Multiple Sclerosis Biomarker NfL Holds Promise as Treatment Monitoring Tool

Ho Jin Kim, MD, PhD, from the Department of Neurology, Research Institute and Hospital of National Cancer Center

Ho Jin Kim, MD, PhD

Serum neurofilament light (NfL) is one step closer to clinical validation, as new findings from a longitudinal analysis suggests it has potential as a monitoring biomarker for the personalization of therapeutics in multiple sclerosis (MS).¹

Over the course of a 2-year period, 17 patients with MS who were undergoing treatment with alemtuzumab (Lemtrada, Sanofi) had 144 sera collected; analysis revealed that serum NfL levels were significantly higher in patients with evidence of disease activity (EDA; n = 11) than those with no evidence of disease activity (NEDA; n = 6; P <.001) as well as levels in 35 age-matched healthy controls (P <.001).

Post-alemtuzumab treatment initiation NfL levels in the EDA group were 26.7 ±33.7 pg/mL (83 samples), while the NEDA group displayed levels at 10.4 ±4.7 pg/mL (44 samples) and the healthy controls showed levels at 5.9 ±2.2 pg/mL (35 samples).

This group of patients was based at the National Cancer Centre in Goyang, Korea, which the investigators, including Ho Jin Kim, MD, PhD, from the Department of Neurology, Research Institute and Hospital of National Cancer Center, acknowledged was of interest due to the fact that the majority of previous studies of the biomarker were conducted in Western countries.

“Consistent with previous results based on Western population, [serum] NfL levels were well-reflected disease activity in Korean MS patients in this study; thus, it suggested that the usefulness of sNfL to monitor treatment response was across racial groups in MS patients,” Kim and colleagues wrote. As the prevalence of MS is much higher in Western populations than Asian ones, they wrote that the study “provided meaningful evidence for the feasibility of [serum] NfL as a biomarker for therapeutic monitoring in Asian patients with MS.”

With regard to the longitudinal analysis, the serum NfL levels were consistently low in patients with NEDA, while there was more variation in patients with EDA, the investigators detailed. Patients with EDA had levels consistently >10.3 pg/mL, which was designated as the cut-off value, and was 2.21 standard deviations above the mean serum NfL levels of 5.87 in healthy controls. The investigators did note this is not a standardized value—a previous study in a Western population suggested a higher cut-off value of 18.2 pg/mL, based on its healthy controls.² Concentrations of serum NfL in this study were detected with the Simoa single molecule array assay, with the lower limit of quantification of sNfL was 0.174pg/mL. All results were comfortably above this limit.

“Future studies based on a larger general population, including diverse racial groups, are warranted to find the optimal cut-off value to design tailored therapeutic strategies,” they wrote.

An increase in serum NfL was associated with both increases in Expanded Disability Status Scale (EDSS) scores and the number of gadolinium-enhancing (Gd+) MRI lesions, and vice versa.

Even in radiologically active status without clinical worsening, the "serum NfL levels were also consistently higher than the cut-off value,” Kim and colleagues wrote.

Results revealed positive (>10.3pg/mL) and negative (≤10.3 pg/mL) status of serum NfL levels using the cut-off value at specific time points of the longitudinal analysis, according to the patient’s status—active either radiologically and/or clinically, or inactive both radiologically and clinically&mdash;which was statistically significant (P <.001).

“The strength of this study was a longitudinal analysis of [serum] NfL levels at multiple time points, unlike most of the previous studies done cross-sectionally,” Kim and coauthors wrote. “Some of the previous studies included follow-up results of [serum] NfL at 1 to 4 time points; however, we individually performed a longitudinal assessment at multiple time points.”

Through this analysis, they noted that they found that serum NfL levels would be useful to monitor ongoing disease activity in patients with MS.

At the 2018 European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) meeting, in Berlin, Germany, Peter A. Calabresi, MD, director of neuroimmunology and professor of neurology at Johns Hopkins University, told NeurologyLive that one way to clinically validate the biomarker is to analyze large cohorts and see if their levels move in the intended direction.

“The people who have elevated levels of the neurofilament, do they end up having more MRI activity over the course of the next year? Or down the road, do they have progression on their EDSS?” Calabresi asked. “We're able to show, at the cohort level, some very nice relationships but now the question is: Can we look at individual patients and is there a cut-off level that would predict who might have the likelihood of this happening to them, individually?”

REFERENCES

1. Hyun JW, Kim Y, Kim G, Kim SH, Kim HJ. Longitudinal analysis of serum neurofilament light chain: A potential therapeutic monitoring biomarker for multiple sclerosis. Mult Scler J. published online March 26, 2019. doi:10.1177/1352458519840757

2. Novakova L, Zetterberg H, Sundstrom P, et al. Monitoring disease activity in multiple sclerosis using serum neurofilament light protein. Neurology 2017;28;89(22):2230-2237. doi: 10.1212/WNL.0000000000004683.