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.

  • Article
  • Published:

Myeloablative conditioning regimens in adult patients with acute myeloid leukemia undergoing allogeneic hematopoietic stem cell transplantation in complete remission: a systematic review and network meta-analysis

Bone Marrow Transplantation volume 58, pages 175–185 (2023)Cite this article

Subjects

Abstract

The optimal myeloablative conditioning (MAC) regimens in adult patients with acute myeloid leukemia (AML) undergoing allogeneic hemopoietic stem cell transplantation (allo-HSCT) in complete remission (CR) remain unclear. We performed a systematic review and network meta-analysis to compare the effects of different MAC regimens. Bayesian network meta-analysis was performed using WinBUGS version 1.4.3. The commonly used MAC regimen Bu/Cy (4-day busulfan for toal 16 mg/kg orally or 12.8 mg/kg intravenously, plus 2-day cyclophosphamide for toal 120 mg/kg intravenously) is chosen as the common comparator. Pooled hazard ratios (HRs) with the associated 95% credibility interval (95% CrI) are obtained for all comparisons. We included 19 eligible studies, involving 8104 AML patients and 9 MAC regimens. Compared with Bu/Cy, 3-day busulfan plus fludarabine and thiotepa (Bu3/Flu/TT) is associated with significantly better overall survival (HR, 0.70; 95% CrI, 0.51 to 0.96) and lower risk of relapse (HR, 0.59; 95% CrI, 0.35 to 0.98). Bu3/Flu/TT is also associated with superior overall survival than Cy/TBI (cyclophosphamide plus total body irradiation), and lower risk of relapse than Bu4/Flu (4-day busulfan plus fludarabine). These results suggest that thiotepa-based new MAC regimen Bu3/Flu/TT is associated with improved outcomes in AML patients undergoing allo-HSCT in CR and worth further investigation.

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

Access options

Buy this article

  • Purchase on SpringerLink
  • Instant access to the full article PDF.

USD 39.95

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

Fig. 1: The flow chart of study selection.
Fig. 2: The network plot depicting all direct comparisons for overall survival.
Fig. 3: Forest plot with HR and 95% CrI for overall survival.
Fig. 4: Forest plot with HR and 95% CrI for non-relapse mortality.
Fig. 5: Forest plot with HR and 95% CrI for cumulative incidences of relapse.
Fig. 6: The two-dimensional graph about NRM and CIR.

Similar content being viewed by others

References

  1. Short NJ, Rytting ME, Cortes JE. Acute myeloid leukaemia. Lancet. 2018;392:593–606.

    Article  Google Scholar 

  2. National Cancer Institute. Cancer Stat Facts: Leukemia—Acute Myeloid Leukemia (AML). 2021. https://seer.cancer.gov/statfacts/html/amyl.html (accessed Jan 7, 2021).

  3. Döhner H, Weisdorf DJ, Bloomfield CD. Acute myeloid leukemia. N. Engl J Med. 2015;373:1136–52.

    Article  Google Scholar 

  4. Cornelissen JJ, Blaise D. Hematopoietic stem cell transplantation for patients with AML in first complete remission. Blood. 2016;127:62–70.

    Article  CAS  Google Scholar 

  5. Koreth J, Schlenk R, Kopecky KJ, Honda S, Sierra J, Djulbegovic BJ, et al. Allogeneic stem cell transplantation for acute myeloid leukemia in first complete remission: systematic review and meta-analysis of prospective clinical trials. Jama. 2009;301:2349–61.

    Article  CAS  Google Scholar 

  6. Döhner H, Estey E, Grimwade D, Amadori S, Appelbaum FR, Büchner T, et al. Diagnosis and management of AML in adults: 2017 ELN recommendations from an international expert panel. Blood. 2017;129:424–47.

    Article  Google Scholar 

  7. Gyurkocza B, Sandmaier BM. Conditioning regimens for hematopoietic cell transplantation: one size does not fit all. Blood. 2014;124:344–53.

    Article  CAS  Google Scholar 

  8. 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 Transpl. 2009;15:1628–33.

    Article  Google Scholar 

  9. Scott BL, Pasquini MC, Logan BR, Wu J, Devine SM, Porter DL, et al. Myeloablative versus reduced-intensity hematopoietic cell transplantation for acute myeloid leukemia and myelodysplastic syndromes. J Clin Oncol. 2017;35:1154–61.

    Article  Google Scholar 

  10. Scott BL, Pasquini MC, Fei M, Fraser R, Wu J, Devine SM, et al. Myeloablative versus reduced-intensity conditioning for hematopoietic cell transplantation in acute myelogenous leukemia and myelodysplastic syndromes-long-term follow-up of the BMT CTN 0901 clinical trial. Transplant Cell Ther. 2021;27:483.e1–e6.

    Article  Google Scholar 

  11. Hartman AR, Williams SF, 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 Transpl. 1998;22:439–43.

    Article  CAS  Google Scholar 

  12. Gupta T, Kannan S, Dantkale V, Laskar S. Cyclophosphamide plus total body irradiation compared with busulfan plus cyclophosphamide as a conditioning regimen prior to hematopoietic stem cell transplantation in patients with leukemia: a systematic review and meta-analysis. Hematol Oncol Stem Cell Ther. 2011;4:17–29.

    Article  CAS  Google Scholar 

  13. Copelan EA, Hamilton BK, Avalos B, Ahn KW, Bolwell BJ, Zhu X, et al. Better leukemia-free and overall survival in AML in first remission following cyclophosphamide in combination with busulfan compared with TBI. Blood. 2013;122:3863–70.

    Article  CAS  Google Scholar 

  14. Nagler A, Rocha V, Labopin M, Unal A, Ben Othman T, Campos A, et al. Allogeneic hematopoietic stem-cell transplantation for acute myeloid leukemia in remission: comparison of intravenous busulfan plus cyclophosphamide (Cy) versus total-body irradiation plus Cy as conditioning regimen—a report from the acute leukemia working party of the European group for blood and marrow transplantation. J Clin Oncol. 2013;31:3549–56.

    Article  CAS  Google Scholar 

  15. Nagler A, Savani BN, Labopin M, Polge E, Passweg J, Finke J, et al. Outcomes after use of two standard ablative regimens in patients with refractory acute myeloid leukaemia: a retrospective, multicentre, registry analysis. Lancet Haematol. 2015;2:e384–92.

    Article  Google Scholar 

  16. Lee JH, Joo YD, Kim H, Ryoo HM, Kim MK, Lee GW, et al. Randomized trial of myeloablative conditioning regimens: busulfan plus cyclophosphamide versus busulfan plus fludarabine. J Clin Oncol. 2013;31:701–9.

    Article  CAS  Google Scholar 

  17. Ben-Barouch S, Cohen O, Vidal L, Avivi I, Ram R. Busulfan fludarabine vs busulfan cyclophosphamide as a preparative regimen before allogeneic hematopoietic cell transplantation: systematic review and meta-analysis. Bone Marrow Transpl. 2016;51:232–40.

    Article  CAS  Google Scholar 

  18. Jethava YS, Sica S, Savani B, Socola F, Jagasia M, Mohty M, et al. Conditioning regimens for allogeneic hematopoietic stem cell transplants in acute myeloid leukemia. Bone Marrow Transpl. 2017;52:1504–11.

    Article  CAS  Google Scholar 

  19. Hutton B, Salanti G, Caldwell DM, Chaimani A, Schmid CH, Cameron C, et al. The PRISMA extension statement for reporting of systematic reviews incorporating network meta-analyses of health care interventions: checklist and explanations. Ann Intern Med. 2015;162:777–84.

    Article  Google Scholar 

  20. Sheth V, Labopin M, Canaani J, Volin L, Brecht A, Ganser A, et al. Comparison of FLAMSA-based reduced intensity conditioning with treosulfan/fludarabine conditioning for patients with acute myeloid leukemia: an ALWP/EBMT analysis. Bone Marrow Transpl. 2019;54:531–9.

    Article  CAS  Google Scholar 

  21. Tierney JF, Stewart LA, Ghersi D, Burdett S, Sydes MR. Practical methods for incorporating summary time-to-event data into meta-analysis. Trials. 2007;8:16.

    Article  Google Scholar 

  22. Woods BS, Hawkins N, Scott DA. Network meta-analysis on the log-hazard scale, combining count and hazard ratio statistics accounting for multi-arm trials: a tutorial. BMC Med Res Methodol. 2010;10:54.

    Article  Google Scholar 

  23. Liao WC, Chien KL, Lin YL, Wu MS, Lin JT, Wang HP, et al. Adjuvant treatments for resected pancreatic adenocarcinoma: a systematic review and network meta-analysis. Lancet Oncol. 2013;14:1095–103.

    Article  Google Scholar 

  24. Rambaldi A, Grassi A, Masciulli A, Boschini C, Mico MC, Busca A, et al. Busulfan plus cyclophosphamide versus busulfan plus fludarabine as a preparative regimen for allogeneic haemopoietic stem-cell transplantation in patients with acute myeloid leukaemia: an open-label, multicentre, randomised, phase 3 trial. Lancet Oncol. 2015;16:1525–36.

    Article  CAS  Google Scholar 

  25. Higgins JP, Green S. Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0 (updated March 2011). The Cochrane Collaboration, 2011. Available from: https://training.cochrane.org/handbooks.

  26. Wells G, Shea B, O’Connell D, Peterson J, Welch V, Losos M, et al. The Newcastle-Ottawa Scale (NOS) for assessing the quality of nonrandomised studies in meta-analyses. 2021. Available from: http://www.ohri.ca/programs/clinical_epidemiology/oxford.asp.

  27. Dias S, Welton NJ, Sutton AJ, Ades A. NICE DSU Technical Support Document 2: a generalised linear modelling framework for pairwise and network meta-analysis of randomised controlled trials. 2011. Available from: http://www.nicedsu.org.uk.

  28. van Beurden-Tan CHY, Franken MG, Blommestein HM, Uyl-de Groot CA, Sonneveld P. Systematic literature review and network meta-analysis of treatment outcomes in relapsed and/or refractory multiple myeloma. J Clin Oncol. 2017;35:1312–9.

    Article  Google Scholar 

  29. Skoetz N, Trelle S, Rancea M, Haverkamp H, Diehl V, Engert A, et al. Effect of initial treatment strategy on survival of patients with advanced-stage Hodgkin’s lymphoma: a systematic review and network meta-analysis. Lancet Oncol. 2013;14:943–52.

    Article  Google Scholar 

  30. Blaise D, Maraninchi D, Archimbaud E, Reiffers J, Devergie A, Jouet JP, et al. Allogeneic bone marrow transplantation for acute myeloid leukemia in first remission: a randomized trial of a busulfan-Cytoxan versus Cytoxan-total body irradiation as preparative regimen: a report from the Group d’Etudes de la Greffe de Moelle Osseuse. Blood. 1992;79:2578–82.

    Article  CAS  Google Scholar 

  31. Blaise D, Maraninchi D, Michallet M, Reiffers J, Jouet JP, Milpied N, et al. Long-term follow-up of a randomized trial comparing the combination of cyclophosphamide with total body irradiation or busulfan as conditioning regimen for patients receiving HLA-identical marrow grafts for acute myeloblastic leukemia in first complete remission. Blood. 2001;97:3669–71.

    Article  CAS  Google Scholar 

  32. Bornhauser M, Kienast J, Trenschel R, Burchert A, Hegenbart U, Stadler M, et al. Reduced-intensity conditioning versus standard conditioning before allogeneic haemopoietic cell transplantation in patients with acute myeloid leukaemia in first complete remission: a prospective, open-label randomised phase 3 trial. Lancet Oncol. 2012;13:1035–44.

    Article  Google Scholar 

  33. Clift RA, Buckner CD, Appelbaum FR, Bearman SI, Petersen FB, Fisher LD, et al. Allogeneic marrow transplantation in patients with acute myeloid leukemia in first remission: a randomized trial of two irradiation regimens. Blood. 1990;76:1867–71.

    Article  CAS  Google Scholar 

  34. Clift RA, Buckner CD, Appelbaum FR, Sullivan KM, Storb R, Thomas ED. Long-term follow-Up of a randomized trial of two irradiation regimens for patients receiving allogeneic marrow transplants during first remission of acute myeloid leukemia. Blood. 1998;92:1455–6.

    Article  CAS  Google Scholar 

  35. Fasslrinner F, Schetelig J, Burchert A, Kramer M, Trenschel R, Hegenbart U, et al. Long-term efficacy of reduced-intensity versus myeloablative conditioning before allogeneic haemopoietic cell transplantation in patients with acute myeloid leukaemia in first complete remission: retrospective follow-up of an open-label, randomised phase 3 trial. Lancet Haematol. 2018;5:e161–e9.

    Article  Google Scholar 

  36. Liu H, Zhai X, Song Z, Sun J, Xiao Y, Nie D, et al. Busulfan plus fludarabine as a myeloablative conditioning regimen compared with busulfan plus cyclophosphamide for acute myeloid leukemia in first complete remission undergoing allogeneic hematopoietic stem cell transplantation: a prospective and multicenter study. J Hematol Oncol. 2013;6:15.

    Article  CAS  Google Scholar 

  37. Zhang WP, Wang ZW, Hu XX, Chen J, Yang D, Song XM, et al. Preconditioning with fludarabine, busulfan and cytarabine versus standard BuCy2 for patients with acute myeloid leukemia: a prospective, randomized phase II study. Bone Marrow Transpl. 2019;54:894–902.

    Article  CAS  Google Scholar 

  38. Farag SS, Bolwell BJ, Elder PJ, Kalaycio M, Lin T, Pohlman B, et al. High-dose busulfan, cyclophosphamide, and etoposide does not improve outcome of allogeneic stem cell transplantation compared to BuCy2 in patients with acute myeloid leukemia. Bone Marrow Transpl. 2005;35:653–61.

    Article  CAS  Google Scholar 

  39. Fedele R, Messina G, Martinello T, Gallo GA, Pontari A, Moscato T, et al. Tolerability and efficacy of busulfan and fludarabine as allogeneic pretransplant conditioning therapy in acute myeloid leukemia: comparison with busulfan and cyclophosphamide regimen. Clin Lymphoma, Myeloma Leuk. 2014;14:493–500.

    Article  Google Scholar 

  40. Giebel S, Labopin M, Sobczyk-Kruszelnicka M, Stelljes M, Byrne JL, Fegueux N, et al. Total body irradiation + fludarabine compared to busulfan + fludarabine as “reduced-toxicity conditioning” for patients with acute myeloid leukemia treated with allogeneic hematopoietic cell transplantation in first complete remission: a study by the Acute Leukemia Working Party of the EBMT. Bone Marrow Transplant. 2021;56:481–91.

    Article  CAS  Google Scholar 

  41. Litzow MR, Perez WS, Klein JP, Bolwell BJ, Camitta B, Copelan EA, et al. Comparison of outcome following allogeneic bone marrow transplantation with cyclophosphamide-total body irradiation versus busulphan-cyclophosphamide conditioning regimens for acute myelogenous leukaemia in first remission. Br J Haematol. 2002;119:1115–24.

    Article  CAS  Google Scholar 

  42. Liu H, Fan ZP, Jiang QL, Huang F, Zhou HS, Zhang X, et al. A comparison of toxicity and efficacy between busulfan plus fludarabine and busulfan plus cyclophosphamide for allogeneic hematopoietic stem cell transplantation in acute myeloid leukemia. Chung-Hua Nei Ko Tsa Chih Chin J Intern Med. 2012;51:880–4.

    Google Scholar 

  43. Morsink LM, Bezerra ED, Othus M, Wood BL, Fang M, Sandmaier BM, et al. Comparative analysis of total body irradiation (TBI)-based and non-TBI-based myeloablative conditioning for acute myeloid leukemia in remission with or without measurable residual disease. Leukemia. 2020;34:1701–5.

    Article  Google Scholar 

  44. Patel SS, Rybicki L, Pohlman B, Bolwell B, Gerds AT, Hamilton BK, et al. Comparative effectiveness of busulfan/cyclophosphamide versus busulfan/fludarabine myeloablative conditioning for allogeneic hematopoietic cell transplantation in acute myeloid leukemia and myelodysplastic syndrome. Hematol/Oncol Stem Cell Ther. 2020;13:160–5.

    Article  CAS  Google Scholar 

  45. Pidala J, Kim J, Anasetti C, Kharfan-Dabaja MA, Nishihori T, Field T, et al. Pharmacokinetic targeting of intravenous busulfan reduces conditioning regimen related toxicity following allogeneic hematopoietic cell transplantation for acute myelogenous leukemia. J Hematol Oncol. 2010;3:36.

    Article  Google Scholar 

  46. Saraceni F, Beohou E, Labopin M, Arcese W, Bonifazi F, Stepensky P, et al. Thiotepa, busulfan and fludarabine compared to busulfan and cyclophosphamide as conditioning regimen for allogeneic stem cell transplant from matched siblings and unrelated donors for acute myeloid leukemia. Am J Hematol. 2018;93:1211–9.

    Article  CAS  Google Scholar 

  47. Saraceni F, Labopin M, Hamladji RM, Mufti G, Socié G, Shimoni A, et al. Thiotepa-busulfan-fludarabine compared to busulfan-fludarabine for sibling and unrelated donor transplant in acute myeloid leukemia in first remission. Oncotarget. 2018;9:3379–93.

    Article  Google Scholar 

  48. Sora F, Grazia CD, Chiusolo P, Raiola AM, Bregante S, Mordini N, et al. Allogeneic hemopoietic stem cell transplants in patients with acute myeloid leukemia (AML) prepared with busulfan and fludarabine (BUFLU) or thiotepa, busulfan, and fludarabine (TBF): a retrospective study. Biol Blood Marrow Transplant. 2020;26:698–703.

    Article  CAS  Google Scholar 

  49. Eder S, Labopin M, Finke J, Bunjes D, Olivieri A, Santarone S, et al. Safety and efficacy of thiotepa-based conditioning for allogeneic transplantation in AML: a survey from the ALWP of the EBMT. Bone Marrow Transpl. 2017;52:238–44.

    Article  CAS  Google Scholar 

  50. Sanz J, Boluda JC, Martín C, González M, Ferrá C, Serrano D, et al. Single-unit umbilical cord blood transplantation from unrelated donors in patients with hematological malignancy using busulfan, thiotepa, fludarabine and ATG as myeloablative conditioning regimen. Bone Marrow Transpl. 2012;47:1287–93.

    Article  CAS  Google Scholar 

  51. Spyridonidis A, Labopin M, Savani BN, Niittyvuopio R, Blaise D, Craddock C, et al. Redefining and measuring transplant conditioning intensity in current era: a study in acute myeloid leukemia patients. Bone Marrow Transplant. 2020;55:1114–25.

    Article  CAS  Google Scholar 

Download references

Funding

SX was supported by National Natural Science Fund (NSFC81800172) and the Project from Army Medical University (2017XQN11). JC was supported by the Logistics Project (AWS17J007). XL was supported by the National Natural Science Fund (NSFC81700185). The funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Author information

Author notes

  1. These authors contributed equally: Chengxin Luo, Guixian Wu.

Authors and Affiliations

  1. Center for Hematology, Southwest Hospital, Third Military Medical University, Chongqing, China

    Chengxin Luo, Guixian Wu, Xiangtao Huang, Yaqun Ding, Yarui Huang, Yu Hou, Jieping Chen & Shuangnian Xu

  2. Key Laboratory of Cancer Immunotherapy of Chongqing, Chongqing, China

    Chengxin Luo, Guixian Wu, Xiangtao Huang, Yaqun Ding, Yarui Huang, Yu Hou, Jieping Chen & Shuangnian Xu

  3. Department of Health Statistics, Third Military Medical University, Chongqing, China

    Qiuyue Song

  4. Department of Hematology, Daping Hospital, Third Military Medical University, Chongqing, China

    Xi Li

Authors
  1. Chengxin Luo
    View author publications

    Search author on:PubMed Google Scholar

  2. Guixian Wu
    View author publications

    Search author on:PubMed Google Scholar

  3. Xiangtao Huang
    View author publications

    Search author on:PubMed Google Scholar

  4. Yaqun Ding
    View author publications

    Search author on:PubMed Google Scholar

  5. Yarui Huang
    View author publications

    Search author on:PubMed Google Scholar

  6. Qiuyue Song
    View author publications

    Search author on:PubMed Google Scholar

  7. Yu Hou
    View author publications

    Search author on:PubMed Google Scholar

  8. Jieping Chen
    View author publications

    Search author on:PubMed Google Scholar

  9. Xi Li
    View author publications

    Search author on:PubMed Google Scholar

  10. Shuangnian Xu
    View author publications

    Search author on:PubMed Google Scholar

Contributions

SNX, JPC, and XL contributed to the study conception and design, supervised the study and made critical revision in the manuscript. CXL and GXW performed database searching, study selection, data extraction, statistical analyses and manuscript writing. XTH, YQD, YRH, and YH helped with data extraction, data checking and data interpretation. QYS contributed to statistical analyses and data interpretation. All authors read and approved the final manuscript.

Corresponding authors

Correspondence to Jieping Chen, Xi Li or Shuangnian Xu.

Ethics declarations

Competing interests

The authors declare no competing interests.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Luo, C., Wu, G., Huang, X. et al. Myeloablative conditioning regimens in adult patients with acute myeloid leukemia undergoing allogeneic hematopoietic stem cell transplantation in complete remission: a systematic review and network meta-analysis. Bone Marrow Transplant 58, 175–185 (2023). https://doi.org/10.1038/s41409-022-01865-6

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Version of record:

  • Issue date:

  • DOI: https://doi.org/10.1038/s41409-022-01865-6

This article is cited by

Search

Advanced search

Quick links