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 Krajinovic; Georg Hempel; Sarah Marktel; Robert Chiesa; Yves Théoret; Troy Lund; Paul J. Orchard; Robert F. Wynn; Jaap Jan Boelens; Arief Lalmohamed

doi:10.1016/j.jtct.2022.01.013

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

^*Corresponding author for this work

Pediatrics

Research output: Contribution to journal › Article › peer-review

15 Scopus citations

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 language	English (US)
Pages (from-to)	196-202
Number of pages	7
Journal	Transplantation and Cellular Therapy
Volume	28
Issue number	4
DOIs	https://doi.org/10.1016/j.jtct.2022.01.013
State	Published - Apr 2022

Funding

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.

Keywords

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

ASJC Scopus subject areas

Transplantation
Molecular Medicine
Hematology
Immunology and Allergy
Cell Biology

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Bognàr, T., Bartelink, I. H., Egberts, T. C. G., Rademaker, C. M. A., Versluys, A. B., Slatter, M. A., Kletzel, M., Nath, C. E., Cuvelier, G. D. E., Savic, R. M., Dvorak, C., Long-Boyle, J. R., Cowan, M. J., Bittencourt, H., Bredius, R. G. M., Güngör, T., Shaw, P. J., Ansari, M., Hassan, M., ... Lalmohamed, A. (2022). 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. Transplantation and Cellular Therapy, 28(4), 196-202. https://doi.org/10.1016/j.jtct.2022.01.013

@article{51b2f12137a04b6c9c4b32050301645c,

title = "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",

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.",

keywords = "Busulfan exposure, Hematopoietic cell transplantation, Sinusoidal obstruction syndrome, Veno-occlusive disease",

author = "Tim Bogn{\`a}r and Bartelink, {Imke H.} and Egberts, {Toine C.G.} and Rademaker, {Carin M.A.} and Versluys, {A. Birgitta} and Slatter, {Mary A.} and Morris Kletzel and Nath, {Christa E.} and Cuvelier, {Geoffrey D.E.} and Savic, {Rada M.} and Christopher Dvorak and Long-Boyle, {Janel R.} and Cowan, {Morton J.} and Henrique Bittencourt and Bredius, {Robbert G.M.} and Tayfun G{\"u}ng{\"o}r and Shaw, {Peter J.} and Marc Ansari and Moustapha Hassan and Maja Krajinovic and Georg Hempel and Sarah Marktel and Robert Chiesa and Yves Th{\'e}oret and Troy Lund and Orchard, {Paul J.} and Wynn, {Robert F.} and Boelens, {Jaap Jan} and Arief Lalmohamed",

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. G{\"u}ng{\"o}r 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: {\textcopyright} 2022 The American Society for Transplantation and Cellular Therapy",

year = "2022",

month = apr,

doi = "10.1016/j.jtct.2022.01.013",

language = "English (US)",

volume = "28",

pages = "196--202",

journal = "Transplantation and Cellular Therapy",

issn = "2666-6367",

publisher = "Elsevier BV",

number = "4",

}

Bognàr, 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, Güngör, T, Shaw, PJ, Ansari, M, Hassan, M, Krajinovic, M, Hempel, G, Marktel, S, Chiesa, R, Théoret, Y, Lund, T, Orchard, PJ, Wynn, RF, Boelens, JJ & Lalmohamed, A 2022, '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', Transplantation and Cellular Therapy, vol. 28, no. 4, pp. 196-202. https://doi.org/10.1016/j.jtct.2022.01.013

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. / Bognàr, Tim; Bartelink, Imke H.; Egberts, Toine C.G. et al.
In: Transplantation and Cellular Therapy, Vol. 28, No. 4, 04.2022, p. 196-202.

Research output: Contribution to journal › Article › peer-review

TY - JOUR

T1 - 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

AU - Bognàr, Tim

AU - Bartelink, Imke H.

AU - Egberts, Toine C.G.

AU - Rademaker, Carin M.A.

AU - Versluys, A. Birgitta

AU - Slatter, Mary A.

AU - Kletzel, Morris

AU - Nath, Christa E.

AU - Cuvelier, Geoffrey D.E.

AU - Savic, Rada M.

AU - Dvorak, Christopher

AU - Long-Boyle, Janel R.

AU - Cowan, Morton J.

AU - Bittencourt, Henrique

AU - Bredius, Robbert G.M.

AU - Güngör, Tayfun

AU - Shaw, Peter J.

AU - Ansari, Marc

AU - Hassan, Moustapha

AU - Krajinovic, Maja

AU - Hempel, Georg

AU - Marktel, Sarah

AU - Chiesa, Robert

AU - Théoret, Yves

AU - Lund, Troy

AU - Orchard, Paul J.

AU - Wynn, Robert F.

AU - Boelens, Jaap Jan

AU - Lalmohamed, Arief

N1 - 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

PY - 2022/4

Y1 - 2022/4

N2 - 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.

AB - 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.

KW - Busulfan exposure

KW - Hematopoietic cell transplantation

KW - Sinusoidal obstruction syndrome

KW - Veno-occlusive disease

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Bognàr T, Bartelink IH, Egberts TCG, Rademaker CMA, Versluys AB, Slatter MA et al. 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. Transplantation and Cellular Therapy. 2022 Apr;28(4):196-202. doi: 10.1016/j.jtct.2022.01.013

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

Abstract

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