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:

Fludarabine/busulfan versus fludarabine/total-body-irradiation (2 Gy) as conditioning prior to allogeneic stem cell transplantation in patients (≥60 years) with acute myelogenous leukemia: a study of the acute leukemia working party of the EBMT

Bone Marrow Transplantation volume 55, pages 729–739 (2020)Cite this article

Subjects

Abstract

Nonmyeloablative (NMA) conditioning regimens facilitate allogeneic stem cell transplantation (alloSCT) in elderly patients and/or in those with comorbidities. The acute leukemia working party (ALWP) of the European Society for Blood and Marrow Transplantation (EBMT) compared the outcomes of patients ≥60 years with AML in first complete remission (CR1), that had received an alloSCT following NMA conditioning, i.e. either fludarabine/busulfan (FB2) or fludarabine/total-body-irradiation-2Gy (FluTBI2Gy). A total of 1088 patients were included (median age 65 years). Donors were matched siblings (MSD) and matched unrelated donors (MUD) in 47% and 53%, respectively. In vivo T-cell depletion (TCD) was applied to 79% and none (0%) of patients in the FB2 and FluTBI2Gy groups, respectively. In the MSD group we found a trend for less extensive cGVHD in patients receiving FB2 with in vivo TCD, HR: 0.49, p = 0.08, and in those without worse NRM, HR: 2.14, p = 0.04, and a trend for more total cGVHD, HR: 1.61, p = 0.09. Patients transplanted from MUDs had a significantly higher incidence of total cGVHD, extensive cGVHD and a worse GRFS with FluTBI2Gy in comparison to FB2, HR: 2.44; p < 0.0001; HR 4.59; p < 0.00001 and HR: 1.35; p = 0.03, respectively. No differences were observed with respect to LFS, OS, RI, NRM, and aGVHD.

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

Fig. 1

Similar content being viewed by others

References

  1. Nagel G, Weber D, Fromm E, Erhardt S, Lübbert M, Fiedler W, et al. Epidemiological, genetic, and clinical characterization by age of newly diagnosed acute myeloid leukemia based on an academic population-based registry study (AMLSG BiO). Ann Hematol. 2017;96:1993–2003.

    Article  Google Scholar 

  2. Sengsayadeth S, Savani BN, Blaise D, Malard F, Nagler A, Mohty M. Reduced intensity conditioning allogeneic hematopoietic cell transplantation for adult acute myeloid leukemia in complete remission—a review from the Acute Leukemia Working Party of the EBMT. Haematologica. 2015;100:859–69.

    Article  Google Scholar 

  3. Giralt S, Estey E, Albitar M, van Besien K, Rondón G, Anderlini P, et al. Engraftment of allogeneic hematopoietic progenitor cells with purine analog-containing chemotherapy: harnessing graft-versus-leukemia without myeloablative therapy. Blood. 1997;89:4531–6.

    Article  CAS  Google Scholar 

  4. Khouri IF, Keating M, Körbling M, Przepiorka D, Anderlini P, O’Brien S, et al. Transplant-lite: induction of graft-versus-malignancy using fludarabine-based nonablative chemotherapy and allogeneic blood progenitor-cell transplantation as treatment for lymphoid malignancies. J Clin Oncol. 1998;16:2817–24.

    Article  CAS  Google Scholar 

  5. Childs R, Clave E, Contentin N, Jayasekera D, Hensel N, Leitman S, et al. Engraftment kinetics after nonmyeloablative allogeneic peripheral blood stem cell transplantation: full donor T-cell chimerism precedes alloimmune responses. Blood. 1999;94:3234–41.

  6. Spitzer TR, McAfee S, Sackstein R, Colby C, Toh HC, Multani P, et al. Intentional induction of mixed chimerism and achievement of antitumor responses after nonmyeloablative conditioning therapy and HLA-matched donor bone marrow transplantation for refractory hematologic malignancies. Biol Blood Marrow Transpl. 2000;6:309–20.

    Article  CAS  Google Scholar 

  7. Ringdén O, Boumendil A, Labopin M, Canaani J, Beelen D, Ehninger G, et al. Outcome of allogeneic hematopoietic stem cell transplantation in patients age >69 years with acute myelogenous leukemia: on behalf of the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation. Biol Blood Marrow Transplant. 2019;25:1975–83.

  8. Storb R, Sandmaier BM. Nonmyeloablative allogeneic hematopoietic cell transplantation. Haematologica. 2016;101:521–30.

    Article  CAS  Google Scholar 

  9. Slavin S, Nagler A, Naparstek E, Kapelushnik Y, Aker M, Cividalli G, et al. Nonmyeloablative stem cell transplantation and cell therapy as an alternative to conventional bone marrow transplantation with lethal cytoreduction for the treatment of malignant and nonmalignant hematologic diseases. Blood. 1998;91:756–63.

    Article  CAS  Google Scholar 

  10. McSweeney PA, Niederwieser D, Shizuru JA, Sandmaier BM, Molina AJ, Maloney DG, et al. Hematopoietic cell transplantation in older patients with hematologic malignancies: replacing high-dose cytotoxic therapy with graft-versus-tumor effects. Blood. 2001;97:3390–400.

    Article  CAS  Google Scholar 

  11. Maris MB, Niederwieser D, Sandmaier BM, Storer B, Stuart M, Maloney D, et al. HLA-matched unrelated donor hematopoietic cell transplantation after nonmyeloablative conditioning for patients with hematologic malignancies. Blood. 2003;102:2021–30.

    Article  CAS  Google Scholar 

  12. Shimoni A, Hardan I, Shem-Tov N, Yeshurun M, Yerushalmi R, Avigdor A, et al. Allogeneic hematopoietic stem-cell transplantation in AML and MDS using myeloablative versus reduced-intensity conditioning: the role of dose intensity. Leukemia. 2006;20:322–8.

  13. Paiano S, Roosnek E, Tirefort Y, Nagy-Hulliger M, Masouridi S, Levrat E, et al. Comparing two types of rabbit ATG prior to reduced intensity conditioning allogeneic hematopoietic SCT for hematologic malignancies. Bone Marrow Res. 2015;2015:980924.

    Article  Google Scholar 

  14. Schetelig J, Bornhäuser M, Kiehl M, Schwerdtfeger R, Kröger N, Runde V, et al. Reduced-intensity conditioning with busulfan and fludarabine with or without antithymocyte globulin in HLA-identical sibling transplantation—a retrospective analysis. Bone Marrow Transpl. 2004;33:483–90.

    Article  CAS  Google Scholar 

  15. Potter VT, Krishnamurthy P, Barber LD, Lim Z, Kenyon M, Ireland RM, et al. Long-term outcomes of alemtuzumab-based reduced-intensity conditioned hematopoietic stem cell transplantation for myelodysplastic syndrome and acute myelogenous leukemia secondary to myelodysplastic syndrome. Biol Blood Marrow Transpl. 2014;20:111–7.

    Article  CAS  Google Scholar 

  16. Devine SM, Owzar K, Blum W, Mulkey F, Stone RM, Hsu JW, et al. Phase II study of allogeneic transplantation for older patients with acute myeloid leukemia in first complete remission using a reduced-intensity conditioning regimen: results from Cancer and Leukemia Group B 100103 (Alliance for Clinical Trials in Oncology). J Clin Oncol. 2015;33:4167–75.

    Article  Google Scholar 

  17. Storb R, Yu C, Wagner JL, Deeg HJ, Nash RA, Kiem H-P, et al. Stable mixed hematopoietic chimerism in DLA-identical littermate dogs given sublethal total body irradiation before and pharmacological immunosuppression after marrow transplantation. Blood. 1997;89:3048–54.

    Article  CAS  Google Scholar 

  18. Niederwieser D, Maris M, Shizuru JA, Petersdorf E, Hegenbart U, Sandmaier BM, et al. Low-dose total body irradiation (TBI) and fludarabine followed by hematopoietic cell transplantation (HCT) from HLA-matched or mismatched unrelated donors and postgrafting immunosuppression with cyclosporine and mycophenolate mofetil (MMF) can induce dura. Blood. 2003;101:1620–9.

    Article  CAS  Google Scholar 

  19. Hegenbart U, Niederwieser D, Sandmaier BM, Maris MB, Shizuru JA, Greinix H, et al. Treatment for acute myelogenous leukemia by low-dose, total-body, irradiation-based conditioning and hematopoietic cell transplantation from related and unrelated donors. J Clin Oncol. 2006;24:444–53.

    Article  CAS  Google Scholar 

  20. Gyurkocza B, Storb R, Storer BE, Chauncey TR, Lange T, Shizuru JA, et al. Nonmyeloablative allogeneic hematopoietic cell transplantation in patients with acute myeloid leukemia. J Clin Oncol. 2010;28:2859–67.

    Article  Google Scholar 

  21. Storb R, Gyurkocza B, Storer BE, Sorror ML, Blume K, Niederwieser D, et al. Graft-versus-host disease and graft-versus-tumor effects after allogeneic hematopoietic cell transplantation. J Clin Oncol. 2013;31:1530–8.

    Article  CAS  Google Scholar 

  22. Blaise D, Tabrizi R, Boher J-M, Le Corroller-Soriano A-G, Bay J-O, Fegueux N, et al. Randomized study of 2 reduced-intensity conditioning strategies for human leukocyte antigen-matched, related allogeneic peripheral blood stem cell transplantation. Cancer. 2013;119:602–11.

    Article  CAS  Google Scholar 

  23. Grimwade D, Walker H, Oliver F, Wheatley K, Harrison C, Harrison G, et al. The importance of diagnostic cytogenetics on outcome in AML: analysis of 1,612 patients entered into the MRC AML 10 trial. Blood. 1998;92:2322–33.

    Article  CAS  Google Scholar 

  24. Ruggeri A, Labopin M, Ciceri F, Mohty M, Nagler A. Definition of GvHD-free, relapse-free survival for registry-based studies: an ALWP-EBMT analysis on patients with AML in remission. Bone Marrow Transplant 2016;51:610–1.

    Article  CAS  Google Scholar 

  25. Glucksberg H, Storb R, Fefer A, Buckner CD, Neiman PE, Clift Ra, et al. Clinical manifestations of graft-versus-host disease in human recipients of marrow from HL-A-matched sibling donors. Transplantation 1974;18:295–304.

    Article  CAS  Google Scholar 

  26. Filipovich A, Weisdorf D, Pavletic S, Socie G, Wingard J, Lee S, et al. National Institutes of Health consensus development project on criteria for clinical trials in chronic graft-versus-host disease: I. Diagnosis and Staging Working Group Report. Biol Blood Marrow Transpl. 2005;11:945–56.

    Article  Google Scholar 

  27. Hoogard P. Frailty model for survival data. Lifetime Data Anal. 1995;1:255–73.

    Article  Google Scholar 

  28. Andersen PK, Klein JPZM. Testing for centre effects in multi-centre survival studies: a Monte Carlo comparison of fixed and random effects tests. Stat Med. 1999;18:1489–500.

    Article  CAS  Google Scholar 

  29. R Core Team. R: a language and environment for statistical computing. Vienna, Austria: R Foundation for Statistical Computing. 2017. https://www.R-project.org/.

  30. Bacigalupo A, Lamparelli T, Bruzzi P, Guidi S, Alessandrino PE, Bartolomeo Pdi, et al. Antithymocyte globulin for graft-versus-host disease prophylaxis in transplants from unrelated donors: 2 randomized studies from Gruppo Italiano Trapianti Midollo Osseo (GITMO). Blood. 2001;98:2942–7.

    Article  CAS  Google Scholar 

  31. >Finke J, Bethge WA, Schmoor C, Ottinger HD, Stelljes M, Zander AR, et al. Standard graft-versus-host disease prophylaxis with or without anti-T-cell globulin in haematopoietic cell transplantation from matched unrelated donors: a randomised, open-label, multicentre phase 3 trial. Lancet Oncol. 2009;10:855–64.

    Article  CAS  Google Scholar 

  32. Kröger N, Solano C, Wolschke C, Bandini G, Patriarca F, Pini M, et al. Antilymphocyte globulin for prevention of chronic graft-versus-host disease. N Engl J Med. 2016;374:43–53.

    Article  Google Scholar 

  33. Walker I, Panzarella T, Couban S, Couture F, Devins G, Elemary M, et al. Pretreatment with anti-thymocyte globulin versus no anti-thymocyte globulin in patients with haematological malignancies undergoing haemopoietic cell transplantation from unrelated donors: a randomised, controlled, open-label, phase 3, multicentre trial. Lancet Oncol. 2016;17:164–73.

    Article  CAS  Google Scholar 

  34. Soiffer RJ, Kim HT, McGuirk J, Horwitz ME, Johnston L, Patnaik MM, et al. Prospective, randomized, double-blind, phase III clinical trial of anti-T-Lymphocyte globulin to assess impact on chronic graft-versus-host disease-free survival in patients undergoing HLA-matched unrelated myeloablative hematopoietic cell transplantation. J Clin Oncol. 2017;35:4003–11.

    Article  CAS  Google Scholar 

  35. Randolph SSB, Gooley TA, Warren EH, Appelbaum FR, Riddell SR. Female donors contribute to a selective graft-versus-leukemia effect in male recipients of HLA-matched, related hematopoietic stem cell transplants. Blood. 2004;103:347–52.

    Article  CAS  Google Scholar 

  36. Baron F, Labopin M, Ruggeri A, Mohty M, Sanz G, Milpied N, et al. Unrelated cord blood transplantation for adult patients with acute myeloid leukemia: higher incidence of acute graft-versus-host disease and lower survival in male patients transplanted with female unrelated cord blood—a report from Eurocord, the Acute Leukemia Working Party, and the Cord Blood Committee of the Cellular Therapy and Immunobiology Working Party of the European Group for Blood and Marrow Transplantation. J Hematol Oncol. 2015;8:107.

    Article  Google Scholar 

  37. Gorin N, Labopin M, Blaise D, Choi G, Socie G, Bourhis J, et al. MM. A haploidentical may be a better choice than a female genoidentical donor to transplant a patient with high risk acute myelogenous leukemia in first remission. Bone Marrow Transpl. 2019;54:564.

    Google Scholar 

  38. Chen Y-B, Coughlin E, Kennedy KF, Alyea EP, Armand P, Attar EC, et al. Busulfan dose intensity and outcomes in reduced-intensity allogeneic peripheral blood Stem Cell Transplantation for Myelodysplastic Syndrome or Acute Myeloid Leukemia. Biol Blood Marrow Transpl. 2013;19:981–7.

    Article  Google Scholar 

  39. Rowley SD, Goldberg SL, Pecora AL, Hsu JS, Brecher BA, Butrin L, et al. Unrelated donor hematopoietic stem cell transplantation for patients with hematologic malignancies using a nonmyeloablative conditioning regimen of fludarabine, low-dose total body irradiation, and rabbit antithymocyte globulin. Biol Blood Marrow Transpl. 2004;10:784–93.

    Article  Google Scholar 

  40. Grosskreutz C, Ross V, Scigliano E, Fruchtman S, Isola L. Low-dose total body irradiation, fludarabine, and antithymocyte globulin conditioning for nonmyeloablative allogeneic transplantation. Biol Blood Marrow Transpl. 2003;9:453–9.

    Article  Google Scholar 

  41. Grosskreutz C, Scigliano E, Osman K, Isola L. Graft versus host disease after stem cell allotransplantation with low-dose total body irradiation, fludarabine, and antithymocyte globulin. Transplantation. 2007;84:598–604.

    Article  Google Scholar 

  42. Admiraal R, Nierkens S, de Witte MA, Petersen EJ, Fleurke G-J, Verrest L, et al. Association between anti-thymocyte globulin exposure and survival outcomes in adult unrelated haemopoietic cell transplantation: a multicentre, retrospective, pharmacodynamic cohort analysis. Lancet Haematol. 2017;4:e183–91.

    Article  Google Scholar 

Download references

Acknowledgements

We thank the EBMT centers that provided data for this study and data managers for their excellent contribution.

Author information

Authors and Affiliations

  1. Department of Hematology and Oncology, Otto-von-Guericke University, Magdeburg, Germany

    Thomas Heinicke

  2. Department of Hematology and Cell Therapy and ALWP EBMT Office, Hospital Saint Antoine Paris, Paris, France

    Myriam Labopin, Emmanuelle Polge & Mohamad Mohty

  3. Medical Clinic and Policlinic 1, Hematology and Cellular Therapy, University Hospital Leipzig, Leipzig, Germany

    Dietger Niederwieser & Uwe Platzbecker

  4. Bone Marrow Transplant Unit L 4043, National University Hospital, Rigshospitalet, Copenhagen, Denmark

    Henrik Sengelov

  5. Department of Hematology, University Medical Center Groningen (UMCG), Groningen, The Netherlands

    Goda Choi

  6. Department of Hematology, Erasmus MC Cancer Institute, University Medical Center Rotterdam, Rotterdam, The Netherlands

    Jan Cornelissen

  7. Institut Paoli Calmettes, Department of Hematology, Centre de Recherche en Cancérologie de Marseille (CRCM), Marseille, France

    Didier Blaise

  8. Department of Haematology, University Medical Centre, Utrecht, The Netherlands

    Jürgen Kuball

  9. University Hospital Maastricht Dept. Internal Med.Hematology/Oncology, Maastricht, Maastricht, The Netherlands

    Gwendolyn van Gorkom

  10. Department of Hematology, Radboud University Medical Centre, Nijmegen, The Netherlands

    Nicolaas Schaap

  11. Department of Haematological Medicine, GKT School of Medicine, King’s College Hospital, London, UK

    Victoria Potter

  12. Département d’Hématologie Clinique, CHU Lapeyronie, Montpellier, France

    Franciane Paul

  13. Department of Medicine, Division of Hematology-Oncology, Vanderbilt University Medical Center, Brentwood, TN, USA

    Bipin N. Savani

  14. Hematology Division and Bone Marrow Transplantation, Chaim Sheba Medical Center, Tel-Hashomer and Tel Aviv University, Tel-Aviv, Israel

    Arnon Nagler

  15. ALWP EBMT Office, Hospital Saint Antoine Paris, Paris, France

    Arnon Nagler

Authors
  1. Thomas Heinicke
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Myriam Labopin
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Emmanuelle Polge
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Dietger Niederwieser
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Uwe Platzbecker
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Henrik Sengelov
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Goda Choi
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Jan Cornelissen
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Didier Blaise
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Jürgen Kuball
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Gwendolyn van Gorkom
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Nicolaas Schaap
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Victoria Potter
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Franciane Paul
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Bipin N. Savani
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. Arnon Nagler
    View author publications

    You can also search for this author in PubMed Google Scholar

  17. Mohamad Mohty
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Thomas Heinicke.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

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

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Heinicke, T., Labopin, M., Polge, E. et al. Fludarabine/busulfan versus fludarabine/total-body-irradiation (2 Gy) as conditioning prior to allogeneic stem cell transplantation in patients (≥60 years) with acute myelogenous leukemia: a study of the acute leukemia working party of the EBMT. Bone Marrow Transplant 55, 729–739 (2020). https://doi.org/10.1038/s41409-019-0720-0

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41409-019-0720-0

This article is cited by

Search

Advanced search

Quick links