Updated views on autologous hematopoietic stem cell transplantation for treatment of multiple sclerosis

Multiple sclerosis (MS) is an inflammatory, putatively autoimmune disease, estimated to affect more than 2 million people worldwide. It affects young adults, especially women. For the large majority of patients it is characterized in its early stages by inflammatory demyelination of the CNS, a phase of the disease that is called relapsing-remitting (RR). In addition, a neurodegenerative process causes irreversible loss of neurologic function, leading to the so-called primary or secondary progressive (PP or SP) MS phenotypes. Disease-modifying therapies (DMT) targeting inflammation have been shown to reduce the disease activity in patients with RRMS, by decreasing the accumulation of lesions detected by magnetic resonance imaging (MRI), the frequency of clinical relapses and, to a lesser extent, slow down the progression of disability as compared to placebo, or, more recently, to standard injectable therapies. However, there are currently no medications that can effectively treat the SPMS phase of the disease; also, some patients with RRMS have an aggressive course and do not respond to conventional DMT. It should be noted that we do not have predictive markers to identify patients who will develop aggressive MS early in the disease and that some patients may obtain long-lasting benefit from currently used drugs.

Against this scenario, immunoablative therapy followed by autologous hematopoietic stem cell transplantation (aHSCT) has been investigated for the past two decades to manage severe and treatment-refractory MS [1]. The target of this treatment is the eradication of self-reactive abnormal immune system by intense immunosuppression, followed by the infusion of autologous hematopoietic stem cells aimed at restoring the hemato-lymphopoietic system. The premise of aHSCT is that it produces an ‘immune reset’, whereby the aberrantly overactive immune system is eliminated by intense immunosuppression, and a more tolerant immunity arises, devoid of or with better control of any disease-inducing cells. Early clinical trials of high-dose immunosuppressive therapy were conducted in patients with advanced disabilities and progressive forms of MS. Many patients continued to lose neurologic function, consistent with the contribution of noninflammatory factors to progressive neurodegeneration. Almost all the studies evaluating aHSCT in MS were observational cohort studies; only one comparative phase II randomized clinical trial assessing the effect of aHSCT versus Mitoxantrone in aggressive RR or SPMS patients has been published (ASTIMS trial) [2]. Despite the lesser number of subjects enrolled (n = 21) and some methodological limitations [2], the results were positive for aHSCT, which reduced by 79% the number of new T2 lesions appearing over 4 years as compared to mitoxantrone (p = 0.00016). Patients enrolled in the ASTIMS trial were mostly progressive patients (67%).

The more recent experience with aHSCT indicates that the therapy may be more successful if instituted in the earlier inflammatory stages of MS [3–5]. Three recent studies of aHSCT in patients with RRMS have been published: the 3-year interim analysis of the high-dose immunosuppression and AutoLogous Transplantation for Multiple Sclerosis trial [3]; a single-center patient cohort enrolled and treated at Northwestern University [4] (Burt, JAMA 2015) and a 4-year follow up of the Swedish multicenter experience [5]. The HALT-MS study included 25 patients treated with aHSCT who all had RRMS and breakthrough disease activity. The Northwestern cohort included 145 patients (81% RRMS). The Swedish study included 41 patients (85% RRMS). The proportion of patients with a complete control of the diseases (no relapses; no disability progression and no MRI activity (new or enlarging T2 lesions or Gd-enhancing lesions)) after 2 years was 83% in the HALT-MS study, 80% in the Northwestern study and 78% in the Swedish study. Furthermore, in the Northwestern cohort, EDSS score improvement was reported from a pretransplant median of 4.0–3.0 (n = 82) at 2 years. These high proportions were maintained over longer follow-up (65–70% after 5 years) [3–5]. It must be noted that these studies used different conditioning regimens and included populations with different proportions of relapsing and progressive patients, so indirect comparisons are difficult.

Since no data are available to directly compare aHSCT with approved DMT, it is tempting to consider the degree of control of disease activity achieved in clinical trials of treatments that have subsequently been licensed. Amongst those trials, the CARE MS-II study [6], comparing Alemtuzumab to interferon beta-1a, in patients failing a previous treatment, is the one having the inclusion criteria closer to those of patients included in aHSCT studies, enrolling patients who failed previous treatment with interferon beta or glatiramer acetate. The proportion of patients with a complete control of the disease after 2 years was 32% in the alemtuzumab arm [6], which is less than half of the proportions observed in aHSCT-treated patients [3–5]. Since the phenotypes of MS in the patients who underwent aHSCT are very different than those usually included in clinical trials, it is difficult to evaluate the efficacy of aHSCT by comparing the outcomes of transplanted patients with that of patients receiving other approved DMTs, yet the differences in the patient populations make the advantage of aHSCT even more readily apparent: the baseline characteristics of the patients included in the CARE MS-II study were much milder than those of patients included in aHSCT studies: the median EDSS was 2.5 in CARE MS-II [6], while it ranged from 4 to 5.5 in the aHSCT studies [3–5]; the median number of previous treatments was 1 in CARE MS-II while it was 2–3 in aHSCT trials [3–5]; on the other hand, the mean age and disease duration were comparable [3–6].

On the other side, the tolerability and safety profile of aHSCT is different than those of the approved DMTs, and adverse events during the early post-transplantation immune recovery are common. The risk of treatment-related mortality in aHSCT is probably the main reason why aHSCT is seen with caution in the neurological community that commonly perceives this risk as unacceptably high; however, an analysis from the European Blood and Marrow Transplantation Group for transplants performed since 2001 reported this risk to be decreased since to 2001 to 1.3% [7], and studies utilizing non-myeloablative immunosuppressive regimes have reported no mortality [5].

In conclusion, the results of the ASTIMS trial together with the recent emerging evidence of the efficacy of this therapeutic approach in early aggressive RRMS strongly support the design of a randomized comparative trial to definitively assess the efficacy and the safety profile of aHSCT in patients with highly active, treatment-resistant MS. Such a trial has been already proposed [8], and the trial design, based on a comparison with the ‘best available treatment option’, is still valid, and should include the new highly active therapeutics that have become available in the last few years, and any comparable or better therapies that are approved in the future. If the results were positive, AHSCT could cover an important and currently unmet need in people with MS and improve their care in a way that has also the potential to be cost-effective [9].

Financial & competing interests disclosure

MP Sormani received consultation fees from TEVA, Novartis, Biogen, Roche, Genzyme, Merck and Vertex. P Muraro declares honoraria for speaking and travel support from Merck Serono, Biogen, Bayer, and Novartis. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Additional information

Notes on contributors

Maria Pia Sormani

Paolo Muraro