Mortality: what risk would you be prepared to take?


Barts-MS rose-tinted-odometer: ZERO-★’S (Black Tuesday – a tear for my beloved country #000000)

As you are aware by now I am a proponent of flipping the pyramid and using high-efficacy DMTs first-line including immune-reconstitution therapies (IRTs) such as alemtuzumab and AHSCT. I justify the latter two options based on the fact that given sufficient time the vast majority of pwMS will become disabled and  the real cost of MS to people with MS cannot be underestimated; loss of employment, poor relationships, cognitive impairment, fatigue, depression, anxiety, etc. I think you get the gist; MS is a bad disease. 

Alemtuzumab and HSCT are the two standout treatment options that offer pwMS the best chances of long-term remission and in some pwMS it may offer a cure. What impresses me about these two options is their impact on the end-organ, i.e. brain volume loss. After rebaselining at 12 months, pwMS treated with these two options lose brain volume on average at a rate that is within the normal range for age. The other DMTs don’t do this. The downside is that these two treatment options come with more risks. These two real-world studies below report 2 deaths out of 121 (2.5%) alemtuzumab-treated patients in Finland and 3 out of 120 HSCT-treated patients in London. Would you be willing to take these chances of dying to treat your MS with the potential for long term remission, possibly a cure and to protect your most precious end-organ the brain? 

Rauma et al. Safety of alemtuzumab in a nationwide cohort of Finnish multiple sclerosis patients. J Neurol. 2021 Jul 13. doi: 10.1007/s00415-021-10664-w.

Background: Alemtuzumab is an effective disease-modifying therapy (DMT) for highly active multiple sclerosis (MS). However, safety concerns limit its use in clinical practice.

Objectives: To evaluate the safety of alemtuzumab in a nationwide cohort of Finnish MS patients.

Methods: In this retrospective case series study, we analyzed the data of all but two MS patients who had received alemtuzumab in Finland until 2019. Data were systematically collected from patient files.

Results: Altogether 121 patients were identified, most of whom had received previous DMTs (82.6%). Median follow-up time after treatment initiation was 30.3 months and exceeded 24 months in 78 patients. Infusion-associated reactions (IARs) were observed in 84.3%, 57.3%, and 57.1% of patients during alemtuzumab courses 1-3, respectively. Serious adverse events (SAEs) were observed in 32.2% of patients, serious IARs in 12.4% of patients, and SAEs other than IARs in 23.1% of patients. Autoimmune adverse events were observed in 30.6% of patients. One patient died of hemophagocytic lymphohistiocytosis, and one patient died of pneumonia. A previously unreported case of thrombotic thrombocytopenic purpura was documented.

Conclusions: SAEs were more frequent in the present cohort than in previous studies. Even though alemtuzumab is a highly effective therapy for MS, vigorous monitoring with a long enough follow-up time is advised.

Nicholas et al. Autologous Haematopoietic Stem Cell Transplantation in Active Multiple Sclerosis: a Real-world Case Series. Neurology. 2021 Jul 12;10.1212/WNL.0000000000012449. 

Objective: to examine outcomes in people with multiple sclerosis (PwMS) treated with autologous hematopoietic stem cell transplantation (AHSCT) in a real-world setting.

Methods: retrospective cohort study on PwMS treated with AHSCT at two centers in London, UK, consecutively between 2012 and 2019 who had ≥ 6 months of follow-up or died at any time. Primary outcomes were survival free of MS relapses, MRI new lesions and worsening of expanded disability status scale (EDSS). Adverse events rates were also examined.

Results: the cohort includes 120 PwMS; 52% had progressive MS (primary or secondary) and 48% had relapsing-remitting MS (RRMS). At baseline, the median expanded disability status scale (EDSS) was 6.0; 90% of the evaluable cases showed MRI activity in the 12 months preceding AHSCT. Median follow-up after AHSCT was 21 months (range 6-85). MS relapse-free survival was 93% at 2 years and 87% at 4 years after AHSCT. No new MRI lesions were detected in 90% of subjects at 2 years and 85% at 4 years. EDSS progression-free survival (PFS) was 75% at 2 years and 65% at 4 years. EBV reactivation and monoclonal paraproteinemia were associated with worse PFS. There were 3 transplant-related deaths within 100 days (2.5%), all following fluid overload and cardiac or respiratory failure.

Conclusions: efficacy outcomes of AHSCT in this real-world cohort are similar to those reported in more stringently selected clinical trial populations, although the risks may be higher.

Classification of evidence: this study is rated Class IV because of the uncontrolled, open-label design.

Conflicts of Interest

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General Disclaimer: Please note that the opinions expressed here are those of Professor Giovannoni and do not necessarily reflect the positions of the Barts and The London School of Medicine and Dentistry nor Barts Health NHS Trust and are not meant to be interpreted as personal clinical advice. 

About the author

Prof G

Professor of Neurology, Barts & The London. MS & Preventive Neurology thinker, blogger, runner, vegetable gardener, husband, father, cook and wine & food lover.


  • No since simvastatin is likely to turn into a positive trial and btk inhibitors as well since they inhibit intrathecal b cells. I probably feel most comfortable being on ocrevus while losing some weight so my risk of disability progression is lowered and as an add on therapy have alpha lipoic acid.

    This should buy me enough time to see the results of these btk inhibitors coming out in 2023 in terms of brain volume loss in the rrms population.

    Add to the fact that Niacin might be tested in the octopus trial and therefore we might have a good idea in 18 months if there were any effect so by 2023.

    Also there is another phase 2 trial of alpha lipoic acid being tested in progressive ms with the expected completion date being in 2023.

    All these reasons put together makes me feel uneasy about taking risks with alemtuzumab or HSCT.

    • Didn’t the BTK inhibitors show “weak” results in the terms of slowing the brain atophy? However given the fact how many trials, new drugs are being currently tested/developed, if I had to chose between going for aHSCT or waiting 24 months to possibly see some breakthrough in DMTs – I think I would wait and hope for the best.

      • No we don’t have any data in terms of brain atrophy. You most likely are referring to Masitinib which is a Tyrosine Kinase inhibitor which is not the same thing as a BTK inhibitor also called BrUtOn Tyrosine kinase inhibitor.

  • Prof G, it is being widely stated by the part of the Bart MS publishers that Alemtuzumab has some great impact on brain atrophy, because it does something to the brain that we can’t yet explain – however it works great for brain atrophy.

    Another part of the publisher state that the low brain atrophy rate after use of Alemtuzumab is only caused by the fact that mean time from disease onset was ~2 years in both of the Lemtrada Trials, and other drugs were tested on some more advanced pwMS.

    Do you think that the favorable results for brain atrophy rate after Alemtuzumab can be achieved even in people who have had MS for 5, 10, 15 years and are still in RRMS?


    • Yep, the CARE-MS2 population had a disease duration of close to 5 years. Many of the HSCT cohorts have had a disease duration much longer than that. Saying this there is clearly an age-dependent effect on BVL in alemtuzumab patients, but the older cohorts still do well.

      There is something different about alemtuzumab and HSCT, which the other DMTs don’t offer. The signal is also in the disability improvement data; a larger proportion of people notice an improvement in disability with these therapies compared to the other DMTs.

      • I always look at the statistics on improving the degree of disability with both eyes closed, it seems to me that this particular value is often stretched …

        In my case I know that before HSCT I had an EDSS of 0.5-1.0 (reduced visual acuity in the left eye ). At qualification, my EDSS was assessed by a neurologist at 2.5, then at the follow-up visits after HSCT, when my condition was examined and I was asked about it, I said that I feel the same as before HSCT and nothing has changed in my case, I still have this reduced severity in my left eye but magically my EDSS dropped to 0.0-0.5, MIRACLE. It seems to me that the most appropriate one will probably always be to look at this statistic in total as “no progression”, although I may be wrong.

        Thank you for your answer, I have to take a look at the CARE-MS2 study assumptions as it seemed to me that it was similar to a 2-year group.

  • For non-active PPMS the risk/benefit is off. Still i asked myself this question a lot and after a lot of thinking i would take a death rate up to 50%. All depends on the chances of long turn remission. This might sound crazy and people might think i am trying to be a tough guy, Well i see myself as a selfish coward who is afraid of a hard life in a wheelchair filled with all kind of comorbidities.

    • I am not so sure…52% progressive, so hardly any recovery. Also, it is very hard to believe that all of 48% RRMS had relapse and all have been in recovery phase. Actually, statistically looking this tells that many people must have had higher edss on the baseline as average is 6 . So, detailed analysis must be done looking on the all parameters in this equation. This could also lead to conclusion that, for example, nobody died who was younger than, let say 50, and with edss below 5? Consequently, conclusion would be that you must perform aHSCT as soon as possible , and possible cure yourself .

  • Would cladrabine normalise brain volume loss for some people treated? And is a safer option and possibly as effective.

    For example the people where cladrabine clears OCBs?

    Or does no OCBs not always correlate with increase brain volume loss?

  • I am tantalised by the abstract, because the summary stats clearly suggest that AHSCT is pretty effective in progressive patients. (Although it’s only a small cohort.) Is it possible to drill down any further – as it looks at this blurry distance to be saying there IS a highly effective treatment for progressive disease – something we all worry does not exist, yet anyway.

    The jeopardy is alarming, but since going on accruing disability and losing brain is also peril, in slower motion, I think I would take the risk.

  • At almost 60, after 35 years with MS, I preferred not to take alemtuzumab, but now I’m in doubt if I made the wrong choice

  • I think this is generally a wrongly stated case and the question. Average edss of 6 definitely gives some insight of general health of people involved in the study; therefore mortality rate is very relative to it. What if the aHSCT is given on the start, with younger and healthier body? In this population, progressive patients actually don’t have any other choice in terms of actual prescription practice? Finally, in 2021 and with the current technology, initial checkup can be done so thoroughly that initial patient selection should eliminate any mortality. How do we make this?

      • I am not so sure…52% progressive, so hardly any recovery. Also, it is very hard to believe that all of 48% RRMS had relapse and all have been in recovery phase. Actually, statistically looking this tells that many people must have had higher edss on the baseline as average is 6 . So, detailed analysis must be done looking on the all parameters in this equation. This could also lead to conclusion that, for example, nobody died who was younger than, let say 50, and with edss below 5? Consequently, conclusion would be that you must perform aHSCT as soon as possible , and possible cure yourself .

  • Our perception of risk and benefit are confused and highly dependent on our observations and inherent bias.
    If you are a consultant neurologist you will be seeing a lot of ill people with rapid progression and feel you need to do something about it.

    If you are recently diagnosed and join an exercise group for people with disabilities (predominantly MS but as an inclusive bunch a couple with ataxia and one with Huntington’s), you have a different sample. The ones with MS consider themselves amongst the lucky ones. The group has being going for around 30 years and some of the original members are still alive and active at 80. Of course this group is biased towards the survivors most of whom lead the most fulfilling life they can rather than waiting for the magic bullet.

    Neither sample capture the full population of pwMS.

    In an ideal world the newly diagnosed would have knowledge of how they would progress and what their treatment options were. Until we are able to so we are left with the status quo where people are put on to stronger drugs if their symptoms warrant it or the flip the pyramid where you apply the big guns (with their inherent risks) to all at the earliest opportunity.

    I have not seen a tree chart plotting out the probability of disability progression (and perhaps I don’t want to). I take comfort from those I know have survived from the pre drug era and live their lives to the full.

    I am not against DMTs and opted for the most effective I was offered. I have had to stop Tecfidera because of low lymphocytes and its associated risk of PML. If I am offered another choice I will look at the risks as well as the benefits.

    When we can predict the benefits and risks on more personal information our choices may be better founded.

  • That was very interesting. I’m feeling exhausted in having to deal with MS for 16 years, spms now to be more specific. Never DMDs. Given the choice, I’d rather work three jobs, but that obviously is not an option. My new doctor may recommend ocrevus. I’m not sure; some other clinician said that at this stage of the game, I’m nearly 60, people would stop even using such drugs.

    Dying is inevitable for everybody, and I am a Christian. But I will admit that I’m really not ready for that yet. And I’m not one to gamble. I used to be very active, including jogging and skating, and as much as a wheelchair makes me cringe, it’s more of a sure thing then the horrific possibility the stress of such meds.

    • Jan! She is greatly understating her pre MS athleticism, she’s kinda a big deal. 😊 Hey, contact me if I guessed right (your houston ms friend)

  • I’m willing to risk it all. I have PPMS. I’m 68 and I’ve been on Ocrevus for the past 4 years. I’m still living independently, but need lots of support. I am willing to continue trying whatever is recommended. The women in my family have lived until the late 90’s and the thought of living in nursing home for years scares me more than death.

    • “’I’m willing to risk it all. I have PPMS. I’m 68”

      Ppms with no lesions usually don’t see improvement but
      you have around 50% chance to stop progression with hsct.
      People your age have done the treatment…It’s not a test of strength
      or endurance but a matter of avoiding infections for 2 weeks when
      your cells are depleted.

  • I appreciate the response by Anonymous, he summarized my notes (somewhere here). Thinking back to my original Intro to MS, I would not have taken the chance with such limited data. As it stands now, probably the right choice, but I do have to deal with some of the things the Dr. mentions. For now, at 63 and 34 years later, sure it’s been a pain in the A; I wonder what life would have been like without MS, but I’m a happy camper and don’t reflect on “what if?”. If I were new to this whole mess again, I’d be looking at and studying outcome stats thoroughly and unless it looked like I was going to be bed-ridden, I’d still say no.

  • Anti-CD20 on its own is basically guaranteed SPMS. The only real “risks” of alemtuzumab are treatable thyroid problems. At the very least everyone should be getting on alemtuzumab if HSCT scares them.

    • There’s a few more risks than just Graves Disease and there is also a significant proportion of pwMS who develop anti-drug immune responses against alemtuzumab over time. Apart from that, point taken.

    • Not given, but give the choice of alemtuzumab. Many neurologists simply don’t give patients the choice as they have decided it is too risky for patients; in other words, they have prejudged patients decisions.

      • Where alemtuzumab is not offered do you think natalizumab used early is as effective to reduce chances of progression to SPMS?

      • I’ve been taking Natalizumub for 16 year’s and NEDA. is a good time to change to HSCT or alemtuzumab .Age 49.

        • “. is a good time to change to HSCT or alemtuzumab .Age 49.”

          Yes because most start progressing in their 50’s…one man posted here he had rrms for 50 years but when spms started it was like night and day difference. hsct is just more effective..and some of the clinics have 2 deaths in 1000 cases
          which is .2….the hsct rate posted in this blog is insanely high.

  • I was diagnosed RRMS in 2018 after CIS in 2015. Currently the only DMT I’ve been offered is interferon. I’m waiting for a 2nd opinion to try and get Ocrevus as I want the most effective treatment possible given what’s available.

    But if Alemtuzumab or AHSCT were available I would probably still opt for Ocrevus. For me, the risks of the other two treatments outweigh the benefits at this point. I’m hopeful that in the next 10-15 years a new generation of treatments will be available given recent progress. If Ocrevus can slow progression (and BVL, 17.5% ORATORIO) my hope is that it will buy enough time for those treatments to be available. I’m the meantime I’ll do what I can to try and keep healthy – Vit D, ALA, Q10, exercise, education etc.

    It might be a gamble that doesn’t pay off, but given the side effects of the other treatments that’s a gamble also. Plus it’s not an option currently. I think it’s a bit of an impossible question, with serious side effects but no clarity on how the disease will progress and at what speed making a rational decision is very difficult.

    • If you are in the UK I believe you legally have the right to any of the first-line therapies, which includes Ocrevus. If you asked for it and were denied, the neurologist who denied you may be breaking the law. Hope you can get the second opinion soon.

  • Absolutely would take this risk on. The risk of NOT treating with high efficacy treatment early is worse in my opinion. As a patient I’d rather end my life early than live a longer one with impairments while watching life disappear little by little. That is a fate much worse than death in my opinion as a pwMS

  • Obviously, for most patients the amount of risk is proportional to their level of disability or EDSS. I’m sure a patient at 0 -2 on the EDSS is less likely to risk the procedure than someone who is higher on the scale.

    • “Obviously, for most patients the amount of risk is proportional to their level of disability or EDSS. ”

      No…you have it backwards..if you are high disability they won’t even give you the treatment.

      One man edss 8.5 wanted hsct to save his one good arm/hand but he was denied treatment as
      they told him any benefits were not worth the risks. Similarly a woman wanted hsct for daughter who could not move her arms or legs and was not accepted.

      • I was not referring to the availability of HSCT and EDSS but the risk aversion and a patient’s level of disability. Patients with higher EDSS are more likely to assume more risk as their disease progresses. On the other hand patients with less disability will tend toward less risky DMTs.

        • “On the other hand patients with less disability will tend toward less risky DMTs.”

          No…this is misguided…this post is making it seem like hsct has 3% mortality…when in reality some foreign clinics it is under
          .2%…also patients assume DMT’s work to stop progression…when they don’t. So they don’t realize they are
          hurting their health on DMT. And neurologists say new dugs are better when Sweden now says Rituximab is worse for your brain than Betaseron which came out in ’93. So no progress in decades. still hear this: “The treatment is not for everyone. Only about five per cent of all patients with MS warrant a bone-marrow transplant, says Freedman. Those who undergo the treatment are among the youngest and also have the most aggressive and debilitating forms of the disease.”….”For other patients, Freedman says, there is ever improving medication that successfully treats them and keeps symptoms at bay…The world of MS treatment has changed dramatically in the past two decades. The first treatment for MS wasn’t approved until 1995. Since then, there has been steady progress.”….Sad…because he doesn’t realize anything about spms…so his patients don’t either until they get it.

    • Not certainly, it highly depends on the personal beliefs and understanding the risks of undertreating MS. I had aHSCT when I was 21 years old, HAD MS for 14 months, EDSS 0.5. Wanted to have it done even earlier but I needed to have MS for at least 12 months to qualify, it was holding me back for 8 months.

  • A couple of years ago when I was single no doubt I would have taken the risk.

    But now, living in a nusery home, where I met my lovely wife, no way I will take this risk.


  • I would take the risk i took the risk being onTysabri -Natalizumub for 15 years and neda. Watching my mother battling cancer with Chemotherapy and Radiology and survived when told she had 5. I take the risk to slow down my ms.

  • There was a point in time where I absolutely would have taken the risk and higher than these numbers. I’m stable now so currently the answer would be no. Looking back I would still support my past self having had more agressive earlier treatment with the risks because I would likely not have some of my irreversable symptoms.

  • I have been diagnosed with RRMS for two years. I follow this blog quite closely and very much appreciate all the research and effort poured into this. I work in healthcare on the clinical side which fortunately allowed me to catch this disease early on.

    I am essentially symptom free at this stage with the exception of reduced visual acuity in one eye at night the last relapse left me with.

    I am currently on tecfidera looking to change. I have wanted to do HSCT since the start but my neurologist is not on board and attributes that to my very mild disease (5 small lesions) and the high risk of HSCT which I can respect.

    I am on the perspective of let’s not risk this disease going anywhere and keep it that way. I currently have the option to switch from tecfidera to rituximab. I would prefer Ocrevus; however I would have to fund that myself which is not ideal.

    I am curious if anyone can share an opinion on going on HSCT with very mild disease as most of the research I have found includes people who have a higher EDSS score than myself or is it better to go on the rituximab?

    Thanks in advance

    • I guess for many pwms is that the case ( low edss, md ms…) until they rapidly go to high edss score…and that is exactly the problem. Doing hsct early seems like almost only choice to prevent that.

  • I like to think I’d have jumped into alemtuzumab first line instead of seventh, but I also know it’s the insidious fear of MS whispering at the back of my neck that amps my tolerance for risk over time. Drugs that used to scare me now seem like cotton candy with ten years of perspective. Then again, partial TM at diagnosis may have been motivation enough to make me beg for a Lemtrada cocktail given a proper discussion of risk. AHSCT? I’m not sure I’ll ever be brave enough, and I hope I never need to find out. I’m all for both being options, though. I fully believe patients need to have more control over the scope of risk they are willing to accept.

  • I guess for many pwms is that the case ( low edss, md ms…) until they rapidly go to high edss score…and that is exactly the problem. Doing hsct early seems like almost only choice to prevent that.

  • I had just finished my first round of Alemtuzumab/Lem by a few months here in Canada when the black box warnings emerged. I had failed spectacularly through my requisite first 2 drugs (2-teired system here) before I could campaign for Lem. Having 6 relapses in my first year, the first of which brought profound continuous vertigo and reduced sensation and weakness from the neck down, thankfully they supported my request for Lem (we don’t really do HSCT here much). As far as I was concerned, it was Lem or nothing. HSCT had too high of a risk for me at that time, even if I could have gotten it. Willingness and/or desperation perhaps, all depends on a person’s threshold and their disease course, I would guess.

    I won’t say the black box warnings didn’t give me pause, it wasn’t just an “in for a penny, in for a pound” thing either–my relapses stopped immediately after my first treatment and a bit of mild recovery took hold. It has been over 5 years now, like a distant dream of how hard my relapses hit (my Grandpa died of PPMS) and I’m still thanking my lucky stars I did it, despite developing quite bad Graves’ disease (the endocrinologist was amazed at my levels, plus 2 rounds of radioiodine, the second of which they doubled the usual dose and I’m still hyperthyroid). I’m also still relapse-free *knock on wood*. The thought of what I had to lose was directly related to my willingness to go extreme early, and, being at the crux of the age where the data I read generally showed it Lem’s effectiveness begins to wane as far as I could tell from my layperson reading (I was just reaching mid thirties).

    I will say, this blog played a huge role in my decision, I went in educated, I read about it voraciously every paper and link. I went in knowing what to expect, the risks then, and the unknown of it being still an early treatment. I knew that if I could have waited longer perhaps it could have been de-risked so I didn’t develop secondary autoimmunities… but I didn’t have the time to burn. I leapt, and I’m grateful I did. Despite everything I could never look back or say no to round 2. Probably I’m grateful I did because it worked.

    The thyroid thing is a pain, yes… it it is a temporary setback, it is easily managed. My MS wasnt. I mostly self manage the thyroid with the help of heart rate monitors and labs, and the docs support me finally in doing that, which is suiting since I first had to self diagnosed MS when no one would listen (“MS does not present with vertigo”–yes, it can, was my grandfather’s first symptom as well, he died with PPMS), I privately paid for an MRI in publicly funded healthcare to go around them to get my way. I diagnosed the Graves when showing up at the ER with a ridiculously high heart rate and the Lem wallet card that said I had a higher risk of Graves (that none of the docs there would listen to or read lol). Once again, I INSISTED on the test and was right (it wasn’t rocket science, apparently the wallet cards are useless here, they tried to ignore it twice until I got on them about it).

    To me it is a bloody shame the hoops people have to jump through in Canada to get to an effective treatment, when I too know that time is brain. I accrued significant cognitive deficits in my time pushing for my treatment, had to push for Neuropsych testing to prove it is much more significant than they were willing to see. That too was played off because I am generally high functioning (or was prior). I’m 3 for 3 now on the diagnosis front, and finally I have medical professionals that listen to me and treat me like a partner or leader in my own care (of which partner in care should always be the case). If I had been uninformed about the consequences of Lem, standing in my way might have made sense. My neuro apologized to me for the Graves and I was taken aback, because I knew with thyroid conditions in my family my likelylood of getting that complication was probably higher, so I banked on it. I told him there is no need to apologize for stopping my MS (or hitting the pause button, if that’s the long-term outcome), I walked into Lemtrada knowing exactly what might happen and I made my peace with that. MS has made me brave, strong, tenacious, impatient and having my priorities straight, even there are significant consequences.

By Prof G



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