Impact of dose and duration of therapy on dexamethasone pharmacokinetics in childhood acute lymphoblastic leukaemia: a report from the UKALL 2011 trial

Research output: Contribution to journalArticle

Authors

  • Rosanna K Jackson
  • Martina Liebich
  • Philip Berry
  • Julie Errington
  • Jizhong Liu
  • Catriona Parker
  • John Moppett
  • Sujith Samarasinghe
  • Rachael Hough
  • Clare Rowntree
  • Nick J Goulden
  • Ajay Vora
  • Vaskar Saha
  • Georg Hempel
  • Julie A E Irving
  • Gareth J Veal

Colleges, School and Institutes

External organisations

  • University of Manchester
  • Department of Haematology, Great Ormond Street Hospital for Children, London, UK.
  • Department of Haematology, University College London Hospital, London, UK.
  • University Hospital of Wales, Cardiff, UK.
  • Department of Paediatric Haematology, Great Ormond Street Hospital, UK.
  • Newcastle University
  • Bristol Royal Hospital for Children
  • University of Münster

Abstract

INTRODUCTION: The use of dexamethasone in acute lymphoblastic leukaemia therapy contributes to short- and long-term toxicities. The UKALL 2011 randomised trial investigated whether a more intense dexamethasone dose (10 mg/m2/d x 14d, short vs 6 mg/m2/d x 28d, standard) would lead to a more rapid cytoreduction and reduced adverse effects associated with longer durations of steroids in induction. The impact of dose and duration on dexamethasone pharmacokinetics was investigated.

METHODS: Blood samples were obtained on one of the first three and last three days of induction dexamethasone dosing at time points up to 8 h after oral administration. Plasma dexamethasone levels were quantified in 1084 plasma samples obtained from 174 children and a population pharmacokinetic model developed.

RESULTS: Drug exposure varied significantly between patients, with a >12-fold variation in AUC0-12h values and a marked overlap in dexamethasone exposures between dose levels. Intuitively, AUC0-12h was significantly higher with short dosing (10 mg/m2/d), but cumulative exposure was significantly higher with standard dosing over 28 days, after a higher cumulative dose. Concomitant rasburicase administration was associated with a 60% higher dexamethasone clearance. Day 8 bone marrow response was comparable between dosing arms, but those with <5% blast count exhibited a greater mean dexamethasone exposure than those with >5%. No statistical differences were observed between arms in terms of steroid-related toxicity or minimal residual disease at the end of induction.

CONCLUSION: The potential significance of dexamethasone AUC0-12h on early response and higher cumulative exposure on the standard arm suggest that duration of therapy and exposure may be more important factors than absolute dose from a clinical pharmacology perspective.

Bibliographic note

Copyright © 2019 Elsevier Ltd. All rights reserved.

Details

Original languageEnglish
Pages (from-to)75-85
Number of pages11
JournalEuropean Journal of Cancer
Volume120
Early online date6 Sep 2019
Publication statusE-pub ahead of print - 6 Sep 2019