Temporal profile of lymphocyte counts and relationship with infections with fingolimod therapy
Temporal profile of lymphocyte counts and relationship with infections with fingolimod therapy
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DOI：
10.1177/1352458513500551
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发表时间：
2014-04-01
影响因子：
5.8
通讯作者：
Cohen, J. A.
中科院分区：
文献类型：
--
作者：
Francis, G.;Kappos, L.;Cohen, J. A.
背景：外周血淋巴细胞减少是Fingolimod治疗的预期药效学结果。目的：本文的目的是评价Fingolimod治疗过程中和治疗后的淋巴细胞动力学，并评估淋巴细胞计数与感染的关系。方法：在三个多发性硬化症(MS)人群中评估淋巴细胞计数及其与感染的关系：(A组)自由阶段3核心研究组(n=1272)；(B组)所有研究组(1个阶段2和2个阶段3研究，加上他们的扩展；n=2315)和(C组)随访组(在Fingolimod停药后；结果：给予Fingolimod 0.5 mg可导致淋巴细胞计数在两周内下降到基线的24%-30%的稳定状态，在治疗期间保持稳定。Fingolimod停药后，平均计数在6-8周内超过正常范围下限，到3个月时达到基线的80%。在A组，服用安慰剂的患者年感染率为1.4，淋巴细胞计数最低的Fingolimod患者的年感染率为1.0(<；0.2×10(9)/L)。未发现严重或机会性感染增加的证据。结论：与安慰剂相比，Fingolimod导致淋巴细胞数量迅速和可逆下降，而感染没有增加。由于Fingolimod通过在次级淋巴器官中的重新分布来减少血淋巴细胞计数，因此不能用外周血淋巴细胞计数来评估患者的淋巴细胞亚群状态。
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 x 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.