Dimethyl fumarate (DMF) is an oral drug approved for Relapsing Multiple Sclerosis (RMS) patients. Grade III lymphopenia is reported in 5-10% DMF-treated patients. Data on lymphocyte count (ALC) recovery after DMF withdrawal following prolonged lymphopenia are still scarce.

To characterize ALC recovery and to identify predictors of slower recovery after DMF interruption.

Multicenter data from RMS patients who started DMF and developed lymphopenia during treatment were collected. In patients with grade II-III lymphopenia, ALCs were evaluated from DMF withdrawal until reaching lymphocyte counts > 800/mm.

Among 1034 patients who started DMF, we found 198 (19.1%) patients with lymphopenia and 65 patients (6.3%) who discontinued DMF due to persistent grade II-III lymphopenia. Complete data were available for 51 patients. All patients recovered to ALC > 800 cells/mm with a median time of 3.4 months. Lower ALCs at DMF suspension (HR 0.98; p = 0.005), longer disease duration (HR 1.29; p = 0.014) and prior exposure to MS treatments (HR 0.03; p = 0.025) were found predictive of delayed ALC recovery.

ALC recovery after DMF withdrawal is usually rapid, nevertheless it may require longer time in patients with lower ALC count at DMF interruption, longer disease duration and previous exposure to MS treatments, potentially leading to delayed initiation of a new therapy.