Division of Hematology, University Hospital of Basel, Basel, Switzerland.
Department of Laboratory Medicine, University Hospital of Basel, Basel, Switzerland.
Bone Marrow Transplant. 2022 Jun;57(6):903-910. doi: 10.1038/s41409-022-01641-6. Epub 2022 Mar 31.
Busulfan (Bu) is widely used in conditioning regimens before allogeneic hematopoietic cell transplantation, with variable metabolism due to interindividual differences of pharmacokinetics (PK). The purpose of this study was to correlate pharmacokinetics and clinical outcomes. Lower-AUC, in range-AUC and higher-AUC were defined as ±25% of the targeted Bu-AUC. In 2019, we changed Bu dosing from 4×/day (Bu-4) to 1×/day (Bu-1) for ease of application. AUC-target range was reached in 46% of patients; 40% were in low-AUC and 14% in high-AUC. Among all toxicities, viral and fungal infections were significantly more frequent in high-AUC compared with low-AUC (20% vs. 8%; p = 0.01 and 37% vs. 17%; p = 0.03). Bu-1 showed lower PK values (66% vs. 36% of Bu-4 in low-AUC; p < 0.01) and higher incidence of mucositis (p = 0.02). Long-term outcomes at 2 years showed a higher non-relapse mortality (NRM) (p < 0.01) and higher relative risk of death in the high-AUC group compared to the other groups. Cumulative incidence of relapse and acute/chronic GvHD were not significantly different. The optimal cut-off in Bu-AUC associated with low NRM was 969 µmol/l*min (ROC AUC 0.67, sensitivity 0.86 and specificity 0.47) for Bu-4. In conclusion, low-AUC BU-PK seems of benefit regarding NRM and survival.
白消安（Bu）广泛用于异基因造血细胞移植前的调理方案，由于药代动力学（PK）的个体差异，其代谢情况各不相同。本研究旨在探讨 PK 与临床结局的相关性。AUC 较低、AUC 正常和 AUC 较高分别定义为目标 Bu-AUC 的±25%。2019 年，我们为了便于应用，将 Bu 剂量从 4 次/天（Bu-4）改为 1 次/天（Bu-1）。46%的患者达到 AUC 目标范围；40%的患者为低 AUC，14%的患者为高 AUC。在所有毒性中，高 AUC 组的病毒和真菌感染发生率明显高于低 AUC 组（20%比 8%；p=0.01 和 37%比 17%；p=0.03）。Bu-1 的 PK 值较低（低 AUC 时 Bu-1 为 Bu-4 的 66%；p<0.01），且黏膜炎发生率较高（p=0.02）。2 年的长期结果显示，高 AUC 组的非复发死亡率（NRM）较高（p<0.01），且与其他组相比，死亡的相对风险较高。复发和急/慢性移植物抗宿主病的累积发生率无显著差异。Bu-AUC 与低 NRM 相关的最佳截断值为 969µmol/l*min（ROC AUC 为 0.67，敏感性为 0.86，特异性为 0.47），用于 Bu-4。总之，低 AUC Bu-PK 似乎对 NRM 和生存有益。
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