Regrets

R

Barts-MS rose-tinted-odometer: ★★

Shortly after leaving Queen Square to take up my current position at Barts and The London Juliet Solomon, a good friend, and one of the research managers who had an office opposite me on the 6th floor of the Institute of Neurology sent me a signed copy of the ‘The Book of Regrets’ she had compiled as a present. She has asked celebrities to write essays on something they had regretted in their lives. The book has become a bestseller with all the proceeds of the sales going to support the National Hospital for Neurology and Neurosurgery. This is the kind of thing Juliet does; she has a very big heart. A mensch!

At the time I thought about what I would write if I was asked to contribute a chapter to the next edition of the book. I am still not sure, but from a professional perspective, my biggest regret is not being more proactive in derisking alemtuzumab as a treatment for MS. It has become clear to me that a small proportion of people with MS (pwMS) who are treated with alemtuzumab and HSCT early in the course of their disease are cured of MS when you use a contemporary definition of an MS cure

If the infusion reactions, infections and secondary autoimmunity problems went away who would choose anything but alemtuzumab to treat their MS?

Infusion reactions: Can we reduce the infusion reactions of alemtuzumab? Yes, we can. Pre-treating with steroids starting the night before and moving from the intravenous to the subcutaneous route would make infusion reactions minor. So why hasn’t this been done? Money! MS centres/units make lucre out of infusing patients. I have used the subcutaneous route to avoid a second about of steroid-induced psychosis, to avoid steroid-induced metabolic mayhem in a patient with MS and type 1 diabetes and in a patient who developed avascular necrosis of one hip after his first course of alemtuzumab. It was remarkable; there were no major alemtuzumab infusion reactions despite these three patients being steroid-free. The pharmacodynamic data, i.e. the cell depletion data for the IV and SC routes are identical. The main reasons for us not switching all our patients to subcutaneous alemtuzumab was money, resource and inertia. In the recent past, we used to make money for the unit by giving infusions. Fortunately, with NHS block contracts, this perverse incentive has disappeared. Sanofi-Genzyme also provides contract nurses who come in to give the infusions and monitor the patients. If we converted our entire alemtuzumab administration programme to a subcutaneous route the workload would fall on our overworked nurses. Our nursing lead in our daycare unit reminded me of this. REGRET 1 we didn’t covert to sc alemtuzumab. 

Secondary autoimmunity: What about preventing or reducing the incidence of secondary autoimmunity?

The immune system has many mechanisms in place to prevent autoimmunity. When you learn how the immune system works it is really quite surprising that autoimmunity is so uncommon. What the immunologists tell us is that there must be a series of underlying biological processes that are causing secondary autoimmunity and if we can work out what these are we can intervene and prevent this complication. This is what Joanne Jones and Alasdair Coles tried to do in Cambridge. Their hypothesis was that because the immune system reboots itself from peripheral memory cells it is more likely to result in an aberrant autoimmune response. They tried rebooting the immune system using more naïve cells from the thymus using the hormone palifermin, which stimulates the thymus to produce more naïve T-cells. Sadly it didn’t work, but at least they tried and they should be congratulated for doing this study.  

Interestingly, when you compare cladribine, another IRT, with alemtuzumab you can’t help but notice that the B-cell reconstitution profiles are very different. With alemtuzumab, they come back very quickly and overshoot their baseline values. We, and others, have hypothesised that if you change the profile of the B cell reconstitution with a small dose of the B cell depleting antibody rituximab you may be able to prevent this secondary autoimmunity. We are really talking about a very small dose of rituximab, i.e. 10-20mg, just enough to delay B cell reconstitution by 4-6 months. I proposed this concept to Genzyme 8 or 9 years ago, but without data to support the hypothesis they were not keen to support an exploratory study. Why didn’t I push to get this funded from another source? If we had done this study back then we would have had the results by now. Can you imagine how impactful this could be for pwMS if we could prevent secondary autoimmunity post-alemtuzumab? REGRET 2 no doing alemtuzumab-rituximab trial and not setting up an adaptive trial platform for testing multiple strategies to prevent secondary autoimmunity post-alemtuzumab.  

Infections: One success story has been the derisking of alemtuzumab-associated infections with prophylactic antibiotics and antivirals, and the proactive approach to baseline infectious disease screening and vaccination. SUCCESS 1 reducing alemtuzumab-associated infections. 

Anti-drug antibodies: Another success story has been exposing alemtuzumab’s problems with anti-drug antibodies (ADAs) and the development of an assay to screen for these antibodies. Why use a therapy, at great expense, that is not going to work because of neutralizing anti-drug antibodies. SUCCESS 2, anti-drug antibody screening.

A big problem that emerged was how alemtuzumab was licensed and used in the USA. The FDA has essentially licensed alemtuzumab with hand-cuffs, therefore, alemtuzumab was and is used as the DMT of last resort in the US. This led to it being used in an older more advanced cohort of pwMS who had comorbidities. In this group of patients, a new adverse event profile emerged, particularly vascular complications. This led to a safety review and the license of alemtuzumab’s use was changed and it is now only used infrequently, second or third -line and often in people with more advanced MS.  I was personally involved with the original EMA submission; it was a real uphill battle to get alemtuzumab licensed as first-line therapy. Allowing the EMA to change how we use alemtuzumab, i.e. making pwMS have to wait to become eligible for the therapy is a travesty. We, Genzyme and MS community, should have made a more robust argument to the CHMP not to change alemtuzumab’s label. REGRET 3 not allowing alemtuzumab to be used first-line in active MS; it can only be used as a first-line agent in patients with rapidly evolving severe (RES) MS (two disabling attacks in a 12 month period). The problem is that very few patients have RES MS as they tend to be treated now before they have their second disabling relapse.  

Finally, my colleagues. Apart from a small group of MSologists, and we know who we are, most MSologists don’t prescribe alemtuzumab. They find the therapy too difficult and risky to use. I have tried to educate and get more of my colleagues to at least offer alemtuzumab as an alternative to HSCT, but to no avail.  In the UK, we were all geared up to do a head-2-head study of alemtuzumab vs. AHSCT. However, once ocrelizumab was licensed the MS community said they would not be able to recruit for this trial so it has now been converted into alemtuzumab or ocrelizumab vs. AHSCT trial. In reality, this study is going to be a head-2-head of ocrelizumab vs. AHSCT study. Not getting the wider MS community to understand how effective alemtuzumab is REGRET 4. Instead of success, we have a generation of refuseniks

The question we need to ask ourselves is do we really want to throw the baby out with the bathwater? We have two, and possibly three, treatment strategies that may cure a minority of pwMS of having MS. Yes, CURE. However, alemtuzumab and HSCT are on the fringe of MS treatments. Why? 

I suppose you are asking about the third option. It may be cladribine. The results of the ORACLE trial of cladribine in patients with clinically isolated syndromes (CIS) are quite remarkable. We are trying to recall the patients from the ORACLE study a decade or more later to see how many are still in remission and haven’t converted to MS. The problem we have is that cladribine is not even a treatment option for CIS despite this stunning data, hence we may be denying a large number of people with CIS, a relatively safe immune reconstitution therapy or IRT, that may prevent many of them from developing MS. The downside of this is the depressing fact that many MSologists still don’t treat CIS (see my blog post on watchful waiting).

Perumal et al. Subcutaneous administration of alemtuzumab in patients with highly active multiple sclerosis. Mult Scler. 2012 Aug;18(8):1197-9.

Alemtuzumab is an anti-CD52 monoclonal antibody with remarkable efficacy in relapsing multiple sclerosis (MS). In clinical trials and off-label use in MS, alemtuzumab has been administered intravenously (IV). Alemtuzumab is approved for chronic lymphoid leukemia as IV. Oncology guidelines recommend alemtuzumab subcutaneous (SC) over IV. There is no report of alemtuzumab SC in MS. We report two patients with highly active relapsing MS who were treated with SC alemtuzumab, had significant improvement and tolerated SC alemtuzumab well without the typical infusion-associated adverse events. SC alemtuzumab in MS warrants further studies as this may enhance patient convenience and minimize infusion-associated adverse events.

Leist et al.  Effect of oral cladribine on time to conversion to clinically definite multiple sclerosis in patients with a first demyelinating event (ORACLE MS): a phase 3 randomised trial. Lancet Neurol. 2014 Mar;13(3):257-67. 

Background: Patients who develop relapsing-remitting multiple sclerosis (MS) present with a first clinical demyelinating event. In this double-blind, multicentre, randomised, phase 3 study we investigated the effect of oral cladribine on conversion to clinically definite MS in patients with a first clinical demyelinating event, when given at the same doses shown to be effective in relapsing-remitting MS.

Methods: Between Oct 21, 2008, and Oct 11, 2010, we recruited patients aged 18-55 years, inclusive, from 160 hospitals, private clinics, or treatment centres in 34 countries. Eligible patients had a first clinical demyelinating event within 75 days before screening, at least two clinically silent lesions of at least 3 mm on a T2-weighted brain MRI scan, and an Expanded Disability Status Scale score of 5.0 or lower. Patients with a first clinical demyelinating event ≤75 days before screening were randomly assigned (1:1:1) to receive cladribine tablets at cumulative doses of 5.25 mg/kg or 3.5 mg/kg or placebo. Randomisation was done with a central web-based randomisation system and was stratified by geographic region. Masking was maintained using a two-physician model. The primary endpoint of this 96-week study was time to conversion to clinically definite MS according to the Poser criteria. This study is registered with ClinicalTrials.gov, number NCT00725985.

Findings: Of 903 participants assessed for eligibility, 616 patients received cladribine 5.25 mg/kg (n=204), cladribine 3.5 mg/kg (n=206), or placebo (n=206). At trial termination on Oct 25, 2011, cladribine was associated with a risk reduction versus placebo for time to conversion to clinically definite MS (hazard ratio [HR] for 5.25 mg/kg=0.38, 95% CI 0.25-0.58, p<0.0001; HR for 3.5 mg/kg=0.33, 0.21-0.51, p<0.0001). Adverse events were reported in 165 (81%) patients in the cladribine 5.25 mg/kg group, 168 (82%) patients in the cladribine 3.5 mg/kg group, and 162 (79%) patients in the placebo group. We noted no increase in risk of adverse events with active treatment versus placebo apart from lymphopenia, which was a severe event in 10 (5%) patients in the 5.25 mg/kg group and four (2%) patients in the 3.5 mg/kg group.

Interpretation: Both doses of cladribine significantly delayed MS diagnosis compared with placebo. The safety profile of cladribine was similar to that noted in a trial in patients with relapsing-remitting MS. Further research could clarify the potential effects of oral cladribine treatment in the early stages of MS.

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.

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.

34 comments

  • Well an elephant in the room would be what about starting an antiretroviral ( HAART) trial in ms ? This sort of trial can be moved forward and potentially cure ms for a majority.

    • Please note the EBV/HERV/viral hypothesis of MS is just that a hypothesis. We have to test the hypothesis by doing well-designed clinical trials. When I get over my COVID-19 blues and my partner in crime Professor Julian Gold gets back to London from Oz we will get back to grant writing and hopefully get our next CHARCOT-PROJECT MS trial off the ground.

      • When you will decide to start those grant writting if you can I would include Dr. Helen tremlett study that should soon be published. The title of her study is : ´´ Human immunodeficiency virus, antiretroviral drugs and multiple sclerosis risk (HIV-MS)´´ Since EBV has the strongest evidence and these antiretroviral drugs can target EBV I would focus my grant writting explanations only on EBV. The reason for that is because it seems more people are open to EBV because of the amount of evidence for EBV compared to HERV.

        • You have been reading the blog too long there is still massive resistence to EBV…I don’t know why

  • The irony in all this is that Patient 2 in your ethical dilemma post would have been very lucky if she had converted to JCV+ many years ago and forced everyone’s hand by limiting the available options.
    How sad!

  • Hello,

    What always confuses me is the phrase “off-label use in MS”, how can neurologist prescribe a drug which is not “meant” to be used in MS? Maybe that’s a stupid question but, is that legal, can a neurologist prescribe it without any consequences?

    What about the administration of the drug, who then takes responsibility for it, are there any hospitals/infusion centres who are willing to take the risk of administration and then of the follow-up blood/thyroid/liver checks etc.?

    If there has been “a large number” of off-label usage of Alemtuzumab in MS, what is there that prevents pwMS from getting that drug on their own, apart from the price tag?

    Cheers!

  • For the purposes of this blog, you wanted to get these regrets out there. I’ve done some really dumb things in my career but I refuse to regret anything. Self recrimination is not good for you. Cannot remember the word for the opposite of regret. MS fog?
    You have been messianic in pursuit of the improvement in QOL for pwMS. Whatever that word is you should be dwelling on it. Regretting at this stage of your career won’t nourish your soul. Believe me, I know this.

  • The cladribine one sticks in the throat. The absence of treatment for cis when data shows 80% later convert to MS is a crime. Considering the amount of money later spent on those patients through the course if their disease it’s also incredibly short sighted / plain dumb

  • Prof G,

    “Do not brood over your past mistakes and failures as this will only fill your mind with grief, regret and depression.” Swami Sivananda

    Don’t be too hard on yourself. From following the blog since the start, I think you take too much on and spread yourself too thinly. I don’t think the academic v clinician conundrum helps.

    My only regret is getting MS. Thanks to Alemtuzumab, 18 years on I can still walk the dog for half an hour. This morning at 6am it was throwing it down, but the smell of the woods and the mass of bluebells easily compensated for the soaking. I think you’ve got enough juice in the engine for one last big project. But you need to rebalance your workload with other activities which don’t involve electronic devices eg watching seals on a Norfolk beach, a weekend rambling through the New Forest, cycling around the Isle of Wight.

  • I’m glad you mentioned cladribine or I would have asked! If it had been available when I was diagnosed I definitely would have opted for it.

    I had my first two relapses years before I was diagnosed. The first cleared quickly and my neuro referral came through months later when there was nothing to see. I learned my lesson and when I developed optic neuritis I went to Moorfields A&E and was seen by the consultant a couple of weeks later because he wanted to recruit me for a trial. But it was only a steroid trial which (as I was already recovering quickly) he thought wouldn’t help me, but if I wanted to help science…? I said no due to too much disruption to my shaky employment situation and my dislike of needles! But if Cladribine had been offered then (end 2014) I think I would have been happy to join that trial. After two relapses and no diagnosis I would have jumped at the chance of avoiding further relapses.

  • Great stuff.

    Questions:
    1. What exactly is CIS ? Is it still being defined as the ‘first demyelinating event’ without any CSF testing being done ? Consider this – a 45 yr old gent presents to the ED with gait problems/falls. A focus of demyelinating lesion shows up on T4, let us say, and he has a level. How many of us do CSF studies in that patient who has a normal brain MRI (let us assume), zero eye issues and the exam itself is relatively unremarkable save the sensory level. Is it still CIS if the CSF shows 7 OCBs, for example and elevated IgG synthesis rate and index ?

    2 What if the patient presents with ON, instead of TM and everything else is the same. For isolated ON, should we do CSF studies ? I do. For both 1 and 2 scenarios. If CSF positivity denotes DIT, are we looking at MS or CIS ? The MAGNIMS criteria probably includes ON as meeting DIS criteria (2018, Tintore M, MSJ) and so even across the Atlantic we have this great divide but I absolutely, 100% of the time, do CSF studies on ALL patients who present w isolated TM or ON and look for DIT criteria. Am I wrong ?

    ‘Jay’ Avasarala

  • I wish i got alemtuzunmab when I got diagnosed, and in fact my neurologist seemed to be pushing for that when i first met her. But alas, my diagnosis came right at the end of the first wave of the pandemic, and I live in what’s possibly the place that, at the time, got hit worst in Europe, so I ended up getting natalizumab.
    It works, but I can’t stop thinking that I’m probably not getting what’s best for my health.

  • Wow. Reading this… My friend who is covered in so many lesions her brain MRI looks like a bowl of popcorn, many holes and brain volume loss. She is now mid 40s. She was infused with Lemtrada (I believe a yrs later is another round of treatment, correct me if I’m wrong) and still continued to decline. Then the popcorn expanded. She went through another round of Lemtrada recently. Total number of years I believe 4 & 3 total rounds). Prior to Lemtrada she was prescribed Aubagio. Instead of another round of Lemtrada, I bet if they had given her the small dose of Ocrevus or Rituximab, she may have been able to avoid this last round of Lemtrada? I wish I saw this sooner, because this last round is hitting her really hard. And in relation to your prophylactic antibiotics and antivirals, they did do this. I have to ask as I am not a Dr, but could they have also added a prophylactic antifungal too such as Diflucan? Since this last round, she has developed thrush that is now becoming systemic! Since being diagnosed (I believe it was end of 2014 as I noticed her walking becoming worse that summer. She also has cerebral palsy & I inquired to her sister asking if cp for any worse. Her sister had been diagnosed with MS a year or so ago with a bad optic neuritis flare). I sadly was diagnosed 6 months after my friend in discussion. Anyways, back to the antifungal… Nothing, and I mean nothing is working. I believe last we talked a few weeks prior, as she lives over an hour away, they were having her take a daily antifungal pill. I myself think if she still has it, they should do IV antifungal. But here’s a good note for her…
    someone who lives in her house contracted Covid, I know, not so good for them. They stayed far away contained except for bathroom. She did NOT catch the Covid!! Yea! Now… to the subcutaneous steroids for the Type 1 diabetic! Omg! Who would’ve thought! I cannot do high dose steroids, nor can I tolerate high dose chemo, but still, I am a Type 1 diabetic since I was 14yrs old, I am now in my mid 50s. I have to be extremely careful with steroids. Not sure if many neuros see this but any raise in blood sugar or if bs gets too low, it actually affects my MS symptoms, and vice-versa. If my MS symptoms are in a bad mood, they affect my blood sugars. My only weapon of choice for when I do have to get steroids (low dose for orthopedic or for when I was on Ocrevus), I am on an insulin pump w/a continuous glucose monitor. I take myself out of automode on the pump, and utilize it’s feature to do a temp basal. I set my temp basal up for the steroids. To figure amount, it depends on the amount of steroids I am getting. Anyways, long end to my comment on your post.. you were correct in your thinking. However, don’t think of these as regrets, it’s never too late. Squeaky wheels get the grease.

  • I’d like to reinforce what Sid and others have said.
    I distinctly recall the letters you wrote to the EMA that you shared on the Blog. You tried to get them to see sense and retain Alem as first line, and the shame of it is that they didn’t listen.
    You’re never able to shoot straight from the blocks either as there’s always the grind of having to put together grant applications and trying to ensure that your trial plans aren’t at risk of springing holes or being a waste of time.
    Time – that other factor that is so indeterminable. How I wish the Covid vaccines had shaken up how all meds are trialled!
    Some of what you’ve expressed I’d therefore assert is more accurately termed as frustration and sadness – that we all experience as PwMS concerning things don’t progress as they should. Perhaps even more so that there are so few ProfGs practising both here and globally.

  • Would prior exposure to Ocrevus substitute for the idea of adding Rituxamab to Alemtuzamab?

    I was offered Alemtuzamab when it was approved but Ocrevus was not. I declined b/c the fear of secondary immunity issues and the need for long term monitoring and possible thyroid drugs felt like a huge risk- in the US without the assurance of having health insurance. Whereas you all are constrained by what the NHS approves, we in the US are constrained by access to insurance.

    • I am not a neuro, but no, prior exposure does not directly address the issue of ADA and secondary autoimmunity. The theory is that a small does of an anti-CD20 shortly after Alem will keep the unregulated b-cells low, and hence reduce the risk of secondary autoimmunity. As Prof.G showed in the charts, with Alem, your b-cells repopulate quicker than your t-cells, so the small dose of anti-CD20 drops those b-cells back down so they have a similar repopulation profile as your t-cells, effectively reducing the risk of ADA and secondary autoimmunity. Honestly, this is why I prefer Clad over Alem.

      Would starting Alem while still depleted from prior use of Ocr have the same de-risking effect? I do not know, but maybe. I would have to say this blogs favorite tag line…..”further studies are needed a to get the answer”…unfortunately.

  • I agree with the “hit hard hit early” strategy to possibly cure MS. Unfortunately I was on interferon from when there was only A,B,C therapies approved and did not switch to a more effective DMT until disability had accrued. I regret not seeking out more aggressive, experimental (I.e. aHSCT) therapies early on even though my neuro never mentioned it. Be your own advocate.

  • Regrets, I’ve had a few
    But then again, too few to mention
    I did what I had to do
    And saw it through without exemption
    I planned each charted course
    Each careful step along the byway
    And more, much more than this
    I did it my way

    [Verse 3]
    Yes, there were times, I’m sure you knew
    When I bit off more than I could chew
    But through it all, when there was doubt
    I ate it up and spit it out
    I faced it all, and I stood tall
    And did it my way

  • Hi Prof G, you said few times Alemtuzumab is not for everyone, where would you draw the line prescribing Ocrelizumab or Alemtuzumab?

    • It is not up to me, but whether or not the patient fulfils the criteria set down by NHS England. Even if they were eligible it would be a guided decision, i.e. I would help the patient make the decision so that they choose the DMT that best suits them. No everyone accepts the risks of alemtuzumab and the burden of monitoring that goes along with it.

      • Thank you for the reply, I also would like to ask in the situation where a patient is asking for your recommendations for him/her, where would you draw the line base on this person’s current disease activity? Or if you were diagnosed with MS when you were 30yo with an average outlook of disease activity, would you choose Alemtuzumab over Ocrelizumab?

        • As I recall, Prof G stated numerous times that if he was diagnosed with MS and he could chose a DMT that he wants, he would probbably go with HSCT/Alemtuzumab. I am not putting words into anyones mouth, that is what I recall from reading most of the articles and comments – I might be wrong on that one.

          • I think a disease activity based decision can actually help, not these red boxes. At least provide some direction? I’m genuinely asking. But I feel Prof G never gets to the point.

  • We all look back in life and now and again we all have regrets. My view on this is that the vast majority of times it’s unfounded. At the time we do the best we can with the information and resources we have. More importantly it’s the intention one has rather than the outcome. So of course you shouldn’t have any regrets, far from it, and definitely NOT retire.
    I once visited a neurologist for my annual consultation. I almost cancelled the appointment as I was a bit under the weather. As is fairly common in the NHS he was running over an hour late. I was his last patient. When I was called in he looked very weary and tired. After 30 minutes I left the room with a spring in my step, made to feel I was the most important patient in the hospital. We all forget how important and under rated these people skills are. The name of the consultant was Professor Gavin Giovannoni.

    I’m sorry, I just can’t understand why you have regrets on not being able to de-risk alemtuzumab. As well as taking on the huge task of fighting the current MS drug system, where would yo find the time?

    Prof, I remember the meeting when you unambiguously and clearly conveyed the pros and cons of Alemtuzumab and left the decision up to me. I think they call that patient empowerment. As I believe in the saying, “Fortune favours the brave”, i decided to go ahead and have the treatment and so glad I did.

    You may have regrets Prof, but all I have is gratitude !

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