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.

Dimethyl fumarate selectively reduces memory T cells in multiple sclerosis patients

“…Our cohort included a wide age range, and age has previously been linked to DMF-induced lymphopenia (4). Therefore, we performed multiple linear regression models to account for age.…”

“…Selective depletion of Th1 and Th17 cells would be expected to be protective in MS and could contribute to the therapeutic effect of DMF. Nevertheless, despite the loss of CXCR3 + and CCR6 + cells among lymphopenic patients taking DMF, these patients have not shown a superior clinical response to the drug to date (4, 31)…”

“…In a small clinical cohort, half of patients treated for >12 months developed lymphocyte counts below the lower limit of normal; CD8+ T cells were preferentially lost (3). In another study, older patients (over 55 years of age), patients with lower baseline ALC, and patients with recent natalizumab (NTZ) exposure appeared to be at higher risk of lymphopenia (4). …”

Dimethyl fumarate in multiple sclerosis: latest developments, evidence and place in therapy

“…From what we know so far from the post-hoc analyses of the clinical trials and incidental retrospective reports, about 30% of DMFtreated MS patients develop a WHO grade I (>800 lymphocytes per μl) or grade II (>500 lymphocytes per μl) lymphocytopenia, and only ~2% a grade III (<500 lymphocytes per μl) lymphocytopenia, usually occurring within the first 6 months of treatment, according to clinical trial data. Various case series from outpatient clinics report differing frequencies of grade III lymphocytopenia ranging approximately from 6-10% after 6 months of DMF therapy, suggesting that there is a positive correlation for the risk of developing lymphocytopenia with increasing age (>55 years), longer disease duration and low lymphocyte counts prior to DMF initiation [Longbrake et al 2015a]. However, in order to gain more precise data on the dynamics of lymphocyte counts under DMF and the frequency of lymphocytopenia as the major risk factor for developing PML under DMF in a real-world setting, prospective monitoring studies with large cohorts are urgently needed.…”

Dimethylfumarate in the treatment of relapsing-remitting multiple sclerosis

“…И только в 4-10% случаев отмечалось снижение до 2-й степени токсичности показателей лейкоцитов (менее 3·10 9 /л) и в 4-7% случаев -до 3-й степени токсичности по-казателей лимфоцитов (менее 0,5·10 9 /л) [17]. Было замечено, что более высокий риск развития лимфо-пении имеют пациенты старше 55 лет, с более низ-кими исходными показателями и после лечения препаратом натализумаб [26].…”