Nearly 100 Treatments for MS and Other Conditions Increase Risk for Progressive Multifocal Leukoencephalopathy

Author(s):

Patients who have 1 of 4 recently identified genetic variants are at 10 times the risk of developing progressive multifocal leukoencephalopathy depending on specific treatments for their condition.

Peggy S. Eis, PhD

A large study presented at the 2023 American Neurological Association (ANA) Annual Meeting, held September 9-12 in Philadelphia, Pennsylvania, showed that nearly 100 treatments used for multiple sclerosis (MS), blood cancers, rheumatoid arthritis and other diseases may increase the risk of developing progressive multifocal leukoencephalopathy (PML). These findings highlight the importance of understanding the risk and options to help prevent future cases of this treatment-induced adverse event among patients.¹

In analyzing the FDA Adverse Event Reporting System, researchers identified 81 treatments and an additional 18 therapies, not reported to the system but in the same class as PML linked treatments, that were associated with PML. The majority of the cautioned treatments were immunosuppressant disease-modifying therapies.

“The increased risk of drug-induced PML in patients testing positive is higher than already-known genetic associations that are used to guide treatments, like BRCA1/2 for breast cancer, yet many neurologists and oncologists may have limited awareness of how many drugs have been linked to PML,” lead author Peggy S. Eis, PhD, chief technology officer at Population Bio, said in a statement.¹ Eis noted that those currently taking those treatments should be tested and also noted surveys showed an alarming rate of patients want to be tested once a genetic test is available to them.

The investigators assessed whether the label for the treatments that patients took listed the risk of PML anywhere on the label and if so, whether it was listed as only a serious adverse event or carried the FDA’s strongest drug label warning, a Boxed Warning. Authors noted that the largest number of PML cases were associated with natalizumab for MS and rituximab for cancer and rheumatoid arthritis, both of which had a Boxed Warning. Notably, authors found that 2 common blood cancer drugs, daratumumab and venetoclax, had no warning of the risk of developing PML on their labels.

Researchers also identified genetic variants in 4 genes including C8B, FCN2, LY9, and STXBP2, that increase a person’s risk of developing PML by 10-fold when taking one of these drugs. Using a free genetic test that is currently available in the US, patients considering taking one of the treatments can learn if they have one of the genetic variants that put them at a higher risk of PML with the specific treatments. Thus, the patients can then consider possible alternative treatments that are not associated with the autoimmune disease.

“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,” Eis said in a statement.1 “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.”

It was also noted in a statement that patients who test positive for any of the genetic variants may want to consider an alternative treatment for their condition that is not associated with PML, such as an interferon-based therapy, glatiramer acetate or teriflunomide, in patients with MS. Even if patients test positive for one of the varients, some may decide to stick with the prescribed PML associated therapies because their efficacy. Having the knowledge of higher genetic risk of these treatments allows both patients and their providers to monitor responses more closely for the disease, such as with more frequent MRIs.

Click here to view the available test for the 4 genetic variants associated with PML.

REFERENCES
1. Largest Study to Date Results in Simple Genetic Risk Test for Nearly 100 Drugs Linked to Often-Fatal Side Effect in Those Being Treated for MS and Other Conditions. News Release. Published September 11, 2023. Accessed September 11, 2023. https://www.newswise.com/articles/largest-study-to-date-results-in-simple-genetic-risk-test-for-nearly-100-drugs-linked-to-often-fatal-side-effect-in-those-being-treated-for-ms-and-other-conditions