Peripheral blood stem cell transplantation in multiple sclerosis with busulfan and cyclophosphamide conditioning: Report of toxicity and immunological monitoring

Multiple sclerosis (MS) is an immune-mediated disease that may be amenable to high-dose immunosuppression with peripheral blood stem cell transplantat ion (SCT) in selected patients. Five MS patients (all women, ages 39-47 yea rs) received granulocyte colony-stimulating factor (G-CSF) for stern cell m obilization, CD34 cell selection for T-cell depletion, a preparatory regime n of busulfan (1 mg/kg x 16 doses) and cyclophosphamide (120 mg/kg), and an tithymocyte globulin (10 mg/kg x 3 doses) at the time of stem cell infusion . Days required to recover absolute neutrophil count >500 were 12 to 1 1 an d platelet count >20,000 were 17 to 58. Posttransplantation infectious comp lications in the first year after SCT occurred in 3 of 5 patients, and I pa tient died at day 22 after SCT from influenza A pneumonia. Neuropathologic study in this patient showed demyelinating plaques with surrounding macroph ages but only rare T cells, In 2 patients, RIS flared transiently with G-CS F Magnetic resonance imaging gadolinium enhancement was present in 3 of 5 p atients before transplantation and 0 of 4 after SCT. There were cerebrospin al fluid oligoclonal bands at 1 year after SCT, similar to the pretransplan tation assays. Sustained suppression of peripheral blood mononuclear cell p roliferative responses to myelin antigens occurred after SCT, but new respo nses to some myelin peptide fragments also developed after SCT. In 1 patien t, enzyme-linked immunospot (ELISPOT) assays done 9 months after SCT showed a predominant T helper 2 (Th2) cytokine pattern. Neurological progression of 1 point on the extended disability status scale was seen in 1 patient 17 months after SCT. Another patient who was neurologically stable died abrup tly 19 months after SCT from overwhelming S. pneumoniae sepsis. The remaini ng patients have had stable MS (follow-up, 18 and 30 months), In summary, o ur experience confirms the high-risk nature of this approach. Further studi es and longer follow-up would be needed to determine the significance of ne w lymphocyte proliferative responses after SCT and the overall effect of th is treatment on the natural history of MS.