TY - JOUR
T1 - Busulfan systemic exposure relative to regimen-related toxicity and acute graft-versus-host disease
T2 - Defining a therapeutic window for IV BuCy2 in chronic myelogenous leukemia
AU - Andersson, Borje S.
AU - Thall, Peter F.
AU - Madden, Timothy
AU - Couriel, Daniel
AU - Wang, Xuemei
AU - Tran, Hai T.
AU - Anderlini, Paolo
AU - De Lima, Marcos
AU - Gajewski, James
AU - Champlin, Richard E.
N1 - Funding Information:
This work was sponsored by the U.S. Food and Drug Administration through Grants FD-R-001112-02 and FD-R-001650-02 and by the National Cancer Institute through P01-CA49639 and 2P30-CA16672.
PY - 2002
Y1 - 2002
N2 - Complete bioavailability of IV busulfan (Bu) provides dose assurance by reducing the interdose and interpatient variability in Bu systemic exposure (Bu-SE) associated with the oral formulation. We hypothesized that Bu-SE, represented by the area under the plasma concentration versus time curve (AUC), would correlate with treatment outcome after allogeneic hematopoietic stem cell transplantation (HSCT) for chronic myelogenous leukemia (CML). Therefore, we analyzed the risk of death, incidence of regimen-related toxicity, and incidence of acute GVHD (aGVHD) as functions of the per dose IV Bu AUC in 36 CML patients who received a HSCT from an HLA-matched family donor after the IV BuCy2 regimen. Per-dose Bu AUCs were calculated for each subject using data obtained for doses 1, 5, 9, and 13. Toxicity was evaluated using the modified National Cancer Institute criteria. Because no patient developed veno-occlusive disease, increased serum bilirubin was used to characterize hepatotoxicity. We found that the probabilities of developing gastrointestinal toxicity (P = .01), hepatotoxicity (P < .01), mucositis (P = .09), and aGVHD (P < .01) all increased with increasing AUC. Further, the risk of death was significantly lower for patients having a per-dose AUC between approximately 950 and 1520 μMol-min, whereas the risk increased sharply with either lower or higher AUC values. These data suggest that an optimal Bu therapeutic window, based on per-dose AUC, exists. Given the ability of IV Bu to provide a more consistent per-dose AUC, these results should be useful in designing future IV Bu-based treatment protocols for stem cell transplantation.
AB - Complete bioavailability of IV busulfan (Bu) provides dose assurance by reducing the interdose and interpatient variability in Bu systemic exposure (Bu-SE) associated with the oral formulation. We hypothesized that Bu-SE, represented by the area under the plasma concentration versus time curve (AUC), would correlate with treatment outcome after allogeneic hematopoietic stem cell transplantation (HSCT) for chronic myelogenous leukemia (CML). Therefore, we analyzed the risk of death, incidence of regimen-related toxicity, and incidence of acute GVHD (aGVHD) as functions of the per dose IV Bu AUC in 36 CML patients who received a HSCT from an HLA-matched family donor after the IV BuCy2 regimen. Per-dose Bu AUCs were calculated for each subject using data obtained for doses 1, 5, 9, and 13. Toxicity was evaluated using the modified National Cancer Institute criteria. Because no patient developed veno-occlusive disease, increased serum bilirubin was used to characterize hepatotoxicity. We found that the probabilities of developing gastrointestinal toxicity (P = .01), hepatotoxicity (P < .01), mucositis (P = .09), and aGVHD (P < .01) all increased with increasing AUC. Further, the risk of death was significantly lower for patients having a per-dose AUC between approximately 950 and 1520 μMol-min, whereas the risk increased sharply with either lower or higher AUC values. These data suggest that an optimal Bu therapeutic window, based on per-dose AUC, exists. Given the ability of IV Bu to provide a more consistent per-dose AUC, these results should be useful in designing future IV Bu-based treatment protocols for stem cell transplantation.
KW - Acute-versus-host disease
KW - Busulfan
KW - Stem cell transplantation
KW - Systemic exposure
UR - http://www.scopus.com/inward/record.url?scp=0036398471&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=0036398471&partnerID=8YFLogxK
U2 - 10.1053/bbmt.2002.v8.pm12374452
DO - 10.1053/bbmt.2002.v8.pm12374452
M3 - Article
C2 - 12374452
AN - SCOPUS:0036398471
SN - 1083-8791
VL - 8
SP - 477
EP - 485
JO - Biology of Blood and Marrow Transplantation
JF - Biology of Blood and Marrow Transplantation
IS - 9
ER -