Progressive Multifocal Leukoencephalopathy (PML)

From MSAA’s MS Research Update 2015

Written and compiled by Stephen Krieger, MD

Tysabri has been increasingly utilized as a disease-modifying therapy in RRMS, though clinical use of this drug has been limited from the outset by the risk of progressive multifocal leukoencephalopathy (PML). PML is a viral brain infection caused by the JC virus, which, when not discovered and treated early, can typically lead to severe disability or death. Many people are exposed to the JC virus (JCV), which typically remains dormant; however, it may become activated and infect the brain when one’s immune system becomes weakened, a condition that may result from immunosuppressive drugs.

Once projected as a universal risk of approximately 1 in 1,000, based on Tysabri’s pivotal trial data, new data presented and published in 2012 allow for the risk of Tysabri-associated PML to be estimated for each individual with increasing precision.

Three risk factors for Tysabri-associated PML have since been identified, allowing for the classification of individuals according to their relative risk of PML.23 The most important risk factor is the presence of JC-virus antibodies. Roughly 50-to-60 percent of adults carry the JCV antibodies, which can now be determined by a simple blood test.

The JCV Antibody Program (STRATIFY-2) began in April 2010, enrolling more than 30,000 people with MS, and will continue for several more years. Testing for JCV antibodies was added to the FDA label for Tysabri in 2012. The JCV antibodies assay is available through Quest Diagnostics, at no charge to patients if ordered with the “STRATIFY JCV™” test form (available from Quest and Biogen). People testing negative for JCV antibodies are at risk for becoming JCV-positive by approx-imately 2-to-3 percent per year. Current recommendations are to re-test JCV antibodies status every six months in JC-virus negative people on Tysabri therapy. Some neurologists may opt to test JC-virus status more frequently, though this goes beyond the current FDA guidance.

The second risk factor for the development of Tysabri-associated PML is the duration of Tysabri treatment. Risk for PML in JCV-positive people increases the longer Tysabri is used. The risk is small in the first year of treatment with Tysabri, likely less than 1 in 1,000. In the second year, this increases to approximately 1 in 500, and beyond two years on Tysabri, the risk increases further.

The third risk factor for the development of Tysabri-associated PML is prior treatment with immune-suppressing medications such as Cytoxan® (cyclophosphamide), Novantrone (mitoxantrone), or other chemotherapy agents. Standard injectable MS disease-modifying therapies (interferons and Copaxone, listed earlier) are not considered immune suppressants, and use of these prior to Tysabri does not increase the risk of PML.

As of Fall 2014, approximately 517 cases were reported of PML24 with Tysabri, while more than 130,000 people have been treated with this medication. The FDA labeling of Tysabri has been updated to further quantify the risk. The new labeling also notes the increased risk from previous use of immunosuppressive medications.

Although PML is always serious, it is no longer always fatal. Early recognition and the quick removal of Tysabri using a procedure called plasmapheresis have improved the outcomes. Early PML diagnosis and treatment increases the survival rate to 80 percent (although often with disability).

In December 2013, the FDA approved a label change for Tysabri. Some of the more notable changes include: indications of approval for first, second, and third-line therapy are the decision of the provider; updated data includes patients on treatment for up to six years; an increased risk of developing herpes encephalitis and meningitis – patients need to be instructed by the provider to immediately report if they experience fever, headache, or confusion; and one patient with acute liver failure is noted.