Drop in Natalizumab-Associated PML Seen in France

By Will Boggs MD

September 06, 2019

NEW YORK (Reuters Health) - The incidence of progressive multifocal leukoencephalopathy (PML) among patients using natalizumab for multiple sclerosis (MS) dropped significantly in France after the introduction of risk-minimization recommendations in 2013, according to data from the French MS registry OFSEP.

"We can really, as neurologists, be active in preventing the risk of PML," said Dr. Sandra Vukusic from Hopital Neurologique Pierre Wertheimer in Bron.

"All MS patients should be tested for JCV (John Cunningham virus) serology before introduction of a second-line therapy, and when negative or positive with a low index, carefully monitored thereafter while on natalizumab," she told Reuters Health by email. "Patients with high index positivity should not be treated with natalizumab."

PML is a rare opportunistic infection caused by JCV. Factors associated with an increased risk of PML include exposure to natalizumab for more than 24 months, previous use of immunosuppressants, and a positive JCV serologic test result.

Despite the widespread use of immunosuppressants in patients with MS, PML was not reported in MS patients until its occurrence in patients treated with natalizumab, Dr. Vukusic and colleagues note in JAMA Neurology, online September 3. The JCV index has been used since 2014 to delineate the risk of PML in patients with JCV-positive results.

The researchers evaluated the evolution of the incidence of natalizumab-associated PML between 2007 and 2016 and the association of risk-minimization procedures with PML incidence before and after their implementation in January 2013.

Among the more than 6,000 natalizumab-exposed patients in the study, 21.7% were exposed to at least one immunosuppressant before natalizumab. The overall mean duration was 39.6 months.

There were 45 patients with definite PML, for a crude incidence rate of 2.00 per 1,000 person-years of exposure to natalizumab. Yearly rates per 1,000 person-years increased until 2013 (3.54) and decreased thereafter to 1.66 in 2015 and 1.82 in 2016.

The incidence of PML in these patients increased 43.9% yearly from 2007 to 2013 and decreased by 23.6% yearly from 2013 to 2016. The decrease remained statistically significant in multivariable analysis.

All 33 centers that responded to a questionnaire reported using JCV test results in the care of their patients. A minority of centers (3/33, 9.1%) never used natalizumab in patients with JCV-positive results, whereas most centers (26/30, 86.7%) used the JCV index, albeit with variable high-risk thresholds.

For patients already taking natalizumab, 96.5% of centers discontinued it in patients with JCV-positive results, after 24 months in half of patients and as early as 12 to 18 months in the other half.

"Although a causal relationship cannot be established, we believe this finding encourages the continuation and reinforcement of educational activities to prevent the risk of PML," the researchers conclude.

"In the future, in the absence of vaccination against JCV, finding new disease-modifying drugs (DMDs) that are at least as efficient as natalizumab but without PML risk would be great," Dr. Vukusic said. "Already, the arrival of new DMDs has made possible to offer alternate choices to natalizumab in JCV-positive patients."

Dr. Nicholas Schwab of the University of Muenster, in Germany, recently reported the use of L-selectin as a possible biomarker of PML risk during natalizumab treatment. He told Reuters Health by email, "Risk stratification by putting 1/3 to 1/2 of patients in the high-risk category is not ultimately helpful. You have to be able to pinpoint the risk better - e.g., by including additional biomarkers."

"Patients are reluctant to stop a working therapy just because they are in a risk group of 1:150 or even 1:100," he said. "If you can include other markers and get that group to 1:50 or lower - then you can really make an impact and stop treatment in all of them."

SOURCE: https://bit.ly/2lYxlQx

JAMA Neurol 2019.