Comparison of FLAMSA-based reduced intensity conditioning with treosulfan/fludarabine conditioning for patients with acute myeloid leukemia: an ALWP/EBMT analysis

Abstract

FLAMSA followed by sequential reduced intensity conditioning and treosulfan/fludarabine are frequently used conditioning approaches used in centers of the European Society for Blood and Marrow Transplantation (EBMT) for older patients with acute myeloid leukemia (AML). It is currently unknown whether any of these regimens is superior to the others in terms of disease control and toxicity. Using the Acute Leukemia Working Party/EBMT multicenter registry we compared the outcomes of AML patients 45–65 of age transplanted between the years 2007 and 2016. A total of 629 patients were included in the analysis: 281 in the Treo/Flu group, 203 in the FLAMSA/TBI group, and 145 in the FLAMSA/Busulfan group. In multivariate analysis, FLAMSA/TBI conditioned patients had a decreased risk of relapse (hazard ratio (HR) = 0.43; 95% confidence interval (CI), 0.25–0.75; p = 0.002) and superior leukemia-free survival (HR = 0.67; 95% CI, 0.45–0.98; p = 0.042) compared to Treo/Flu conditioned patients. Rates of acute graft-versus-host disease (GVHD) were significantly higher in the FLAMSA/TBI group compared to the Treo/Flu group (HR = 2.004; 95% CI, 1.09–3.67; p = 0.024). Overall survival, non-relapse mortality, and chronic GVHD were not significantly impacted by the specific regimen used. The choice of either FLAMSA/TBI, FLAMSA/Bu, or Treo/Flu results in no major impact on survival of older AML patients.

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References

  1. 1.

    Giralt S, Estey E, Albitar M, van Besien K, Rondon 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.

  2. 2.

    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.

  3. 3.

    Giralt S, Thall PF, Khouri I, Wang X, Braunschweig I, Ippolitti C, et al. Melphalan and purine analog-containing preparative regimens: reduced-intensity conditioning for patients with hematologic malignancies undergoing allogeneic progenitor cell transplantation. Blood. 2001;97:631–7.

  4. 4.

    Oran B, Giralt S, Saliba R, Hosing C, Popat U, Khouri I, et al. Allogeneic hematopoietic stem cell transplantation for the treatment of high-risk acute myelogenous leukemia and myelodysplastic syndrome using reduced-intensity conditioning with fludarabine and melphalan. Biol Blood Marrow Transplant. 2007;13:454–62.

  5. 5.

    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.

  6. 6.

    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.

  7. 7.

    Schmid C, Schleuning M, Ledderose G, Tischer J, Kolb HJ. Sequential regimen of chemotherapy, reduced-intensity conditioning for allogeneic stem-cell transplantation, and prophylactic donor lymphocyte transfusion in high-risk acute myeloid leukemia and myelodysplastic syndrome. J Clin Oncol. 2005;23:5675–87.

  8. 8.

    Schmid C, Schleuning M, Schwerdtfeger R, Hertenstein B, Mischak-Weissinger E, Bunjes D, et al. Long-term survival in refractory acute myeloid leukemia after sequential treatment with chemotherapy and reduced-intensity conditioning for allogeneic stem cell transplantation. Blood. 2006;108:1092–9.

  9. 9.

    Ringden O, Labopin M, Schmid C, Sadeghi B, Polge E, Tischer J, et al. Sequential chemotherapy followed by reduced-intensity conditioning and allogeneic haematopoietic stem cell transplantation in adult patients with relapse or refractory acute myeloid leukaemia: a survey from the Acute Leukaemia Working Party of EBMT. Br J Haematol. 2017;176:431–9.

  10. 10.

    Malard F, Labopin M, Stuhler G, Bittenbring J, Ganser A, Tischer J, et al. Sequential intensified conditioning regimen allogeneic hematopoietic stem cell transplantation in adult patients with intermediate- or high-risk acute myeloid leukemia in complete remission: a study from the Acute Leukemia Working Party of the European Group for Blood and Marrow Transplantation. Biol Blood Marrow Transplant. 2017;23:278–84.

  11. 11.

    Holtick U, Shimabukuro-Vornhagen A, Chakupurakal G, Theurich S, Leitzke S, Burst A, et al. FLAMSA reduced-intensity conditioning is equally effective in AML patients with primary induction failure as well as in first or second complete remission. Eur J Haematol. 2016;96:475–82.

  12. 12.

    Nagler A, Labopin M, Beelen D, Ciceri F, Volin L, Shimoni A, et al. Long-term outcome after a treosulfan-based conditioning regimen for patients with acute myeloid leukemia: a report from the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation. Cancer. 2017;123:2671–9.

  13. 13.

    Shimoni A,Labopin M,Savani B,Hamladji RM,Beelen D,Mufti G, et al. Intravenous busulfan compared with treosulfan- based conditioning for allogeneic stem-cell transplantation in acute myeloid leukemia: a study on behalf of the Acute Leukemia Working Party of EBMT. Biol Blood Marrow Transplant. 2018;24:751–7.

  14. 14.

    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;15:1628–33.

  15. 15.

    Grimwade D, Hills RK, Moorman AV, Walker H, Chatters S, Goldstone AH, et al. Refinement of cytogenetic classification in acute myeloid leukemia: determination of prognostic significance of rare recurring chromosomal abnormalities among 5876 younger adult patients treated in the United Kingdom Medical Research Council trials. Blood. 2010;116:354–65.

  16. 16.

    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.

  17. 17.

    Martino R, Romero P, Subira M, Bellido M, Altes A, Sureda A, et al. Comparison of the classic Glucksberg criteria and the IBMTR Severity Index for grading acute graft-versus-host disease following HLA-identical sibling stem cell transplantation. International Bone Marrow Transplant Registry. Bone Marrow Transplant. 1999;24:283–7.

  18. 18.

    Martin PJ, Lee SJ, Przepiorka D, Horowitz MM, Koreth J, Vogelsang GB, et al. National Institutes of Health Consensus Development Project on Criteria for Clinical Trials in Chronic Graft-versus-Host Disease: VI. The 2014 Clinical Trial Design Working Group Report. Biol Blood Marrow Transplant. 2015;21:1343–59.

  19. 19.

    Vigorito AC, Campregher PV, Storer BE, Carpenter PA, Moravec CK, Kiem HP, et al. Evaluation of NIH consensus criteria for classification of late acute and chronic GVHD. Blood. 2009;114:702–8.

  20. 20.

    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.

  21. 21.

    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 durable complete chimerism and sustained remissions in patients with hematological diseases. Blood. 2003;101:1620–9.

  22. 22.

    Blaise D, Tabrizi R, Boher JM, Le Corroller-Soriano AG, Bay JO, Fegueux N, et al. Randomized study of 2 reduced-intensity conditioning strategies for human leukocyte antigen-matched, related allogeneic peripheral blood stem cell transplantation: prospective clinical and socioeconomic evaluation. Cancer. 2013;119:602–11.

  23. 23.

    Baron F, Labopin M, Peniket A, Jindra P, Afanasyev B, Sanz MA, et al. Reduced-intensity conditioning with fludarabine and busulfan versus fludarabine and melphalan for patients with acute myeloid leukemia: a report from the Acute Leukemia Working Party of the European Group for Blood and Marrow Transplantation. Cancer. 2015;121:1048–55.

  24. 24.

    Casper J, Wolff D, Knauf W, Blau IW, Ruutu T, Volin L, et al. Allogeneic hematopoietic stem-cell transplantation in patients with hematologic malignancies after dose-escalated treosulfan/fludarabine conditioning. J Clin Oncol. 2010;28:3344–51.

  25. 25.

    Kroger N, Shimoni A, Zabelina T, Schieder H, Panse J, Ayuk F, et al. Reduced-toxicity conditioning with treosulfan, fludarabine and ATG as preparative regimen for allogeneic stem cell transplantation (alloSCT) in elderly patients with secondary acute myeloid leukemia (sAML) or myelodysplastic syndrome (MDS). Bone Marrow Transplant. 2006;37:339–44.

  26. 26.

    Shimoni A, Shem-Tov N, Volchek Y, Danylesko I, Yerushalmi R, Nagler A. Allo-SCT for AML and MDS with treosulfan compared with BU-based regimens: reduced toxicity vs reduced intensity. Bone Marrow Transplant. 2012;47:1274–82.

  27. 27.

    Holtick U, Herling M, Pflug N, Chakupurakal G, Leitzke S, Wolf D, et al. Similar outcome after allogeneic stem cell transplantation with a modified FLAMSA conditioning protocol substituting 4 Gy TBI with treosulfan in an elderly population with high-risk AML. Ann Hematol. 2017;96:479–87.

  28. 28.

    Sakellari I, Mallouri D, Gavriilaki E, Batsis I, Kaliou M, Constantinou V, et al. Survival advantage and comparable toxicity in reduced-toxicity treosulfan-based versus reduced-intensity busulfan-based conditioning regimen in myelodysplastic syndrome and acute myeloid leukemia patients after allogeneic hematopoietic cell transplantation. Biol Blood Marrow Transplant. 2017;23:445–51.

  29. 29.

    Casper J, Holowiecki J, Trenschel R, Wandt H, Schaefer-Eckart K, Ruutu T, et al. Allogeneic hematopoietic SCT in patients with AML following treosulfan/fludarabine conditioning. Bone Marrow Transplant. 2012;47:1171–7.

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Acknowledgements

We thank the data managers of the EBMT/ALWP and participating EBMT centers.

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Correspondence to Arnon Nagler.

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The authors declare that they have no conflict of interest.

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Sheth, V., Labopin, M., Canaani, J. 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 Transplant 54, 531–539 (2019). https://doi.org/10.1038/s41409-018-0288-0

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