Busulfan systemic exposure relative to regimen-related toxicity and acute graft-versus-host disease: Defining a therapeutic window for IV BuCy2 in chronic myelogenous leukemia

Borje S. Andersson, Peter F. Thall, Timothy Madden, Daniel Couriel, Xuemei Wang, Hai T. Tran, Paolo Anderlini, Marcos De Lima, James Gajewski, Richard E. Champlin

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    166 Scopus citations

    Abstract

    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.

    Original languageEnglish (US)
    Pages (from-to)477-485
    Number of pages9
    JournalBiology of Blood and Marrow Transplantation
    Volume8
    Issue number9
    DOIs
    StatePublished - Jan 1 2002

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    Keywords

    • Acute-versus-host disease
    • Busulfan
    • Stem cell transplantation
    • Systemic exposure

    ASJC Scopus subject areas

    • Hematology
    • Transplantation

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