Effect of cladribine tablets on lymphocyte reduction and repopulation dynamics in patients with relapsing multiple sclerosis
Effect of cladribine tablets on lymphocyte reduction and repopulation dynamics in patients with relapsing multiple sclerosis
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DOI：
10.1016/j.msard.2019.01.038
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发表时间：
2019-04-01
影响因子：
4
通讯作者：
Dangond, Fernando
中科院分区：
文献类型：
--
作者：
Comi, Giancarlo;Cook, Stuart;Dangond, Fernando
背景资料：多发性硬化患者的免疫重建疗法（IRT）用于短期、间歇性治疗期，以诱导免疫重置并允许随后的无治疗期。克拉屈滨片被认为是一种IRT，可导致CD 19（+）B细胞和T细胞的选择性和短暂性减少，随后重建适应性免疫功能。目的：描述2年生存期和随后2年生存期延长研究以及PREMIERE登记研究汇总数据中长期淋巴细胞计数变化的特征方法：数据来自随机分配至安慰剂组（n= 435）或克拉屈滨片10 mg组的患者（MAVENCLAD（R）; 2年内累积剂量为3.5 mg/kg，称为克拉屈滨片剂3.5 mg/kg; n= 685），包括在PREMIERE登记研究中花费的时间，以提供长期随访数据。该研究调查了首次给药后312周的绝对淋巴细胞计数（ALC）和240周的B和T细胞亚群，患者接受安慰剂或克拉屈滨片剂3.5 mg/kg，作为两个短期给药方案。在每个治疗年的第1个月和第2个月开始时每周进行一次治疗（4或5天），随后不再进行进一步的积极治疗。克拉屈滨片3.5 mg/kg治疗导致B和T淋巴细胞选择性减少。在第1年和第2年，淋巴细胞在治疗后不久开始恢复。到第84周，即第2年克拉屈滨片剂末次给药后约30周，中位ALC恢复至正常范围，CD 19（+）B细胞恢复至阈值。到第96周（第2年克拉屈滨片剂末次给药后约43周），中位CD 4（+）T细胞计数恢复至阈值。中位CD 8（+）细胞计数从未下降到阈值以下。结论：这些结果显示了克拉屈滨片3.5 mg/kg治疗后淋巴细胞计数变化的动力学。免疫细胞再增殖结果提供了克拉屈滨片剂可能代表一种形式的IRT的进一步证据。
Background: Immune reconstitution therapies (IRT) for patients with multiple sclerosis are used for short, intermittent treatment periods to induce immune resetting and allow subsequent treatment-free periods. Cladribine tablets are postulated to be an IRT that causes selective and transient reductions in CD19(+) B cells and T cells, followed by reconstitution of adaptive immune function.Objective: To characterize long-term lymphocyte count changes in pooled data from the 2-year CLARITY and subsequent 2-year CLARITY Extension studies, and the PREMIERE registry (Long-term CLARITY cohort).Methods: Data from patients randomized to placebo (n= 435) or cladribine tablets 10 mg (MAVENCLAD (R); 3.5 mg/kg cumulative dose over 2 years, referred to as cladribine tablets 3.5 mg/kg; n= 685) in CLARITY or CLARITY Extension, including time spent in the PREMIERE registry were pooled to provide long-term follow-up data. The study investigated absolute lymphocyte counts (ALC) up to 312 weeks and B and T cell subsets up to 240 weeks after the first dose, in patients receiving placebo or cladribine tablets 3.5 mg/kg administered as two short (4 or 5 days) weekly treatments at the start of months 1 and 2 in each treatment year, followed by no further active treatment.Results: Treatment with cladribine tablets 3.5 mg/kg resulted in selective reductions in B and T lymphocytes. Lymphocyte recovery began soon after treatment in each of years 1 and 2. Median ALC recovered to the normal range and CD19(+) B cells recovered to threshold values by week 84, approximately 30 weeks after the last dose of cladribine tablets in year 2. Median CD4(+) T cell counts recovered to threshold values by week 96 (approximately 43 weeks after the last dose of cladribine tablets in year 2). Median CD8(+) cell counts never dropped below the threshold value.Conclusion: These results show the dynamics of lymphocyte count changes following treatment with cladribine tablets 3.5 mg/kg. The immune cell repopulation results provide further evidence that cladribine tablets may represent a form of IRT.