Pai, Aswin Anand;
Mohanan, Ezhilpavai;
Panetta, John C;
Kulkarni, Uday P;
Stallon Illangeswaran, RS;
Balakrishnan, Balaji;
Jayaraman, Agila;
... Balasubramanian, Poonkuzhali; + view all
(2024)
Treosulfan Exposure Predicts Thalassemia-Free Survival in Patients with Beta Thalassemia Major Undergoing Allogeneic Hematopoietic Cell Transplantation.
Clinical Pharmacology & Therapeutics
, 115
(1)
pp. 116-125.
10.1002/cpt.3078.
Preview |
Text
Standing_Clin Pharma and Therapeutics - 2023 - Pai - Treosulfan Exposure Predicts Thalassemia‐Free Survival in Patients with Beta.pdf Download (5MB) | Preview |
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.
| Type: | Article |
|---|---|
| Title: | Treosulfan Exposure Predicts Thalassemia-Free Survival in Patients with Beta Thalassemia Major Undergoing Allogeneic Hematopoietic Cell Transplantation |
| Location: | United States |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1002/cpt.3078 |
| Publisher version: | https://doi.org/10.1002/cpt.3078 |
| Language: | English |
| Additional information: | Copyright © 2023 The Authors. Clinical Pharmacology & Therapeutics published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics. This is an open access article under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits use, distribution and reproduction in any medium, provided the original work is properly cited. |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health > Infection, Immunity and Inflammation Dept |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10179683 |
Loading...
Loading...Loading...Loading...Archive Staff Only
 |
View Item |
