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Reduced intensity versus non-myeloablative conditioning regimen for haploidentical transplantation and post-transplantation cyclophosphamide in complete remission acute myeloid leukemia: a study from the ALWP of the EBMT

Bone Marrow Transplantation volume 57, pages 1421–1427 (2022)Cite this article

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Abstract

The optimal conditioning regimen prior haploidentical stem cell transplantation (Haplo-SCT) with post transplantation cyclophosphamide (PT-Cy) for acute myeloid leukemia (AML) remains unknown. A non-myeloablative conditioning (NMAC) regimen (cyclophosphamide + fludarabine + TBI 2 Gy [CyFluTBI]) is a safe approach, but relapse incidence remains high in this setting. Alternatively, a reduced intensity conditioning (RIC) regimen combining thiotepa and reduced-dose busulfan with fludarabine (TBF) may decrease AML relapse. However, an excess of toxicity may counterbalance this potential benefit. We retrospectively compared CyFluTBI vs. TBF in CR AML patients who underwent Haplo-SCT with PT-Cy, in two different populations based on age. We analyzed 490 patients. In patients aged <60 years (n = 203), we observed a higher RI (HR = 3.59, 95% CI = 1.75–7.37, p < 0.01), lower LFS (HR = 1.98, 95% CI = 1.22–3.22, p < 0.01) and lower OS (HR = 1.73, 95% CI = 1.04–2.88, p = 0.04) in the CyFluTBI group, without significant difference in NRM. In older patients (n = 287), we observed that conditioning regimen did not significantly influence LFS (HR = 0.90, 95% CI = 0.56–1.44, p = 0.65), OS (HR = 0.81, 95% CI = 0.49–1.32, p = 0.39) and RI (HR = 1.78, 95% CI = 0.90–3.50, p = 0.10), but showed that CyFluTBI was associated with a significantly lower risk of NRM (HR = 0.48, 95% CI = 0.25–0.92, p = 0.03). Thus, younger patients seem to benefit from conditioning intensification from CyFluTBI to TBF regimens prior PT-Cy Haplo-SCT for CR AML, while older ones do not.

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Fig. 1: Outcome after Haplo-SCT in patients aged <60 years according to conditioning regimen.
Fig. 2: Outcome after Haplo-SCT in patients aged ≥60 years according to conditioning regimen.

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Data availability

Data is available on a specific request to the ALWP of EBMT.

References

  1. 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 

  2. Blaise D, Devillier R, Lecoroller-Sorriano A-G, Boher J-M, Boyer-Chammard A, Tabrizi R, et al. Low non-relapse mortality and long-term preserved quality of life in older patients undergoing matched related donor allogeneic stem cell transplantation: a prospective multicenter phase II trial. Haematologica. 2015;100:269–74.

    Article  Google Scholar 

  3. 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)/Blood and Marrow Transplant Clinical Trial Network 0502. J Clin Oncol. 2015;33:4167–75.

    Article  Google Scholar 

  4. Luznik L, O’Donnell PV, Symons HJ, Chen AR, Leffell MS, Zahurak M, et al. HLA-haploidentical bone marrow transplantation for hematologic malignancies using nonmyeloablative conditioning and high-dose, posttransplantation cyclophosphamide. Biol Blood Marrow Transpl. 2008;14:641–50.

    Article  CAS  Google Scholar 

  5. Ciurea SO, Zhang M-J, Bacigalupo AA, Bashey A, Appelbaum FR, Aljitawi OS, et al. Haploidentical transplant with posttransplant cyclophosphamide vs matched unrelated donor transplant for acute myeloid leukemia. Blood. 2015;126:1033–40.

    Article  CAS  Google Scholar 

  6. Cytryn S, Abdul-Hay M. Haploidentical hematopoietic stem cell transplantation followed by ‘post-cyclophosphamide’: The future of allogeneic stem cell transplant. Clin Hematol Int. 2020;2:49–58.

    Article  Google Scholar 

  7. Kasamon YL, Bolaños-Meade J, Prince GT, Tsai H-L, McCurdy SR, Kanakry JA, et al. Outcomes of nonmyeloablative HLA-haploidentical blood or marrow transplantation with high-dose post-transplantation cyclophosphamide in older adults. J Clin Oncol. 2015. https://doi.org/10.1200/JCO.2014.60.4777.

  8. Devillier R, Granata A, Fürst S, Harbi S, Faucher C, Weiller P-J, et al. Low incidence of chronic GVHD after HLA-haploidentical peripheral blood stem cell transplantation with post-transplantation cyclophosphamide in older patients. Br J Haematol. 2017;176:132–5.

    Article  CAS  Google Scholar 

  9. Brunstein CG, Fuchs EJ, Carter SL, Karanes C, Costa LJ, Wu J, et al. Alternative donor transplantation after reduced intensity conditioning: results of parallel phase 2 trials using partially HLA-mismatched related bone marrow or unrelated double umbilical cord blood grafts. Blood. 2011;118:282–8.

    Article  CAS  Google Scholar 

  10. McCurdy SR, Kanakry JA, Showel MM, Tsai H-L, Bolaños-Meade J, Rosner GL, et al. Risk-stratified outcomes of nonmyeloablative HLA-haploidentical BMT with high-dose posttransplantation cyclophosphamide. Blood. 2015;125:3024–31.

    Article  CAS  Google Scholar 

  11. Raiola A, Dominietto A, Varaldo R, Ghiso A, Galaverna F, Bramanti S, et al. Unmanipulated haploidentical BMT following non-myeloablative conditioning and post-transplantation CY for advanced Hodgkin’s lymphoma. Bone Marrow Transpl. 2014;49:190–4.

    Article  CAS  Google Scholar 

  12. Di Stasi A, Milton DR, Poon LM, Hamdi A, Rondon G, Chen J, et al. Similar transplantation outcomes for acute myeloid leukemia and myelodysplastic syndrome patients with haploidentical versus 10/10 human leukocyte antigen-matched unrelated and related donors. Biol Blood Marrow Transpl. 2014;20:1975–81.

    Article  Google Scholar 

  13. Cieri N, Greco R, Crucitti L, Morelli M, Giglio F, Levati G, et al. Post-transplantation cyclophosphamide and sirolimus after haploidentical hematopoietic stem cell transplantation using a treosulfan-based myeloablative conditioning and peripheral blood stem cells. Biol Blood Marrow Transpl. 2015;21:1506–14.

    Article  CAS  Google Scholar 

  14. Chiusolo P, Bug G, Olivieri A, Brune M, Mordini N, Alessandrino PE, et al. A modified post-transplant cyclophosphamide regimen, for unmanipulated haploidentical marrow transplantation, in acute myeloid leukemia: a multicenter study. Biol Blood Marrow Transpl. 2018;24:1243–9.

    Article  CAS  Google Scholar 

  15. 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 

  16. 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 

  17. Shulman HM, Sullivan KM, Weiden PL, McDonald GB, Striker GE, Sale GE, et al. Chronic graft-versus-host syndrome in man. A long-term clinicopathologic study of 20 Seattle patients. Am J Med. 1980;69:204–17.

    Article  CAS  Google Scholar 

  18. 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 Transpl. 2016;51:610–1.

    Article  CAS  Google Scholar 

  19. Kaplan E, Meier P. Nonparametric estimation from incomplete observations. J Am Stat Assoc. 1958;53:457–81.

    Article  Google Scholar 

  20. Prentice RL, Kalbfleisch JD, Peterson AV, Flournoy N, Farewell VT, Breslow NE. The analysis of failure times in the presence of competing risks. Biometrics. 1978;34:541–54.

    Article  CAS  Google Scholar 

  21. Kanate AS, Nagler A, Savani B. Summary of scientific and statistical methods, study endpoints and definitions for observational and registry-based studies in hematopoietic. Cell Transplant Clin Hematol Int. 2020;2:2–4.

    Article  Google Scholar 

  22. 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 

  23. Ringdén O, Labopin M, Ehninger G, Niederwieser D, Olsson R, Basara N, et al. Reduced intensity conditioning compared with myeloablative conditioning using unrelated donor transplants in patients with acute myeloid leukemia. J Clin Oncol. 2009;27:4570–7.

    Article  Google Scholar 

  24. 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.

    Article  CAS  Google Scholar 

  25. 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:e161–9.

    Article  Google Scholar 

  26. Rubio MT, Savani BN, Labopin M, Piemontese S, Polge E, Ciceri F, et al. Impact of conditioning intensity in T-replete haplo-identical stem cell transplantation for acute leukemia: a report from the acute leukemia working party of the EBMT. J Hematol Oncol. 2016;9:25.

    Article  Google Scholar 

  27. Solomon SR, St Martin A, Shah NN, Fatobene G, Al Malki MM, Ballen KK, et al. Myeloablative vs reduced intensity T-cell-replete haploidentical transplantation for hematologic malignancy. Blood Adv. 2019;3:2836–44.

    Article  Google Scholar 

  28. Santoro N, Labopin M, Ciceri F, Van Lint MT, Nasso D, Blaise D, et al. Impact of conditioning intensity on outcomes of haploidentical stem cell transplantation for patients with acute myeloid leukemia 45 years of age and over. Cancer. 2019;125:1499–506.

    Article  CAS  Google Scholar 

  29. Gagelmann N, Kröger N. Dose intensity for conditioning in allogeneic hematopoietic cell transplantation: can we recommend ‘when and for whom’ in 2021? Haematologica. 2021;106:1794–804.

    Article  CAS  Google Scholar 

  30. Aoudjhane M, Labopin M, Gorin NC, Shimoni A, Ruutu T, Kolb H-J, et al. Comparative outcome of reduced intensity and myeloablative conditioning regimen in HLA identical sibling allogeneic haematopoietic stem cell transplantation for patients older than 50 years of age with acute myeloblastic leukaemia: a retrospective survey from the Acute Leukemia Working Party (ALWP) of the European group for Blood and Marrow Transplantation (EBMT). Leukemia. 2005;19:2304–12.

    Article  CAS  Google Scholar 

  31. 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 

  32. 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 

  33. 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: prospective clinical and socioeconomic evaluation. Cancer. 2013;119:602–11.

    Article  CAS  Google Scholar 

  34. Bacigalupo A, Raiola AM, Lamparelli T, Gualandi F, Occhini D, Bregante S, et al. Thiotepa-based reduced intensity conditioning regimen: a 10 year follow up. Bone Marrow Transpl. 2007;40:1091–3.

    Article  CAS  Google Scholar 

  35. 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 Transpl. 2020;26:698–703.

    Article  CAS  Google Scholar 

  36. Pagliardini T, Castagna L, Harbi S, Porta MD, Rey J, Fürst S, et al. Thiotepa, fludarabine, and busulfan conditioning regimen before T Cell-Replete haploidentical transplantation with post-transplant cyclophosphamide for acute myeloid leukemia: a bicentric experience of 100 patients. Biol Blood Marrow Transpl. 2019;25:1803–9.

    Article  CAS  Google Scholar 

  37. Bazarbachi A, Labopin M, Blaise D, Forcade E, Socié G, Berceanu A, et al. Comparable outcomes of haploidentical transplant with TBF conditioning versus matched unrelated donor with fludarabine/busulfan conditioning for acute myeloid leukemia. Bone Marrow Transpl. 2021;56:622–34.

    Article  CAS  Google Scholar 

  38. Saraceni F, Scortechini I, Fiorentini A, Dubbini MV, Mancini G, Federici I, et al. Conditioning regimens for frail patients with acute leukemia undergoing allogeneic stem cell transplant: how to strike gently. Clin Hematol Int. 2021;3:153–60.

    Article  Google Scholar 

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Acknowledgements

We thank Emmanuelle Polge and Irma Khvedelidze from the EBMT Paris Study Unit. The list of participating centers is provided in the Supplementary Appendix 1.

Author information

Authors and Affiliations

  1. Hematology and Transplantation, Institut Paoli-Calmettes, Aix Marseille Univ, CNRS, INSERM, CRCM, Marseille, France

    Raynier Devillier & Didier Blaise

  2. EBMT Statistical Unit, Paris, France

    Jacques-Emmanuel Galimard & Myriam Labopin

  3. Hematology and Transplant Center, IRCCS Ospedale Policlinico San Martino, Genova, Italy

    Anna Maria Raiola

  4. Centre for Haematology, Imperial College London, Hammersmith Hospital, London, UK

    Jiri Pavlu

  5. Transplantation Unit, Department of Oncology and Hematology, Instituto Clinico Humanitas, Milano, Italy

    Luca Castagna

  6. Hôpital St. Louis, Dept.of Hematology – BMT, Paris, France

    Gerard Socié

  7. Département d’Oncologie, Service d’Hématologie, Hôpitaux Universitaires De Genève and Faculty of Medicine, University of Geneva, Geneva, Switzerland

    Yves Chalandon

  8. Grande Ospedale Metropolitano Bianchi Melacrino Morelli - Centro Unico Trapianti Alberto Neri - Reggio Calabria, Calabria, Italy

    Massimo Martino

  9. University Hospital Dresden Medizinische Klinik und Poliklinik I, TU Dresden, Germany

    Friedrich Stölzel

  10. Goethe-Universitaet, Medizinische Klinik II, Hämatologie, Medizinische Onkologie, Frankfurt, Germany

    Gesine Bug

  11. S.S.C.V.D Trapianto di Cellule Staminali, A.O.U Citta della Salute e della Scienza di Torino, Torino, Italy

    Benedetto Bruno

  12. University Hospital Centre Zagreb, Zagreb, Croatia

    Radovan Vrhovac

  13. University of Amiens: CHU Amiens, Service d’Hematologie, Amiens, France

    Amandine Charbonnier

  14. Azienda Ospedali Riuniti di Ancona, Department of Hematology, Ancona University, Ancona, Italy

    Attilio Olivieri

  15. CHU ESTAING, Service d’hématologie, Clinique Adulte, Clermont-Ferrand, France

    Jacques-Olivier Bay

  16. Department of Hematology, Hosp. Reina Sofia, Córdoba Hospital, Córdoba, Spain

    Herrera Arroyo

  17. CHU de Lille, LIRIC, INSERM U995, Université de Lille, Lille, France

    Ibrahim Yakoub-Agha

  18. Kings College Hospital, Dept. of Haematological Medicine, Denmark Hill, London, UK

    Daniele Avenoso

  19. Philipps Universitaet Marburg, University Hospital Giessen and Marburg, Campus Marburg, Baldingerstr., Marburg, Germany

    Andreas Neubauer

  20. Universite Paris IV, Hopital la Pitié-Salpêtrière, Hematologie Clinique, Paris, France

    Stéphanie Nguyen

  21. CHU Bordeaux, Hôpital Haut-L’évêque, - Pessac, Bordeaux, France

    Edouard Forcade

  22. Hematology, Saint Antoine University Hospital, Paris, France

    Eolia Brissot & Mohamad Mohty

  23. Division of Hematology and Medical Oncology, Vanderbilt University Medical Center, Nashville, TN, USA

    Bipin Savani

  24. Hematology Division, Chaim Sheba Medical Center, Tel-Hashomer, Israel

    Arnon Nagler

Authors
  1. Raynier Devillier
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Contributions

RD designed the study. RD, JEG and MM interpreted the data, and wrote the manuscript draft and final version. JEG and ML performed the statistical analysis. RD, DB, AMR, JP, LC, GS, YC, MM, FS, GB, BB, RV, AC, AO, JOB, HA, IYA, DA, AN, SN, EF, EB, BS, AN, and MM provided patient data. All authors contributed to the manuscript and critically reviewed the final version.

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Correspondence to Raynier Devillier.

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Devillier, R., Galimard, JE., Labopin, M. et al. Reduced intensity versus non-myeloablative conditioning regimen for haploidentical transplantation and post-transplantation cyclophosphamide in complete remission acute myeloid leukemia: a study from the ALWP of the EBMT. Bone Marrow Transplant 57, 1421–1427 (2022). https://doi.org/10.1038/s41409-022-01674-x

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