title: Clinical and In Vitro Studies on Impact of High-Dose Etoposide Pharmacokinetics Prior Allogeneic Hematopoietic Stem Cell Transplantation for Childhood Acute Lymphoblastic Leukemia on the Risk of Post-Transplant Leukemia Relapse.
abstract: The impact of etoposide (VP-16) plasma concentrations on the day of allogeneic hematopoietic stem cell transplantation (allo-HSCT) on leukemia-free survival in children with acute lymphoblastic leukemia (ALL) was studied. In addition, the in vitro effects of VP-16 on the lymphocytes proliferation, cytotoxic activity and on Th1/Th2 cytokine responses were assessed. In 31 children undergoing allo-HSCT, VP-16 plasma concentrations were determined up to 120 h after the infusion using the HPLC-UV method. For mentioned in vitro studies, VP-16 plasma concentrations observed on allo-HSCT day were used. In 84 % of children, VP-16 plasma concentrations (0.1-1.5 μg/mL) were quantifiable 72 h after the end of the drug infusion, i.e. when allo-HSCT should be performed. In 20 (65 %) children allo-HSCT was performed 4 days after the end of the drug infusion, and VP-16 was still detectable (0.1-0.9 μg/mL) in plasma of 12 (39 %) of them. Post-transplant ALL relapse occurred in four children, in all of them VP-16 was detectable in plasma (0.1-0.8 μg/mL) on allo-HSCT day, while there was no relapse in children with undetectable VP-16. In in vitro studies, VP-16 demonstrated impact on the proliferation activity of stimulated lymphocytes depending on its concentration and exposition time. The presence of VP-16 in plasma on allo-HSCT day may demonstrate an adverse effect on graft-versus-leukemia (GvL) reaction and increase the risk of post-transplant ALL relapse. Therefore, if 72 h after VP-16 administration its plasma concentration is still above 0.1 μg/mL then the postponement of transplantation for next 24 h should be considered to protect GvL effector cells from transplant material.
authors.affiliation: Department of Physical Pharmacy and Pharmacokinetics, Poznan University of Medical Sciences, Święcickiego 6, 60-781, Poznań, Poland. jsobiak@ump.edu.pl.
authors.forename: Joanna
authors.initials: J
authors.lastname: Sobiak
authors.affiliation: Department of Cancer Immunology, Poznan University of Medical Sciences, Poznań, Poland.
authors.forename: Urszula
authors.initials: U
authors.lastname: Kazimierczak
authors.affiliation: Department of Cancer Immunology, Poznan University of Medical Sciences, Poznań, Poland.|Department of Pathophysiology, Faculty of Medical Sciences, University of Warmia and Mazury, Olsztyn, Poland.
authors.forename: Dariusz W
authors.initials: DW
authors.lastname: Kowalczyk
authors.affiliation: Department of Physical Pharmacy and Pharmacokinetics, Poznan University of Medical Sciences, Święcickiego 6, 60-781, Poznań, Poland.
authors.forename: Maria
authors.initials: M
authors.lastname: Chrzanowska
authors.affiliation: Department of Pediatric Hematology and Oncology, Collegium Medicum, Nicolaus Copernicus University, Bydgoszcz, Poland.
authors.forename: Jan
authors.initials: J
authors.lastname: Styczyński
authors.affiliation: Department of Pediatric Hematology and Oncology, Collegium Medicum, Nicolaus Copernicus University, Bydgoszcz, Poland.
authors.forename: Mariusz
authors.initials: M
authors.lastname: Wysocki
authors.affiliation: Department of Pediatric Oncology, Hematology and Transplantology, Poznan University of Medical Sciences, Poznań, Poland.
authors.forename: Dawid
authors.initials: D
authors.lastname: Szpecht
authors.affiliation: Department of Pediatric Oncology, Hematology and Transplantology, Poznan University of Medical Sciences, Poznań, Poland.
authors.forename: Jacek
authors.initials: J
authors.lastname: Wachowiak
mesh_terms: D000293:Adolescent; D000972:Antineoplastic Agents, Phytogenic / Q000009:adverse effects / Q000493:pharmacokinetics*; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D002648:Child; D018572:Disease-Free Survival; D054796:Drug Dosage Calculations; D005047:Etoposide / Q000009:adverse effects / Q000493:pharmacokinetics*; D005260:Female; D020544:Graft vs Leukemia Effect / Q000187:drug effects*; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000401:mortality / Q000628:therapy*; D012008:Recurrence; D012306:Risk; D013602:T-Lymphocytes, Cytotoxic / Q000187:drug effects* / Q000276:immunology; D058408:Th1-Th2 Balance / Q000187:drug effects; D014184:Transplantation, Homologous
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D005047:Etoposide
keywords: Conditioning; Etoposide; Graft versus leukemia; Hematopoietic stem cell transplantation; Pediatric acute lymphoblastic leukemia