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.

Academic MS Center Zuyderland Department of Neurology Zuyderland Medical Center Sittard Geleen the Netherlands

Azienda Ospedaliera di Rilievo Nazionale San Giuseppe Moscati Avellino Avellino Italy

Center of Neuroimmunology Service of Neurology Hospital Clinic de Barcelona Barcelona Spain

Central Clinical School Monash University Melbourne Victoria Australia

CHUM MS Center and Universite de Montreal Montreal Quebec Canada

Cliniques Universitaires Saint Luc Brussels Belgium

CORe Department of Medicine University of Melbourne Melbourne Victoria Australia

Department of Haematology 1st Faculty of Medicine Charles University Prague and General University Hospital Prague Czech Republic

Department of Haematology 3rd Faculty of Medicine Charles University Prague and University Hospital Kralovske Vinohrady Prague Czech Republic

Department of Haematology Austin Health Melbourne Victoria Australia

Department of Haematology Haukeland University Hospital Bergen Norway

Department of Haematology Sheffield Teaching Hospitals NHS Foundation Trust Sheffield United Kingdom

Department of Haematology St Vincent's Hospital Sydney Sydney New South Wales Australia

Department of Medical and Surgical Sciences and Advanced Technologies GF Ingrassia Catania Italy

Department of Medical Sciences Neurology Uppsala University Uppsala Sweden

Department of Medicine School of Clinical Sciences Monash University Melbourne Victoria Australia

Department of Medicine Sultan Qaboos University Hospital Al Khodh Oman

Department of Neurology and Center of Clinical Neuroscience 1st Faculty of Medicine Charles University Prague and General University Hospital Prague Czech Republic

Department of Neurology Antwerp University Hospital Edegem Belgium

Department of Neurology Austin Health Melbourne Victoria Australia

Department of Neurology Box Hill Hospital Melbourne Victoria Australia

Department of Neurology Buffalo General Medical Center Buffalo New York

Department of Neurology Centro Hospitalar Universitario de Sao Joao Porto Portugal

Department of Neurology Faculty of Medicine University of Debrecen Debrecen Hungary

Department of Neurology Hacettepe University Hospitals Ankara Turkey

Department of Neurology Haukeland University Hospital Bergen Norway

Department of Neurology John Hunter Hospital Hunter New England Health Newcastle New South Wales Australia

Department of Neurology Razi University Hospital Manouba Tunis Tunisia

Department of Neurology Sheffield Teaching Hospitals NHS Foundation Trust Sheffield United Kingdom

Department of Neurology St Vincent's Hospital Sydney Sydney New South Wales Australia

Department of Neurology The Alfred Hospital Melbourne Victoria Australia

Department of Neurology University Hospital Ghent Ghent Belgium

Dipartimento di Scienze Biomediche e Neuromotorie Università di Bologna Bologna Italy

Division of Neurology Department of Medicine Amiri Hospital Sharq Kuwait

Dokuz Eylul University Konak Izmir Turkey

Faculty of Medicine of Tunis University of Tunis El Manar Tunis Tunisia

Flinders University Adelaide South Australia Australia

Garibaldi Hospital Catania Italy

Groene Hart Ziekenhuis Gouda the Netherlands

Haydarpasa Numune Training and Research Hospital Istanbul Turkey

Hospital de Galdakao Usansolo Galdakao Spain

Hospital Universitario Donostia San Sebastián Spain

Institute of Immunology and Infectious Diseases Sir Charles Gairdner Hospital Murdoch University Perth Western Australia Australia

IRCCS Istituto delle Scienze Neurologiche di Bologna Bologna Italy

Liverpool Hospital Sydney New South Wales Australia

Menzies Institute for Medical Research University of Tasmania Hobart Tasmania Australia

Monash Medical Centre Melbourne Victoria Australia

Monash University Melbourne Victoria Australia

Multiple Sclerosis Center University of Catania Catania Italy

Nehme and Therese Tohme Multiple Sclerosis Center American University of Beirut Medical Center Beirut Lebanon

Neuroimmunology Centre Department of Neurology Royal Melbourne Hospital Melbourne Victoria Australia

Neurologic Clinic and Policlinic Departments of Medicine and Clinical Research University Hospital and University of Basel Basel Switzerland

Ottawa Hospital Research Institute University of Ottawa Ottawa Ontario Canada

Perron Institute University of Western Australia Nedlands Western Australia Australia

Royal Brisbane and Women's Hospital Brisbane Queensland Australia

Royal Hobart Hospital Hobart Tasmania Australia

School for Mental Health and Neuroscience Maastricht University Maastricht the Netherlands

School of Medicine and Public Health University Newcastle Newcastle New South Wales Australia

St Vincent's Clinical School University of New South Wales Sydney New South Wales Australia

Translational Neurosciences Research Group Faculty of Medicine and Health Sciences University of Antwerp Wilrijk Belgium

Universidade Metropolitana de Santos Santos Brazil

Université Catholique de Louvain Ottignies Louvain la Neuve Belgium

University Hospital Reina Sofia Cordoba Spain

University of Melbourne Melbourne Victoria Australia

University of Ottawa Department of Medicine Ottawa Hospital Research Institute Ottawa Ontario Canada

University of Queensland Brisbane Queensland Australia

University of Sydney Sydney New South Wales Australia

UOC Neurologia Azienda Sanitaria Unica Regionale Marche AV3 Macerata Italy

Westmead Hospital Sydney New South Wales Australia

Komentář v

JAMA Neurol. 2023 Jul 1;80(7):669-672. doi: 10.1001/jamaneurol.2023.0467. PubMed

Zobrazit více v PubMed

Muraro PA, Martin R, Mancardi GL, Nicholas R, Sormani MP, Saccardi R. Autologous haematopoietic stem cell transplantation for treatment of multiple sclerosis. Nat Rev Neurol. 2017;13(7):391-405. doi:10.1038/nrneurol.2017.81 PubMed DOI

Atkins HL, Bowman M, Allan D, et al. . Immunoablation and autologous haemopoietic stem-cell transplantation for aggressive multiple sclerosis: a multicentre single-group phase 2 trial. Lancet. 2016;388(10044):576-585. doi:10.1016/S0140-6736(16)30169-6 PubMed DOI

Burman J, Iacobaeus E, Svenningsson A, et al. . Autologous haematopoietic stem cell transplantation for aggressive multiple sclerosis: the Swedish experience. J Neurol Neurosurg Psychiatry. 2014;85(10):1116-1121. doi:10.1136/jnnp-2013-307207 PubMed DOI

Burt RK, Balabanov R, Han X, et al. . Association of nonmyeloablative hematopoietic stem cell transplantation with neurological disability in patients with relapsing-remitting multiple sclerosis. JAMA. 2015;313(3):275-284. doi:10.1001/jama.2014.17986 PubMed DOI

Krasulová E, Trneny M, Kozák T, et al. . High-dose immunoablation with autologous haematopoietic stem cell transplantation in aggressive multiple sclerosis: a single centre 10-year experience. Mult Scler. 2010;16(6):685-693. doi:10.1177/1352458510364538 PubMed DOI

Nash RA, Hutton GJ, Racke MK, et al. . High-dose immunosuppressive therapy and autologous HCT for relapsing-remitting MS. Neurology. 2017;88(9):842-852. doi:10.1212/WNL.0000000000003660 PubMed DOI PMC

Burt RK, Balabanov R, Burman J, et al. . Effect of nonmyeloablative hematopoietic stem cell transplantation vs continued disease-modifying therapy on disease progression in patients with relapsing-remitting multiple sclerosis: a randomized clinical trial. JAMA. 2019;321(2):165-174. doi:10.1001/jama.2018.18743 PubMed DOI PMC

Sharrack B, Petrie J, Coles A, Snowden JA. Is stem cell transplantation safe and effective in multiple sclerosis? BMJ. 2022;377:e061514. doi:10.1136/bmj-2020-061514 PubMed DOI

Muraro PA, Pasquini M, Atkins HL, et al. ; Multiple Sclerosis–Autologous Hematopoietic Stem Cell Transplantation (MS-AHSCT) Long-term Outcomes Study Group . Long-term outcomes after autologous hematopoietic stem cell transplantation for multiple sclerosis. JAMA Neurol. 2017;74(4):459-469. doi:10.1001/jamaneurol.2016.5867 PubMed DOI PMC

Granqvist M, Boremalm M, Poorghobad A, et al. . Comparative effectiveness of rituximab and other initial treatment choices for multiple sclerosis. JAMA Neurol. 2018;75(3):320-327. doi:10.1001/jamaneurol.2017.4011 PubMed DOI PMC

Kalincik T, Horakova D, Spelman T, et al. ; MSBase Study Group . Switch to natalizumab versus fingolimod in active relapsing-remitting multiple sclerosis. Ann Neurol. 2015;77(3):425-435. doi:10.1002/ana.24339 PubMed DOI

Kalincik T, Brown JWL, Robertson N, et al. ; MSBase Study Group . Treatment effectiveness of alemtuzumab compared with natalizumab, fingolimod, and interferon beta in relapsing-remitting multiple sclerosis: a cohort study. Lancet Neurol. 2017;16(4):271-281. doi:10.1016/S1474-4422(17)30007-8 PubMed DOI

Iaffaldano P, Lucisano G, Pozzilli C, et al. ; Italian iMed-Web database . Fingolimod versus interferon beta/glatiramer acetate after natalizumab suspension in multiple sclerosis. Brain. 2015;138(pt 11):3275-3286. doi:10.1093/brain/awv260 PubMed DOI

Barbin L, Rousseau C, Jousset N, et al. ; CFSEP and OFSEP groups . Comparative efficacy of fingolimod vs natalizumab: a French multicenter observational study. Neurology. 2016;86(8):771-778. doi:10.1212/WNL.0000000000002395 PubMed DOI PMC

Spelman T, Magyari M, Piehl F, et al. . Treatment escalation vs immediate initiation of highly effective treatment for patients with relapsing-remitting multiple sclerosis: data from 2 different national strategies. JAMA Neurol. 2021;78(10):1197-1204. doi:10.1001/jamaneurol.2021.2738 PubMed DOI PMC

Kalincik T, Sormani MP. Comparative effectiveness of rituximab in multiple sclerosis. Nat Rev Neurol. 2021;17(1):3-4. doi:10.1038/s41582-020-00412-5 PubMed DOI

Hernán MA. Methods of public health research: strengthening causal inference from observational data. N Engl J Med. 2021;385(15):1345-1348. doi:10.1056/NEJMp2113319 PubMed DOI

Tappenden P, Wang Y, Sharrack B, et al. . Evaluating the clinical effectiveness of autologous haematopoietic stem cell transplantation versus disease-modifying therapy in multiple sclerosis using a matching-adjusted indirect comparison: an exploratory study from the Autoimmune Diseases Working Party (ADWP) of the European Society of Bone and Marrow Transplantation (EBMT). Bone Marrow Transplant. 2020;55(7):1473-1475. doi:10.1038/s41409-019-0747-2 PubMed DOI

Sharrack B, Saccardi R, Alexander T, et al. ; European Society for Blood and Marrow Transplantation (EBMT) Autoimmune Diseases Working Party (ADWP) and the Joint Accreditation Committee of the International Society for Cellular Therapy (ISCT) and EBMT (JACIE) . Autologous haematopoietic stem cell transplantation and other cellular therapy in multiple sclerosis and immune-mediated neurological diseases: updated guidelines and recommendations from the EBMT Autoimmune Diseases Working Party (ADWP) and the Joint Accreditation Committee of EBMT and ISCT (JACIE). Bone Marrow Transplant. 2020;55(2):283-306. doi:10.1038/s41409-019-0684-0 PubMed DOI PMC

Polman CH, Reingold SC, Banwell B, et al. . Diagnostic criteria for multiple sclerosis: 2010 revisions to the McDonald criteria. Ann Neurol. 2011;69(2):292-302. doi:10.1002/ana.22366 PubMed DOI PMC

Thompson AJ, Banwell BL, Barkhof F, et al. . Diagnosis of multiple sclerosis: 2017 revisions of the McDonald criteria. Lancet Neurol. 2018;17(2):162-173. doi:10.1016/S1474-4422(17)30470-2 PubMed DOI

Polman CH, Reingold SC, Edan G, et al. . Diagnostic criteria for multiple sclerosis: 2005 revisions to the “McDonald Criteria”. Ann Neurol. 2005;58(6):840-846. doi:10.1002/ana.20703 PubMed DOI

Moore JJ, Massey JC, Ford CD, et al. . Prospective phase II clinical trial of autologous haematopoietic stem cell transplant for treatment refractory multiple sclerosis. J Neurol Neurosurg Psychiatry. 2019;90(5):514-521. doi:10.1136/jnnp-2018-319446 PubMed DOI

Roos I, Malpas C, Leray E, et al. ; MSBase and OFSEP . Disease reactivation after cessation of disease-modifying therapy in patients with relapsing-remitting multiple sclerosis. Neurology. 2022;99(17):e1926-e1944. doi:10.1212/WNL.0000000000201029 PubMed DOI PMC

MSBase study protocol. Accessed July 6, 2022. https://www.msbase.org/about-us/documents-and-resources/

Kalincik T, Kuhle J, Pucci E, et al. ; MSBase Scientific Leadership Group and MSBase Study Group . Data quality evaluation for observational multiple sclerosis registries. Mult Scler. 2017;23(5):647-655. doi:10.1177/1352458516662728 PubMed DOI

Schumacher GA, Beebe G, Kibler RF, et al. . Problems of experimental trials of therapy in multiple sclerosis: report by the panel on the evaluation of experimental trials of therapy in multiple sclerosis. Ann N Y Acad Sci. 1965;122:552-568. doi:10.1111/j.1749-6632.1965.tb20235.x PubMed DOI

Kalincik T, Cutter G, Spelman T, et al. . Defining reliable disability outcomes in multiple sclerosis. Brain. 2015;138(Pt 11):3287-3298. doi:10.1093/brain/awv258 PubMed DOI

Hernán MA, Robins JM. Using big data to emulate a target trial when a randomized trial is not available. Am J Epidemiol. 2016;183(8):758-764. doi:10.1093/aje/kwv254 PubMed DOI PMC

Rosenbaum PR. Observational Studies. 2nd ed. Springer-Verlag; 2002.

Belachew S, Phan-Ba R, Bartholomé E, et al. . Natalizumab induces a rapid improvement of disability status and ambulation after failure of previous therapy in relapsing-remitting multiple sclerosis. Eur J Neurol. 2011;18(2):240-245. doi:10.1111/j.1468-1331.2010.03112.x PubMed DOI

Mancardi GL, Sormani MP, Gualandi F, et al. ; ASTIMS Haemato-Neurological Collaborative Group, On behalf of the Autoimmune Disease Working Party (ADWP) of the European Group for Blood and Marrow Transplantation (EBMT); ASTIMS Haemato-Neurological Collaborative Group On behalf of the Autoimmune Disease Working Party ADWP of the European Group for Blood and Marrow Transplantation EBMT . Autologous hematopoietic stem cell transplantation in multiple sclerosis: a phase II trial. Neurology. 2015;84(10):981-988. doi:10.1212/WNL.0000000000001329 PubMed DOI

Bar-Or A, Calkwood JC, Chognot C, et al. . Effect of ocrelizumab on vaccine responses in patients with multiple sclerosis: the VELOCE study. Neurology. 2020;95(14):e1999-e2008. doi:10.1212/WNL.0000000000010380 PubMed DOI PMC

Pasquini MC, Griffith LM, Arnold DL, et al. . Hematopoietic stem cell transplantation for multiple sclerosis: collaboration of the CIBMTR and EBMT to facilitate international clinical studies. Biol Blood Marrow Transplant. 2010;16(8):1076-1083. doi:10.1016/j.bbmt.2010.03.012 PubMed DOI PMC

Sormani MP. Real-world studies provide reliable comparisons of disease modifying therapies in MS: no. Mult Scler. 2020;26(2):161-162. doi:10.1177/1352458519845837 PubMed DOI

Kalincik T, Butzkueven H. Observational data: understanding the real MS world. Mult Scler. 2016;22(13):1642-1648. doi:10.1177/1352458516653667 PubMed DOI

Bovis F, Signori A, Carmisciano L, et al. . Expanded disability status scale progression assessment heterogeneity in multiple sclerosis according to geographical areas. Ann Neurol. 2018;84(4):621-625. doi:10.1002/ana.25323 PubMed DOI

De-escalating and discontinuing disease-modifying therapies in multiple sclerosis