[PD5.006] Prolonged Reduction in Circulating Lymphocytes after Discontinuation of FTY720 (Fingolimod): Possible Relationship to Duration of Therapy
Mark R. Keezer, Yves Lapierre, Igor Shames, David Haegert, Amit Bar-Or, Jack Antel, Montreal, QC, Canada
OBJECTIVE: Our goal was to determine the recovery rate of circulating lymphocytes following drug cessation in patients treated with FTY720 and to examine lymph node histology in a case with prolonged circulating lymphopenia. BACKGROUND: The sphingosine 1 phosphate receptor agonist FTY720 (fingolimod) inhibits re-circulation of CCR7 bearing lymphocytes that enter regional lymph nodes. Tedesco-Silva (2004) had reported that circulating lymphocyte numbers recovered within 4-6 weeks after drug cessation in non-MS individuals who received FTY720 for 3 months. DESIGN/METHODS: Serial circulating lymphocyte values were determined in 5 females taking part in the open-label extension phases of FTY720 clinical trials (1.25mg daily). Therapy was interrupted because of protocol defined criteria (lymphocytes <0.2 x109/L, increased liver enzymes, intercurrent disease). No one had relapses on or off therapy. RESULTS: Three patients (age 51/EDSS 6, 41/ 2 and 42/ 1) in the extension phase for 12, 14 and 54 months recovered normal lymphocyte values within 2 months. In a 4th patient (age 58/EDSS 1) on extension therapy for 54 months, lymphocyte counts remained depressed (0.3; normal = 0.8-1.2) 4 months after stopping therapy. Patient 5 (age 56/EDSS 1) stopped therapy after 33 months due to a lung lesion that was resected 1 month later. Her lymphocytes were 0.4 at the time of resection and remained 0.3-0.4 over the next 24 months. The lesion was a necrotizing non-tuberculous granuloma with no recurrence without subsequent treatment. Lymph nodes in the resected tissue were histologically unremarkable with no significant para-cortical expansion or follicular hyperplasia. CONCLUSIONS/RELEVANCE: Peripheral lymphocyte counts remained depressed beyond the currently expected time period in 2 patients following cessation of long-term FTY720 therapy. Regional lymph node architecture was preserved in the one available patient. Exploration of larger datasets will determine the true incidence of prolonged lymphopenia and whether time to recovery of circulating lymphocytes may provide a potential biomarker for guiding continued therapy.
Category - MS and Related Diseases - Clinical Science
Thursday, April 15, 2010 7:30 AM
Poster Discussion Session V: Multiple Sclerosis and Related Diseases: Drug Mechanisms (7:30 AM-12:00 PM)
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