Elsevier

The Lancet Neurology

Volume 8, Issue 3, March 2009, Pages 244-253
The Lancet Neurology

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Autologous non-myeloablative haemopoietic stem cell transplantation in relapsing-remitting multiple sclerosis: a phase I/II study

https://doi.org/10.1016/S1474-4422(09)70017-1Get rights and content

Summary

Background

Autologous non-myeloablative haemopoietic stem cell transplantation is a method to deliver intense immune suppression. We evaluated the safety and clinical outcome of autologous non-myeloablative haemopoietic stem cell transplantation in patients with relapsing-remitting multiple sclerosis (MS) who had not responded to treatment with interferon beta.

Methods

Eligible patients had relapsing-remitting MS, attended Northwestern Memorial Hospital, and despite treatment with interferon beta had had two corticosteroid-treated relapses within the previous 12 months, or one relapse and gadolinium-enhancing lesions seen on MRI and separate from the relapse. Peripheral blood haemopoietic stem cells were mobilised with 2 g per m2 cyclophosphamide and 10 μg per kg per day filgrastim. The conditioning regimen for the haemopoietic stem cells was 200 mg per kg cyclophosphamide and either 20 mg alemtuzumab or 6 mg per kg rabbit antithymocyte globulin. Primary outcomes were progression-free survival and reversal of neurological disability at 3 years post-transplantation. We also sought to investigate the safety and tolerability of autologous non-myeloablative haemopoietic stem cell transplantation.

Findings

Between January, 2003, and February, 2005, 21 patients were treated. Engraftment of white blood cells and platelets was on median day 9 (range day 8–11) and patients were discharged from hospital on mean day 11 (range day 8–13). One patient had diarrhoea due to Clostridium difficile and two patients had dermatomal zoster. Two of the 17 patients receiving alemtuzumab developed late immune thrombocytopenic purpura that remitted with standard therapy. 17 of 21 patients (81%) improved by at least 1 point on the Kurtzke expanded disability status scale (EDSS), and five patients (24%) relapsed but achieved remission after further immunosuppression. After a mean of 37 months (range 24–48 months), all patients were free from progression (no deterioration in EDSS score), and 16 were free of relapses. Significant improvements were noted in neurological disability, as determined by EDSS score (p<0·0001), neurological rating scale score (p=0·0001), paced auditory serial addition test (p=0·014), 25-foot walk (p<0·0001), and quality of life, as measured with the short form-36 (SF-36) questionnaire (p<0·0001).

Interpretation

Non-myeloablative autologous haemopoietic stem cell transplantation in patients with relapsing-remitting MS reverses neurological deficits, but these results need to be confirmed in a randomised trial.

Funding

Division of Immunotherapy, Northwestern University.

Introduction

Most patients with multiple sclerosis (MS) present with intermittent symptoms that are commonly, at least partially, reversible; this form of the disease is termed relapsing-remitting MS. Over time, most patients eventually develop secondary-progressive MS, which manifests as irreversible and gradual neurological impairments that often progress without acute relapses.1 Autologous haemopoietic stem cell transplantation for MS was first done by Fassas and co-workers2 and has subsequently been repeated in many countries. These studies were done mostly in patients with late secondary-progressive MS, although some have included patients with primary-progressive, relapsing-remitting, or relapsing-progressive MS.

In most patients, haemopoietic stem cell transplantation for secondary progressive MS did not improve the neurological disability;3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 consequently, outcome was generally reported as duration of stabilisation of neurological disability (ie, results were reported as progression-free survival, defined as the probability of no sustained increase in Kurtzke expanded disability status scale [EDSS] score by at least 1 point after transplantation compared with pretransplantation score) rather than improvement. Post-transplantation progression-free survival varies substantially between studies and has been reported as either 61% or 73% at 2 years,3, 4 between 36% and 77% at 3 years,5, 6, 7, 8, 9, 10, 11 and between 58% and 75% at 3 to 6 years.12, 13, 14

However, the EDSS, which is a validated and widely used scale to measure outcomes in MS, is not a linear scale. Without a transplant, the time for a patient to progress by 1 point on the EDSS varies in accordance with the baseline score and the duration of MS. For example, the mean time to progression by 1 point on the EDSS is longer for patients with scores at the lower and higher ends of the scale and shorter for patients with scores of between 3 and 5 points.15 An analysis of the natural history of a group of patients with MS who did not have haemopoietic stem cell transplantation suggested that the risk of sustained progression (a sustained increase in EDSS score of at least 1 point) was 50% by 7 years and 70% by 15 years.16 The likelihood of progression is also affected by baseline EDSS score: 34% of patients with an EDSS score of 3·0 to 3·5 points at entry progressed compared with 62% of patients with EDSS scores of 4·0–5·5 points.16

The investigators in many transplantation studies for progressive MS selected patients whose EDSS score had increased by 1 point in the year before treatment. Whether this criterion selects for patients with more rapidly progressive disability or selects for patients whose new EDSS score is less likely to change over the next few years because they have just reached a new plateau EDSS score is unclear. Therefore, without a randomised trial, we cannot ascertain whether haemopoietic stem cell transplantation alters the progression-free survival of patients with secondary-progressive MS. Furthermore, haemopoietic stem cell transplantation does not reverse neurological disability in the late progressive phase of MS.3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14

The rationale behind autologous haemopoietic stem cell transplantation for MS is to reset the immune system; that is, to produce new and self-tolerant lymphocytes from the haemopoietic stem cell (immune stem cell) transplant after chemotherapy-induced elimination of self-reactive or autoreactive lymphocytes.17

Neurological deficits during the late secondary-progressive phase of MS are mostly caused by neurodegeneration from axonal atrophy,18, 19, 20 for which no immune-based therapy, including haemopoietic stem cell therapy, has been effective for reversing the deficits. By contrast, during the relapsing-remitting phase of MS, demyelination is mediated by immune cells.21 First-line therapy for relapsing-remitting MS is immune modulation, which ameliorates the inflammatory processes that mediate the damage to the CNS. Current therapies to treat the relapsing-remitting or progressive phases of MS are designed to delay progression of the disease, rather than reverse neurological disability. In this study of autologous haemopoietic stem cell transplantation we treated patients with relapsing-remitting MS who had failed to respond to immune modulation but were still at an inflammatory stage, rather than wait until their MS becomes predominately neurodegenerative. This will enable us to ascertain whether haemopoietic stem cell transplantation during the relapsing-remitting phase of MS can reverse neurological disability.

Section snippets

Patients

Patients were eligible if they were aged between 18 and 55 years, had MS according to the revised McDonald criteria, met the Poser criteria for clinically definite MS,22 and had failed to respond to at least 6 months' therapy with interferon beta. Failure was defined as two or more clinical relapses with documented neurological changes that were treated with intravenous corticosteroids during the year before study entry; or at least one relapse treated with methylprednisolone and, on a separate

Results

Between January, 2003, and February, 2005, 21 patients (11 women and 10 men) with MS had autologous haemopoietic stem cell transplantation. The median age at the time of transplantation was 33 years (range 20 to 53 years) and the median duration of disease before transplantation was 5 years (range 1·5 to 10·0 years). The median baseline EDSS score was 3·1 points (range 2·0 to 5·5 points). Table 1 summarises the pretransplantation characteristics of the patients.

The median infused dose of

Discussion

We report the results of autologous haemopoietic stem cell transplantation for relapsing-remitting MS. After a mean follow-up of 3 years, progression-free survival was 100%. By contrast with haemopoietic stem cell transplantation in patients with progressive MS, 81% of our patients had reversal of neurological disability and a sustained improvement in EDSS score of 1 point or more. However, the recruitment of patients with recent relapsing disease might not enable a true baseline EDSS score to

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