Theragenomic medicine: First case of fumarate-linked progressive multifocal leukoencephalopathy (PML) in nonlymphopenic patient

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April 11, 2015 – Dutch clinicians report what they believe is the first case of progressive multifocal leukoencephalopathy (PML) after treatment with compounded dimethyl fumarate (DMF) in a patient without severe lymphocytopenia. This situation was “previously thought to be unlikely,” Dennis Nieuwkamp, MD, Department of Neurology, University Medical Center Utrecht, the Netherlands, told Medscape Medical News in a recent interview. “Our case suggests that lymphocyte numbers need not reflect the level of immune suppression, making us conclude that lymphocyte function is important, not merely lymphocyte number. This is clearly an area for future research,” Dr Nieuwkamp said. Dr Nieuwkamp and the PML in Dutch MS Patients Consortium describe the case in a letter to the editor in the New England Journal of Medicine on April 9.

The 64-year-old woman presented on July 18, 2014, 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 treatment of psoriasis since June 2012. Brain MRI showed multiple subcortical white matter lesions. PML IILeukocyte and lymphocyte counts were normal before DMF treatment but reached a nadir of 4000 cells and 792 cells/mm3, respectively, in June 2014. Cerebrospinal fluid (CSF) showed normal levels of leukocytes, protein, and glucose. At that time, a diagnosis of PML was considered, the clinicians say, but CSF was negative for JC virus (JCV) DNA. Treatment with DMF was discontinued, and the patient received the diagnosis of atypical ischemic stroke.

The patient experienced progressive hemiparesis and somnolence, and subsequent MRI showed rapid and widespread dissemination of lesions suggestive of PML–immune reconstitution inflammatory syndrome (IRIS). She initiated treatment with mefloquine, mirtazapine, and glucocorticoids; however, she continued to deteriorate and died. PML was confirmed on histologic analysis of brain tissue and positive results on polyermase chain reaction assay for JC virus DNA in brain tissue and CSF.

Remain Alert 

“In our opinion, this case represents DMF-associated PML, since other immunosuppressive medications or coexisting medical conditions were absent,” Dr Nieuwkamp and colleagues say. They note that the number of patients being treated with DMF is “rapidly increasing” after approval of delayed-release DMF (i.e, Dimethyl Fumarate (Tecfidera)) as a first-line treatment for relapsing-remitting multiple sclerosis (MS) and this case “raises important questions with respect to safety monitoring.” They caution that although more than 100,000 patients with MS have been treated with Tecfidera since 2013, the safety profile for long-term treatment is “unknown. DMF-related PML occurring in association with severe lymphocytopenia (<500 lymphocytes/mm3) prompted a recommendation by the American Food and Drug Administration (FDA) to monitor lymphocyte counts in patients receiving fumarates to help prevent opportunistic infections, such as PML. “Doctors treating patients with fumaric esters for MS or psoriasis should be alert of PML both in lymphopenic and in non-lymphopenic patients,” Dr Nieuwkamp told Medscape Medical News.

In a companion letter in the New England Journal of Medicine, Mark Novas, MD, from Biogen Idec, Cambridge, Massachusetts, and colleagues describe the 54-year-old woman with MS who was treated Tecfidera and died of complications related to aspiration pneumonia and PML with severe prolonged lymphocytopenia.

Catherine Falcetti, associate director, public affairs, at Biogen told Medscape Medical News, “The Tecfidera case that appears in the NEJM is not a new PML case. This is the report detailing the patient case we reported in October 2014, which was in the setting of prolonged, severe lymphopenia, a known risk factor for PML that can be monitored with complete blood count testing.”

 After the case was reported, the US Tecfidera label was updated to advise physicians to obtain a complete blood count, including lymphocyte count, before initiating Tecfidera, after 6 months, and every 6 to 12 months thereafter and to consider interrupting treatment if lymphocyte counts less than 0.5 × 109/L persist for more than 6 months, Falcetti said.

Dr Novas and colleagues note in their letter that in controlled and uncontrolled studies of MS patients, mean lymphocyte count decreased by about 30% during the first year of treatment with delayed-release DMF. The mean lymphocyte count then plateaued and remained above the lower limit of the normal range. Roughly 2% of patients had reduced lymphocyte counts (<500 cells/mm3) that persisted for more than 6 months. “Periodic monitoring of absolute lymphocyte counts to identify patients at increased risk for severe, prolonged lymphocytopenia and consideration of treatment interruption in these patients may mitigate the risk of PML. Studies to evaluate the effect of delayed-release DMF on lymphocyte subgroups are ongoing,” Dr Novas and colleagues write.

The information / correspondance  on the issue can be found here:

N Engl J Med. 2015;372:1474-1478.

Nieuwkamp Letter

Novas Letter

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About the Author
Joseph Gut - thasso Ph.D.; Professor in Pharmacology and Toxicology. Senior expert in theragenomic and personalized medicine and individualized drug safety. Senior expert in pharmaco- and toxicogenetics. Senior expert in human safety of drugs, chemicals, environmental pollutants, and dietary ingredients.
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