Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Article
  • Published:

Graft Rejection

Busulfan concentration and graft rejection in pediatric patients undergoing hematopoietic stem cell transplantation

Abstract

We retrospectively analyzed the relationship between busulfan average steady-state plasma concentration (CSS) and graft rejection in 53 children receiving busulfan/cyclophosphamide (BU/CY) preparative regimens prior to hematopoietic stem cell transplantation (HSCT). Patients received a total oral busulfan dose of 11 to 28 mg/kg followed by a total cyclophosphamide dose of 120 to 335 mg/kg in preparation for allogeneic grafts (HLA-matched or HLA partially matched sibling, parent or unrelated donor). Graft rejection occurred in eight (15%) patients. Busulfan CSS (P = 0.0024) was the only statistically significant predictor of rejection on univariate logistic regression analysis, with the risk of rejection decreasing with an increase in busulfan CSS. Severe (grade 3 or 4) regimen-related toxicity (RRT) occurred in four patients. Ten patients (19%) had a busulfan CSS higher than 900 ng/ml, one of whom had severe RRT. Higher and variable doses of cyclophosphamide may explain the lack of a relationship between busulfan CSS and RRT in children. It may be possible to improve the outcome of HSCT in pediatric patients receiving the BU/CY regimen through optimization of busulfan CSS and better definition of the contribution of activated cyclophosphamide metabolites to toxicity.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Figure 1

Similar content being viewed by others

References

  1. Tutschka PJ, Santos GW . Bone marrow transplantation in the busulfan-treated rat. III. Relationship between myelosuppression and immunosuppression for conditioning bone marrow recipients Transplantation 1977 24: 52 62

    Article  CAS  PubMed  Google Scholar 

  2. Santos GW, Tutschka PJ . Marrow transplantation in the busulfan-treated rat: preclinical model of aplastic anemia J Natl Cancer Inst 1974 53: 1781 1785

    CAS  PubMed  Google Scholar 

  3. Storb R, Weiden PL, Graham TC et al. Hemopoietic grafts between DLA-identical canine littermates following dimethyl myleran. Evidence for resistance to grafts not associated with DLA and abrogated by antithymocyte serum Transplantation 1977 24: 349 357

    Article  CAS  PubMed  Google Scholar 

  4. Storb R, Buckner CD, Dillingham LA, Thomas ED . Cyclophosphamide regimens in rhesus monkey with and without marrow infusion Cancer Res 1970 30: 2195 2203

    CAS  PubMed  Google Scholar 

  5. Storb R, Prentice RL, Thomas ED . Marrow transplantation for treatment of aplastic anemia. An analysis of factors associated with graft rejection New Engl J Med 1977 296: 61 66

    Article  CAS  PubMed  Google Scholar 

  6. Santos GW, Tutschka PJ, Brookmeyer R et al. Marrow transplantation for acute nonlymphocytic leukemia after treatment with busulfan and cyclophosphamide New Engl J Med 1983 309: 1347 1353

    Article  CAS  PubMed  Google Scholar 

  7. Tutschka PJ, Copelan EA, Klein JP . Bone marrow transplantation for leukemia following a new busulfan and cyclophosphamide regimen Blood 1987 70: 1382 1388

    CAS  PubMed  Google Scholar 

  8. Woods WG, Kobrinsky N, Buckley JD et al. Timed-sequential induction therapy improves postremission outcome in acute myeloid leukemia: a report from the Children's Cancer Group Blood 1996 87: 4979 4989

    CAS  PubMed  Google Scholar 

  9. Hassan M, Oberg G, Bekassy AN et al. Pharmacokinetics of high-dose busulphan in relation to age and chronopharmacology Cancer Chemother Pharmacol 1991 28: 130 134

    Article  CAS  PubMed  Google Scholar 

  10. Hassan M, Ljungman P, Bolme P et al. Busulfan bioavailability Blood 1994 84: 2144 2150

    CAS  PubMed  Google Scholar 

  11. Grochow LB, Krivit W, Whitley CB, Blazar B . Busulfan disposition in children Blood 1990 75: 1723 1727

    CAS  PubMed  Google Scholar 

  12. Regazzi MB, Locatelli F, Buggia I et al. Disposition of high-dose busulfan in pediatric patients undergoing bone marrow transplantation Clin Pharmacol Ther 1993 54: 45 52

    Article  CAS  PubMed  Google Scholar 

  13. Vassal G, Gouyette A, Hartmann O et al. Pharmacokinetics of high-dose busulfan in children Cancer Chemother Pharmacol 1989 24: 386 390

    Article  CAS  PubMed  Google Scholar 

  14. Vassal G, Deroussent A, Challine D et al. Is 600 mg/m2 the appropriate dosage of busulfan in children undergoing bone marrow transplantation? Blood 1992 79: 2475 2479

    CAS  PubMed  Google Scholar 

  15. Slattery JT, Sanders JE, Buckner CD et al. Graft-rejection and toxicity following bone marrow transplantation in relation to busulfan pharmacokinetics [published erratum appears in Bone Marrow Transplant 1996 Oct; 18(4): 829] Bone Marrow Transplant 1995 16: 31 42

    CAS  PubMed  Google Scholar 

  16. Gibbs JP, Murray G, Risler L et al. Age-dependent tetrahydrothiophenium ion formation in young children and adults receiving high-dose busulfan Cancer Res 1997 57: 5509 5516

    CAS  PubMed  Google Scholar 

  17. Gibbs JP, Liacouras CA, Baldassano RN, Slattery JT . Up-regulation of glutathione S-transferase activity in enterocytes of young children Drug Metab Dispos 1999 27: 1466 1469

    CAS  PubMed  Google Scholar 

  18. Bolinger AM, Zangwill AB, Slattery JT et al. An evaluation of engraftment, toxicity and busulfan concentration in children receiving bone marrow transplantation for leukemia or genetic disease Bone Marrow Transplant 2000 25: 925 930

    Article  CAS  PubMed  Google Scholar 

  19. Grochow LB . Busulfan disposition: the role of therapeutic monitoring in bone marrow transplantation induction regimens Semin Oncol 1993 20: 18 25

    CAS  PubMed  Google Scholar 

  20. 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

    CAS  PubMed  Google Scholar 

  21. Petersdorf EW, Gooley TA, Anasetti C et al. Optimizing outcome after unrelated marrow transplantation by comprehensive matching of HLA class I and II alleles in the donor and recipient Blood 1998 92: 3515 3520

    CAS  PubMed  Google Scholar 

  22. Slattery JT, Risler LJ . Therapeutic monitoring of busulfan in hematopoietic stem cell transplantation Ther Drug Monit 1998 20: 543 549

    Article  CAS  PubMed  Google Scholar 

  23. Bearman SI, Appelbaum FR, Buckner CD et al. Regimen-related toxicity in patients undergoing bone marrow transplantation J Clin Oncol 1988 6: 1562 1568

    Article  CAS  PubMed  Google Scholar 

  24. Bolinger AM, Zangwill AB, Slattery JT et al. Target dose adjustment of busulfan using pharmacokinetic parameters in pediatric patients undergoing bone marrow transplantation for malignancy or genetic disease Blood 1999 94: 145a

    Google Scholar 

  25. Pawlowska AB, Blazar BR, Angelucci E et al. 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

    Article  CAS  PubMed  Google Scholar 

  26. 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

    CAS  PubMed  Google Scholar 

  27. Baker KS, Bostrom B, DeFor T et al. Busulfan pharmacokinetics do not predict relapse in acute myeloid leukemia Bone Marrow Transplant 2000 26: 607 614

    Article  CAS  PubMed  Google Scholar 

  28. Woods WG, Neudorf S, Gold S et al. A comparison of allogeneic bone marrow transplantation, autologous bone marrow transplantation, and aggressive chemotherapy in children with acute myeloid leukemia in remission: a report from the Children's cancer group Blood 2001 97: 56 62

    Article  CAS  PubMed  Google Scholar 

  29. McDonald GB, Ren S, Bouvier ME et al. Venoocclusive disease of the liver and cyclophosphamide pharmacokinetics: a prospective study in marrow transplant patients Hepatology 1999 17: 314A

    Google Scholar 

  30. DeLeve LD . Cellular target of cyclophosphamide toxicity in the murine liver: role of glutathione and site of metabolic activation Hepatology 1996 24: 830 837

    Article  CAS  PubMed  Google Scholar 

  31. Lee JL, Gooley T, Bensinger W et al. Veno-occlusive disease of the liver after busulfan, melphalan, and thiotepa conditioning therapy: incidence, risk factors, and outcome Biol Blood Marrow Transplant 1999 5: 306 315

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Rights and permissions

Reprints and permissions

About this article

Cite this article

McCune, J., Gooley, T., Gibbs, J. et al. Busulfan concentration and graft rejection in pediatric patients undergoing hematopoietic stem cell transplantation. Bone Marrow Transplant 30, 167–173 (2002). https://doi.org/10.1038/sj.bmt.1703612

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.bmt.1703612

Keywords

This article is cited by

Search

Quick links