Opinion

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EDITORIAL

Hematopoietic Stem Cell Transplantation for MS Extraordinary Evidence Still Needed Stephen L. Hauser, MD

Multiple sclerosis (MS) is a central nervous system disorder characterized by inflammation, loss of the insulating tissue (myelin) surrounding and protecting nerve axons, and multifocal scarring.1 Multiple sclerosis is a prototypic autoimmune disease likely mediated Related article page 275 by pathogenic T and B lymphocytes. There has been substantial progress in the management of MS during the past decade, with 10 variably effective therapies now available and approved by the US Food and Drug Administration (FDA). These therapies suppress the early relapsing-remitting form of MS; however, the late neurodegenerative phase of the disease, progressive MS, remains largely untreatable. Therapeutic success has encouraged investigators to turn their attention to ever more ambitious goals. Could MS be cured, at least in some patients? Could damage to myelin be repaired? And most importantly, could a means to prevent or treat progressive MS be discovered? It has long been a goal to selectively reprogram or “reboot” the adaptive immune system to restore homeostasis and permanently eliminate pathogenic clones that drive autoimmune inflammation and tissue destruction. This is in essence the goal of hematopoietic stem cell transplantation (HSCT) regimens. Typically, hematopoietic stem cells are first mobilized and harvested from the patient’s peripheral blood (or taken directly from bone marrow), and then reinfused following ablation or partial ablation of the patent’s immune system, a process termed conditioning. In theory, the recipient would be repopulated with a naive immune system lacking the culprit autoimmune memory cells. Regimens used in autologous human stem cell transplantation have involved various intensities in terms of the conditioning regimen used, but these generally consist of combinations of chemotherapy, lymphocyte-depleting monoclonal antibodies, thymocyte globulin, or irradiation. To date, more than 700 patients with MS have been treated in this way, using ablative protocols of varying intensity.2 In this issue of JAMA, Burt and colleagues3 summarize the findings from their open-label study of autologous HSCT for MS using a less intensive conditioning regimen consisting of cyclophosphamide and either thymocyte globulin or alemtuzumab. One advantage of less intensive regimens is that they have fewer adverse effects compared with more intensive ablative regimens. One hundred forty-five patients were studied at a single center, and half were followed up for at least 2 years.

The primary outcome was reversal or progression of disability, as measured by change in the Expanded Disability Status Scale (EDSS) score of 1.0 or greater. The authors report that EDSS scores improved significantly from a pretransplant median of 4.0 to 3.0 (n = 82) at 2 years and to 2.5 (n = 36) at 4 years, with significant improvement in disability (ie, decrease in EDSS score of ≥1.0) in 41 patients (50%) at 2 years and in 23 patients (64%) at 4 years. Among the secondary outcomes, 4-year relapse-free survival was 80% and progression-free survival was 87%. Patients also experienced improvement in other functional measures (as assessed by the Neurologic Rating Scale and the Multiple Sclerosis Functional Composite score) and in quality of life, as well as reduction in brain T2 lesion volume as measured by magnetic resonance imaging (MRI). As is often the case with uncontrolled case series, the study has numerous methodological limitations. Some are likely unimportant, but others could be critical in interpreting the results of the study and are important to consider. First, at study entry, inflammatory disease activity was quite high as measured by the number of gadoliniumenhanced MRI lesions at baseline. It is likely that some patients had experienced recent MS attacks, and a reduction in disability observed during the follow-up period could have represented, at least in part, the expected gradual recovery from relapses. Second, the substantial reductions reported in the total volume of abnormal white matter measured by MRI (T2 lesion volume) are out of proportion to any reasonable expectation based on prior MS trials. The findings of such apparent improvement likely resulted from Burt et al’s failure to correct for baseline inflammation and accompanying edema. Third, the co-mingling of patients with relapsing-remitting and progressive MS, as well as the small proportion of patients who were followed up beyond year 2, make any conclusions beyond this follow-up point uncertain. According to Carl Sagan, “extraordinary claims require extraordinary evidence,” a standard that is not always met in this report, and not claimed by the authors. Even though the authors appropriately acknowledge many of the limitations associated with their case series, their statement that “to our knowledge, this is the first report of significant and sustained improvement in the EDSS score following any treatment for MS” could be challenged. In addition to the possibility that some patients may have been naturally improving at entry into the study, patients who were doing well might have been more likely to return for follow-up (ie, a type of healthy survivor bias), and the EDSS assessments may be suspect because they were unblinded. Furthermore, other highly efficacious MS thera-

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Opinion Editorial

pies such as alemtuzumab, used in the conditioning regimen in this report, have also shown improvement in EDSS scores.4 Although it is true, as the authors indicate, that HSCT “unlike standard immune-based drugs, it is designed to reset rather than suppress the immune system,” there is little evidence in the literature and none in the current study to support any claim that potentially pathogenic clones have been eliminated or that the immune system has been reset by the nonmyeloablative regimen used in this study. Despite these limitations, the report by Burt et al3 has numerous positive aspects. The surrogate outcome data related to MRI measures of focal brain inflammation are impressive. The observed decline in gadolinium-enhanced lesions is positive and consistent with earlier reports using HSCT regimens in patients with relapsing-remitting MS.2 Given that gadoliniumenhanced lesions reasonably serve as a surrogate for MS relapses, this gives some credence to the favorable reported clinical outcomes. Reported improvements in other functional measures, although obtained in an unblinded fashion, are also consistent with the EDSS score improvements. When MRI and clinical data are combined to create a disease-free survival metric (Figure 2 in the article), the observed 80% disease-free survival at 2 years is also robust and impressive, especially compared with expected disease-free survival rates in patients with relapsing-remitting MS managed with conventional injectable therapies (interferon or glatiramer acetate) of only approximately 20%.4-6 It is also noteworthy that a nearly identical 2-year disease-free survival rate (82.8%) was recently reported by Nash et al7 in their HALT-MS prospective study of 25 patients with relapsing-remitting MS. The disease-free survival rates with HSCT are also impressive compared with historical data from trials of other high-intensity regimens used for MS, such as natalizumab8 and alemtuzumab.4 The study by Burt et al, taken together with other available evidence, enables several conclusions to be made with reasonable confidence. First, autologous HSCT does not appear to be effective against established progressive forms of MS and, absent new ARTICLE INFORMATION Author Affiliation: Department of Neurology, University of California, San Francisco. Corresponding Author: Stephen L. Hauser, MD, Department of Neurology, University of California, 675 Nelson Rising Ln, San Francisco, CA 94158 ([email protected]). Conflict of Interest Disclosures: Dr Hauser has completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and reported serving on scientific advisory boards for Symbiotix, Annexon, and Bionure. REFERENCES 1. Hauser SL, Chan JR, Oksenberg JR. Multiple sclerosis: prospects and promise. Ann Neurol. 2013; 74(3):317-327. 2. Atkins HL, Freedman MS. Hematopoietic stem cell therapy for multiple sclerosis: top 10 lessons learned. Neurotherapeutics. 2013;10(1):68-76.

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data, additional trials of these protocols are probably not indicated for patients with progressive MS.2 Second, immunosuppressive regimens that include HSCT appear to be effective against the relapsing-remitting form of MS, at least over several years of observation. However, it is by no means clear that the beneficial effects result from the infusion of stem cells rather than from the conditioning regimen. Given the availability of highly effective FDA-approved therapies against relapsing-remitting MS, it would seem reasonable to use these proven monotherapies in the clinical setting before considering complex HSCT regimens. Studies that delineate the role of HSCT specifically in improving outcomes relative to conditioning regimens alone are needed before this therapy should be deployed outside of the clinical research setting. Even if the ultimate role of HSCT is only to improve the safety of immunosuppressive regimens used for MS by shortening the period of dangerous immune suppression, this approach could still represent a valuable adjunct. Third, the mechanism of action of autologous HSCT in MS needs to be clarified. There seems little question that at least some elements of the adaptive immune repertoire are altered,9 but also that suppressive or regulatory influences are increased following treatment.10 It would be of considerable interest to assess whether the oligoclonal immunoglobulin and oligoclonal B cells, characteristic of MS and conveniently measured in the cerebrospinal fluid,11 are abrogated by the HSCT regimen. If they are not, this would suggest that the regimen failed to reset the autoimmune process in the central nervous system. Fourth, it is important to remember that MS is a chronic disease, usually arising in young adults and lasting throughout the lifespan. Many important disability-related outcomes take many years or decades to develop. To understand the role of any therapy for MS, and especially an intensive regimen with uncertain long-term risk, very long follow-up periods are required to meaningfully assess if the disease has indeed been rebooted over the long-term, and also to increase confidence that these therapies have not caused undue harm.

3. Burt RK, Balabanov R, Han X, et al. Association of nonmyeloablative hematopoietic stem cell transplantation with neurological disability in patients with relapsing-remitting multiple sclerosis. JAMA. doi:10.1001/jama.2014.17986. 4. Coles AJ, Twyman CL, Arnold DL, et al. Alemtuzumab for patients with relapsing multiple sclerosis after disease-modifying therapy. Lancet. 2012;380(9856):1829-1839. 5. Lublin FD, Cofield SS, Cutter GR, et al. Randomized study combining interferon and glatiramer acetate in multiple sclerosis. Ann Neurol. 2013;73(3):327-340. 6. Bevan CJ, Cree BA. Disease activity free status: a new end point for a new era in multiple sclerosis clinical research? JAMA Neurol. 2014;71(3):269-270. 7. Nash RA, Hutton GJ, Racke MK, et al. High-dose immunosuppressive therapy and autologous Hematopoietic Cell Transplantation for Relapsing-Remitting Multiple Sclerosis (HALT-MS): a 3-year interim report. JAMA Neurol. doi:10.1001 /jamaneurol.2014.3780.

8. Polman CH, O’Connor PW, Havrdova E, et al. A randomized, placebo-controlled trial of natalizumab for relapsing multiple sclerosis. N Engl J Med. 2006;354(9):899-910. 9. Abrahamsson SV, Angelini DF, Dubinsky AN, et al. Non-myeloablative autologous haematopoietic stem cell transplantation expands regulatory cells and depletes IL-17 producing mucosal-associated invariant T cells in multiple sclerosis. Brain. 2013;136(pt 9):2888-2903. 10. Muraro PA, Robins H, Malhotra S, et al. T cell repertoire following autologous stem cell transplantation for multiple sclerosis. J Clin Invest. 2014;124(3):1168-1172. 11. Palanichamy A, Apeltsin L, Kuo TC, et al. Immunoglobulin class-switched B cells form an active immune axis between CNS and periphery in multiple sclerosis. Sci Transl Med. 2014;6(248): 248ra106.

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Hematopoietic stem cell transplantation for MS: extraordinary evidence still needed.

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