MS Speaks

From the New England Journal of Medicine, April 8, 2015. There is another letter in the same issue about a psoriasis patient who also died of PML while taking Tecfidera. It will be posted below in another message window.

PML in a Patient with Lymphocytopenia Treated with Dimethyl Fumarate

To the Editor:

We report the case of a 54-year-old woman with multiple sclerosis who was treated with delayed-release dimethyl fumarate (DMF; Tecfidera, Biogen Idec) and who died on October 13, 2014, from complications related to aspiration pneumonia and progressive multifocal leukoencephalopathy (PML) with severe, prolonged lymphocytopenia.

The patient, who had received the diagnosis of multiple sclerosis in 1996 and had been treated with glatiramer acetate, was randomly assigned to the placebo group in the 2-year Determination of the Efficacy and Safety of Oral Fumarate in Relapsing–Remitting Multiple Sclerosis (DEFINE) trial. She subsequently received delayed-release DMF (at a dose of 240 mg three times daily) for 4.5 years in the open-label extension study. Twelve months after the initiation of delayed-release DMF, severe lymphocytopenia (lymphocyte count, 290 to 580 cells per cubic millimeter) developed and persisted for 3.5 years.

Although the patient had no clinical disease activity since the first month of active treatment, she presented with new neurologic signs and symptoms consistent with a relapse in multiple sclerosis (severe gait disorder, speech disorder, and difficulties in left arm coordination) on August 11, 2014. Her condition did not improve with the administration of intravenous methylprednisolone (1 g once daily on August 11 to 13, 2 g once daily on August 20 to 22, and 2 g once daily on September 20 to 22) and plasmapheresis for the suspected relapse (5 courses, 1 per day; September 26 to 30). Delayed-release DMF treatment was discontinued on August 23. PML was diagnosed on the basis of results on magnetic resonance imaging ... and positive results on polymerase-chain-reaction assay for JC virus DNA in cerebrospinal fluid obtained by means of lumbar puncture on October 7. The patient had received no previous immunosuppressant drugs or natalizumab.

Since delayed-release DMF was approved in the United States in March 2013, more than 135,000 patients with multiple sclerosis have been treated, representing approximately 112,000 person-years of exposure as of December 31, 2014. As of September 26, 2014, a total of 3112 patients with multiple sclerosis had received delayed-release DMF in clinical trials, representing approximately 7429 person-years of exposure. To date, there has been no overall increase in the risk of serious infection, including other opportunistic infections. However, delayed-release DMF can cause lymphocytopenia, a known risk factor for PML. Thus, a contributory role of lymphocytopenia in this patient cannot be ruled out.

In controlled and uncontrolled studies involving patients with multiple sclerosis, there was a decrease in the mean lymphocyte count of approximately 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 ....

 Approximately 2% of patients had reduced lymphocyte counts (<500 cells per cubic millimeter) that persisted for more than 6 months.In this subgroup of patients, which was identifiable within the first year of treatment, lymphocyte counts of less than 500 per cubic millimeter were generally maintained with continued therapy.... 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.

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Thorsten Rosenkranz, M.D.
Asklepios Klinik Saint Georg, Hamburg, Germany
Mark Novas, M.D.
Biogen Idec, Cambridge, MA
mark.novas@biogenidec.com

[References omitted]

The letter can be seen here.