Dimethyl fumarate-associated lymphopenia: Risk factors and clinical significance

Abstract

Background: Dimethyl fumarate (DMF), a disease-modifying therapy for multiple sclerosis (MS), causes lymphopenia in a fraction of patients. The clinical significance of this is unknown. Several cases of progressive multifocal leukoencephalopathy in lymphopenic fumarate-treated patients have raised concerns about drug safety. Since lymphocytes contribute to MS pathology, lymphopenia may also be a biomarker for response to the drug.

Objective: The objective of this manuscript is to evaluate risk factors for DMF-induced lymphopenia and drug failure in a real-world population of MS patients.

Methods: We conducted a retrospective cohort study of 221 patients prescribed DMF at a single academic medical center between March 2013 and February 2015.

Results: Grade 2-3 lymphopenia developed in 17% of the total cohort and did not resolve during DMF treatment. Older age (>55), lower baseline absolute lymphocyte count and recent natalizumab exposure increased the risk of developing moderate to severe lymphopenia while on DMF. Lymphopenia was not predictive of good clinical response or of breakthrough MS activity on DMF.

Conclusions: Lymphopenia develops in a significant minority of DMF-treated patients, and if grade 2 or worse, is unlikely to resolve while on the drug. Increased vigilance in lymphocyte monitoring and infection awareness is particularly warranted in older patients and those switching from natalizumab.

Keywords: Multiple sclerosis; dimethyl fumarate; drug safety; lymphopenia; progressive multifocal leukoencephalopathy.

Figure 1.

Patients developing lymphopenia remain lymphopenic throughout DMF treatment. Baseline ALCs (a) include nine patients on fingolimod. Longitudinal ALCs were monitored for patients developing grade 1 (b), grade 2 (c) and grade 3 (d) lymphopenia. Nine lymphopenic patients discontinued DMF; subsequent ALC recovery is plotted (e). Two patients who transitioned to fingolimod therapy are not shown. Dotted lines represent ALC 1000, 800, and 500, the cutoff values for grade 1, 2, and 3 lymphopenia, respectively. DMF: dimethyl fumarate; ALC: absolute lymphocyte count.

Figure 2.

Older age, lower baseline ALC and recent natalizumab exposure are risk factors for DMF-induced lymphopenia. Kaplan Meier analyses were used to model the cumulative incidence of DMF-induced grade 3 (a)–(d) or combined grade 2 + 3 (e)–(h) lymphopenia. P values represent the log rank test for differences between groups. DMF: dimethyl fumarate; ALC: absolute lymphocyte count; DMT: disease-modifying therapy. Quartile 1 ALC: 200–1380, quartile 2: 1381–1815; quartile 3: 1816–2400; quartile 4: 2401–5000.

Figure 3.

DMF-induced lymphopenia does not predict good clinical response to therapy. Kaplan Meier analyses were used to model the cumulative incidence of breakthrough MS activity, defined as a clinical relapse or evidence of active disease on MRI. P values represent the log rank test for differences between groups. DMF: dimethyl fumarate; MS: multiple sclerosis; MRI: magnetic resonance imaging; ALC: absolute lymphocyte count.