Comparative Effectiveness of Autologous Hematopoietic Stem Cell Transplant vs Fingolimod, Natalizumab, and Ocrelizumab in Highly Active Relapsing-Remitting Multiple Sclerosis
Tomáš Kalinčík, Sifat Sharmin, Izanne Roos, Mark S. Freedman, Harold Atkins, Joachim Burman, Jennifer Massey, Ian Sutton, Barbara Withers, Richard Macdonell, Andrew Grigg, Øivind Torkildsen, Lars Bø, Anne Kristine Lehmann, Eva Havrdová, Eva Krasulová, Marek Trněný, Tomáš Kozák, Anneke van der Walt, Helmut Butzkueven, Pamela McCombe, Olga Skibina, Jeannette Lechner‐Scott, Barbara Willekens, Elisabetta Cartechini, Serkan Özakbaş, Raed Alroughani, Jens Kühle, Francesco Patti, Pierre Duquette, Alessandra Lugaresi, Samia J. Khoury, Mark Slee, Recai Türkoğlu, Suzanne Hodgkinson, Nevin John, Davide Maimone, María José Sá, Vincent Van Pesch, Oliver Gerlach, Guy Laureys, Liesbeth Van Hijfte, Rana Karabudak, Daniele Spitaleri, Tünde Csépány, Riadh Gouider, Tamara Castillo‐Triviño, Bruce Taylor, Basil Sharrack, John A. Snowden, MSBase Study Group Collaborators, MSBase Study Group Authors, Dana Horáková, Katherine Buzzard, Murat Terzi, Alexandre Prat, Marc Girard, Pierre Grammond, Michael Barnett, Grace Stewart, Marco Onofrj, Guillermo Izquierdo, Sara Eichau, François Grand’Maison, Julie Prévost, Bart Van Wijmeersch, Maria Pia Amato, Vahid Shaygannejad, Cavit Boz, R. Fernandez Bolanos, Aysun Soysal, Cristina Ramo‐Tello, Claudio Solaro, Claudio Gobbi, José Antonio Cabrera-Gómez, E Roullet, Cees Zwanikken, Leontien Den Braber‐Moerland, Norma Deri, Maria Luisa Saladino, Edgardo Cristiano, Juan Ignacio Rojas, Cárlos Vrech, Cameron Shaw, Neil Shuey, Mike Boggild, Ik Lin Tan, Todd A. Hardy, D. Decoo, Fraser Moore, Jiwon Oh, Patrice H. Lalive, Radek Ampapa, Thor Petersen, Celia Oreja‐Guevara, Ángel Pérez Sempere, José Andrés Domínguez, Sarah Besora, Stella Hughes, Orla Gray
Abstract
Importance: Autologous hematopoietic stem cell transplant (AHSCT) is available for treatment of highly active multiple sclerosis (MS). Objective: To compare the effectiveness of AHSCT vs fingolimod, natalizumab, and ocrelizumab in relapsing-remitting MS by emulating pairwise trials. Design, Setting, and Participants: This comparative treatment effectiveness study included 6 specialist MS centers with AHSCT programs and international MSBase registry between 2006 and 2021. The study included patients with relapsing-remitting MS treated with AHSCT, fingolimod, natalizumab, or ocrelizumab with 2 or more years study follow-up including 2 or more disability assessments. Patients were matched on a propensity score derived from clinical and demographic characteristics. Exposure: AHSCT vs fingolimod, natalizumab, or ocrelizumab. Main outcomes: Pairwise-censored groups were compared on annualized relapse rates (ARR) and freedom from relapses and 6-month confirmed Expanded Disability Status Scale (EDSS) score worsening and improvement. Results: Of 4915 individuals, 167 were treated with AHSCT; 2558, fingolimod; 1490, natalizumab; and 700, ocrelizumab. The prematch AHSCT cohort was younger and with greater disability than the fingolimod, natalizumab, and ocrelizumab cohorts; the matched groups were closely aligned. The proportion of women ranged from 65% to 70%, and the mean (SD) age ranged from 35.3 (9.4) to 37.1 (10.6) years. The mean (SD) disease duration ranged from 7.9 (5.6) to 8.7 (5.4) years, EDSS score ranged from 3.5 (1.6) to 3.9 (1.9), and frequency of relapses ranged from 0.77 (0.94) to 0.86 (0.89) in the preceding year. Compared with the fingolimod group (769 [30.0%]), AHSCT (144 [86.2%]) was associated with fewer relapses (ARR: mean [SD], 0.09 [0.30] vs 0.20 [0.44]), similar risk of disability worsening (hazard ratio [HR], 1.70; 95% CI, 0.91-3.17), and higher chance of disability improvement (HR, 2.70; 95% CI, 1.71-4.26) over 5 years. Compared with natalizumab (730 [49.0%]), AHSCT (146 [87.4%]) was associated with marginally lower ARR (mean [SD], 0.08 [0.31] vs 0.10 [0.34]), similar risk of disability worsening (HR, 1.06; 95% CI, 0.54-2.09), and higher chance of disability improvement (HR, 2.68; 95% CI, 1.72-4.18) over 5 years. AHSCT (110 [65.9%]) and ocrelizumab (343 [49.0%]) were associated with similar ARR (mean [SD], 0.09 [0.34] vs 0.06 [0.32]), disability worsening (HR, 1.77; 95% CI, 0.61-5.08), and disability improvement (HR, 1.37; 95% CI, 0.66-2.82) over 3 years. AHSCT-related mortality occurred in 1 of 159 patients (0.6%). Conclusion: In this study, the association of AHSCT with preventing relapses and facilitating recovery from disability was considerably superior to fingolimod and marginally superior to natalizumab. This study did not find evidence for difference in the effectiveness of AHSCT and ocrelizumab over a shorter available follow-up time.