Impact of treosulfan exposure on clinical outcome after allogeneic stem cell transplantation in children: A substudy of 2 phase 2 trials
Language English Country England, Great Britain Media print-electronic
Document type Journal Article, Multicenter Study, Clinical Trial, Phase II
Grant support
medac GmbH
PubMed
39563212
DOI
10.1111/bcp.16339
Knihovny.cz E-resources
- Keywords
- paediatrics, stem cell transplantation, treosulfan,
- MeSH
- Antineoplastic Agents, Alkylating * pharmacokinetics administration & dosage adverse effects MeSH
- Busulfan * analogs & derivatives pharmacokinetics administration & dosage adverse effects MeSH
- Child MeSH
- Transplantation, Homologous MeSH
- Infant MeSH
- Humans MeSH
- Adolescent MeSH
- Graft vs Host Disease epidemiology prevention & control etiology MeSH
- Child, Preschool MeSH
- Transplantation Conditioning * methods adverse effects MeSH
- Hematopoietic Stem Cell Transplantation * methods adverse effects MeSH
- Treatment Outcome MeSH
- Check Tag
- Child MeSH
- Infant MeSH
- Humans MeSH
- Adolescent MeSH
- Male MeSH
- Child, Preschool MeSH
- Female MeSH
- Publication type
- Journal Article MeSH
- Clinical Trial, Phase II MeSH
- Multicenter Study MeSH
- Names of Substances
- Antineoplastic Agents, Alkylating * MeSH
- Busulfan * MeSH
- treosulfan MeSH Browser
AIMS: Allogeneic haematopoietic stem cell transplantation (allo-HSCT) is a vital treatment for various paediatric malignant and nonmalignant diseases. The conditioning treatment before allo-HSCT is crucial for successful engraftment. Treosulfan, a cytotoxic prodrug, has gained popularity due to its lower toxicity compared to traditional alkylating agents used for conditioning treatment. METHODS: We investigated the relationship between pharmacokinetics and pharmacodynamics of treosulfan in paediatric patients, in a substudy pooling from 2 multicentre phase 2 clinical trials. A total of 83 children with malignant and nonmalignant diseases received treosulfan-based conditioning. Treosulfan exposure and its relationship with clinical outcomes, including survival, graft failure and graft-vs.-host disease, were investigated. RESULTS: Our findings reveal no significant association between treosulfan exposure and the key clinical outcomes or toxicity (P-values between .22 and .99), if the dosing is based on the approved product information. CONCLUSION: These findings suggest that treosulfan exposure after standardized body surface area-based dosing is appropriate in paediatric allo-HSCT.
Bambino Gesu Children's Hospital Rome Italy
Department of Haematology Great Ormond Street Hospital London UK
Department of Pediatrcs University Medical Center Ulm Ulm Germany
Department of Pediatric Hematology Oncology and BMT Wroclaw Medical University Wroclaw Poland
Department of Pediatrics Jena University Hospital Jena Germany
Department of Pediatrics University Hospital Wuerzburg Wuerzburg Germany
Hannover Medical School Hannover Germany
Peaditric Haematology Oncology and BMT University Hospital Muenster Muenster Germany
Sheffield Children's NHS Foundation Trust Sheffield UK
See more in PubMed
Zaucha‐Prazmo A, Sadurska E, Pieczonka A, et al. Risk factors for transplant outcomes in children and adolescents with non‐malignant diseases following allogeneic hematopoietic stem cell transplantation. Ann Transplant. 2019;24:374‐382. Published 2019 Jun 25. doi:10.12659/AOT.915330
Hartley JA, O'Hare CC, Baumgart J. DNA alkylation and interstrand cross‐linking by treosulfan. Br J Cancer. 1999;79(2):264‐266. doi:10.1038/sj.bjc.6690043
European Medicines Agency. Decision number (2019) 4858 of 20 jun 2019. https://eur-lex.europa.eu/legal-content/EN/TXT/?uri=OJ:C:2019:252:TOC. Accessed 04 July 2024.
Chiesa R, Standing JF, Winter R, et al. Proposed therapeutic range of Treosulfan in reduced toxicity pediatric allogeneic hematopoietic stem cell transplant conditioning: results from a prospective trial. Clin Pharmacol Ther. 2020;108(2):264‐273. doi:10.1002/cpt.1715
Rosser SPA, Lee S, Kohli S, et al. Evaluation of treosulfan cumulative exposure in paediatric patients through population pharmacokinetics and dosing simulations. Br J Clin Pharmacol. 2023;89(4):1413‐1424. doi:10.1111/bcp.15599
van der Stoep MYEC, Bertaina A, Moes DJAR, et al. Impact of Treosulfan exposure on early and long‐term clinical outcomes in pediatric allogeneic hematopoietic stem cell transplantation recipients: a prospective multicenter study. Transpl Cell Ther. 2022;28(2):99.e1‐99.e7. doi:10.1016/j.jtct.2021.09.018
Li X, Kalwak K, Beier R, et al. Population pharmacokinetic modeling of treosulfan and rationale for dose recommendation in children treated for conditioning prior to allogeneic hematopoietic stem cell transplantation. Drug Metab Pharmacokinet. 2023;52:100515. doi:10.1016/j.dmpk.2023.100515
Sykora KW, Beier R, Schulz A, et al. Treosulfan vs busulfan conditioning for allogeneic bmt in children with nonmalignant disease: a randomized phase 2 trial. Bone Marrow Transplant. 2024;59(1):107‐116. doi:10.1038/s41409‐023‐02135‐9
Kalwak K, Mielcarek M, Patrick K, et al. Treosulfan‐fludarabine‐thiotepa‐based conditioning treatment before allogeneic hematopoietic stem cell transplantation for pediatric patients with hematological malignancies. Bone Marrow Transplant. 2020;55(10):1996‐2007. doi:10.1038/s41409‐020‐0869‐6
Beier R, Hilger R, Sedlacek P, Greil J, Sauer M, Sykora K‐W. Treosulfan pharmacology in children: results of a feasibility study. Bone Marrow Transplant. 2012;47:S41‐S42.
Maiolica A, Meunier L, Bialleck S, Guhde I, Wood S, Struwe P. Bioanalytical determination of treosulfan and its active metabolites. Paper presented at European bioanalysis forum 7th open meeting. 20 November 2014. Barcelona, Spain.
Rosser SPA, Brewer A, Gabriel M, et al. Outcomes from hematopoietic stem cell transplantation following treosulfan‐based conditioning: a clinical and pharmacokinetic analysis. Pediatr Transplant. 2024;28(4):e14780. doi:10.1111/petr.14780
Mohanan E, Panetta JC, Lakshmi KM, et al. Pharmacokinetics and pharmacodynamics of Treosulfan in patients with thalassemia major undergoing allogeneic hematopoietic stem cell transplantation. Clin Pharmacol Ther. 2018;104(3):575‐583. doi:10.1002/cpt.988
Główka F, Kasprzyk A, Romański M, et al. Pharmacokinetics of treosulfan and its active monoepoxide in pediatric patients after intravenous infusion of high‐dose treosulfan prior to HSCT. Eur J Pharm Sci. 2015;68:87‐93. doi:10.1016/j.ejps.2014.12.010
European Medicines Agency. Summary of opinion (post authorisation). Trecondi https://www.ema.europa.eu/en/documents/smop/chmp-post-authorisation-summary-positive-opinion-trecondi-ii-14_en.pdf. Accessed 04 July 2024.
