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

Biol Blood Marrow Transplant. 2002;8(9):477-85. doi: 10.1053/bbmt.2002.v8.pm12374452.


Complete bioavailability of i.v. 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 i.v. Bu AUC in 36 CML patients who received a HSCT from an HLA-matched family donor after the i.v. 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 microMol-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 i.v. Bu to provide a more consistent per-dose AUC, these results should be useful in designing future i.v.V Bu-based treatment protocols for stem cell transplantation.

Publication types

  • Clinical Trial
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Acute Disease
  • Adolescent
  • Adult
  • Antineoplastic Combined Chemotherapy Protocols / administration & dosage*
  • Antineoplastic Combined Chemotherapy Protocols / toxicity
  • Area Under Curve
  • Biological Availability
  • Busulfan / administration & dosage
  • Busulfan / pharmacokinetics*
  • Busulfan / toxicity*
  • Cyclophosphamide / administration & dosage
  • Dose-Response Relationship, Drug
  • Drug-Related Side Effects and Adverse Reactions
  • Female
  • Graft vs Host Disease / chemically induced
  • Graft vs Host Disease / prevention & control
  • Hematopoietic Stem Cell Transplantation
  • Humans
  • Infusions, Intravenous
  • Leukemia, Myelogenous, Chronic, BCR-ABL Positive / drug therapy*
  • Leukemia, Myelogenous, Chronic, BCR-ABL Positive / mortality
  • Leukemia, Myelogenous, Chronic, BCR-ABL Positive / therapy
  • Male
  • Middle Aged
  • Survival Analysis
  • Transplantation Conditioning / adverse effects
  • Transplantation Conditioning / standards
  • Transplantation, Homologous
  • Treatment Outcome


  • Cyclophosphamide
  • Busulfan

Supplementary concepts

  • BUCY-2 protocol