Biology of Blood and Marrow Transplantation
Volume 14, Issue 6 , Pages 672-684 , June 2008

Once Daily i.v. Busulfan and Fludarabine (i.v. Bu-Flu) Compares Favorably with i.v. Busulfan and Cyclophosphamide (i.v. BuCy2) as Pretransplant Conditioning Therapy in AML/MDS

  • Borje S. Andersson

      Affiliations

    • Department of Stem Cell Transplantation and Cellular Therapy, U.T. M.D. Anderson Cancer Center, Houston, Texas
    • Corresponding Author InformationCorrespondence and reprint requests: Borje S. Andersson, MD, PhD, Department of Stem Cell Transplantation and Cellular Therapy, U.T. M.D. Anderson Cancer Center, 1515 Holcombe Blvd., Unit 423, Houston, TX 77030-4009.
  • ,
  • Marcos de Lima

      Affiliations

    • Department of Stem Cell Transplantation and Cellular Therapy, U.T. M.D. Anderson Cancer Center, Houston, Texas
  • ,
  • Peter F. Thall

      Affiliations

    • Department of Biostatistics, U.T. M.D. Anderson Cancer Center, Houston, Texas
  • ,
  • Xuemei Wang

      Affiliations

    • Department of Biostatistics, U.T. M.D. Anderson Cancer Center, Houston, Texas
  • ,
  • Daniel Couriel

      Affiliations

    • Department of Stem Cell Transplantation and Cellular Therapy, U.T. M.D. Anderson Cancer Center, Houston, Texas
  • ,
  • Martin Korbling

      Affiliations

    • Department of Stem Cell Transplantation and Cellular Therapy, U.T. M.D. Anderson Cancer Center, Houston, Texas
  • ,
  • Soonja Roberson

      Affiliations

    • Department of Stem Cell Transplantation and Cellular Therapy, U.T. M.D. Anderson Cancer Center, Houston, Texas
  • ,
  • Sergio Giralt

      Affiliations

    • Department of Stem Cell Transplantation and Cellular Therapy, U.T. M.D. Anderson Cancer Center, Houston, Texas
  • ,
  • Betty Pierre

      Affiliations

    • Department of Stem Cell Transplantation and Cellular Therapy, U.T. M.D. Anderson Cancer Center, Houston, Texas
  • ,
  • James A. Russell

      Affiliations

    • Alberta Bone Marrow Transplant Program, Calgary, AB, Canada
  • ,
  • Elizabeth J. Shpall

      Affiliations

    • Department of Stem Cell Transplantation and Cellular Therapy, U.T. M.D. Anderson Cancer Center, Houston, Texas
  • ,
  • Roy B. Jones

      Affiliations

    • Department of Stem Cell Transplantation and Cellular Therapy, U.T. M.D. Anderson Cancer Center, Houston, Texas
  • ,
  • Richard E. Champlin

      Affiliations

    • Department of Stem Cell Transplantation and Cellular Therapy, U.T. M.D. Anderson Cancer Center, Houston, Texas

References 

  1. Bhagwatwar HP, Phadungpojna S, Chow DS, Andersson BS. Formulation and stability of busulfan for intravenous administration in high-dose chemotherapy. Cancer Chemother Pharmacol. 1996;37:401–408
  2. Thall PF, Champlin RE, Andersson BS. Comparison of 100-day mortality rates associated with i.v. busulfan and cyclophosphamide vs other preparative regimens in allogeneic bone marrow transplantation for chronic myelogenous leukemia: bayesian sensitivity analyses of confounded treatment and center effects. Bone Marrow Transplant. 2004;33:1191–1199
  3. de Lima M, Anagnostopoulous A, Munsell M, et al. Non-ablative versus reduced intensity conditioning regimens in the treatment of acute myeloid leukemia and high-risk myelodysplastic syndrome. Dose is relevant for long-term disease control after allogeneic hematopoietic stem cell transplantation. Blood. 2004;104:865–872
  4. Shimoni A, Hardan I, Shem-Tov N, et al. Allogeneic hematopoietic stem-cell transplantation in AML and MDS using myeloablative versus reduced-intensity conditioning: the role of dose intensity. Leukemia. 2006;20:322–328
  5. Shimoni A, Hardan I, Shem-Tov N, et al. Comparison between two fludarabine-based reduced-intensity conditioning regimens before allogeneic hematopoietic stem-cell transplantation: fludarabine/Melphalan is associated with higher incidence of acute graft-versus-host disease and non-relapse mortality and lower incidence of relapse than fludarabine/busulfan. Leukemia. 2007;21:2109–2116
  6. 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
  7. Kashyap A, Wingard J, Cagnoni P, et al. Intravenous vs 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
  8. Jones RJ, Lee KS, Beschorner WE, et al. Venoocclusive disease of the liver following bone marrow transplantation. Transplantation. 1987;44:778–783
  9. McDonald GB, Slatter JT, Bouvier ME, et al. Cyclophosphamide metabolism, liver toxicity, and mortality following hematopoietic stem cell transplantation. Blood. 2003;101:2043–2048
  10. Slatter 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
  11. Andersson BS, Couriel D, Madden T, et al. Busulfan systemic exposure relative to regimen-related toxicity and acute graft vs. host disease; defining a therapeutic window for IV BuCy2 in chronic myelogenous leukemia. Biol Blood Marrow Transplant. 2002;8:477–485
  12. Hassan M, Ljungman P, Ringden O, et al. The effect of busulphan and its 4-hydroxy metabolite: time interval influence on therapeutic efficacy and therapy-related toxicity. Bone Marrow Transplant. 2000;25:915–924
  13. Williams CB, Day SD, Reed MD, et al. Dose modification protocol using intravenous busulfan (Busulfex) and cyclophosphamide followed by autologous or allogeneic peripheral stem cell transplantation in patients with hematologic malignancies. Biol Blood Marrow Transplant. 2004;10:614–623
  14. Mamlouk K, Saracino G, Berryman RB, et al. Modification of the Bu/Cy myeloablative regimen using daily parenteral busulfan: reduced toxicity without the need for pharmacokinetic monitoring. Bone Marrow Transplant. 2005;35:747–754
  15. Terenzi A, Aristei C, Aversa F, et al. Efficacy of fludarabine as an immunosuppressor for bone marrow transplantation conditioning: preliminary results. Transplantation Proc. 1996;28:3101
  16. Gandhi V, Plunkett W. Clinical pharmacology of fludarabine. Clin Pharmacokinet. 2002;41:93–103
  17. 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
  18. Russell JA, Tran HT, Quinlan BN, 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
  19. Russell JA, Savoie ML, Balogh A, et al. Allogeneic transplantation for adult acute leukemia in first and second remission with a novel regimen incorporating daily intravenous busulfan, fludarabine, 400 cGy total-body irradiation, and thymoglobulin. Biol Blood Marrow Transplant. 2007;13:814–821
  20. Nguyen L, Leger F, Lennon S, Puozzo C. Intravenous busulfan in adults prior to haematopoietic stem cell transplantation: a population pharmacokinetic study. Cancer Chemother Pharmacol. 2006;57:191–198
  21. Madden T, de Lima M, Thapar N, et al. Pharmacokinetics of once daily IV busulfan as part of pretransplant preparative regimens; a comparison with an every 6 hour dosing schedule. Biol Blood Marrow Transplant. 2007;13:56–64
  22. Geddes M, Kangarloo SB, Naveed F, et al. High busulfan exposure is associated with worse outcomes in a daily IV busulfan and fludarabine allogeneic transplant regimen. Biol Blood Marrow Transplant. 2008;14:220–228
  23. Yau JC, LeMaistre CF, Andersson BS, et al. Allogeneic bone marrow transplantation for hematological malignancies following etoposide, cyclophosphamide and fractionated total body irradiation. Am J Hematol. 1992;41:40–44
  24. Przepiorka D, Ippoliti C, Giralt S, et al. A phase I-II study of high dose thiotepa, busulfan and cyclophosphamide as a preparative regimen for allogeneic marrow transplantation. Bone Marrow Transplant. 1994;14:449–453
  25. Przepiorka D, Khouri I, Thall P, et al. Thiotepa, busulfan and cyclophosphamide as a preparative regimen for allogeneic transplantation for advanced chronic myelogenous leukemia. Bone Marrow Transplant. 1999;23:977–981
  26. Giralt S, Thall PF, Khouri I, et al. Melphalan and purine analog-containing preparative regimens: reduced-intensity conditioning for patients with hematologic malignancies undergoing allogeneic progenitor cell transplantation. Blood. 2001;97:631–637
  27. Kebriaei P, Saliba RM, Ma C, et al. Allogeneic hematopoietic stem cell transplantation after rituximab-containing myeloablative preparative regimen for acute lymphoblastic leukemia. Bone Marrow Transplant. 2006;38:203–209
  28. Marks DI, Forman SJ, Blume KG, et al. A comparison of cyclophosphamide and total body irradiation with etoposide and total body irradiation as conditioning regimens for patients undergoing sibling allografting for acute lymphoblastic leukemia in first or second complete remission. Biol Blood Marrow Transplant. 2006;12:438–453
  29. Estey E, Thall PF, Giles F, et al. Gemtuzumab ozogamycin with or without interleukin 2 in patients 65 years of age or older with untreated AML and high-risk MDS: comparison with idarubicin + continuous-infusion high-dose cytosine arabinoside. Blood. 2002;99:4343–4349
  30. Thall PF, Wang X. Bayesian sensitivity analyses of confounded treatment effects. In: Crowley JC, Pauler DP, eds. Handbook of Statistics in Clinical Oncology, 2nd ed., revised and expanded. Boca Raton, FL: Chapman & Hall/CRC Taylor Francis Group, 2006:523-540.
  31. Keating MJ, Smith TL, Gehan EA, et al. Factors related to length of complete remission in adult acute leukemia. Cancer. 1980;45:2017–2029
  32. Greenberg P, Cox C, LeBeau M, et al. International scoring system for evaluating prognosis in myelodysplastic syndromes. Blood. 1997;89:2079–2088
  33. 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;8:145–154
  34. De Lima M, Champlin RE, Thall PF, et al. Phase I/II study of gemtuzumab ozogamicin added to fludarabine, melphalan and allogeneic hematopoietic stem cell transplantation for high-risk CD33 positive myeloid leukemias and myelodysplastic syndrome. Leukemia. 2008;22:258–264
  35. Przepiorka D, Khouri I, Ippoliti C, et al. Tacrolimus and minidose methotrexate for prevention of acute graft-versus-host disease after HLA-mismatched marrow or blood stem cell transplantation. Bone Marrow Transplant. 1999;24:763–768
  36. Körbling M, Huh YO, Durett A, et al. Allogeneic blood stem cell transplantation: peripheralization and yield of donor-derived primitive hematopoietic progenitor cells (CD34+ Thy-1dim) and lymphoid subsets, and possible predictors of engraftment and graft-versus-host disease. Blood. 1995;86:2842–2848
  37. Przepiorka D, Smith TL, Folloder J, et al. Risk factors for acute graft-versus-host disease after allogeneic blood stem cell transplantation. Blood. 1999;94:1465–1470
  38. Snedecor GW, Cochoran WG. Statistical Methods. 7th ed.. Ames, IA: The Iowa State University Press; 1980;
  39. Kaplan EL, Meier P. Nonparametric estimator from incomplete observations. J Am Stat Assoc. 1958;53:457–481
  40. Mantel N. Evaluation of survival data and two new rank order statistics arising in its consideration. Cancer Chemother Rep. 1966;60:163–170
  41. Johnson V. A Bayesian χ2 test for goodness-of-fit. Ann Stat. 2004;32:2361–2384
  42. Venables WN, Ripley BD. Modern Applied Statistics With Splus. 3rd ed.. New York: Springer; 1999;
  43. WinBugs Version 1.4. Imperial College & Medical Research Council (MRC), UK.
  44. Vassal G. Pharmacologically-guided dose adjustment of busulfan in high-dose chemotherapy regimens: rationale and pitfalls (review). Anticancer Res. 1994;14:2363–2370
  45. de Lima M, Wang X, Thall PF, et al. Long-term follow-up of IV busulfan (Bu) with fludarabine (FLU) vs IV Bu with cyclophosphamide (Cy) as pre (allogeneic) transplant conditioning therapy for AML/MDS. Blood. 2006;108:322
  46. Chae YS, Sohn SK, Kim JG, et al. New myeloablative conditioning regimen with fludarabine and busulfan for allogeneic stem cell transplantation: comparison with BuCy2. BMT. 2007;40:541–547
  47. McCune JS, Batchelder A, Deeg HJ, et al. Cyclophosphamide following targeted oral busulfan as conditioning for hematopoietic cell transplantation: pharmacokinetics, liver toxicity, and mortality. Biol Blood Marrow Transplant. 2007;13:853–862
  48. Chang C, Sorer BE, Scott BL, et al. Hematopoietic cell transplantation in patients with myelodysplastic syndrome or acute myeloid leukemia arising from myelodysplastic syndrome: similar outcomes in patients with de novo disease and disease following prior therapy or antecedent hematologic disorder. Blood. 2007;110:1379–1387
  49. Hallemeier C, Girgis M, Blum W, et al. Outcomes of adults with acute myelogenous leukemia in remission given 550 cGy of single-exposure total body irradiation, cyclophosphamide, and unrelated donor bone marrow transplants. Biol Blood Marrow Transplant. 2004;10:310–319
  50. Alyea EP, Kim HT, Ho V, et al. Impact of conditioning regimen intensity on outcome of allogeneic hematopoietic cell transplantation for advanced acute myelogenous leukemia and myelodysplastic syndrome. Biol Blood Marrow Transplant. 2006;12:1047–1055
  51. Burnett AK, Wheatley K, Goldstone AH, et al. The value of allogeneic bone marrow transplant in patients with acute myeloid leukaemia at differing risk of relapse: results of the UK MRC AML 10 trial. Br J Haematol. 2002;118:385–400
  52. Burnett AK. Evaluating the contribution of allogeneic and autologous transplantation to the management of acute myeloid leukemia in adults. Cancer Chemother Pharmacol. 2001;48(Suppl 1):S53–S58

PII: S1083-8791(08)00118-3

doi: 10.1016/j.bbmt.2008.03.009

Biology of Blood and Marrow Transplantation
Volume 14, Issue 6 , Pages 672-684 , June 2008