Characterizing absolute lymphocyte count profiles in dimethyl fumarate-treated patients with MS: Patient management considerations

Abstract

Background: Delayed-release dimethyl fumarate (DMF), indicated for the treatment of patients with relapsing-remitting multiple sclerosis (MS), is a disease-modifying therapy with potential immunomodulatory and neuroprotective effects. In clinical trials, DMF was associated with reduced white blood cell and absolute lymphocyte counts. Current US prescribing information recommends obtaining a complete blood count, including absolute lymphocyte count (ALC), before initiating and during DMF treatment.

Methods: We conducted an integrated analysis of phase 2b/3/long-term extension studies of DMF in MS (N = 2,470) to characterize ALC profiles.

Results: Mean ALCs decreased by 30% during the first year and then plateaued, remaining above the lower limit of normal (LLN). Among patients treated ≥6 months (N = 2,099), 2.2% experienced ALCs <500 mm³ persisting ≥6 months. ALCs remained ≥LLN in 84% and 76% of patients during the first 6 and 12 months, respectively; of these, 0.1% and 0%, respectively, developed ALCs <500 mm³ persisting ≥6 months at any time. Evidence of ALC improvement following DMF discontinuation was observed. DMF efficacy was not substantially different in patients with and without lymphopenia.

Conclusion: Lymphocyte monitoring provides effective means for early identification of patients at risk for developing severe, prolonged lymphopenia.

Figure 1.. Mean ALCs (±SE) throughout time

(A) Patients treated with lower doses of DMF^a, DMF 240 mg bid, or DMF 240 mg tid. (B) Patients with ALCs <500 mm³ persisting ≥6 months vs all other patients. ALC = absolute lymphocyte count; BL = baseline; DMF = dimethyl fumarate; LLN = lower limit of normal. ^aDMF, delayed-release DMF (also known as gastro-resistant DMF). ^bBaseline (week 0) n includes all patients for whom a baseline ALC value was available. ^cMean ALCs throughout time are presented out to approximately 5 years (week 240), as this is the minimum follow-up for patients remaining on study in ENDORSE.

Figure 2.. ALCs following treatment discontinuation in 9 patients with ALCs <500 mm³ for at least 6 months

ALC = absolute lymphocyte count; DMF = dimethyl fumarate; LLN = lower limit of normal. ^aDMF, delayed-release DMF (also known as gastro-resistant DMF).

Figure 3.. ARR reduction at 2 years in patients with and without lymphopenia in DEFINE and CONFIRM

Results represent ARR reductions in patients in the DMF bid group with lymphopenia (at least 1 ALC aDMF, delayed-release DMF (also known as gastro-resistant DMF). ^bBased on negative binomial regression, adjusted for baseline EDSS score (≤2.0 vs >2.0), baseline age (<40 vs ≥40 years), region, and number of relapses in the 1 year before study entry.