Curative potential of fludarabine, melphalan, and non-myeloablative dosage of busulfan in elderly patients with myeloid malignancy

  • Tomoaki UedaEmail author
  • Tomoyasu Jo
  • Kazuya Okada
  • Yasuyuki Arai
  • Takayuki Sato
  • Takeshi Maeda
  • Tatsuhito Onishi
  • Yasunori Ueda
Original Article


Although the combination of fludarabine and high-dose melphalan (FLU/MEL) has been widely used in allogeneic stem cell transplantation, high-dose MEL causes life-threatening adverse events, especially in elderly patients. To reduce the toxicity of MEL without losing its antileukemic effect, we formulated a regimen comprising FLU (125 mg/m2), MEL (100 mg/m2), and a non-myeloablative busulfan dosage [4 mg/kg orally (oral) or 3.2 mg/kg intravenously (iv); FLU/MEL/BU]. We retrospectively analyzed 32 patients with myeloid malignancies who received FLU/MEL/BU at our institute. Median age was 59 years and the median observation period after allo-SCT was 8.2 years. The disease status of most of the patients (97%) at transplantation was controlled. The rate of neutrophil engraftment was 93.3%. The 5-year overall survival (OS), disease-free survival (DFS), non-relapse mortality (NRM), and relapse rate (RR) were 68.5%, 62.1%, 22.0%, and 15.9%, respectively, in all patients. Notably, the outcome of FLU/MEL/iv BU was excellent, with the 5-year OS and DFS being 75.6% and 70.8%, respectively, accompanied by a reduced 5-year NRM and RR of 19.3% and 9.8%, respectively. In conclusion, FLU/MEL/BU, particularly FLU/MEL/iv BU, has curative potential for controlled myeloid malignancies.


Allogeneic stem cell transplantation Conditioning regimen Myeloid malignancy Busulfan Melphalan 



This study was conducted at Kurashiki Central Hospital’s Department of Hematology/Oncology. We would like to thank all clinicians, medical staffs, and patients who contributed to this research.

Author contributions

TU and YU designed the study and analyzed the data. Transplantation was performed by TU, TJ, KO, YA, TS, TM, and TO with assistance from YU. The manuscript was written by TU and YU with assistance from TJ, KO, YA, TS, TM, and TO.

Compliance with ethical standards

Conflict of interest

The authors declare no conflict of interest.


  1. 1.
    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(3):631–7.CrossRefGoogle Scholar
  2. 2.
    Kroger N, Sayer HG, Schwerdtfeger R, Kiehl M, Nagler A, Renges H, et al. Unrelated stem cell transplantation in multiple myeloma after a reduced-intensity conditioning with pretransplantation antithymocyte globulin is highly effective with low transplantation-related mortality. Blood. 2002;100(12):3919–24.CrossRefGoogle Scholar
  3. 3.
    van Besien K, Artz A, Smith S, Cao D, Rich S, Godley L, et al. Fludarabine, melphalan, and alemtuzumab conditioning in adults with standard-risk advanced acute myeloid leukemia and myelodysplastic syndrome. J Clin Oncol. 2005;23(24):5728–38.CrossRefGoogle Scholar
  4. 4.
    Tauro S, Craddock C, Peggs K, Begum G, Mahendra P, Cook G, et al. Allogeneic stem-cell transplantation using a reduced-intensity conditioning regimen has the capacity to produce durable remissions and long-term disease-free survival in patients with high-risk acute myeloid leukemia and myelodysplasia. J Clin Oncol. 2005;23(36):9387–93.CrossRefGoogle Scholar
  5. 5.
    Aisa Y, Mori T, Kudo M, Yashima T, Kondo S, Yokoyama A, et al. Oral cryotherapy for the prevention of high-dose melphalan-induced stomatitis in allogeneic hematopoietic stem cell transplant recipients. Support Care Cancer. 2005;13(4):266–9.CrossRefGoogle Scholar
  6. 6.
    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 Transpl. 2009;44(9):601–5.CrossRefGoogle Scholar
  7. 7.
    Shimoni A, Hardan I, Shem-Tov N, Rand A, Herscovici C, Yerushalmi R, et al. Comparison between two fludarabine-based reduced-intensity conditioning regimens before allogeneic hematopoietic stem-cell transplantation: fludarabine/melphalan is associated with higher incidence of acute graft-versus-host disease and non-relapse mortality and lower incidence of relapse than fludarabine/busulfan. Leukemia. 2007;21(10):2109–16.CrossRefGoogle Scholar
  8. 8.
    Sonis ST, Oster G, Fuchs H, Bellm L, Bradford WZ, Edelsberg J, et al. Oral mucositis and the clinical and economic outcomes of hematopoietic stem-cell transplantation. J Clin Oncol. 2001;19(8):2201–5.CrossRefGoogle Scholar
  9. 9.
    Herbers AH, de Haan AF, van der Velden WJ, Donnelly JP, Blijlevens NM. Mucositis not neutropenia determines bacteremia among hematopoietic stem cell transplant recipients. Transpl Infect Dis. 2014;16(2):279–85.CrossRefGoogle Scholar
  10. 10.
    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 Transpl. 2014;49(9):1170–1175.CrossRefGoogle Scholar
  11. 11.
    Przepiorka D, Weisdorf D, Martin P, Klingemann HG, Beatty P, Hows J et al. 1994 Consensus conference on acute GVHD grading. Bone Marrow Transpl. 1995;15(6): 825–828.Google Scholar
  12. 12.
    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 Transpl. 2005;11(12):945–956.CrossRefGoogle Scholar
  13. 13.
    Kanda Y. Investigation of the freely available easy-to-use software 'EZR' for medical statistics. Bone Marrow Transpl. 2013;48(3):452–8.CrossRefGoogle Scholar
  14. 14.
    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 Transpl. 2007;13(4):454–62.CrossRefGoogle Scholar
  15. 15.
    Bryant A, Nivison-Smith I, Pillai ES, Kennedy G, Kalff A, Ritchie D, et al. Fludarabine melphalan reduced-intensity conditioning allotransplanation provides similar disease control in lymphoid and myeloid malignancies: analysis of 344 patients. Bone Marrow Transpl. 2014;49(1):17–23.CrossRefGoogle Scholar
  16. 16.
    Kawamura K, Kako S, Mizuta S, Ishiyama K, Aoki J, Yano S, et al. Comparison of conditioning with fludarabine/busulfan and fludarabine/melphalan in allogeneic transplantation recipients 50 years or older. Biol Blood Marrow Transpl. 2017;23(12):2079–87.CrossRefGoogle Scholar
  17. 17.
    Miyao K, Sawa M, Kuwatsuka Y, Ozawa Y, Kato T, Kohno A, et al. Influence of melphalan plus fludarabine-conditioning regimen in elderly patients aged 55 years with hematological malignancies. Bone Marrow Transpl. 2016;51(1):157–60.CrossRefGoogle Scholar
  18. 18.
    Kekre N, Marquez-Malaver FJ, Cabrero M, Pinana J, Esquirol A, Soiffer RJ, et al. Fludarabine/busulfan versus fludarabine/melphalan conditioning in patients undergoing reduced-intensity conditioning hematopoietic stem cell transplantation for lymphoma. Biol Blood Marrow Transpl. 2016;22(10):1808–15.CrossRefGoogle Scholar
  19. 19.
    Vera-Llonch M, Oster G, Ford CM, Lu J, Sonis S. Oral mucositis and outcomes of allogeneic hematopoietic stem-cell transplantation in patients with hematologic malignancies. Support Care Cancer. 2007;15(5):491–6.CrossRefGoogle Scholar
  20. 20.
    Sugita J, Matsushita T, Kashiwazaki H, Kosugi M, Takahashi S, Wakasa K, et al. Efficacy of folinic acid in preventing oral mucositis in allogeneic hematopoietic stem cell transplant patients receiving MTX as prophylaxis for GVHD. Bone Marrow Transpl. 2012;47(2):258–64.CrossRefGoogle Scholar
  21. 21.
    Hudspeth MP, Heath TS, Chiuzan C, Garrett-Mayer E, Nista E, Burton L, et al. Folinic acid administration after MTX GVHD prophylaxis in pediatric allo-SCT. Bone Marrow Transpl. 2013;48(1):46–9.CrossRefGoogle Scholar
  22. 22.
    Blennow O, Mattsson J, Remberger M. Pre-engraftment blood stream infection is a risk factor for acute GVHD grades II-IV. Bone Marrow Transpl. 2013;48(12):1583–4.CrossRefGoogle Scholar
  23. 23.
    Johansson JE, Ekman T. Gut toxicity during hemopoietic stem cell transplantation may predict acute graft-versus-host disease severity in patients. Dig Dis Sci. 2007;52(9):2340–5.CrossRefGoogle Scholar
  24. 24.
    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(24):3863–70.CrossRefGoogle Scholar
  25. 25.
    Eapen M, Brazauskas R, Hemmer M, Perez WS, Steinert P, Horowitz MM, et al. Hematopoietic cell transplant for acute myeloid leukemia and myelodysplastic syndrome: conditioning regimen intensity. Blood Adv. 2018;2(16):2095–103.CrossRefGoogle Scholar
  26. 26.
    Aoki J, Seo S, Kanamori H, Tanaka M, Fukuda T, Onizuka M, et al. Impact of low-dose TBI on outcomes of reduced intensity conditioning allogeneic hematopoietic stem cell transplantation for AML. Bone Marrow Transpl. 2016;51(4):604–6.CrossRefGoogle Scholar
  27. 27.
    Curtis RE, Rowlings PA, Deeg HJ, Shriner DA, Socie G, Travis LB, et al. Solid cancers after bone marrow transplantation. N Engl J Med. 1997;336(13):897–904.CrossRefGoogle Scholar
  28. 28.
    Baker KS, Ness KK, Steinberger J, Carter A, Francisco L, Burns LJ, et al. Diabetes, hypertension, and cardiovascular events in survivors of hematopoietic cell transplantation: a report from the bone marrow transplantation survivor study. Blood. 2007;109(4):1765–72.CrossRefGoogle Scholar
  29. 29.
    Giridhar P, Mallick S, Rath GK, Julka PK. Radiation induced lung injury: prediction, assessment and management. Asian Pac J Cancer Prev. 2015;16(7):2613–7.CrossRefGoogle Scholar
  30. 30.
    Nakasone H, Fukuda T, Kanda J, Mori T, Yano S, Kobayashi T, et al. Impact of conditioning intensity and TBI on acute GVHD after hematopoietic cell transplantation. Bone Marrow Transpl. 2015;50(4):559–65.CrossRefGoogle Scholar
  31. 31.
    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
  32. 32.
    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 Transpl. 2016;22(3):499–504.CrossRefGoogle Scholar
  33. 33.
    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 Transpl. 2016;22(10):1844–50.CrossRefGoogle Scholar
  34. 34.
    Ueda T, Maeda T, Kusakabe S, Fujita J, Fukushima K, Yokota T, et al. 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. Int J Hematol. 2019;109(2):197–205.CrossRefGoogle Scholar
  35. 35.
    Damlaj M, Alkhateeb HB, Hefazi M, Partain DK, Hashmi S, Gastineau DA, et al. Fludarabine-busulfan reduced-intensity conditioning in comparison with fludarabine-melphalan is associated with increased relapse risk in spite of pharmacokinetic dosing. Biol Blood Marrow Transpl. 2016;22(8):1431–9.CrossRefGoogle Scholar
  36. 36.
    Flowers ME, Inamoto Y, Carpenter PA, Lee SJ, Kiem HP, Petersdorf EW, et al. Comparative analysis of risk factors for acute graft-versus-host disease and for chronic graft-versus-host disease according to National Institutes of Health consensus criteria. Blood. 2011;117:3214–9.CrossRefGoogle Scholar
  37. 37.
    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
  38. 38.
    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
  39. 39.
    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

© Japanese Society of Hematology 2019

Authors and Affiliations

  • Tomoaki Ueda
    • 1
    • 2
    Email author
  • Tomoyasu Jo
    • 1
    • 3
  • Kazuya Okada
    • 1
  • Yasuyuki Arai
    • 1
    • 3
  • Takayuki Sato
    • 1
  • Takeshi Maeda
    • 1
  • Tatsuhito Onishi
    • 1
  • Yasunori Ueda
    • 1
  1. 1.Department of Hematology/OncologyKurashiki Central HospitalKurashikiJapan
  2. 2.Department of Hematology and OncologyOsaka University Graduate School of MedicineSuitaJapan
  3. 3.Department of Hematology and Oncology, Graduate School of MedicineKyoto UniversityKyotoJapan

Personalised recommendations