Biology of Blood and Marrow Transplantation
Volume 13, Issue 7 , Pages 853-862 , July 2007

Cyclophosphamide following Targeted Oral Busulfan as Conditioning for Hematopoietic Cell Transplantation: Pharmacokinetics, Liver Toxicity, and Mortality

  • Jeannine S. McCune

      Affiliations

    • Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington
    • University of Washington School of Pharmacy, Seattle, Washington
    • Corresponding Author InformationCorrespondence and reprint requests: Jeannine S. McCune, PharmD, Department of Pharmacy, Box 357630, University of Washington, Seattle, WA 98195.
    • ,
  • Ami Batchelder

      Affiliations

    • Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington
    • ,
  • H. Joachim Deeg

      Affiliations

    • Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington
    • University of Washington School of Medicine, Seattle, Washington
    • ,
  • Ted Gooley

      Affiliations

    • Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington
    • ,
  • Scott Cole

      Affiliations

    • Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington
    • ,
  • Brian Phillips

      Affiliations

    • Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington
    • ,
  • H. Gary Schoch

      Affiliations

    • Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington
    • ,
  • George B. McDonald

      Affiliations

    • Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington
    • University of Washington School of Medicine, Seattle, Washington

Received 25 January 2007 ,Accepted 29 March 2007.

References 

  1. Santos GW. Busulfan (Bu) and cyclophosphamide (Cy) for marrow transplantation. Bone Marrow Transplant. 1989;4(Suppl 1):236–239
  2. Slattery JT, Sanders JE, Buckner CD, et al. Graft-rejection and toxicity following bone marrow transplantation in relation to busulfan pharmacokinetics. Bone Marrow Transplant. 1995;16:31–42
  3. Grochow LB. Busulfan disposition: the role of therapeutic monitoring in bone marrow transplantation induction regimens. Semin Oncol. 1993;20:18–25
  4. Dix SP, Wingard JR, Mullins RE, et al. Association of busulfan area under the curve with veno-occlusive disease following BMT. Bone Marrow Transplant. 1996;17:225–230
  5. Slattery JT, Clift RA, Buckner CD, et al. Marrow transplantation for chronic myeloid leukemia: the influence of plasma busulfan levels on the outcome of transplantation. Blood. 1997;89:3055–3060
  6. Radich JP, Gooley T, Bensinger W, et al. HLA-matched related hematopoietic cell transplantation for chronic-phase CML using a targeted busulfan and cyclophosphamide preparative regimen. Blood. 2003;102:31–35
  7. DeLeve LD, Wang X. Role of oxidative stress and glutathione in busulfan toxicity in cultured murine hepatocytes. Pharmacology. 2000;60:143–154
  8. McCune JS, Gibbs JP, Slattery JT. Plasma concentration monitoring of busulfan: does it improve clinical outcome?. Clin Pharmacokinet. 2000;39:155–165
  9. Kashyap A, Wingard J, Cagnoni P, et al. Intravenous versus oral busulfan as part of a busulfan/cyclophosphamide preparative regimen for allogeneic hematopoietic stem cell transplantation: decreased incidence of hepatic venoocclusive disease (HVOD), HVOD-related mortality, and overall 100-day mortality. Biol Blood Marrow Transplant. 2002;8:493–500
  10. Lee JH, Choi SJ, Lee JH, et al. Decreased incidence of hepatic veno-occlusive disease and fewer hemostatic derangements associated with intravenous busulfan vs oral busulfan in adults conditioned with busulfan + cyclophosphamide for allogeneic bone marrow transplantation. Ann Hematol. 2005;84:321–330
  11. Deeg HJ, Storer B, Slattery JT, et al. Conditioning with targeted busulfan and cyclophosphamide for hemopoietic stem cell transplantation from related and unrelated donors in patients with myelodysplastic syndrome. Blood. 2002;100:1201–1207
  12. Deeg HJ, Storer BE, Boeckh M, et al. Reduced incidence of acute and chronic graft-versus-host disease with the addition of thymoglobulin to a targeted busulfan/cyclophosphamide regimen. Biol Blood Marrow Transplant. 2006;12:573–584
  13. Williams CB, Day SD, Reed MD, et al. Dose modification protocol using intravenous busulfan (Busulfex) and cyclophosphamide followed by autologous or allogeneic peripheral blood stem cell transplantation in patients with hematologic malignancies. Biol Blood Marrow Transplant. 2004;10:614–623
  14. DeLeve LD. Cellular target of cyclophosphamide toxicity in the murine liver: role of glutathione and site of metabolic activation. Hepatology. 1996;24:830–837
  15. McDonald GB, Slattery JT, Bouvier ME, et al. Cyclophosphamide metabolism, liver toxicity, and mortality following hematopoietic stem cell transplantation. Blood. 2003;101:2043–2048
  16. Gibbs JP, Gooley T, Corneau B, et al. The impact of obesity and disease on busulfan oral clearance in adults. Blood. 1999;93:4436–4440
  17. Andersson BS, Kashyap A, Gian V, et al. Conditioning therapy with intravenous busulfan and cyclophosphamide (i.v. BuCy2) for hematologic malignancies prior to allogeneic stem cell transplantation: a phase II study. Biol Blood Marrow Transplant. 2002;8:145–154
  18. Slattery JT, Kalhorn TF, McDonald GB, et al. Conditioning regimen-dependent disposition of cyclophosphamide and hydroxycyclophosphamide in human marrow transplantation patients. J Clin Oncol. 1996;14:1484–1494
  19. Petersdorf EW. HLA matching in allogeneic stem cell transplantation. Curr Opin Hematol. 2004;11:386–391
  20. Petersdorf EW, Anasetti C, Martin PJ. Limits of HLA mismatching in unrelated hematopoietic cell transplantation. Blood. 2004;104:2976–2980
  21. Marr KA, Leisenring W, Crippa F, et al. Cyclophosphamide metabolism is affected by azole antifungals. Blood. 2004;103:1557–1559
  22. Kalhorn TF, Howald WN, Cole S, et al. Rapid quantitation of cyclophosphamide metabolites in plasma by liquid chromatography-mass spectrometry. J Chromatogr B Anal Technol Biomed Life Sci. 2006;835:105–113
  23. McDonald GB, Hinds MS, Fisher LD, et al. Veno-occlusive disease of the liver and multiorgan failure after bone marrow transplantation: a cohort study of 355 patients. Ann Intern Med. 1993;118:255–267
  24. Yule SM, Boddy AV, Cole M, et al. Cyclophosphamide metabolism in children. Cancer Res. 1995;55:803–809
  25. Yule SM, Boddy AV, Cole M, et al. Cyclophosphamide pharmacokinetics in children. Br J Clin Pharmacol. 1996;41:13–19
  26. Yule SM, Price L, Cole M, Pearson AD, Boddy AV. Cyclophosphamide metabolism in children following a 1-h and a 24-h infusion. Cancer Chemother Pharmacol. 2001;47:222–228
  27. Yule SM, Price L, McMahon AD, Pearson AD, Boddy AV. Cyclophosphamide metabolism in children with non-Hodgkin’s lymphoma. Clin Cancer Res. 2004;10:455–460
  28. Tasso MJ, Boddy AV, Price L, Wyllie RA, Pearson AD, Idle JR. Pharmacokinetics and metabolism of cyclophosphamide in paediatric patients. Cancer Chemother Pharmacol. 1992;30:207–211
  29. Qiu R, Yao A, Vicini P, et al. Diminishing the risk of nonrelapse mortality in hematopoietic stem cell transplantation: prediction of exposure to the cyclophosphamide metabolite carboxyethylphosphoramide mustard. Clin Pharmacol Ther. 2004;76:270–280
  30. Yule SM, Walker D, Cole M, et al. The effect of fluconazole on cyclophosphamide metabolism in children. Drug Metab Dispos. 1999;27:417–421
  31. Yule SM, Walker D, Pearson AD, Idle JR. Potential inhibition of alkylating agent metabolism by fluconazole. Eur J Clin Microbiol Infect Dis. 1994;13:1086–1087
  32. de Jonge ME, Huitema AD, Rodenhuis S, Beijnen JH. Clinical pharmacokinetics of cyclophosphamide. Clin Pharmacokinet. 2005;44:1135–1164
  33. Hassan M, Ljungman P, Ringden O, et al. The effect of busulphan on the pharmacokinetics of cyclophosphamide and its 4-hydroxy metabolite: time interval influence on therapeutic efficacy and therapy-related toxicity. Bone Marrow Transplant. 2000;25:915–924
  34. Anderson GD. A Mechanistic Approach to Antiepileptic Drug Interactions. New York: Marcel Dekker, Inc; 2004;
  35. Potschka H, Fedrowitz M, Loscher W. Multidrug resistance protein MRP2 contributes to blood-brain barrier function and restricts antiepileptic drug activity. J Pharmacol Exp Ther. 2003;306:124–131
  36. Huang Z, Roy P, Waxman DJ. Role of human liver microsomal CYP3A4 and CYP2B6 in catalyzing N-dechloroethylation of cyclophosphamide and ifosfamide. Biochem Pharmacol. 2000;59:961–972
  37. Ren S, Yang JS, Kalhorn TF, Slattery JT. Oxidation of cyclophosphamide to 4-hydroxycyclophosphamide and deschloroethylcyclophosphamide in human liver microsomes. Cancer Res. 1997;57:4229–4235
  38. Qiu R, Kalhorn TF, Slattery JT. ABCC2-mediated biliary transport of 4-glutathionylcyclophosphamide and its contribution to elimination of 4-hydroxycyclophosphamide in rat. J Pharmacol Exp Ther. 2004;308:1204–1212
  39. Faucette SR, Wang H, Hamilton GA, et al. Regulation of CYP2B6 in primary human hepatocytes by prototypical inducers. Drug Metab Dispos. 2004;32:348–358
  40. de Jonge ME, Huitema AD, van Dam SM, Beijnen JH, Rodenhuis S. Significant induction of cyclophosphamide and thiotepa metabolism by phenytoin. Cancer Chemother Pharmacol. 2005;55:507–510
  41. Chen TL, Passos-Coelho JL, Noe DA, et al. Nonlinear pharmacokinetics of cyclophosphamide in patients with metastatic breast cancer receiving high-dose chemotherapy followed by autologous bone marrow transplantation. Cancer Res. 1995;55:810–816
  42. Sladek NE, Doeden D, Powers JF, Krivit W. Plasma concentrations of 4-hydroxycyclophosphamide and phosphoramide mustard in patients repeatedly given high doses of cyclophosphamide in preparation for bone marrow transplantation. Cancer Treat Rep. 1984;68:1247–1254
  43. Geraci JP, Mariano MS, Jackson KL. Radiation hepatology of the rat: microvascular fibrosis and enhancement of liver dysfunction by diet and drugs. Radiat Res. 1992;129:322–332
  44. Tutschka PJ, Copelan EA, Klein JP. Bone marrow transplantation for leukemia following a new busulfan and cyclophosphamide regimen. Blood. 1987;70:1382–1388
  45. Lichtman SM, Ratain MJ, Van Echo DA, et al. Phase I trial of granulocyte-macrophage colony-stimulating factor plus high-dose cyclophosphamide given every 2 weeks: a cancer and leukemia group B study. J Natl Cancer Inst. 1993;85:1319–1326
  46. Brodsky RA, Sensenbrenner LL, Smith BD, et al. Durable treatment-free remission after high-dose cyclophosphamide therapy for previously untreated severe aplastic anemia. Ann Intern Med. 2001;135:477–483
  47. Akay H, Akay T, Secilmis S, Kocak Z, Donderici O. Hepatotoxicity after low-dose cyclophosphamide therapy. South Med J. 2006;99:1399–1400
  48. Mok CC, Wong WM, Shek TW, Ho CT, Lau CS, Lai CL. Cumulative hepatotoxicity induced by continuous low-dose cyclophosphamide therapy. Am J Gastroenterol. 2000;95:845–846
  49. Goldberg JW, Lidsky MD. Cyclophosphamide-associated hepatotoxicity. South Med J. 1985;78:222–223
  50. Peters WP, Henner WD, Grochow LB, et al. Clinical and pharmacologic effects of high dose single agent busulfan with autologous bone marrow support in the treatment of solid tumors. Cancer Res. 1987;47:6402–6406
  51. Ayash LJ, Wright JE, Tretyakov O, et al. Cyclophosphamide pharmacokinetics: correlation with cardiac toxicity and tumor response. J Clin Oncol. 1992;10:995–1000
  52. Petros WP, Broadwater G, Berry D, et al. Association of high-dose cyclophosphamide, cisplatin, and carmustine pharmacokinetics with survival, toxicity, and dosing weight in patients with primary breast cancer. Clin Cancer Res. 2002;8:698–705
  53. Nieto Y, Cagnoni PJ, Bearman SI, Shpall EJ, Matthes S, Jones RB. Cardiac toxicity following high-dose cyclophosphamide, cisplatin, and BCNU (Stamp-I) for Breast cancer. Biol Blood Marrow Transplant. 2000;6:198–203
  54. Grochow LB, Jones RJ, Brundrett RB, et al. Pharmacokinetics of busulfan: correlation with veno-occlusive disease in patients undergoing bone marrow transplantation. Cancer Chemother Pharmacol. 1989;25:55–61
  55. Hassan M, Oberg G, Ljungman P. Correlation between hepatic veno-occlusive disease (VOD) and busulphan levels using limited sampling model for dose estimation. Blood. 1997;251a
  56. Kashyap A, Synold T, Parker P, O’Donnell MR, Nademanee A, Forman SJ. First dose area under the curve (AUC) of oral busulfan predicts risk of developing veno-occlusive diseases (VOD) in adult allogeneic bone marrow tranplant (BMT) patients. Proc ASCO. 1997;16:215a
  57. Pawlowska AB, Blazar BR, Angelucci E, Baronciani D, Shu XO, Bostrom B. Relationship of plasma pharmacokinetics of high-dose oral busulfan to the outcome of allogeneic bone marrow transplantation in children with thalassemia. Bone Marrow Transplant. 1997;20:915–920
  58. Poonkuzhali B, Srivastava A, Quernin MH, et al. Pharmacokinetics of oral busulphan in children with beta thalassaemia major undergoing allogeneic bone marrow transplantation. Bone Marrow Transplant. 1999;24:5–11
  59. Nilsson C, Forsman J, Hassan Z, et al. Effect of altering administration order of busulphan and cyclophosphamide on the myeloablative and immunosuppressive properties of the conditioning regimen in mice. Exp Hematol. 2005;33:380–387
  60. Meresse V, Hartmann O, Vassal G, et al. Risk factors for hepatic veno-occlusive disease after high-dose busulfan-containing regimens followed by autologous bone marrow transplantation: a study in 136 children. Bone Marrow Transplant. 1992;10:135–141
  61. Russell JA, Tran HT, Quinlan D, et al. Once-daily intravenous busulfan given with fludarabine as conditioning for allogeneic stem cell transplantation: study of pharmacokinetics and early clinical outcomes. Biol Blood Marrow Transplant. 2002;8:468–476
  62. Bornhauser M, Storer B, Slattery JT, et al. Conditioning with fludarabine and targeted busulfan for transplantation of allogeneic hematopoietic stem cells. Blood. 2003;102:820–826
  63. de Lima M, Couriel D, Thall PF, et al. Once-daily intravenous busulfan and fludarabine: clinical and pharmacokinetic results of a myeloablative, reduced-toxicity conditioning regimen for allogeneic stem cell transplantation in AML and MDS. Blood. 2004;104:857–864

PII: S1083-8791(07)00236-4

doi: 10.1016/j.bbmt.2007.03.012

Biology of Blood and Marrow Transplantation
Volume 13, Issue 7 , Pages 853-862 , July 2007

Article Tools

* Image Usage & Resolution