Advertisement

International Journal of Hematology

, Volume 109, Issue 2, pp 197–205 | Cite as

Addition of melphalan to fludarabine/busulfan (FLU/BU4/MEL) provides survival benefit for patients with myeloid malignancy following allogeneic bone-marrow transplantation/peripheral blood stem-cell transplantation

  • Tomoaki UedaEmail author
  • Tetsuo Maeda
  • Shinsuke Kusakabe
  • Jiro Fujita
  • Kentaro Fukushima
  • Takafumi Yokota
  • Hirohiko Shibayama
  • Yoshiaki Tomiyama
  • Yuzuru Kanakura
Original Article

Abstract

A conditioning regimen with fludarabine and myeloablative dose of busulfan (FLU/BU4) has been commonly used in allogeneic hematopoietic cell transplantation (allo-HCT). However, there are two major problems with this regimen: insufficient anti-leukemic effect, especially in advanced cases, and slow time to complete donor-type chimerism, especially T-cell chimerism. To overcome these issues, we designed a combination regimen with FLU (150 mg/m2), intravenous BU (12.8 mg/kg), and melphalan (100 mg/m2) (FLU/BU4/MEL) and conducted retrospective analyses of treatment outcomes at our institute. Forty-two patients with myeloid malignancies received allogeneic bone-marrow transplantation or peripheral blood stem-cell transplantation (allo-BMT/PBSCT) with FLU/BU4/MEL regimen. The median age of patients was 46.5 years (20–63 years). Thirteen patients (31%) did not achieve complete hematological remission at transplantation. All patients examined achieved complete whole and T-cell chimerism within 1 month after allo-HCT. The 4-year overall survival and disease-free survival rates were 66.0% [95% confidence interval (CI) 49.4–78.3%] and 59.5% (95% CI 43.2–72.6%) in all patients, and 49.4% (95% CI 19.7–73.6%) and 38.5% (95% CI 14.1–62.8%) in patients who were not in remission. In conclusion, FLU/BU4/MEL showed curative potential, even in patients with advanced myeloid malignancies, accompanied by achievement of rapid complete chimerism after allo-BMT/PBSCT.

Keywords

Allogeneic bone-marrow transplantation/peripheral blood stem-cell transplantation Conditioning regimen Myeloid malignancy Intravenous busulfan Melphalan 

Notes

Acknowledgements

This study was conducted at the Department of Hematology and Oncology, Osaka University Hospital. We would like to thank all clinicians and patients who contributed to this research. Funding was provided by Otsuka Pharmaceutical (Grant no. 12908149).

Author contributions

TU and TM designed the study and analyzed the data. Transplantation was performed by TU, TM, SK, JF, and KF with assistance from TY, HS, YT, and YK. The manuscript was written by TU, TM, TY, and YK with assistance from KF, JF, HS, and YT.

Compliance with ethical standards

Conflict of interest

The authors received research funding from Otsuka Pharmaceutical Co., Ltd.

References

  1. 1.
    Alatrash G, de Lima M, Hamerschlak N, Pelosini M, Wang X, Xiao L, et al. Myeloablative reduced-toxicity i.v. busulfan-fludarabine and allogeneic hematopoietic stem cell transplant for patients with acute myeloid leukemia or myelodysplastic syndrome in the sixth through eighth decades of life. Biol Blood Marrow Transplant. 2011;17(10):1490–6.CrossRefGoogle Scholar
  2. 2.
    de Lima M, Couriel D, Thall PF, Wang X, Madden T, Jones R, et al. Once-daily intravenous busulfan and fludarabine: clinical and pharmacokinetic results of a myeloablative, reduced-toxicity conditioning regimen for allogeneic stem cell transplantation in AML and MDS. Blood. 2004;104(3):857–64.CrossRefGoogle Scholar
  3. 3.
    Chunduri S, Dobogai LC, Peace D, Saunthararajah Y, Quigley J, Chen YH, et al. Fludarabine/i.v. BU conditioning regimen: myeloablative, reduced intensity or both? Bone Marrow Transplant. 2008;41(11):935–40.CrossRefGoogle Scholar
  4. 4.
    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(15):1525–36.CrossRefGoogle Scholar
  5. 5.
    Eapen M, Brazauskas R, Hemmer M, Perez WS, Steinert P, Horowitz MM, et al. Hematopoietic cell transplantat for acute myeloid leukemia and myelodysplastic syndrome: conditioning regimen intensity. Blood Adv. 2018;2(16):2095–103.CrossRefGoogle Scholar
  6. 6.
    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. 2015;51(2):232–40.CrossRefGoogle Scholar
  7. 7.
    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.CrossRefGoogle Scholar
  8. 8.
    Shimoni A, Hardan I, Shem-Tov N, Yerushalmi R, Nagler A. Allogeneic hematopoietic stem-cell transplantation in AML and MDS using myeloablative versus reduced-intensity conditioning: long-term follow-up. Leukemia. 2010;24(5):1050–2.CrossRefGoogle Scholar
  9. 9.
    Saito B, Fukuda T, Yokoyama H, Kurosawa S, Takahashi T, Fuji S, et al. Impact of T cell chimerism on clinical outcome in 117 patients who underwent allogeneic stem cell transplantation with a busulfan-containing reduced-intensity conditioning regimen. Biol Blood Marrow Transplant. 2008;14(10):1148–55.CrossRefGoogle Scholar
  10. 10.
    Koreth J, Kim HT, Nikiforow S, Milford EL, Armand P, Cutler C, et al. Donor chimerism early after reduced-intensity conditioning hematopoietic stem cell transplantation predicts relapse and survival. Biol Blood Marrow Transplant. 2014;20(10):1516–21.CrossRefGoogle Scholar
  11. 11.
    Peterlin P, Delaunay J, Guillaume T, Gastinne T, Mahé B, Dubruille V, et al. Complete donor T cell chimerism predicts lower relapse incidence after standard double umbilical cord blood reduced-intensity conditioning regimen allogeneic transplantation in adults. Biol Blood Marrow Transplant. 2015;21(1):180–4.CrossRefGoogle Scholar
  12. 12.
    Przepiorka D, Weisdorf D, Martin P, Klingemann HG, Beatty P, Hows J, 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. Bone Marrow Transplant. 1995;15(6):825–8.Google Scholar
  13. 13.
    Filipovich AH, Weisdorf D, Pavletic S, Socie G, Wingard JR, Lee SJ, 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 Transplant. 2005;11(12):945–56.CrossRefGoogle Scholar
  14. 14.
    Kanda Y. Investigation of the freely available easy-to-use software ‘EZR’ for medical statistics. Bone Marrow Transplant. 2012;48(3):452–8.CrossRefGoogle Scholar
  15. 15.
    Schanz J, Tuchler H, Sole F, Mallo M, Luno E, Cervera J, et al. New comprehensive cytogenetic scoring system for primary myelodysplastic syndromes (MDS) and oligoblastic acute myeloid leukemia after MDS derived from an international database merge. J Clin Oncol. 2012;30(8):820–9.CrossRefGoogle Scholar
  16. 16.
    Armand P, Kim HT, Logan BR, Wang Z, Alyea EP, Kalaycio ME, et al. Validation and refinement of the Disease Risk Index for allogeneic stem cell transplantation. Blood. 2014;123(23):3664–71.CrossRefGoogle Scholar
  17. 17.
    Ishida H, Adachi S, Hasegawa D, Okamoto Y, Goto H, Inagaki J, et al. Comparison of a fludarabine and melphalan combination-based reduced toxicity conditioning with myeloablative conditioning by radiation and/or busulfan in acute myeloid leukemia in Japanese children and adolescents. Pediatr Blood Cancer. 2015;62(5):883–9.CrossRefGoogle Scholar
  18. 18.
    Jaiswal SR, Chakrabarti A, Chatterjee S, Bhargava S, Ray K, O’Donnell P, et al. Haploidentical peripheral blood stem cell transplantation with post-transplantation cyclophosphamide in children with advanced acute leukemia with fludarabine-, busulfan-, and melphalan-based conditioning. Biol Blood Marrow Transplant. 2016;22(3):499–504.CrossRefGoogle Scholar
  19. 19.
    Yamamoto H, Uchida N, Yuasa M, Kageyama K, Ota H, Kaji D, et al. A novel reduced-toxicity myeloablative conditioning regimen using full-dose busulfan, fludarabine, and melphalan for single cord blood transplantation provides durable engraftment and remission in nonremission myeloid malignancies. Biol Blood Marrow Transplant. 2016;22(10):1844–50.CrossRefGoogle Scholar
  20. 20.
    Vokurka S, Steinerova K, Karas M, Koza V. Characteristics and risk factors of oral mucositis after allogeneic stem cell transplantation with FLU/MEL conditioning regimen in context with BU/CY2. Bone Marrow Transplant. 2009;44(9):601–5.CrossRefGoogle Scholar
  21. 21.
    Popat U, de Lima MJ, Saliba RM, Anderlini P, Andersson BS, Alousi AM, et al. Long-term outcome of reduced-intensity allogeneic hematopoietic SCT in patients with AML in CR. Bone Marrow Transplant. 2012;47(2):212–6.CrossRefGoogle Scholar
  22. 22.
    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(7):1048–55.CrossRefGoogle Scholar
  23. 23.
    Kharfan-Dabaja MA, Labopin M, Bazarbachi A, Hamladji RM, Blaise D, Socie G, et al. Comparing i.v. BU dose intensity between two regimens (FB2 vs FB4) for allogeneic HCT for AML in CR1: a report from the Acute Leukemia Working Party of EBMT. Bone Marrow Transplant. 2014;49(9):1170–5.CrossRefGoogle Scholar
  24. 24.
    Russell JA, Kangarloo SB, Williamson T, Chaudhry MA, Savoie ML, Turner AR, et al. Establishing a target exposure for once-daily intravenous busulfan given with fludarabine and thymoglobulin before allogeneic transplantation. Biol Blood Marrow Transplant. 2013;19(9):1381–6.CrossRefGoogle Scholar
  25. 25.
    Morty M, Avinens O, Faucher C, Viens P, Blaise D, Eliaou JF. Predictive factors and impact of full donor T-cell chimerism after reduced intensity conditioning allogeneic stem cell transplantation. Haematologica. 2007;92(7):1004–6.CrossRefGoogle Scholar
  26. 26.
    El-Cheikh J, Vazquez A, Crocchiolo R, Furst S, Calmels B, Castagna L, et al. Acute GVHD is a strong predictor of full donor CD3+ T cell Chimerism after reduced intensity conditioning allogeneic stem cell transplantation. Am J Hematol. 2012;87:1074–8.CrossRefGoogle Scholar
  27. 27.
    Minagawa K, Yamamori M, Katayama Y, Matsui T. Mycophenolate mofetil: fully utilizing its benefits for GvHD prophylaxis. Int J Hematol. 2012;96:10–25.CrossRefGoogle Scholar
  28. 28.
    Miyamoto T, Takashima S, Kato K, Takase K, Yoshimoto G, Yoshida S, et al. Comparison of cyclosporine and tacrolimus combined with mycophenolate mofetil in prophylaxis for graft-versus-host disease after reduced-intensity umbilical cord blood transplantation. Int J Hematol. 2017;105(1):92–9.CrossRefGoogle Scholar
  29. 29.
    Nakane T, Nakamae H, Yamaguchi T, Kurosawa S, Okamura A, Hidaka M, et al. Use of mycophenolate mofetil and a calcineurin inhibitor in allogeneic hematopoietic stem-cell transplantation from HLA-matched siblings or unrelated volunteer donors: Japanese multicenter phase II trials. Int J Hematol. 2017;105(4):485–96.CrossRefGoogle Scholar
  30. 30.
    Verhaak RG, Goudswaard CS, van Putten W, Bijl MA, Sanders MA, Hugens W, et al. Mutations in nucleophosmin (NPM1) in acute myeloid leukemia (AML): association with other gene abnormalities and previously established gene expression signatures and their favorable prognostic significance. Blood. 2005;106(12):3747–54.CrossRefGoogle Scholar
  31. 31.
    Kottaridis PD, Gale RE, Frew ME, Harrison G, Langabeer SE, Belton AA, et al. The presence of a FLT3 internal tandem duplication in patients with acute myeloid leukemia (AML) adds important prognostic information to cytogenetic risk group and response to the first cycle of chemotherapy: analysis of 854 patients from the United Kingdom Medical Research Council AML 10 and 12 trials. Blood. 2001;98(6):1752–9.CrossRefGoogle Scholar
  32. 32.
    Cairoli R, Beghini A, Grillo G, Nadali G, Elice F, Ripamonti CB, et al. Prognostic impact of c-KIT mutations in core binding factor leukemias: an Italian retrospective study. Blood. 2006;107(9):3463–8.CrossRefGoogle Scholar

Copyright information

© The Japanese Society of Hematology 2018

Authors and Affiliations

  • Tomoaki Ueda
    • 1
    Email author
  • Tetsuo Maeda
    • 1
  • Shinsuke Kusakabe
    • 1
  • Jiro Fujita
    • 1
  • Kentaro Fukushima
    • 1
  • Takafumi Yokota
    • 1
  • Hirohiko Shibayama
    • 1
  • Yoshiaki Tomiyama
    • 2
  • Yuzuru Kanakura
    • 1
  1. 1.Department of Hematology and OncologyOsaka University Graduate School of MedicineSuitaJapan
  2. 2.Department of Blood TransfusionOsaka University HospitalSuitaJapan

Personalised recommendations