Autologous hematopoietic stem cell transplantation in multiple sclerosis: 20 years of experience.

Intense immunosuppression followed by autologous hematopoietic stem cell transplantation (AHSCT) has been widely used in the last 20 years for the treatment of aggressive forms of autoimmune disorders, especially multiple sclerosis (MS). All clinical studies, although small and uncontrolled, demonstrate a great efficacy of this procedure in halting inflammation and disease activity, even in those patients affected by "malignant forms" of MS. The long-term follow-up has also revealed the possible maintenance of positive results in the course of time, and this evidence is supported by immunological data that suggest the possibility of a resetting of the immune system after AHSCT. The safety of AHSCT has improved in the last years, but the transplant related mortality is still nowadays of about 1-2 %, pointing out that a careful selection of patients to submit to AHSCT is mandatory. The long clinical experience allowed to identify the ideal candidate: a young patient, with a short disease duration, with recurring and disabling relapses and the presence of inflammatory activity on brain magnetic resonance scans, unresponsive to approved therapies. A large, randomized clinical study comparing AHSCT with the best approved therapies is still necessary to confirm the role of transplantation in MS treatment.

Autologous hematopoietic stem cell transplantation in multiple sclerosis: a phase II trial.

OBJECTIVE: To assess in multiple sclerosis (MS) the effect of intense immunosuppression followed by autologous hematopoietic stem cells transplantation (AHSCT) vs mitoxantrone (MTX) on disease activity measured by MRI. METHODS: We conducted a multicenter, phase II, randomized trial including patients with secondary progressive or relapsing-remitting MS, with a documented increase in the last year on the Expanded Disability Status Scale, in spite of conventional therapy, and presence of one or more gadolinium-enhancing (Gd+) areas. Patients were randomized to receive intense immunosuppression (mobilization with cyclophosphamide and filgrastim, conditioning with carmustine, cytosine-arabinoside, etoposide, melphalan, and anti-thymocyte globulin) followed by AHSCT or MTX 20 mg every month for 6 months. The primary endpoint was the cumulative number of new T2 lesions in the 4 years following randomization. Secondary endpoints were the cumulative number of Gd+ lesions, relapse rate, and disability progression. Safety and tolerability were also assessed. Twenty-one patients were randomized and 17 had postbaseline evaluable MRI scans. RESULTS: AHSCT reduced by 79% the number of new T2 lesions as compared to MTX (rate ratio 0.21, p = 0.00016). It also reduced Gd+ lesions as well as the annualized relapse rate. No difference was found in the progression of disability. CONCLUSION: Intense immunosuppression followed by AHSCT is significantly superior to MTX in reducing MRI activity in severe cases of MS. These results strongly support further phase III studies with primary clinical endpoints. The study was registered as EUDRACT No. 2007-000064-24.

Low intensity lympho-ablative regimen followed by autologous hematopoietic stem cell transplantation in severe forms of multiple sclerosis: A MRI-based clinical study.

BACKGROUND: Autologous hematopoietic stem cell transplantation (AHSCT) has been successfully used to treat aggressive forms of multiple sclerosis (MS) that are unresponsive to approved therapies. In the last years, in view of the risk of mortality related to the procedure, the utilization of low-intensity conditioning regimens has been considered. OBJECTIVE: To report magnetic resonance imaging (MRI) and clinical data in a small cohort of patients treated with a low-intensity lympho-ablative regimen, followed by AHSCT. METHODS: Seven patients affected by relapsing-remitting MS (RRMS) underwent AHSCT, with cyclophosphamide 120 mg/kg in 2 days as the conditioning regimen; and were then followed with serial MRI evaluations until 36 months, with clinical evaluations until 60 months. RESULTS: The mean number of gadolinium (Gd)-enhancing lesions significantly decreased after treatment, but a complete suppression of inflammatory activity was not obtained. No deaths occurred, but every patient developed adverse events, although not severe. After 5 years of follow-up, two patients remained stable, one patient markedly improved and four patients had a mild progression of the disease. Only one patient experienced a relapse after treatment. CONCLUSION: A low-intensity conditioning regimen with AHSCT has a profound effect on MRI inflammation and relapses, but is not able to completely abrogate MRI activity and disease progression of aggressive RRMS.