Association Between the Magnitude of Intravenous Busulfan Exposure and Development of Hepatic Veno-Occlusive Disease in Children and Young Adults Undergoing Myeloablative Allogeneic Hematopoietic Cell Transplantation

Tim Bognàr, Imke H. Bartelink, Toine C.G. Egberts, Carin M.A. Rademaker, A. Birgitta Versluys, Mary A. Slatter, Morris Kletzel, Christa E. Nath, Geoffrey D.E. Cuvelier, Rada M. Savic, Christopher Dvorak, Janel R. Long-Boyle, Morton J. Cowan, Henrique Bittencourt, Robbert G.M. Bredius, Tayfun Güngör, Peter J. Shaw, Marc Ansari, Moustapha Hassan, Maja KrajinovicGeorg Hempel, Sarah Marktel, Robert Chiesa, Yves Théoret, Troy Lund, Paul J. Orchard, Robert F. Wynn, Jaap Jan Boelens, Arief Lalmohamed

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish (US)
Pages (from-to)196-202
Number of pages7
JournalTransplantation and Cellular Therapy
Volume28
Issue number4
DOIs
StatePublished - Apr 2022

Bibliographical note

Funding Information:
Financial disclosure: There are no disclosures to report. Conflict of interest statement: M. Ansari received traveling grants from Jazz pharmaceuticals. H. Bittencourt is on the advisory board from Jazz Pharmaceutics. T. Güngör is on the advisory board from Jazz Pharmaceutics. C.C. Dvorak is a consultant for Jazz Pharmaceuticals. J.J. Boelens is a consultant for Avrobio, BlueRock, Race Oncology, Advanced Clinical, Omeros, and Sanofi and on the advisory board for Medexus, Equillium, Sobi. Authorship statement: T.B. T.C.G.E. I.H.B. C.M.A.R. A.B.V. J.J.B. and A.L. contributed to the conception, study management and design of the study. T.B. I.H.B. T.C.G.E. and A.L. contributed to data analysis and manuscript writing. All authors critically reviewed the manuscript and approved the final version. Financial disclosure: See Acknowledgments on page 200.

Publisher Copyright:
© 2022 The American Society for Transplantation and Cellular Therapy

Keywords

  • Busulfan exposure
  • Hematopoietic cell transplantation
  • Sinusoidal obstruction syndrome
  • Veno-occlusive disease

PubMed: MeSH publication types

  • Journal Article
  • Observational Study

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