Temporal profile of lymphocyte counts and relationship with infections with fingolimod therapy.
BACKGROUND
Reduction in peripheral blood lymphocytes is an expected pharmacodynamic outcome of fingolimod therapy.


OBJECTIVE
The objective of this article is to evaluate lymphocyte dynamics during and after fingolimod therapy and assess the relationship between lymphocyte counts and infections.


METHODS
Lymphocyte counts and their relationship with infections were evaluated in three multiple sclerosis (MS) populations: (Group A) FREEDOMS phase 3 core study group (n = 1272); (Group B) All Studies group (one phase 2 and two phase 3 studies, plus their extensions; n = 2315); and (Group C) Follow-up group (after fingolimod discontinuation; n = 538).


RESULTS
Administration of fingolimod 0.5 mg led to reductions in lymphocyte counts to a steady-state of 24%-30% of baseline values within two weeks, which remained stable while on therapy. Following fingolimod discontinuation, average counts exceeded the lower limit of normal range within six to eight weeks, and were 80% of baseline values by three months. In Group A, infection rates per patient-year were 1.4 with placebo and 1.0 in fingolimod-treated patients who had the lowest lymphocyte counts (< 0.2 × 10(9)/l). No evidence was seen for an increase in serious or opportunistic infections.


CONCLUSIONS
Fingolimod induces a rapid and reversible reduction in lymphocyte counts without an increase in infections relative to placebo. Because fingolimod reduces blood lymphocyte counts via redistribution in secondary lymphoid organs, peripheral blood lymphocyte counts cannot be utilized to evaluate the lymphocyte subset status of a patient.
Novartis Pharmaceuticals Corporation-NJ, USA.
G
G
Francis
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L
Kappos
P
P
O'Connor
W
W
Collins
D
D
Tang
F
F
Mercier
J A
JA
Cohen
D000293:Adolescent; D000328:Adult; D005260:Female; D000068876:Fingolimod Hydrochloride; D006801:Humans; D007166:Immunosuppressive Agents / Q000627:therapeutic use*; D007239:Infections / Q000453:epidemiology*; D018655:Lymphocyte Count; D008214:Lymphocytes / Q000187:drug effects*; D008297:Male; D008875:Middle Aged; D009103:Multiple Sclerosis / Q000188:drug therapy* / Q000276:immunology*; D011409:Propylene Glycols / Q000627:therapeutic use*; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D055815:Young Adult
D007166:Immunosuppressive Agents; D011409:Propylene Glycols; D000068876:Fingolimod Hydrochloride; D013110:Sphingosine
FREEDOMS; Fingolimod; TRANSFORMS; infection; lymphocyte count; multiple sclerosis; pooled analysis