Elsevier

The Lancet Neurology

Volume 7, Issue 7, July 2008, Pages 626-636
The Lancet Neurology

Review
Autologous haematopoietic stem-cell transplantation in multiple sclerosis

https://doi.org/10.1016/S1474-4422(08)70138-8Get rights and content

Summary

Intense immunosuppression followed by autologous haematopoietic stem-cell transplantation has been assessed over the past few years as a possible new therapeutic strategy in severe forms of multiple sclerosis. Pioneering studies began in 1995, and since then, more than 400 patients worldwide have been treated with this procedure. Small uncontrolled studies show that about 60–70% of treated cases do not progress in the follow-up period of at least 3 years. Transplant-related mortality, which was 5–6% in the first reported series, has reduced in the past 5 years to 1–2%. Relapses dramatically decrease and inflammatory MRI activity is almost completely suppressed. Autologous haematopoietic stem-cell transplantation is associated with qualitative immunological changes in the blood, suggesting that, beyond its immunosuppressive potential, it could also have some beneficial effect for the resetting of the immune system. Patients with severe, rapidly worsening multiple sclerosis who are unresponsive to approved therapies could be candidates for this treatment, but its clinical efficacy has still to be shown in large, prospective, controlled studies.

Introduction

Multiple sclerosis (MS) is a chronic inflammatory disease mediated by autoreactive T cells and, to a lesser extent, by B cells that invade and colonise the CNS causing oligodendrocyte damage, demyelination, and axonal loss.1 The currently available treatments include steroids for the acute phase of the relapse, immunomodulating agents (eg, interferon beta and glatiramer acetate), immunosuppressive therapies (eg, mitoxantrone), and, more recently, a humanised monoclonal antibody, natalizumab, which has a selective adhesion-molecule inhibitor effect.2 Although many patients respond fairly well to the approved treatments, some patients continue to rapidly deteriorate and accumulate significant motor and cognitive disabilities.3 The search for more effective therapies is thus necessary and must be pursued.

Intense immunosuppression followed by autologous haematopoietic stem-cell transplantation (AHSCT) has been assessed as a possible new therapeutic strategy in severe autoimmune disorders,4 particularly as it has been shown to be efficacious in animal models of immune-mediated diseases.5, 6 The rationale relies on the eradication of the self-reactive immune cells by intense immunosuppression and the achievement of a full immune reconstitution on the engraftment of autologous haemato-lymphopoietic stem cells. Moreover, treatment with AHSCT is associated with profound qualitative immunological changes,7 which suggests that, beyond its immunosuppressive potential, AHSCT could also have some benefit through the resetting of the immune system, which could become tolerant of self antigens over an extended period of time. Pioneering studies on AHSCT in MS started in 1995,8 and more than 400 cases have since been treated worldwide. Although the clinical efficacy of AHSCT has not yet been shown in large randomised controlled studies, new relevant data have been added in the past few years, especially on the activity and toxicity of the various conditioning regimens used, transplant-related mortality, MRI changes after the procedure, and immunological renewal induced by transplantation. In this Review, we aim to assess the accumulated data on this procedure.

Section snippets

AHSCT in animal models of autoimmune disease

In general, animals that spontaneously develop autoimmune disorders or animals in which the autoimmune disease is induced by immunisation towards specific antigens are treated with intense immunosuppressive therapy (conditioning regimen), including total body irradiation (TBI) with or without other immunosuppressive drugs, and are then rescued by an intravenous injection of a suspension of bone-marrow cells.9 The graft can be obtained from (1) a healthy animal of another strain (allogeneic

Autologous transplants in MS

In principle, allogeneic transplantation can cure an autoimmune disease through the replacement of a defective immune system with a new one harvested from a healthy individual. After the immunosuppression induced by the conditioning regimen, the eradication of autoreactive clones in the recipient could be completed by the donor's immune system. This event (graft vs autoimmunity) has been shown in experimental models, but not yet in controlled clinical trials.24 Allogeneic transplantation in

Clinical outcome

Neurological outcome in AHSCT has been assessed in small phase I/II studies done by single centres,8, 35, 36, 37, 40, 41, 44, 45, 47, 52, 53, 54, 63 and by collaborative efforts of various teams from several countries (table).33, 38, 39, 42, 48, 49 All studies reported the feasibility of the procedure, transplant-related toxicity and mortality, MRI as a measure of disease activity, and neurological outcome after transplantation. Two retrospective reports on patients with MS registered in the

Toxicity and transplant-related mortality

Toxic effects can occur during all phases of transplantation, and are usually defined as early when they appear within the first 100 days after transplantation and as late thereafter. In the mobilising and conditioning period, flares of disease associated with G-CSF injection, allergic reactions induced by ATG, fever, and mucositis can occur. As reported in phase I/II prospective studies,33, 44 the administration of cyclophosphamide with or without steroids during the mobilisation phase

MRI and inflammation

AHSCT has the capacity to completely suppress gadolinium (Gd)-enhancing MRI activity, and this effect is maintained with time. No other treatment for MS has this profound and persistent effect on inflammation, without any maintenance treatment. All the studies that have assessed MRI report this remarkable property.33, 36, 38, 39, 44, 52, 53 In one of these studies,38 10 patients were examined with a triple dose of Gd (which is far more sensitive at detecting disease activity than the standard

Immunological changes

After AHSCT, a profound decrease in the CD4+ T-cell subset with an inverted CD4/CD8 ratio persists for at least 1–2 years.39, 52 However, circulating B cells and natural killer cells recover within 3 months.33, 44, 52 Whereas in the first months, memory T cells rapidly recover and the naïve subset is suppressed,39 at 2 years of follow-up, an increase in naïve CD4 T cells over memory cells has been shown.7 More importantly, the phenotypic and T-cell-receptor-excision-circle analysis of naïve

Ongoing studies

The Autologous Stem-cell Transplantation International MS trial (ASTIMS)95 is a multicentre, prospective randomised phase II study supported by the EBMT, and is currently underway. The primary endpoint is the number of new T2 lesions on MRI examination. The inclusion criteria are as follows: (1) patients with clinically defined MS; (2) EDSS score of 3·5–6·5; (3) age 18–50 years; (4) secondary progressive forms with or without relapses, or relapsing-remitting cases with a documented worsening on

Selection of patients and future perspectives

According to animal and clinical data accumulated to date,100 the patient who is most likely to benefit from AHSCT, or other intense immunosuppressive therapies,101 is a relatively young patient who is still ambulatory, with a relapsing-remitting or a relapsing-progressive clinical course, who has failed the conventional approved immunomodulatory (interferon beta or glatiramer acetate) therapies, and has also failed or relapsed during therapy with natalizumab and conventional immunosuppressive

Conclusions

Since the introduction of AHSCT, many questions have been clarified, but the unresolved problems are still numerous.103, 104 The main limitations are that AHSCT is not a cure for MS, it is a therapy with substantial toxic effects and has a TRM of around 1–2%, there is no consensus on the best conditioning regimen with the highest ratio between efficacy and toxicity, and, although indications about inclusion criteria are becoming clear, treatment of patients with MS in the early phase of the

Search strategy and selection criteria

The search for pertinent articles was done in PubMed from 1997, to April 15, 2008, combining the terms “autologous haematopoietic stem cell transplantation” and “bone marrow transplantation” with the terms “multiple sclerosis”, “malignant forms of multiple sclerosis”, “multiple sclerosis MRI”, and “immunological changes”. All published papers were evaluated, and we disregarded only publications that were repeats of previous papers. Four abstracts from the 2007 European Committee for

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