AHSCT in pwMS: Not all squares are red

A

For many pwMS, autologous hematopoietic stem cell therapy (AHSCT) is considered as the holy grail to control MS disease activity. Based on the outcomes in people with very active disease, AHSCT is definitely more effective than any other DMT we currently have in our armamentarium, especially when used early. Comparative studies revealed that the proportion for whom no evidence of disease activity (NEDA) was achieved at 2 years was 7–16% for placebo, 13–27% for platform therapies (e.g. interferon) and 22–48% for other active drugs. Among patients who underwent AHSCT, the proportion was at 70–92% and thus considerably higher. Evidently, these numbers spark discussions at many internet fora and MS communities, and many have taken the shot and booked tickets to Moscow. At least until one week ago. 

Source: https://commons.wikimedia.org/wiki/File:Red_square_Moscow_cityscape_(8309148721).jpg

As nobody wants the feeling of having ignored the existence of such an effective therapy, the more hesitant pwMS often discuss the matter with their MS consultant. In pwMS who are very active and have failed on second line MS treatments, there is expert consensus about the usefulness of AHSCT. However, very often also pwMS who are stable on anti-CD20 or who fail on first line therapies wonder whether they should consider AHSCT. In this situation, it’s important to be aware about the short and long term burden of AHSCT. 

Short term

There are the obvious facts such as the small but existing mortality risk with AHSCT (in the most recent cohorts 0.3% but most likely higher in more disabled pwMS) and the frequent adverse events related to immune suppression (e.g. neutropenic fever, sepsis, urinary infections and viral reactivations) which will affect almost all individuals. The bulk of these severe adverse events took place in the first month after the conditioning regimen which is clearly the eye of the storm. 

Long term

Infertility

Alkylating agents such as cyclophosphamide, busulfan and melphalan fulfill an import role in lymphodepletive stem cell regimens. They are part of the initial stem cell mobilisation procedures and of the conditioning regimens before the actual stem cell infusion. However, alkylating agents are toxic to both ovaries and testes and the degree of toxicity is dependent on age, sex and cumulative dose. Cyclophosphamide is most studied agent.

In female pwMS, cyclophosphamide may lead to infertility and premature menopause which manifests as an irregular or absent menstrual cyclus (amenorrhea). Treatment-induced damage includes depletion of ovarian follicles and shrinkage and fibrosis of the ovaries. Some pwMS who develop amenorrhea during treatment may subsequently recover ovarian function. Conversely, some women with apparent preservation of ovarian function during and after treatment may develop premature ovarian insufficiency years later. Women treated before the age of 25 are at lower risk of infertility than those treated after the age of 30. 

The following data illustrate these points:

  • A meta-analysis including 1388 women (mean age 27.7) receiving IV cyclophosfamide for systemic rheumatic diseases found that sustained absence of menstrual cycle occurred in 273 women (19.7%). 
  • A report of 84 women who were menstruating prior to IV cyclophosphamide treatment for lupus or vasculitis demonstrated the importance of age. Chronic absence of menstrual cycle did not develop in any of the 22 women younger than 26 years of age but occurred 14 of the 20 women older than age 35.
  • Out of 43 female pwMS who underwent AHSCT, 30 (70%) recovered menses after a mean time of 6.8 months. Among pwMS who recovered menstrual cycle, 1 experienced premature menopause at 31, 3 years post-AHSCT. 

In male pwMS, cyclophosphamide causes a decrease in sperm count (oligospermia) and in some individuals also irreversible absence of sperm cells (azoospermia). Overall, approximately 70% of male patients who receive less than 7.5 g/m2 will regain fertility. As an example, a study of 35 men with lupus found that 86 percent of those with prior cyclophosphamide treatment had very poor sperm quality, compared with 45 percent of the men without prior cyclophosphamide. 

Secondary autoimmune diseases

Secondary autoimmune diseases have been reported after AHSCT between one in ten to twenty individuals. One of the hypothesis about their occurrence is an imbalance between B and T cell regeneration. The secondary autoimmune diseases have mainly included hyper/hypothyroidism but also less frequent occurrences of immune thrombocytopenic purpura and acquired factor VIII deficiency (hemophilia) which both manifest with a tendency to bleed or bruise easily. Higher incidence of secondary autoimmune diseases (around 20%) have been reported but apply to regimens with CD34+ selection which are not frequently used. 

Brain atrophy

Accelerated brain volume loss has been noted following aHSCT in pwMS. As with other MS treatments, this is often interpreted as ‘pseudoatrophy’, which refers to brain volume loss due to resolution of brain edema rather than loss of brain parenchyma. However, early spikes in neurofilament concentrations (and thus brain debris) have clearly indicated that the initial brain volume loss post-AHSCT exceeds what can be expected from its anti-inflammatory effect. A large study on untreated pwMS showed values of annual brain volume loss of −0.49%  and −0.64 % for pwRRMS and pwSPMS, respectively. After AHSCT, the rates of annual brain volume loss are about four to six times higher in the first 12-24 months compared to baseline.  “Chemo brain” or “chemo fog” are terms used to describe cancer treatment–related cognitive impairment and also applies to the brain volume loss shortly after AHSCT. For most pwMS, its effects are short-lived but for some can be permanent. 

Malignancies

Cyclophosphamide has been associated with bladder carcinoma and the development of hematological malignancies. In an AHSCT trial with long-term follow-up, 9 of 281 treated patients were diagnosed with a malignancy. However, no organ-specific prevalence was detected excepted for myelodysplastic syndromes (3/9 cases) which are associated with exposure to cytotoxic drugs. 

Twitter:@SmetsIde

Disclaimer: Please note that the opinions expressed here are those of dr. Ide Smets and do not necessarily reflect the position of the Barts and The London School of Medicine and Dentistry nor Barts Health NHS Trust.

Questions? 

  • Have you ever considered AHSCT while being stable on first or second line MS treatment?
  • Have you ever dismissed AHSCT because of the long term side effects?
  • If you have had AHSCT or if you seriously considered AHSCT:
    • Were you informed about these long term consequences?
    • Where did you find most useful information on the topic?

About the author

Ide Smets

72 comments

  • Do you not think that when citing the HALT-MS study that it might have been appropriate to point out that HALT-MS was myeloablative HSCT, and not non-myeloablative HSCT as used in U.K., Russia and Mexico?

    You must know that the complications and risks associated with BEAM are higher than they are in the non-myeloablative HSCT option. You’re comparing apples and oranges…but not making that clear to your readers.

    It might have been more appropriate to reference data from London, Russia or Mexico, or even the MIST trials, as you seemed to lead with Russia, which is an entirely different protocol from the procedure used by Dr Nash in HALT-MS.

    Slightly disingenuous and more than a little misleading…

    • Hi Alison, I get your point and that would have been the best comparison. Nonetheless, no matter which protocol you choose there is no doubt about the fact that short term side effects related to the immune depletion are frequent and impactful. In the real world London nonmyeloablative cohort there was a mortality rate of 2.5% and 90% had at least one early complication which were not graded according to severity. In the MIST trial there were indeed only grade 3 adverse events. There is no way of exactly predicting how vulnerable an individual will be based on current published cohorts, but it will be a combination of age, disability level, comorbidities and AHSCT regimen.

      • Yes, I know about the London mortality rate – and the reasons behind it – my husband was part of that cohort. And as you say, the closest comparable protocol (MIST) was significantly different in terms of the mortality rate. 2.5% is unacceptable and they’ve learned from it – the risk now is probably closer to 0.5%, which is still above average. The mortality rate for Russia and Mexico is now under 0.2% but they do use Rituximab and not rATG. The myeloablative protocol comes with a much higher mortality rate than the non-myelo protocol, and that does need to be emphasised.

        • Hi Alison, I omitted the sentence with the exact numbers of grade 3/4 side effects because it clouds the overall message that AHSCT is a good option for pwMS who have aggressive MS but that there is a significant burden to the therapy that might not be worth if if you are stable on first or second line or have not tried second line.

          • Ultimately, that decision needs to fall with the patient, after being given all the facts and not half a story.

            We know that many of the DMDs offered first line and second line are only FAO able of slowing down progression, whereas HSCT has been proven to halt progression.

            There is currently a culture of misinformation from neurologists, and they need to be disseminating the facts of HSCT. All of them.

            Of course HSCT isn’t suitable for everyone, but it’s certainly suitable for more than the 0.2% of the U.K. MS population that’s been able to access it here to date. It needs to change.

      • I write for a living. If I drafted something for a client which was misleading or factually inaccurate, I would be asked to edit it until it was correct. The same should apply here.

        You have a unique and privileged position to help people going through the hardest time of their lives. To effectively dismiss Alison’s legitimate concerns about accuracy with “well, whichever protocol you choose (it doesn’t matter)….” is irresponsible. It does matter.

        By using countries, data, protocols and outcomes interchangably, you’ve created a word salad – this is not helpful to anyone trying to consider risks and benefits. I believe this blog is linked to Barts – a world-renowned centre of excellence; this is not a good reflection of your brand.

        The problem here is the attempt to shoehorn in Russia – maybe an attempt to heighten news value. There were multiple other useful ways to present this EG – is it better to get AHSCT in the UK or abroad, or which method of AHSCT is most effective – ATG vs Rituximab? That would have been helpful; I would have bitten your hand off for it. This whole debate is inhernely newsworthy – it didn’t need a sexy angle.

        I can’t tell you how frustrating this situation is for patients. We’re told AHSCT is the best option, but it’s almost impossible to get it on the NHS. Then, we’re given articles like this with unclear info about going abroad…

        Please, talk to AIMS and get the facts together on this. As you say – AHSCT is definitely more effective than any other DMT and it’s the only source of hope for a lot of people..

        • Dear susie, Apologies if you find this article misleading; this was obviously not my intention. I had already omitted the sentence with the exact number of adverse events as they indeed distract pwMS from the overall message. The point I wanted to make is that there is a significant burden associated with AHSCT that is worth it when having aggressive MS but might not be justifiable when you are stable on first or second line treatment or have not tried second line treatment. For the record, I do agree that AHSCT should be more readily available and that many pwMS are unrightfully denied access to this very efficient therapy. However, I do not agree that risk vs. benefits of AHSCT add up in everyone and this mainly because of the effects on fertility and brain atrophy. It is true that many of the articles I have used as a reference stem from different patient populations and AHSCT regimens and you correctly highlight we need more uniform and long-term data on AHSCT in MS.

          • You’ve completely disregarded the point that Susie was making here. She, like me, was referencing that you used Russia as an ‘in’ into this topic, but then proceeded to use stats from a completely different protocol. However you dress it up, that is misleading.

            As she said – if you do want to talk to AIMS, please do reach out. We’d be more than happy to talk to you.

      • Thank you for having the guts to run my comment, and reply. I’m sorry I was a bit harsh but I’m just so exhausted by the dialogue on this, which is even more confusing than it needs to be. If neuros worked with AIMS and people who’ve done this overseas we could create a really powerful resource.

        I don’t know whether all the side effects you have listed apply to the procedure in MX or Russia? Can you help?

        Anyway, forgive my slight vent. And thank you for talking about AHSCT – that’s the most important thing.

        • As far as I can deduct from the Moscow/Mexico websites, their regimens also contain cyclophoshamide, and there is no way around the fact that alkylating agents are a high-risk therapy when it comes to infertility – especially at older +30 age. One of the related problems is that it’s often very time-consuming to get cryopreservation organised (in the UK).

  • Thank you, Ide. V informative.

    Something, as a patient, that I feel is overlooked in discussions like these is the following: a discussion of risks in a relative framework.

    Nothing is without risk. The relative risks are rarely expressed. The risk that MS presents is one, often the elephant in the room. It is a life-long, incurable (aHSCT is not the ‘cure’ some seem to think it is!) disabling illnesses. The disability accrued is irreversible so the clock of decline is always ticking. Faster for some than others.

    Prof K recently said 10% of patients will make it through the disease without any form of therapeutic intervention. Even if it were 50% who wants to bet their future outcomes on those odds.

    As a patient, this dramatically, really dramatically, shifts my personal risk tolerance. The potential unpleasantness of aHSCT (or other highly effective DMTs like, say, Alemtuzumab) , when set against the almost certain spectre of decline through physical and mental disability, goes from v scary to well worth the risk.

    The discussion regarding pharmaceutical intervention should be a comparative and collaborative exercise, rather than just plonking a load of undoubtedly scary things there without discussing how they relate to inevitable effects of MS.

    To what extent are these undisputed risks manageable by the medics? Can any be eliminated or mitigated by the ‘forewarned is forearmed’ principle and thereby influencing the risk/reward calculation?

    Managing the out of sync rates of repletion of B and T cells and the risks this presents is, I understand, something that can be addressed if rates are monitored and appropriate interventions are made early.

    Giving prophylactic antibiotics during the period of immune reconstitution has been refined and tuned from experience.

    Risks are not eliminated but mitigated. To what extent the growing knowledge and experience affects the stark numbers expressed isn’t discussed.

    As a patient I feel that v few (I have yet to meet one) Neurologists are comfortable having the discussion where the risks of intervention are set against the unvarnished assessment of the long term risks of treating MS in an underpowered way.

    The understandable heuristic of a newly diagnosed patient reading a Patient Information Leaflet and baulking at the horrifying sounding side effects never seems to be challenged. An entirely sane reaction.

    As a theoretical exercise: I wonder where the UK cohort of all newly diagnosed MS patients (in, say, the last 10y) would be, regarding decline in their condition, were there to have only been treated with Cladribine, Alemtuzumab, or aHSCT?

    It’d be interesting from a quality of life and a health economics point of view. Additionally, the accrual of experience in wide-scale usage of these therapies would likely have led to even better medical management of the undisputed risks.

    I’ll get off my soapbox now;)

    • I agree we need direct comparison between the different DMT options, including AHSCT, and long-term follow-up studies that allow us to judge how to help pwMS not in two years from now but in two decades. Until we have this information, every risk assessment is definitely incomplete.

      • In the absence of hard, definitive, unquestionable data, then based on the fact that the odds are 90% against me (in round terms but as I said it could be 70% or even 50%) I must either bury my head in the sand, and lord knows I did that for far too long, make a risk/reward judgement.

        The rewards are fighting the disabling disease and trying to stay as close to normal for as long as normal or giving in to the inevitable and allowing myself to follow the well-known and all too well-trodden path of irreversible physical and mental deterioration.

        The risks are well documented and altogether more definitively enumerated. I don’t have another 5, 10, 15 etc years to wait for that data. The loaded gun (of failing to act) that is against my head is the ontological reality that I must deal with.

        It is not a difficult choice to make despite the absence of some absolute data. Time is not my friend in MS.

      • Why is no one organising these studies? I keep reading the same thing over and over through the years ‘we need head to head trials’. Is there a lack of funding? Pharma will obviously want to compare with the least effective (INF + Aubagio). We know these meds are unacceptably ineffective anyway. As a patient I am trying to understand why MS research is so slow. What can we do to help research skyrocket? Why is noone funding MS? Yes not too many people get it but it’s also not that extremely rare. And yes I understand that research takes time, but having seen the rate research has progressed with the past couple of decades I do think it’s quite slow. I was diagnosed in 2017 and I was started on Copaxone which was invented in 1996

    • Hello Dominic- I think your response makes a good point as I have been very “pro”, “get your head out of the sand”. There is more “hope” (and I don’t really like that word here), for some, by pushing very hard, but they need a full understanding of the pros and cons (as much as they can understand). I say this recalling a recent Facebook post where the wife of a 60-something MSr was newly diagnosed as having transitioned to SPMS, in apparent unexpected horror, blaming the neuro. Her grown kids were urging the selling the house, to go to Mexico for AHSCT and she was seeking advice, which being Facebook, was the completely wrong place to go if her hopes were to get some good objective information in the midst of her panic. I commented in favor of not selling the house and urged further learning.

  • Your Blog post is a little confusing – a mixture of long term consequences and adverse reactions from various AGSCT regimen’s and for people with various kinds of MS. It reads as though you want to discourage – if you were giving this information to me to help me make my decision I would I’m agréais say it doesn’t meet the informed consent criteria as it’s misleading. It certainly isn’t what Dr Kazmi will tell you.
    I find it more than a little insulting that someone feels we have not considered a lot of these side effects but my response is – what’s the other option? What else can you offer me? The answer for me was of course rapidly worsening disability- as a physiotherapist myself I know where I was heading – and I was not looking forward to the future. I had taken all the fancy new drugs offered – pretty much destroyed my immune system anyway with so many different drugs, and still I had increasing disability; as my EDSS hit 4.5 I was at the point where I was out of treatment options and I thankfully heard about AHSCT, did my research, paid to see a private neurologist and then thankfully was accepted in the UK on NHS criteria. I’m 2.5years out with NEDA my EDSS is 3.5. I’m working full time. I’m a mother of 3 and a wife. I walk my 3 dogs. I have my life back. I have no atrophy on my post AHSCT scans. Yes I’m in the menopause. Yes I have some side effects. But I have a life, some hope and a future. That’s what AHSCT gave me that no other treatment could.

  • I remember reading about it and immediately dismissing it as too risky. But then it hit the press and my colleagues were convinced there was a cure for my MS…

  • Laying in hospital at barts now waiting for my numbers to come up after having mine done last week. There is a number of short term risks that dont get discussed heavily enough and side effects, its not for the feint hearted but neither is what ms would of potentially done to someone on my course curve. Personally id do it again in a heartbeat rather than lose more of myself to this disease.

    • I was in Barts yesterday. I would have waved through the window had I known 😉

      Did you get it as part of the StarMS trial that Dr Turner is the PI for at Barts?

      Br,

      Dominic
      theMSguide.com

      • Hi dom! I didnt realise you were here would of been lovely to have met! No i was accepted through nhs after failing tysabri for a year whilst on concurrent steroids through 2021. Would love to have a chat at somepoint, btw rachel is a good friend and am looking forward to following her transplant on your youtube 🙂

      • When I was diagnosed with highly aggressive RRMS in 2016 I was initially pleased and hopeful when I was offered Tysabri or Lemtrada as first line treatment. I chose Tysabri as I had already researched HSCT and thought that may be the next option should my MS progress. Within 30 months on Tysabri I declined from EDSS 1.5 -2 to 6. “No no you’re fine” said my neuro who refused to accept I was progressing as “MRI says no” despite the obvious physical decline. I was also not told my PML risk had increased to 4. “Let’s sign you up for another 2 years of Tysabri”

        Now I was told that “we think Tysabri has an 85% chance of slowing relapses/progression but we don’t know how it works”. Hmm that versus 100% chance of progression if I do nothing”. HSCT has 75-85% chance of halting progression. I’m not a statistician but even my MS riddled brain can work out which number wins.

        How much discussion is actually held re side effects of any of the treatments offered?How truly informed are patients when they get to choose their poison?

        I found out everything I know about HSCT from AIMS charity and I went to Russia in full knowledge of the risks, as I’d done my own research.

        3 years post and EDSS is now 3.5. Go figure why Neurologists are not providing full facts or options about any of the treatments out there.

        At least tell people the truth. The greatest barrier to progress is fear.

        Stop fear-mongering.

  • This is from the BMJ a couple of years ago:

    “Multiple sclerosis has the worst life expectancy of all the neurological conditions considered in the Public Health England report — with 73% of patients dying before the age of 75.
    The situation may (may?) be changing with the use of DMARDs, but right now the PHE report makes it clear that the mean age at death in the UK for people with MS is 66. This is almost exactly the same as that in France (66.6 ± 13.9 years: 68.2 ± 13.9 in women and 64.1 ± 13.5 in men). (1)
    Since the “most common age at death [in the UK in 2007-11] was 85.6 years for men and 88.3 years for women” (2), MS clearly does not currently have the “small impact on life expectancy” that the MS Trust suggests (3)”

    It’s not just the earlier life expectancy that needs to be taken into account. It’s also the last 10-15 years of an MSer’s life eg sat in in wheelchair in a nappy or lying in bed fed through a tube. My MS nurse has some nightmare stories about end stage MS. The mortality rates of AHSCT are almost irrelevant compared to what happens to MSers after 20, 25, 30 years. The choice should be up to individual MSers. If you don’t like the risks, don’t go for AHSCT.

    Remember Mussolini – I’d rather spend one day as a lion than 100 years as a sheep. For those who know the risks, have thought them through, and are accept them, let them go for it.

      • Ide,

        We’ve had DMTs for c.25+ years and Natalizumab has been around since c.2005. Even with the most effective DMTs there is still progression / smouldering MS. I don’t believe anyone diagnosed with PPMS today can be offered any treatment which significantly changes their future ie compared to someone diagnosed with PPMS 25 years ago.

        MS cuts lives short – I think we can agree with that. For some it might be 10 years shorter than the average lifespan and for others it might be 25 years shorter (I have known several MSers who have died in their late 50s and early 60s). The point I’d really like to make is that MS is like cancer – eating away at brain and spinal cord tissue. We should be treating it like cancer. Oncologists don’t start their cancer patients on low efficacy safe treatments. Why do neurologists have to treat their MS patients differently given that MS shortens lives and results in increasing disability? Treat it like cancer should be the approach. Flip the pyramid. Ditch the pretty much useless CRAB DMTs. Add a therapy which addresses smouldering MS / ebv infection to a highly effective DMT. It’s not rocket science, but for some reason many neuros are happy to watch their patients become progressively disabled and justify it on the grounds of safety ie discouraging the use of the most effective but more risky treatments.

        • ‘Like cancer’ – well said. Who has ever heard of someone with a confirmed malignancy being thrust a handful of leaflets, being told to choose a drug and come back in a few months to see how the tumour is growing? That’s absurd yet it is often the case with MS.

      • Fingolimod gives you 3 ,5 years against placebo

        For placebo-treated patients with minimal disability (EDSS 1) it took 8.95 years until increased limitation in walking ability (EDSS 4) and 18.48 years to require walking assistance (EDSS 6). Treating patients with DMTs delayed these times significantly by 3.51 years (95% confidence limit: 3.19, 3.96) and by 3.09 years (2.60, 3.72), respectively

        https://medicalxpress.com/news/2022-02-ways-patients-multiple-sclerosis-impairment.html

        Oh and yes cardiac and liver toxicity during those years every year

  • Your article is rather one sided. It speaks of the risks of HSCT but without fully addressing the risks of the other DMT’s and the massive risks of living with under-treated MS with a significantly less effective DMT or going untreated. Compared to the risks of living with poorly managed MS I will be choosing HSCT. Living disabled with MS will also make me infertile in a way as I don’t feel capable of caring for a child in my current health with the prospect that I will only get worse (slowed a little by the medium effectiveness medication I’m allowed on the NHS). You also don’t explain that having one autoimmune condition already increases your risk of having developing a second autoimmune condition. How many of those people would have developed a second condition anyway regardless of HSCT. When you weigh up all the risks and benefits I will be having HSCT despite my neuro claiming my current DMT is sufficient. The research already says that it is not the optimal DMT, but they won’t pay for a high effectiveness drug in my health board.

  • Unfortunately I feel this article is confusing for people researching HSCT talking about myleo and non myleo without really defining what you mean.

    To answer some of your questions:
    My husband had HSCT in Moscow in 2018 to halt the progression of his SPMS. Yes we were fully informed of both short term and long term risks but when you have a 💯 chance of continuing your progression we decided it was the best choice. After all the only thing our Neurologist suggested was installing a chair lift in our home.

    You also ask where we obtained our information. Shocking in a way but totally relied on the expertise and experience found in the Facebook groups where you can read about the good, the bad and the ugly. Over the years I’ve realised this is where the majority of HSCT patients go as it’s virtually impossible to obtain objective and truthful information from their Healthcare provider.

    For any prospective HSCT patients reading this blog please look at the UK Charity AIMS who provide a wealth of information and support to anyone considering HSCT.

    https://www.aimscharity.org/

  • And then there is me… hsct straight from diagnosis, highly active /rapidly evolving rrms and still new lesions appear… I have no regrets though, it was the only option that made sense. Although perhaps myeloablative might have held me stable a little longer than 1 year post!
    These articles are not so helpful if the treatment is not actually accessible to the average pwms , hopefully this changes before long

  • A brave post Ide and judging by the reaction, may be the last one on HSCT for a while. This is very relevant to my own case. I was booked to go to Moscow in April – i wont be going now but my decision was made before the invasion. I am currently on Ocrelizumab, my scans are stable but i can still feel a gradual worsening and carry the mental burden of the disease. Part of the appeal of HSCT for me would be to feel free of MS, even if thats not the case. To feel that i have done as much as i can. It becomes tiring always chasing, always reading, always waiting for the next break through in science, worrying about the next break through of the disease.

    In the end my decision not to go to Russia was based on the fact that i am on a highly effective therapy, have a reasonable QoL (EDSS 1) have a young family and can probably pull together the funds to be treated in the UK should the need arise but also, because its a very tough thing to make a decision based on the experience of facebook group members and to go against the advice of 2/3 neurologists that i have seen. They do treat a lot of people with MS after all and whilst there are no crystal balls they are surely in a reasonable position to see how the disease course of others on my path has played out. I do have a couple of questions:

    1) a lot of people talk about HSCT as ‘halting progression’. Is that the case? dont the studies tell you that as you move away from the treatment 3, 4, 5 years on that disease is reactivating in an increasing number or that disability worsens

    2) The picture painted by many HSCT proponents is that PwMS will inevitably end up disabled, in a nursing home, wheelchair or another grisly end. However, isnt the proportion of PwMS that end up in a wheelchair actually quite low?

    3) Do we truly know the long term impacts of such an invasive therapy?

    • With regard to point 2, I think it’s just a matter of time. MS is a progressive disease ie it gets worse – you gradually work your way up the EDSS (disability scale). EDSS 0 is no disability and EDSS is 10. EDSS is requires a wheelchair. Individuals vary – I know a 24 year old in a wheelchair and a 65 year old who uses a walking stick. Going to the local MS society was an eye opener for me in terms of the number of people in wheelchairs. Unfortunately neuros don’t have the technology / tools to provide a prognosis ie how quickly or slowly you will progress. This would make things a lot easier in terms of selecting (or not) a higher risk treatment.

    • All of these questions – and more – are answered in the U.K. forums that you speak of.

      Interestingly, AIMS is part of a larger collective of agencies who are trying to make HSCT more accessible – all of those agencies (HSCT experienced neurologists, haematologists, and charities) agree that the number one obstacle to access is the lack of knowledge about HSCT among neurologists. Neurologists are not the specialists when it comes to HSCT – haematologists are, and that’s what we need to actively change.

      That said, we fully support your choice to change your mind on HSCT. It’s an incredibly personal decision and clearly one you’ve taken after a lot of thought – everyone who could potentially benefit should have that choice and that opportunity. And that includes many with progressive disease too – the data supports that.

      There is long term data available for HSCT, and the idea that most people are failing at 3,4,5 years simply isn’t accurate.

      Do have a look at our website where we have collated most of the relevant HSCT research. You’re right that the evidence in the forums is largely anecdotal (not always, because many of the people speaking from experience have actually been a part of the Peer-reviewed trials that have taken place), but anecdotal evidence has its place too.

    • 1) AHSCT does not halt progression entirely, but definitely more than any other DMT. If you have progressive MS at the outset, you would have approximately 50% chance of halting progression 5-10 years later.
      2) From natural history untreated cohorts before disease-modifying treatments (DMTs) were introduced, we know that for an untreated pwMS it takes a median 11.4 years to reach EDSS 4/not being able to walk unrestricted anymore, 23 years to reach EDSS 6/walking with a cane and 33 years to reach EDSS of 7/having to use a wheelchair. And this was before the DMT era which has definitely significantly delayed these milestones. However, the problem is that it’s not the disability but the cognitive impairment that is most disabling in the early disease course. It’s unclear to what extent AHSCT can impact on cognition (as it is for most other DMT’s).
      3) No, longest FU I have seen is about 10 years.

      • Thanks for the response Ide…..the halting progression point is an interesting one. The studies all seem to show that the % reduces with time so patients are still left playing the squid game. I’m not suddenly against HSCT. I just decided Russia was not the right option for me right now. I do also have that bit of hope that the treatment landscape could look quite different in 5 years time if you can make it that far relatively unscathed. However, I’m sure the last cohort of patients felt the same

      • Ide,

        Thanks for your post. As you can tell from many responses there is a lot of frustration out there. I can see why – in 2022 we have MSers having to use their savings to go to Russia or Mexico to get what appears to be the most effective treatment (with higher risks).

        “From natural history untreated cohorts before disease-modifying treatments (DMTs) were introduced, we know that for an untreated pwMS it takes a median 11.4 years to reach EDSS 4/not being able to walk unrestricted anymore, 23 years to reach EDSS 6/walking with a cane and 33 years to reach EDSS of 7/having to use a wheelchair.”

        I’ve seen these figures before. I’m slightly wary of them as my neuro published an article ten years or so ago with a finding that the average lifespan of an MSer after diagnosis was 30 years. Seeing some young MSers (in their late 20s) using wheelchairs doesn’t fit with the 33 years (average) for an MSer to use a wheelchair. The different stats / averages makes it even more difficult to properly assess risk.

  • About 1.5 years post 1st line HSCT in Mexico myself (24M). I personally both read primary sources (MIST trial, earlier data), watched YouTube videos including Dr. Burt presenting on his findings, as well as some others. BartsMS was a key resource as well for a deep dive. I did join the FB groups and probed online forums as well. In the end I decided the risk of mortality/severe side effects were under 5%, and the chance of freezing my EDSS at 0 high. I had a somewhat rough scan, but no lasting symptoms, and wanted to keep it that way. So far so good, stable since diagnosis MRI. Didn’t really have complications that I noticed beyond asymptomatic neutropenia a few months out, but never got sick at all the whole time since. I did fertility preservation just in case, haven’t gone in yet to see if it’s necessary but will soon. I knew if I did anything else and progressed I would have regretted it. I think it is a risk tolerance thing and it wouldn’t be the right choice for everyone. I was offered Ocrevus/Cladrabine originally, which at least was a good “hit it hard” original recommendation from my doctor. Thanks for taking the time to write this post and respond to feedback.

  • Dear Dr Smets,
    I’m afraid that your article doesn’t give a true representation of non-myeloablative HSCT as given by Russia, Mexico and the UK. It’s almost as if you’re trying to frighten people!
    For example, you tell of the risk of bladder malignancy caused by Cyclophosphamide, but you fail to mention that another drug (Mesna) is used to ameliorate that risk.
    In answer to your questions:
    I had successful HSCT for PPMS in Russia, in 2014, and have remained in remission ever since – almost eight years to date. It was the best thing that I could ever have done for my health. I was very aware of the potential risks, having done lots of research beforehand. That involved reading every published peer reviewed paper I could get my hands on, and actually speaking in person to the doctors involved in HSCT and to my own haematologist. The one person who had no idea about HSCT was my neurologist, ironically.

    • Even with Mesna add-on some people will still develop hemorrhagic cystitis and thus be exposed to the toxic metabolite of cyclophosphamide. The risk of a secondary bladder malignancy is reduced with Mesna but not gone.

      From the SmPC:
      As with all cytotoxic therapy, treatment with cyclophosphamide involves the risk of secondary tumours and their precursors as sequelae.

      The risk of urinary tract cancer as well as the risk of myelodysplastic alterations, partly progressing to acute leukemias, is increased. Other malignancies reported after use of cyclophosphamide or regimens with cyclophosphamide include lymphomas, thyroid cancer, and sarcomas.

      In some cases, the second malignancy developed several years after cyclophosphamide treatment had been discontinued. Malignancy has also been reported after in utero exposure.

      The risk of bladder cancer can be markedly reduced by hemorrhagic cystitis prophylaxis.

  • I have considered it over Lemtrada, and I have considered it over spending the next 20 years on antiCD20 treatment, so no, I have not dismissed the only other current option because of possible long term side effects.

  • Ide firstly thank you very much for taking the time to post this information and answer questions.

    One of the problems I have come across when looking at AHSCT is the lack of reliable information around the protocols if you are looking outside the UK. I watched Dr Ben Turner on the MSGuide and I think he did a great job at explaining the protocols. Because the UK medical community are generally against people going overseas for AHSCT it is not that easy to work out where you should go if they can’t get approval in the UK, and Mexico and Russia seem the obvious places. It would be useful to have more information

    It would be useful to have clarity on-
    1. what they see as the benefits/risks of rATG in the UK/North America/Europe rather than rituximab in Mexico/Russia.
    2. Mexico split their cyclophosphamide across 2 weeks rather than 4 days, so although the same cumulative dose, this is not the same dose with the same effect (as is often claimed); they claim it is less toxic.
    3. Are there advantages to BEAM/rATG in certain patient groups (although in theory higher risk Italy have had no deaths since 2007 I believe)

    If the MS Society?AIMS/MSTrust could to do something on this, and provide proper scientific advice on the risk/benefit of the protocols for those who want to go abroad they can get a sense of where best to spend their money from full myelo in Israel, BEAM in Italy to non-myelo Mexico and so on (not sure what all the different centres do). It would allow people make a risk/benefit assessment of the protocol they want to use and the associated costs.

    The comment from anonymous is really relevant on the return of MS following AHSCT “Although perhaps myeloablative might have held me stable a little longer than 1 year post!”

    Thanks again Ide for posting this article!

    • These are really good questions which I cannot immediately answer, but I’m also not sure whether there is a sound answer available. I will touch base with Ben Turner, and if I get simple answers I will feed it back to you.

      • Thanks for your reply Ide, and if Ben Turner has any answers or comments that would be great. I will email the MS Society today to see if they will consider expanding their information on AHSCT overseas. The Facebook groups/forums are useful for providing practical information and patient experiences but at the moment they are commenting on the efficacy and toxicity of protocols, and people are making decisions based on this information.

  • Thank you for amending and updating the article, Ide. This reads much better and isn’t as misleading. You make some valid points. HSCT isn’t something that should be undertaken lightly, and everything in your article should be explained to the patient so they can make a balanced decision.

    There are, of course, risks attached to HSCT (as with DMDs – only this week I was reading about the increased risk of melanoma with particular high efficacy DMDs), but what’s important is that the patient gets to make a decision based on all the facts.

    Many with MS would choose to absorb the risks of HSCT in exchange for a chance to halt their progression. When one compares the risks attached to HSCT with a 100% chance of deterioration once MS reaches the progressive stage (as it will within a certain timeframe for approx 80% of patients), for many the choice is clear.

    I think it’s important for neurologists to truly put themselves in the patient’s shoes when it comes to treatment options – at AIMS we’re really not seeing that at the moment, and it’s something we are fighting to change. HSCT needs to be made more available to more patients, and yes, they need to know the potential risks as well as the potential benefits.

    • “When one compares the risks attached to HSCT with a 100% chance of deterioration once MS reaches the progressive stage (as it will within a certain timeframe for approx 80% of patients), for many the choice is clear.”

      One could argue the above statement is grossly misleading and suggests that if one does not have HSCT, there is a 100% chance of deterioration. Where is the scientific and peer reviewed data supporting that claim?

      I do appreciate anyone who advocates for pwms and supports a patients decision to pick the MS treatment of their choice. However, to say HSCT is a cure and provides a significantly higher benefit compared to other high efficacy DMTs is not true, not supported by any peer reviewed data I have seen, and could give pwms a false sense of hope.

      I just felt the frustration towards Ide expressed in the above comments was a bit unnecessary.

      Good article Ide!

      • There is plenty of peer reviewed data going back 20 years so it’s not accurate to say there is no data. No one has said it’s a cure but if you consider progression free survival of 5years in context of progression free survival of 5 years in cancer terms – it would be considered as such

        • Anon 12:59pm – I did not say there was no data on the efficacy or benefits of HSCT, I said there was no data supporting it provides a significantly higher benefit over the high-efficacy DMTs (e.g., OCR, NAT, ALUM, CLAD). Prof. K mentioned someone is addressing this lack of data and is conducting a study of just that, HSCT vs. High-Efficacy DMTs.

          Correct, no one has said HSCT is a cure, but advocates for the procedure sure try and make it seem like it is a cure.

          As a cancer survivor I am going to have to disagree with your 5-year comparison. I was not cured of cancer, rather my cancer has been in remission for the past 18 years. It can always return, as I have active cancer cells.

      • It suggests nothing of the kind. The fact is that most people diagnosed with RRMS will eventually transition to SPMS by 20 years. The exact percentage varies, but 80% is the one I’ve seen most often – the US MS Society actually states this is 90%

        By definition, secondary progressive is characterised by a steady worsening of disability. That’s the nature of it. My husband had HSCT when he had reached this stage (he was unlucky – the transition to SPMS took a mere 5 years from diagnosis for him) and there was a marked difference. His symptoms increased and he was most definitely on a downhill trajectory. It seemed to us that he had new symptoms every month if not every week.

        I’d like to reiterate that nowhere have I ever said that ‘HSCT is a cure for MS’ – I go out of my way to say the opposite. There is no cure for MS, but HSCT has been shown to halt progression in the overwhelming majority, and reverse symptoms in many. Symptom reversal is more likely in patients with highly active inflammation (which is usually RRMS patients), but progressive patients have seen symptomatic reversal too – including my husband who had – and still has – an EDSS of 6.5.

        I do resent it somewhat when people put words in my mouth! Do re-read what I wrote. I’ve simply stated the facts.

        As an HSCT-focused charity we’re dealing with pre and post-HSCT MS patients every day. Even in the cases where HSCT hasn’t worked for someone they usually tell us that they are glad they tried it.

        I don’t know if you saw the original article, but Ide has taken the comments on board and amended the misleading elements

        • Alison – As I said before, I do appreciate anyone who advocates for pwms. I did not mean any ill will. I am glad your husband has found a treatment to help slow/stop this horrible disease. In the four years since my diagnosis, I am now EDSS 5 and have tried three different high-efficacy DMTs, yet I continue to progress, so I fully understand the desire to stop disease progression.

          My frustration comes with how the HSCT community (in general) attacks anyone who might disagree with their point of view. I did read your comments and that is why I posted my thoughts, yet I am sorry for suggesting you said HSCT is a cure when that was not what you stated.

          I just feel many HSCT advocates are one-sided in their perspective and seem to SUGGEST HSCT is a cure; however, it has only really been shown to slow progression in most and halt progression in some. HSCT cannot regrow nerves or repair damaged myelin, nor can any DMT so we are all hoping for the best result, no matter the course we decide to take.

          Several of the high efficacy DMTs have been shown to provide similar benefits to HSCT, yet with a much lower risk profile and less ancillary damage, IMO. For example, here is a Prof. G lead study on Cladribne, which shows after 10 years 68% of study participants did not need any further DMTs and showed no sign of further progression.

          https://medical.emdserono.com/content/dam/web/health-care/biopharma/web/USMI/congress-presentations/Cladribine-2-Giovannoni-G-et-al-CLASSIC-MS-Long-term-Efficacy-and-Real-World-Treatment-Phase-III-Parent.pdf

          In comparison, the conclusion from one of the studies linked on your charity’s website (Long-term Clinical Outcomes of Hematopoietic Stem Cell Transplantation in Multiple Sclerosis), found very similar results and benefits for HSCT, with RRMS cohort at 71% and PPMS at 57% being disease free after 10 years. However, the risk profile of this approach is much higher.

          My point is I hope the HSCT community is a bit more balanced in their approach and advocacy. If not, we could end up with more pwms taking out second mortgages to get HSCT, when maybe a high efficacy DMT would have sufficed, if taken early enough in the disease stage.

          https://www.the-scientist.com/news-opinion/northwestern-university-stem-cell-therapy-clinic-closes-abruptly–66401

          https://ipscell.com/2019/01/upbeat-burt-team-pub-on-stem-cells-for-ms-comes-with-uneasy-back-story/

  • I came off Tysabri to have HSCT. I was offered Alemtuzumab but after researching the effectiveness and long term side effects of it decided that compared to HSCT the latter was the better option. I found information about Alemtuzumab on the internet; speaking to a top London MS neurologist and patients who had the treatment. I saw two different MS neurologists involved with HSCT and gained a lot of information from the Facebook forums for HSCT; gaining feedback from thousands of veterans from around the world, who voiced the pros and cons.

      • No. It shouldn’t. Yet it’s a better source of information than patients are getting from most neurologists.

      • Go to the FB Alemtuzumab user group and
        You will see and learn and like me be totally shocked how many fail on it. And
        Read their frustration when they are
        Told they’re progressive and ineligible for
        More infusions.

        • I used the files on the Facebook forums to help research HSCT and the information was more accurate and in greater depth than the MS Society website at that time (it has improved since). I didn’t research Alemtuzumab on Facebook but one of the MS neurologists that I saw advised me to avoid it. Opting for HSCT was the right choice for me, my EDSS has dropped and it’s great being off all those horrendous MS DMTs.

          • AIMS has been, and is, working with the MS Society to improve the information they share on HSCT. They asked us to go through the website and suggest amendments. It great that the changes are apparent. We are currently working with them on a resource for patients, and for neurologists, which will be published on their website. We will be including something similar on our own website.

  • I would suggest to add references to the statements made in this blog.

    Brain atrophy after bone marrow transplantation for treatment of multiple sclerosis. (https://pubmed.ncbi.nlm.nih.gov/27246142/)

    Conclusion: Following IA/aHSCT, MS patients showed accelerated whole-brain atrophy that was likely associated with treatment-related toxicity and degeneration of “committed” tissues. Atrophy eventually slowed to that expected from normal aging, suggesting that stopping inflammatory activity in MS can reduce secondary degeneration and atrophy.

    Please provide data that for some PwMS BVL can be permanent. The way I interpret this paper HSCT actually slows downs BVL in the long run to normal brain ageing.

    On (long term) side effects relating to bladder cancer I cannot find any data to support this claim in HSCT for MS of other autoimmune diseases. I would suggest to read papers of the EBMT addressing these topics.

    https://www.ebmt.org/research/publications?area_category_target_id=All&group_category_target_id%5B0%5D=49

    Like:

    Immune Reconstitution Following Autologous Hematopoietic Stem Cell Transplantation for Multiple Sclerosis: A Review on Behalf of the EBMT Autoimmune Diseases Working Party
    (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8846289/#B54)

    In the old days Cyclo was used as a DMT and administered as an immunomodulating agent over years and yes back then there was a higher incidence of bladder cancer especially in combination with the use of indwelling catheters. https://pubmed.ncbi.nlm.nih.gov/9598480/

    To my knowledge there is no supporting evidence HSCT in Autoimmune diseases can cause bladder cancer. Yes cyclo uses over the long term can potentially cause bladder cancer. That is one of the reasons why cyclo is administered in 4 to 5 consecutive days in combination with Mesna and flushed out immediately with extra fluids etc to limit potential bladder scarring.

    Perhaps its an idea to ask someone at the EBMT to write a guest blog on HSCT in MS? Could be interesting.

  • I often return to these blog articles to read the comments and see where the conversation went. There are a lot of smart MSr’s here and I have to say the accumulation of response, on this article by Dr. Smets, is the best I’ve seen for thorough, smart, thoughtful analysis from affected people.

    So I wanted to add, if not too late, a few thoughts related to what I’ve read. So I’m 64 and have had MS for at least 35 years. I walk, smile, find things to joke about and enjoy myself. MS was not the end. When it all started, it took about 7 years for things to really start falling apart. And that included not only physical stuff, but employment and relationship stuff, which in my opinion was more severe than the physical. Within that first 7 years I became a strict Swank diet person, began interferon 1b and was treated aggressively with strong steroids quickly (less than 5 days) every time I had a relapse. Steroid treatments became unnecessary by 2000, I continued interferon for 25 years (even though I developed antibodies) and modified my Swank to allow beef or pork twice a month and perhaps a few other goodies. I also smoked and partied sometimes during my 35 year MS history, so keep that in mind. And my cousin, diagnosed at the about the same time, has lived a pristine life all her life, and her outcome appears equal to or less successful than mine. In terms of CRABs compared to newer DMTs, I have also always believed that using injectables as a comparison in trials for new DMTs could be inaccurate as I believe that many on “CRAB” DMTs do not follow their proper regimens, as needles are just not fun, and therefore easy to avoid. That is, some people do not do well on CRAB DMTs because they don’t follow the instructions, and the manufacturers of newer DMTs know this when comparisons are made (I believe).

    If I were newly diagnosed now, it would be much more difficult to make a choice. Back then, I made about the only choices available. Today, I would probably go the HSCT route. I’d want to be B cell depleted once, not forever. And how it would have all turned out if my choices were greater back in 1995, who knows? Any better? Worse? The same? And how would I have attributed my outcome?

    So in conclusion, I think a big part of the MS conundrum and tragedy is psychological. When one learns that MS is the end of life as you knew it, how can one handle that in an effective manner? The truth needs to be told and understood as soon as possible, at least for those of us who believe we can make a difference. Some kind of effective coaching needs to be input for others, and I don’t even know if that could make a difference.

    Please be aware that improvements with me happened slowly. Other declines mostly, but not 100%, halted by 2000. Yes, my bladder sucks and I limp, but so what. I’m 64. Wear a diaper and give up jogging. Other things are more important now. For example, I have to go back right now to figuring out how best to try and survive a nuclear war, so excuse me…

    These are all nice posts. I have never seen the flavor of MS expressed so well, even if inadvertently. Good luck everyone. Tuff stuff.

    • Add On- any one interested, I also had my amalgam fillings removed along side of the other interventions, by 1997. And there were a lot. As a matter of fact, first symptoms (numbness of face) happened right after a large pseudo root canal made of amalgam.

  • I am both glad it exists and also, glad alemtuzumab seems to have worked for me after 6 other medicines did not. I am always fascinated by the range of risk tolerance in PwMS, though. Some refuse any treatment at all, or think anti-CD20 is to far, where for me alemtuzumab was welcomed even with the side effect profile. HSCT, though, sounds like a step too far for me personally. I’m well into my 40s and past having more children, yet the fertility aspect is still something my hindbrain finds alarming. I hope I never need to make this choice, but I also hope others find success with it.

    Thank you for this post, it’s excellent.

  • Dear Dr Smets,

    Thank you for sharing your research and thoughts on DMTs and other treatments for people with MS. Rarely discussed, but nevertheless important, is the impact of low carbohydrate diets on people with Relapsing Remitting MS, like me. I follow a Keto diet, eating no meat, bread, sugar or wheat and have not only lost weight but have less brain fog,. Along with regular swimming and visits to the gym, I am slowly working on my balance and memory problems, but my MS sees to be stable – as is my weight! (I also have PCOS). And it costs the NHS nothing…

By Ide Smets

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