, it is fair to say that your argument is rather speculative/sensationalist, and not grounded in a particularly strong understanding of the facts. Also worth noting (re your claims that there is some time bomb waiting to happen) that HSCT using far more ablative regimens than used for MS have been carried out for hematological malignancies for approaching 60 years, to the tune of 2-3 million treated patients to date. It is a therapy administered by pretty much every oncology center worldwide, on a near daily basis – with the same biological goal (lympho-ablation and reconstitution). Hardly some recently discovered/poorly understood experimental therapy on a par with CCSVI, as you continue to claim.

    I’m sure HSCT may accelerate immune senescence to a degree, but I’d suggest anyone considering the treatment takes their advice on the extent of the associated risks relating to that from a qualified haematologist/immunologist, rather than your puddle-deep armchair understanding!

    Respect and good luck to everyone and their personal treatment decisions, whatever they may be.

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  17. Re:" We describe the first treatment to fully halt all detectable CNS inflammatory activity in patients with multiple sclerosis for a prolonged period in the absence of any ongoing disease-modifying drugs." This sounds like a cure for MS. Yes, it is the most aggressive form of treatment but zero Gd enhancing lesions or new T2 lesions and normalization of brain atrophy after 13 yrs. Would Barts MS team agree?

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    1. Yes, it's very impressive but as you will appreciate, the procedure is extremely gruelling and the numbers treated so far are low. It's interesting that some developed thyroid problems as seen with Lemtrada perhaps indicating a propensity to develop B cell dependent autoimmunity down the line.
      Certainly it would seem to be an option for those with aggressive MS.
      It's a great piece of work.

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