Autologous Hematopoietic Stem Cell Transplantation in Severe Multiple Sclerosis. The Brazilian Experience with Two Conditioning Regimes: BEAM and High-Dose Cyclophosphamide.

Introduction: Multiple sclerosis (MS) is a chronic, inflammatory and demyelinating disease of the central nervous system (CNS) leading to gradual axonal degeneration. It is a classical auto-immune disease, thus high-dose chemotherapy followed by autologous hematopoietic stem cell transplantation (AHSCT) could “reset” the immune disorder by controlling autoreactive clones and by restoring self-tolerance after immunological recovery.

Objectives: Describe the experience of the Brazilian Cooperative Group of AHSCT for Autoimmune Diseases in 41 MS patients followed-up to five years.

Methods: Stem cells were mobilized from the bone marrow with Cy (2g/m²) and Filgrastim (10μg/kg/d SC), collected by leukapheresis and cryopreserved. Patients were conditioned with BEAM (BCNU 300 mg/m2, cytarabine 200 mg/m2, etoposide 200 mg/m2 ×4, melphalan 140 mg/m2) and horse antilymphocyte globulin (ATG) 90 mg/kg) or cyclophosphamide (CY) 50 mg/kg ×4 and rabbit ATG (rATG) 4.5 mg/kg, followed by stem cell infusion. Quality of life was assessed by the Short Form-36 Health Survey Questionnaire (SF-36).

Results: Between January 2001 and June 2006, 21 patients received BEAM/ATG and 20 received CY/ATG. Medium age was 42 years (27–53 years), 24 (58.5%) were females, 33 (80.4%) had secondary progressive MS form, 80.95% had EDSS (Expanded Disability Status Scale) 6.0 or higher. No significant difference was seen between the groups regarding age, sex, disease presentation and EDSS. The mean number of CD34+ infused cells was 8.8×106/kg (2,5– 25.13×106/kg). Mean engraftment was 9,3 days (7–10 days) for neutrophils and 13 days (7–24 days) for platelets. 18 patients (46%) had neutropenic fever, 8 (20.0%) had pneumonia and 5 (12.5%) had allergic reactions to lymphoglobulin. Three patients (14.3%) died in the BEAM group due to conditioning regiment toxicity, sepsis and alveolar hemorrhage. Mean hospital stay was 35.47 days (20–168 days) in the BEAM group and 20.15 days (14–32 days) in the CY group (p<0,0001). EDSS-based disease progress in six months to a year was similar in both groups (p = 0.54). Disease worsening was detected in 6/18 patients in the BEAM group and 4/14 in the Cy group. Median follow-up was 17 months. Disease-free survival 4 years post-transplant was 65%. 31/41 patients completed SF-36 after transplantation and they exhibited improvement in their general health status at 100 days post-transplant (p = 0.02).

Conclusion: In our study, a less intensive conditioning regimen (CY + rATG) was associated with similar neurological outcomes but also with less toxicity when compared to BEAM regimen. The majority of patients had an improvement in their quality of live. Longer follow-up is required to assess the therapeutic effectiveness of both regimens in MS progression.