Seydoux Claire, Passweg Jakob R, Heim Dominik, Halter Joerg, Rentsch Katharina M, Medinger Michael
Division of Hematology, University Hospital of Basel, Basel, Switzerland.
Division of Hematology, University Hospital of Basel, Basel, Switzerland.
Transplant Cell Ther. 2025 Aug;31(8):571-583. doi: 10.1016/j.jtct.2025.04.019. Epub 2025 May 13.
Therapeutic drug monitoring of busulfan (Bu) used as conditioning for allogeneic stem cell transplantation (allo-HSCT) is recommended as pharmacokinetics (PK) display variability. Since 2019, we give Bu 1x/d (Bu-Q24) instead of 4x/d (Bu-Q6) for practical convenience, despite limited studies evaluating the best way of application. Our aim was to analyze the correlation between Bu administration (Bu-Q6 versus Bu-Q24), Bu-PK and clinical outcome in adult patients receiving Bu as conditioning regimen for allo-HSCT. This was a retrospective study of 256 adult patients receiving a myeloablative chemotherapeutic regimen containing Bu to treat hematological malignancies. The population was separated into 2 groups according to Bu administration, namely Bu-Q6 and Bu-Q24. A total of 133 patients received Bu-Q6 and 123 Bu-Q24. Bu-Q6 patients were more commonly treated with cyclophosphamide and Bu-Q24 with fludarabine. Bu-Q6 showed lower cumulative area-under-the-curve (AUC) values than Bu-Q24 (63.78 mgh/L in Bu-Q6 and 70.12 mgh/L in Bu-Q24, P = .06). Only 44% of the patients fell within the 1st AUC FDA target range in Bu-Q6 versus 62% in Bu-Q24 (P < .01). Overall, Bu-Q24 appeared to be superior to Bu-Q6 for most outcomes, showing lower incidence of toxicity grade ≥ II (78% versus 90%, P = .02), with less uro-renal (14% in Bu-Q24 versus 26% in Bu-Q6; P = .02), pulmonary (2% versus 8%, P = .05) and gastro-intestinal toxicities (10% versus 17%, P < .01). Patient receiving Bu-Q24 had fewer infections (51% versus 65%; P = .04), particularly bacterial (33% versus 47%, P = .03) and fungal infections (10% versus 20%; P = .03). At 2 yr, Bu-Q24 tended to have lower treatment-related mortality (TRM) (5% versus 10%, P = .13), relapse rate (37% versus 42%, P = .55) and incidence of acute and chronic graft-versus-host-disease (24% versus 28%; 32% versus 36%, respectively). The overall survival (OS) was 81% (95% CI 74% to 89%) in Bu-Q24 and 69% (95% CI 62% to 77%, P = .03) in Bu-Q6. The only benefit of Bu-Q6 was mucositis grade ≥ III, with an incidence of 36% versus 60% in Bu-Q24 (P < .01). Patients with a cumulative AUC < 59.11 mg*h/L had the lowest TRM, without impact on the OS. Bu clearance was largely influenced by BMI and age > 60 yr. Bu administered once a day shows benefit both in the short and long term compared to Bu administered 4 times a day, but data are heterogeneus, Bu-Q24 being more commonly associated with use of fludarabine, Bu-Q6 with use of cyclophosphamide in this study.
由于药代动力学（PK）存在变异性，推荐对用于异基因造血干细胞移植（allo-HSCT）预处理的白消安（Bu）进行治疗药物监测。自2019年以来，为了实际操作方便，我们采用每日1次（Bu-Q24）给予Bu，而非每日4次（Bu-Q6），尽管评估最佳应用方式的研究有限。我们的目的是分析在接受Bu作为allo-HSCT预处理方案的成年患者中，Bu给药方式（Bu-Q6与Bu-Q24）、Bu-PK与临床结局之间的相关性。这是一项对256例接受含Bu的清髓性化疗方案治疗血液系统恶性肿瘤的成年患者的回顾性研究。根据Bu给药方式将患者分为2组，即Bu-Q6组和Bu-Q24组。共有133例患者接受Bu-Q6治疗，123例接受Bu-Q24治疗。接受Bu-Q6治疗的患者更常联用环磷酰胺，而接受Bu-Q24治疗的患者更常联用氟达拉滨。Bu-Q6组的累积曲线下面积（AUC）值低于Bu-Q24组（Bu-Q6组为63.78mg·h/L，Bu-Q24组为70.12mg·h/L，P = 0.06）。在Bu-Q6组中，仅44%的患者AUC值落在FDA首个目标范围内，而在Bu-Q24组中这一比例为62%（P < 0.01）。总体而言，对于大多数结局，Bu-Q24似乎优于Bu-Q6，其≥II级毒性的发生率较低（78%对90%，P = 0.02），泌尿-肾脏毒性（Bu-Q24组为14%，Bu-Q6组为26%；P = 0.02）、肺部毒性（2%对8%，P = 0.05）和胃肠道毒性（10%对17%，P < 0.01）均较少。接受Bu-Q24治疗的患者感染较少（51%对65%；P = 0.04），尤其是细菌感染（33%对47%，P = 0.03）和真菌感染（10%对20%；P = 0.0）。在2年时，Bu-Q24组的治疗相关死亡率（TRM）有降低趋势（5%对10%，P = 0.13），复发率（37%对42%，P = 0.55）以及急慢性移植物抗宿主病的发生率（分别为24%对28%；32%对36%）也较低。Bu-Q24组的总生存率（OS）为81%（95%CI 74%至89%），Bu-Q6组为69%（95%CI 62%至77%，P = 0.03）。Bu-Q6的唯一优势是≥III级黏膜炎，其发生率为36%，而Bu-Q24组为60%（P < 0.01）。累积AUC < 59.11mg·h/L的患者TRM最低，且对OS无影响。Bu清除率在很大程度上受体重指数和年龄>60岁的影响。与每日4次给予Bu相比，每日1次给予Bu在短期和长期均显示出益处，但数据存在异质性，在本研究中，Bu-Q24更常与氟达拉滨联用，Bu-Q6更常与环磷酰胺联用。
