Assessing the Incidence of Lymphopenia with the Use of Dimethyl Fumarate in Multiple Sclerosis

Background: Dimethyl fumarate (DMF) is an oral medication approved for the treatment of relapsing Multiple Sclerosis (MS). In pivotal MS studies involving DMF, there was a mean decrease of approximately 30% in absolute lymphocyte count (ALC). Additionally, approximately 5% of patients in these studies developed grade 3 lymphopenia (ALC<500). It has been postulated that the nuclear factor erythroid 2-related factor 2 (Nrf2) pathway may be implicated in DMF-associated lymphopenia, yet the clinical significance of this is yet to be established.

Objectives: The aim of our study was to assess the incidence of lymphopenia among MS patients taking DMF under routine care and to stratify rates according to grades of severity in order to glean insight for clinical application.

Methods: A retrospective chart review was conducted on all patients seen in our MS clinic who were prescribed DMF between March 2013 and March 2015 under routine clinical care.  Those who began treatment and had available pre- and post-dosing complete blood counts (CBC) that included levels of ALC were included in analysis. Patients were excluded if their pre-CBCs occurred more than 6 months prior to starting DMF. In this study, lymphopenia was classified by severity into grade I (ALC 800-1000), grade II (ALC 500-799), and grade III (ALC <500).

Results: A total of 311 patients were prescribed DMF. Of these, 210 met criteria for inclusion. The average pre-CBC ALC was 2203. This included 7 patients who started DMF with pre-existing grade I, II, or III lymphopenia. The average post-CBC was 1508. This included patients who had discontinued DMF. Therefore, on average there was a decrease in ALC by 31.5% from pre-CBC to any post-CBC. There were 71 patients (33.8%) who experienced lymphopenia of any grade after starting DMF. Grade I lymphopenia occurred in 49 (23.3%); grade II lymphopenia occurred in 33 (15.7%); and grade III lymphopenia occurred in 10 patients (4.8%).

Conclusions: Results from our study are consistent with previously published data. However, studies are scarce, and there remains limited understanding of the mechanism by which DMF-related lymphopenia occurs and its role in clinical sequelae, such as infection. There is a growing understanding of DMF’s action on haematopoietic stem cell (HSC) function which may help elucidate this role: by up-regulating Nrf2, DMF may affect the cyclin D-dependent pathway in cell-cycle regulation and disrupt the balance between HSC quiescence and self-renewal, potentially impacting ALC. However, further studies are needed to investigate this, as well as to assess the incidence of lymphopenia with DMF use and its clinical implications in patients with MS.