Researchers Confirm 4 Genes Associated with Increased Risk of Developing PML

Researchers have identified 4 genes associated with an increased risk of developing progressive multifocal leukoencephalopathy (PML) in patients taking 99 different PML-linked drugs for a variety of conditions, including multiple sclerosis (MS), blood cancers, and rheumatoid arthritis. This study resulted in the development of a simple, low-cost genetic test to assess patient risk prior to PML-linked drug treatment. These results were presented at ANA 2023, the 148th Annual Meeting of the American Neurological Association.

Researchers validated 4 candidate PML risk genetic variants from the largest genetic study to date of PML by focusing on immune-modulating genes (the C8B, FCN2, LY9, and STXBP2 genes) from a cohort of 336 PML infection cases, 94 of whom had MS and developed PML after exposure to PML-linked drugs. Adverse PML case data was gathered from the Food and Drug Administration Adverse Event Reporting System (FAERS). Researchers determined there is a 9-fold increased risk of PML infection in patients with at least 1 of the 4 genetic risk variants when taking a PML-linked drug, and Tysabri (natalizumab; Biogen, Cambridge, MA) was associated with the highest number of PML cases.

PML is a potentially fatal neurologic condition caused by reactivation of the John Cunningham virus (JCV), and at least 50% of the adult population is seropositive for JCV. There are no treatments for PML, but the genetic test offers preventive solutions for doctors and patients considering PML-linked drug therapies as a potential treatment option. This test also could indicate the need for doctors to closely monitor for PML in at-risk patients receiving PML-linked therapies.

As lead study author Peggy S. Eis notes, “There are no treatments to cure PML, so prevention is the best defense, including knowing your genetic risk. Even though the chance of developing PML is very low for some of these drugs, patients should still be screened given the ease and low cost of doing so relative to the avoidable potential consequences for those who do test positive. Clearly, warning labels on some of these drugs need to be updated and can now include a requirement for genetic testing before these drugs are prescribed.”

The test for the 4 PML-associated genetic variants is available for free in the United States through pmlrisktest.org.