title: Association of busulfan exposure with survival and toxicity after haemopoietic cell transplantation in children and young adults: a multicentre, retrospective cohort analysis.
abstract: BACKGROUND
  Intravenous busulfan combined with therapeutic drug monitoring to guide dosing improves outcomes after allogeneic haemopoietic cell transplantation (HCT). The best method to estimate busulfan exposure and optimum exposure in children or young adults remains unclear. We therefore assessed three approaches to estimate intravenous busulfan exposure (expressed as cumulative area under the curve [AUC]) and associated busulfan AUC with clinical outcomes in children or young adults undergoing allogeneic HCT.
  
  
  METHODS
  In this retrospective analysis, patients from 15 centres in the Netherlands, USA, Canada, Switzerland, UK, Italy, Germany, and Australia who received a busulfan-based conditioning regimen between March 18, 2001, and Feb 12, 2015, were included. Cumulative AUC was calculated by numerical integration using non-linear mixed effect modelling (AUCNONMEM), non-compartmental analysis (AUC from 0 to infinity [AUC0-∞] and to the next dose [AUC0-τ]), and by individual centres using various approaches (AUCcentre). The main outcome of interest was event-free survival. Other outcomes of interest were graft failure or relapse, or both; transplantation-related mortality; acute toxicity (veno-occlusive disease or acute graft versus-host disease [GvHD]); chronic GvHD; overall survival; and chronic-GvHD-free event-free survival. We used propensity-score-adjusted Cox proportional hazard models, Weibull models, and Fine-Gray competing risk regressions for statistical analyses.
  
  
  RESULTS
  790 patients were enrolled, 674 of whom were included: 274 (41%) with malignant and 400 (59%) with non-malignant disease. Median age was 4·5 years (IQR 1·4-10·7). The median busulfan AUCNONMEMwas 74·4 mg × h/L (95% CI 31·1-104·6), which correlated with the standardised method AUC0-∞(r2=0·74), but the latter correlated poorly with AUCcentre(r2=0·35). Estimated 2-year event-free survival was 69·7% (95% CI 66·2-73·0). Event-free survival at 2 years was 77·0% (95% CI 72·1-82·9) in the 257 patients with an optimum intravenous busulfan AUC of 78-101 mg × h/L compared with 66·1% (60·9-71·4) in the 235 patients at the low historical target of 58-86 mg × h/L and 49·5% (29·2-66·0) in the 44 patients with a high (>101 mg × h/L) busulfan AUC (p=0·011). Compared with the low AUC group, graft failure or relapse occurred less frequently in the optimum AUC group (hazard ratio [HR] 0·57, 95% CI 0·39-0·84; p=0·0041). Acute toxicity (HR 1·69, 1·12-2·57; p=0·013) and transplantation-related mortality (2·99, 1·82-4·92; p<0·0001) were significantly higher in the high AUC group (>101 mg × h/L) than in the low AUC group (<78 mg × h/L), independent of indication; no difference was noted between AUC groups for chronic GvHD (<78 mg × h/L vs ≥78 mg × h/L, HR 1·30, 95% CI 0·73-2·33; p=0·37).
  
  
  CONCLUSIONS
  Improved clinical outcomes are likely to be achieved by targeting the busulfan AUC to 78-101 mg × h/L using a new validated pharmacokinetic model for all indications.
  
  
  BACKGROUND
  Research Allocation Program and the UCSF Helen Friller Family Comprehensive Cancer Center and the Mt Zion Health Fund of the University of California, San Francisco.
authors.affiliation: Department of Medicine, University of California San Francisco, CA, USA.
authors.forename: Imke H
authors.initials: IH
authors.lastname: Bartelink
authors.affiliation: Clinical Pharmacy Department, University Medical Center Utrecht, Utrecht, Netherlands; Division of Pharmacoepidemiology and Clinical Pharmacology, Utrecht University, Utrecht, Netherlands.
authors.forename: Arief
authors.initials: A
authors.lastname: Lalmohamed
authors.affiliation: Clinical Pharmacy Department, University Medical Center Utrecht, Utrecht, Netherlands.
authors.forename: Elisabeth M L
authors.initials: EM
authors.lastname: van Reij
authors.affiliation: Pediatric Allergy, Immunology, and Bone Marrow Transplantation Division, University of California San Francisco, CA, USA.
authors.forename: Christopher C
authors.initials: CC
authors.lastname: Dvorak
authors.affiliation: Department of Bioengineering and Therapeutic Sciences, University of California San Francisco, CA, USA.
authors.forename: Rada M
authors.initials: RM
authors.lastname: Savic
authors.affiliation: Leiden University Medical Center, Leiden, Netherlands.
authors.forename: Juliette
authors.initials: J
authors.lastname: Zwaveling
authors.affiliation: Leiden University Medical Center, Leiden, Netherlands.
authors.forename: Robbert G M
authors.initials: RG
authors.lastname: Bredius
authors.affiliation: Clinical Pharmacy Department, University Medical Center Utrecht, Utrecht, Netherlands; Division of Pharmacoepidemiology and Clinical Pharmacology, Utrecht University, Utrecht, Netherlands.
authors.forename: Antoine C G
authors.initials: AC
authors.lastname: Egberts
authors.affiliation: Division of Pediatrics, Blood and Marrow Transplantation Program, University Medical Center Utrecht, Utrecht, Netherlands.
authors.forename: Marc
authors.initials: M
authors.lastname: Bierings
authors.affiliation: Stem Cell Transplant Program, Ann and Robert H Lurie Children's Hospital of Chicago, Chicago, IL, USA.
authors.forename: Morris
authors.initials: M
authors.lastname: Kletzel
authors.affiliation: Division of Blood and Marrow Transplantation, The Children's Hospital at Westmead, Sydney, NSW, Australia.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Shaw
authors.affiliation: Division of Blood and Marrow Transplantation, The Children's Hospital at Westmead, Sydney, NSW, Australia.
authors.forename: Christa E
authors.initials: CE
authors.lastname: Nath
authors.affiliation: Department of Clinical Pharmacy, Westfälische Wilhelms-Universität Münster, Institut für Pharmazeutische und Medizinische Chemie, Münster, Germany.
authors.forename: George
authors.initials: G
authors.lastname: Hempel
authors.affiliation: Département de l'Enfant et de l'Adolescent, Hôpital des Enfants, Geneva, Switzerland.
authors.forename: Marc
authors.initials: M
authors.lastname: Ansari
authors.affiliation: Charles-Bruneau Cancer Center, Department of Pediatrics, Faculty of Medicine, University of Montreal, Montreal, QC, Canada.
authors.forename: Maja
authors.initials: M
authors.lastname: Krajinovic
authors.affiliation: Department of Pharmacology, University of Montreal, Montreal, QC, Canada; Clinical Pharmacology Unit, Centre Hospitalier Universitaire Sainte-Justine, Montreal, QC, Canada.
authors.forename: Yves
authors.initials: Y
authors.lastname: Théorêt
authors.affiliation: Charles-Bruneau Cancer Center, Department of Pediatrics, Faculty of Medicine, University of Montreal, Montreal, QC, Canada.
authors.forename: Michel
authors.initials: M
authors.lastname: Duval
authors.affiliation: Department of Bioengineering and Therapeutic Sciences, University of California San Francisco, CA, USA; InsightRX, San Francisco, CA, USA.
authors.forename: Ron J
authors.initials: RJ
authors.lastname: Keizer
authors.affiliation: Charles-Bruneau Cancer Center, Department of Pediatrics, Faculty of Medicine, University of Montreal, Montreal, QC, Canada.
authors.forename: Henrique
authors.initials: H
authors.lastname: Bittencourt
authors.affiliation: Division of Experimental Cancer Medicine, Clinical Research Centre, Laboratory Medicine, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Moustapha
authors.initials: M
authors.lastname: Hassan
authors.affiliation: Division of Stem Cell Transplantation and Children's Research Center, University Children's Hospital Zürich, Zürich, Switzerland.
authors.forename: Tayfun
authors.initials: T
authors.lastname: Güngör
authors.affiliation: Department of Haematology and Bone Marrow Transplantation, The Royal Manchester Children's Hospital, Manchester, UK.
authors.forename: Robert F
authors.initials: RF
authors.lastname: Wynn
authors.affiliation: Bone Marrow Transplantation Department, Great Ormond Street Hospital for Children, London, UK.
authors.forename: Paul
authors.initials: P
authors.lastname: Veys
authors.affiliation: CancerCare Manitoba, Winnipeg, MB, Canada.
authors.forename: Geoff D E
authors.initials: GD
authors.lastname: Cuvelier
authors.affiliation: Stem Cell Program, IRCCS San Raffaele Scientific Institute, Milan, Italy.
authors.forename: Sarah
authors.initials: S
authors.lastname: Marktel
authors.affiliation: Bone Marrow Transplantation Department, Great Ormond Street Hospital for Children, London, UK; Stem Cell Program, IRCCS San Raffaele Scientific Institute, Milan, Italy.
authors.forename: Robert
authors.initials: R
authors.lastname: Chiesa
authors.affiliation: Pediatric Allergy, Immunology, and Bone Marrow Transplantation Division, University of California San Francisco, CA, USA.
authors.forename: Morton J
authors.initials: MJ
authors.lastname: Cowan
authors.affiliation: The Institute of Cellular Medicine, Newcastle University, Newcastle, UK.
authors.forename: Mary A
authors.initials: MA
authors.lastname: Slatter
authors.affiliation: Department of Hematopoietic Cell Transplant, Hematology, and Oncology, University of Minnesota Masonic Children's Hospital, Minneapolis, MN, USA.
authors.forename: Melisa K
authors.initials: MK
authors.lastname: Stricherz
authors.affiliation: Department of Hematopoietic Cell Transplant, Hematology, and Oncology, University of Minnesota Masonic Children's Hospital, Minneapolis, MN, USA.
authors.forename: Cathryn
authors.initials: C
authors.lastname: Jennissen
authors.affiliation: Department of Clinical Pharmacy, University of California San Francisco, CA, USA.
authors.forename: Janel R
authors.initials: JR
authors.lastname: Long-Boyle
authors.affiliation: Division of Pediatrics, Blood and Marrow Transplantation Program, University Medical Center Utrecht, Utrecht, Netherlands; Laboratory of Translational Immunology, University Medical Center Utrecht, Utrecht, Netherlands. Electronic address: j.j.boelens@umcutrecht.nl.
authors.forename: Jaap Jan
authors.initials: JJ
authors.lastname: Boelens
mesh_terms: D000293:Adolescent; D000328:Adult; D019540:Area Under Curve; D002066:Busulfan / Q000008:administration & dosage* / Q000493:pharmacokinetics* / Q000627:therapeutic use / Q000633:toxicity; D002648:Child; D002675:Child, Preschool; D015331:Cohort Studies; D018572:Disease-Free Survival; D004305:Dose-Response Relationship, Drug; D005260:Female; D006084:Graft Rejection / Q000453:epidemiology; D006085:Graft Survival / Q000187:drug effects; D006086:Graft vs Host Disease / Q000453:epidemiology; D018380:Hematopoietic Stem Cell Transplantation / Q000009:adverse effects* / Q000401:mortality*; D006801:Humans; D007223:Infant; D008297:Male; D012008:Recurrence; D012189:Retrospective Studies; D019172:Transplantation Conditioning / Q000009:adverse effects / Q000379:methods*; D014184:Transplantation, Homologous / Q000009:adverse effects* / Q000401:mortality*; D016896:Treatment Outcome
chemical_list: D002066:Busulfan