Biogen has reported a fourth case of PML with Tecfidera -- this one in a patient with only moderate lymphopenia -- to U.S. and European regulators, raising new questions about the drug's safety.

The latest case occurred in a 61-year-old female with relapsing-remitting multiple sclerosis, who'd been taking Tecfidera for 22 months before being diagnosed with PML.

She had grade 2 lymphopenia, at 600 cells/mm3, for 6 months before developing symptoms of PML, which included left arm weakness and apraxia, according to information provided to MedPage Today. Severe grade 3 lymphopenia occurs when lymphocyte levels drop below 500 cells/mm3.

"To my understanding, at least one of the cases did not demonstrate grade 3 lymphopenia but only grade 2," said Ari Green, MD, of the University of California San Francisco. "This complicates using lymphocyte counts as a means to track risk of PML, as a not insignificant portion of patients on Tecfidera develop grade 2 lymphopenia." (Those estimates range from 11% to 21%.)

The patient had previously taken natalizumab (Tysabri) for 6 years and 4 months, but the company said that prior exposure wasn't considered a confounder in this case.

Few other details about the case were made available. Neither Biogen nor the FDA or the European Medicines Agency (EMA) would comment on the case.

This is not the first case of a patient with moderate lymphopenia developing PML while taking a dimethyl fumarate product. Last April, researchers reported in the New England Journal of Medicine the case of a 64-year-old female patient who died from PML after 2 years on a compounded formulation of dimethyl fumarate for psoriasis (Psorinovo). Her lowest lymphocyte count was 792 cells/mm3.

A 69-year-old man taking Biogen's Fumaderm dimethyl fumarate brand for psoriasis developed PML with only moderate grade 2 lymphopenia at a range of 724 to 738 cells/mm3. The case was reported in Neurology Neuroimmunology and Neuroinflammation.

A third case did not involve PML, but a 23-year-old male a patient without any lymphopenia developed shingles from varicella zoster virus infection after only 2 months on the Fagron brand of dimethyl fumarate for psoriasis. The case was reported in a letter in the New England Journal of Medicine.

Although questions remain about the best way to use lymphopenia to determine PML risk with Tecfidera, some experts have raised concerns about the interval of lymphocyte screening on the drug's label.

Tecfidera's label calls for a baseline lymphocyte count, followed by another check-in after 6 months and then regular checks every 6 to 12 months thereafter. Physicians should consider stopping therapy in those whose levels stay below 500 cells/mm3 for 6 months.

However, European regulators recently recommended checking lymphocyte counts every 3 months, and reconsidering treatment in patients who maintain grade 3 lymphopenia for longer than 6 months.

The EMA also recommends checking lymphocyte count monthly for those on Fumaderm, and stopping therapy in all patients who develop grade 3 severe lymphopenia.

Tecfidera's label also only mentions one case of PML, which is outdated given the total of four cases now reported.

Nor does the label discuss the potential role of JCV antibody testing to determine PML risk -- despite the fact that many clinicians are already performing such screening on MS patients. They use it, however, mostly to determine whether patients should go on natalizumab, which carries a stronger risk of PML than most other MS drugs.

Tecfidera is currently seen as a safer choice if a patient is indeed JCV antibody positive.

"The risk [of PML] does not appear to be high enough to warrant routine assessment of JCV antibody status in all patients on Tecfidera," Green said. "Many antimetabolites have a low risk of PML and I would consider both Gilenya and Tecfidera in that risk class for now."

Most of the specialists contacted by MedPage Today said they're not so concerned with FDA label changes, but they would like drugmaker Biogen to be more forthcoming about the details of the PML cases.

"I think the current FDA warning letter is sufficient -- although without a risk mitigation and registration program from the FDA we can't be sure that there aren't more cases for Tecfidera than what has been reported," Green said.

"I have no opinion about what FDA should do," said Dennis Bourdette, MD, of Oregon Health and Science University. "I would like Biogen to be providing more information and follow up on the cases that have occurred."

Tecfidera has been available on the U.S. market as a treatment for MS since 2013.

A Biogen spokesperson confirmed that there have been 588 cases of PML with natalizumab since 2004, representing a global incidence of four per 1,000 treated patients.

The company pulled the drug from the market shortly after it was approved in 2004 -- after two PML cases were discovered -- and relaunched it 16 months later with a risk evaluation and mitigation strategy (REMS) in place.