Phase I study of dose-escalated busulfan with fludarabine and alemtuzumab as conditioning for allogeneic hematopoietic stem cell transplant: reduced clearance at high doses and occurrence of late sinusoidal obstruction syndrome/veno-occlusive disease
Phase I study of dose-escalated busulfan with fludarabine and alemtuzumab as conditioning for allogeneic hematopoietic stem cell transplant: reduced clearance at high doses and occurrence of late sinusoidal obstruction syndrome/veno-occlusive disease
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DOI：
10.3109/10428194.2010.520773
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发表时间：
2010-11-01
影响因子：
2.6
通讯作者：
Van Besien, Koen
中科院分区：
文献类型：
--
作者：
O'Donnell, Peter H.;Artz, Andrew S.;Van Besien, Koen
异基因造血细胞移植（alloHCT）后疾病复发仍然很常见，需要改善预处理方案。已知白消安暴露与结局之间存在剂量-反应关系。使用个体实时监测白消安曲线下面积（AUC），我们旨在确定氟达拉滨/阿仑单抗预处理方案中白消安的最大耐受AUC。36例晚期恶性血液病患者接受了治疗。试验剂量和预处理剂量1后的白消安水平允许靶向随后的AUC和高于4800 μ mol-min/L的起始AUC的剂量递增。白消安试验剂量的清除率并不总是足以预测治疗剂量AUC，平均而言，试验剂量清除率比治疗剂量清除率快。当研究修改为使用调节剂量1药代动力学时，达到了准确的靶向治疗AUC，并且剂量递增是可能的。重度迟发性窦阻塞综合征/静脉闭塞性疾病（SOS/VOD）是在AUC水平为6800 μ mol-min/L的5/8例患者中观察到的剂量限制性毒性。SOS/VOD的风险与观察到的最高AUC（AUC（max））相关，而不是与平均累积AUC（AUC（avg））相关。白消安剂量递增至最大耐受AUC为5800 μ mol-min/L，高于当前标准白消安方案所达到的水平，使用第一次预处理剂量的实时药代动力学监测是准确和可实现的。目前正在II期研究接受白消安/氟达拉滨/阿仑单抗作为alloHCT预处理的患者的AUC。
Disease recurrence after allogeneic hematopoietic cell transplant (alloHCT) remains common, making improvements in conditioning regimens desirable. A dose-response relationship between busulfan exposure and outcome is known. Using individual real-time monitoring of the busulfan area under the curve (AUC), we aimed to determine the maximum-tolerated busulfan AUC in a conditioning regimen with fludarabine/alemtuzumab. Thirty-six patients with advanced hematologic malignancies were treated. Busulfan levels after a test dose and conditioning dose 1 allowed targeting of subsequent AUCs and dose-escalation above the starting AUC of 4800 mu mol-min/L. Clearance of busulfan test doses was not always sufficiently predictive of treatment dose AUC and, on average, test dose clearance was faster than treatment dose clearance. When the study was modified to use conditioning dose 1 pharmacokinetics instead, accurately targeted treatment AUCs were achieved, and dose-escalation was possible. Severe, late-occurring sinusoidal obstruction syndrome/veno-occlusive disease (SOS/VOD) was the dose-limiting toxicity seen in 5/8 patients at an AUC level of 6800 mu mol-min/L. The risk for SOS/VOD correlated with the highest observed AUC (AUC(max)) rather than with the average cumulative AUC (AUC(avg)). Busulfan dose-escalation to a maximum-tolerated AUC of 5800 mu mol-min/L-higher than that achieved by current standard busulfan regimens-was accurate and achievable using real-time pharmacokinetics monitoring of the first conditioning dose. This AUC is now being studied in phase II for patients receiving busulfan/fludarabine/alemtuzumab as alloHCT conditioning.