Dimethyl Fumarate (DMF) has emerged as an effective therapy for relapsing-remitting multiple sclerosis (RR-MS). Common side effects include gastrointestinal disturbance and flushing, almost one third of patients withdrew from the pivotal phase III study. Reduction in absolute white cell and lymphocyte counts have been associated with therapy. A much rarer, life-threatening consequence of DMF-associated lymphopenia is progressive multifocal leukoencephalopathy (PML). Older patients and those who experience severe (<0.5 x 109 cells/litre) and prolonged lymphopenia (6 months or longer) are deemed to be at greatest risk.The evidence for prolonged lymphopenia as the sole factor for PML in DMF therapy is, however, not yet unequivocal, leading to a degree of historical variation in practice. Although the licensing summary suggests halting DMF at the threshold of prolonged lymphopenia, evidence on rate of recovery from lymphopenia is lacking.
To enable clinicians to accurately counsel patients commencing DMF therapy using evidence-based recommendations. Specifically, the generation of an estimated treatment failure rate and reasons for this. Beyond this, the rate of recovery from severe lymphopenia (<0.5x109 cells/litre) following termination of therapy will also be observed.
Retrospective analysis of patient data in two NHS foundation trusts (Hull University Hospitals and York Teaching Hospital). The following data was collected from patient databases and anonymised: Sex, Date of commencement of therapy, Date of RRMS diagnosis, Change to DMF therapy, Lymphocyte count at baseline and during therapy, Reason for halting or altering DMF regime (i.e. lymphopenia, adverse events or patient/clinician concerns). SPSS was used for data analysis.
N=275. 36.7% of patients terminated DMF treatment, with 52.9% doing so due to side effects (predominantly gastrointestinal and flushing) and 11.5% due to lymphopenia. No PML cases were reported. 12% of patients experienced at least one episode of lymphopenia. Mean months to 2 or more episodes of lymphopenia was 21.39 (SD 11.42) with 29% experiencing lymphopenia for over 6 months. Of those with lymphopenia, mean days to return to normal lymphocyte count was 131 (SD 95.6). Baseline lymphocyte counts were 0.5 x 109 cells/litre lower in those who went on to experience lymphopenia (P= 0.000081).
Prolonged lymphopenia remains a relatively uncommon adverse effect in most patients taking DMF. The most common cause of treatment failure is side effects. Stopping therapy is likely to be the most effective manner of correcting a prolonged lymphopenia, however this study was unable to accurately estimate rate of correction due to variation in sampling frequency. In line with others, this study suggests that lower baseline lymphocyte counts are associated with lymphopenia during DMF treatment and rigorous monitoring is especially important in this cohort.