Alemtuzumab update

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A review of the benefits and risks of alemtuzumab (including fatal reactions) in the treatment of multiple sclerosis has now concluded and recommended a revised indication, additional contraindications, and strengthened monitoring requirements before, during and after treatment. Patients offered alemtuzumab should be alerted to the early risks of cardiovascular events and thrombocytopenia around the time of infusion and to the delayed risk of immune-mediated reactions. Healthcare professionals should inform patients what to do if they develop any symptoms of these disorders.

https://www.gov.uk/drug-safety-update/lemtrada-alemtuzumab-updated-restrictions-and-strengthened-monitoring-requirements-following-review-of-serious-cardiovascular-and-immune-mediated-reactions

Contents

  1. Restricted indication and new contraindications for use
  2. Frequencies of reactions reported
  3. Revised monitoring requirements for alemtuzumab infusions
    1. Before starting alemtuzumab infusions
    2. During alemtuzumab infusions
    3. After completing alemtuzumab infusions
  4. Updated risk management programme
  5. Report any suspected adverse drug reactions on a Yellow Card

Advice for healthcare professionals:

Restricted indication

  • alemtuzumab should only be used as single disease-modifying therapy in adults with either:
    • highly active relapsing-remitting multiple sclerosis despite a full and adequate course of treatment with at least one disease-modifying therapy or
    • rapidly evolving severe relapsing-remitting multiple sclerosis defined as 2 or more disabling relapses in 1 year, and with one or more gadolinium enhancing lesions on brain magnetic resonance imaging (MRI) or a significant increase in T2-lesion load compared to a recent MRI scan

New contraindications and revised monitoring requirements

  • alemtuzumab is contraindicated in patients with:
    • severe active infection until complete resolution
    • uncontrolled hypertension
    • a history of arterial dissection of the cervicocephalic arteries
    • a history of stroke
    • a history of angina or myocardial infarction
    • clotting abnormalities including treatment with antiplatelet or anticoagulant therapy
    • autoimmune diseases (apart from multiple sclerosis)
  • only administer alemtuzumab in a hospital with ready access to intensive care facilities
  • monitor patients closely before, during, and after alemtuzumab infusions for cardiovascular reactions and non-immune thrombocytopenia (see Revised monitoring requirements)
  • monitor patients for autoimmune disorders for at least 48 months after the last infusion – some autoimmune reactions have been reported after this routine monitoring period

Advice to give to patients

  • alert patients receiving alemtuzumab to the signs and symptoms of serious adverse reactions described within a few days of an infusion and to seek urgent medical attention if they develop the following:
  • chest pain, coughing up blood, or breathing difficulty
  • drooping of the face, severe headache, neck pain, weakness on one side, or difficulty speaking
  • skin or eyes turning yellow, or dark urine, abdomen pain, bleeding or bruising easily (signs of liver damage)
  • fever, swollen glands, bruising, or rash

COI multiple

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31 comments

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  • Thanks doc. One question I always have as someone treated with alemtuzumab is exactly when your risk of secondary autoimmunity following treatment expires? The protocol is four years of monthly bloods &c – which must add up to a fearful expense for the NHS – but are the risks gone after four years?

    I’ve gathered that peak time for secondary unpleasantness is about three years on. But I’m guessing that some risk surely must remain beyond the monitoring period. Might there be an argument for bloods to be taken annually after that? The NICE people don’t appear to have addressed that.

    • The risk is year 1-3 from dosing and is rarer after 5 years so this is why 4 years post dose monitoring

      • gotcha, thanks doc. I’m just fretting about how long it might take to even get a first test if my thyroid goes bananas in Y5 and compulsory monitoring finished the previous year. I’m lethargic enough already thay I might not spot it even when I’m worriting away about it.

        • The main reason for monitoring was initially to look for platelet deficiencny as a marker of ITP. There are other autoimmunities that are much more common such as an over or underactive thyroid. However thyroid measures would probably be part of any standard blood test that your GP could look for and the good news is if you have thyroid problems you should get free prescriptions in UK….

  • This is a very helpful and timely post. Is there a website where raw data (or do we have to go the old way, and search using search phrases such as alemtuzumab, cardiac effects, dissection, etc) is available for this drug’s side-effects ?

    • “On November 29, 2018 FDA is warning that rare but serious cases of stroke and tears in the lining of arteries in the head and neck have occurred in patients with multiple sclerosis or MS shortly after they received Lemtrada, active ingredient alemtuzumab. These problems can lead to permanent disability and even death”

      There were a number of strokes and vessels tears and vascular side effects that were picked up during post-marketing monitoring and the

  • Thank for posting this valuable information MD1. And thank you for keeping this blog “fact based” and providing the readers with (mostly) unbiased opinions.

    If one was to follow another MS blog, all one hears about is HSCT and Alemtuzumab, which is surprising given the results of the CLASSIC-MS trial showed strong efficacy and durability of CLAD over a 10-year period. Yet the author of the blog continues to mostly advocate for ALEM/HSCT, so now there is a legion of blog followers who think the only effective MS treatment is ALEM/HSCT. If one wants to advocate for pwms to make their own DMT decisions, then the conversation should include (1) the RISKs of these treatments, not just the benefits; and (2) efficacy and durability of each class of DMT compared to one another.

    Plus, I was also surprised to read this nugget…….. “Cladribine possibly when used very early. It is likely MS is T-cell mediated disease and you need to target both B and T cells. The jury is out on anti-CD20 therapies in terms of how good they are at targeting smouldering MS.”

    I have posted the following information before, but just in case……..these two studies show similar efficacy and durability of HSCT and CLAD over a 10-year period ……….but which one has a safer risk profile? (rhetorical question).

    10 Year Follow-Up Clad: https://2021abstracts.cmscscholar.org/2021/10/25/classic-ms-long-term-efficacy-and-real-world-treatment-patterns-for-patients-with-relapsing-multiple-sclerosis-who-received-cladribine-tablets-in-phase-iii-parent-trials/

    10 Year Follow-Up HSCT: https://n.neurology.org/content/96/8/e1215

    Thank you for keeping it real MD!!

    • Tommy, people who get cladribine are not having spontaneous recovery of lost function, people who get alemtuzumab and HSCT are.

      As to the “risks” of these treatments, they are barely worth considering in comparison to the risks of not hitting MS as hard as possible as early as possible. Perhaps the other DMTs should have “increased brain and spinal cord damage compared to current best available therapy” listed as a risk on their labels, that would probably help patients and doctors put treatable thyroid problems in perspective.

    • Isn’t it possible that you do need to target both and that the B-cell therapies do target both, at least to some extent?

    • Tommy, I was interested in your view and have looking at the links and wondering about the comparison in terms of efficacy with these studies you posted; the CLAD one has 36.6% showing no evidence of disease reactivation based on clinical outcomes in the 4 years following last parent study dose (I can see 82.8% were not requiring further disease-modifying therapy, but I can’t see how that is relevant; if 63.4% of these patients are having disease reactivation I don’t understand why only 17.3% would require further treatment).

      The Italian AHSCT study shows 71.3 disability worsening–free survival at 10 years (RRMS), and looking at 5 years the NEDA-3 rates of are approximately 65% depending on the protocol used for RRMS. The endpoints are not comparable with the CLAD study looking at risk of reaching EDSS 7 while the AHSCT study looking at long-term 6-month confirmed disability worsening as measured by EDSS. I don’t think you can compare these and conclude that they are equal.

      • Guess you are right, HSCT/ALEM are the unspoken magic “cure” for MS and anyone who uses another DMT is a fool. Got it!

        • Wow, not sour at all (sounds quite nutty tbh)… why all the ****-hurt about people doing well on HSCT and Alem? What sane person can begrudge any MSer who gets a prolonged reprieve from disease activity, relapses, lesions, and progression? I did the latter, am 5-6 years relapse, progression and lesion free after 2 treatment.

          People like you seem to forget that some decline incredibly fast from first dx (EDSS 4-5 on first relapse was me, I was headed for a wheelchair so fast); and thus, those folks warrant a heavy hitter med (even with extreme risks), and some don’t qualify for other meds for various reasons (the best med available in my country was Tysabri when I was diagnosed, but I was JC+ with a high titre, the next best med being Tecfidera, then Alem came out it was magic). I made that decision by looking at the data prior to ever coming to this blog… so, please get over yourself, and get over your insane ranting butt-hurt (that’s exactly what it sounds like btw a personal vendetta that makes you look bad, not the ones you’re ranting about).

          If Alem ever fails me, Clab is my next thing (I don’t fancy the risks of continued immune suppression that compounds over time, another thing that people like you don’t likely don’t consider very well–some people make their own, informed choices by reading the data). Perhaps you might consider spending less time on a vendetta and more time learning to read the data.

          • You appear to be confirming Tommyboy’s impression most eloquently.
            Well done!

    • The UK was a big user of alemtuzumab and used it early (first line) in MS and I believe that the vascular problems were not really an issue. In the US because of the third line it was used late after failing two other drugs and so the person may have developed more co-corbidities for vascular disease

  • Has anything changed recently to create this brouhaha ? Am I correct that cardiac side effects are the reason for ‘new’ recommendations ?

    If something is new, how does this jibe with fda.accessdata.gov for the drug ? Presumably, the list of complications is NOW is it ? Or is this ALL based on post-marketing surveillance ?

  • Thanks for the update MD.
    As someone who received Alem in 2016/17 I’m always glad to be made aware of all the latest info.

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