IRCCS Humanitas Research Hospital-Humanitas Cancer Center, Milan, Italy.
Fondazione IRCCS Policlinico San Matteo, Clinical and Experimental Pharmacokinetics Unit(,) Pavia, Italy.
Transplant Cell Ther. 2021 Nov;27(11):912.e1-912.e6. doi: 10.1016/j.jtct.2021.08.006. Epub 2021 Aug 14.
Busulfan (Bu) is an alkylating agent routinely used for conditioning regimens before allogeneic stem cell transplantation (allo-SCT). Bu shows wide pharmacokinetic (PK) variability among patients. Patients can have a higher systemic exposure (expressed as area under the curve [AUC]) with an increased risk of toxicity or a lower AUC with a higher probability of graft rejection and/or disease relapse. After i.v. administration, an optimal Bu therapeutic window (AUC target of 16,000 to 24,000 μM·minute) has been identified. The use of PK-guided Bu dosing leads to improved overall survival (OS) and progression-free survival (PFS) compared with fixed-dose administration in a variety of hematologic diseases. The aim of this study was to evaluate the outcomes and feasibility of a reduced-toxicity conditioning (RTC) regimen comprising thiotepa, Bu, and fludarabine (TBF) with therapeutic drug monitoring of Bu in patients with hematologic disorders. We report on 41 adult patients with myeloid or lymphoid malignancies who underwent an allo-SCT with a PK-guided Bu-based RTC regimen between January 2019 and October 2020. Patients received a total Bu dose to achieve a target AUC of 16,000 μM·minute in combination with Flu and thiotepa. The median time to absolute neutrophil count recovery and transfusion-independent platelet count recovery was 23 days (range, 15 to 42 days) and 29 days (range, 14 to 97 days), respectively. The cumulative incidence (CI) of nonrelapse mortality was 7% at 100 days and 13% at 1 year. Grade 3 liver toxicity was observed in 6 patients. One patient developed sinusoidal obstruction syndrome at day +27. Grade 3 mucositis occurred in 18 patients. Looking at grade ≥3 infections, the CI was 29% at 30 days, 34% at 60 days, 44% at 100 days, and 56% at 1 year. The 180-day CI of grade II-IV acute graft-versus-host disease (GVHD) was 15%, and the 1-year CI of overall chronic GVHD was 20%. With a median follow-up of alive patients of 14.4 months (range, 3.2 to 24 months), the CI of relapse at 1 year was 6%. The 1-year PFS was 81%, and 1-year OS was 84%. In conclusion, these data support the efficacy of PK-guided Bu dose in the context of a TBF conditioning regimen and the feasibility of therapeutic dosage monitoring of i.v. Bu for patients with hematologic diseases. © 2021 American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc.
白消安（Bu）是一种烷化剂，常用于异基因造血干细胞移植（allo-SCT）前的预处理方案。Bu 在患者中的药代动力学（PK）变异性很大。患者可能具有更高的全身暴露（以曲线下面积 [AUC] 表示），从而增加毒性风险，或者具有较低的 AUC，从而增加移植物排斥和/或疾病复发的可能性。静脉给药后，已经确定了最佳 Bu 治疗窗（AUC 目标为 16,000 至 24,000 μM·分钟）。与固定剂量给药相比，PK 指导的 Bu 给药可改善各种血液系统疾病患者的总生存率（OS）和无进展生存率（PFS）。本研究旨在评估含硫替哌、Bu 和氟达拉滨（TBF）的减毒预处理（RTC）方案在血液系统疾病患者中的结果和可行性，并对 Bu 进行治疗药物监测。我们报告了 41 例接受 allo-SCT 的血液系统恶性肿瘤成人患者，他们在 2019 年 1 月至 2020 年 10 月期间接受了基于 PK 指导的 Bu 为基础的 RTC 方案。患者接受了总 Bu 剂量，以达到 16,000 μM·分钟的目标 AUC，与 Flu 和硫替哌联合使用。中性粒细胞绝对计数恢复和非输血依赖血小板计数恢复的中位时间分别为 23 天（范围为 15 至 42 天）和 29 天（范围为 14 至 97 天）。100 天时非复发死亡率的累积发生率（CI）为 7%，1 年时为 13%。6 例患者出现 3 级肝毒性。1 例患者在第+27 天出现窦状隙阻塞综合征。18 例患者发生 3 级黏膜炎。观察≥3 级感染，30 天时 CI 为 29%，60 天时 CI 为 34%，100 天时 CI 为 44%，1 年时 CI 为 56%。180 天时 2 至 4 级急性移植物抗宿主病（GVHD）的 CI 为 15%，1 年时总慢性 GVHD 的 CI 为 20%。在存活患者的中位随访时间为 14.4 个月（范围为 3.2 至 24 个月）时，1 年时的复发率为 6%。1 年的 PFS 为 81%，1 年的 OS 为 84%。总之，这些数据支持在 TBF 预处理方案中使用 PK 指导的 Bu 剂量的有效性，以及对血液系统疾病患者进行静脉 Bu 治疗剂量监测的可行性。
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