Lately, there has been a lot of of debate about the position of aHSCT in the MS treatment field. Evolving insights fuelled by the actions of MS charities and the conclusions of the recent ECTRIMS focused workshop on aHSCT have triggered the Dutch Association of Neurologists to change their point of view on the matter, namely that there is no role for aHSCT in the context of MS treatment. In May 2022, their official position changed, and they now acknowledge – still cautiously – that there are well-selected pwMS who might benefit from aHSCT (young, low EDSS, short disease duration). This is an important step forward for pwMS in The Netherlands as it is very difficult for expensive therapies to be reimbursed by health care providers without the official back-up of this organisation. Remember: Revolution is nothing more than evolution at hindsight.
This policy change sparked awareness through the MS landscape, and we get a large number of referrals to evaluate whether aHSCT would still be useful. The majority of these referrals concerns people who are untreated or treated with a first-line DMT and who have already reached the progressive disease stage making this call a lot more difficult. To clarify, by progressive disease I refer to pwMS who have a considerable disease duration (e.g. 10 years) and experience accrual of disability for several years (e.g. reduction in walking range) without evidence of new/enhancing lesions on MRI brain/spinal cord or no abrupt changes in disability level compatible with relapses.
What do we know about the effect of aHSCT in people with progressive MS?
- There are no large trials to assess efficacy and safety of aHSCT in strictly progressive pwMS.
- The ECTRIMS focused workshop concluded that aHSCT trials/single arm observational cohorts in progressive MS have yielded variable rates of progression-free survival (PFS) ranging from 36% to more than 70% at 5 years follow-up. Although comparisons are flawed by different inclusion criteria for aHSCT vs. traditional DMTs, they are all we have. Hence, the following numbers: at two years of follow-up, the PFS for siponimod in secondary progressive pwMS was 80% and 70% for ocrelizumab in primary progressive pwMS. At 5 years follow-up, about 50% of progressive pwMS treated with ocrelizumab were ‘progression-free’.
- In all published cohorts, efficacy is consistently higher in people with lower EDSS, relapsing remitting MS, younger age and shorter disease duration at baseline and with recent inflammatory activity. In a meta-analysis (n=764, 15 studies), the proportion of relapsing pwMS included in an aHSCT study was the most important factor determining outcome with 75% vs. 92% 2-year PFS when < or ≥ 44% of included individuals were relapsing, respectively. Another meta-analysis (n=732, 18 studies) looked at PFS in people with and without contrast enhancement at baseline, and showed a 77% PFS in people with vs. 47% in people without contrast enhancement. Along this line, subgroup analysis of a meta-analysis (n=1626, 27 studies) indicated that PFS was 81% and 60% in relapsing vs.secondary progressive MS.
- Transplant related mortality (TRM) is higher in people with higher disabilty levels (TRM 3.2% when EDSS > 5.5 vs. 0.3% when ≤ 5.5) and with a progressive disease course (TRM 3.4% in studies with less than 44% of people with relapsing MS and 1.0% in studies with ≥ 44% of relapsing MS).
Based on these numbers, it seems reasonable to conclude that the effect of aHSCT in progressive pwMS is modest, and comes with a significantly different benefit/risk profile compared to other treatments approved for treating progressive MS such as ocrelizumab and siponimod. Therefore, aHSCT is in my opinion not a valid treatment strategy for people with progressive MS who continue to progress but show no inflammation when being adequately treated with siponimod or ocrelizumab. Nonetheless, this debate highlights a much bigger need in the MS field which extends way beyond the aHSCT discussion: the identification of people with progressive MS who still have treatable inflammation. It is a well-kept secret that MRI is not always sufficiently sensitive and that we currently lack other reliable biomarkers.
Disclaimer: Please note that the opinions expressed here are those of dr. Ide Smets and do not necessarily reflect the position of the Barts and The London School of Medicine and Dentistry nor Barts Health NHS Trust.