Cyclophosphamide Pulse Therapy after Natalizumab Discontinuation for Multiple Sclerosis: a multicenter study.

Importance: Natalizumab discontinuation induces the recurrence of Multiple Sclerosis (MS) disease activity: Currently no therapeutic approach has been found able to abolish disease reactivation. Objective: To collect data from patients with MS switching from natalizumab to cyclophosphamide. Design: Retrospective multicentre study. Setting: Nine Multiple Sclerosis Centers in Italy. Participants: A total of 47 patients with clinically definite RR-MS switched to cyclophosphamide after natalizumab discontinuation. Two patients were excluded from the analysis because received less than 12 natalizumab infusions. The remaining 45 patients were subdivided into two main groups: Early Treatment (period of washout between natalizumab and cyclophosphamide 1 to 3 months), Late Treatment (washout between natalizumab and cyclophosphamide higher than 3 months). Intervention: Cyclophosphamide intravenous pulses after natalizumab discontinuation. Main outcome measure: Number of relapses, Expanded Disability Status Scale scores, number of new T2/fluidattenuated inversion recovery lesions and contrast-enhancing lesions on brain magnetic resonance imaging, rebound effect, adverse events. Results: In the Early Treatment group, only 3/23 patients (13%) experienced a clinical relapse and only 2 out of 13 (15%) patients showed brain Magnetic Resonance Imaging (MRI) activity at 3 months, while none developed MRI activity at 6 months after cyclophosphamide introduction. In the Late Treatment Group 12/22 patients (63%) had relapses during the washout period and 4/22 (40%) after the introduction of cyclophosphamide; MRI disease activity was shown in 5/9 (56%) at 3 months and in 5/14 (36%) at 6 months after cyclophosphamide introduction. Conclusions and relevance: These data show that cyclophosphamide could be able to reduce disease reactivation after natalizumab, in particular with a short washout period after natalizumab discontinuation. It can be suggested that a short period (3-6 months) of cyclophosphamide monthly pulses could be used as “re-induction” treatment in patients discontinuing natalizumab.