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PML during dimethyl fumarate treatment of multiple sclerosis: how does lymphopenia matter?

Neurology. 2016 June 24. DOI: http:/​/​dx.​doi.​org/​10.​1212/​WNL.​0000000000002900. pii: 10.1212/WNL.0000000000002900. [Epub ahead of print]

Authors/Editors: Lehmann-Horn K, Horst P, Grein P, Leppmeier U, Teuber-Hanselmann S, Hemmer B, Berthele A.
Publication Date: 2016



Progressive multifocal leukoencephalopathy (PML), which is caused by the John Cunningham virus (JCV), is a rare brain disease that results in persistent neurologic disability or death. In multiple sclerosis (MS), PML is a major concern in patients treated with natalizumab, and treatment duration (more than 2 years), preceding immunosuppression, and JCV antibody serostatus are identified risk factors, which are used for risk stratification, patient monitoring, and counseling. In 2013 and 2014, dimethyl fumarate (DMF) was approved for the treatment of relapsing-remitting forms of MS in the United States and Europe (Tecfidera, Biogen), and was—as an oral drug with a presumably favorable safety profile—quickly adopted by patients and doctors. Interestingly, the drug causes lymphopenia to a variable extent. While the underlying mechanism is largely unknown, lymphopenia seems not to be a prerequisite for the drug’s efficacy on MS disease activity.1 Similar to fumaric acid ester compounds used in the treatment of psoriasis, DMF is now noted as another drug conferring the risk of PML to patients.2 As a consequence, the US Food and Drug Administration has released a safety announcement,3 and recently the European Medicines Agency (EMA) has issued updated safety recommendations to minimize PML risk.4 Both agencies suggest that Common Terminology Criteria for Adverse Events grade 3 lymphopenia (below 500/mL) prolonged for more than 6 months is a relevant risk factor, and the EMA recommends complete blood counts every 3 months to identify patients at risk. However, we saw a case of PML indicating that this recommendation is insufficient to protect patients with MS on DMF from developing the disease.

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