Abstract
Background: Alemtuzumab is a highly effective drug for the treatment of multiple sclerosis (MS), characterized by specific patterns of depletion and repopulation. As an induction-like treatment concept, two mandatory infusion courses can inhibit long-term disease activity in the majority of patients, and additional courses can successfully manage subsequent re-emergence of disease activity. Currently, there are no biomarkers to identify patients with re-emergent disease activity requiring retreatment.Methods: In this study, we systematically characterized 16 MS patients commencing alemtuzumab. Clinical parameters, MRI and detailed immunoprofiling were conducted every 3 months for up to 84 months.Results: Alemtuzumab led to significant decrease in clinical disease activity in all evaluated patients. Nine out of 16 patients presented with no evidence of disease activity (NEDA)-3 up to 84 months (“complete-responder”), while 7 patients demonstrated clinical or/and subclinical MRI disease activity and received alemutzumab retreatment (“partial-responder”). In both response categories, all T- and B-cell subsets were markedly depleted after alemtuzumab therapy. In particular, absolute numbers of Th1 and Th17 cells were markedly decreased and remained stable below baseline levels—this effect was particularly pronounced in complete-responders. While mean cell numbers did not differ significantly between groups, analysis of event-driven immunoprofiling demonstrated that absolute numbers of Th1 and Th17 cells showed a reproducible increase starting 6 months before relapse activity. This change appears to predict emergent disease activity when compared with stable disease.Conclusion: Studies with larger patient populations are needed to confirm that frequent immunoprofiling may assist in evaluating clinical decision-making of alemtuzumab retreatment.
Highlights
The anti-CD52 antibody alemtuzumab (ATZ) exerts its clinical efficacy via a specific pattern of depletion and repopulation of different immune cell subsets in active, relapsing-remitting multiple sclerosis (RRMS) [1,2,3,4,5,6]
ATZ 12 mg was infused on Abbreviations: APC, antigen-presenting cells; ATZ, alemtuzumab; AUC, Areas under the Curve; CR, complete-responder; CTS, comparable time segment; DC, dendritic cells; EDSS, expanded disability status scale; Fluorescence-Activated Cell Sorting (FACS), fluorescenceactivated cell sorting; FCS, fetal calf serum; IFN-gamma, interferon-gamma; IL, interleukin; MRI, magnet-resonance imaging; MS, multiple sclerosis; NEDA, no evidence of disease activity; NK cell, natural killer cell; PBMC, peripheral blood mononuclear cells; PR, partial responder; RFS, relapse-free survival; ROC, Receiver Operating Characteristic; RRMS, relapsing-remitting multiple sclerosis
Prior to ATZ treatment, 13 patients were treated with injectables, one patient received natalizumab, and two patients were treatment naive (Figure 1)
Summary
The anti-CD52 antibody alemtuzumab (ATZ) exerts its clinical efficacy via a specific pattern of depletion and repopulation of different immune cell subsets in active, relapsing-remitting multiple sclerosis (RRMS) [1,2,3,4,5,6]. Specific cellular repopulation patterns appear to be responsible for the longterm efficacy of ATZ that persists years after the last course of therapy [9, 10]: T cells remained depleted years after the last ATZ course, but B cells repopulate quickly, even overshooting baseline levels several months after ATZ treatment in the most cases [10,11,12] These depletion-repopulation kinetics are purportedly responsible for the positive, long-term effects of ATZ on disease activity, and for its established side-effect profile, including secondary autoimmunity [10, 13, 14]. There are no biomarkers to identify patients with re-emergent disease activity requiring retreatment
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