Using alemtuzumab in real-life is far more complicated than you realise. Does this explain the lack of confidence amongst neurologists about using alemtuzumab? #ClinicSpeak #NeuroSpeak #MSBlog
The following recommendations paper from a group of EU experts doesn’t address the real issues with using alemtuzumab. Why? May because it was drafted and co-written by a third-party vendor and subsequently proof-read and checked by Sanofi-Genzyme.
The acknowledgements at the end of the paper state: ‘This manuscript was reviewed by Darren P.
Baker PhD, and Neli Boyanova MD, of Sanofi Genzyme. Editorial
support (assistance in drafting and editing of the manuscript text and
tables, as directed by authors, data checking and incorporation of
comments from reviewers, and assisting with the submission process) was provided by Steve Banner at Fishawack Communications Ltd.,
funded by Sanofi Genzyme. This was the only funding provided for
the development of this manuscript. This article is based on the
outcomes of a European Advisory Board, held in Vienna, Austria, in
November 2013, during which a panel of European MS experts
provided insights, guidance, and recommendations regarding best
practices for alemtuzumab treatment and compliance with ongoing
monitoring requirements designed to mitigate potential adverse
events.
Compliance with Ethical Standards
Funding The advisory board was funded by Sanofi Genzyme. All
advisors received honoraria payments for their participation. Open
access fee was funded by the Medical University of Innsbruck.’
Baker PhD, and Neli Boyanova MD, of Sanofi Genzyme. Editorial
support (assistance in drafting and editing of the manuscript text and
tables, as directed by authors, data checking and incorporation of
comments from reviewers, and assisting with the submission process) was provided by Steve Banner at Fishawack Communications Ltd.,
funded by Sanofi Genzyme. This was the only funding provided for
the development of this manuscript. This article is based on the
outcomes of a European Advisory Board, held in Vienna, Austria, in
November 2013, during which a panel of European MS experts
provided insights, guidance, and recommendations regarding best
practices for alemtuzumab treatment and compliance with ongoing
monitoring requirements designed to mitigate potential adverse
events.
Compliance with Ethical Standards
Funding The advisory board was funded by Sanofi Genzyme. All
advisors received honoraria payments for their participation. Open
access fee was funded by the Medical University of Innsbruck.’
In other words the author’s were handcuffed by the SpC and what Sanofi-Genzyme are legally allowed to say. If I was writing this article the kind of issues that I would have discussed would have tried to address the following questions:
Alemtuzumab (Lemtrada™) is a humanized monoclonal antibody approved in more than 50 countries. Within the European Union, alemtuzumab is indicated for the treatment of adult patients with relapsing-remitting multiple sclerosis (RRMS) with active disease defined by clinical or imaging features; in the USA, the indication states that alemtuzumab should generally be reserved for the treatment of patients with relapsing forms of multiple sclerosis who have had an inadequate response to two or more disease-modifying therapies (DMTs). In clinical trials, alemtuzumab demonstrated efficacy in treatment-naïve patients with active RRMS and those relapsing on prior DMTs, with a consistent and manageable safety and tolerability profile. The European Union indication provides physicians with significant flexibility regarding treatment decisions, affording the opportunity for individualized treatment. Thus, alemtuzumab may be an appropriate treatment choice across a broad range of patients with RRMS, including, for example, treatment-naïve patients with active disease, patients with highly active disease, or for patients relapsing on prior DMTs. There are several practicalities to consider when using alemtuzumab, including the unique dosing regimen, administered via intravenous infusion on 5 consecutive days at baseline and on 3 consecutive days 12 months later, and as-needed retreatment (3 consecutive days at least 12 months after the last course) in cases of disease recurrence. Additionally, routine monthly monitoring is required for up to 48 months after the last infusion to promptly identify potentially serious autoimmune adverse events. Given these considerations, it is beneficial to gain insight into how alemtuzumab is being used in the real-world clinical setting. Here, we report recommendations from European multiple sclerosis experts regarding best practices for alemtuzumab treatment, including management of adverse events and compliance with ongoing safety monitoring requirements.
- Should you consider alemtuzumab in patients with MS who have only had one clinical attack?
- How exactly do you transition patients at high-risk of PML from natalizumab to alemtuzumab?
- How exactly do you transition patients from fingolimod to alemtuzumab? Would you be guided by the peripheral blood lymphocyte counts? Would these principles apply to other DMTs associated with lymphopaenia?
- How do you define an alemtuzumab treatment failure?
- How many courses of alemtuzumab do you give before you consider the pwMS are non-responders?
- What treatments can be given post-alemtuzumab? How would you give these treatments?
- What do you do if someone has a relapse several months before the next course of alemtuzumab is due? Can you give the next course early?
- Can you give the next course of alemtuzumab if someone has persistent lymphopaenia post-alemtuzumab; if no, at what level would you recommend not retreating (grade 1 >800-1000/mm3, grade 2 > 500-800/mm3, grade 3 > 200-500/mm3 or grade 4 < 200/mm3)?
- When do you test for neutralising anti-alemtuzumab antibodies (NABs)? How do you test for NABs?
- What do you do if someone does not deplete their peripheral lymphocytes with alemtuzumab? Do you call these individuals non-responders?
- Apart from autoimmune thyroid, anti-GBM and ITP, what about the other autoimmune diseases that you need to be vigilant about post alemtuzumab; i.e. neutropaenia, haemolytic aneamia, bullous skin disease, acquired haemophilia, pernicious anaemia, vasculitis, TTP, etc.?
- What about infectious complications post alemtuzumab, i.e. listeriosis, nocardiosis, zoster?
- What recommendations regarding Listeria prophylaxis would you give? What works, what doesn’t?
- What should we be telling pwMS to do regarding preventing Listerial, Nocardial and fungal infections?
- Should we be using anti-viral prophylaxis with alemtuzumab?
- What about baseline TB, HIV, hepatitis, and HPV (cervical smear) screening?
- When would live vaccines be potentially safe post-alemtuzumab?
- What about travel and exposure to exotic infections?
- What is the optimal protocol for reducing infusion related events? Can you avoid steroids?
- Is there any way of predicting who will develop secondary autoimmunity? Are there any therapeutic strategies to prevent secondary autoimmunity?
- What about CMV reactivation post-alemtuzumab? Is it a problem? Should we screen for it?
- What is the best strategies for engaging pwMS with their own pharmacovigilance? What do you do if someone is non-compliant with their pharmacovigilance? Can you use point-of-care testing for alemtuzumab pharmacovigilance?
- What do you do if someone develops PML post-alemtuzumab? Are there any strategies for managing this situation?
As you can see there are many more questions about using alemtuzumab in real-life than is covered in these recommendations. May be this explains why the uptake of alemtuzumab, outside large centres in the UK, is so much lower than one would expect for such an effective and transformational therapy. Knowing, or addressing the, answers to some of these questions may help make neurologists more confident about using alemtuzumab. Building confidence is a multifaceted process and takes time and transparency.
Berger et al. Alemtuzumab Use in Clinical Practice: Recommendations from European Multiple Sclerosis Experts. CNS Drugs. 2016 Nov 23.
Alemtuzumab (Lemtrada™) is a humanized monoclonal antibody approved in more than 50 countries. Within the European Union, alemtuzumab is indicated for the treatment of adult patients with relapsing-remitting multiple sclerosis (RRMS) with active disease defined by clinical or imaging features; in the USA, the indication states that alemtuzumab should generally be reserved for the treatment of patients with relapsing forms of multiple sclerosis who have had an inadequate response to two or more disease-modifying therapies (DMTs). In clinical trials, alemtuzumab demonstrated efficacy in treatment-naïve patients with active RRMS and those relapsing on prior DMTs, with a consistent and manageable safety and tolerability profile. The European Union indication provides physicians with significant flexibility regarding treatment decisions, affording the opportunity for individualized treatment. Thus, alemtuzumab may be an appropriate treatment choice across a broad range of patients with RRMS, including, for example, treatment-naïve patients with active disease, patients with highly active disease, or for patients relapsing on prior DMTs. There are several practicalities to consider when using alemtuzumab, including the unique dosing regimen, administered via intravenous infusion on 5 consecutive days at baseline and on 3 consecutive days 12 months later, and as-needed retreatment (3 consecutive days at least 12 months after the last course) in cases of disease recurrence. Additionally, routine monthly monitoring is required for up to 48 months after the last infusion to promptly identify potentially serious autoimmune adverse events. Given these considerations, it is beneficial to gain insight into how alemtuzumab is being used in the real-world clinical setting. Here, we report recommendations from European multiple sclerosis experts regarding best practices for alemtuzumab treatment, including management of adverse events and compliance with ongoing safety monitoring requirements.
CoI: multiple
Excuse my total ignorance of how these things work and therefore the possibility that this is a completely dumb question:- But can't a group of clinicians with the most experience of Alemtuzumab, such as yourself ProfG, club together to answer all those questions you've posed this morning? As someone who received Alemtuzumab two weeks ago, and thought I'd done a good job of obtaining pretty much all pertinent information, I have to say your list of questions raises a whole heap of things I realise I'm ignorant of!
Hi Fi, these are questions that Sanofi-Genzyme are reluctant to address, presumably for commercial reasons and they're the ones holding the data, which can be a tortuous process getting hold of.But please don't worry, Alemtuzumab has been incredibly effective for many in stopping their relapses but the more we know, the more effective the management of potential negative side-effects, which is in everyone's interests.
Re: "I have to say your list of questions raises a whole heap of things I realise I'm ignorant of!"Some of these are rhetorical questions, but we have addressed most of these on the blog over the last few years. The good news is that someone from outside the UK has volunteered to do a guest post to answer as many of these questions as possible. The reason why alemtuzumab is not being adopted by many neurologists is that they want the drug derisked as much as possible. Sometimes derisking is simply providing information.
Thank you both for the reassurance and the additional clarification. I felt confident of having made an informed decision to have Alemtuzumab and agree fully that: 'the more we know the better the side effects can be managed', and 'sometimes derisking is simply providing information' This is true for me in respect of the recent blog concerning opportunistic infections. I have already made a list of the things mentioned in the list of questions that I don't think I've sufficient understanding of, but maybe I'll wait for the guest post!Dare I say: 'Knowledge is power' Thanks again.
Hi Fi,If there's any questions you have, feel free to ask them here and we'll do our best to answer them and good luck with the treatment!"Dare I say: 'Knowledge is power'" Indeed you may, it's why this blog exists.All the bestMD2
I would think monitoring T-cell count, #8, would be the most important. if patient dropped below 200 then they would be most susceptible to opportunistic infections. CMV prophylaxis would be a good idea.
Re: "CMV prophylaxis would be a good idea."We have had one patient with CMV reactivation who we treated off-label; he had vasculitis. I think CMV reactivation is more common than we realise, but does not seem to be a problem when using alemtuzumab for MS.
"As you can see there are many more questions about using alemtuzumab in real-life than is covered in these recommendations. May be this explains why the uptake of alemtuzumab, outside large centres in the UK, is so much lower than one would expect for such an effective and transformational therapy. Knowing, or addressing the, answers to some of these questions may help make neurologists more confident about using alemtuzumab. Building confidence is a multifaceted process and takes time and transparency."Poor dears (neuros without confidence in lemtrada). Speaking of confidence (while the neuros are building theirs I guess), I read these questions on an MS forum this morning:Person with MS1: The reality of not working and being on disability is not a great as it sounds. The purpose for college education, career growth and financial security are all gone. What do you say when someone asks, "What do you do?"Person with MS 2: Hi pepps what's your thoughts on dating with MS?I've been single for a while now I've had no confidence what so ever… Thought I might give it another shot ??? Thoughts??Who's going to build their confidence while neuros build theirs in lemtrada? Time being brain and neuros have theirs while people with MS are losing theirs at varying speeds….I learnt about MS in 2014. I'm still not clear how much damage the gaps in treatment when the escalating approach is used and involves 4 changes of DMTs in say 2 or 3 years.
I've lost a great deal of confidence in Lemtrada when the results of the extension study were presented in a very misleading way. The true results haven't been released let alone explained. If I was a neurologist I'd be questioning why the drug manufacturer has avoided publishing the results we all want to hear. Clearly there's something to hide or the results are not too encouraging.
We tried to answer at least some of the questions in an independent practical review:https://msddjournal.biomedcentral.com/articles/10.1186/s40893-016-0011-1
Re. Alemtuzumab and number 16 on the list ” What about baseline screening……..and HPV (cervical smear) screening? ”
But my understanding is that HPV screening is not a standard part of a cervical smear test in the UK, it’s only if abnomal cells are found, the cells are tested for HPV.
Should there be a positive or negative HPV test done in the UK, prior to first infusion and annaully after??
Many thanks.