Wednesday, 27 June 2018

Stem cell therapies for MS - why we need to get it right

Hi, my name is Niall (pronounced Neil) and I'm a neurologist working with people affected by MS in the West of Scotland area.

I grew up in Lanarkshire and I became interested in MS when I was working as a trainee in Dundee.  It's a complex disease and looking after people affected by MS in clinic gives you a chance to get to know them a bit over the years which is quite nice.  It's also fairly sad when you see how much damage uncontrolled MS can do to a person.





Socially, outside my doctor life, I know about 7 or 8 people who have MS.  Friends from when I grew up, people I went to uni with, parents of friends and spouses of friends. MS is everywhere and you can't tell just by looking at someone.  It's part of everyday life.


We are getting better at treating MS but we have a lot of work to do.  Often people are scared as they are in a very uncertain situation and they will look to non-mainstream places for treatment.  I could tell you some heartbreaking stories but I won't.


We really need more effective treatments for late stage MS and progressive MS.  We need something that will stop MS and ideally repair damage.  We don't have that yet.  Some people claim that stem cells are the answer to everything.


Sadly we are not there yet.

I look after a number of people who have gone abroad and paid privately for what they have been told are stem cell treatments.  Some of them have paid up to £60,000 for treatment. Unfortunately, I have not seen any real evidence that these treatments have helped although some people do report a benefit. I'm just upset that a person has spent their savings on a treatment which, to my eyes, does not appear to have helped.


I would advise anyone thinking about travelling to pay privately for treatment to think long and hard about it.


The recent stem cell trial from Sheffield is impressive but some points should be considered.


1 - It was very small - only 55 people were given stem cells

2 - The control group wasn't very good - again, only 55 people on an inconsistent set of treatments
3 - The trial was for people with highly active relapsing remitting MS, not progressive disease.
4 - While disability scores improved in many people this is not unusual in relapsing remitting MS as a person recovers from a relapse.
5 - We cannot say this treatment is any better than alemtuzumab

In this procedure stem cells are taken from the patient and stored.  The remaining bone marrow is then destroyed with toxic drugs which obliterates the immune system.  The stored stem cells are then given back to the patient in a drip, replacing the old bone marrow and allowing a new immune system to form. There is a risk of life threatening infection and the toxic drugs could make you sterile.


If stem cell treatment was a drug, it would never be licensed with this evidence and we wouldn't be allowed to use it.


We need a bigger trial and I think this will be happening in the near future.


Ideally this trial would

1 - compare autologous haematopoietic stem cell transplantation with alemtuzumab
2 - have large numbers of patients (ideally several hundred on each side)
3 - happen in centres throughout the UK
4 - initially focus on RRMS but then be repeated in PPMS and /or SPMS

I think that stem cell transplantation will turn out to be a very good treatment for early relapsing remitting MS but I cannot predict that it will be better than alemtuzumab. Sadly, there is no evidence that stem cells will repair established damage.  A large, well conducted trial is needed.


If a larger trial proves that stem cell treatment is as good as or better than alemtuzumab I think we will use it widely.  Overall this treatment approach may prove to be much cheaper than many of our drugs.  


I just want us to get it right.  We need to know that stem cells will work for people with MS so that we can use this treatment routinely in the NHS. I don't want to see more people spending their life savings on treatment of dubious quality in another country when there is not enough evidence for us to know that it works.


Right now we do not have enough evidence to routinely recommend stem cell treatment.



For more information:

The MS Trust have a page on Stem Cells for MS.

The Euro Stem Cell and the Closer Look at Stem Cells websites both give more objective information on the issues surrounding stem cell treatments. This patient handbook is pretty good.

Please share your thoughts, experiences and questions in the comments.

14 comments:

  1. Hi Niall
    Yesterday I saw my neurologist to ascertain whether or not Alemtuzumab was proving effective, and luckily for me last weeks mri shows no sign of disease activity.
    In preparation for the opposite results I had produced some bullet point notes to inform our discussions concerning the rationale of further treatment with Alemtuzumab or HSCT. Significantly drawing on this site I'd noted that I do not wish to have stem cells, largely due to the impact of chemo on neuro reserve (especially pertinent as a 54yr old) and the lack of head-to-head studies.
    As I contemplate this, after reading your post, I am struck yet again, with how incredible fortunate I am, how very lucky to have met the criteria for Alemtuzumab and to have responded to it!
    But when I think about how I'd feel if there was nothing available to me as I watched myself drop to bits, then I know I would contemplate courses of action such as going abroad for treatment. Also, though rarely highlighted we do not have ms in isolation and the impact on my family and friends, most especially my husband and son to yesterday's good news was striking. Do I think that they too would be keen for me to seek treatment elsewhere, in different circumstances, yes I do!
    Pandora's box has been opened and there's no closing it now - HSCT is out there - real or fake and I have to assert that the position statement of: clinicians can't routinely recommend stem cells is somehow missing the point. Perhaps, it will be better providing clear advice what is involved in having HSCT and on where abroad provides the genuine treatment for those patients clearly determined to pursue that course of action.
    Yesterday in my delight I thought about the others with ms not in the same boat. Ever since reading a post by ProfG it has haunted me and it came to mind again - a young woman he saw devastated she has disease recurrence after stem cell treatment abroad. Had she been fully informed she may have gone ahead anyway and would still have been distraught with what ProfG had to tell her, but it wouldn't also have been a complete, nasty surprise!
    I hope that the improved trials and comparison with Alemtuzumab go ahead quickly, but PwMS don't have the time to wait.

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  2. Hi Fi

    Many thanks for taking the time to read my post and comment

    I am glad that alemtuzumab has helped you.

    For years, doctors have used various treatments with poor evidence and have done untold harm to patients. Books such as Bad Pharma or Bad Science by Ben Goldacre discuss these issues very well. While HSCT is out there, we have a duty as doctors, to do our best to protect the people who come to us for help from harm. Any treatment that works can also cause harm and we have a duty to properly collect evidence so we can properly educate people affected by MS when they make their decisions.

    I fear that some people pay thousands of pounds for 'stem cells' and are actually just injected with dirty water. Hopefully the treatment will be available in the UK as part of a proper trial in due course.

    We cannot ethically routinely recommend stem cells because we do not have enough evidence to be sure that we are doing the right thing. Doctors regularly harm patients with licensed drugs used for the correct indications. We need to be able to have that level of information before we recommend stem cells.

    If we had as much evidence for stem cells as we do for alemtuzumab, cladribine or avonex I would be offering it next week (if the NHS would pay for it, which they would as it is relatively cheap).

    Thanks again

    Niall

    ReplyDelete
    Replies
    1. With the arrival of Cladribine and Ocrelizumab, do you personally think it is still worth choosing Alemtuzumab in treating more severe cases of MS, bearing in mind its far more risky side effect profile? Do you have up-to-date info on the impact of these drugs on brain atrophy?

      Delete
    2. I hadn't intended my response to advocate that UK clinicians routinely recommend HSCT but rather that the reality of people taking themselves abroad is addressed in a pro-active manner that falicities the minimising of risk and distress to those who choose to go abroad for treatment. I'd hope doctors can make clear they don't support or endorse, but if it's going to happen anyway that they will advice and guide, including, as mentioned, centres to trust or avoid. I sadly suspect that any other position will be all too easily be perceived as practitioner ignorance or arrogance or that it's treatment blocking, typical of the usual failings of the NHS. This way I'd hope that patients care and protection is facilitated, especially as it's the NHS that will supply the care following injection with dirty water. I only hope that other centres are quickly able to offer HSCT to the patients who are eligible as those in London do, including my own, especially as patients can now go 'treatment shopping' in a way that wasn't conceived of a few short years ago.

      I do comment from a lack of experience, having had no direct contact with anyone who's been abroad for stem cells and I may look to read one or both the books you've mentioned to become more informed of the wider issues.

      Delete
    3. I am happy to give a person with MS any licensed medication that they are eligible for. As I doctor, I know I'm vulnerable to heuristics (being swayed by my personal experience) and I have seen bad things happen to people because of drugs. However, I realise that my personal experience may be a statistical abnormality and I shouldn't let that bias my advice to patients. I can't give anyone ocrelizumab yet but I have prescribed a few people cladribine and they seem to be happy. I'm happy to give someone alemtuzumab if they want it and they fully understand the safety data.

      Sadly, I have no new atrophy data and I'm looking forward to seeing new data as much as you are.

      Best wishes

      Niall

      Delete
  3. "this treatment is any better than alemtuzumab"

    3 times repeated in the same text


    Authors’ reply
    We would like to thank the
    correspondents for raising an
    important concern—that the ultimate
    goal of treatment is to prevent longterm
    progression of the disease not
    just reduce MRI activity or relapses.
    There was prolonged suppression
    of all measurable inflammatory
    activity in our study cohort.1 For most
    patients, stopping inflammation
    led to stability in their neurological
    examination and many showed
    significant recoveries that have been
    sustained for many years. However,
    some continued to progress—clearly
    stopping further inflammatory
    events failed to influence what was
    likely a secondary degenerative
    process that had already surpassed
    an unknown threshold. Older
    patients, those with longer disease
    duration, and those with advanced
    disability have inferior outcomes after
    autologous haematopoietic stem cell
    transplantation (aHSCT).2,3 Is this a
    clue that might help us understand

    the biological threshold that leads
    to progression in the absence of
    inflammation? Could it be due to
    exhaustion of CNS repair processes?
    The correspondents are concerned
    that short follow-up might lead to
    underestimation of progression
    because they observed late progression
    in a patient with relapsing-remitting
    multiple sclerosis at the time of aHSCT
    for concurrent acute lymphocytic
    leukaemia. They are particularly
    concerned because at the time of
    aHSCT, the patient had mild disease
    with no evidence of disability. We have
    followed our patients for up to 16 years
    and have yet to see progression return
    in any whose disabilities had stabilised
    or improved. None of our patients had
    mild disease—rather they all had highly
    active inflammatory disease with
    progression to be eligible for the study.
    This makes our results that much
    more striking because such patients
    would be expected to progress in the
    timeframe of follow-up in our report.
    Although the transplant conditioning
    regimen and donor source used by
    the correspondents are not stated, we
    believe early intervention in patients
    with highly inflammatory multiple
    sclerosis before significant damage
    occurs to the CNS is an effective
    means for long-term prevention of
    progression. This early intervention
    uses a high intensity immunedepleting
    conditioning regimen to
    eliminate autoreactive immunity,
    followed by aHSCT with a graft
    depleted of immune cells to prevent
    reintroduction of autoreactive cells
    and allow lymphopoiesis to generate a
    naïve immune system.



    ReplyDelete
  4. Existing treatments for multiple
    sclerosis are increasingly effective
    but extremely expensive and
    more complicated. A single aHSCT
    procedure resulting in decades long
    disease remission without the need
    for ongoing treatment would be a
    very acceptable alternative for most
    patients—especially those that have
    already shown a high level of disease
    with resistance to most therapies

    *Harold Atkins, Mark S Freedman
    hatkins@ohri.ca

    ReplyDelete
  5. Several phase 2 trials have shown that chemotherapy with autologous stem cell support can stop ms and improve both functional level and QoL. The persons who improved in functional level and QoL in these trials were not recovering from relapses (the participants in the trials were examined before and during the trials). For instance "The Swedish Experience" https://jnnp.bmj.com/content/85/10/1116.long , Burt's trial from Chicago https://jamanetwork.com/journals/jama/fullarticle/2091305 and the review by Muraro et al. (not free access) https://www.nature.com/articles/nrneurol.2017.81.

    According to the EBMT registry the mortality of HSCT-treatment has been 0.2 % the last 5 years. Also the side effect profile of HSCT-treatment clearly is better than that of alemtuzumab. For instance 30-40 % develop thyroid disease following Lemtrada-treatment, as opposed to appr. 8 % after HSCT-treatment.

    Other benefits of HSCT-treatment as compared to DMD-treatment - for instance alemtuzumab -is that with HSCT-treatment the MS patients are spared the adverse effects of the DMDs, persistent disease symptoms, permanent immunodeficiency and additional irreversible damage to their CNS.

    So why have the health authorities failed to fund a randomised controlled trial (phase 3 trial) on HSCT-treatment for MS? Because policymakers, politicians and doctors accept that multinational pharmaceutical companies purchase political and medical influence, and because they provide jobs, tax revenues and private profit in the USA and influential EU countries.

    Many centers offering HSCT-treatment against ms are university hospitals or approved private hospitals. For instance Carreggi University Hospital in Florence, the Pirogov public hospital in Moscow and Clinica Universidad de Navarra in Pamplona. These hospitals do not have less standards than for instance Norwegian or Scottish hospitals.

    ReplyDelete
    Replies
    1. "Several phase 2 trials have shown that chemotherapy with autologous stem cell support can stop ms and improve both functional level and QoL."
      Given that there will be compromised blood:brain barrier integrity , which normally excludes many chemotherapy agents from the CNS in some pwMS being given chemotherapy the potential penetration of chemo to the CNS may be enhanced. So there is the possibility that this could be deleterious in some cases.

      Delete
  6. Sorry to post this again, but I really think Niall should see it. It's a video from the Stop MS campaign about the truly stunning results of Metformin in conjunction with remyelinating drugs on rats with MS (really exciting bit is at 33:33).
    https://stopms.mssociety.org.uk/annual-lecture.html
    After seeing this, I started on Metformin with Clemastine a few weeks ago. I know this sounds unlikely, but I seem to be seeing changes already. I have had MS for more than 20 years and am in a poor state of health. However, for the last week, I have been able to get in and out of bed without assistance. Before starting the Metformin, I hadn't been able to into bed unaided for several months and I hadn't been able to get up in the morning unaided for something like a year. Other things are improving too, which is something I've never seen, since being diagnosed with MS, even though I've been on powerful DMTs.

    ReplyDelete

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