Thursday, 14 May 2015

HSCT-The Hamburg Experience

Stellmann JP, Stürner KH, Ufer F, Havemeister S, Pöttgen J, Ayuk Ayuketang F, Kröger N, Friese MA, Heesen C. Stem cell transplantation for multiple sclerosis : Hamburg experiences and state of international research Nervenarzt. 2015 May 10. [Epub ahead of print]
BACKGROUND: Autologous hematopoietic stem cell transplantation (aHSCT) is still not the standard treatment for highly inflammatory multiple sclerosis (MS). Even though randomized controlled trials are lacking, predictors for treatment response have been established. Since 2007, ten patients have received aHSCT in Hamburg.
OBJECTIVE: To present observational data from patients treated in Hamburg and a review of the literature.
METHODS:Descriptive statistics were used for evaluating the course of the expanded disability status scale (EDSS) as a measure for clinical outcome, magnetic resonance imaging (MRI) and neuropsychology. New gadolinium and T2-MRI uptake lesions per scan were compared.
RESULTS: The Hamburg series can be divided in two groups, one group including four patients with chronic progressive MS with low inflammatory activity (median EDSS = 6.25, 0.5 relapses per year, no gadolinium-enhancing lesions) and the other group including six patients with mild to moderate disability, relapses and inflammatory activity (median EDSS = 4.25, 1 relapse per year, 2 gadolinium-enhancing lesions). The median follow-up was 2.4 years. While the first group did not seem to benefit from aHSCT, an improvement in five out of six patients was observed in the second group. New T2 lesions occurred within the first 6 months but gadolinium-enhancing lesions were not observed (p < 0.05). A systematic literature search identified a higher efficacy of aHSCT in younger, less disabled MS patients with inflammatory activity, similar to the findings from Hamburg.
CONCLUSION: Cohort reports describe aHSCT as a safe and efficient treatment option in highly inflammatory MS. Based on these data aHSCT seems to be a reasonable option in selected patients with highly inflammatory MS but a randomized controlled trial is warranted.
The article is German but the abstract seems to to reflect a view that HSCT is most active in RRMS. HSCT may not be inert in progressive MSers but it is probable that people with active MS lesions & relapses could be a subset of progressive MSers that could benefit, but more is clearly needed to get progressive MS under effective control. 

16 comments:

  1. Looking at the diagram alone, it seems that being struck by lighting is potentially beneficial? Okay, I should probably bother to read more of the text. Or perhaps I should try (quoting the genius of Terry Pratchett) standing on a hilltop in a thunderstorm wearing wet copper armour and shouting "All gods are b*******!" Actually, with PPMS, I think I'd prefer that to HSCT.

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    1. HSCT has potential but we just have to realistic that for PPMS/SPMS you probably need more or if I say what I currently think you need more. HSCt may be part of that equation but it may not be.

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  2. I think the concept of HSCT assumes your immune system regenerates after the process. However, the is dependent on the function of the thymus which is the organ that new t cells are generated in.

    It seems that as you age the thymus becomes less productive and in some patients your CD4+ t cells never fully recover. If you don't care about having these cells I guess that is OK, but it raises the question of what is the longterm consequence of this? Cancer surveillance would be my concern.

    Here is an article describing this:

    http://www.ncbi.nlm.nih.gov/pubmed/15776111

    I think for progressive MS there is obviously other mechanisms involved besides the adaptive immune system which is why most researchers have concluded this as well as other immunosuppressive therapies are not appropriate.

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    1. I think you are misguided to conclude that "most researchers have concluded this as well as other immunosuppressive therapies are not appropriate".

      On what basis do you say this? Where is your evidence? This maybe your opinion but that is all it is.

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    2. You do still produce T cells from the bone marrow after Thymic involution just less than you produce when the thymus is fully active before puberty.

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    3. So tell me one therapy that has been approved for RRMS has been shown to be effective in PPMS? Since the answer to this question is none and all RRMS therapies function by suppresiing, sequester in or modifying the adaptive immune system I think this is a fair conclusion .

      But I guess I should have stated that the vast majority of researchers believe this to be the case. Just like the vast majority of climate scientists believe global warming is real. It's only those on the lunatic fringe that see things in a different way. I guess you must be part of the later category.

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    4. Yes your bone marrow still has the capacity to produce t cells. The point is these cells have to go through the thymus for positive and negative selection before they are released to the periphery.

      Are you saying Team G thinks t cells go straight from the bone marrow to circulation? This wouldn't surprise me.

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    5. No. The thymus is still there but is much smaller but presumably still able to influence positive and negative selection. if it wasn't still functional post puberty for selection presumably adults would develop autoimmunity and though some do, the majority don't.

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    6. I agree that immunosuppressive agents do not stop progression and there are other mechanisms. I have spoken to BartsMSblog and they misread the comment and they didn't notice the comment was about progressive MS. So Barts mistakeas the comment wasn't about MS drug naysayers . However I think it is unwise to to say that immunosuppressives do nothing in PPMS/SPMS because it is clear that at least 15% or more have relapsing activity, relapses are occurring in SPMS for years and therefore this aspect will respond to current DMT. This was seen in the recent fingolimod treat and I suspect this will be seen in the up coming ascend trial with tysabri.

      Why are they not used this is because of risks and they are not considered cost effective and so seldom used (if this is what you mean researchers think is not appropriate) but once a cheap safe option is found it should be a the bedrock for neuroprotectives, because adaptive immune responses are a feature of MS and I am sure this is part of the positive responses claimed with HSCT.

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    7. T cell selection can also occur in areas other than the thymus.

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    8. "...with each decade of patient age, the percentage of patients demonstrating a vigorous recovery of naive T cells and even the rate of that recovery declined (Figure 3C). For example, recovery of naive cell levels to 200 cells/μl occurred within 6–12 months after transplant in patients in 3 of 5 patients in their 30s. In the 3 of 13 patients in their 40s who achieved a level of 200 cells/μl, this degree of recovery was delayed into the second year.
      No patient over 50 years recovered a level of 200 naive cells/μl within 2 years after transplant."

      It seems in older people the reconstruction of your t cells is many due to the memory cells as opposed to recent thymic emigrants.

      The notion that HSCT eliminates all of your t cells is a falacy. If you don't believe me listen to Dr. James Bowen regarding this subject:

      https://youtu.be/1EMKoaBysOk

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  3. Given the high failure rate of hsct is it surprising the view that not all t cells are elliminated.
    No to smug anon 11.35 where is the evidence published about what most researchers think. I see papaers upon papers about T cell therapies and neurportotection aiming for progressive disease its half the EAE output

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    1. If T cells are not being derived from the thymus after HSCT as suggested in the article above then where are they coming from? The stems cells extracted before the procedure? Good thought but these are not t cells.

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    2. There may be residual cells left after HSCT and there can expand and repopulate

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  4. So of the autoimmunities that alemtuzumab causes, I assume that the thyroid and kidney autoimmunities are one shot deals - once they've taken the target organ out, it's gone. ITP sounds like it can potentially last for much much longer and can be resistant to treatment.

    So if you get ITP and lose NEDA after alemtuzumab wod HSCT potentially sort out both the Inflammatory component of MS and the ITP?

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    1. Possibly if it gets rid of the anti-platelet antibody producing cells.

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