Recent Stem Cell Research Study: Positive Results, But Includes Significant Limitations

Recently, there has been significant media coverage about a study published in the Journal of American Medical Association (JAMA) in January (Burt et al, 2015). This study explored the association of stem cell transplants and neurological disability in patients with MS. In this issue of eMS news, we explore this study in a bit more depth. While the results overall were positive, there were some key functional aspects which might limit the interpretations that may be drawn.

Study Summary
The objective of the study was to determine the association of stem cell transplantation with neurological disability and other clinical outcomes in patients with MS. There are many types of stem cell transplantation. The cells in this and several other recent studies were hematopoietic stem cells (HSCs) which are derived from bone marrow. These cells might constitute or help “reboot” the immune system after prior therapy meant to suppress, or in other studies, completely remove, the resident immune-based cells.

The study involved 145 patients studied at a single center, Northwestern University in Chicago, who either had relapsing-remitting MS or secondary-progressive MS. The patients were treated with powerful immuno-suppressants. In this study, this involved doses of cyclophosphamide and alemtuzumab. Alemtuzumab was recently approved by the FDA for use in relapsing forms of MS. For reasons that were not discussed, some patients received cyclophosphamide and anti-thymocyte globulin, instead of alemtuzumab. This was followed by an infusion of the HSCs which were removed and stored prior to the infusion of the immunosuppressants. Half of the patients were followed up for at least 2 years, some for longer.

Notably, this study focused on the disability level as the primary outcome measure, rather than number of relapses. This is an important and positive aspect because progression of disability is viewed as a more reliable measure of disease progression than number of relapses. The Expanded Disability Status Scale (EDSS) is a method of quantifying disability in MS.

The results of the study showed improvement in disability in patients who have active, relapsing-remitting MS and who have also failed other disease modifying therapies (DMTs). At the end of 4 years, of the evaluable patients, 87% had no change or improvement on their EDSS, while 13% worsened. At 2 years, 41 patients had significant improvement in disability. And at 4 years, 23 patients had significant improvement in disability.

Problematic Aspects
While these are positive results for patients, it is important to examine the substantial limitations of the study.

No Control Group
The study did not include a control group. This is important because a control group is an essential part of most research designs, allowing researchers to eliminate and isolate variables. Different types of variation inherent in every study can skew data, so control groups provide a baseline to demonstrate how effective particular treatments are in comparison to no treatment, or to a different active treatment.

In this case, because the immune cells were impacted to varying degrees in patients and they were treated with different combinations of therapies, it is unclear whether the positive results were due to shutting down the immune system with the powerful immunosuppressants prior to infusion of HSCs, or due to the stem cell implantation itself. The authors recognize this shortcoming and indicate that further studies, including control groups and randomization, will be needed to reach definitive conclusions.

Unknown Stability of Patients
In order to participate in the study, patients needed to have had a relapse at some point during the one year leading up to the study. And, because there was no control group, the study required that patients be compared to themselves. However, the study never indicated whether or not the patients were stable upon entering the trial, which means they might have been continuing to improve after recent steroids just prior to entering the trial. Nor did it indicate at what point during the last year the patients had a relapse.

So a key question becomes - was the patient’s last relapse 364 days ago, or 10 days ago?  The answer would have a significant impact on the stability status of the patient upon beginning treatment. And without that information, it’s impossible to know whether their improvement was due to the normal waning of their disease as might be expected during a remission, or whether it was due to the treatment they received during the study.

No Positive Effects in Patients with Progressive
This approach did not work with Progressive MS patients. Patients with Progressive MS likely have a great degree of degeneration of their nervous system, rather than active inflammation. Like the standard disease modifying therapies presently in use in MS, the use of immune suppression followed by HSC infusions likely will have its biggest effect reducing inflammation, but little impact on repairing an already damaged nervous system. Studies with neural precursor cells, or stem cells which have entered a pathway leading to becoming actual nerve cells, may be more likely to actually repair the nervous system and be helpful for progressive patients.

Bigger Picture
The area of stem cells and stem cell research to treat diseases, including MS, is vast. There are different ways of preparing or “rebooting” patients’ immune systems and different ways of administering and harvesting stem cells for infusion. Many questions remain, including how do you best target the stem cells to the nervous system and have the greatest impact on disease progression?

We will explore the issue of stem cell research in an upcoming issue of InforMS magazine, including an in-depth interview with Dr. John Corboy.