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

Abstract

Multiple sclerosis (MS) is an immune-mediated disease that may be amenable to high-dose immunosuppression with peripheral blood stem cell transplantation (SCT) in selected patients. Five MS patients (all women, ages 39-47 years) received granulocyte colony-stimulating factor (G-CSF) for stem cell mobilization, CD34 cell selection for T-cell depletion, a preparatory regimen of busulfan (1 mg/kg x 16 doses) and cyclophosphamide (120 mg/kg), and antithymocyte 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 14 and platelet count >20,000 were 17 to 58. Posttransplantation infectious complications in the first year after SCT occurred in 3 of 5 patients, and 1 patient died at day 22 after SCT from influenza A pneumonia. Neuropathologic study in this patient showed demyelinating plaques with surrounding macrophages but only rare T cells. In 2 patients, MS flared transiently with G-CSF. Magnetic resonance imaging gadolinium enhancement was present in 3 of 5 patients before transplantation and 0 of 4 after SCT. There were cerebrospinal fluid oligoclonal bands at 1 year after SCT, similar to the pretransplantation assays. Sustained suppression of peripheral blood mononuclear cell proliferative responses to myelin antigens occurred after SCT, but new responses to some myelin peptide fragments also developed after SCT. In 1 patient, 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 abruptly 19 months after SCT from overwhelming S. pneumoniae sepsis. The remaining patients have had stable MS (follow-up, 18 and 30 months). In summary, our experience confirms the high-risk nature of this approach. Further studies and longer follow-up would be needed to determine the significance of new lymphocyte proliferative responses after SCT and the overall effect of this treatment on the natural history of MS.

Hematopoietic Stem Cell Therapy for Multiple Sclerosis: Top 10 Lessons Learned

“…Treatment-related mortality ranged from 4 [30] to 20 % [42] during the first decade of HSCT for MS. This may in part reflect the selection of patients with advanced disability, as well as the use of high-intensity conditioning regimens.…”

Brazilian experience with two conditioning regimens in patients with multiple sclerosis: BEAM/horse ATG and CY/rabbit ATG

“…By contrast, non-myeloablative regimens selectively target the immune compartment for ablation without irreversible erasure of the BM's ability to regenerate hematopoiesis. Intense myeloablative regimens used to treat MS, such as BU/ CY 27 and CY/TBI/antilymphocyte globulin (CY/TBI/ ATG), 28 showed significant treatment-related mortality. An intermediate-intensity conditioning regimen, BEAM (BCNU, cytosine arabinoside, melphalan and etoposide) is better tolerated and has a lower morbidity and mortality rate.…”

“…34 The mortality rate of HSCT for MS in studies with relatively large samples is described in Table 1. [25][26][27][28][29][30][35][36][37][38][39][40][41][42][43][44][45] Although these studies use myeloablative conditioning regimens of varying intensity, non-myeloablative regimens have been advocated for autologous HSCT of autoimmune diseases. 46 Recently, one of these latter studies was published using CY/rATG and it reported no deaths among 21 patients with relapsing-remitting MS. 31 There is a controversy regarding the analysis of the immune system modifications as increases in naive CD4 þ T cells over memory cells 20 and the fact that more intensive regimens seem to present better results than less intensive regimens.…”

Autologous hematopoietic cell transplantation in multiple sclerosis

“…Initially, several regimens included the use of total body irradiation (TBI) [10] and busulfan [11,14,15]. These regimens were associated with high morbidity and mortality [14,16].…”

“…Initially, several regimens included the use of total body irradiation (TBI) [10] and busulfan [11,14,15]. These regimens were associated with high morbidity and mortality [14,16]. TBI was postulated to accelerate progression of disability in patients with secondary and primary progressive forms of MS as a result of the radiation-induced axonal damage [17].…”