School of Pharmacy, University of Washington, Box 357630, Seattle, WA 98195-7630, USA.
Cancer Chemother Pharmacol. 2012 Jan;69(1):263-72. doi: 10.1007/s00280-011-1736-3. Epub 2011 Sep 11.
Sixteen patients diagnosed with various hematologic malignancies participated in a phase II study evaluating the addition of rabbit antithymocyte globulin (rATG, Thymoglobulin(®)) to the hematopoietic cell transplant (HCT) conditioning regimen of IV fludarabine monophosphate (fludarabine) and targeted intravenous (IV) busulfan (fludarabine/(T)busulfan). Our goal was to evaluate pharmacologic biomarkers pertinent to both medications in these patients.
We characterized the interpatient variability of pharmacologic biomarkers relevant to busulfan, specifically busulfan concentration at steady state, and fludarabine, specifically F-ara-A area under the curve (AUC) and fludarabine triphosphate (F-ara-ATP) intracellular accumulation and concentration in separate CD4(+) and CD8(+) T-lymphocyte populations.
Acute and chronic graft versus host disease (GvHD) occurred in 11 patients and one patient, respectively. Four patients died before day +100 of non-relapse causes, which met the protocol stopping guidelines. The cumulative incidence of relapse was 25% at 3 year post-HCT. Interpatient variability in the busulfan- and fludarabine-relevant pharmacologic biomarkers was 2.1- to 2.5-fold. F-ara-A AUC and accumulated F-ara-ATP in CD8(+) cells had the highest hazard ratio for non-relapse mortality and overall survival, respectively. However, neither achieved statistical significance.
The low rates of GvHD, particularly in its chronic form, were encouraging, and further biomarker studies are warranted to optimize the fludarabine/(T)busulfan/rATG conditioning regimen.
16 名被诊断患有各种血液系统恶性肿瘤的患者参与了一项 II 期研究，该研究评估了在 IV 氟达拉滨单磷酸盐（氟达拉滨）和靶向静脉（IV）白消安（氟达拉滨/（T）白消安）造血细胞移植（HCT）预处理方案中添加兔抗胸腺细胞球蛋白（rATG，Thymoglobulin®）的效果。我们的目标是评估这些患者与两种药物相关的药效学生物标志物。
我们描述了与白消安相关的药效学生物标志物的个体间变异性，特别是稳态时的白消安浓度，以及氟达拉滨，特别是氟达拉滨 AUC 和氟达拉滨三磷酸（F-ara-ATP）在 CD4+和 CD8+T 淋巴细胞群体中的细胞内积累和浓度。
11 名患者发生急性和慢性移植物抗宿主病（GvHD），1 名患者发生慢性 GvHD。4 名患者因非复发原因在 +100 天前死亡，符合方案停止标准。HCT 后 3 年的复发累积发生率为 25%。与白消安和氟达拉滨相关的药效学生物标志物的个体间变异性为 2.1-2.5 倍。CD8+细胞中 F-ara-A AUC 和积累的 F-ara-ATP 对非复发死亡率和总生存率的风险比最高。然而，两者均未达到统计学意义。
GvHD 的低发生率，特别是慢性形式，令人鼓舞，需要进一步的生物标志物研究来优化氟达拉滨/（T）白消安/rATG 预处理方案。
