Autologous hematopoietic stem cell transplantation in multiple sclerosis: a phase II trial

Giovanni L Mancardi¹, Maria P Sormani², Francesca Gualandi², Albert Saiz², Eric Carreras², Elisa Merelli², Amedea Donelli², Alessandra Lugaresi², Paolo Di Bartolomeo², Maria R Rottoli², Alessandro Rambaldi², Maria P Amato², Luca Massacesi², Massimo Di Gioia², Luisa Vuolo², Daniela Currò², Luca Roccatagliata², Massimo Filippi², Umberto Aguglia², Pasquale Iacopino², Dominique Farge², Riccardo Saccardi²; 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

Collaborators, Affiliations

Collaborators

E Capello, A Uccelli, F Bagigalupo, A M Repice, E Portaccio, A Barillaro, C Russo, G De Luca, D Farina, A Tartaro, Y Blanco, J Berenguer, P Bresciani, A Cuoghi, P Zonari

Affiliations

¹ From the MRI Center for Neurological Diseases (L.R.), Department of Neuroscience, Rehabilitation, Ophthalmology, Genetics, and Maternal and Child Health (G.L.M., D.C.), and the Biostatistic Unit, Department of Health Sciences (M.P.S., L.R.), University of Genova; the Bone Marrow Transplantation Unit (F.G.), S. Martino Hospital, Genova, Italy; the Service of Neurology (A.S.) and the Hematology Department (E.C.), Institut d'Investigacions Biomèdiques Agustí Pi i Sunyer, Hospital Clínic, University of Barcelona, Spain; the Department of Neurosciences (E.M.) and the Bone Marrow Transplantation Unit, Department of Hematology and Oncology (A.D.), University of Modena and Reggio Emilia; the MS Center, Department of Neuroscience, Imaging and Clinical Sciences (A.L.), University Gabriele D'Annunzio, Chieti-Pescara; the Bone Marrow Transplant Center, Department of Hematology (P.D.B.), Spirito Santo Hospital, Pescara; the Multiple Sclerosis Unit Ospedale Papa Giovanni XXIII (M.R.R.), Bergamo; the Hematology and Bone Marrow Transplant Unit Azienda Ospedaliera Papa Giovanni XXIII (A.R.), Bergamo; Division Neurology 1 (M.P.A.) and Division Neurology 2, Drug and Child Health (L.M., L.V.), Department of Neurosciences, and Bone Marrow Transplantation Unit (M.D.G., R.S.), Careggi University Hospital, University of Firenze; the Neuroimaging Research Unit (M.F.), Institute of Experimental Neurology, Division of Neuroscience, San Raffaele Scientific Institute, Vita-Salute San Raffaele University, Milan; the Department of Medical and Surgical Sciences (U.A.), Magna Graecia University of Catanzaro; the Advanced Cellular Therapy Center IRCCS "Istituto Tumori Giovanni Paolo II" Bari (P.I.), Italy; and the Internal Medicine and Vascular Disease Unit (D.F.), Assistance Publique Hospitaux de Paris (AP-HP) INSERM U 796, Paris 7 University, Saint-Louis Hospital, Paris, France. glmancardi@neurologia.unige.it.
² From the MRI Center for Neurological Diseases (L.R.), Department of Neuroscience, Rehabilitation, Ophthalmology, Genetics, and Maternal and Child Health (G.L.M., D.C.), and the Biostatistic Unit, Department of Health Sciences (M.P.S., L.R.), University of Genova; the Bone Marrow Transplantation Unit (F.G.), S. Martino Hospital, Genova, Italy; the Service of Neurology (A.S.) and the Hematology Department (E.C.), Institut d'Investigacions Biomèdiques Agustí Pi i Sunyer, Hospital Clínic, University of Barcelona, Spain; the Department of Neurosciences (E.M.) and the Bone Marrow Transplantation Unit, Department of Hematology and Oncology (A.D.), University of Modena and Reggio Emilia; the MS Center, Department of Neuroscience, Imaging and Clinical Sciences (A.L.), University Gabriele D'Annunzio, Chieti-Pescara; the Bone Marrow Transplant Center, Department of Hematology (P.D.B.), Spirito Santo Hospital, Pescara; the Multiple Sclerosis Unit Ospedale Papa Giovanni XXIII (M.R.R.), Bergamo; the Hematology and Bone Marrow Transplant Unit Azienda Ospedaliera Papa Giovanni XXIII (A.R.), Bergamo; Division Neurology 1 (M.P.A.) and Division Neurology 2, Drug and Child Health (L.M., L.V.), Department of Neurosciences, and Bone Marrow Transplantation Unit (M.D.G., R.S.), Careggi University Hospital, University of Firenze; the Neuroimaging Research Unit (M.F.), Institute of Experimental Neurology, Division of Neuroscience, San Raffaele Scientific Institute, Vita-Salute San Raffaele University, Milan; the Department of Medical and Surgical Sciences (U.A.), Magna Graecia University of Catanzaro; the Advanced Cellular Therapy Center IRCCS "Istituto Tumori Giovanni Paolo II" Bari (P.I.), Italy; and the Internal Medicine and Vascular Disease Unit (D.F.), Assistance Publique Hospitaux de Paris (AP-HP) INSERM U 796, Paris 7 University, Saint-Louis Hospital, Paris, France.

PMID: 25672923
DOI: 10.1212/WNL.0000000000001329

Clinical Trial

Autologous hematopoietic stem cell transplantation in multiple sclerosis: a phase II trial

Giovanni L Mancardi et al. Neurology. 2015.

. 2015 Mar 10;84(10):981-8.

doi: 10.1212/WNL.0000000000001329. Epub 2015 Feb 11.

Authors

Collaborators

E Capello, A Uccelli, F Bagigalupo, A M Repice, E Portaccio, A Barillaro, C Russo, G De Luca, D Farina, A Tartaro, Y Blanco, J Berenguer, P Bresciani, A Cuoghi, P Zonari

Affiliations

¹ From the MRI Center for Neurological Diseases (L.R.), Department of Neuroscience, Rehabilitation, Ophthalmology, Genetics, and Maternal and Child Health (G.L.M., D.C.), and the Biostatistic Unit, Department of Health Sciences (M.P.S., L.R.), University of Genova; the Bone Marrow Transplantation Unit (F.G.), S. Martino Hospital, Genova, Italy; the Service of Neurology (A.S.) and the Hematology Department (E.C.), Institut d'Investigacions Biomèdiques Agustí Pi i Sunyer, Hospital Clínic, University of Barcelona, Spain; the Department of Neurosciences (E.M.) and the Bone Marrow Transplantation Unit, Department of Hematology and Oncology (A.D.), University of Modena and Reggio Emilia; the MS Center, Department of Neuroscience, Imaging and Clinical Sciences (A.L.), University Gabriele D'Annunzio, Chieti-Pescara; the Bone Marrow Transplant Center, Department of Hematology (P.D.B.), Spirito Santo Hospital, Pescara; the Multiple Sclerosis Unit Ospedale Papa Giovanni XXIII (M.R.R.), Bergamo; the Hematology and Bone Marrow Transplant Unit Azienda Ospedaliera Papa Giovanni XXIII (A.R.), Bergamo; Division Neurology 1 (M.P.A.) and Division Neurology 2, Drug and Child Health (L.M., L.V.), Department of Neurosciences, and Bone Marrow Transplantation Unit (M.D.G., R.S.), Careggi University Hospital, University of Firenze; the Neuroimaging Research Unit (M.F.), Institute of Experimental Neurology, Division of Neuroscience, San Raffaele Scientific Institute, Vita-Salute San Raffaele University, Milan; the Department of Medical and Surgical Sciences (U.A.), Magna Graecia University of Catanzaro; the Advanced Cellular Therapy Center IRCCS "Istituto Tumori Giovanni Paolo II" Bari (P.I.), Italy; and the Internal Medicine and Vascular Disease Unit (D.F.), Assistance Publique Hospitaux de Paris (AP-HP) INSERM U 796, Paris 7 University, Saint-Louis Hospital, Paris, France. glmancardi@neurologia.unige.it.
² From the MRI Center for Neurological Diseases (L.R.), Department of Neuroscience, Rehabilitation, Ophthalmology, Genetics, and Maternal and Child Health (G.L.M., D.C.), and the Biostatistic Unit, Department of Health Sciences (M.P.S., L.R.), University of Genova; the Bone Marrow Transplantation Unit (F.G.), S. Martino Hospital, Genova, Italy; the Service of Neurology (A.S.) and the Hematology Department (E.C.), Institut d'Investigacions Biomèdiques Agustí Pi i Sunyer, Hospital Clínic, University of Barcelona, Spain; the Department of Neurosciences (E.M.) and the Bone Marrow Transplantation Unit, Department of Hematology and Oncology (A.D.), University of Modena and Reggio Emilia; the MS Center, Department of Neuroscience, Imaging and Clinical Sciences (A.L.), University Gabriele D'Annunzio, Chieti-Pescara; the Bone Marrow Transplant Center, Department of Hematology (P.D.B.), Spirito Santo Hospital, Pescara; the Multiple Sclerosis Unit Ospedale Papa Giovanni XXIII (M.R.R.), Bergamo; the Hematology and Bone Marrow Transplant Unit Azienda Ospedaliera Papa Giovanni XXIII (A.R.), Bergamo; Division Neurology 1 (M.P.A.) and Division Neurology 2, Drug and Child Health (L.M., L.V.), Department of Neurosciences, and Bone Marrow Transplantation Unit (M.D.G., R.S.), Careggi University Hospital, University of Firenze; the Neuroimaging Research Unit (M.F.), Institute of Experimental Neurology, Division of Neuroscience, San Raffaele Scientific Institute, Vita-Salute San Raffaele University, Milan; the Department of Medical and Surgical Sciences (U.A.), Magna Graecia University of Catanzaro; the Advanced Cellular Therapy Center IRCCS "Istituto Tumori Giovanni Paolo II" Bari (P.I.), Italy; and the Internal Medicine and Vascular Disease Unit (D.F.), Assistance Publique Hospitaux de Paris (AP-HP) INSERM U 796, Paris 7 University, Saint-Louis Hospital, Paris, France.

PMID: 25672923
DOI: 10.1212/WNL.0000000000001329

Abstract

Objective: To assess in multiple sclerosis (MS) the effect of intense immunosuppression followed by autologous hematopoietic stem cells transplantation (AHSCT) vs mitoxantrone (MTX) on disease activity measured by MRI.

Methods: We conducted a multicenter, phase II, randomized trial including patients with secondary progressive or relapsing-remitting MS, with a documented increase in the last year on the Expanded Disability Status Scale, in spite of conventional therapy, and presence of one or more gadolinium-enhancing (Gd+) areas. Patients were randomized to receive intense immunosuppression (mobilization with cyclophosphamide and filgrastim, conditioning with carmustine, cytosine-arabinoside, etoposide, melphalan, and anti-thymocyte globulin) followed by AHSCT or MTX 20 mg every month for 6 months. The primary endpoint was the cumulative number of new T2 lesions in the 4 years following randomization. Secondary endpoints were the cumulative number of Gd+ lesions, relapse rate, and disability progression. Safety and tolerability were also assessed. Twenty-one patients were randomized and 17 had postbaseline evaluable MRI scans.

Results: AHSCT reduced by 79% the number of new T2 lesions as compared to MTX (rate ratio 0.21, p = 0.00016). It also reduced Gd+ lesions as well as the annualized relapse rate. No difference was found in the progression of disability.

Conclusion: Intense immunosuppression followed by AHSCT is significantly superior to MTX in reducing MRI activity in severe cases of MS. These results strongly support further phase III studies with primary clinical endpoints. The study was registered as EUDRACT No. 2007-000064-24.

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Autologous hematopoietic stem cell transplantation in multiple sclerosis: a phase II trial

Collaborators

Affiliations

Autologous hematopoietic stem cell transplantation in multiple sclerosis: a phase II trial

Authors

Collaborators

Affiliations

Abstract

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MeSH terms

Substances

LinkOut - more resources

Full Text Sources

Medical