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.

Conditioning

Busulfan fludarabine vs busulfan cyclophosphamide as a preparative regimen before allogeneic hematopoietic cell transplantation: systematic review and meta-analysis

Abstract

We aimed to evaluate the efficacy and toxicity profile of busulfan–fludarabine (Bu–Flu) compared with busulfan–cyclophosphamide (Bu–Cy) as a preparative regimen for patients undergoing allogeneic hematopoietic cell transplantation. We performed a systematic review and meta-analysis of all comparative trials, both randomized controlled trials (RCTs) and non-randomized. Our search yielded 15 trials recruiting 1830 patients. Four trials were RCTs and 11 were either one-arm intervention trials compared with historical controls or retrospective studies. There was a lower risk for non-relapse mortality (NRM) at 100 days in patients given Bu–Flu regimen compared with those given Bu–Cy regimen (relative risk (RR) 0.56; 95% confidence interval (CI) 0.34–0.92, 8 trials); however, there were no differences in all-cause mortality at 100 days (RR 0.85; 95% CI 0.56–1.30, 9 trials) and at the end of study (RR 0.81; 95% CI 0.64–1.02, 13 trials). The risks of sinusoidal obstruction syndrome (SOS) and microbiologically documented infections were lower in patients given Bu–Flu regimen (RR 0.34; 95% CI 0.19–0.62, 8 trials and RR 0.79; 95% CI 0.64–0.97, 2 trials, respectively); however, risk for SOS was no longer lower when performing sensitivity analysis according to RCTs. Engraftment kinetics, risk of grade 3–4 mucositis, GvHD, relapse and NRM at the end of the study were all similar between the two groups. We conclude that both regimens have similar efficacy profiles, whereas toxicity is lower with the Bu–Flu regimen.

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
Figure 2
Figure 3

References

  1. Gooley TA, Chien JW, Pergam SA, Hingorani S, Sorror ML, Boeckh M et al. Reduced mortality after allogeneic hematopoietic-cell transplantation. N Engl J Med 2010; 363: 2091–2101.

    Article  CAS  Google Scholar 

  2. Gyurkocza B, Sandmaier BM . Conditioning regimens for hematopoietic cell transplantation: one size does not fit all. Blood 2014; 124: 344–353.

    Article  CAS  Google Scholar 

  3. De Lima M, Couriel D, Thall PF, Wang X, Madden T, Jones R 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.

    Article  CAS  Google Scholar 

  4. Bacigalupo A, Ballen K, Rizzo D, Giralt S, Lazarus H, Ho V et al. Defining the intensity of conditioning regimens: working definitions. Biol Blood Marrow Transplant 2009; 15: 1628–1633.

    Article  Google Scholar 

  5. Dickersin K, Scherer R, Lefebvre C . Identifying relevant studies for systematic reviews. BMJ 1994; 309: 1286–1291.

    Article  CAS  Google Scholar 

  6. Hahn T, Wall D, Camitta B, Davies S, Dillon H, Gaynon P et al. The role of cytotoxic therapy with hematopoietic stem cell transplantation in the therapy of acute lymphoblastic leukemia in adults: an evidence-based review. Biol Blood Marrow Transplant 2006; 12: 1–30.

    Article  CAS  Google Scholar 

  7. Liu DH, Xu LP, Zhang XH, Wang Y, Yan CH, Wang JZ et al. Substitution of cyclophosphamide in the modified BuCy regimen with fludarabine is associated with increased incidence of severe pneumonia: A prospective, randomized study. Int J Hematol 2013; 98: 708–715.

    Article  CAS  Google Scholar 

  8. Lee J-H, Joo Y-D, Kim H, Ryoo HM, Kim MK, Lee G-W et al. Randomized trial of myeloablative conditioning regimens: busulfan plus cyclophosphamide versus busulfan plus fludarabine. J Clin Oncol 2013; 31: 701–709.

    Article  CAS  Google Scholar 

  9. Lee JH, Choi J, Kwon KA, Lee S, Oh SY, Kwon H-C et al. Fludarabine-based myeloablative regimen as pretransplant conditioning therapy in adult acute leukemia/myelodysplastic syndrome: comparison with oral or intravenous busulfan with cyclophosphamide. Korean J Hematol 2010; 45: 102–108.

    Article  CAS  Google Scholar 

  10. Liu H, Zhai X, Song Z, Sun J, Xiao Y . Busulfan plus fludarabine as a myeloablaive conditiong regimen compared with busulfan plus cyclophosphamide for acute myeloid leukemia in first complete remission undergoing allogeneic hematopoietic stem cell transplantation: a prospective. J Hematol Oncol 2013; 6: 15.

    Article  CAS  Google Scholar 

  11. Andersson BS, de Lima M, Thall PF, Wang X, Couriel D, Korbling M et al. 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. Biol Blood Marrow Transplant 2008; 14: 672–684.

    Article  CAS  Google Scholar 

  12. Chae YS, Sohn SK, Kim JG, Cho YY, Moon JH, Shin HJ et al. New myeloablative conditioning regimen with fludarabine and busulfan for allogeneic stem cell transplantation: comparison with BuCy2. Bone Marrow Transplant 2007; 40: 541–547.

    Article  CAS  Google Scholar 

  13. Andersson BS, de Lima M, Thall PF, Madden T, Russell JA, Champlin RE . Reduced-toxicity conditioning therapy with allogeneic stem cell transplantation for acute leukemia. Curr Opin Oncol 2009; 21: S11–S15.

    Article  CAS  Google Scholar 

  14. Wong AM, Allen JC, Goh YT, Linn YC, Loh SMY, Diong CP et al. Single center retrospective analysis of BU-based conditioning regimens in allogeneic transplantation. Bone Marrow Transplant 2012; 47: 181–189.

    Article  CAS  Google Scholar 

  15. Bredeson C, Zhang M . Outcomes following HSCT using fludarabine, busulfan, and thymoglobulin: a matched comparison to allogeneic transplants conditioned with busulfan and. Biol Blood Marrow Transplant 2008; 14: 993–1003.

    Article  CAS  Google Scholar 

  16. Vokurka S, Steinerova K, Karas M, Koza V . Characteristics and risk factors of oral mucositis after allogeneic stem cell transplantation with FLU/MEL conditioning regimen in context with BU/CY2. Bone Marrow Transplant 2009; 44: 601–605.

    Article  CAS  Google Scholar 

  17. Shin HC, Lee YJ, Moon JH, Lee SJ, Kang BW, Chae YS et al. Feasibility of non-TBI conditioning with busulfan and fludarabine for allogeneic stem cell transplantation in lymphoid malignancy. Korean J Intern Med 2012; 27: 72–83.

    Article  CAS  Google Scholar 

  18. Raida L, Tucek P, Vondrakova J, Rusinakova Z, Faber E, Indrak K . Comparison of conditioning regimens BU-CY and FLU-BU12-TG used in the patients undergoing allogeneic stem cell transplantation (SCT) for acute myeloid leukemia (AML). Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub 2011; 155: 327–332.

    Article  CAS  Google Scholar 

  19. Fedele R, Moscato T, Massara E, Messina G, OI, Pontari A et al. Fludarabine and busulfan as conditioning regimen in allogeneic stem cell transplantation: comparison with BuCy2. Abstract P1084 EBMT 2012; 47: s418–s419.

    Google Scholar 

  20. Rambaldi A, Grassi A, Micò C, Oldani E, Boschini C, Busca A et al. Myeloablative, reduced toxicity versus standard conditioning in AML: a randomized clinical trial from Gruppo Italiano Trapianto di Midollo Osseo (GITMO)no title. Bone Marrow Transplant 2015; 50: s52–s53.

    Google Scholar 

  21. Coiteux V, Leclercq P, Vasseur T, Wemeau M, De Berranger E, RD, Magro L et al. Myeloablative fludarabine plus busulfan IV (FB4) regiman compares favourable with cyclophosphaminde plus busulfan (BUCY) in patients undergoing allo-SCT for myeloid malignancy. Hematologica 2013; 98: s371.

    Article  Google Scholar 

  22. Song I, Ryu H, Choi Y, Lee H, Yun H, Kim DJ S . Busulfan/cyclophosphamode vs. busulfan/fludarabine conditioning for allogeneic haematopoietic stem cell transplantation in patients with AML/MDS: a single-center retrospective analysis. Abstract B1675 EHA 2013.

  23. Liu DH, Huang LPX XJ . Higher incidence of severe pneumonia after conditioning with busulfan-fludarabine compared to busulfan-cyclophosphamide in a perspective, randomized study. Hematologica 2012; 97: s183.

    Article  Google Scholar 

  24. González de Villambrosia S, Moretó A, Núñez AB J, Yáñez L, Insunza AI A . Comparison Of IV busulfan and fludarabine vs IV busulfan and cyclophosphamide as conditioning regimen in myeloabaltive allogeneic stem cell transplantation. Hematologica 2008; 93: s192.

    Google Scholar 

  25. Park S, Hong JY, Choi MK, Kim YS, Lee JY, Lim SH et al. Comparison of BuCy (Busulfan plus Cyclophosphamide) Versus FluBu4 (Fludarabine plus Busulfan) As a Conditioning Regimen for Allogeneic Stem Cell Transplantation. ASH Annu Meet Abstr 2012; 120: 4522.

    Google Scholar 

  26. Jaimovich G, Requejo A, Milovic V, Escobar NF, Drelichman G, Real J et al. Comparison of IV busulfan and fludarabine vs oral busulfan plus cyclophosphamide as myeloablative conditioning regimens for acute leukemias and myelodisplastic syndromes. ASH Annu Meet Abstr 2011; 118: 4575.

    Google Scholar 

  27. Mohty M, Labopin M, Socie G, Milpied N-J, Attal M, Blaise D et al. Comparison of busulfan and cyclophosphamide (Bu-Cy)-based standard myeloablative conditioning (MAC) vs. fludarabine and busulfan (Flu-Bu)-based reduced-intensity conditioning (RIC) prior to allogeneic stem cell transplantation (allo-SCT) from an HLA ident. ASH Annu Meet Abstr 2009; 114: 3364.

    Google Scholar 

  28. De Lima M, Wang X, Thall PF, Couriel D, Jones RB, Shpall EJ 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. ASH Annu Meet Abstr 2006; 108: 322.

    Google Scholar 

  29. Altman J, Venepalli N, Monreal J, Rashid K, Gordon L, Winter J et al. Oral busulfan and cyclophosphamide or IV busulfan and fludarabine for allogeneic HSCT in hematologic malignancies? ASH Annu Meet Abstr 2006; 108: 2940.

    Google Scholar 

  30. Kozuka T, Ishimaru F, Matsuo K, Nakashima H, Fujii N, Matsuoka K et al. Early kinetics of engraftment following reduced-intensity stem cell transplantation: fludarabine and cyclophosphamide versus fludarabine and busulfan. ASH Annu Meet Abstr 2006; 108: 2957.

    Google Scholar 

  31. De Lima M, Couriel D, Shahjahan M, Alamo J, Thall PF, Russell J et al. IV busulfan (Bu) with fludarabine (Flu) or cyclophosphamide (Cy) - comparing ablative conditioning regimens for allogeneic transplantation in AML/MDS. ASH Annu Meet Abstr 2004; 104: 97.

    Google Scholar 

  32. Przepiorka D, Weisdorf D, Martin P, Klingemann HG, Beatty P, Hows J et al. 1994 Consensus Conference on acute GVHD grading. Bone Marrow Transplant 1995; 15: 825–828.

    CAS  Google Scholar 

  33. Pasquini M, Le-Rademacher J, Kato K, Zhu X, McCarthy P, Ho V et al. Comparison of myeloablative intravenous busulfan with cyclophosphamide (BuCy) or fludarabine (BuFlu) prior to haematopoietic cell transplantation (HCT) for myeloid malignancies. Bone Marrow Transplant 2013; 48: s61–s62. Available at http://registration.akm.ch/einsicht.php?XNABSTRACT_ID=170217&XNSPRACHE_ID=2&XNKONGRESS_ID=179&XNMASKEN_ID=900.

    Google Scholar 

  34. Russell JA, Tran HT, Quinlan D, Chaudhry A, Duggan P, Brown C 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 

  35. Ram R, Herscovici C, Dahan D, Israeli M, Dreyer J, Peck A et al. Tailoring the GVHD prophylaxis regimen according to transplantation associated toxicities-Substituting the 3rd dose of methotrexate to mycophenolate mofetil. Leuk Res 2014; 38: 913–917.

    Article  CAS  Google Scholar 

  36. Bartelink IH, van Reij EML, Gerhardt CE, van Maarseveen EM, de Wildt A, Versluys B et al. Fludarabine and exposure-targeted busulfan compares favorably with busulfan/cyclophosphamide-based regimens in pediatric hematopoietic cell transplantation: maintaining efficacy with less toxicity. Biol Blood Marrow Transplant 2014; 20: 345–353.

    Article  CAS  Google Scholar 

  37. Wang F, Huang X, Liu D, Chen H, Wang Y, Tang F et al. [The efficacy and safety of modified busulfan/fludarabine conditioning regimen in elderly or drug-intolerable patients with hematologic malignancies]. Zhonghua nei ke za zhi 2013; 52: 1028–1032.

    Google Scholar 

  38. Alatrash G, de Lima M, Hamerschlak N, Pelosini M, Wang X, Xiao L et al. Myeloablative reduced-toxicity i.v. busulfan-fludarabine and allogeneic hematopoietic stem cell transplant for patients with acute myeloid leukemia or myelodysplastic syndrome in the sixth through eighth decades of life. Biol Blood Marrow Transplant 2011; 17: 1490–1496.

    Article  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to S Ben-Barouch.

Ethics declarations

Competing interests

The authors declare no conflict of interest.

Additional information

Supplementary Information accompanies this paper on Bone Marrow Transplantation website

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Ben-Barouch, S., Cohen, O., Vidal, L. et al. Busulfan fludarabine vs busulfan cyclophosphamide as a preparative regimen before allogeneic hematopoietic cell transplantation: systematic review and meta-analysis. Bone Marrow Transplant 51, 232–240 (2016). https://doi.org/10.1038/bmt.2015.238

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/bmt.2015.238

This article is cited by

Search

Quick links