RESUMEN
BACKGROUND: Patients with relapsing-remitting multiple sclerosis (RRMS) may experience breakthrough disease despite effective interferon beta (IFNß) therapy. Fludarabine (FLU) is a chemotherapeutic agent used in lymphoproliferative disorders that may be synergistic when combined with immunomodulatory therapy to control active multiple sclerosis (MS). OBJECTIVE: The objective of this study was to explore the safety and tolerability of FLU versus monthly methylprednisolone (MP) in IFNß-treated RRMS patients with breakthrough disease. Clinical and MRI effects of IFNß-1a plus FLU were evaluated. METHODS: Eighteen patients with breakthrough disease [⩾2 relapses over the prior year and ⩾1.0-point increase in Expanded Disability Status Scale (EDSS) score sustained for ⩾3 months] after >1 year of IFNß therapy were enrolled in this prospective, open-label, randomized, proof-of-concept, pilot study. Patients received intravenous (IV) MP 1 g daily for 3 days and then were randomized to receive 3 monthly IV infusions of FLU 25 mg/m(2) daily for 5 consecutive days (n = 10) or MP 1 g (n = 8). All patients maintained their intramuscular IFNß-1a treatment throughout the study. Analyses explored safety signals and directional trends; this preliminary study was not powered to detect clinically meaningful differences. RESULTS: Both combination treatments were safe and well tolerated, with all adverse events mild. Patients treated with IFNß-1a plus FLU had similar relapse rates, EDSS scores, and MS Functional Composite scores, but significantly less acute corticosteroid use for on-study relapses and better responses on some MRI outcomes, versus patients treated with IFNß-1a plus MP. CONCLUSIONS: Further study of FLU for breakthrough disease in patients with RRMS is warranted.