Pai, Aswin Anand; Mohanan, Ezhilpavai; Panetta, John C; Kulkarni, Uday P; Stallon Illangeswaran, RS; Balakrishnan, Balaji; Jayaraman, Agila; ... Balasubramanian, Poonkuzhali; + view all Pai, Aswin Anand; Mohanan, Ezhilpavai; Panetta, John C; Kulkarni, Uday P; Stallon Illangeswaran, RS; Balakrishnan, Balaji; Jayaraman, Agila; Edison, Eunice S; Kavitha, ML; Devasia, Anup J; Fouzia, NA; Korula, Anu; Abraham, Aby; George, Biju; Srivastava, Alok; Mathews, Vikram; Standing, Joseph F; Balasubramanian, Poonkuzhali; - view fewer (2023) Treosulfan Exposure Predicts Thalassemia-free Survival In Patients With Beta Thalassemia Major (TM) Undergoing Allogeneic Hematopoietic Cell Transplantation. Clinical Pharmacology & Therapeutics 10.1002/cpt.3078. (In press).

Text Treosulfan Exposure Predicts Thalassemia free Survival In Patients.pdf - Accepted Version Access restricted to UCL open access staff until 18 October 2024. Download (1MB)

Abstract

A toxicity-reduced conditioning regimen with Treosulfan, Fludarabine, and Thiotepa in patients with high-risk β- thalassemia major has significantly improved 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 seventy-seven patients using a validated LC-MS/MS method, and the PK parameters were estimated using nlmixr2. The influence of Treosulfan & 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 (1655 vs. 2037 mg*h/L, p=0.07). Pharmacodynamic modeling analysis to identify therapeutic cut-off revealed that Treosulfan exposure ≥1660 mg*hr/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 PreHCT risk factors also revealed Treosulfan exposure <1660mg*h/L (HR=3.23; 95% 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.

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