A new international research study of progressive multifocal leukoencephalopathy (PML), a rare but often fatal brain infection has identified a strong link between four genetic variants and nearly a nine-fold increased risk of developing the infection—with one of the variants exhibiting a risk nearly 33 times higher.
“It’s critical to be able to identify genetic mutations that greatly increase a person’s risk of this devastating infection,” said Lawrence Steinman, MD, professor of neurology and neurological sciences, pediatrics, and genetics at Stanford University who was not a part of the study. “Preventative screening for these variants should become part of the standard of care. I wish we had more powerful tools like this for other therapies.” Steinman’s lab developed Tysabri, a powerful multiple sclerosis (MS) medication that was temporarily withdrawn from the market because of PML and now carries a black box warning.
Currently, eight FDA approved medications come with a black box warning for PML, the strongest labeling warning given by the FDA intended to draw attention to a medication’s potential serious, or life threatening side effects when given to certain people. An additional 30 drugs carry PML warnings including some of the most effective drugs for treating MS, Crohn’s disease, blood cancers, rheumatoid arthritis, and others. In all, PML cases have been reported to the FDA for patients of more than 75 approved drugs.
Progressive multifocal leukoencephalopathy (PML) is a rare and often lethal brain disorder caused by the common polyomavirus 2, also known as JC virus (JCV). JCV is a typically benign virus carried by as much as 80% of the population, but in a small percentage of immunosuppressed individuals, JCV is reactivated and infects the brain, causing devastating neurological defects.
For this current study, published this week in Frontiers in Neuroscience, the research team first identified four genetic variants that were far more common in patients that developed drug-induced PML. The investigators then looked for these variants in the ideal control group: MS patients who carried JCV and were taking a high-risk drug for years, but who did not develop PML.
Within this cohort, nearly 11% of patients with PML tested positive for at least one of the four variants. To put this finding in perspective, these variants explain a higher percentage of PML cases than BRCA mutations in breast cancer cases. Most importantly, the predictive power of the genetic variants exceeded the levels that have prompted the FDA to require genetic screening for other risky medications. “Measures of clinical validity and utility compare favorably to other genetic risk tests, such as BRCA1 and BRCA2 screening for breast cancer risk and HLA-B*15:02 pharmacogenetic screening for pharmacovigilance of carbamazepine to prevent Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis,” the researchers wrote.
The study found that in people taking PML-inducing drugs, having one of four genetic variants increased the risk of PML 8.7 times on average—with one of the variants exhibiting a risk nearly 33 times higher—when patients any of the dozens of FDA-approved drugs known to trigger the infection.
With this data in hand, the hope now is that a PML genetic risk test can be implemented for screening patients taking or considering treatment with a PML-linked drug to decrease the incidence of PML and better identifying which patients will benefit from PML linked medications, and which patients should be treated with others not linked to the infection.
