Korean J Hematol.  2009 Mar;44(1):1-7. 10.5045/kjh.2009.44.1.1.

The Effectiveness of Once-daily Intravenous Busulfan as a Conditioning Regime for Hematopoietic Stem Cell Transplantation in Children with Acute Myelogenous Leukemia

• Park SS
• Kwak JW
• Lim YT

• KMID: 2252166
• DOI: http://doi.org/10.5045/kjh.2009.44.1.1

Abstract

BACKGROUND: There have recently been some reports suggesting that once-daily intravenous busulfan (IV Bu) as a conditioning regime for hematopoietic stem cell transplantation (HSCT) possibly reduces the toxicities without influencing the clinical outcome as compared with the traditional 4 times daily dosage schedule. We report here on the clinical outcome of once-daily IV Bu as a conditioning regime for HSCT in children with AML at a single treatment center.
METHODS
We retrospectively analyzed nine AML children who received HSCT with using the once-daily IV Bu (110~130 mg/m2 on 4 consecutive days) conditioning regimen at the Department of Pediatrics, Pusan National University Hospital from 2003 to 2007.
RESULTS
The median age at HSCT was 8.25 years. As for the conditioning regimens, the HLA-matched sibling peripheral HSCT (N=4) was Flu/Bu, the CBT and unrelated BMT (N=4) was Flu/Bu/ATG and the autologous HSCT (N=1) was Bu/Cy. There was only one case of primary graft failure in an unrelated donor CBT recipient. The median time to neutrophil engraftment was 14 days and the median time to platelet engraftment was 19 days. The transplant-related toxicities were acceptable; there were no case with CNS toxicity and VOD was observed in two cases (1 mild case of VOD and 1 moderate case of VOD). Acute GVHD was noted in two cases (1 case of grade I and 1 case of IV). With a median follow up of 33 months, there were two cases of relapse and two cases of death.
CONCLUSION
Once-daily IV Bu as a conditioning regimen for HSCT in children with AML was well tolerated and convenient with relatively moderate toxicities, but additional studies are needed to determine the therapeutic efficacy and pharmacokinetics of once-daily IV Bu in children who are undergoing HSCT.

Keyword

Intravenous busulfan; Once-daily administration; Acute myelogenous leukemia; Hematopoietic stem cell transplantation; Children

MeSH Terms

Appointments and Schedules
Blood Platelets
Busulfan
Child
Follow-Up Studies
Hematopoietic Stem Cell Transplantation
Hematopoietic Stem Cells
Humans
Leukemia, Myeloid, Acute
Neutrophils
Pediatrics
Recurrence
Retrospective Studies
Siblings
Transplants
Unrelated Donors
Busulfan

Reference

References

1. Copelan EA, Deeg HJ. Conditioning for allogeneic marrow transplantation in patients with lymphohematopoietic malignancies without the use of total body irradiation. Blood. 1992; 80:1648–58.

2. 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; 25:925–30.

3. 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.

4. Hassan M, Ljungman P, Bolme P, et al. Busulfan bioavailability. Blood. 1994; 84:2144–50.

5. Vassal G, Challine D, Koscielny S, et al. Chronophar-macology of high-dose busulfan in children. Cancer Res. 1993; 53:1534–7.

6. Schuler US, Renner UD, Kroschinsky F, et al. Intravenous busulphan for conditioning before autologous or allogeneic human blood stem cell transplantation. Br J Haematol. 2001; 114:944–50.

7. Kashyap A, Wingard J, Cagnoni P, et al. Intravenous versus oral busulfan as part of a busulfan/cyclo-phosphamide 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.

8. Andersson BS, Kashyap A, Gian V, 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; 8:145–54.

9. Park YH, Lee S, Kim YJ, et al. Safety and pharmacokinetics of intravenous busulfan as conditioning prior to allogeneic stem cell transplantation. Korean J Hematol. 2002; 37:127–33.

10. McCune JS, Gibbs JP, Slattery JT. Plasma concentration monitoring of busulfan: does it improve clinical outcome? Clin Pharmacokinet. 2000; 39:155–65.

11. Zwaveling J, den Hartigh J, Lankester AC, Guchelaar HJ, Egeler RM, Bredius RG. Once-daily intravenous busulfan in children prior to stem cell transplantation: study of pharmacokinetics and early clinical outcomes. Anticancer Drugs. 2006; 17:1099–105.

13. Madden T, de Lima M, Thapar N, et al. Pharmacokinetics of once-daily IV busulfan as part of pretransplantation preparative regimens: a comparison with an every 6-hour dosing schedule. Biol Blood Marrow Transplant. 2007; 13:56–64.

14. 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; 8:468–76.

15. 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; 104:857–64.

16. Davies SM, Weisdorf DJ, Haake RJ, et al. Second infusion of bone marrow for treatment of graft failure after allogeneic bone marrow transplantation. Bone Marrow Transplant. 1994; 14:73–7.

17. Cancer Therapy Evaluation Program. Common Terminology Criteria for Adverse Events (CTCAE) v3.0. Available at. http://ctep.cancer.gov.

18. Jones RJ, Lee KS, Beschorner WE, et al. Venoocclusive disease of the liver following bone marrow transplantation. Transplantation. 1987; 44:778–83.

19. Glucksberg H, Storb R, Feter A, et al. Clinical manifestations of graft-versus-host disease in human recipients of marrow from HL-A-matched sibling donors. Transplantion. 1974; 18:295–304.

20. 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; 47:6402–6.

22. Fernandez HF, Tran HT, Albrecht F, Lennon S, Caldera H, Goodman MS. 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; 8:486–92.

23. Bartelink IH, Bredius RG, Ververs TT, et al. Once-daily intravenous busulfan with therapeutic drug monitoring compared to conventional oral busulfan improves survival and engraftment in children undergoing allogeneic stem cell transplantation. Biol Blood Marrow Transplant. 2008; 14:88–98.