Reducing the Risk of PML During MS Treatment

NASHVILLE—For patients with multiple sclerosis (MS) who receive treatment with natalizumab, progressive multifocal leukoencephalopathy (PML) can be avoided, according to research presented at the 2018 CMSC Annual Meeting. “You can actually prevent this disease from occurring because we have risk-limiting strategies in many circumstances,” said Joseph R. Berger, MD, Professor of Neurology at the Hospital of the University of Pennsylvania in Philadelphia.

Joseph R. Berger, MD

Long-Term Use of Natalizumab Is Associated With Increased PML Risk

Unlike other conditions such as HIV, MS itself is not linked to a higher risk of PML, said Dr. Berger. Instead, it is the medications that introduce the risk, he said, with at least three, and possibly four, drugs posing a risk to patients.

“We know that the risk with natalizumab is incredibly high in the context of John Cunningham virus [JCV] antibody positivity and prolonged therapy,” Dr. Berger said. “You can safely give natalizumab for a short period of time when treating patients with aggressive MS. I will frequently employ that strategy even in the context of JCV antibody positivity.” There is no risk of PML when natalizumab is used for under eight months, Dr. Berger said.“If you leave people on the drug indefinitely, there is a substantial risk of developing PML,” said Dr. Berger. “Individuals who have been on the drug for two years, who have seen prior immunosuppressant therapy, who are JCV antibody positive—that group of individuals develops PML at rates of one in 50 to one in 100.” These levels are “even higher than those in the HIV population before the rise of antiretroviral medications,” he added.

As of November 30, 2017, 177,800 patients have received natalizumab in the postmarketing setting, and 756 cases of PML have been reported as of December 7, 2017. All but three of those cases were in patients with MS, and the overall incidence was 4.19 out of 1,000.

Dr. Berger recommended regular screening MRIs for PML in patients taking natalizumab and advised physicians to be on alert for the appearance of new neurologic symptoms or a new or increasing JCV antibody index.

Drugs With Low and Unknown Risks

Two other MS drugs, fingolimod and dimethyl fumarate, entail a low risk of PML. The numbers of PML cases reported for these drugs are 19 and five, respectively, as of February 2018, said Dr. Berger. Two of the patients receiving fingolimod who developed PML had had earlier exposure to natalizumab.

For JC antibody positive patients receiving dimethyl fumarate, the risk of PML may be eliminated when the treatment is discontinued and their lymphocyte count decreases to a level below 500 per µL Dr. Berger said.

“Unfortunately for fingolimod, we do not have a defined risk-mitigation strategy,” he said. However, researchers have noticed that PML has occurred more often in older people on fingolimod, possibly because of the aging of the immune system.

Alemtuzumab, ocrelizumab (with rituximab as proxy), and teriflunomide (with leflunomide as proxy), entail an unknown risk of PML, according to Dr. Berger. There have been three cases of PML associated with ocrelizumab and one associated with teriflunomide, but all were carry-overs from natalizumab or fingolimod exposure or occurred after natalizumab exposure.

What should a physician do if a patient develops PML? Stopping the drug and restoring the immune system are crucial steps, Dr. Berger said. Although evidence indicates that plasma exchange clears natalizumab, “there is no study that demonstrates that it is in the patient’s best interest,” said Dr. Berger. A retrospective study found no improvement in morbidity or mortality after plasma exchange.

Multiple strategies to treat PML, including immunizations and inhibitors of DNA replication, have failed to make an impact so far, said Dr. Berger. These strategies did not show benefits in clinical trials, and evidence does not support them.