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Lookup NU author(s): Professor Mary Slatter
This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).
© 2022 The American Society for Transplantation and Cellular Therapy. Intravenous busulfan is widely used as part of myeloablative conditioning regimens in children and young adults undergoing allogeneic hematopoietic cell transplantation (HCT). Hepatic veno-occlusive disease/sinusoidal obstruction syndrome (VOD/SOS) is a serious clinical problem observed with busulfan-based conditioning HCT. The development of VOD/SOS may be associated with busulfan exposure. Getting more insight into the association between busulfan exposure and the development of VOD/SOS enables further optimization of dosing and treatment strategies. The objective of this study was to assess the association between the magnitude of busulfan exposure and the occurrence of VOD/SOS in children and young adults undergoing myeloablative conditioning with a busulfan-containing regimen before allogeneic HCT. In this observational study we included all patients who underwent allogeneic HCT with intravenous busulfan as part of the conditioning regimen at 15 pediatric transplantation centers between 2000 and 2015. The endpoint was the development of VOD/SOS. The magnitude of busulfan exposure was estimated using nonlinear mixed effect modeling and expressed as the maximal concentration (Cmax; day 1 and day 1 to 4 Cmax), cumulative area under the curve (AUC; day 1, highest 1-day AUC in 4 days, and 4-day cumulative AUC), cumulative time above a concentration of 300 µg/L, and clearance on day 1. A total of 88 out of 697 patients (12.6%) developed VOD/SOS. The number of alkylators in the conditioning regimen was a strong effect modifier; therefore we stratified the regression analysis for the number of alkylators. For patients receiving only busulfan as one alkylator (36.3%, n = 253), cumulative busulfan exposure (>78 mg × h/L) was associated with increased VOD/SOS risk (12.6% versus 4.7%; odds ratio [OR] = 2.95, 95% confidence interval [CI] 1.13 to 7.66). For individuals receiving busulfan with one or two additional alkylators (63.7%, n = 444), cumulative busulfan exposure (≤78 and >78 mg × h/L) did not further increase the risk of VOD/SOS (15.4% versus 15.2%; OR = 1.03, 95% CI 0.61 to 1.75). The effect of the magnitude of busulfan exposure on VOD/SOS risk in children and young adults undergoing HCT is dependent on the number of alkylators. In patients receiving busulfan as the only alkylator, higher cumulative busulfan exposure increased the risk of VOD/SOS, whereas in those receiving multiple alkylators, the magnitude of busulfan exposure did not further increase this risk.
Author(s): Bognar T, Bartelink IH, Egberts TCG, Rademaker CMA, Versluys AB, Slatter MA, Kletzel M, Nath CE, Cuvelier GDE, Savic RM, Dvorak C, Long-Boyle JR, Cowan MJ, Bittencourt H, Bredius RGM, Gungor T, Shaw PJ, Ansari M, Hassan M, Krajinovic M, Hempel G, Marktel S, Chiesa R, Theoret Y, Lund T, Orchard PJ, Wynn RF, Boelens JJ, Lalmohamed A
Publication type: Article
Publication status: Published
Journal: Transplantation and Cellular Therapy
Year: 2022
Volume: 28
Issue: 4
Pages: 196-202
Print publication date: 01/04/2022
Online publication date: 19/01/2022
Acceptance date: 13/01/2022
Date deposited: 23/03/2022
ISSN (print): 2666-6375
ISSN (electronic): 2666-6367
Publisher: Elsevier BV
URL: https://doi.org/10.1016/j.jtct.2022.01.013
DOI: 10.1016/j.jtct.2022.01.013
PubMed id: 35065280
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