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Augmented FLAMSA-Bu versus FluBu2 reduced-intensity conditioning in patients with active relapsed/refractory acute myeloid leukemia: an EBMT analysis

Bone Marrow Transplantation volume 57, pages 934–941 (2022)Cite this article

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Abstract

Comparative data of fludarabine, cytarabine and amsacrine (FLAMSA) chemotherapy followed by busulfan (Bu)-based reduced-intensity conditioning (RIC) (FLAMSA-Bu) versus RIC regimens are lacking in patients with active relapsed/refractory (R/R) acute myeloid leukemia (AML) at the time of allogeneic hematopoietic stem cell transplantation (alloSCT). Here, we retrospectively analyzed outcomes after FLAMSA-Bu versus fludarabine/busulfan (FluBu2) conditioning in this patient population. A total of 476 patients fulfilled the inclusion criteria, of whom 257 received FluBu2 and 219 FLAMSA-Bu. Median follow-up was 41 months. Two-year non-relapse mortality (21%), graft-versus-host disease-free, relapse-free survival (24%) and chronic graft-versus-host disease (GVHD) (29%) were not statistically different between cohorts. FLAMSA-Bu was associated with lower 2-year relapse incidence (RI) (38 vs 49% after FluBu2, p = 0.004), and increased leukemia-free survival (LFS) (42 vs 29%, p = 0.001), overall survival (47 vs 39%, p = 0.008) and grades II-IV acute GVHD (36 vs 20%, p = 0.001). In the multivariate analysis, FLAMSA-Bu remained associated with lower RI (HR 0.69, p = 0.042), increased LFS (HR 0.74, p = 0.048) and a higher risk of acute GVHD (HR 2.06, p = 0.005). Notwithstanding the limitations inherent in this analysis, our data indicate that FLAMSA-Bu constitutes a tolerable conditioning strategy, resulting in a long-term benefit in a subset of patients reaching alloSCT with active disease.

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Fig. 1: Transplantation outcomes after FluBu2 or FLAMSA-Bu conditioning.

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References

  1. Kurosawa S, Yamaguchi T, Miyawaki S, Uchida N, Sakura T, Kanamori H, et al. Prognostic factors and outcomes of adult patients with acute myeloid leukemia after first relapse. Haematologica. 2010;95:1857–64.

    Article  Google Scholar 

  2. Ravandi F, Cortes J, Faderl S, O’Brien S, Garcia-Manero G, Verstovsek S, et al. Characteristics and outcome of patients with acute myeloid leukemia refractory to 1 cycle of high-dose cytarabine-based induction chemotherapy. Blood. 2010;116:5818–23.

    Article  CAS  Google Scholar 

  3. Wattad M, Weber D, Döhner K, Krauter J, Gaidzik VI, Paschka P, et al. Impact of salvage regimens on response and overall survival in acute myeloid leukemia with induction failure. Leukemia. 2017;31:1306–13.

    Article  CAS  Google Scholar 

  4. Cortes JE, Khaled S, Martinelli G, Perl AE, Ganguly S, Russell N, et al. Quizartinib versus salvage chemotherapy in relapsed or refractory FLT3-ITD acute myeloid leukaemia (QuANTUM-R): a multicentre, randomised, controlled, open-label, phase 3 trial. Lancet Oncol. 2019;20:984–97.

    Article  CAS  Google Scholar 

  5. Perl AE, Martinelli G, Cortes JE, Neubauer A, Berman E, Paolini S, et al. Gilteritinib or chemotherapy for relapsed or refractory FLT3-mutated AML. N Engl J Med. 2019;381:1728–40.

    Article  CAS  Google Scholar 

  6. Uy GL, Aldoss I, Foster MC, Sayre PH, Wieduwilt MJ, Advani AS, et al. Flotetuzumab as salvage immunotherapy for refractory acute myeloid leukemia. Blood. 2021;137:751–62.

    Article  CAS  Google Scholar 

  7. Stahl M, Menghrajani K, Derkach A, Chan A, Xiao W, Glass J, et al. Clinical and molecular predictors of response and survival following venetoclax therapy in relapsed/refractory AML. Blood Adv. 2021;5:1552–64.

    Article  CAS  Google Scholar 

  8. Duval M, Klein JP, He W, Cahn JY, Cairo M, Camitta BM, et al. Hematopoietic stem-cell transplantation for acute leukemia in relapse or primary induction failure. J Clin Oncol. 2010;28:3730–8.

    Article  Google Scholar 

  9. Othus M, Appelbaum FR, Petersdorf SH, Kopecky KJ, Slovak M, Nevill T, et al. Fate of patients with newly diagnosed acute myeloid leukemia who fail primary induction therapy. Biol Blood Marrow Transpl. 2015;21:559–64.

    Article  Google Scholar 

  10. 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 

  11. Loke J, Malladi R, Moss P, Craddock C. The role of allogeneic stem cell transplantation in the management of acute myeloid leukaemia: a triumph of hope and experience. Br J Haematol. 2020;188:129–46.

    Article  Google Scholar 

  12. 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.

    Article  Google Scholar 

  13. 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.

    Article  CAS  Google Scholar 

  14. 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 Transpl. 2017;23:278–84. 

    Article  Google Scholar 

  15. 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 

  16. Przepiorka D, Weisdorf D, Martin P, Klingemann HG, Beatty P, Hows JTE. 1994 consensus conference on acute GVHD grading. Bone Marrow Transpl. 1995;15:825–8.

    CAS  Google Scholar 

  17. Lee SJ, Vogelsang G, Flowers MED. Chronic graft-versus-host disease. Biol Blood Marrow Transpl. 2003;9:215–33.

    Article  CAS  Google Scholar 

  18. 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;116:354–66.

    Article  CAS  Google Scholar 

  19. Hougaard P. Frailty models for survival data. Lifetime Data Anal. 1995;1:255–73.

    Article  CAS  Google Scholar 

  20. Andersen P, Klein J, Zhang M. 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 

  21. Craddock C, Jackson A, Loke J, Siddique S, Hodgkinson A, Mason J, et al. Augmented reduced-intensity regimen does not improve postallogeneic transplant outcomes in acute myeloid leukemia. J Clin Oncol. 2021;39:768–78.

    Article  CAS  Google Scholar 

  22. Ruggeri A, Battipaglia G, Labopin M, Ehninger G, Beelen D, Tischer J, et al. Unrelated donor versus matched sibling donor in adults with acute myeloid leukemia in first relapse: An ALWP-EBMT study. J Hematol Oncol. 2016;9:1–8. 

    Article  Google Scholar 

  23. Rodríguez-Arbolí E, Labopin M, Tischer J, Brecht A, Ganser A, Finke J, et al. FLAMSA-based reduced-intensity conditioning versus myeloablative conditioning in younger patients with relapsed/refractory acute myeloid leukemia with active disease at the time of allogeneic stem cell transplantation: an analysis from the acute leukemia. Biol Blood Marrow Transpl. 2020;26:2165–73.

    Article  Google Scholar 

  24. 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 Transpl. 2020;55:1114–25.

    Article  CAS  Google Scholar 

  25. Hourigan CS, Dillon LW, Gui G, Logan BR, Fei M, Ghannam J, et al. Impact of conditioning intensity of allogeneic transplantation for acute myeloid leukemia with genomic evidence of residual disease. J Clin Oncol. 2020;38:1273–83.

    Article  CAS  Google Scholar 

  26. Craddock C, Nagra S, Peniket A, Brookes C, Buckley L, Nikolousis E, et al. Factors predicting long-term survival after T-cell depleted reduced intensity allogeneic stem cell transplantation for acute myeloid leukemia. Haematologica. 2010;95:989–95.

    Article  Google Scholar 

  27. Aoudjhane M, Labopin M, Gorin NC, Shimoni A, Ruutu T, Kolb HJ, 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. Leukemia. 2005;19:2304–12.

    Article  CAS  Google Scholar 

  28. Luger SM, Ringdén O, Zhang M-J, Perez WS, Bishop MR, Bornhäuser M, et al. Similar outcomes using myeloablative versus reduced intensity allogeneic transplant. Bone Marrow Transpl. 2012;47:203–11.

    Article  CAS  Google Scholar 

  29. 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 

  30. Couriel DR, Saliba RM, Giralt S, Khouri I, Andersson B, de Lima M, et al. Acute and chronic graft-versus-host disease after ablative and nonmyeloablative conditioning for allogeneic hematopoietic transplantation. Biol Blood Marrow Transpl. 2004;10:178–85.

    Article  Google Scholar 

  31. Bornhäuser 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 

  32. Sorror ML, Maris MB, Storb R, Baron F, Sandmaier BM, Maloney DG, et al. Hematopoietic cell transplantation (HCT)-specific comorbidity index: a new tool for risk assessment before allogeneic HCT. Blood. 2005;106:2912–9.

    Article  CAS  Google Scholar 

  33. Schmid C, Labopin M, Schaap N, Veelken H, Schleuning M, Stadler M, et al. Prophylactic donor lymphocyte infusion after allogeneic stem cell transplantation in acute leukaemia—a matched pair analysis by the Acute Leukaemia Working Party of EBMT. Br J Haematol. 2019;184:782–7.

    Article  CAS  Google Scholar 

  34. Burchert A, Bug G, Fritz LV, Finke J, Stelljes M, Röllig C, et al. Sorafenib maintenance after allogeneic hematopoietic stem cell transplantation for acute myeloid leukemia with FLT3-internal tandem duplication mutation (SORMAIN). J Clin Oncol. 2020;38:2993–3002.

    Article  Google Scholar 

  35. Xuan L, Wang Y, Huang F, Fan Z, Xu Y, Sun J, et al. Sorafenib maintenance in patients with FLT3-ITD acute myeloid leukaemia undergoing allogeneic haematopoietic stem-cell transplantation: an open-label, multicentre, randomised phase 3 trial. Lancet Oncol. 2020;21:1201–12.

    Article  CAS  Google Scholar 

  36. Bug G, Burchert A, Wagner EM, Kröger N, Berg T, Güller S, et al. Phase I/II study of the deacetylase inhibitor panobinostat after allogeneic stem cell transplantation in patients with high-risk MDS or AML (PANOBEST trial). Leukemia. 2017;31:2523–5.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

ERA is a recipient of a Río Hortega academic clinical fellowship (CM19/00194) from the Instituto de Salud Carlos III, Spain. We thank all the patients included in the study and their families, as well as the investigators and data managers from the participating EBMT sites.

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Authors and Affiliations

  1. Department of Hematology, Hospital Universitario Virgen del Rocío, Instituto de Biomedicina de Sevilla (IBIS/CSIC/CIBERONC), University of Seville, Seville, Spain

    Eduardo Rodríguez-Arbolí

  2. Service d’Hématologie Clinique et Thérapie Cellulaire, Hôpital Saint-Antoine, AP-HP, Sorbonne University, and INSERM UMRs 938, Paris, France

    Myriam Labopin, Eolia Brissot & Mohamad Mohty

  3. Department of Haematology, Hemostasis, Oncology and Stem Cell Transplantation, Hannover Medical School, Hannover, Germany

    Matthias Eder

  4. Deutsche Klinik für Diagnostik, KMT Zentrum, Wiesbaden, Germany

    Arne Brecht

  5. Medizinische Klinik m. S. Hämatologie, Onkologie und Tumorimmunologie, Charité Universitätsmedizin Berlin, Berlin, Germany

    Igor Wolfgang Blau

  6. CHU Institut Universitaire du Cancer Toulouse, Oncopole, Toulouse, France

    Anne Huynh

  7. CHU Bordeaux, Hôpital Haut-Lévêque, Pessac, France

    Edouard Forcade

  8. Department of Internal Medicine III, University Hospital of Munich-Grosshadern, LMU, Munich, Germany

    Johanna Tischer

  9. Medizinische Klinik II Hematology & Oncology, Universitätsklinikum Tübingen, Tübingen, Germany

    Wolfgang Bethge

  10. RM Gorbacheva Research Institute, Pavlov University, St Petersburg, Russia

    Sergey Bondarenko

  11. Klinikum Rechts der Isar, III Med Klinik der TU, Munich, Germany

    Mareike Verbeek

  12. CHU Grenoble Alpes, Université Grenoble Alpes, Service d’Hématologie, CS, 10217, Grenoble, France

    Claude Eric Bulabois

  13. Med. Klinik und Poliklinik II, Universitaetsklinikum Würzburg, Wuerzburg, Germany

    Hermann Einsele

  14. Medizinische Klinik und Poliklinik I, University Hospital Carl Gustav Carus Dresden, TU Dresden, Dresden, Germany

    Friedrich Stölzel

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

    Bipin Savani

  16. BMT Unit, University Hospital of Patras, Patras, Greece

    Alexandros Spyridonidis

  17. Bone Marrow Transplantation Program, Department of Internal Medicine, American University of Beirut, Beirut, Lebanon

    Ali Bazarbachi

  18. Department of Bone Marrow Transplantation and Onco-Hematology, Maria Sklodowska-Curie National Research Institute of Oncology, Gliwice Branch, Gliwice, Poland

    Sebastian Giebel

  19. Department of Hematology and Oncology, Augsburg University Hospital, Augsburg, Germany

    Christoph Schmid

  20. Department of Bone Marrow Transplantation, Chaim Sheba Medical Center, Tel Hashomer, Israel

    Arnon Nagler

Authors
  1. Eduardo Rodríguez-Arbolí
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Contributions

ERA and MM conceived and designed the study. ML performed the statistical analyses. ERA wrote the draft version of the manuscript. BS, AS, AB, SG, EB, CS, AN, and MM reviewed the manuscript and contributed to its final version. ME, AB, IWB, AH, EF, JT, WB, SB, MV, CEB, HE, and FS were the principal investigators at the centers recruiting the highest number of patients for the study. All authors critically reviewed the manuscript and approved its final version.

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Correspondence to Eduardo Rodríguez-Arbolí.

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Competing interests

ERA and CS have received speaker fees from Eurocept Pharmaceuticals. The remaining authors declare no competing financial interests.

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Rodríguez-Arbolí, E., Labopin, M., Eder, M. et al. Augmented FLAMSA-Bu versus FluBu2 reduced-intensity conditioning in patients with active relapsed/refractory acute myeloid leukemia: an EBMT analysis. Bone Marrow Transplant 57, 934–941 (2022). https://doi.org/10.1038/s41409-022-01611-y

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