Lymphocyte decline and reconstitution after discontinuation in patients with severe, prolonged lymphopenia treated with delayed-release dimethyl fumarate

Objective: Examine the dynamics and clinical implications of on-treatment absolute lymphocyte count (ALC) decline, and post-treatment ALC reconstitution, in patients treated with dimethyl fumarate (DMF) for relapsing-remitting multiple sclerosis (RRMS). Background: DMF demonstrated favorable benefit-risk in RRMS patients, with no observed increase of infections, aside from rare PML cases. The DMF label recommends considering treatment interruption for patients with severe, prolonged lymphopenia (ALC 9 /L ≥6 months). Design/Methods: An integrated analysis of the Phase 2b, Phase 3 (DEFINE/CONFIRM) and extension (ENDORSE) DMF studies was conducted. Data from first DMF exposure were analyzed. ALCs were assessed at weeks 4, 8, 12, and every 12 weeks thereafter, and patients categorized by ALCs accordingly. Results: The analysis population comprised 2513 patients. Among 2470 patients with any on-treatment ALC, mean ALC decreased ~30% during year 1 before stabilizing above the lower limit of normal (0.91×10 9 /L). Incidence rate per patient-year of serious infection (0.01) and serious herpes zoster ( 9 /L, 51% (31/61) developed severe, prolonged lymphopenia. Of 53 (2.1%) patients who developed severe, prolonged lymphopenia, most (44/53, 83%) were ≤3 years of initiating DMF. Of these, 34 continued treatment for median (range) 72 (16–97) months before discontinuation, with ALCs followed for ≥6 months post-DMF. After 6 months post-DMF, 41% (14/34) had ≥1 ALC ≥0.8×10 9 /L, and 24% (8/34) had ≥1 ALC ≥0.91×10 9 /L. Conclusions: Lymphocyte decline is well-characterized during long-term (up to 10 years) DMF treatment. No increased incidence of serious or opportunistic infection was observed. ALCs generally increased after discontinuation following severe lymphopenia. Monitoring ALC is an effective way to identify patients at risk for prolonged lymphopenia. Study Supported by: Biogen Disclosure: Dr. Fox has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Received compensation for serving as consultant or speaker from Allozyne, Avanir, Biogen Idec, Novartis, Questcor, and Teva Pharmaceutical Industries. Dr. Fox has received research support from Biogen (clinical trial contracts) and Novartis (research study support). Dr. Chan has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Bayer, Biogen, Genzyme, Merck, Novartis, Roche, Sanofi-Aventis, Teva Neuroscience, UCB. Dr. Chan has received research support from Genzyme and UCB. Dr. Gold has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Teva Pharmaceutical Industries Ltd., Biogen Idec, Bayer Schering Pharma, and Novartis. Dr. Gold has received personal compensation in an editorial capacity for Therapeutic Advances in Neurological Diseases, Experimental Neurology and the Journal of Neuroimmunology. Dr. Gold has received research support from Teva Pharmaceutical Industries Ltd., Biogen Idec, Bayer Schering Pharma, Genzyme, Merck Serono, and Novartis. Dr. Phillips has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with consulting fees from Acorda, Biogen, Genentech, Genzyme, Merck Serono, Sanofi-Aventis, and Xenoport. Dr. Yang has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with employee of and holds stock/stock options in Biogen. Dr. Yang holds stock and/or stock options in employee of and holds stock/stock options in Biogen, which sponsored research in which Dr. Yang was involved as an investigator. Dr. Yang holds stock and/or stock options in employee of and holds stock/stock options in Biogen. Dr. Liu has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Employee of Biogen. Dr. Liu holds stock and/or stock options in Holds stock/stock options in Biogen. Dr. Chalkias has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Employee of and holds stock/stock options in Biogen. Dr. Chalkias holds stock and/or stock options in Employee of and holds stock/stock options in Biogen, which sponsored research in which Dr. Chalkias was involved as an investigator. Dr. Chalkias holds stock and/or stock options in Employee of and holds stock/stock options in Biogen. Dr. Mehta has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Employee of and holds stock/stock options in Biogen. Dr. Mehta holds stock and/or stock options in Employee of and holds stock/stock options in Biogen, which sponsored research in which Dr. Mehta was involved as an investigator. Dr. Mehta holds stock and/or stock options in Employee of and holds stock/stock options in Biogen. Dr. Miller has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with employee of and holds stock/stock options in Biogen. Dr. Miller holds stock and/or stock options in employee of and holds stock/stock options in Biogen, which sponsored research in which Dr. Miller was involved as an investigator. Dr. Miller holds stock and/or stock options in employee of and holds stock/stock options in Biogen.