Haematopoietic stem cell transplant versus immune-reconstitution therapy in relapsing multiple sclerosis

Abstract

In the treatment of relapsing-remitting multiple sclerosis, autologous hematopoietic stem cell transplant and immune-reconstitution therapies show several similarities. These treatment strategies have not yet been compared head-to-head. This study emulated pairwise trials of comparative effectiveness of stem cell transplant vs. immune-reconstitution therapies cladribine and alemtuzumab. This cohort/registry study of comparative treatment effectiveness included data from 7 specialist multiple sclerosis centres with autologous hematopoietic stem cell programs (RESCUE-MS) and international MSBase registry during 2006-2023. The study included patients with relapsing-remitting multiple sclerosis treated with autologous hematopoietic stem cell transplant, cladribine or alemtuzumab, with a minimum of 2-month follow-up before commencing study therapy and ≥2 disability assessments after commencing the study therapy. Patients were matched on a propensity score derived from their clinical and demographic characteristics. The matched groups were compared on annualised relapse rates freedom from relapses and 6-month confirmed disability worsening and improvement (measured with Expanded Disability Status Scale). The matching of 143 (stem cell) to 283 cladribine-treated patients and of 134 (stem cell) to 562 alemtuzumab-treated patients reduced the measured differences between the groups by 98% and 96%, respectively. The matched patients had high mean disease activity (>0.8 relapses in the prior 2 years), mean Expanded Disability Status Scale scores of 3-4, and were followed-up for a mean of 3.8-3.9 (stem cell), 1.9 (cladribine) or 4.5 years (alemtuzumab). Compared to cladribine, stem cell transplant was associated with a lower risk of relapses (mean annualised relapse rate ± standard deviation 0.05±0.28 vs. 0.16±0.39, respectively; hazard ratio 0.24, 95% confidence interval 0.15-0.41), similar risk of disability worsening (hazard ratio 0.70, 95% confidence interval 0.34-1.43) and higher probability of disability improvement (hazard ratio 2.19, 95% confidence interval 1.31-3.66). Compared to alemtuzumab, stem cell transplant was associated with a lower risk of relapses (mean annualised relapse rate ± standard deviation 0.04±0.23 vs. 0.09±0.21, respectively; hazard ratio 0.52, 95% confidence interval 0.29-0.93), similar risk of disability worsening (hazard ratio 0.95, 95% confidence interval 0.53-1.72) and higher probability of disability improvement (hazard ratio 2.03, 95% confidence interval 1.23-3.34). 34% of patients treated with stem cell transplant experienced delayed complications, mainly infections. No treatment-associated deaths were reported. Among patients with active relapsing-remitting multiple sclerosis and moderate disability, autologous hematopoietic stem cell transplant is superior to cladribine and alemtuzumab at suppressing relapses and enabling recovery of neurological function. The high effectiveness of stem cell transplant is likely attributable to a complex interplay of immune suppression and reconstitution.

Keywords: disability; disease modifying therapy; propensity score; relapses; stem cells.