Prospective validation of the PML risk biomarker
            <scp>l</scp>
            -selectin and influence of natalizumab extended intervals

Schwab, Nicholas; Schneider‐Hohendorf, Tilman; Pignolet, Béatrice; Bucciarelli, Florence; Scandella, Lise; Ciron, Jonathan; Biotti, Damien; Lebrun-Frénay, Christine; Mathey, Guillaume; Clavelou, Pierre; Pelletier, Jean; Ostkamp, Patrick; Meinl, Ingrid; Windhagen, Susanne; Klotz, Luisa; Groß, Catharina C.; Meuth, Sven G.; Deisenhammer, Florian; Brassat, David; Wiendl, Heinz

doi:10.1212/wnl.0000000000008135

Cited by 9 publications

(4 citation statements)

References 7 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…It also requires periodic testing to monitor if JCV-negative patients seroconvert and/or if the JCV index has exceeded the upper index value of 1.5 (18,77). Other non-genetic biomarker tests have been investigated, such as CD62L/L-selectin and lipid-specific immunoglobulin M bands in patients on natalizumab (19,78), but none have been routinely implemented in the clinical setting. Therefore, there is a high unmet need for better risk stratification tools and our PML variants could be implemented in a simple, inexpensive genotyping test.…”

Section: Discussionmentioning

confidence: 99%

Germline Genetic Risk Variants for Progressive Multifocal Leukoencephalopathy

Eis

Bruno²,

Richmond³

et al. 2020

Front. Neurol.

View full text Add to dashboard Cite

show abstract

Section: Discussionmentioning

confidence: 99%

Germline Genetic Risk Variants for Progressive Multifocal Leukoencephalopathy

Eis

Bruno²,

Richmond³

et al. 2020

Front. Neurol.

View full text Add to dashboard Cite

show abstract

“…Conversely, a lesser receptor saturation has been suggested to be responsible for the reduced risk of PML with extended‐interval dosing 32 . Two other relevant cellular attributes that are influenced by natalizumab treatment and which (partially) recover on longer infusion schedules are expression of α 4 ‐integrin and L‐selectin 33,34 . The corollary is that the lower risk on a 5‐ or 6‐week infusion schedule, 5 and the higher incidence in Europe are, in all likelihood, simply two sides of the same coin.…”

Section: Discussionmentioning

confidence: 99%

Improving risk‐stratification of natalizumab‐associated PML

Tugemann¹,

Berger

2021

Ann Clin Transl Neurol

View full text Add to dashboard Cite

Based on publicly available data, we reevaluated current algorithms for stratifying the risk of progressive multifocal leukoencephalopathy (PML) in natalizumab‐treated patients with multiple sclerosis, and found that there are a number of issues. First and foremost, our analysis highlights the necessity of separate PML incidence assessments for the U.S. versus Europe, and indicates that the risk in John Cunningham virus (JCV) antibody‐negative patients may be higher than previously communicated. Additionally, we advocate introducing a low‐risk JCV index threshold of 0.45 for individuals with prior exposure to an immunosuppressant, and setting the low‐risk threshold at 0.6 instead of 0.9 for those without such pretherapies. On the other hand, the risk of PML on natalizumab, in general, appears to not only plateau but to actually decrease after about 5 years of continuous dosing.

show abstract

“…The authors subsequently suggested that CD62 L might be evaluated as a potential biomarker in future studies for balancing efficacy and safety in EID. 49 …”

Section: Extended-interval Dosing - An Emerging Strategy To Mitigate ...mentioning

confidence: 99%

“…The authors subsequently suggested that CD62 L might be evaluated as a potential biomarker in future studies for balancing efficacy and safety in EID. 49 In a similar effort to optimize and personalize natalizumab therapy, a multicenter study by Punet-Ortiz et al measured serum levels of natalizumab and expression of α4β1 integrin on the surface of peripheral blood lymphocytes. 50 Their results indicate a dose-dependent relationship between serum drug concentrations and α4β1 integrin surface expression.…”

Section: Biomarkersmentioning

confidence: 99%

Natalizumab extended-interval dosing in multiple sclerosis to mitigate progressive multifocal leukoencephalopathy risk: initial study evidence and real-world experience

Perncezky

Sellner

2022

J Cent Nerv Syst Dis

View full text Add to dashboard Cite

The high efficacy of natalizumab in the treatment of relapsing-remitting multiple sclerosis (MS) is without controversy. Indeed, effective disease control was not only demonstrated in the pivotal trials but has been corroborated impressively in real-world observations. This monoclonal IgG4 antibody blocks the α4β1 integrin-mediated leukocyte-endothelial interaction and thereby inhibits the migration of immune cells to the brain parenchyma. However, treatment with natalizumab carries the risk of progressive multifocal leukoencephalopathy (PML). This potentially lethal side effect is a significant limitation for treatment initiation and long-term therapy. Natalizumab is given intravenously or subcutaneously in the standard dose of 300 mg every 4 weeks, allowing drug concentrations at levels that ensure continuous α4β1 integrin receptor saturation on the surface of immune cells. Extended-interval dosing (EID) is an emerging treatment approach that aims to mitigate the natalizumab-related PML risk by prolonging the standard infusion intervals to 6 weeks or even more. This treatment approach may abrogate the PML risk due to improved immune surveillance within the central nervous system while maintaining clinical efficacy. Moreover, even an individual interval dosing can be envisioned based on the availability of a biomarker that is capable of monitoring both safety and efficacy aspects. This review summarizes the early and encouraging evidence for EID from observational and randomized-controlled trials and discusses current limitations and upcoming challenges for introducing a tailored treatment approach.

show abstract

Prospective validation of the PML risk biomarker l -selectin and influence of natalizumab extended intervals

Cited by 9 publications

References 7 publications

Germline Genetic Risk Variants for Progressive Multifocal Leukoencephalopathy

Germline Genetic Risk Variants for Progressive Multifocal Leukoencephalopathy

Improving risk‐stratification of natalizumab‐associated PML

Natalizumab extended-interval dosing in multiple sclerosis to mitigate progressive multifocal leukoencephalopathy risk: initial study evidence and real-world experience

Contact Info

Product

Resources

About