Monday, 24 February 2014

Bone marrow stem cells to replace the immune system effectively silences RRMS

Are you prepared to have a bone marrow transplant? #MSBlog #MSResearch

"Bone marrow transplantation (BMT) using your own stem cells is the ultimate human experiment in an autoimmune disease. The hypothesis is simple; let's ablate or destroy your immune system and then let your immune system reboot from scratch using harvested stem cells. It sounds straight forward but it is not. firstly, it is very difficult to destroy your immune system so  that when it reboots there is a chance the autoimmune cells will repopulate, i.e. your MS will return. Whilst you are waiting for your immune system to recover you are at high risk of complications from the treatment, i.e. infections, bleeding and anaemia. During this period you need bone marrow support. I did my house job on a haematology oncology ward and I used to look after the bone marrow transplant patients. Boy do they get sick and sick quickly. BMT is not for the faint hearted."


"It is very difficult, if not impossible to do randomised double-blind placebo-controlled trials to test BMT as a treatment strategy. Therefore we have to rely on observational data and compare it with natural history data of MS to get an idea of its effectiveness. The Swedish study below is in keeping with other country-wide data; BMT is a very effective treatment for highly-active RRMS. The problem is if you use this treatment in SPMSers that don't so as well; i.e. it may stop relapes and MRI activity but it does not stop non-relapsing progressive disease. In fact the chemotherapy that is used to ablate the immune system is often neurotoxic (damages neurons) and may make hasten disease progression. We showed in collaboration with the group in Rotterdam that chemotherapy in BMT increases the amount of neurofilament released into the peripheral blood and the level of neurofilaments correlated with disease progression. Neurofilaments are a structural protein inside neurons and axons and are released when the neuron or axon are damaged."

"Would you take the risk of BMT? You need to remember  that BMT is the ultimate induction therapy and potentially offers a cure. Similarly, to alemtuzumab therapy, we need to wait 15 to 20 years to see if these MSers rendered NEDA (no evident disease activity) are cured or will they come back with SPMS?"

"How does this fit in with the EBV hypothesis? Not sure, but BMT destroys the B-cell pool and hence targets EBV. There are some reports of people becoming EBV negative post BMT. So the fact that BMT works as a treatment for MS does not exclude EBV as a potential cause of MS."


Burman et al. Autologous haematopoietic stem cell transplantation for aggressive multiple sclerosis: the Swedish experience. J Neurol Neurosurg Psychiatry. 2014 Feb 19. 

BACKGROUND: Autologous haematopoietic stem cell transplantation (HSCT) is a viable option for treatment of aggressive MS. No randomised controlled trial has been performed, and thus, experiences from systematic and sustained follow-up of treated MSers constitute important information about safety and efficacy. In this observational study, we describe the characteristics and outcome of the Swedish MSers treated with HSCT.

METHODS: Neurologists from the major hospitals in Sweden filled out a follow-up form with prospectively collected data. Fifty-two MSers were identified in total; 48 were included in the study and evaluated for safety and side effects; 41 MSers had at least 1 year of follow-up and were further analysed for clinical and radiological outcome. In this cohort, 34 MSers (83%) had relapsing-remitting MS, and mean follow-up time was 47 months.

RESULTS: At 5 years, relapse-free was 87%; MRI event-free 85%; expanded disability status scale (EDSS) score progression-free survival 77%; and disease-free survival (no relapses, no new MRI lesions and no EDSS progression) 68%. Presence of gadolinium-enhancing lesions prior to HSCT was associated with a favourable outcome (disease-free survival 79% vs 46%, p=0.028). There was no mortality. The most common long-term side effects were herpes zoster reactivation (15%) and thyroid disease (8.4%).

CONCLUSIONS: HSCT is a very effective treatment of inflammatory active MS and can be performed with a high degree of safety at experienced centres.

25 comments:

  1. I am not sure if I quite understand this. Does HSCT slow down MSers abnormal speed of brain atrophy (cognitive decline) as well?
    This would be a decisive point for some of us.

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    1. Re: "Does HSCT slow down MSers abnormal speed of brain atrophy (cognitive decline) as well?"

      There is accelerated atrophy in the first year; we think this is pseudoatrophy and possibly related to neurotoxicity from the chemotherapy. After the 1st year the rate of atrophy appears to stabilise at a rate compatible with normal ageing. This data has been presented by Prof. Mark Freedman, Ottawa, at several meetings but has yet to be formally published.

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  2. If I had highly active disease, I would opt for HSCT. There are two types of HSCT. The first of which is myeoblative which is more thourogh in destroying your immune system and requires that you undergo re-immunisation such as that for an infant would need.

    The second type is non-myeoblative which is much less aggressive and does not require re-immunization. Dr. Richard Burt of Northwestern University is conducting a non-myeoblative trial right now for those who fail standard of care including Tysabri. The other acceptance criteria is evidence of inflammatory disease.

    We will have to see the result but from what I have heard it is effective and safe. I would be interested if his protocol produces neurofilliamant in the blood.

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    1. Guest post with Dr. Burt at Northwestern would be interesting.

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  3. Why is the thumbnail for this article the same as the one for "Natulizumab after 5-10yrs"?

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    1. Because HSCT, Tysabri, Campath, etc. are all running experiments. If the disease is halted after a long period (15-20 yrs.) MS is an autoimmune disease and these therapies are basically cures for early RRMS. However, if progression continues after a long period, MS is something else.

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  4. Prof G,

    You keep referring to the 15-20 year experiment i.e. If induction of NEDA results in a cure (no longer comes back) or if the patients succumbs to SPMS anyway regardless of NEDA being achieved. If the latter turns out to be true, what caused the neurodegeneration? Is it right to use people for such an experiment. In 20 years time you'll be with your pipe and slippers enjoying a retirement. I'll be going to neuro appointments dreading the words you're now SP. Surely, researchers can't stand idle for the next 20 years!

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    1. Re: "You keep referring to the 15-20 year experiment..."

      The original alemtuzumab cohort from Cambridge is on average over 10 years of follow-up. Some of the orginal BMT cohorts are in the same time period. Let's hope it is good news when these get published.

      Biogen-Idec have just stopped their long-term follow-up. Why? Some of my colleagues have suggest that it is because a large number of MSers in this group were entering the SPMS phase. Biogen-Idec have offered a different reason.

      Don't tell my wife, but I don't intend retiring. There is a chance I will still be around in 20 years time.

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    2. Dear Mrs G,

      Your husband is not planning to retire. I'm guessing he enjoys doing the Times crossword with Prof Mouse and occassionaly helping with cleaning out the mice cages. Please encourage him to put down his tuning fork at 60. If the NEDA experiment fails / EBV theory doesn't pan out, we need fresh ideas from the new Turks of neurology.

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    3. I have my "marigolds" and a camera waiting to see the cleaning,

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    4. What is the reason Bigen-Idec have proffered as the reason for not completing the long term follow up of Alemtuzumab and is this the same drug as Campath and lemtrada?

      Regards as always.

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    5. The reason Biogen Idec would not do anything about long term follow up of Alemtuzumab/Lemtrada/Campath-1H is that it is not their drug.

      I suspect that ProfG meant the follow up of natiluzimab, which is a biogen product.

      Will that stop progression we will find out as the ASCEND trial is ongoing, I suspect that its best activity will be to change the slope of progression and doubt it will stop progression given that every immune-modulator has not stopped progression.

      Why say that.....because people in clinics have seen people on Tysabri who appear to progress.

      Surely there is a duty of care to have this data available as it helps choice.
      To allow pharma not to publish stuff because they don't like the answer would be a bad result but without proper database show will this happen.

      However what is the comparison too, historical data as we have seen this can be problematic

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    6. Maybe they are worried that people drop out, switch that biases the studied however there are an awful lot of people on the drug.

      The question we also need an answer to is if stopping relapses, stops or slows progression. Then we need to know is how early is early and do we need to start after diagnosis Natalizumab is first line it is also second line there must be data that is informative, but who has access to this and who collects this. If Pharma have control of the data you will probably only what they want you to see.

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  5. Relevant article.

    http://www.ottawacitizen.com/health/Ottawa+doctors+behind+breakthrough+multiple+sclerosis+study/8189161/story.html

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    1. The work by Freedman & Colleagues appears still not to have been published one year one

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    2. Why do you think that is?

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  6. Just a question? How long did they study bone marrow transplants for leukemia patients before approving them? No one with MS has 20 years to see what the results will be! There is a huge group of people wanting to have it done, and wanting it to be approved by the FDA and yet we seriously believe the big pharmas lobby against it, because once you go through HSCT, you no longer need their drugs or any other drugs! Two years of Copaxone would pay for the HSCT treatment in Chicago, Denver or Seattle. I would willingly give up the medicine as a trade off for my insurance company covering the cost and not forcing me to go to another country to have it done.

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  7. There is also emerging evidence that it is beneficial for SPMS, at least early; the factor relating to its success is EDSS. Even Dr. Burt's original studies admitted that in early SPMS where EDSS was <6.0, none of the 9 patients studied progressed. Also, he is alone in not treating SPMS with HSCT. Russia, Israel, Heidelberg, and India, among others, treat this evolutionary form of MS, with success. Moscow's recently published data of 52 SPMS patients with low EDSS scores, 4.0 or less, showed remarkable PFS for 5 years. (72%) And other studies have a similar SPMS PFS to five years of 70-75%. So, I disagree with the theory that HScT only causes progression/neurotoxicity. As mentioned above, early atrophy is pseudo atrophy and a recent review in a neurology journal (ref. to follow) showed atrophy approaching normal population's after three years. In addition, some of the early atrophy studies involved early aggressive chemo or TBI/busulphan and other such long abandoned regiments. The literature review is replete with HSCT's effectiveness in low EDSS SPMS.

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  8. I am sure I am not alone in finding it a bit suspect that they have not published the results of this life-changing MS treatment.
    Most researchers want to publish their results and share the good news.
    Why are these holding back?

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  9. Eight neurologists have looked at my MRI and said that it is typical of an MS patient but I have been symptom free for at least 12 years. I had a bone marrow transplant for cancer 25 years ago. It would be interesting to find out what percentage of people with MS lesions who are symptom free had bone marrow transplants. I realize that some people with with lesions do not have MS and that looking at the statistics would not be scientifically valid because it is not a double blind study but givrn the difficulty of the BMT research, this would seem to be worthwhile.

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  10. Hi I heard the BMT-based therapy was being extended, I was wondering how can I get my sister to participate. Thanks for any help you may be able to provide

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  11. Hi my uncle is suffering from BM biopsy I need the good hospital details in Bangalore Just I want to know wat will be the procedure for diagnosis for Bone Marrow Transplant

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  12. Autologous Bone Marrow Transplantation in Multiple Sclerosis: Biomarker Relevance for Patient Recruitment and Follow up
    J Clin Cell Immunol 2016, 7: 455. 7:0, (2016)
    http://dx.doi.org/10.4172/2155-9899.1000455

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  13. Recommended to expand the knowledge on the subject.

    Autologous Bone Marrow Transplantation in Multiple Sclerosis: Biomarker Relevance for Patient Recruitment and Follow up
    J Clin Cell Immunol 2016, 7: 455. 7:0, (2016)
    http://dx.doi.org/10.4172/2155-9899.1000455

    ReplyDelete

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