TY - JOUR
T1 - Association between Busulfan Exposure and Outcome in Children Receiving Intravenous Busulfan before Hematologic Stem Cell Transplantation
AU - Bartelink, Imke H.
AU - Bredius, Robert G.M.
AU - Belitser, Svetlana V.
AU - Suttorp, Marit M.
AU - Bierings, Marc
AU - Knibbe, Catherijne A.J.
AU - Egeler, Maarten
AU - Lankester, Arjan C.
AU - Egberts, Atoine C.G.
AU - Zwaveling, Juliette
AU - Boelens, Jaap Jan
N1 - Funding Information:
Financial disclosure : This work was supported in part by The Dutch Top Institute Pharma. The authors acknowledge the cooperation of the medical and nursing staff, data managers, and pharmacy staff of the Departments of Hematology and Immunology and Clinical Pharmacy of University Medical Center Utrecht and Leiden University Medical Center. They thank Drs M. Danhof, L. Ball, and L. Sanders for their contributions to the design of the study and the preparation of the manuscript. Author contributions: I.B. performed and designed research, analyzed the data, and wrote the manuscript; R.B. performed and designed research, collected data, and contributed to the writing of the manuscript; S.B. performed statistical analysis and contributed to the writing of the manuscript; M.S. collected and analyzed data; M.B. contributed to the writing of the manuscript; C.K. contributed to the study design and to the writing of the manuscript; M.E. collected data and contributed to the writing of the manuscript; A.L. collected data and contributed to the writing of the manuscript; A.E. contributed to the study design and the writing of the manuscript; J.Z. contributed to the study design, collected data, and contributed to the writing of the manuscript; and J.B. designed and performed research, analyzed data, and wrote the manuscript.
Copyright:
Copyright 2009 Elsevier B.V., All rights reserved.
PY - 2009/2
Y1 - 2009/2
N2 - Busulfan, combined with therapeutic drug monitoring-guided dosing, is associated with higher event-free survival (EFS) rates due to fewer graft failures/relapses and lower toxicity. The optimal target area under the curve (AUC) and dosing schedule of intravenous busulfan in children undergoing hematopoietic stem cell transplantation (HSCT) remain unclear, however. We conducted a retrospective analysis of the association between busulfan exposure and clinical outcome in 102 children age 0.2 to 21 years who received busulfan 1 or 4 times daily before undergoing HSCT (46 malignant and 56 nonmalignant indications). EFS and overall survival after a median of 2 years of follow-up were 68% and 72%, respectively. EFS was optimal when the exposure of busulfan (AUC) was 78 mg*h/L (95% confidence interval = 74 to 82 mg*h/L). Acute graft-versus-host disease (aGVHD) grade II-IV occurred more frequently with greater busulfan exposure. The addition of melphalan was an independent risk factor; melphalan use combined with high busulfan exposure (AUC > 74 mg*h/L) was associated with high incidences of aGVHD (58%), veno-occlusive disease (66%), and mucositis grade III-IV (26%). Dosing frequency (1 or 4 times daily) was not related to any outcome. In conclusion, dose targeting of busulfan to a narrow therapeutic range was found to increase EFS in children. Adding melphalan to optimal busulfan exposure is associated with a high incidence of toxicity.
AB - Busulfan, combined with therapeutic drug monitoring-guided dosing, is associated with higher event-free survival (EFS) rates due to fewer graft failures/relapses and lower toxicity. The optimal target area under the curve (AUC) and dosing schedule of intravenous busulfan in children undergoing hematopoietic stem cell transplantation (HSCT) remain unclear, however. We conducted a retrospective analysis of the association between busulfan exposure and clinical outcome in 102 children age 0.2 to 21 years who received busulfan 1 or 4 times daily before undergoing HSCT (46 malignant and 56 nonmalignant indications). EFS and overall survival after a median of 2 years of follow-up were 68% and 72%, respectively. EFS was optimal when the exposure of busulfan (AUC) was 78 mg*h/L (95% confidence interval = 74 to 82 mg*h/L). Acute graft-versus-host disease (aGVHD) grade II-IV occurred more frequently with greater busulfan exposure. The addition of melphalan was an independent risk factor; melphalan use combined with high busulfan exposure (AUC > 74 mg*h/L) was associated with high incidences of aGVHD (58%), veno-occlusive disease (66%), and mucositis grade III-IV (26%). Dosing frequency (1 or 4 times daily) was not related to any outcome. In conclusion, dose targeting of busulfan to a narrow therapeutic range was found to increase EFS in children. Adding melphalan to optimal busulfan exposure is associated with a high incidence of toxicity.
KW - Allogeneic stem cell transplantation
KW - Busulfan
KW - Pediatrics
KW - Therapeutic drug monitoring
UR - http://www.scopus.com/inward/record.url?scp=58249143575&partnerID=8YFLogxK
U2 - 10.1016/j.bbmt.2008.11.022
DO - 10.1016/j.bbmt.2008.11.022
M3 - Article
C2 - 19167683
AN - SCOPUS:58249143575
VL - 15
SP - 231
EP - 241
JO - Biology of Blood and Marrow Transplantation
JF - Biology of Blood and Marrow Transplantation
SN - 1083-8791
IS - 2
ER -