From the New England Journal of Medicine, April 8, 2015 (see another letter from the same issue in the post above this one). This is a letter about a psoriasis patient who died of PML while taking Tecfidera and contains some remarks about possible safety concerns for this drug.
PML in a Patient without Severe Lymphocytopenia Receiving Dimethyl Fumarate
To the Editor:
Fumaric acid esters, which are prescribed for the treatment of psoriasis and multiple sclerosis, are considered to have a favorable risk profile. However, treatment-related progressive multifocal leukoencephalopathy (PML) has been described in association with long-lasting, severe lymphocytopenia (<500 lymphocytes per cubic millimeter). This has led to the recommendation that lymphocyte counts should be monitored in patients receiving these drugs in order to prevent opportunistic infections such as PML. Here, we report a case of fatal PML after treatment with compounded dimethyl fumarate (DMF) in a patient without severe lymphocytopenia.
On July 18, 2014, a 64-year-old woman presented with a 2-week history of progressive apraxia. She had been receiving topical glucocorticoids and compounded delayed-release DMF (Psorinovo; compounding pharmacy, Mierlo-Hout) for the treatment of psoriasis since June 2012. Magnetic resonance imaging (MRI) of the brain showed multiple subcortical white-matter lesions .... Leukocyte and lymphocyte counts were normal before DMF treatment but reached a nadir of 4000 cells and 792 cells per cubic millimeter, respectively, in June 2014.
Analysis of the cerebrospinal fluid showed normal levels of leukocytes, protein, and glucose. The patient was seronegative for the human immunodeficiency virus. At that time, a diagnosis of PML was considered. However, testing of the cerebrospinal fluid for JC virus DNA on polymerase-chain-reaction (PCR) assay was negative. Treatment with DMF was discontinued, and the patient received the diagnosis of atypical ischemic stroke.
Owing to progressive hemiparesis and somnolence, she was transferred to our hospital on August 14, 2014. Follow-up MRI showed a rapid and widespread dissemination of lesions suggestive of PML–immune reconstitution inflammatory syndrome (IRIS)....Treatment with mefloquine, mirtazapine, and glucocorticoids was initiated. The patient's condition continued to deteriorate, and she died on August 26, 2014. PML was confirmed on histologic analysis of brain tissue ...and positive results on PCR assay for JC virus DNA in brain tissue and cerebrospinal fluid ....
In our opinion, this case represents DMF-associated PML, since other immunosuppressive medications or coexisting medical conditions were absent. To our knowledge, this is the first reported case of compounded DMF–associated PML in a patient without severe lymphocytopenia, a situation that was previously thought to be unlikely.
Since the number of patients who are being treated with DMF is rapidly increasing after approval of delayed-release DMF (Tecfidera) as first-line treatment for relapsing–remitting multiple sclerosis, our case raises important questions with respect to safety monitoring. Although more than 100,000 patients with multiple sclerosis have been treated with Tecfidera since 2013, the safety profile for long-term treatment is unknown. On October 22, 2014, the first case of PML in a patient receiving Tecfidera was reported; this patient had persistent, severe lymphocytopenia. Our case shows that PML can develop during treatment with compounded DMF in patients in whom reduced lymphocyte counts are less severe than those in cases that have been reported previously.
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Dennis J. Nieuwkamp, M.D., Ph.D.
Jean-Luc Murk, M.D., Ph.D.
Charlotte H.P. Cremers, M.D.
University Medical Center Utrecht, Utrecht, the Netherlands
d.nieuwkamp@umcutrecht.nl
Joep Killestein, M.D., Ph.D.
VU University Medical Center, Amsterdam, the Netherlands
Marco C. Viveen, B.A.S.
Wim Van Hecke, M.D.
University Medical Center Utrecht, Utrecht, the Netherlands
Daphne W. Frijlink, M.D.
Medical Center Zuiderzee, Lelystad, the Netherlands
Mike P. Wattjes, M.D., Ph.D.
Bob W. van Oosten, M.D., Ph.D.
VU University Medical Center, Amsterdam, the Netherlands
[References and supplementary material omitted]
The letter can be seen
here.