Barts-MS rose-tinted-odometer: ★★★★★ (aquamarine on a very rainy Friday in London, #00FFBF)
I recently had a patient of mine who has been desperate to be treated with alemtuzumab actually ask if he can change his mind and rather be referred for AHSCT (autologous hematopoietic stem cell transplantation). Why? Because the chances of being put into long term remission, and hence potentially being cured of having MS, seems to be much higher with AHSCT. This particular patient has no concerns about the risks associated with alemtuzumab or AHSCT. The most important concern on his radar is his long term outcome. He wants a healthy brain when he gets older.
This is why this most recent paper on the long term outcome of Italian patients who received AHSCT adds to the mounting evidence base of the effectiveness of AHSCT. In patients with relapsing-remitting treated with AHSCT, MS 86% and 71% were free of disability worsening at 5 and 10 years, respectively. These figures for patients with progressive MS were 71% and 57% at 5 and 10 years, respectively.
The results are less impressive when using NEDA-3 status, i.e. no relapses, MRI activity or disability progression. For patients with RRMS, probabilities of achieving NEDA3 status were 62% at 5 years and 41% at 10 years, respectively. However, and importantly, in the subgroup of patients with RRMS who underwent AHSCT with the BEAM+ATG conditioning protocol, which is more aggressive, NEDA-3 status was achieved in 68% and 55% of subjects at 5 and 10 years, respectively.
In subjects with progressive MS, NEDA-3 status was only achieved 51% and 37% of subjects at 5 and 10 years, respectively.
On average, disability scores improved in relapsing-remitting subjects and got worse in subjects with progressive disease, which implies that AHSCT does not stop smouldering disease. However, almost all subjects had failed one or more DMTs prior to AHSCT. The latter is important. The average EDSS was ~6.0 and most patients had a disease duration of longer than 10 years. This makes me wonder how better the results would be if AHSCT was done earlier in the course of MS, i.e. before too much damage to the brain and spinal cord had accumulated. This is why we really need to test AHSCT as first-line therapy in MS. Could AHSCT done early stop/reverse or prevent the establishment of smouldering disease? In other words, does AHSCT cure people from having MS? This is why a trial of AHSCT in very early MS, i.e. as a first-line treatment, is a no-brainer to me.
Please note that three deaths occurred due to AHSCT, which was 1.4% of the entire study population.
The take home messages are:
- AHSCT is the most effective DMT we have for treating MS.
- RRMS responds better to AHSCT than progressive MS.
- BEAM+ATG conditioning protocol is superior to cyclophosphamide-based protocols.
- Mortality remains relatively high with AHSCT.
- The results would be much better than this if patients had had AHSCT earlier in the course of their disease.
I was criticised yesterday for suggesting lifestyle changes to pwMS when I had no idea what it was like to have MS. It was implied that unless you have lived with MS, i.e. the lived experience, I shouldn’t be making any lifestyle recommendations to pwMS particularly around weight loss and diet. What I can say is that I have treated and followed thousands of people with MS and I know enough that if I had MS I would have no hesitation in wanting to be treated first-line with AHSCT or alemtuzumab and to manage all the lifestyle issues I referred to in my post ‘ASK NOT‘.
What underpins my decision to be treated with alemtuzumab and AHSCT first-line is the data missing from this paper on the end-organ; both of these treatments will on average normalise brain volume loss in treated subjects. In other words, these treatments are on top of the ladder when it comes to preventing end-organ damage. The downside of AHSCT is that the brain takes a significant neurotoxicity hit from the chemotherapy with accelerated brain volume loss in year one. In addition, there is also the high, but delayed secondary malignancy risk and high mortality risk associated with AHSCT that needs to be taken into account. Therefore, alemtuzumab probably wins out on safety as a potential first-line therapy. Please remember being treated with alemtuzumab does not exclude you from being treated with AHSCT at a later stage.
Boffa et al. Long-Term Clinical Outcomes of Hematopoietic Stem Cell Transplantation in Multiple Sclerosis. Neurology. 2021 Jan 20;10.1212/WNL.0000000000011461. doi: 10.1212/WNL.0000000000011461.
Objective: To determine whether autologous hematopoietic stem cell transplantation (aHSCT) is able to induce durable disease remission in people with multiple sclerosis (MS), we analyzed the long-term outcomes after transplant in a large cohort of MS patients.
Methods: To be included, a minimum data set (consisting of age, MS phenotype, EDSS at baseline, information on transplant technology and at least 1 follow-up visit after transplant) was required.
Results: 210 patients were included [relapsing-remitting (RR)MS=122(58%)]. Median baseline EDSS was 6(1-9), mean follow-up was 6.2(±5.0) years. Among RRMS patients, disability worsening-free survival (95%CI) was 85.5%(76.9-94.1%) at 5 years and 71.3%(57.8-84.8%) at 10 years. In patients with progressive MS, disability worsening-free survival was 71.0%(59.4-82.6%) and 57.2%(41.8-72.7%) at 5 and 10 years, respectively. In RRMS patients, EDSS significantly reduced after aHSCT [p=0.001; mean EDSS change per year -0.09 (95%CI=-0.15 to -0.04%)]. In RRMS patients, the use of the BEAM+ATG conditioning protocol was independently associated with a reduced risk of NEDA-3 failure [HR=0.27(0.14-0.50), p<0.001]. Three patients died within 100-days from aHSCT (1.4%); no deaths occurred in patients transplanted after 2007.
Conclusions: aHSCT prevents disability worsening in the majority of patients and induces durable improvement in disability in patients with RRMS. The BEAM+ATG conditioning protocol is associated with a more pronounced suppression of clinical relapses and MRI inflammatory activity.
Classification of evidence: This study provides Class IV evidence that for people with MS, aHSCT induces durable disease remission in most patients.
General Disclaimer: Please note that the opinions expressed here are those of Professor Giovannoni and do not necessarily reflect the positions of the Barts and The London School of Medicine and Dentistry nor Barts Health NHS Trust and are not meant to be interpreted as personal clinical advice.