Serum neurofilament light chain correlations in patients with a first clinical demyelinating event in the REFLEX study: a post hoc analysis

Jens Kuhle; David Leppert; Giancarlo Comi; Nicola de Stefano; Ludwig Kappos; Mark S Freedman; Andrea Seitzinger; Sanjeev Roy

doi:10.1177/17562864241239101

Serum neurofilament light chain correlations in patients with a first clinical demyelinating event in the REFLEX study: a post hoc analysis

Ther Adv Neurol Disord. 2024 Mar 29:17:17562864241239101. doi: 10.1177/17562864241239101. eCollection 2024.

Authors

Jens Kuhle^{1

2}, David Leppert³, Giancarlo Comi⁴, Nicola de Stefano⁵, Ludwig Kappos³, Mark S Freedman⁶, Andrea Seitzinger⁷, Sanjeev Roy⁸

Affiliations

¹ Department of Neurology, University Hospital Basel, Petersgraben 4, Basel CH-4031, Switzerland.
² Multiple Sclerosis Centre and Research Center for Clinical Neuroimmunology and Neuroscience (RC2NB), Departments of Biomedicine and Clinical Research, University Hospital and University of Basel, Spitalstrasse 2, Basel CH-4031, Switzerland.
³ Multiple Sclerosis Centre and Research Center for Clinical Neuroimmunology and Neuroscience (RC2NB), Departments of Biomedicine and Clinical Research, University Hospital and University of Basel, Basel, Switzerland.
⁴ Casa di Cura Privata del Policlinico, Università Vita-Salute San Raffaele, Milan, Italy.
⁵ Department of Medicine, Surgery and Neuroscience, University of Siena, Siena, Italy.
⁶ Department of Medicine and the Ottawa Hospital Research Institute, University of Ottawa, Ottawa, ON, Canada.
⁷ Biostatistics, Merck Healthcare KGaA, Darmstadt, Germany.
⁸ Global Clinical Development - Immunology, Ares Trading S.A. (an affiliate of Merck KGaA), Eysins, Switzerland.

Abstract

Background: In REFLEX, subcutaneous interferon beta-1a (sc IFN β-1a) delayed the onset of multiple sclerosis (MS) in patients with a first clinical demyelinating event (FCDE).

Objectives: This post hoc analysis aimed to determine whether baseline serum neurofilament light (sNfL) chain can predict conversion to MS and whether correlations exist between baseline sNfL and magnetic resonance imaging (MRI) metrics.

Methods: sNfL was measured for 494 patients who received sc IFN β-1a 44 μg once weekly (qw; n = 168), three times weekly (tiw; n = 161), or placebo (n = 165) over 24 months. Median baseline sNfL (26.1 pg/mL) was used to define high/low sNfL subgroups. Hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated using Cox's proportional hazard model to determine factors influencing the risk of conversion to MS. Kaplan-Meier estimates calculated median time-to-conversion to MS (McDonald 2005 criteria) or clinically definite MS (CDMS; Poser criteria). Correlations between sNfL and MRI findings were assessed using Spearman's rank correlation coefficient (r).

Results: Multivariable models indicated that high baseline sNfL was associated with the likelihood of converting to MS and inversely to time-to-conversion (HR = 1.3, 95% CI: 1.03-1.64; p = 0.024). Significant additional factors affecting conversion to McDonald MS were on-study treatment (sc IFN β-1a/placebo; qw: HR = 0.59, 95% CI: 0.46-0.76; tiw: HR = 0.45, 95% CI: 0.34-0.59), classification of FCDE (monofocal/multifocal; HR = 0.69, 95% CI: 0.55-0.85), and most baseline imaging findings (T2 and T1 gadolinium-enhancing [Gd+] lesions; HR = 1.02, 95% CI: 1.01-1.03 and HR = 1.07, 95% CI: 1.03-1.11); all p ⩽ 0.001. Conversion to CDMS showed similar results. At month 24, sNfL was strongly correlated with a mean number of combined unique active (r = 0.71), new T2 (r = 0.72), and new T1 Gd+ (r = 0.60) lesions; weak correlations were observed between sNfL and clinical outcomes for all treatment groups.

Conclusion: Higher baseline sNfL was associated with an increased risk of MS conversion, a risk that was mitigated by treatment with sc IFN β-1a tiw.

Trial registration: ClinicalTrials.gov identifier: NCT00404352. Date registered: 28 November 2006.

Keywords: interferon beta-1a; multiple sclerosis; serum neurofilament light chain.

Associated data

ClinicalTrials.gov/NCT00404352