Case study: are undefined treatment benefits worth the risk?
This patient on natalizumab has no evident disease activity, but progressive and accelerated brain volume loss. She is keen to switch to HSCT or alemtuzumab. What should she do?
Case study
AÂ 40-year old woman started natalizumab as a first-line therapy 11 years ago after presenting with two disabling relapses in a four-month period. She has done exceptionally well on natalizumab, i.e. she is NEDA-3 (no evident disease activity) with no relapses, no MRI activity and no change in her EDSS (disability). In fact, her original disabilities from her initial two relapses recovered. At present she is fully functional, working full-time and very active physically. For example, she plays competitive tennis in her local sports club and ran the London marathon 2 years ago. Her current EDSS is 1.0.
The problem is that her serial annual MRI studies demonstrate that she has progressive macroscopic (visible by the naked eye) brain volume loss. Being an intelligent woman and a self-taught MS expert she knows this is a poor prognostic sign and she wants to stop natalizumab and have HSCT or alemtuzumab. She is aware that alemtuzumab and HSCT have a greater impact than natalizumab on end-organ damage or brain volume loss. After HSCT and alemtuzumab treatment brain volume loss is on average in the normal range.
Prof G, would you recommend I switch treatments and can I do this under in the NHS?Â
Prof G’s Opinion
Under the current London MS HSCT guidelines she would not be eligible for HSCT as she has not failed natalizumab; please note, progressive-accelerated brain volume loss is not considered a treatment failure.
What about alemtuzumab? Applying NHS England guidelines as written she would not be eligible for alemtuzumab as her MS is inactive at present. However, one could argue that we need to go back to 2010 when she started natalizumab and ask ourselves now would she have been eligible back then if alemtuzumab had been available? The answer is yes as she had what we call rapidly evolving severe MS. In 2021 someone with rapidly evolving severe MS can be treated with alemtuzumab first-line. Â
Some of my colleagues agree with the retrospective application of guidelines others don’t. I think we really are our patient advocates and we should do what we think is in their best interests. If we don’t look after your patient’s interests who else will?
Please note that this patient is JCV negative. If, however, she seroconverted to being JCV positive it would be easier to justify to NHS England for the switch to alemtuzumab, i.e. NHSE guidelines support the principle of derisking PML (progressive multifocal leukoencephalopathy).
The one thing I can’t tell this patient is whether or not alemtuzumab or HSCT will have an impact on her brain volume loss as we simply don’t have the data from a cohort of patients making the switch from natalizumab to alemtuzumab 10+ years into their disease. In other words, will the smouldering or real MS that causes the accelerated brain volume loss, respond to a potent IRT(immune reconstitution therapy) 11 years after diagnosis? This patient understands there is no data on natalizumab-switchers to support her request, but she is willing to take the risk of either alemtuzumab or HSCT.
What I didn’t say to you is that this lady has already made the decision that she wants to be treated with AHSCT, either on the NHS (not possible at present), abroad at one of the reputable private BMT units or in the private sector within the UK. The problem we have is that we have no idea what will happen to her BVL once she makes the switch. I suspect she will have accelerated BVL in the first year post-AHSCT, which is well described and is likely to be due to the neurotoxicity of the chemotherapy. After year-1 the BVL may or may not normalise. We have no idea what happens to the MS brain after being subjected to smouldering MS pathology on natalizumab for a decade or more.
Fortunately, we do have data from interferon-beta to alemtuzumab switching and, yes, after 2 years of interferon-beta therapy switching to alemtuzumab does normalise BVL. What is clear from the 8-year alemtuzumab follow-up data is that the rate of brain volume loss is age-dependent. Being in the 35-45 year age group the BVL was 0.13% per annum on alemtuzumab. When you compare this to the 0.06% per annum in study subjects 18-25 years of age you realise how important age is in determining treatment effects on the end-organ. This is an example of age determining an outcome, in this case, the size of the brain. Â
Is this data sufficient to talk this young woman down from her decision to have AHSCT and to go with alemtuzumab? What do you think? As a new subscriber, this patient will be reading this Newsletter and it may affect her decision.Â
Another thing that examining cases such as this have taught me is that having annual brain volume measurements in patients on DMTs would be very helpful clinically. Subtle annual brain volume changes may not be reliable but changes over 4 years or more could help with treatment decisions.Â
If she and her consultant decide to go with alemtuzumab their case would need to be presented to a multidisciplinary team before proceeding. She would have to sign-up to the monitoring requirements and give consent to have alemtuzumab, i.e. acknowledge that she is taking the risks of treatment. In this case, I would also recommend they add to the consent that we don’t really know the benefits of alemtuzumab treatment on the end-organ after being on natalizumab for 10 years.Â
Please note that if this patient was JCV positive and at risk of PML we would need to make sure there was no asymptomatic PML present. Carrying over PML from natalizumab to alemtuzumab is a life-threatening complication. Alemtuzumab’s action can’t be reversed and it takes many months for immune reconstitution to occur, which is required to fight the JC virus. This is why I am extra vigilant and do an MRI and CSF analysis before making the switch and in reality would recommend a bridge to another agent, for example, fingolimod. Fingolimod has a reversible mode of action, so if PML emerged after switching from natalizumab it can be stopped to allow the immune system to fight the JC viral infection.  Â
Obviously, this patient would need to have all the baseline infectious screens done and be prepared to start antibiotic prophylaxis and maintain the listeria diet to prevent early infectious complications. The decision to be treated with alemtuzumab is not an easy one particularly when the benefits are undefined. However, this patient informs me that she doesn’t want to have regrets. In particular, she doesn’t want to develop secondary progressive MS in the future or severe cognitive impairment knowing that she could have had a more effective treatment in the past. The latter is a dilemma many patients with MS have to live with.Â
So in conclusion, with all the caveats above, I would personally support this patient’s decision to switch from natalizumab to alemtuzumab. If they decided to go the private route for AHSCT I would obviously continue to manage their MS after AHSCT.
Please feel free to ask any questions about this patient and any issues her case raises.
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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 Barts and The London School of Medicine and Dentistry nor Barts Health NHS Trust. The advice is intended as general advice and should not be interpreted as being personal clinical advice. If you have problems please tell your own healthcare professional who will be able to help you.
Can i ask a question about 'chemo brain' - does this affect everyone who has chemo or is it the specific agents used in HSCT for MS? i know we have less brain to lose than the average joe. Also, i am sure that i read a post from MD that the initial shrinkage is exaggerated so that 2% of BVL is not necessarily equivalent to 10 years of 0.2?
the retrospective qualification is an interesting approach. By the same virtue, would someone eligible for alemtuzumab as a first line agent in 2015/16/17/18 be able to make a case for it now? i suspect not