Long-term prognostic value of longitudinal measurements of blood neurofilament levels

Abstract

Objective: To assess the long-term prognostic value of an integral of longitudinal measurements of plasma neurofilament light chain levels (NfL_long) over 12 and 24 months vs single neurofilament light chain (NfL) measurements in patients with relapsing-remitting MS (RRMS) and its additional value when combined with clinical and MRI measures.

Methods: This analysis included continuously fingolimod-treated patients with RRMS from the 24-month FTY720 Research Evaluating Effects of Daily Oral therapy in Multiple Sclerosis (FREEDOMS)/12-month Trial Assessing Injectable Interferon vs FTY720 Oral in Relapsing-Remitting Multiple Sclerosis (TRANSFORMS) phase 3 trials and their long-term extension, LONGTERMS. Patients were classified into high (≥30 pg/mL, n = 110) and low (<30 pg/mL, n = 164) NfL categories based on the baseline (BL) NfL value or the geometric mean NfL_long calculated over 12 and 24 months to predict disability-related outcomes and brain volume loss (BVL). The additional prognostic value of NfL was quantified using the area under the receiver operating characteristic (ROC) curve.

Results: A single high (vs low) NfL measure at BL was prognostic of a higher risk of reaching Expanded Disability Status Scale (EDSS) score ≥4 earlier (hazard ratio [HR] = 2.19; 95% CI = 1.21-3.97) and higher BVL over 120 months (difference: -1.12%; 95% CI = -2.07 to -0.17). When NfL_long was measured over 24 months, high NfL was associated with a higher risk of reaching EDSS score ≥4 (HR = 7.91; 95% CI = 2.99-20.92), accelerated 6-month confirmed disability worsening (HR = 3.14; 95% CI = 1.38-7.11), and 20% worsening in the Timed 25-Foot Walk Test (HR = 3.05; 95% CI = 1.38-6.70). Area under the ROC curve was consistently highest in models combining NfL with clinical and MRI measures.

Conclusions: NfL_long had a higher prognostic value than single NfL assessments on long-term outcomes in RRMS. Combining it with clinical and MRI measures increased sensitivity and specificity to predict long-term disease outcomes.

Classification of evidence: This study provides Class I evidence that NfL_long was more strongly associated with long-term outcomes than single NfL assessments in patients with RRMS.

Figure 1. Kaplan-Meier plots of time to event by NfL assessment for disability outcomes (A) at BL, (B) over 12 months, and (C) over 24 months

The reference visit is defined as BL for A, M12 for B, and M24 for C. (1.1) EDSS score ≥4 (only patients with an initial BL EDSS <4 were analyzed); (1.2) 6m-CDW (change of ≥1.5 in EDSS score if initial EDSS = 0, ≥1 if initial EDSS between 1 and 5, or ≥0.5 if initial EDSS >5); (1.3) 20% worsening in the T25FWT; (1.4) 20% worsening in the 9HPT; and (1.5) 20% worsening in the PASAT (only patients with an initial PASAT score >0 were analyzed). 6m-CDW = 6-month confirmed disability worsening; 9HPT = 9-Hole Peg Test; BL = baseline; EDSS = Expanded Disability Status Scale; M = month; NfL = neurofilament light chain; PASAT = Paced Auditory Serial Addition Test; T25FWT = Timed 25-Foot Walk Test.

Figure 2. Estimated mean PBVC from BL by NfL assessment (A) at BL, (B) over 12 months, and (C) over 24 months

The reference visit is defined as BL for (A), M12 for (B), and M24 for (C). In (A), where the categorization was performed by BL NfL (before study drug initiation), more patients were categorized as having high NfL (n = 110) compared with (B) (n = 61) and (C) (n = 22) where patients were categorized by a geometric mean under fingolimod treatment. *p ≤ 0.05, **p ≤ 0.001, and ***p ≤ 0.0001 for high vs low NfL. BL = baseline; M = month; NfL = neurofilament light chain; PBVC = percentage brain volume change; SE = standard error.

Figure 3. ROC curves for analyses of ARBA, EDSS ≥4, 6m-CDW, and 20% worsening in the T25FWT, 9HPT, and PASAT at M84

Models with/without predictor NfL (A) at BL, (B) over 12 months, and (C) over 24 months, for (3.1) ARBA up to −0.4%, (3.2) EDSS score ≥4, (3.3) 6m-CDW, (3.4) 20% worsening in the T25FWT, (3.5) 20% worsening in the 9HPT, and (3.6) 20% worsening in the PASAT. 6m-CDW = 6-month confirmed disability worsening; 9HPT = 9-Hole Peg Test; ARBA = annualized rate of brain atrophy; BL = baseline; EDSS = Expanded Disability Status Scale; M = month; NfL = neurofilament light chain; PASAT = Paced Auditory Serial Addition Test; ROC = receiver operating characteristic; T25FWT = Timed 25-Foot Walk Test.