Fourth PML Case With Tecfidera in MS Calls for Vigilance

December 17, 2015

After a fourth case of progressive multifocal leukoencephalopathy (PML) linked to the multiple sclerosis (MS) drug dimethyl fumarate (Tecfidera, Biogen), it is becoming more widely accepted that even the "safer" immunosuppressant agents may cause dangerous adverse effects, albeit rarely, and vigilance on this issue is required, experts say.

Tecfidera, an oral agent taken twice daily, has been available for the treatment of MS since 2013. The generic compound, dimethyl fumarate, and similar products containing fumaric acid esters have long been used to treat psoriasis. As well as the four cases of PML in patients with MS, about 10 cases in patients with psoriasis have been linked to such products, Ari Green, MD, from the University of California San Francisco, told Medscape Medical News.

There have also been three cases of PML with fingolimod, another oral MS treatment thought to be relatively safe in terms of opportunistic infections.

PML is a rare but potentially fatal brain infection caused by the JC virus. It is seen mainly in immunosuppressed individuals and has been a particular problem with the potent immunosuppressant natalizumab (Tysabri), an effective treatment for MS.

Biogen acknowledged to Medscape Medical News that a fourth case has occurred but declined to disclose case details.

"We can confirm that we have reported a fourth case of progressive multifocal leukoencephalopathy (PML) from October 2015 associated with Tecfidera treatment in an MS patient that had experienced prolonged lymphopenia," a spokesperson for Biogen public affairs noted. "We are not providing case details on this particular AE [adverse event] other than through normal medical, regulatory and safety channels."

Mark S. Freedman MD, professor of neurology at University of Ottawa, Ontario, Canada, said the following information about the latest PML case had been circulated to Canadian neurologists: The patient is a 61-year-old woman with relapsing-remitting MS who presented with left arm weakness and apraxia; the diagnosis of PML was confirmed on basis of clinical, MRI, and positive results on polymerase chain reaction in cerebrospinal fluid after the patient had taken the drug for 22 months.

Lymphocyte counts had fallen steadily since she started the drug and had stabilized at 600 cells/mm3. Treatment was discontinued after PML diagnosis, and lymphocyte counts rose to 1100 cells/mm3 by 6 weeks. No data on lymphocyte subsets are available. The patient was known to be anti-JCV antibody positive before starting the drug. The patient is reportedly stable and is not hospitalized. 

Prior treatments included natalizumab for 6 years, which was stopped 2 months before starting dimethyl fumarate, so PML was diagnosed 24 months after discontinuation of natalizumab. Other previous treatments included β-interferon (Avonex) and intravenous immunoglobulin

Grade 2 Lymphopenia

Dr Green pointed out that this case is of particular interest because it has previously been thought that patients at the greatest risk for PML on dimethyl fumarate had very low lymphocyte counts: below 500 cells/mm3 (grade 3 lymphopenia).

"But now we have a PML case which has occurred with a grade 2 lymphopenia, which is much more common, occurring in about 10% to 20% of MS patients taking this drug," he said. "That is a cause for concern."

At present, recommendations advise regular monitoring of lymphocyte count in patients taking this drug.

"In the US the advice is to test lymphocyte counts every 6 months — in Europe it is every 3 months — and to stop the drug if levels are low. You could perhaps try a drug holiday — this is easier with Tecfidera than some other agents. But now we have a case of PML in a patient with a lymphocyte count of 600 we need to try and find additional screening approaches. We need to learn more about what is happening to different lymphocyte subsets and function."

Dr Freedman elaborated: "There are some thoughts that a rising CD4/CD8 ratio indicates a specific loss of CD8 cells, the ones that are thought to guard the most against PML. So this might be the next focus."

Dr Green recommends that in the meantime, clinicians should follow the recommendations on lymphocyte testing, inform the patient of the risk, and stay vigilant.

"Even though we have a case of PML with grade 2 lymphopenia, there is still a sense that there is a greater risk with lower lymphocyte counts," he said. "So it is still important to monitor this. We just can't use it as a complete method of stratification anymore."

He points out that PML with dimethyl fumarate and fingolimod are still very rare and do not compare with the risk seen with natalizumab.

"Natalizumab has a PML risk of about 1 in 250 in all comers, whereas I would say the risk with Tecfidera and fingolimod is at least 100-fold less so far," Dr Green said. "But patients on Tecfidera have not been treated for as long as those on natalizumab so more cases may emerge. The fumarate acid esters have also been associated with other opportunistic infections such as varicella zoster and Kaposi's sarcoma, and fingolimod has been linked to herpes virus infections and cryptococcal meningitis, but again these are all relatively rare."

Dr Green notes that unlike the situation with dimethyl fumarate, monitoring lymphocyte counts is not useful for screening for PML risk with natalizumab or fingolimod.

Risk Still Small

He still believes this is a useful drug. "I don't want to be alarmist. The risk does seem very small. There will be some risk of PML with almost all immunosuppressant drugs — we see the same thing in other conditions where immunosuppressants are used such as RA [rheumatoid arthritis] and lupus."

But he adds that perhaps it is not as safe as was first thought. "There was a perception when this drug came out that it was safer than the others — but real-world experience informs us of the true picture. I would say it is still a relatively safe drug and these few cases wouldn't discourage me from using it — I will just be more aware and vigilant."

Two other MS experts asked for comment on this latest case of PML with dimethyl fumarate expressed similar views.

Jeffrey Cohen, MD, Cleveland Clinic, Ohio, said, "I don't think it changes how we view PML with fumarates: it's very rare, the frequency appears to be comparable to that with all potent immune drugs, the risk may be increased with patients on Tecfidera with prolonged low lymphocyte count, but the situation is not comparable to that with natalizumab, which is a special case."

Edward Fox, MD, Multiple Sclerosis Clinic of Central Texas,  Round Rock, added: "As with most of the PML cases, the patient with this latest case was older, a likely risk factor for opportunistic infections. I think that other than natalizumab, which has a much higher risk, all the orals and infusibles will have a modest risk level of 1:1000 or less.  

"All patients on these drugs need to be informed about the risks and alerted to notify the prescriber for any clinical changes," he added. "Getting a JCV-Ab [JC virus antibody] test will be controversial, as we don't know whether we should be changing our prescribing habits based on this information. It's a fluid, ongoing situation. I will likely have a modified opinion at some point during 2016."

Dr Freedman, however, is much more outspoken on the issue and believes these PML cases could signal the end of the road for this drug.

"I always knew that there would be PML with Tecfidera as it was shown in the psoriasis world — it was just a matter of time," he said. "So in my mind the drug was never safe. Coupled with the fact that it is difficult to get people on this drug due to tolerability issues and that it has no clear advantage over any of the other drugs, I think it is a matter of time (and PML cases) before the FDA wisens up and pulls it from the market. I do not think this drug will endure."

Dr Green has served on clinical trial steering committee for Novartis. Dr Freedman has received honoraria for consultancy/advisory board activity from Bayer Healthcare, Biogen Idec, Chugai, EMD Canada, Genzyme, Novartis, Sanofi-Aventis, and Teva Canada Innovation. Dr Cohen receives fees from EMD Serono, Genentech, Genzyme, Innate Immunotherapeutics, and Vaccinex. Dr Fox reports he has received personal consulting fees from Novartis, Biogen Idec, GlaxoSmithKline, MedDay, Questcor, Teva, and XenoPort; has served on advisory committees for Biogen Idec and Novartis; and received research grant funding from Novartis.

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