Short- or long-sighted

S

I saw three patients 9-and-half-years after starting treatment with alemtuzumab as first-line therapy, yesterday. It was a remarkable experience. Only one of the three patients had needed a third cycle of alemtuzumab. All are in long-term remission; i.e. flat-lining on the EDSS, relapse-free and with no MRI activity (NEDA-3). Their EDSS scores yesterday were 1.0, 1.5 and 2.0. All of them are fully functional, with no physical and cognitive restrictions and described themselves as being well. One patient suggested to me she doesn’t have MS anymore. One patient has had ITP and recovered from it. All three patients have normally functioning immune systems with normal total lymphocyte counts. None of them is concerned about infections, travel, vaccinations or secondary malignancies. This is why treating MS with an immune reconstitution therapy, such as alemtuzumab, is so appealing.

I have a dream that this will be the new normal and all people with MS in future will have similar experiences. I sincerely hope the EMA allows people with MS to be treated and managed the same way as these three patients of mine have. I still have had no response from the EMA to my letter below. Maybe they don’t care?

Can anybody tell me from testing their vision if they are short- or long-sighted?

Open letter the EMA sent  on the 20th August 2019

European Medicines Agency
Amsterdam 

Dear Sir/Madam

Alemtuzumab has transformed the MS treatment landscape. It not only provides superior short term efficacy, but a significant number of patients treated with alemtuzumab note improvement in disability. However, its main advantage over other DMTs is that a large proportion of patients go into longterm remission and normalise the rate of their brain volume loss. In regard to the latter, this is unprecedented in comparison to other licensed MS disease-modifying therapies, with the possible exception of haemopoietic stem cell transplantation (HSCT), which is not licensed and hence not widely available to treat patients with MS in Europe.  Alemtuzumab, therefore, is the only realistic alternative to HSCT, which has become a very popular treatment choice amongst people with multiple sclerosis, in particular, ‘digital natives’ who get their information online. As with all DMTs the earlier you use them the more effective they are and the greater the benefit to the individual patient. Alemtuzumab is, therefore, an important treatment option for people with MS; being able to offer alemtuzumab early as a treatment option is an important factor in my clinical practice to dissuade many Britsih patients from travelling abroad for HSCT. 

At our centre, Barts Health NHS Trust, we have now treated over 250 patients with alemtuzumab with over 40% being treated with alemtuzumab first-line. Patients receiving alemtuzumab first-line tend to have more active disease and less favourable baseline prognostic profile. Despite its side effect profile and the need for monthly monitoring, many patients are willing to take on the risks and the burden of monitoring to be treated with the most effective licensed DMT first-line. All our patients are extensively counselled about the risks and benefits of alemtuzumab treatment and sign an informed consent and a patient contract agreeing to the mandatory monitoring programme. We feel the use of alemtuzumab in the correct environment is relatively safe and the adverse events manageable. Not having alemtuzumab for use in early active disease would mean patients having to wait to fail several other, less effective, licensed DMTs prior to accessing alemtuzumab. I firmly believe in the concept that ‘time is brain and spinal cord’ in MS and delaying access to the most effective treatment would limit our ability to optimise the management of MS in patients with more active disease and in those with a poor prognostic profile. In addition, shifting the use of alemtuzumab to a population of patients with more advanced disease would unfavourably change the benefit-risk profile of alemtuzumab and make it less appealing as a  treatment option. 

The real-life data of alemtuzumab clearly supports it as being the most effective DMT on the market and its other attributes in relation to its posology make it a very appealing therapy; for example in women wanting to start or extend their families.  

In summary, limiting alemtuzumab to a third-line, last resort DMT, will severely limit our treatment options for managing this devastating disease. Alemtuzumab offers many patients with MS a real hope of living as normal a life as possible, however, this option does depend on using alemtuzumab early in the course of the disease. I, therefore, appeal to the MS community and the European Medicine Agency to consider these factors when reviewing the benefits and risks of alemtuzumab as a treatment for MS. 

Yours faithfully 

GAVIN GIOVANNONI

CoI: multiple

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.

37 comments

    • The answer is in the Snellen chart. The data looks like alemtuzumab when used early prevents, or delays by decades, the onset of SPMS. If you use alemtuzumab late (3rd-line), i.e. as the FDA and EMA want us to use it, then it is unlikely to prevent SPMS. I also suspect that a proportion of MSers treated with alemtuzumab, or for that matter HSCT or cladribine, may actually be cured. The question is how to define a cure in MS? Just imagine these three patients flat-lining at 15, 20, and 25 years; I can and wouldn’t be surprised if that happened.

      • Shouldn’t Medicine have a single definition of cure. For instance if your cancer free for 5 years you are considered cured. OK MS takes it effect over a longer duration. However it’s still a cure if no symptoms for 5 years. And if it does rear it’s ugly head after 5 years then it’s a new disease?

        • You’re dead right. Five years is a statistic not actually a proven cure. That’s why there’s been a campaign to help cancer patients following discharge after the all clear.

          • In cancer, as in MS, we avoid using the C-word or Cure. The oncologists use NEDD (no evident detectable disease) and MSoloists NEDA (no evidence of disease activity). As you know most people who are NEDA are not cured.

      • Is Alemtuzumab back on release? Didn’t they put a hold on it?

        Ps The possible delay of DECADES is in my mind (a pwMS)the best thing to a cure.

        I have asked this question before but nobody ever answers….do they treat cancer softly softly, or do they go in with the big guns first?

        • Re: “…do they treat cancer softly, or do they go in with the big guns first?”

          It depends on the type of cancer and its stage. Sometimes, for example with prostate cancer in the elderly, chronic lymphoid leukaemia, myeloma or papillary carcinoma of the thyroid, you watchfully wait. With other types of cancer, it is surgery and big guns.

          • Thanks for that.
            We know that about 80% go on from RRMS to the next (worse) stage. How can us patients let it be known we want to be treated aggressively from the start? Would writing to NICE have any effect?

            Is Alemtuzumab still on hold for new referrals and what would be the next best of the current crop?

          • Re: “Is Alemtuzumab still on hold for new referrals and what would be the next best of the current crop?”

            Yes, the EMA still has it on hold.

  • Prof G,

    Thanks for this positive post. I’m in a similar position, but 13 years after my first Alemtuzumab infusion. I have a slightly higher EDSS score as I had fairly aggressive relapses and didn’t start treatment until 3 years after diagnosis. I wish I could have started Alemtuzumab straight away but was initially put on an injectible (as Alemtuzumab wasn’t a licensed therapy at that time).

    For most, Alemtuzumab appears to be an excellent therapy for suppressing relapses, MRI activity and pushing back SPMS. It also does wonders to your mindset – able to plan for the future, hopefully remaining in a good enough condition should any therapies that promote repair ever make it to market.

    I hope the EMA see sense.

  • This really evidences, albeit at a minimal level, the validity of treating early with one of the more effective treatments. It equally challenges the escalation model and most importantly the EMA slapping Article 20 onto Alemtuzumab.
    DO I WISH YOU WERE BEING HEARD LOUD AND CLEAR!

    Perspective is an interesting thing and how it evolves over time. Those with a diagnosis of SPMS or PPMS must struggle to read of such positive news. Even I, as someone not quite two years post treatment, am still concerned and alert to risks such as infections. Whilst having eased off from being hyper-vigilant, my monthly screening and nurse monitoring and knowing that thyroid problems most typically occur at three years reinforces this.
    Then I’d add what I’ve continued to learn from the Blog – have flu vaccination, potential risks from such as reduced uptake of childhood vaccinations etc, etc.

    May I ask: Did you raise with these patients the issue of smouldering MS?

    Did you think it pertinent to remind them that, to date, Alem can’t be considered a cure and that they need to remain alert to signs of deterioration, especially with the patient who suggested she doesn’t have MS anymore?

    Or will it be increasingly the case that neuros such as yourself will feel able to positively endorse such a positive perspective with NEDA3 of more than five years?

    • We recommend to our patients to read the blog and we have research days to update them on emerging topics. I did mention delayed worsening due to early ageing to two of the patients yesterday as they are at the age when this occurs (50s), the other patient is in her 30s.

      • Regarding the research day. We are still waiting for UCL (Queen Square) to host the next one; it has been 3 years since the last London research day. Although we did host a Barts-MS research day in the Western Isles last year.

      • “I did mention delayed worsening due to early ageing to two of the patients yesterday as they are at the age when this occurs (50s),”

        Is there anything the patients can do about this (I’m in the same position)? Such a frustrating disease. Even when you go for the big guns against the disease it still comes back to bite you.

    • Re: “Or will it be increasingly the case that neuros such as yourself will feel able to positively endorse such a positive perspective with NEDA3 of more than five years?”

      The answer is in the Snellen chart. Have you cracked it yet?

  • How does Alemtuzumab compare with other highly effective therapies such as Ocrelizumab and Natalizumab when used first-line and at diagnosis, or close to it? For those people who have stayed on these maintenance therapies long-term and been on them from early on in their disease course are they just as effective? Are these statistics available? Thank you.

  • Sounds very positive for these patients and I hope it continues to go well for them.

    I would note, however, that I saw, felt no change in the first 10 years of my slow PPMS.

    • People with PPMS are the unlucky few who miss out on the relapsing-remitting phase of MS. When they present they have had the disease smouldering away for a decade or more. So by the time we start treatment in PPMSers it is late in the course of the disease, hence the limited treatment effect of the therapies.

      • Yes, it fits with my experience that I have had smouldering but not much immune system reaction. I personally don’t feel so unlucky in that, 2 decades from first signs, I’m doing very well in many ways and require no medications. And no treatment means no side effects at least, no monitoring. But I am hoping there will be antivirals and neuroprotectives. Soon…

  • https://multiple-sclerosis-research.org/2019/01/beyond-neda/
    FROM JANUARY:
    Prof G
    January 26, 2019 at 9:42 am

    I think we now need to compare HSCT to alemtuzumab to see which one comes out on top in terms of efficacy and safety. If HSCT wins then we are going to have to upscale our HSCT units to cope with the avalanche. We would also have to consider offering HSCT first-line.
    …………………………..

    Prof G….are these still your thoughts with regards to HSCT and Alemtuzumab?

    • Yes, nothing has changed. I am slightly concerned about comments and events with Richard Burt’s HSCT unit in Chicago. A lot of the hype around HSCT is based on his data.

  • Very important Snellen chart. Two questions that arise:
    Why dont all professors in MS, internationally, meet and agree to do an academic head to head randomized trial for all highly effective DMTs including HSCT? This would answer all questions and stop all ”speculative” arguments that arise when comparing DMTs by comparing different studies with different designs and by post hoc analyses that can be biased.
    Also, early treatment is bound to early diagnosis. Better education for neurologists, GPs, physiotherapists about when fIrst MS symptoms should be ”suspected”. Time from first symptoms to diagnosis can decrease.

    • They haven’t been tested. The serum NFL assay is not being used in routine clinical practice at the moment. We are waiting for the assay to be validated. However, based on the presented data of alemtuzumab on pbNFL levels presented at ECTRIMS 2018 they have about a 50% chance of having levels below 8pg/mL.

  • I only wish that neurologists in Australia shared your views. Here newly diagnosed young msers are unlikely to be offered alemtuzamab as the risks are considered too great. When are the people with the disease going to be treated as adults and be allowed to make their own decisions about how much risk they take in their treatment.

    • Alemtuzumab, and for that matter HSCT and cladribine, is not for everyone. The message I am promoting is that it is about choice.

  • Hit hard and early! I think it is the most important, but please do not get the SPMS label when patients got Alem later.
    I know a wo

  • Hit hard and early! That’s the most important, but i know a lady who use interferon from the end of 90’s and she is able to stand. And when she started it, her condition was the same. So interferon stabilised her MS (in spite of the fact she was wheelchair user). So maybe alemtuzumab could be game-changer later on the disease too. Ok-ok with residual sympthoms but possible stable disease… Hope it’s gonna be true.
    And hope Alem gonna be pot. 1st line again.

  • Treat early and effectively to prevent disability 👊🏼
    This is really promising and has given me hope. Lemtrada is my first DMD and I was diagnosed very early before I accrued a lot of disability so that has renewed my hope a little. I’m not sure if it’s the EMA position of whether I’m still adjusting to the diagnosis but I haven’t felt so positive about it all lately so this is just what I needed to read

  • Hello Dr Giovanni, I find your posts both fascinating and exceptionally informative. This is my first post, I will try to keep it brief. In 2012 I experienced a quick onset of pins and needles in my feet, which moved up my legs, my feet were quite uncomfortable to put shoes on never mind walk on. I was quickly diagnosed with Transverse Myelitis, Antivirals & Steroids gave. 1 lesion on spine, no brain scan until 5 months later, showed a number of white spots but Neuro did not diagnose MS, conservative in his approach, his words not mine. Advised residual inflammation would leave me with certain sensory issues. Fast forward 3 years, numerous scans and a lumbar puncture I was eventually diagnosed 2015. Placed on Tecfidera, 18 months, further lesion in neck area. Unsuitable for Tysabri due to high positive JCV, Lemtrada Round 1 June 17, Round 2 July 18. MRI’s Jan 18 & July 19 both show no new evidence of MS related activity.
    Since 2012 my symptoms have worsened, sensory issues more prevalent – tightness in torso, bruised like feeling in rib cage, joint pain and sensory issues in legs and feet. Neuro and GP believe/advise symptoms are a result of initial diagnosis of Transverse Myelitis. I take several medications for the pain but it only helps a little. Neuro reports that I suffer from intractable pain which is difficult to treat. When my symptoms go into overdrive I worry that it is another lesion or SPMS. I queried if I would have had lemtrada as a 1st line treatment would it have prevented how I feel now? However Neuro advises no as TM is root cause of my symptoms, I struggle with this as I feel worse now than I did several months after TM diagnosis???? What’s your views on this?
    Many Thanks in Advance

By Prof G

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