Department of Hematology, Christian Medical College, Vellore, India.
Sree Chitra Tirunal Institute for Medical Sciences and Technology, Thiruvananthapuram, India.
Clin Pharmacol Ther. 2024 Jan;115(1):116-125. doi: 10.1002/cpt.3078. Epub 2023 Nov 7.
A toxicity-reduced conditioning regimen with treosulfan, fludarabine, and thiotepa in patients with high-risk β-thalassemia major has significantly improved hematopoietic stem cell transplantation (HCT) outcomes. However, complications resulting from regimen-related toxicities (RRTs), mixed chimerism, and graft rejection remain a challenge. We evaluated the dose-exposure-response relationship of treosulfan and its active metabolite S, S-EBDM, in a uniform cohort of patients with β-thalassemia major to identify whether therapeutic drug monitoring (TDM) and dose adjustment of treosulfan is feasible. Plasma treosulfan/S, S-EBDM levels were measured in 77 patients using a validated liquid chromatography with tandem mass spectrometry method, and the pharmacokinetic parameters were estimated using nlmixr2. The influence of treosulfan and S, S-EBDM exposure, and GSTA1/NQO1 polymorphisms on graft rejection, RRTs, chimerism status, and 1-year overall survival (OS), and thalassemia-free survival (TFS) were assessed. We observed that treosulfan exposure was lower in patients with graft rejection than those without (1,655 vs. 2,037 mg•h/L, P = 0.07). Pharmacodynamic modeling analysis to identify therapeutic cutoff revealed that treosulfan exposure ≥1,660 mg•hour/L was significantly associated with better 1-year TFS (97% vs. 81%, P = 0.02) and a trend to better 1-year OS (90% vs. 69%, P = 0.07). Further, multivariate analysis adjusting for known pre-HCT risk factors also revealed treosulfan exposure <1,660 mg•h/L (hazard ratio (HR) = 3.23; 95% confidence interval (CI) = 1.12-9.34; P = 0.03) and GSTA1*B variant genotype (HR = 3.75; 95% CI = 1.04-13.47; P = 0.04) to be independent predictors for inferior 1-year TFS. We conclude that lower treosulfan exposure increases the risk of graft rejection and early transplant-related mortality affecting TFS. As no RRTs were observed with increasing treosulfan exposure, TDM-based dose adjustment could be feasible and beneficial.
用三氟尿苷、氟达拉滨和噻替哌进行毒性降低的预处理方案可显著改善高危β地中海贫血患者的造血干细胞移植（HCT）结局。然而，与方案相关的毒性（RRT）、混合嵌合体和移植物排斥等并发症仍然是一个挑战。我们评估了在统一的β地中海贫血患者队列中三氟尿苷及其活性代谢物 S，S-EBDM 的剂量-暴露-反应关系，以确定是否可行治疗药物监测（TDM）和三氟尿苷剂量调整。使用经过验证的液相色谱-串联质谱法测量了 77 例患者的血浆三氟尿苷/S，S-EBDM 水平，并使用 nlmixr2 估计了药代动力学参数。评估了三氟尿苷和 S，S-EBDM 暴露以及 GSTA1/NQO1 多态性对移植物排斥、RRTs、嵌合体状态以及 1 年总生存（OS）和无地中海贫血生存（TFS）的影响。我们观察到，与无排斥反应的患者相比，发生排斥反应的患者的三氟尿苷暴露较低（1655 vs. 2037mg·h/L，P=0.07）。进行药效动力学建模分析以确定治疗截止值显示，三氟尿苷暴露≥1660mg·小时/L 与更好的 1 年 TFS（97% vs. 81%，P=0.02）和更好的 1 年 OS（90% vs. 69%，P=0.07）显著相关。此外，调整已知的预处理风险因素的多变量分析也显示，三氟尿苷暴露量<1660mg·h/L（风险比（HR）=3.23；95%置信区间（CI）=1.12-9.34；P=0.03）和 GSTA1*B 变异基因型（HR=3.75；95%CI=1.04-13.47；P=0.04）是 1 年 TFS 较差的独立预测因素。我们得出结论，较低的三氟尿苷暴露会增加移植物排斥和早期与移植相关的死亡风险，从而影响 TFS。由于随着三氟尿苷暴露的增加未观察到 RRTs，因此基于 TDM 的剂量调整可能是可行且有益的。
