Framing the DMT debate

Gavin Giovannoni
Apr 15, 2019 · 7 min read

Since the EMA starting doubting itself and running scared on alemtuzumab, an initiating an Article 20 review of its benefits and risks at the request of the European Commission, I have been inundated with emails and queries.

“Gavin, didn’t you see this coming? Surely, alemtuzumab should never have been licensed as a 1st-line treatment for active MS? Clearly, the FDA got this right and the EMA made a mistake?”

What we are all forgetting in this debate is how bad MS can be as a disease and most of the early damage occurs occultly before people with the disease and their close ones realise the extent of the damage. What is lost in MS is lost forever. We have no magic treatment that can repair the damage and turn back the clock, which is why this Article 20 alemtuzumab review is so critical for the field. If the regulators take away the ability of pwMS to assess and weigh-up their own risks we will be turning back the clock decades.

Early effective treatment in MS is about prevention; preventing the accrual of irreversible damage and give pwMS the opportunity to age relatively normally. If alemtuzumab becomes a 3rd or 2nd line option it will be forcing pwMS to seek alternative treatment strategies and it will increase, not decrease, health tourism for HSCT abroad. Is this what we want?

If alemtuzumab does become a 3rd-line treatment as currently being proposed I am going to actively push for HSCT to become a 1st-line treatment option? If I had MS why would I want to watch and wait whilst I failed one or two DMTs before getting to the very high efficacy IRTs (immune reconstitution therapies) that have the biggest impact on preventing end-organ damage, reversing disability and inducing long-term remission? In addition, both of these treatment options are considered to be the most cost-effective DMTs available.

Recently, when asked which DMT would I choose if I had MS, I have started saying HSCT. When I admitted this a few weeks ago one of my patients, who I have been looking after for over a decade, sent me an email stating how upset she was that I had never offered her HSCT. I clearly need to explain my position so as not to upset anyone else.

HSCT is not on offer as a routine NHS therapy. At the moment HSCT is only considered a 3rd-line treatment in the most active patients. Another problem is that it is not on offer across the country. There are only a handful of MS centres that are prepared to refer their patients for HSCT. This means that access to HSCT is not equitable and explains why an increasing number of patients travel abroad, at great personal cost, to receive this therapy.

The block in access to HSCT seems to be at the level of the neurologist/MSologist. NHS England guidelines for bone marrow transplant (BMT) units allow them discretionary use of up to 15% of their HSCT procedures to treat autoimmune conditions, which includes multiple sclerosis. As BMT units exist across the country access to these units would simply require a referral from a neurologist to the unit to request HSCT as a treatment for MS. The latter, however, is unlikely to happen unless the local MSologist champions HSCT as a procedure and gets their local haematology unit on board. It always takes a local champion to make things happen.

Another factor that has changed in the last 10 years is the strength of the evidence demonstrating how effective HSCT really is as a treatment for MS. The most recent MIST trial, the first large randomised controlled trial, and several meta-analyses of HSCT, confirm that HSCT is a very effective therapy. At the same time, the risks associated with HSCT have improved and the mortality in most BMT units is now well below 1% for MS. This has now tipped the scales in favour of HSCT becoming a mainstream treatment for MS.

There is however resistance from the MS community about HSCT been offered as first-line therapy. Why? I suspect because the risk: benefit profile of HSCT has yet to be compared in a head-2-head study against our most effective licensed treatment, alemtuzumab. This why we are planning to do a head-2-head study of alemtuzumab vs. HSCT in the hope of generating this evidence. If the EMA makes alemtuzumab 3rd-line this trial will be jeopardy; too few patients will wait for alemtuzumab. Maybe we can change the trial design and compare HSCT to ocrelizumab? This would not be asking the same question and ocrelizumab, as maintenance therapy, is likely to be superior to HSCT using NEDA as the outcome over a 2 to 5-year timeframe. If we forced this route I would suggest using brain volume loss as the primary outcome in years 2 and 3, after rebaselining at 12 months. What do you think?

We know already that HSCT will be more cost-effective than alemtuzumab and ocrelizumab, but will it be more effective and as safe?

Please remember that most of the proponents of HSCT as a treatment for MS recognise that the major benefits from treatment will only be derived if HSCT is used early in the course of the disease. This explains why most BMT units don’t offer HSCT to pwMS with more advanced, or progressive, MS. However, this does not stop private, fee-for-service, units offering HSCT to all-comers.

If you have the money and are willing to travel abroad you will be able to find a BMT unit that will treat you. I think this is wrong and will not happen in the NHS if and when HSCT becomes widely available. We have to be honest with our patients about the risks and the benefits of HSCT and why we will limit HSCT to those who will benefit the most. In fact, there is evidence that more advanced patients may actually be made worse by HSCT; the chemotherapy used to ablate the immune system is neurotoxic and may speed up the neuronal loss. In addition, infections are common when you have HSCT and infections are well known to worsen MS disability in more advanced disease.

Please be aware that HSCT is not for the faint-hearted. It is a risky therapy with serious adverse events and quite a high mortality. Even a mortality rate of 0.3–0.5% is high when compared to licensed DMTs. Should this stop us from offering HSCT first-line? I think not. If we have been prepared to offer alemtuzumab, with its risk profile as a first-line treatment, why not HSCT? Most pwMS would agree that the decision regarding what is an acceptable risk to take should be taken by the patient and their families, and not the neurologist or other HCP. There is data showing that neurologists are much more risk-averse than pwMS. Neurologists need to acknowledge this bias, which is likely to be an unconscious bias, and let their patients make the decision.

What I am really trying to do by stating that if I had MS I would choose HSCT as my treatment is to reframe the DMT debate, particularly in relation to access to highly effective DMTs. By focusing on HSCT as a first-line treatment it should at least make you consider what your treatment objectives are in MS.

Framing is another a cognitive bias that was identified by Daniel Kahneman, the Nobel laureate, and his partner Amos Tversky. By moving the frame upwards, or to the right, i.e to include HSCT as a 1st-line therapy, it makes it more likely for pwMS and their neurologists will choose more effective, but arguably safer, treatments 1st-line.

We now know that people who start on a low to moderate efficacy DMT do worse on average than those who start on a high or very high efficacy therapies do better. Despite this, the majority of pwMS are not told this and are started on a low efficacy or platform DMTs without ever being given the option of a high efficacy DMT. Why? It is not due to lack of access to treatments as we now have several NICE and NHS England approved high efficacy DMTs available as first-line treatments.

So yes, if I had active MS I would want to have the full spectrum of high-efficacy DMTs available to choose from including HSCT. I would want to know about their relative efficacy and what the aim of the treatments are. I would certainly want to have a discussion about the possibility of a potential cure.

By reframing the spectrum of efficacy by including HSCT within the frame we may nudge pwMS and their neurologists to move up the treatment ladder and choose a high efficacy DMT sooner when they have more brain to protect.

Unfortunately, HSCT as a first-line option is not going to happen any time soon, which is why I am trying to nudge the community to start debating the issue in earnest.

CoI: multiple

Gavin Giovannoni

Written by

Neurologist, researcher, avid reader, ms & preventive neurology thinker, blogger, runner, gardener, husband, father, dog-owner, cook and wine & food lover.

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