Impact of Treosulfan Exposure on Early and Long-Term Clinical Outcomes in Pediatric Allogeneic Hematopoietic Stem Cell Transplantation Recipients: A Prospective Multicenter Study

Stoep, M Y E C van der; Bertaina, Alice; Moes, Dirk Jan A R; Algeri, Mattia; Bredius, Robbert G. M.; Smiers, Frans J.; Berghuis, Dagmar; Buddingh, Emilie P.; Mohseny, Alexander B.; Guchelaar, Henk‐Jan; Locatelli, Franco; Zwaveling, J.; Lankester, Arjan C.

doi:10.1016/j.jtct.2021.09.018

Cited by 17 publications

(19 citation statements)

References 26 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In terms of survival, Chiesa et al showed a relationship between exposure and OS, while Mohanan et al hinted towards a trend and Van der Stoep et al did not observe a relationship. These differences could possibly be explained by interindividual variability in exposure between the studies, which was higher in the studies of Chiesa et al and Mohanan et al Also, no relationship with EFS was found ( Mohanan et al, 2018 ; van der Stoep et al, 2021 ) and overall, it is noticed that Treo is well tolerated, with limited regimen-related toxicities, while still achieving good results when it comes to clinical outcome. Together, these results indicate a moderate exposure-toxicity relationship, but a relationship with survival is not evident and consistent.…”

Section: Chemotherapymentioning

confidence: 84%

“…For Treo, there seems to be some relationship with clinical outcome, however contrasting results are reported. High exposure increases the risk of skin toxicity and, in one study, an association with mortality is seen ( van der Stoep et al, 2017 ; Chiesa et al, 2020 ; van der Stoep et al, 2021 ). A cumulative target concentration of 4,800 mg*h/L is suggested in this particular study.…”

Section: Discussionmentioning

confidence: 99%

“…A trend was seen for low AUC to be associated with poor donor engraftment (≤20%), but this was observed only in univariable analysis. The authors propose a therapeutic target of cAUC 4,800 mg*h/L, corresponding with 1,600 mg*h/L daily (Chiesa et al, 2020) (Mohanan et al, 2018;van der Stoep et al, 2021) and overall, it is noticed that Treo is well tolerated, with limited regimen-related toxicities, while still achieving good results when it comes to clinical outcome. Together, these results indicate a moderate exposure-toxicity relationship, but a relationship with survival is not evident and consistent.…”

Section: Treosulfanmentioning

confidence: 99%

Section: Chemotherapymentioning

confidence: 99%

“…High Treo exposure (>1750 mg*h/ L) on day 1 was associated with all grade mucositis, but not with mucositis ≥ grade 2. High Treo exposure was also associated with ≥ grade 2 skin toxicity (van derStoep et al, 2021).While there seems to be a relationship with Treo PK and mucositis in the first study ofVan der Stoep et al, this was not confirmed by Mohanan and Chiesa et al Furthermore, in a more recent study of Van der Stoep et al, only a relationship between exposure and all grade mucositis was seen, but not with grade 2 or higher, which is clinically more relevant. However, in both studies of Van der Stoep et al as well as the study of Chiesa et al, high Treo exposure was related to the risk of ≥ grade 2 skin toxicity.…”

mentioning

confidence: 93%

See 4 more Smart Citations

Therapeutic Drug Monitoring of Conditioning Agents in Pediatric Allogeneic Stem Cell Transplantation; Where do We Stand?

et al. 2022

Self Cite

View full text Add to dashboard Cite

Allogeneic hematopoietic stem cell transplantation (HSCT) is an established curative treatment that has significantly improved clinical outcome of pediatric patients with malignant and non-malignant disorders. This is partly because of the use of safer and more effective combinations of chemo- and serotherapy prior to HSCT. Still, complications due to the toxicity of these conditioning regimens remains a major cause of transplant-related mortality (TRM). One of the most difficult challenges to further improve HSCT outcome is reducing toxicity while maintaining efficacy. The use of personalized dosing of the various components of the conditioning regimen by means of therapeutic drug monitoring (TDM) has been the topic of interest in the last decade. TDM could play an important role, especially in children who tend to show greater pharmacokinetic variability. However, TDM should only be performed when it has clear added value to improve clinical outcome or reduce toxicity. In this review, we provide an overview of the available evidence for the relationship between pharmacokinetic parameters and clinical outcome or toxicities of the most commonly used conditioning agents in pediatric HSCT.

show abstract

Section: Chemotherapymentioning

confidence: 84%

Section: Discussionmentioning

confidence: 99%

Section: Treosulfanmentioning

confidence: 99%

Section: Chemotherapymentioning

confidence: 99%

mentioning

confidence: 93%

See 3 more Smart Citations

Therapeutic Drug Monitoring of Conditioning Agents in Pediatric Allogeneic Stem Cell Transplantation; Where do We Stand?

et al. 2022

Self Cite

View full text Add to dashboard Cite

show abstract

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

Pai,

Mohanan,

Panetta

et al. 2023

Clin Pharma and Therapeutics

View full text Add to dashboard Cite

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.

show abstract

Feasibility study of busulfan, fludarabine, and thiotepa conditioning regimen for allogeneic hematopoietic stemcell transplantationfor children and young adults with nonmalignant disorders

Fraser

Castillo

Cascio

et al. 2023

Pediatric Blood & Cancer

View full text Add to dashboard Cite

Background Hematopoietic stem cell transplant (HSCT) is the only curative treatment for several pediatric non‐malignant disorders. A widely used conditioning backbone is busulfan, fludarabine, and rabbit anti‐thymocyte globulin (rATG). Thiotepa has improved engraftment when added to this regimen, however the minimum effective dose (MED) of thiotepa to achieve engraftment while minimizing toxicities has not been well established. Objectives The primary objective of this prospective feasibility study was to determine the MED of thiotepa (5mg/kg) in combination with reduced‐dose busulfan, fludarabine or cyclophosphamide, and rATG required to achieve engraftment in >90% of HSCT recipients for non‐malignant disorders with acceptable toxicity. Results Six patients who received fully matched HSCT were enrolled. Patient diagnoses included Wiskott‐Aldrich syndrome (n = 1), CD40L deficiency (n = 1), sickle cell disease (n = 2), autoinflammatory syndrome (n = 1), and paroxysmal nocturnal hemoglobinuria (n = 1). All six patients achieved engraftment prior to Day +42 and five patients had stable full donor engraftment. Two of the six patients (33%) developed acute GVHD and/or chronic GHVD, both of whom had sickle cell disease. At a median follow‐up of 2.25 years post‐transplant, all patients were alive without evidence of disease recurrence. None of the patients experienced grade 4 or 5 toxicities. Three out of six patients (50%) developed grade 3 adverse events. Neurocognitive functioning of children under 10 years of age was not adversely affected by this regimen. Conclusion This approach shows acceptable toxicity and reliable engraftment in children with non‐malignant disorders receiving related or unrelated HLA‐matched transplants.

show abstract

Impact of Treosulfan Exposure on Early and Long-Term Clinical Outcomes in Pediatric Allogeneic Hematopoietic Stem Cell Transplantation Recipients: A Prospective Multicenter Study

Cited by 17 publications

References 26 publications

Therapeutic Drug Monitoring of Conditioning Agents in Pediatric Allogeneic Stem Cell Transplantation; Where do We Stand?

Therapeutic Drug Monitoring of Conditioning Agents in Pediatric Allogeneic Stem Cell Transplantation; Where do We Stand?

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

Feasibility study of busulfan, fludarabine, and thiotepa conditioning regimen for allogeneic hematopoietic stemcell transplantationfor children and young adults with nonmalignant disorders

Contact Info

Product

Resources

About