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Proposed Therapeutic Range of Treosulfan in Reduced Toxicity Pediatric Allogeneic Hematopoietic Stem Cell Transplant Conditioning: Results From a Prospective Trial

Lookup NU author(s): Dr Zohreh Nademi, Professor Andrew Gennery, Professor Andrew Cant, Professor Sophie Hambleton, Dr Terence Flood, Elizabeth Rogerson, Dr Mary Slatter

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This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).


Abstract

© 2019 The Authors. Clinical Pharmacology & Therapeutics published by Wiley Periodicals, Inc. on behalf of American Society for Clinical Pharmacology and Therapeutics.Treosulfan is given off-label in pediatric allogeneic hematopoietic stem cell transplant. This study investigated treosulfan's pharmacokinetics (PKs), efficacy, and safety in a prospective trial. Pediatric patients (n = 87) receiving treosulfan-fludarabine conditioning were followed for at least 1 year posttransplant. PKs were described with a two-compartment model. During follow-up, 11 of 87 patients died and 12 of 87 patients had low engraftment (≤ 20% myeloid chimerism). For each increase in treosulfan area under the curve from zero to infinity (AUC(0-∞)) of 1,000 mg hour/L the hazard ratio (95% confidence interval) for mortality increase was 1.46 (1.23–1.74), and the hazard ratio for low engraftment was 0.61 (0.36–1.04). A cumulative AUC(0-∞) of 4,800 mg hour/L maximized the probability of success (> 20% engraftment and no mortality) at 82%. Probability of success with AUC(0-∞) between 80% and 125% of this target were 78% and 79%. Measuring PK at the first dose and individualizing the third dose may be required in nonmalignant disease.


Publication metadata

Author(s): Chiesa R, Standing JF, Winter R, Nademi Z, Chu J, Pinner D, Kloprogge F, McLellen S, Amrolia PJ, Rao K, Lucchini G, Silva J, Ciocarlie O, Lazareva A, Gennery AR, Doncheva B, Cant AJ, Hambleton S, Flood T, Rogerson E, Devine K, Prunty H, Heales S, Veys P, Slatter M

Publication type: Article

Publication status: Published

Journal: Clinical Pharmacology and Therapeutics

Year: 2019

Volume: 108

Issue: 2

Pages: 264-273

Print publication date: 01/08/2020

Online publication date: 07/11/2019

Acceptance date: 28/10/2019

Date deposited: 08/01/2020

ISSN (print): 0009-9236

ISSN (electronic): 1532-6535

Publisher: Nature Publishing Group

URL: https://doi.org/10.1002/cpt.1715

DOI: 10.1002/cpt.1715

PubMed id: 31701524


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