Busulfan systemic exposure relative to regimen-related toxicity and acute graft-versus-host disease: Defining a therapeutic window for IV BuCy2 in chronic myelogenous leukemia
Busulfan systemic exposure relative to regimen-related toxicity and acute graft-versus-host disease: Defining a therapeutic window for IV BuCy2 in chronic myelogenous leukemia
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DOI：
10.1053/bbmt.2002.v8.pm12374452
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发表时间：
2002-01-01
影响因子：
4.3
通讯作者：
Champlin, RE
中科院分区：
文献类型：
--
作者：
Andersson, BS;Thall, PF;Champlin, RE
静脉注射白消安(Bu)的完全生物利用度通过减少与口服制剂相关的Bu全身暴露(Bu-SE)的剂量间和患者间变异性来提供剂量保证。我们推测，以血药浓度-时间曲线(AUC)下面积表示的Bu-SE可能与慢性粒细胞白血病(CML)异基因造血干细胞移植(HSCT)后的治疗结果相关。因此，我们分析了36例CML患者的死亡风险、与方案相关的毒性发生率和急性移植物抗宿主病(AGVHD)的发生率，这些患者在静脉注射BuCy2方案后接受了来自HLA相合的家庭供者的HSCT。使用剂量1、5、9和13的数据计算每个受试者的每个剂量的Bu AUC。使用修改的国家癌症研究所标准评估毒性。因为没有患者发生静脉闭塞疾病，所以血清胆红素升高被用来表征肝脏毒性。我们发现，随着AUC的增加，发生胃肠道毒性(P=.01)、肝毒性(P<；.01)、粘膜炎(P=.09)和aGVHD(P<；.01)的概率均增加。此外，每剂AUC在约950至1520muMol-min之间的患者的死亡风险显著较低，而AUC值较低或较高的患者死亡风险急剧增加。这些数据表明，基于每剂量AUC的最佳Bu治疗窗口是存在的。考虑到静脉注射Bu能够提供更一致的每剂量AUC，这些结果应该有助于设计未来基于IV Bu的干细胞移植治疗方案。
Complete bioavailability of IV busulfan (Bu) provides dose assurance by reducing the interdose and interpatient variability in Bu systemic exposure (Bu-SE) associated with the oral formulation. We hypothesized that Bu-SE, represented by the area under the plasma concentration versus time curve (AUC), would correlate with treatment outcome after allogeneic hematopoietic stem cell transplantation (HSCT) for chronic myelogenous leukemia (CML). Therefore, we analyzed the risk of death, incidence of regimen-related toxicity, and incidence of acute GVHD (aGVHD) as functions of the per dose IV Bu AUC in 36 CML patients who received a HSCT from an HLA-matched family donor after the IV BuCy2 regimen. Per-dose Bu AUCs were calculated for each subject using data obtained for doses 1, 5, 9, and 13. Toxicity was evaluated using the modified National Cancer Institute criteria. Because no patient developed veno-occlusive disease, increased serum bilirubin was used to characterize hepatotoxicity. We found that the probabilities of developing gastrointestinal toxicity (P = .01), hepatotoxicity (P < .01), mucositis (P = .09), and aGVHD (P < .01) all increased with increasing AUC. Further, the risk of death was significantly lower for patients having a per-dose AUC between approximately 950 and 1520 muMol-min, whereas the risk increased sharply with either lower or higher AUC values. These data suggest that an optimal Bu therapeutic window, based on per-dose AUC, exists. Given the ability of IV Bu to provide a more consistent per-dose AUC, these results should be useful in designing future IV Bu-based treatment protocols for stem cell transplantation.