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Autologous Stem Cell Transplantation International Multiple Sclerosis (ASTIMS) trial: a randomised, phase II, controlled, multicentre trial
G.L. Mancardi, M.P. Sormani, F. Gualandi, A. Saiz, E. Carreras, E. Merelli, A. Donelli, A. Lugaresi, P. Di Bartolomeo, A. Rambaldi, M. Rottoli, M.P. Amato, L. Massacesi, M. Di Gioia, L. Vuolo, D. Currņ, L. Roccatagliata, E. Capello, A. Uccelli, P. Iacopino, U. Aguglia, M. Filippi, R. Saccardi (Genoa, Barcelona, Modena, Chieti, Bergamo, Florence, Reggio Calabria, Milan, IT)
Background. Autologous Stem Cell Transplantation International Multiple Sclerosis (ASTIMS) trial is a multicentre, prospective, randomized, single blinded phase II study comparing the activity of autologous stem cell transplantation (AHSCT: BEAM, carmustine, cytosine-arabinoside, etoposide and melphalan) versus Mitoxantrone (MTX) therapy for the treatment of patients with severe multiple sclerosis (MS) unresponsive to conventional therapy.
Methods. Inclusion criteria were clinically and laboratory definite MS , with an EDSS between 3.5 and 6,5; 18 to 50 years of age; a secondary progressive (SP) or relapsing remitting (RR) severe clinical course in the last year, defined as a deterioration of at least 1 point at EDSS or 0.5 if EDSS was > 5.5, despite conventional therapy; and the presence of one or more Gadolinium (Gd) enhancing areas at MRI. The primary endpoint was the cumulative number of new T2 weighted lesions at MRI in the 4 years following treatment. Secondary endpoints were the number of Gd enhancing lesions, clinical progression, relapses, early and late adverse effects. The study started on 2004 and on November 2009, with 21 enrolled cases, 9 in the AHSCT and 12 in the Mitoxantrone arm, the Steering Committee decided to terminate the accrual of patients and the analysis of data was done during the spring of 2012.
Results. The median cumulative number of new T2 lesions counted over 4 years was 2.5 in the AHSCT arm as compared to 8 in the MTX arm (relative reduction= 80%, p=0.00016). All the patients treated with AHSCT (100%) had no Gd enhancing lesions during the 4 years follow up, while 56% of the MTX patients had at least one Gd positive lesion during follow up (p=0.029, Fisher exact test). The annualized relapse rate was 0.19 in the AHSCT vs 0.6 in the MTX arm (p=0.026). No significant difference in EDSS change was found between two treatment arms. Serious adverse events occurred and resolved in 3 cases treated with AHSCT.
Conclusions. ASTIMS is the first multicenter, prospective, randomized, phase II study that demonstrates the superiority of AHSCT vs standard immunosuppressive therapy on MRI measures in MS, adding new data for the organization of a prospective, randomized, controlled phase III study.
G.L. Mancardi, M.P. Sormani, F. Gualandi, A. Saiz, E. Carreras, E. Merelli, A. Donelli, A. Lugaresi, P. Di Bartolomeo, A. Rambaldi, M. Rottoli, M.P. Amato, L. Massacesi, M. Di Gioia, L. Vuolo, D. Currņ, L. Roccatagliata, E. Capello, A. Uccelli, P. Iacopino, U. Aguglia, M. Filippi, R. Saccardi (Genoa, Barcelona, Modena, Chieti, Bergamo, Florence, Reggio Calabria, Milan, IT)
Background. Autologous Stem Cell Transplantation International Multiple Sclerosis (ASTIMS) trial is a multicentre, prospective, randomized, single blinded phase II study comparing the activity of autologous stem cell transplantation (AHSCT: BEAM, carmustine, cytosine-arabinoside, etoposide and melphalan) versus Mitoxantrone (MTX) therapy for the treatment of patients with severe multiple sclerosis (MS) unresponsive to conventional therapy.
Methods. Inclusion criteria were clinically and laboratory definite MS , with an EDSS between 3.5 and 6,5; 18 to 50 years of age; a secondary progressive (SP) or relapsing remitting (RR) severe clinical course in the last year, defined as a deterioration of at least 1 point at EDSS or 0.5 if EDSS was > 5.5, despite conventional therapy; and the presence of one or more Gadolinium (Gd) enhancing areas at MRI. The primary endpoint was the cumulative number of new T2 weighted lesions at MRI in the 4 years following treatment. Secondary endpoints were the number of Gd enhancing lesions, clinical progression, relapses, early and late adverse effects. The study started on 2004 and on November 2009, with 21 enrolled cases, 9 in the AHSCT and 12 in the Mitoxantrone arm, the Steering Committee decided to terminate the accrual of patients and the analysis of data was done during the spring of 2012.
Results. The median cumulative number of new T2 lesions counted over 4 years was 2.5 in the AHSCT arm as compared to 8 in the MTX arm (relative reduction= 80%, p=0.00016). All the patients treated with AHSCT (100%) had no Gd enhancing lesions during the 4 years follow up, while 56% of the MTX patients had at least one Gd positive lesion during follow up (p=0.029, Fisher exact test). The annualized relapse rate was 0.19 in the AHSCT vs 0.6 in the MTX arm (p=0.026). No significant difference in EDSS change was found between two treatment arms. Serious adverse events occurred and resolved in 3 cases treated with AHSCT.
Conclusions. ASTIMS is the first multicenter, prospective, randomized, phase II study that demonstrates the superiority of AHSCT vs standard immunosuppressive therapy on MRI measures in MS, adding new data for the organization of a prospective, randomized, controlled phase III study.