Oxford, UK—More than three dozen drugs include a progressive multifocal leukoencephalopathy (PML) warning in their prescribing information in the United States or in product characteristics cited by the European Medicines Agency.

Among them are alemtuzumab, brentuximab vedotin, dimethyl fumarate, efalizumab, fingolimod, ibrutinib, and natalizumab. Anti-CD20 antibodies (also known as B-cell depletion therapies) such as obinutuzumab, ocrelizumab, ofatumumab, and rituximab also are on the list.

PML, an aggressive demyelinating disorder, is caused by the reactivation of the "John Cunningham" virus (JCV) in immunosuppressed individuals. Sometimes triggered by prescription drugs, it can be fatal and is often severe and debilitating, with nearly 70% of survivors suffering from an ongoing neurologic disability. No approved treatment is available.

Now, new research has confirmed a strong link between four genetic mutations and PML. The researchers suggested their findings, published in Frontiers in Neurology, will allow screening to identify patients with the highest risk of PML.

An international team of researchers found that in those taking PML-inducing drugs, having one of four genetic variants increased the risk of PML 8.7 times on average. One of the variants actually increased risk 33-fold.

The report pointed out that eight medications carry a Black Box Warning for PML, and more than 30 additional drugs carry other PML warnings. It added that overall, PML cases have been reported to the FDA in patients on more than 75 drugs, including many of the most effective treatments for multiple sclerosis (MS), blood cancers, rheumatoid arthritis, Crohn’s disease, and organ transplant rejection.

PML, which is caused by JCV, a usually harmless virus carried by up to 80% of the population, occurs when the virus reactivates and attacks the brain. The study is the first to explain why the virus leads to PML in some people but not others.

The researchers demonstrated that four genetic variants were far more common in patients who developed drug-induced PML than in the general population. Then, they looked for those variants in a control group of MS patients who carried JCV and were taking a high-risk drug for years but who did not develop PML.

Nearly 11% of patients with PML tested positive for at least one of the four variants. That is not inconsequential. Study authors pointed out that the variants explained a higher percentage of PML cases than the well-known BRCA mutations can explain breast cancer cases. Their predictive power exceeds levels that have led the FDA to require genetic screening for other risky medications, they added.

With more immunosuppressant therapies being developed, PML cases are increasing. More than 500 cases in the FDA’s adverse event reporting system were reported in 2021. Millions of patients in the U.S. are potentially affected.

“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 in California, who was not affiliated with the study. His laboratory developed Tysabri, a powerful MS medication that was temporarily withdrawn from the market because of PML and now carries a Black Box Warning. “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,” Dr. Steinman said in a press release.

The report advised that while immunosuppression in JCV-seropositive individuals that develop PML can be due to a variety of underlying diseases and/or drugs, three are most prominent: HIV infections, hematologic malignancies (i.e., lymphoproliferative diseases such as leukemias, lymphomas, and multiple myeloma); autoimmune disorders, such as rheumatoid arthritis; and systemic lupus erythematosus.

“HIV-infected acquired immunodeficiency syndrome (AIDS) patients represent the largest proportion of PML cases (approximately 50%),” according to the study. “Rates in this population substantially dropped after the 1996 introduction of highly active antiretroviral therapy (HAART), although at least 10% of HIV patients who are considered ‘immunological non-responders’ to antiviral therapies could continue to have elevated PML risk similar to the pre-1996 era. Conversely, iatrogenic PML (i.e., resulting from drug exposure) is on the rise with the growing number of immunosuppressant therapies used to treat various immune disorders.”

The authors added that iatrogenic PML risk was high enough for psoriasis patients taking efalizumab, brand-name Raptiva, that the therapy was withdrawn from the market worldwide in 2009 based upon a PML incidence rate of 0.158% or approximately 16 in 10,000. MS patients on disease-modifying therapies remain the largest proportion of iatrogenic PML cases, they noted.

The content contained in this article is for informational purposes only. The content is not intended to be a substitute for professional advice. Reliance on any information provided in this article is solely at your own risk.