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:

Conditioning Regimens

Intravenous busulfan for allogeneic hematopoietic stem cell transplantation in infants: clinical and pharmacokinetic results

Bone Marrow Transplantation volume 32, pages 647–651 (2003)Cite this article

Summary:

High-dose busulfan is an important component of myeloablative regimens. Variable drug exposure may occur following oral administration. Therefore, the use of intravenous busulfan has been advocated. Previous work has suggested a cumulative dosage of 16 mg/kg for haematopoietic transplantation in children less than 3 years of age, but only limited data are available in infants. Pharmacokinetics of intravanous busulfan administered at the suggested dosage were studied in 14 infants (median age 4.7 months). Busulfan plasma concentrations were measured by either GC-MS or HPLC-UV. In seven patients, the dose was decreased to target an area- under- the- curve of 600–1300 μmol min. The median total dose given was 13.8 mg/kg. All patients engrafted. Severe veno-occlusive disease occurred in one patient. Our study demonstrates that a cumulative dosage of 16 mg/kg is associated with higher exposure than expected in infants. We suggest an initial dose of 0.8 mg/kg followed by pharmacokinetically guided dose adjustment.

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

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

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

Figure 1

Similar content being viewed by others

References

  1. Fernandez HF et al. Evaluation of safety and pharmacokinetics of administering intravenous busulfan in a twice-daily or daily schedule to patients with advanced hematologic malignant disease undergoing stem cell transplantation. Biol Blood Marrow Transplant 2002; 8: 486–492.

    Article  CAS  Google Scholar 

  2. Russell JA 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.

    Article  CAS  Google Scholar 

  3. Santos GW et al. Marrow transplantation for acute nonlymphocytic leukemia after treatment with busulfan and cyclophosphamide. N Engl J Med 1983; 309: 1347–1353.

    Article  CAS  Google Scholar 

  4. Hartman AR, Williams S, Dillon JJ . Survival, disease-free survival and adverse effects of conditioning for allogeneic bone marrow transplantation with busulfan/cyclophosphamide vs total body irradiation: a meta-analysis. Bone Marrow Transplant 1998; 22: 439–443.

    Article  CAS  Google Scholar 

  5. Bleyzac N et al. Improved clinical outcome of paediatric bone marrow recipients using a test dose and Bayesian pharmacokinetic individualization of busulfan dosage regimens. Bone Marrow Transplant 2001; 28: 743–751.

    Article  CAS  Google Scholar 

  6. Yeager AM et al. Optimization of busulfan dosage in children undergoing bone marrow transplantation: a pharmacokinetic study of dose escalation. Blood 1992; 80: 2425–2428.

    CAS  Google Scholar 

  7. Tran HT et al. Individualizing high-dose oral busulfan: prospective dose adjustment in a pediatric population undergoing allogeneic stem cell transplantation for advanced hematologic malignancies. Bone Marrow Transplant 2000; 26: 463–470.

    Article  CAS  Google Scholar 

  8. Sandstrom M et al. Population pharmacokinetic analysis resulting in a tool for dose individualization of busulphan in bone marrow transplantation recipients. Bone Marrow Transplant 2001; 28: 657–664.

    Article  CAS  Google Scholar 

  9. Vassal G . Pharmacologically-guided dose adjustment of busulfan in high-dose chemotherapy regimens: rationale and pitfalls (review). Anticancer Res 1994; 14: 2363–2370.

    CAS  Google Scholar 

  10. Bolinger AM 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  Google Scholar 

  11. Dupuis LL, Najdova M, Saunders EF . Retrospective appraisal of busulfan dose adjustment in children. Bone Marrow Transplant 2000; 26: 1143–1147.

    Article  CAS  Google Scholar 

  12. Baker KS et al. Busulfan pharmacokinetics do not predict relapse in acute myeloid leukemia. Bone Marrow Transplant 2000; 26: 607–614.

    Article  CAS  Google Scholar 

  13. Andersson BS et al. Conditioning therapy with intravenous busulfan and cyclophosphamide (IV BuCy2) for hematologic malignancies prior to allogeneic stem cell transplantation: a phase II study. Biol Blood Marrow Transplant 2002; 8: 145–154.

    Article  CAS  Google Scholar 

  14. Hassan Z et al. Pharmacokinetics of liposomal busulphan in man. Bone Marrow Transplant 2001; 27: 479–485.

    Article  CAS  Google Scholar 

  15. Andersson BS et al. Acute safety and pharmacokinetics of intravenous busulfan when used with oral busulfan and cyclophosphamide as pretransplantation conditioning therapy: a phase I study. Biol Blood Marrow Transplant 2000; 6: 548–554.

    Article  CAS  Google Scholar 

  16. Olavarria E et al. A phase I/II study of multiple-dose intravenous busulfan as myeloablation prior to stem cell transplantation. Leukemia 2000; 14: 1954–1959.

    Article  CAS  Google Scholar 

  17. Wall D et al. Phase II trial of intravenous busulfan (Busulfex) with cyclophosphamide in pediatric allogeneic hematopoietic cell transplantation (HSC): pharmacokinetics, toxicity and efficacy (A Pediatric Blood and Marrow Transplant Consortium study). in: 42nd Annual Meeting of the American Society of Hematology Vol 97 edn. Hematology, A.S.o. (Blood, San Francisco, CA 2000).

  18. Cremers S et al. Pharmacokinetics of intravenous busulfan in children prior to stem cell transplantation. Br J Clin Pharmacol 2002; 53: 386–389.

    Article  CAS  Google Scholar 

  19. McDonald GB 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.

    Article  CAS  Google Scholar 

  20. McDonald GB, Sharma P, Matthews DE, Shulman HM, Thomas ED . The clinical course of 53 patients with venocclusive disease of the liver after marrow transplantation. Transplantation 1985; 39: 603–608.

    Article  CAS  Google Scholar 

  21. Lai WK et al. Routine analysis of plasma busulfan by gas chromatography-mass fragmentography. Clin Chem 1998; 44: 2506–2510.

    CAS  PubMed  Google Scholar 

  22. Quernin MH et al. Quantification of busulfan in plasma by gas chromatography-mass spectrometry following derivatization with tetrafluorothiophenol. J Chromatogr B Biomed Sci Appl 1998; 709: 47–56.

    Article  CAS  Google Scholar 

  23. Kaplan EL, Meir P . Nonparametric estimation from incomplete observations. J Am Stat Assoc 1958; 53: 457–481.

    Article  Google Scholar 

  24. Dix SP et al. Association of busulfan area under the curve with veno-occlusive disease following BMT. Bone Marrow Transplant 1996; 17: 225–230.

    CAS  Google Scholar 

  25. Vassal G, Gouyette A, Hartmann O, Pico JL, Lemerle J . Pharmacokinetics of high-dose busulfan in children. Cancer Chemother Pharmacol 1989; 24: 386–390.

    Article  CAS  Google Scholar 

  26. Vassal G et al. Busulfan disposition below the age of three: alteration in children with lysosomal storage disease. Blood 1993; 82: 1030–1034.

    CAS  Google Scholar 

  27. Andersson BS et al. 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: 477–485.

    Article  CAS  Google Scholar 

  28. Hassan M, Oberg G, Bjorkholm M, Wallin I, Lindgren M . Influence of prophylactic anticonvulsant therapy on high-dose busulphan kinetics. Cancer Chemother Pharmacol 1993; 33: 181–186.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

JH Dalle is a fellow of La Fondation Charles Bruneau.

Author information

Authors and Affiliations

  1. Service d'Hématologie et Oncologie Pédiatrique, Hôpital Sainte Justine, Montréal, QC, Canada

    J H Dalle, Y Theoret, M Duval, D Larocque, M F Vachon & M A Champagne

  2. Methodist Children's Hospital of South Texas, San Antonio, TX, USA

    D Wall & C Taylor

  3. Department of Pathology and Laboratory Medicine, University of Pennsylvania Medical Center, Philadelphia, PA, USA

    L Shaw & J Gardiner

Authors
  1. J H Dalle
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. D Wall
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Y Theoret
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. M Duval
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. L Shaw
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. D Larocque
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. C Taylor
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. J Gardiner
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. M F Vachon
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. M A Champagne
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to M A Champagne.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Dalle, J., Wall, D., Theoret, Y. et al. Intravenous busulfan for allogeneic hematopoietic stem cell transplantation in infants: clinical and pharmacokinetic results. Bone Marrow Transplant 32, 647–651 (2003). https://doi.org/10.1038/sj.bmt.1704209

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.bmt.1704209

Keywords

This article is cited by

Search

Advanced search

Quick links