Association of busulfan exposure with survival and toxicity after haemopoietic cell transplantation in children and young adults: a multicentre, retrospective cohort analysis.
Association of busulfan exposure with survival and toxicity after haemopoietic cell transplantation in children and young adults: a multicentre, retrospective cohort analysis.
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DOI：
10.1016/s2352-3026(16)30114-4
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发表时间：
2016-11
影响因子：
24.7
通讯作者：
Boelens, Jaap Jan
中科院分区：
文献类型：
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作者：
Bartelink, Imke H.;Lalmohamed, Arief;van Reij, Elisabeth M. L.;Dvorak, Christopher C.;Savic, Rada M.;Zwaveling, Juliette;Bredius, Robbert G. M.;Egberts, Antoine C. G.;Bierings, Marc;Kletzel, Morris;Shaw, Peter J.;Nath, Christa E.;Hempel, George;Ansari, Marc;Krajinovic, Maja;Theoret, Yves;Duval, Michel;Keizer, Ron J.;Bittencourt, Henrique;Hassan, Moustapha;Gungor, Tayfun;Wynn, Robert F.;Veys, Paul;Cuvelier, Geoff D. E.;Marktel, Sarah;Chiesa, Robert;Cowan, Morton J.;Slatter, Mary A.;Stricherz, Melisa K.;Jennissen, Cathryn;Long-Boyle, Janel R.;Boelens, Jaap Jan
静脉注射白消安（IV-白消安）结合治疗药物监测来指导剂量，可改善同种异体造血细胞移植（allo-HCT）后的结局。估计白消安暴露量的最佳方法以及儿童/年轻人的最佳暴露量仍不清楚。因此，我们评估了三种估计 IV-Bu 暴露量（表示为曲线下累积面积；AUC）和相关白消安 AUC 与接受异基因 HCT 的儿童/年轻人临床结果的方法。在这项回顾性分析中，纳入了来自 15 个中心接受基于白消安的预处理方案的患者（0.1-30.4 岁）。累积 AUC 是通过使用非线性混合效应模型 (AUCNONMEM) 的数值积分、非房室分析（AUC0-无穷大和 AUC 至剂量间隔 AUC0-tau 结束）以及各个中心使用各种方法 (AUCcenter) 来计算的。感兴趣的主要结果是无事件生存期（EFS）。其他感兴趣的结局包括总生存期、移植失败、复发、移植相关死亡率 (TRM)、急性毒性（静脉闭塞病 (VOD) 和/或急性移植物抗宿主病 (aGvHD)、慢性 GvHD (cGvHD) 和无 cGVHD 无事件生存期 (GEFS)。使用了倾向评分调整的 Cox 比例风险模型、Weibull 模型和 Fine-Gray 竞争风险回归。纳入了 674 名患者（41% 恶性，59% 非恶性）估计 2 年 EFS 为 69.7%，中位白消安 AUCNONMEM 为 74.4 mg*h/L（CI95% 31.1–104.6 mg*h/L）。 中位 AUCNONMEM 与 AUCcenter 相关性较差（R2 = 0.254）。 78-101 mg*h/L 的 2 年 EFS 为 81%，而低 AUC 组 (<78 mg*h/L) 和高白消安 AUC 组分别为 66.1% 和 49.5% (P=0.011)。高 AUC 组的毒性、cGvHD 和 TRM 显着较高（HR 1.69、2.99 和 1.30），与适应症无关。这些结果表明，通过针对所有适应症使用新的经过验证的药代动力学模型，将白消安 AUC 设定为 78-101 mg*h/L，可以改善临床结果。
Intravenous-busulfan (IV-busulfan) combined with therapeutic drug monitoring to guide dosing improves outcomes after allogeneic hematopoietic cell transplantation (allo-HCT). The best method to estimate busulfan exposure and the optimal exposure in children/young adults remains unclear. We therefore evaluated three approaches to estimate IV-Bu exposure (expressed as cumulative-area-under-the-curve; AUC) and associated busulfan-AUC with clinical outcomes in children/young adults undergoing allo-HCT. In this retrospective analysis, patients (0.1–30.4 years) receiving busulfan-based conditioning regimen from 15 centers were included. Cumulative AUC was calculated by numerical integration using non-linear mixed effect modeling (AUCNONMEM), non-compartmental analysis (AUC0-infinity and AUC to the end of the dose interval AUC0-tau) and by individual centers using a variety of approaches (AUCcenter). Main outcome of interest was event-free survival (EFS). Other outcomes of interest were overall survival, graft-failure, relapse, transplantation related mortality (TRM), acute toxicity (veno-occlusive disease (VOD) and/or acute graft versus-host disease (aGvHD), chronic GvHD (cGvHD) and cGVHD-free event-free survival (GEFS). Propensity score adjusted cox proportional hazard models, Weibull models, and Fine-Gray competing risk regressions were used. 674 patients were included (41% malignant, 59% non-malignant) Estimated 2-year EFS was 69.7%. The median busulfan AUCNONMEM was 74.4 mg*h/L (CI95% 31.1–104.6 mg*h/L). The median AUCNONMEM correlated poorly with AUCcenter (R2 = 0.254). Patients with optimal IV-busulfan AUC of 78–101 mg*h/L showed 81% EFS at 2 years compared to 66.1% and 49.5% in the low (<78 mg*h/L) and high (>101 mg*h/L) busulfan AUC group respectively (P=0.011). Graft-failure/relapse occurred more frequently in the low AUC group (HR=1.75 P<0.001). Acute toxicity, cGvHD and TRM was significantly higher in the high AUC group (HR 1.69, 2.99 and 1.30), independent of indication. These results demonstrate that improved clinical outcomes may be achieved by targeting the busulfan-AUC to 78–101 mg*h/L using a new validated pharmacokinetic-model for all indications.