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

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 leas...

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Autores principales: Chiesa, Robert, Standing, Joseph F., Winter, Robert, Nademi, Zohreh, Chu, Jan, Pinner, Danielle, Kloprogge, Frank, McLellen, Susan, Amrolia, Persis J., Rao, Kanchan, Lucchini, Giovanna, Silva, Juliana, Ciocarlie, Oana, Lazareva, Arina, Gennery, Andrew R., Doncheva, Bilyana, Cant, Andrew J., Hambleton, Sophie, Flood, Terence, Rogerson, Elizabeth, Devine, Kirsty, Prunty, Helen, Heales, Simon, Veys, Paul, Slatter, Mary
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7484914/
https://www.ncbi.nlm.nih.gov/pubmed/31701524
http://dx.doi.org/10.1002/cpt.1715
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author Chiesa, Robert
Standing, Joseph F.
Winter, Robert
Nademi, Zohreh
Chu, Jan
Pinner, Danielle
Kloprogge, Frank
McLellen, Susan
Amrolia, Persis J.
Rao, Kanchan
Lucchini, Giovanna
Silva, Juliana
Ciocarlie, Oana
Lazareva, Arina
Gennery, Andrew R.
Doncheva, Bilyana
Cant, Andrew J.
Hambleton, Sophie
Flood, Terence
Rogerson, Elizabeth
Devine, Kirsty
Prunty, Helen
Heales, Simon
Veys, Paul
Slatter, Mary
author_facet Chiesa, Robert
Standing, Joseph F.
Winter, Robert
Nademi, Zohreh
Chu, Jan
Pinner, Danielle
Kloprogge, Frank
McLellen, Susan
Amrolia, Persis J.
Rao, Kanchan
Lucchini, Giovanna
Silva, Juliana
Ciocarlie, Oana
Lazareva, Arina
Gennery, Andrew R.
Doncheva, Bilyana
Cant, Andrew J.
Hambleton, Sophie
Flood, Terence
Rogerson, Elizabeth
Devine, Kirsty
Prunty, Helen
Heales, Simon
Veys, Paul
Slatter, Mary
author_sort Chiesa, Robert
collection PubMed
description 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.
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spelling pubmed-74849142020-09-18 Proposed Therapeutic Range of Treosulfan in Reduced Toxicity Pediatric Allogeneic Hematopoietic Stem Cell Transplant Conditioning: Results From a Prospective Trial Chiesa, Robert Standing, Joseph F. Winter, Robert Nademi, Zohreh Chu, Jan Pinner, Danielle Kloprogge, Frank McLellen, Susan Amrolia, Persis J. Rao, Kanchan Lucchini, Giovanna Silva, Juliana Ciocarlie, Oana Lazareva, Arina Gennery, Andrew R. Doncheva, Bilyana Cant, Andrew J. Hambleton, Sophie Flood, Terence Rogerson, Elizabeth Devine, Kirsty Prunty, Helen Heales, Simon Veys, Paul Slatter, Mary Clin Pharmacol Ther Research 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. John Wiley and Sons Inc. 2019-12-14 2020-08 /pmc/articles/PMC7484914/ /pubmed/31701524 http://dx.doi.org/10.1002/cpt.1715 Text en © 2019 The Authors. Clinical Pharmacology & Therapeutics published by Wiley Periodicals, Inc. on behalf of American Society for Clinical Pharmacology and Therapeutics. This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
spellingShingle Research
Chiesa, Robert
Standing, Joseph F.
Winter, Robert
Nademi, Zohreh
Chu, Jan
Pinner, Danielle
Kloprogge, Frank
McLellen, Susan
Amrolia, Persis J.
Rao, Kanchan
Lucchini, Giovanna
Silva, Juliana
Ciocarlie, Oana
Lazareva, Arina
Gennery, Andrew R.
Doncheva, Bilyana
Cant, Andrew J.
Hambleton, Sophie
Flood, Terence
Rogerson, Elizabeth
Devine, Kirsty
Prunty, Helen
Heales, Simon
Veys, Paul
Slatter, Mary
Proposed Therapeutic Range of Treosulfan in Reduced Toxicity Pediatric Allogeneic Hematopoietic Stem Cell Transplant Conditioning: Results From a Prospective Trial
title Proposed Therapeutic Range of Treosulfan in Reduced Toxicity Pediatric Allogeneic Hematopoietic Stem Cell Transplant Conditioning: Results From a Prospective Trial
title_full Proposed Therapeutic Range of Treosulfan in Reduced Toxicity Pediatric Allogeneic Hematopoietic Stem Cell Transplant Conditioning: Results From a Prospective Trial
title_fullStr Proposed Therapeutic Range of Treosulfan in Reduced Toxicity Pediatric Allogeneic Hematopoietic Stem Cell Transplant Conditioning: Results From a Prospective Trial
title_full_unstemmed Proposed Therapeutic Range of Treosulfan in Reduced Toxicity Pediatric Allogeneic Hematopoietic Stem Cell Transplant Conditioning: Results From a Prospective Trial
title_short Proposed Therapeutic Range of Treosulfan in Reduced Toxicity Pediatric Allogeneic Hematopoietic Stem Cell Transplant Conditioning: Results From a Prospective Trial
title_sort proposed therapeutic range of treosulfan in reduced toxicity pediatric allogeneic hematopoietic stem cell transplant conditioning: results from a prospective trial
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7484914/
https://www.ncbi.nlm.nih.gov/pubmed/31701524
http://dx.doi.org/10.1002/cpt.1715
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