More than 100 experts involved in pioneering stem cell transplantation to treat multiple sclerosis (MS) gathered in Sheffield on 20 January for the 3rd International Symposium on Stem Cell Treatment in Multiple Sclerosis. Leading neurology and transplant haematology specialists from across the globe joined with patients and MS charities to share latest advances in what they described as this 'game-changing' treatment.
Approximately 89,000 people in England have diagnosed multiple sclerosis, with the relapsing-remitting form affecting 85-90% of them at the time of diagnosis. About 4000 people are newly-diagnosed each year. As formal diagnosis can be complicated and prolonged, true figures may be higher. Annual costs per patient are estimated at between £11,400 and £36,500 depending on level of disability.
'Rebooting' the Immune System
Autologous haematopoietic stem cell transplantation (AHSCT) involves obliterating the patient's faulty immune system before "rebooting it" with an injection of the patient's own harvested stem cells and bone marrow following a course of chemotherapy. The aim is to reset the immune system to a point before it caused MS.
The treatment is intensive, and patients must generally recuperate in isolation to avoid infection, necessitating around a month in hospital, followed by 3-6 months for full revivification. However, findings from the Multiple Sclerosis International Stem Cell Transplant (MIST) trial, a collaboration of researchers from Sheffield along with colleagues in Brazil, Sweden, and the US, showed that the treatment could stabilise the disease, and in some cases improve symptoms of disability, in patients with highly active relapsing MS.
The MIST research trial involved just over 100 patients who had had two or more relapses within the previous year, despite taking a disease modifying therapy (DMT). The researchers randomised 55 patients to AHSCT along with cyclophosphamide (200 mg/kg) and antithymocyte globulin (6 mg/kg) and compared their outcome with that of 55 control patients who were prescribed a DMT of a different class or higher efficacy than the DMT taken during the previous year.
Of the original 110 participants, 103 remained in the trial, with 98 assessed at year 1 and 23 evaluated annually for 5 years. The average follow-up period was 2.8 years.
One Year Progression Hazard Ratio 0.07
On follow up to 1 year, disease progression occurred in three patients in the HSCT group and 34 patients in the DMT group. There were too few events to calculate median time to progression in the AHSCT group; however, it was 24 months (interquartile range, 18-48 months) in the DMT group, giving a hazard ratio of 0.07 (95% CI 0.02 to 0.24; P <0.001).
The AHSCT group showed improvements in scores on the Expanded Disability Status Scale (EDSS) by a little over one point (mean 3.38 to 2.36), whereas in the DMT group mean disability levels increased (0.67 increase in mean EDSS, from 3.31 to 3.98).
The control patients were allowed to switch to AHSCT if they had disability progression (defined as a worsening of EDSS score of 1 point or more) after 1 year in the study. The mean EDSS scores for the 30 patients thus moved over improved from 5.2 to 2.6 following AHSCT.
The benefits of stem cell transplantation continued to 5 years, at which point relapses had occurred in 85.2% of those on standard DMT compared with 15.4% of the AHSCT group. There were no deaths or nonhematopoietic grade 4 toxicities (such as myocardial infarction, sepsis, or other disabling or potential life-threatening events) in the transplanted group. Infection was the most common side effect; two patients developed idiopathic thrombocytopenic purpura, and four developed autoimmune thyroid disease.
'Significantly Prolonged Time to Disease Progression'
The researchers concluded: "Treatment with nonmyeloablative [A]HSCT compared with disease-modifying therapy resulted in a significantly prolonged time to disease progression."
The UK MIST researchers were Professor Basil Sharrack consultant neurologist, and Professor John Snowden, consultant haematologist, both of Sheffield Teaching Hospitals NHS Foundation Trust, who co-hosted the symposium at the Sheffield Institute for Translational Neuroscience. They described the MIST trial results as "hugely encouraging".
"AHSCT has been shown to be highly effective in stabilising, and even reversing disability, in certain patients with MS," said Prof Snowden.
At the meeting he presented an update from the forthcoming UK phase 3 StarMS trial, which will build on the results of the landmark MIST trial, the first in the world to show that stem cell transplantation could reverse disability in patients with multiple sclerosis.
Like MIST, StarMS will compare DMT with AHSCT. The £2.3 m trial will be led by Professors Snowden and Sharrack along with Paulo Muraro, professor of neurology at Imperial College London. It aims to recruit 198 patients across 19 NHS sites and follow them for 24 months. The meeting also heard that sub-studies of the trial aim to shed new light on the precise mechanism that the immune system uses to repair itself to stop inflammation in stem cell transplantation. Successful results from the StarMS trial could see AHSCT offered as a first-line treatment for patients with aggressive MS in the near future.
Treatment 'Life Changing' for Some
The meeting also heard from Dr Catherine Godbold of the MS Society, who pointed out that merely running the trial StarMS trial will help expand AHSCT capacity by training new centres to offer the treatment – which many patients say they have been unable to access so far.
She added: "People in our community tell us all the time how important the issue of [A]HSCT is to them. We hear lots of stories from people with MS who've had HSCT, through the NHS, privately or abroad. People with different forms of MS and at [different] stages of their MS. For some people, it can be absolutely life changing. Others don't feel it helped them as much. And there are people who, after weighing up all the options, decided HSCT wasn't right for them.
"We believe StarMS has an important role to play in improving access to HSCT in the UK. We helped bring the people together to get it funded and we provided a letter of support to the MHRA on changing the eligibility criteria. If positive, the evidence may help clinicians feel more confident in referring patients for HSCT and potentially make it easier to access on the NHS."
Guidelines from the National Institute for Health and Care Excellence (NICE) do not currently include AHSCT, but NICE intends to appraise the treatment through its Multiple Technology Appraisal (MTA) Process, to assess its clinical and cost effectiveness for previously treated relapsing-remitting multiple sclerosis. No date has yet been set for publication.
The StarMS trial is being funded through a National Institute for Health and Care Research and Medical Research Council partnership.