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

Abstract

The optimal conditioning for patients with acute myeloid leukemia in first complete remission treated with allogeneic hematopoietic cell transplantation (allo-HCT) has not been defined so far. In this retrospective study, we compared two “reduced-toxicity” regimens: intravenous busulfan at a total dose of 9.6 mg/kg (3 days) + fludarabine (Bu3/Flu) and total body irradiation at a dose of 8 Gy + fludarabine (TBI8Gy/Flu). In the entire study cohort (n = 518), the probabilities of overall survival (OS), leukemia-free survival (LFS), relapse and non-relapse mortality (NRM) at 2 years for Bu3/Flu and TBI8Gy/Flu were 62% vs. 72.5% (p = 0.051), 59.5% vs. 65% (p = 0.15), 30% vs. 20% (p = 0.01), and 10% vs. 14% (p = 0.18), respectively. In multivariate model for patients <50 years old, TBI8Gy/Flu was associated with improved LFS (hazard ratio (HR) = 0.5, p = 0.04), OS (HR = 0.31, p = 0.004), and survival free from both graft-versus-host disease and relapse (HR = 0.55, p = 0.03), as well as tendency to reduced risk of relapse (HR = 0.53, p = 0.08). Among patients aged 50 years or older the use of TBI8Gy/Flu was associated with increased incidence of NRM (HR = 3.9, p = 0.0009), with no significant impact on other outcome measures. We conclude that the use of TBI8Gy/Flu as “reduced-toxicity” regimen may be advised in younger patients with AML referred for allo-HCT.

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Fig. 1: Comparison of Bu3/Flu and TBI8Gy/Flu for patients <50 years old.
Fig. 2: Comparison of Bu3/Flu and TBI8Gy/Flu for patients aged 50 years or older.

References

  1. 1.

    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.

    Article  Google Scholar 

  2. 2.

    Giralt S, Ballen K, Rizzo D, Bacigalupo A, Horowitz M, Pasquini M, et al. Reduced-intensity conditioning regimen workshop: defining the dose spectrum. Report of a workshop convened by the center for international blood and marrow transplant research. Biol Blood Marrow Transplant. 2009;15:367–9.

    Article  Google Scholar 

  3. 3.

    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 

  4. 4.

    Ringdén O, Ruutu T, Remberger M, Nikoskelainen J, Volin L, Vindeløv L, et al. A randomized trial comparing busulfan with total body irradiation as conditioning in allogeneic marrow transplant recipients with leukemia: a report from the Nordic Bone Marrow Transplantation Group. Blood. 1994;83:2723–30.

    Article  Google Scholar 

  5. 5.

    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 

  6. 6.

    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:e384–392.

    Article  Google Scholar 

  7. 7.

    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 

  8. 8.

    Passweg JR, Labopin M, Cornelissen J, Volin L, Socié G, Huynh A, et al. Acute Leukemia Working Party of the European Blood and Marrow Transplant Group (EBMT). Conditioning intensity in middle-aged patients with AML in first CR: no advantage for myeloablative regimens irrespective of the risk group-an observational analysis by the Acute Leukemia Working Party of the EBMT. Bone Marrow Transplant. 2015;50:1063–8.

    Article  CAS  Google Scholar 

  9. 9.

    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.

  10. 10.

    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.

  11. 11.

    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 transplantation. Clin Hematol Int. 2020;2:2–4.

    Google Scholar 

  12. 12.

    Gooley TA, Leisenring W, Crowley J, Storer BE. Estimation of failure probabilities in the presence of competing risks: new representations of old estimators. Stat Med. 1999;18:695–706.

    Article  CAS  Google Scholar 

  13. 13.

    Fine JP, Gray RJ. A proportional hazards model for subdistribution of a competing risk. J Am Stat Assoc. 1999;94:496–509.

    Article  Google Scholar 

  14. 14.

    Liu DH, Xu LP, Zhang XH, Wang Y, Yan CH, Wang JZ, et al. Substitution of cyclophosphamide in the modified Bucy regimen with fludarabine Is associated with increased incidence of severe pneumonia: a prospective, randomized study. Int J Hematol. 2013;98:708–15.

    Article  CAS  Google Scholar 

  15. 15.

    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 

  16. 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. 17.

    Rambaldi A, Grassi A, Masciulli A, Boschini C, Micò 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 

  18. 18.

    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 Transplant. 2016;51:232–40.

    Article  CAS  Google Scholar 

  19. 19.

    Mohty M, Malard F, Blaise D, Milpied N, Furst S, Tabrizi R, et al. Reduced-toxicity conditioning with fludarabine, once-daily intravenous busulfan, and antithymocyte globulins prior to allogeneic stem cell transplantation: results of a multicenter prospective phase 2 trial. Cancer. 2015;121:562–9.

    Article  CAS  Google Scholar 

  20. 20.

    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 

  21. 21.

    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–e169.

    Article  Google Scholar 

  22. 22.

    Socié G, Clift RA, Blaise D, Devergie A, Ringden O, Martin PJ, et al. Busulfan plus cyclophosphamide compared with total-body irradiation plus cyclophosphamide before marrow transplantation for myeloid leukemia: long-term follow-up of 4 randomized studies. Blood. 2001;98:3569–74.

    Article  Google Scholar 

  23. 23.

    Bredeson C, LeRademacher J, Kato K, Dipersio JF, Agura E, Devine SM, et al. Prospective cohort study comparing intravenous busulfan to total body irradiation in hematopoietic cell transplantation. Blood. 2013;122:3871–8.

    Article  CAS  Google Scholar 

  24. 24.

    Buchali A, Feyer P, Groll J, Massenkeil G, Arnold R, Budach V. Immediate toxicity during fractionated total body irradiation as conditioning for bone marrow transplantation. Radiother Oncol. 2000;54:157–62.

    Article  CAS  Google Scholar 

  25. 25.

    Leiper AD. Late effects of total body irradiation. Arch Dis Child. 1995;72:382–5.

    Article  CAS  Google Scholar 

  26. 26.

    Potdar RR, Gupta S, Giebel S, Savani BN, Varadi G, Nagler A, et al. Current Status and perspectives of irradiation-based conditioning regimens for patients with acute leukemia undergoing hematopoietic stem cell transplantation. Clin Hematol Int. 2019;1:19–27.

    Article  Google Scholar 

  27. 27.

    Giebel S, Miszczyk L, Slosarek K, Moukhtari L, Ciceri F, Esteve J, et al. Extreme heterogeneity of myeloablative total body irradiation techniques in clinical practice: a survey of the Acute Leukemia Working Party of the European Group for Blood and Marrow Transplantation. Cancer. 2014;120:2760–5.

    Article  Google Scholar 

  28. 28.

    Andersson BS, Valdez BC. Pretransplant conditioning with fludarabine and IV busulfan, reduced toxicity and increased safety without compromising antitumor efficacy and overall treatment effect? Bone Marrow Transplant. 2016;51:919–20.

    Article  CAS  Google Scholar 

  29. 29.

    Andersson BS, Thall PF, Valdez BC, Milton DR, Al-Atrash G, Chen J, et al. Fludarabine with pharmacokinetically guided IV busulfan is superior to fixed-dose delivery in pretransplant conditioning of AML/MDS patients. Bone Marrow Transplant. 2017;52:580–7.

    Article  CAS  Google Scholar 

  30. 30.

    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  CAS  Google Scholar 

  31. 31.

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

    Article  Google Scholar 

  32. 32.

    Andersen PK, Klein JP, Zhang MJ. Testing for centre effects in multi-centre survival studies: a Monte Carlo comparison of fixed and random effects tests. Stat Med. 1999;18:1489–1500.

    Article  CAS  Google Scholar 

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Acknowledgements

We sincerely thank the centers of the EBMT for contributing patient information and data collection. Principal investigators of the contributing institutions are listed below.

Principle investigators of the contributing institutions

Sonja Martin15, Patrice Chevallier16, Andreas Neubauer17, Gandhi Damaj18, Yener Koc19, Arnold Ganser20, Matthew Collin21, Ibrahim Yakoub-Agha22, Hakan Ozdogu23, Mercedes Colorado Araujo24, Maija Itäla-Remes25, Kim Orchard26, Cecilia Isaksson27, Wolfgang Bethge28, Hans Martin29, Mahmoud Aljurf30, Edgar Faber31, Dolores Caballero32, Pavel Zák33, Xavier Leleu34, Jacques-Olivier Bay35, Pierre-Simon Rohrlich36, Nicolaus Kröger37, Anne Huynh38, Kerstin Schäfer-Eckart39, Noel Milpied40, Stig Lenhoff41, Aloysius Ho42, Jose Luis Bello López43, Nicola Mordini44, Bruno Lioure45, Kazimierz Halaburda46, Attilio Olivieri47, Tobias Gedde-Dahl48, Rachel Protheroe49, Johanna Tischer50, Matthias Klammer51, Johannes Clausen52, Victoria Potter53, Marco Ladetto54, Herve Tilly55, Eric Deconinck56, Arne Brecht57, Lutz Peter Müller58, Thomas Heinicke59, Juan Pio Torres Carrete60, Ali Bazarbachi61, Péter Reményi62, Marie Thérèse Rubio63, Renato Fanin64, Jose Antonio Pérez-Simón65, Murawski Niels66, J. L. Diez-Martin67, Mutlu Arat68, Olivier Hermine69, Gerard Socié70, Jan J. Cornelissen71, Stella Santarone72, Denis Guyotat73, Claude Eric Bulabois74, Paolo Bernasconi75, Jan-Erik Johansson76, Radovan Vrhovac77, Hildegard Greinix78, José Luis López Lorenzo79, Shashikant Apte80, Charles Craddock81, Guido Kobbe82, Mohsen Al Zahrani83, Peter Dreger84, Andrzej Lange85, Abdelghani Tbakhi86, Ellen Meijer87, Carlos Vallejo Llamas88, Josep Maria Ribera Santasusana89, Paolo Corradini90, Fabio Benedetti91, Alessandro Rambaldi92, Virginie Gandemer93, Jean-Valère Malfuson94, Ain Kaare95, Antonio Risitano96, Mario Petrini97, Carmine Selleri98, Depei Wu99.

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Giebel, S., Labopin, M., Sobczyk-Kruszelnicka, M. 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 (2020). https://doi.org/10.1038/s41409-020-01050-7

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