静脉用白消安预处理的造血干细胞移植患儿白消安暴露与结局的相关性。

Association between busulfan exposure and outcome in children receiving intravenous busulfan before hematopoietic stem cell transplantation.

机构信息

*Charles-Bruneau Cancer Center, CHU Sainte-Justine Research Center, Montreal, Canada; †Department of Pediatrics, Onco-Hematology Division, CHU Sainte-Justine, Montreal, Canada; ‡CANSEARCH Research Center, Faculty of Medicine, Geneva University, Geneva, Switzerland; §Clinical Pharmacology Unit, CHU Sainte-Justine Research Center, Montreal, Canada; ¶Department of Pharmacology, Faculty of Medicine, University of Montreal, Montreal, Canada; ‖Department of Pediatrics, Stem Cell Transplantation Unit, St Anna Children's Hospital, Vienna, Austria; **Department of Pediatrics Onco-Hematology Division, CHU Sainte-Justine Research Center, Montreal, Canada.

出版信息

Ther Drug Monit. 2014 Feb;36(1):93-9. doi: 10.1097/FTD.0b013e3182a04fc7.

DOI:10.1097/FTD.0b013e3182a04fc7

PMID:24061446

Abstract

BACKGROUND AND OBJECTIVE

Intravenous (IV) busulfan (Bu) combined with therapeutic drug monitoring-guided dosing is associated with better event-free survival (EFS), lower transplant-related mortality. But optimal target steady-state concentration (Css) of Bu in children undergoing hematopoietic stem cell transplantation (HSCT) remains unclear. This study aimed to evaluate the relation between Css of Bu and clinical outcomes in children receiving Bu before HSCT.

METHODS

This study includes 75 children receiving IV Bu in 16 doses, with first dose assigned based on age. Bu first-dose pharmacokinetic parameters were estimated from Bu plasma concentrations measured at 6 time points by high-performance liquid chromatography. Doses were adjusted at the fifth dose to a target Css of 600-900 ng/mL. Cumulative incidence of overall survival (OS), EFS, transplant-related mortality, acute graft-versus host disease (aGVHD), and other toxicities in relation to Css of Bu were analyzed using Kaplan-Meier curves in univariate and Cox's proportional hazards model in multivariate analysis.

RESULTS

After the first dose, median Css was 578 (325-1227) ng/mL. Forty-one patients had Bu IV dose increased by > 10%. Neutrophil and platelet recoveries, grade 2-4 aGVHD, and nonrelapse mortality (NRM) incidences were 90%, 91%, 12%, and 13%, respectively. Relapse incidence was 33%. Incidence of veno-occlusive disease, hemorrhagic cystitis, and lung toxicities were 13%, 24%, and 7%, respectively. OS and EFS were 70% and 58%. First-dose Bu Css >600 ng/mL was associated with a higher NRM (P < 0.001) and grade 2-4 aGVHD (P = 0.04), a lower EFS (P < 0.001), and OS (P = 0.001).

CONCLUSIONS

This study demonstrated a significant association between the first-dose pharmacokinetics of Bu and NRM, OS, and EFS. Bu therapeutic drug monitoring provides information that potentially influences outcomes of HSCT in pediatric patients.

摘要

背景与目的

静脉（IV）白消安（Bu）联合治疗药物监测指导剂量与更好的无事件生存（EFS）、更低的移植相关死亡率相关。但是，在接受造血干细胞移植（HSCT）的儿童中，Bu 的最佳稳态浓度（Css）目标仍不清楚。本研究旨在评估接受 HSCT 前接受 Bu 治疗的儿童的 Bu Css 与临床结局之间的关系。

方法

本研究纳入 75 例接受 16 剂 IV Bu 的儿童，首剂根据年龄分配。通过高效液相色谱法测量 6 个时间点的 Bu 血浆浓度，估算 Bu 首剂量药代动力学参数。在第 5 剂时将剂量调整至 600-900ng/mL 的目标 Css。使用 Kaplan-Meier 曲线进行单变量分析，使用 Cox 比例风险模型进行多变量分析，分析 Bu Css 与总生存（OS）、EFS、移植相关死亡率、急性移植物抗宿主病（aGVHD）和其他毒性的累积发生率之间的关系。

结果

首剂后，中位数 Css 为 578（325-1227）ng/mL。41 例患者 Bu IV 剂量增加>10%。中性粒细胞和血小板恢复、2-4 级 aGVHD 和非复发死亡率（NRM）的发生率分别为 90%、91%、12%和 13%。复发率为 33%。静脉阻塞性疾病、出血性膀胱炎和肺毒性的发生率分别为 13%、24%和 7%。OS 和 EFS 分别为 70%和 58%。首剂 Bu Css>600ng/mL 与较高的 NRM（P<0.001）和 2-4 级 aGVHD（P=0.04）、较低的 EFS（P<0.001）和 OS（P=0.001）相关。