Association of busulfan exposure with survival and toxicity after haemopoietic cell transplantation in children and young adults: a multicentre, retrospective cohort analysis.

Autor:	Bartelink IH; Department of Medicine, University of California San Francisco, CA, USA., Lalmohamed A; Clinical Pharmacy Department, University Medical Center Utrecht, Utrecht, Netherlands; Division of Pharmacoepidemiology and Clinical Pharmacology, Utrecht University, Utrecht, Netherlands., van Reij EM; Clinical Pharmacy Department, University Medical Center Utrecht, Utrecht, Netherlands., Dvorak CC; Pediatric Allergy, Immunology, and Bone Marrow Transplantation Division, University of California San Francisco, CA, USA., Savic RM; Department of Bioengineering and Therapeutic Sciences, University of California San Francisco, CA, USA., Zwaveling J; Leiden University Medical Center, Leiden, Netherlands., Bredius RG; Leiden University Medical Center, Leiden, Netherlands., Egberts AC; Clinical Pharmacy Department, University Medical Center Utrecht, Utrecht, Netherlands; Division of Pharmacoepidemiology and Clinical Pharmacology, Utrecht University, Utrecht, Netherlands., Bierings M; Division of Pediatrics, Blood and Marrow Transplantation Program, University Medical Center Utrecht, Utrecht, Netherlands., Kletzel M; Stem Cell Transplant Program, Ann and Robert H Lurie Children's Hospital of Chicago, Chicago, IL, USA., Shaw PJ; Division of Blood and Marrow Transplantation, The Children's Hospital at Westmead, Sydney, NSW, Australia., Nath CE; Division of Blood and Marrow Transplantation, The Children's Hospital at Westmead, Sydney, NSW, Australia., Hempel G; Department of Clinical Pharmacy, Westfälische Wilhelms-Universität Münster, Institut für Pharmazeutische und Medizinische Chemie, Münster, Germany., Ansari M; Département de l'Enfant et de l'Adolescent, Hôpital des Enfants, Geneva, Switzerland., Krajinovic M; Charles-Bruneau Cancer Center, Department of Pediatrics, Faculty of Medicine, University of Montreal, Montreal, QC, Canada., Théorêt Y; Department of Pharmacology, University of Montreal, Montreal, QC, Canada; Clinical Pharmacology Unit, Centre Hospitalier Universitaire Sainte-Justine, Montreal, QC, Canada., Duval M; Charles-Bruneau Cancer Center, Department of Pediatrics, Faculty of Medicine, University of Montreal, Montreal, QC, Canada., Keizer RJ; Department of Bioengineering and Therapeutic Sciences, University of California San Francisco, CA, USA; InsightRX, San Francisco, CA, USA., Bittencourt H; Charles-Bruneau Cancer Center, Department of Pediatrics, Faculty of Medicine, University of Montreal, Montreal, QC, Canada., Hassan M; Division of Experimental Cancer Medicine, Clinical Research Centre, Laboratory Medicine, Karolinska Institutet, Stockholm, Sweden., Güngör T; Division of Stem Cell Transplantation and Children's Research Center, University Children's Hospital Zürich, Zürich, Switzerland., Wynn RF; Department of Haematology and Bone Marrow Transplantation, The Royal Manchester Children's Hospital, Manchester, UK., Veys P; Bone Marrow Transplantation Department, Great Ormond Street Hospital for Children, London, UK., Cuvelier GD; CancerCare Manitoba, Winnipeg, MB, Canada., Marktel S; Stem Cell Program, IRCCS San Raffaele Scientific Institute, Milan, Italy., Chiesa R; Bone Marrow Transplantation Department, Great Ormond Street Hospital for Children, London, UK; Stem Cell Program, IRCCS San Raffaele Scientific Institute, Milan, Italy., Cowan MJ; Pediatric Allergy, Immunology, and Bone Marrow Transplantation Division, University of California San Francisco, CA, USA., Slatter MA; The Institute of Cellular Medicine, Newcastle University, Newcastle, UK., Stricherz MK; Department of Hematopoietic Cell Transplant, Hematology, and Oncology, University of Minnesota Masonic Children's Hospital, Minneapolis, MN, USA., Jennissen C; Department of Hematopoietic Cell Transplant, Hematology, and Oncology, University of Minnesota Masonic Children's Hospital, Minneapolis, MN, USA., Long-Boyle JR; Department of Clinical Pharmacy, University of California San Francisco, CA, USA., Boelens JJ; 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.
Jazyk:	angličtina
Zdroj:	The Lancet. Haematology [Lancet Haematol] 2016 Nov; Vol. 3 (11), pp. e526-e536. Date of Electronic Publication: 2016 Oct 13.
DOI:	10.1016/S2352-3026(16)30114-4
Abstrakt:	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 (AUC NONMEM ), non-compartmental analysis (AUC from 0 to infinity [AUC 0-∞ ] and to the next dose [AUC 0-τ ]), and by individual centres using various approaches (AUC centre ). 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. Findings: 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 AUC NONMEM was 74·4 mg × h/L (95% CI 31·1-104·6), which correlated with the standardised method AUC 0-∞ (r 2 =0·74), but the latter correlated poorly with AUC centre (r 2 =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). Interpretation: 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. Funding: 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. (Copyright © 2016 Elsevier Ltd. All rights reserved.)
Databáze:	MEDLINE
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