Lymphocyte reconstitution after DMF discontinuation in clinical trial and real-world patients with MS

Abstract

BackgroundDelayed-release dimethyl fumarate (DMF) has demonstrated robust efficacy in treating patients with relapsing-remitting multiple sclerosis. Decreases in absolute lymphocyte count (ALC) are a well-known pharmacodynamic effect of DMF treatment, but lymphocyte recovery dynamics are not well characterized after discontinuation of DMF.MethodsData sources included the Biogen DMF integrated clinical trial data set, a retrospective US chart abstraction study, and data from MSBase. We assessed rate and time course of lymphocyte reconstitution after DMF discontinuation.ResultsThe majority of patients who developed lymphopenia while treated with DMF and subsequently discontinued treatment experienced ALC reconstitution. The median time to reach ALC ≥0.8 × 109/L was 2–4 months after discontinuation for patients treated in real-world data sets; the median time to reach ALC ≥0.91 × 109/L was 2 months after discontinuation in DMF clinical trials. Severity of lymphopenia on treatment and decline in ALC within the first 6 months did not affect the ALC reconstitution rate after DMF discontinuation; rather, on-treatment lymphopenia duration influenced the reconstitution rate. In patients with severe, prolonged lymphopenia for ≥3 years, lymphocyte reconstitution to ≥0.91 × 109/L was 12–18 months vs 2–3 months in patients with lymphopenia persisting <6 months.ConclusionsThe majority of patients who discontinued DMF due to lymphopenia experienced ALC reconstitution within 2–4 months following DMF discontinuation. This may help guide clinicians in managing patients who develop lymphopenia during DMF treatment. Prolonged lymphopenia on DMF treatment is associated with slow lymphocyte recovery after DMF discontinuation.

Safety and efficacy of delayed-release dimethyl fumarate in patients with relapsing-remitting multiple sclerosis: 9 years’ follow-up of DEFINE, CONFIRM, and ENDORSE

“…Patients with severe prolonged lymphopenia (i.e., severe lymphopenia that lasted for ⩾6 months) were analyzed separately ( N = 38) as this cohort is not considered representative of current DMF use based on current ALC monitoring recommendations; these data have been previously presented. 7…”

“…In addition, it has been demonstrated that reconstitution rate is dependent upon duration of lymphopenia, specifically if lymphopenia persists >6 months, the estimated rate of reconstitution is significantly slower compared with patients with less persistent lymphopenia. 7…”

Persisting lymphopenia and dimethyl fumarate: A clinical commentary

“…Clinical trial and real-world data demonstrate that also grade III lymphopenia is usually reversible, with the duration of lymphopenia before treatment cessation as a major determinant of the interval to ALC recovery. 3 In patients with severe, prolonged lymphopenia for ⩾3 years, lymphocyte reconstitution was longer (12-18 months) than in patients with lymphopenia persisting for < 6months (2-3 months). In the reported patient, grade III lymphopenia was detected at 6 months after treatment start and treatment was stopped after 12 months according to current guidelines.…”

“…In the clinical study program, no association of lymphocyte recovery and early drops of ALC within the first 6 months on treatment were observed. 3 Yet, higher incidence of prolonged and severe lymphopenia in patients with early ALC decrease argues for frequent laboratory testing; the European label was recently updated to recommend enhanced vigilance in patients with lymphopenia. 4 This is of importance considering recent population-based data on incomplete adherence to laboratory testing with potential sex differences.…”

Persistent severe lymphopenia 5 years after dimethyl fumarate discontinuation

“…6 Interestingly, duration of therapy once grade III lymphopenia has developed is an important factor in lymphocyte reconstitution rate 6,9 A study revealed that the majority of patients who discontinued DMF within 6 months of grade III lymphopenia onset demonstrated lymphocyte reconstitution above the lower limit of normal (⩾0.91 × 10 9 /L) within 2-4 months following therapy discontinuation whereas patients who remained on DMF for 3 years after grade III lymphopenia onset required 12-18 months on average for lymphocyte reconstitution after DMF cessation. 9 The importance and implications of lymphopenia in the setting of DMF therapy may not be fully appreciated, but a persistent low ALC is a risk factor for acquiring opportunistic infections, including progressive multifocal leukoencephalopathy (PML). 5 Here, we present a patient who developed grade III lymphopenia within 6 months of DMF initiation, and despite treatment cessation 6 months later.…”