Dataset Information

Treosulfan Exposure Predicts Thalassemia-Free Survival in Patients with Beta Thalassemia Major Undergoing Allogeneic Hematopoietic Cell Transplantation.

ABSTRACT: 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.

SUBMITTER: Pai AA

PROVIDER: S-EPMC7615782 | biostudies-literature | 2024 Jan

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Treosulfan Exposure Predicts Thalassemia-Free Survival in Patients with Beta Thalassemia Major Undergoing Allogeneic Hematopoietic Cell Transplantation.

Pai Aswin Anand AA Mohanan Ezhilpavai E Panetta John C JC Kulkarni Uday P UP Illangeswaran Raveen Stephen Stallon RSS Balakrishnan Balaji B Jayaraman Agila A Edison Eunice S ES Lakshmi Kavitha M KM Devasia Anup J AJ Fouzia Nambiathayil Aboobacker NA Korula Anu A Abraham Aby A George Biju B Srivastava Alok A Mathews Vikram V Standing Joseph F JF Balasubramanian Poonkuzhali P

Clinical pharmacology and therapeutics 20231107 1

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 ma ...[more]

PMID: 37846495

Similar Datasets

Project description:BackgroundAllogeneic hematopoietic stem cell transplantation (allo-HSCT) has proven to be an effective curative intervention for children with β-thalassemia major (β-TM). They are susceptible to growth disorders due various factors. The primary objective of this study was to investigate the growth and development of children with β-TM both before and after undergoing allo-HSCT during a one-year follow-up period.MethodsAccording to the international reference standards for child growth established by the World Health Organization in 2006, participants were divided into two groups based on their Z scores: weight-for-age Z scores (WAZ), height-for-age Z scores (HAZ), and body mass index-for-age Z scores (BAZ) before allo-HSCT. The first group included children with normal nutritional levels (-2≤ Z scores ≤2), while the second group consisted of children with malnutrition (Z scores <-2 or >2). Measurements of weight, height, and body mass index (BMI) were recorded at six time points: prior to allo-HSCT (T0), and 1 month (T1), 3 months (T3), 6 months (T6), 9 months (T9), and 12 months (T12) following the procedure.ResultsAmong the 56 children diagnosed with β-TM, 25% were malnourished prior to HSCT. In the group with normal nutrition, mean WAZ (P=0.04) and HAZ (P<0.001) values were significantly higher at T12 compared to T0; however, mean BAZ was similar at T12 and T0 (P=0.61). In contrast, in the malnutrition group, no significant differences were observed in mean WAZ (P=0.12), HAZ (P=0.27), or BAZ (P=0.75) values between T12 and T0. Notably, the incidence of increased HAZ was significantly more prevalent in children aged seven years or younger than in those older than seven years (P=0.01).ConclusionsChildren diagnosed with β-TM who had normal nutritional levels at the time of allo-HSCT showed significant growth improvements within one year of follow-up compared to their pre-transplantation state. Additionally, the age at which allo-HSCT was performed may substantially influence post-transplantation growth rates. Regular monitoring of growth and development from the time of diagnosis is crucial to ensure optimal nutritional status at the time of allo-HSCT, thereby enhancing the prognosis for these children after transplantation.

Project description:PurposeTo analyze factors influencing tacrolimus (TAC) trough concentration (C0) in β-thalassemia major (β-TM) pediatric patients after allogeneic hematopoietic stem cell transplantation (Allo-HSCT) and to investigate the effects of genotype polymorphism and drug-drug interactions on TAC trough concentration in children with β-TM. Furthermore, to analyze the correlation between TAC C0 and efficacy and adverse reactions.Patients and methodsProspectively collection of demographic information and details of combined treatment of patients with β-TM receiving HSCT, and genotypes of CYP3A4, CYP3A5, and ABCB1 (rs1045642, rs1128503, rs2032582) were obtained for each patient. Univariate analysis and multiple linear regression analysis were used to investigate influencing factors on TAC C0. The impact of different genotypes and the co-administration of azole antifungal drugs on β-TM patients receiving TAC were evaluated, together with the correlation between acute graft-versus-host disease (aGVHD), infection, and liver injury of TAC C0.ResultsA total of 46 patients with 587 concentration data were included. The multiple linear regression results showed that the patient's sex, weight, postoperative time, hemoglobin, platelet count, serum cystatin C, and combined voriconazole were independent influencing factors of the infusion trough concentration/daily dose, C0/Div. Age, body surface area, postoperative time, co-administration of voriconazole, and CYP3A4*18B are independent influencing factors of C0/Dpo. Group comparisons showed that voriconazole can affect TAC C0 administered intravenously (IV) and orally in β-TM pediatric patients, while patient genotype can affect TAC C0 during oral administration. TAC C0 does not correlate with aGVHD or liver injury, but infection may be associated with TAC C0.ConclusionThe concentration of TAC should be closely monitored when co-administered with voriconazole. It is worth considering that the influence of genotype on the trough concentration of oral TAC and individualized drug administration warrant investigation. Finally, this study indicated that C0 is not suitable as an indicator of the efficacy of TAC.

Dataset Information

Treosulfan Exposure Predicts Thalassemia-Free Survival in Patients with Beta Thalassemia Major Undergoing Allogeneic Hematopoietic Cell Transplantation.

Publications

Treosulfan Exposure Predicts Thalassemia-Free Survival in Patients with Beta Thalassemia Major Undergoing Allogeneic Hematopoietic Cell Transplantation.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets