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March 14, 2023; 100 (11) Research Article

Hematopoietic Stem Cell Transplantation in People With Active Secondary Progressive Multiple Sclerosis

View ORCID ProfileGiacomo Boffa, Alessio Signori, Luca Massacesi, View ORCID ProfileAlice Mariottini, Elvira Sbragia, Salvatore Cottone, Maria Pia Amato, Claudio Gasperini, Lucia Moiola, Stefano Meletti, Anna Maria Repice, Vincenzo Brescia Morra, Giuseppe Salemi, Francesco Patti, View ORCID ProfileMassimo Filippi, Giovanna De Luca, View ORCID ProfileGiacomo Lus, Mauro Zaffaroni, View ORCID ProfilePatrizia Sola, Antonella Conte, Riccardo Nistri, View ORCID ProfileUmberto Aguglia, Franco Granella, Simonetta Galgani, Luisa Maria Caniatti, View ORCID ProfileAlessandra Lugaresi, View ORCID ProfileSilvia Romano, Pietro Iaffaldano, View ORCID ProfileEleonora Cocco, Riccardo Saccardi, Emanuele Angelucci, Maria Trojano, Giovanni Luigi Mancardi, Maria Pia Sormani, Matilde Inglese, on behalf of the Italian BMT-MS Study Group and the Italian MS Register
First published December 21, 2022, DOI: https://doi.org/10.1212/WNL.0000000000206750
Giacomo Boffa
From the Department of Neurology, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health (G.B., E.S., G.L.M., M.I.), University of Genoa; Biostatistics Unit (A.S., M.P.S.), Department of Health Sciences, University of Genoa; Department of Neurosciences Drugs and Child Health (L. Massacesi, A.M.), University of Florence; and Department of Neurology 2 (L. Massacesi, A.M., A.M.R.), Careggi University Hospital, Florence; Department of Neurology (S.C.), A.R.N.A.S. CIVICO, Palermo; Department NEUROFARBA (M.P.A.), Section Neurological Sciences University of Florence; IRCCS Fondazione Don Carlo Gnocchi, (M.P.A) Florence; Department of Neurology (C.G.), Ospedale San Camillo-Forlanini, Rome; Neurology Unit (L. Moiola, M.F.), Neurorehabilitation Unit (F.M.), Neurophysiology Service (F.M.), Neuroimaging Research Unit, Division of Neuroscience (F.M.), IRCCS San Raffaele Scientific Institute, Milan, Italy; Vita-Salute San Raffaele University (F.M.), Milan; Department Biomedical Metabolic and Neural Sciences (S.M.), University of Modena and Reggio Emilia, Modena, Italy; Department of Neuroscience, Neurology Unit (S.M., P.S.), Azienda Ospedaliera Universitaria, Modena; Neurosciences and Reproductive and Odontostomatological Sciences (V.B.M.), University “Federico II,” Naples; Department of Biomedicine, Neurosciences and Advanced Diagnostics (G.S.), University of Palermo; Department of Medical and Surgical Sciences and Advanced Technologies (F.P.), AOU Policlinico-San Marco, University of Catania; MS Centre, Neurology Unit (G.D.L.), SS. Annunziata University Hospital, Chieti; Department of Advanced Medical and Surgical Sciences (G.L.), 2nd Division of Neurology, University of Campania “Luigi Vanvitelli,” Naples; Centro Sclerosi Multipla (M.Z.), ASST della Valle Olona, Ospedale di Gallarate, Italy; IRCCS Neuromed (A.C.), Pozzilli (IS); Department of Human Neuroscience (A.C., R.N.) and Dipartimento di Neuroscienze, Salute Mentale e Organi di Senso (NESMOS) (S.R.) Sapienza University, Rome; S.Andrea Multiple Sclerosis Center (R.N.), Sapienza University, Rome; S.Andrea Hospital (S.R.), Rome; Department of Medical and Surgical Sciences (U.A.), Magna Greacia University of Catanzaro; Unit of Neurosciences, Department of Medicine and Surgery (F.G.), University of Parma; Department of Neurosciences (S.G.), San Camillo-Forlanini Hospital, Rome; Department of Neuroscience and Rehabilitation (L.M.C.), Azienda Ospedaliero-Universitaria di Ferrara; IRCCS Istituto delle Scienze Neurologiche di Bologna (A.L.); Dipartimento di Scienze Biomediche e Neuromotorie (A.L.), Università di Bologna; Department of Basic Medical Sciences, Neurosciences and Sense Organs (P.I., M.T.), University of Bari Aldo Moro; Department of Medical Science and Public Health (E.C), University of Cagliari, Cagliari; Multiple Sclerosis Center, Binaghi Hospital, ASL Cagliari; Department of Cellular Therapies and Transfusion Medicine (R.S.), Careggi University Hospital, Florence; Ematologia e Terapie Cellulari (E.A.), Ospedale Policlinico IRCCS San Martino (M.P.S.), Genoa; Istituti Clinici Scientifici Maugeri (G.L.M.), Pavia; Ospedale Policlinico IRCCS San Martino (M.I.), Genoa, Italy.
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Alessio Signori
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Luca Massacesi
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Alice Mariottini
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Elvira Sbragia
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Salvatore Cottone
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Maria Pia Amato
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Claudio Gasperini
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Lucia Moiola
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Anna Maria Repice
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Vincenzo Brescia Morra
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Giuseppe Salemi
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Francesco Patti
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Massimo Filippi
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Giovanna De Luca
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Giacomo Lus
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Mauro Zaffaroni
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Patrizia Sola
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Antonella Conte
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Riccardo Nistri
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Franco Granella
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Simonetta Galgani
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Luisa Maria Caniatti
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Alessandra Lugaresi
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Silvia Romano
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Pietro Iaffaldano
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Eleonora Cocco
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Riccardo Saccardi
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Emanuele Angelucci
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Maria Trojano
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Giovanni Luigi Mancardi
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Maria Pia Sormani
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Matilde Inglese
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Hematopoietic Stem Cell Transplantation in People With Active Secondary Progressive Multiple Sclerosis
Giacomo Boffa, Alessio Signori, Luca Massacesi, Alice Mariottini, Elvira Sbragia, Salvatore Cottone, Maria Pia Amato, Claudio Gasperini, Lucia Moiola, Stefano Meletti, Anna Maria Repice, Vincenzo Brescia Morra, Giuseppe Salemi, Francesco Patti, Massimo Filippi, Giovanna De Luca, Giacomo Lus, Mauro Zaffaroni, Patrizia Sola, Antonella Conte, Riccardo Nistri, Umberto Aguglia, Franco Granella, Simonetta Galgani, Luisa Maria Caniatti, Alessandra Lugaresi, Silvia Romano, Pietro Iaffaldano, Eleonora Cocco, Riccardo Saccardi, Emanuele Angelucci, Maria Trojano, Giovanni Luigi Mancardi, Maria Pia Sormani, Matilde Inglese, on behalf of the Italian BMT-MS Study Group and the Italian MS Register
Neurology Mar 2023, 100 (11) e1109-e1122; DOI: 10.1212/WNL.0000000000206750

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Abstract

Background and Objectives Uncontrolled evidence suggests that autologous hematopoietic stem cell transplantation (AHSCT) can be effective in people with active secondary progressive multiple sclerosis (SPMS). In this study, we compared the effect of AHSCT with that of other anti-inflammatory disease-modifying therapies (DMTs) on long-term disability worsening in active SPMS.

Methods We collected data from the Italian Bone Marrow Transplantation Study Group and the Italian Multiple Sclerosis Register. Patients were considered eligible if treatment had been started after the diagnosis of SPMS. Disability worsening was assessed by the cumulative proportion of patients with a 6-month confirmed disability progression (CDP) according to the Expanded Disability Status Scale (EDSS) score. Key secondary endpoints were the EDSS time trend after treatment start and the prevalence of disability improvement over time. Time to first CDP was assessed by means of proportional hazard Cox regression models. A linear mixed model with a time × treatment group interaction was used to assess the longitudinal EDSS time trends. Prevalence of improvement was estimated using a modified Kaplan-Meier estimator and compared between groups by bootstrapping the area under the curve.

Results Seventy-nine AHSCT-treated patients and 1975 patients treated with other DMTs (beta interferons, azathioprine, glatiramer-acetate, mitoxantrone, fingolimod, natalizumab, methotrexate, teriflunomide, cyclophosphamide, dimethyl fumarate, and alemtuzumab) were matched to reduce treatment selection bias using propensity score and overlap weighting approaches. Time to first CDP was significantly longer in transplanted patients (hazard ratio [HR] = 0.50; 95% CI = 0.31–0.81; p = 0.005), with 61.7% of transplanted patients free from CPD at 5 years. Accordingly, EDSS time trend over 10 years was higher in patients treated with other DMTs than in AHSCT-treated patients (+0.157 EDSS points per year compared with −0.013 EDSS points per year; interaction p < 0.001). Patients who underwent AHSCT were more likely to experience a sustained disability improvement: 34.7% of patients maintained an improvement (a lower EDSS than baseline) 3 years after transplant vs 4.6% of patients treated by other DMTs (p < 0.001).

Discussion The use of AHSCT in people with active SPMS is associated with a slowing of disability progression and a higher likelihood of disability improvement compared with standard immunotherapy.

Classification of Evidence This study provides Class III evidence that autologous hematopoietic stem cell transplants prolonged the time to CDP compared with other DMTs.

Glossary

AHSCT=
autologous hematopoietic stem cell transplantation;
ARR=
annualized relapse rate;
ATG=
antithymocyte globulin;
AUC=
area under the curve;
CDP=
confirmed disability progression;
DMT=
disease-modifying therapy;
EDSS=
Expanded Disability Status Scale;
HR=
hazard ratio;
IQR=
interquartile range;
MSMs=
marginal structural models;
OW=
overlap weighting;
PS=
propensity score;
SMDs=
standardized mean differences;
SPMS=
secondary progressive multiple sclerosis

Footnotes

  • Go to Neurology.org/N for full disclosures. Funding information and disclosures deemed relevant by the authors, if any, are provided at the end of the article.

  • Italian BMT-MS Study Group coinvestigators are listed in the Appendix 2 at the end of the article.

  • Submitted and externally peer reviewed. The handling editor was Deputy Editor Olga Ciccarelli, MD, PhD, FRCP.

  • ↵* These authors contributed equally to this work.

  • Class of Evidence: NPub.org/coe

  • Received March 13, 2022.
  • Accepted in final form November 15, 2022.
  • © 2022 American Academy of Neurology
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