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Impact of alemtuzumab pharmacokinetics on T-cell dynamics, graft-versus-host disease and viral reactivation in patients receiving allogeneic stem cell transplantation with an alemtuzumab-based T-cell-depleted graft.
Transplant Immunology ( IF 1.6 ) Pub Date : 2019-06-14 , DOI: 10.1016/j.trim.2019.06.001
Floris C Loeff 1 , Esther H M van Egmond 1 , Dirk J A R Moes 2 , Charissa Wijnands 1 , Peter A Von Dem Borne 1 , Hendrik Veelken 1 , J H Frederik Falkenburg 1 , Inge Jedema 1 , Constantijn J M Halkes 1
Affiliation  

Administration of alemtuzumab (targeting the CD52 antigen) to the patient (in-vivo) or to the graft (in-vitro) before allogeneic stem cell transplantation (alloSCT) decreases the incidence of graft-versus-host disease (GvHD). Effectiveness of this treatment relies on depletion of donor T cells. Currently, no data are available on alemtuzumab pharmacokinetics and pharmacodynamics in patients who received combined in-vivo and in-vitro alemtuzumab-based T-cell depletion. In this prospective study, we analyzed alemtuzumab pharmacokinetics and its effect on the circulating T cells in 36 patients who received an allogeneic T-cell-depleted graft by addition of 20 mg alemtuzumab “to the bag” with or without prior alemtuzumab (30 mg cumulative dose intravenously) as part of the conditioning regimen. Effective T-cell depletion was shown for all patients, even though alemtuzumab plasma levels varied considerably. Peak alemtuzumab levels were observed directly after graft infusion and were not associated with the number of circulating T cells pre-infusion, but with plasma volumes of the patients. All patients engrafted, confirming feasibility of this transplantation protocol. Only three patients with low alemtuzumab levels developed acute GvHD (grade II in 2 patients and grade III in 1 patient). Persistence of circulating alemtuzumab at 3 weeks after transplantation had prevented reconstitution of CD52-positive T cells when alemtuzumab plasma levels were above 0.7 μg/mL. However, overall T-cell reconstitution did not correlate with the levels of alemtuzumab exposure, due to early reconstitution of CD52-negative alemtuzumab-resistant T cells. The protective effect of these cells likely explains the low incidence of Epstein-Barr-virus- and cytomegalovirus-related disease despite circulating alemtuzumab.



中文翻译:

接受基于alemtuzumab的T细胞贫乏的异基因干细胞移植的患者,Alemtuzumab药代动力学对T细胞动力学,移植物抗宿主病和病毒激活的影响。

在同种异体干细胞移植(alloSCT)前向患者(体内)或移植物(体外)施用阿仑单抗(靶向CD52抗原)可降低移植物抗宿主病(GvHD)的发生率。这种治疗的有效性取决于供体T细胞的消耗。目前,尚无关于接受基于体内和体外基于alemtuzumab的T细胞联合排除的患者的alemtuzumab药代动力学和药效学数据。在这项前瞻性研究中,我们分析了36名接受同种异体T细胞缺失移植物的患者的Alemtuzumab药代动力学及其对循环T细胞的影响,方法是在有或没有事先Alemtuzumab的情况下向袋中添加20 mg Alemtuzumab(累积30 mg静脉注射)作为调理方案的一部分。显示所有患者的有效T细胞耗竭,即使alemtuzumab血浆水平变化很大。移植后直接观察到阿仑单抗的峰值水平,与输注前循环T细胞的数量无关,但与患者的血浆容量有关。所有患者均被植入,证实了该移植方案的可行性。仅有3名阿仑单抗水平低的患者出现了急性GvHD(2名患者为II级,1名患者为III级)。当alemtuzumab血浆水平高于0.7μg/ mL时,移植后3周持续循环的alemtuzumab阻止了CD52阳性T细胞的重建。但是,由于CD52阴性的耐Alemtuzumab的T细胞的早期重建,总体T细胞的重建与Alemtuzumab的暴露水平不相关。

更新日期:2019-06-14
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