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Stem cells may halt Multiple Sclerosis symptoms

Use of chemotherapy followed by autologous haematopoietic stem cell transplantation (aHSCT) has fully stopped clinical relapses and development of new brain lesions in 23 of 24 patients with multiple sclerosis (MS) — for a prolonged period without needing ongoing medication. But there is risk.


According to a new phase 2 clinical trial, published in The Lancet, eight out of 23 patients had a sustained improvement in their disability 7.5 years after treatment. This is the first such treatment to produce this level of disease control or neurological recovery from MS. But, related risks might still limit its use.


MS is among the most common chronic inflammatory diseases of the central nervous system. Around 2 million people are affected worldwide. It is caused by immune system attacks on the body — autoimmunity.


A few specialized treatment centers offer aHSCT for MS. The procedure involves harvesting bone marrow stem cells from the patient, administering chemotherapy to suppress the patient's immune system, then reintroducing those stem cells back into the patient's blood stream to "reset" their immune system and stop the attacks. However, many patients relapse after treatment.


Dr Harold L Atkins and Dr Mark S. Freedman from The Ottawa Hospital and the University of Ottawa, Ottawa, Canada, with colleagues tested whether complete destruction, rather than suppression of the immune system during aHSCT would reduce relapse in patients and increase long-term disease remission.


They enrolled 24 patients aged 18-50 from three Canadian hospitals who had all previously undergone standard immunosuppressive therapy which did not control the MS. All patients had poor prognosis and their disability ranged from moderate to requiring assistance in walking 100m (about 300 feet), according to scores on the Expanded Disability Status Scale (EDSS).

Researchers used aHSCT as is currently administered, but completely destroyed the immune system before transplantation using a chemotherapy regimen of busulfan, cyclophosphamide and rabbit anti-thymocyte globulin.

Dr Atkins explained that this treatment is "similar to that used in other trials, except our protocol uses stronger chemotherapy and removes immune cells from the stem cell graft product. The chemotherapy we use is very effective at crossing the blood-brain barrier and this could help eliminate the damaging immune cells from the central nervous system."


The primary outcome of the study was multiple sclerosis activity-free survival at 3 years (as measured by relapses of MS symptoms, new brain lesions, and sustained progression of EDSS scores) which occurred in 69.6% of patients after transplantation.


Out of the 24 patients, one patient died from hepatic necrosis and sepsis caused by chemotherapy — that one death equated to 4% of the 24 patients having received treatment. Prior to their treatment, each patient on average had experienced 1.2 relapses per year. After treatment, no relapse occurred in any of the surviving 23 patients during follow up of between 4 and 13 years. Patients' clinical outcomes were mirrored by their freedom from detectable new disease activity on MRI images taken following treatment. While the initial 24 MRI scans revealed 93 brain lesions, after treatment only one out of those 327 scans showed a new lesion.

Furthermore, progressive brain deterioration typical of MS slowed to a rate associated with normal aging in 9 patients with the longest follow-up, and 8 of 23 patients (about 35%) had a sustained improvement in their EDSS score at 7.5 years after treatment. At 3 years, 6 patients (37%) were able to reduce or stop receiving disability insurance and return to work or school. Eight (33%) of the 24 patients had a moderate toxic effect and 14 (58%) patients had only a mild toxic effect related to transplantation.


"The sample size of 24 patients is very small, and no control group was used for comparison with the treatment group. Larger clinical trials will be important to confirm these results.

"Since this is an aggressive treatment, the potential benefits should be weighed against the risks of serious complications associated with aHSCT, and this treatment should only be offered in specialist centres experienced both in multiple sclerosis treatment and stem cell therapy, or as part of a clinical trial.

"Future research will be directed at reducing the risks of this treatment as well as understanding which patients would best benefit from treatment."


Mark Freedman MD, Senior Scientist, Neuroscience Program, Ottawa Hospital Research Institute, Professor of Medicine, Department of Neurology, University of Ottawa; and, Director, Multiple Sclerosis Research Unit, Neurology, Ottawa Hospital-General


Dr Freedman highlights the need to interpret the results with caution: Writing in a linked Comment, Dr Jan Dörr, from the NeuroCure Clinical Research Center, Charité-Universitätsmedizin, Berlin, Germany, adds: "These results are impressive and seem to outbalance any other available treatment for multiple sclerosis. This trial is the first to show complete suppression of any inflammatory disease activity in every patient for a long period...However, aHSCT has a poor safety profile, especially with regards to treatment-related mortality."


"So, will this study change our approach to treatment of multiple sclerosis? Probably not in the short term, mainly because the mortality rate will still be considered unacceptably high.

"Over the longer term (and) in view of the increasing popularity of using early aggressive treatment, there may be support for considering aHSCT less as a rescue therapy and more as a general treatment option, provided the different protocols are harmonised and optimised.

"The tolerability and safety profile can be further improved, and prognostic markers become available to identify patients at risk of poor prognosis in whom a potentially more hazardous treatment might be justified."

Dr Jan Dörr, the NeuroCure Clinical Research Center, Charité-Universitätsmedizin, Berlin, Germany.


Findings
Between diagnosis and aHSCT, 24 patients had 167 clinical relapses over 140 patient-years with 188 Gd-enhancing lesions on 48 pre-aHSCT MRI scans. Median follow-up was 6·7 years (range 3·9–12·7). The primary outcome, multiple sclerosis activity-free survival at 3 years after transplantation was 69·6% (95% CI 46·6–84·2). With up to 13 years of follow-up after aHSCT, no relapses occurred and no Gd enhancing lesions or new T2 lesions were seen on 314 MRI sequential scans. The rate of brain atrophy decreased to that expected for healthy controls. One of 24 patients died of transplantation-related complications. 35% of patients had a sustained improvement in their Expanded Disability Status Scale score.

Interpretation
We describe the first treatment to fully halt all detectable CNS inflammatory activity in patients with multiple sclerosis for a prolonged period in the absence of any ongoing disease-modifying drugs. Furthermore, many of the patients had substantial recovery of neurological function despite their disease's aggressive nature.

Funding
Multiple Sclerosis Scientific Research Foundation.
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Sep 20, 2016   Fetal Timeline   Maternal Timeline   News   News Archive   



The primary outcome of the study was multiple sclerosis activity-free survival at 3 years
(as measured by relapses of MS symptoms, new brain lesions, and sustained EDSS scores)
.
Image Credit:
The Hospital for Sick Children

 
 
 


 

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