Managing breakthrough disease activity during treatment with natalizumab in relapsing-remitting multiple sclerosis.

Abstract

Introduction: Failure of natalizumab to control disease activity in multiple sclerosis (MS) is an uncommon event. It is currently unknown whether switching to an alternative high-efficacy disease-modifying therapy offers any benefits over continuing natalizumab Objectives/Aims: To evaluate the effect of the choice of disease modifying therapy on disease outcomes following failure of natalizumab. Method(s): Patients from the MSBase cohort with failure of natalizumab therapy, defined as relapses occurring during treatment, were identified. Multivariable Andersen-Gill proportional hazard models were used to compare the associations of five treatment strategies with the risk of further relapses following failure of natalizumab. Post-natalizumab treatment decisions were included as a time-dependent exposure. Secondary analyses evaluated the effect of treatment decisions on the risk of subsequent new MRI activity, expanded disability status scale (EDSS) worsening, and disease-activity free survival. Three sensitivity analyses were undertaken including (a) only patients treated with natalizumab for at least 12 months prior to failure, (b) only patients not treated with high-efficacy therapies prior to natalizumab, and (c) both relapses and >=3 new or gadolinium-enhancing lesions on MRI as the definition of natalizumab treatment failure. Result(s): Of the 1,037 natalizumab-treated patients who fulfilled the inclusion criteria, 35 switched to anti-CD20 therapy (ocrelizumab, rituximab), and 25 switched to alemtuzumab, 897 continued natalizumab, and 80 de-escalated or stopped treatment. The mean annualised relapse risk for patients continuing natalizumab in the first year post failure was 0.25 (SD=0.52). Following natalizumab failure, switch to an anti-CD20 therapy was associated with a lower risk of relapses (HR=0.48, 95%CI=0.27-0.84) compared to continuing natalizumab. Treatment de-escalation or cessation were associated with increased risks of subsequent relapses (HR=1.46, 95%CI=1.15-1.85; HR=2.08, 95%CI=1.22-3.55, respectively). We did not find any evidence of a difference for switching to alemtuzumab, or for the secondary outcomes. These results were replicated in all sensitivity analyses. Conclusion(s): Following failure of natalizumab, switching to B-cell depleting agents is associated with a clinically meaningful reduction in the risk of relapses compared to continuing natalizumab therapy. Clinicians should consider B-cell depletion following clinical activity during treatment with natalizumab.