Hematopoietic Stem Cell Transplant Outperforms Certain MS Disease-Modifying Therapies in Efficacy, Recovery of Disability

Tomas Kalincik, MD, PhD

In an observational comparative effectiveness study of patients with relapsing-remitting multiple sclerosis (MS), findings showed that over a 5-year period, treatment with autologous hematopoietic stem cell transplant (AHSCT) was associated with substantially lower relapse rate than fingolimod (Gilenya; Novartis) and marginally lower relapse rate than natalizumab (Tysabri; Biogen). The study did not find evidence for difference in effectiveness between AHSCT and ocrelizumab (Ocrevus; Genentech) over a shorter available follow-up time.¹

Published in JAMA Neurology, the trial featured 4915 individuals across 6 specialist MS centers with AHSCT programs and an international MSBase registry who were compared on annualized relapse rates (ARR), freedom from relapses, and 6-month confirmed Expanded Disability Status Scale (EDSS) score worsening and improvement. In total, 167 were treated with AHSCT, 2558 received fingolimod, 1490 natalizumab, and 700 with ocrelizumab. The prematch AHSCT cohort was younger and with greater disability than the disease-modifying therapy cohorts.

Led by Tomas Kalincik, MD, PhD, head of the Clinical Outcomes Research Unit at the University of Melbourne, patients treated with AHSCT showed fewer relapses than those treated with fingolimod (ARR mean, 0.09 [SD, 0.30] vs 0.20 [SD, 0.44], respectively; P <.001). There was no between-group difference in the cumulative hazards of 6-month confirmed disability worsening over up to 5 years (HR, 1.70; 95% CI, 0.91-3.17); however, the association of AHSCT with facilitating 6-month confirmed improvement of disability was superior over fingolimod (HR, 2.70; 95% CI, 1.71-4.26).

"The observation that AHSCT showed superiority in clinical outcomes over fingolimod and, to a lesser extent, natalizumab, but not ocrelizumab, is intriguing," Kalincik et al wrote. "While this may be attributed to the shorter study follow-up available in the ocrelizumab cohort, it may also be due to the differences in the mechanisms of action among the therapies. Fingolimod and natalizumab are antitrafficking agents, sequestrating lymphocytes outside of the central nervous system, whereas ocrelizumab acts through depletion of CD20-positive cells, a mechanism that is more similar to the immunosuppressive effect of AHSCT."

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In comparison with natalizumab, the ARR observed in the AHSCT group was marginally lower (0.08 [SD, 0.31] vs 0.10 [SD, 0.34]; P = .03), as also confirmed by cumulative hazard of relapses (HR, 0.51; 95% CI, 0.34-0.74). There was no evidence for difference in the 6-month confirmed disability between the 2 groups (HR, 1.06; 95% CI, 0.54-2.09) with similar proportions of patients who experienced disability worsening by years 2 and 5. Similar to fingolimod, treatment with AHSCT resulted in superior 6-month confirmed disability improvement over the 5-year follow-up in comparison with natalizumab (HR, 2.68; 95% CI, 1.72-4.18).

With only 3 years of analyzable follow-up data between ocrelizumab and ASHCT, investigators found that the risk of relapses between the groups was similar (mean ARR, 0.09 [SD, 0.34] vs 0.06 [SD, 0.32], respectively; P = .86). This observation was moderately robust to potential unmeasured confounding (Γ = 40%).The 2 groups also demonstrated a similar rate of proportions of patients who remained free from 6-month confirmed disability worsening (HR, 1.77; 95% CI, 0.61-5.08) and experienced 6-month confirmed disability improvement (HR, 1.37; 95% CI, 0.66-2.82).

In terms of safety for AHSCT-treated patients who were matched in at least 1 of the pairwise analyses (n = 159), 23.3% (n = 37) experienced febrile neutropenia during mobilization, 11.3% (n = 18) experienced serum sickness, and 8.8% (n = 14) required intensive care unit admission. In total, 82 serious adverse events were recorded in 58 patients after discharge post-AHSCT, most of which were infections (59.8%), especially of viral etiology (41.5%). Specifically, Epstein-Barr virus, cytomegalovirus, and herpes simplex or zoster, were among the most common. One patient experienced a treatment-related death due to veno-occlusive disease of the liver postbusulfan.

"Although AHSCT requires a complex treatment procedure, its one-off nature may offer practical advantages over the continuously administered therapies," the study investigators concluded. "AHSCT is associated with considerable risks, but the risk of treatment-associated mortality is low."

REFERENCE
1. Kalincik T, Sharmin S, Roos I, et al. Comparative effectiveness of autologous hematopoietic stem cell transplant vs fingolimod, natalizumab and ocrelizumab in highly active relapsing-remitting multiple sclerosis. JAMA Neurol. 2023;80(7);702-713. doi:10.1001/jamaneurol.2023.1184