International Journal of Hematology

, Volume 110, Issue 3, pp 347–354 | Cite as

Conditioning regimen with a 75% dose of standard busulfan/cyclophosphamide plus fludarabine before cord blood transplantation in older patients with AML and MDS

  • Takanori OhtaEmail author
  • Yasuhiro Sugio
  • Hiroshi Imanaga
  • Seidou Oku
  • Yuju Ohno
Original Article


In this retrospective study, we aimed to establish a conditioning regimen for older patients receiving cord blood transplantation (CBT). This study included 21 older patients [median age 65 (58–73) years] with acute myeloid leukemia and myelodysplastic syndrome who underwent single CBT following a conditioning regimen comprising fludarabine (FLU) 125–175 mg/m2, busulfan (BU) 9.6 mg/kg, and cyclophosphamide (CY) 90 mg/kg. Twelve patients (57.1%) were considered high or very high risk according to the disease risk index. Nineteen achieved neutrophil engraftment at a median of 19 days (range 14–29 days) after CBT (cumulative incidence 90.5%). During a median observation period of 24.3 months, the overall survival (OS) rates at 100 days and 2 years were 76.2% and 47.6%, respectively, with cumulative 2-year relapse and non-relapse mortality (NRM) rates of 19.0% and 38.1%, respectively. Infectious disease was the leading cause of NRM (n = 5) and occurred within 100 day post-transplantation in two patients. This suggested that the administration of a reduced BU/CY plus FLU regimen to older patients receiving CBT enables an early recovery with high neutrophil engraftment, relapse suppression, and acceptable NRM rates.


Cord blood transplantation Older patients Fludarabine Busulfan Cyclophosphamide 



We are extremely thankful for all the patients who participated in this study and their families, and physicians, nurses, and pharmacists who assisted with this study. We would like to thank Enago ( for the English language review.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflicts of interest.


  1. 1.
    Yanada M, Naoe T. Acute myeloid leukemia in older adults. Int J Hematol. 2012;96:186–93.CrossRefPubMedGoogle Scholar
  2. 2.
    Estey E, Döhner H. Acute myeloid leukemia. Lancet. 2006;368:1894–907.CrossRefPubMedGoogle Scholar
  3. 3.
    Appelbaum FR, Gundacker H, Head DR, Slovak ML, Willman CL, Godwin JE, et al. Age and acute myeloid leukemia. Blood. 2006;107:3481–5.CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    Konuma T, Tsukada N, Kanda J, Uchida N, Ohno Y, Miyakoshi S, et al. Comparison of transplant outcomes from matched sibling bone marrow or peripheral blood stem cell and unrelated cord blood in patients 50 years or older. Am J Hematol. 2016;91:E284–92.CrossRefPubMedGoogle Scholar
  5. 5.
    Tong J, Sun Z, Liu H, Geng L, Ding K, Wang X, et al. A myeloablative conditioning regimen with fludarabine demonstrates good results in UCBT for 30 pediatric patients with hematologic malignancies, especially acute lymphoblastic leukemia. Neoplasma. 2014;61:593–600.CrossRefPubMedGoogle Scholar
  6. 6.
    Konuma T, Ooi J, Takahashi S, Tomonari A, Tsukada N, Kato S, et al. Second myeloablative allogeneic stem cell transplantation (SCT) using cord blood for leukemia relapsed after initial allogeneic SCT. Leuk Res. 2009;33:840–2.CrossRefPubMedGoogle Scholar
  7. 7.
    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.CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Kawabata H, Tohyama K, Matsuda A, Araseki K, Hata T, Suzuki T, et al. Validation of the revised Innternational Prognostic Scoring System in patients with myelodysplastic syndrome in Japan: results from a prospective multicenter registry. Int J Hematol. 2017;106:375–84.CrossRefPubMedGoogle Scholar
  9. 9.
    Greenberg PL, Tuechler H, Schanz J, Sanz G, Garcia-Manero G, Solé F, et al. Revised international prognostic scoring system for myelodysplastic syndromes. Blood. 2012;120:2454–65.CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    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;123:3664–71.CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Bearman SI, Appelbaum FR, Buckner CD, Petersen FB, Fisher LD, Clift RA, et al. Regimen-related toxicity in patients undergoing bone marrow transplantation. J Clin Oncol. 1988;6:1562–8.CrossRefPubMedGoogle Scholar
  12. 12.
    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.CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Przepiorka D, Weisdorf D, Martin P, Klingemann HG, Beatty P, Hows J, et al. Consensus conference on acute GVHD grading. Bone Marrow Transplant 1995. 1994;15:825–8.Google Scholar
  14. 14.
    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.CrossRefPubMedGoogle Scholar
  15. 15.
    Konuma T, Kato S, Isobe M, Mizusawa M, Oiwa-Monna M, Takahashi S, et al. Reduced-toxicity myeloablative conditioning consisting of fludarabine/busulfan/low-dose TBI/G-CSF-combined cytarabine in single cord blood transplantation for elderly patients with non-remission myeloid malignancies. Biol Blood Marrow Transplant. 2018. Scholar
  16. 16.
    Kanda Y. Investigation of the freely available easy-to-use software ‘EZR’ for medical statistics. Bone Marrow Transplant. 2013;48:452–8.CrossRefPubMedGoogle Scholar
  17. 17.
    Weisdorf D, Eapen M, Ruggeri A, Zhang MJ, Zhong X, Brunstein C, et al. Alternative donor transplantation for older patients with acute myeloid leukemia in first complete remission: a center for international blood and marrow transplant research-eurocord analysis. Biol Blood Marrow Transplant. 2014;20:816–22.CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Uchida N, Wake A, Takagi S, Yamamoto H, Kato D, Matsuhashi Y, et al. Umbilical cord blood transplantation after reduced-intensity conditioning for elderly patients with hematologic diseases. Biol Blood Marrow Transplant. 2008;14:583–90.CrossRefPubMedGoogle 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;22:1844–50.CrossRefPubMedGoogle Scholar
  20. 20.
    Sun Z, Liu H, Luo C, Geng L, Zheng C, Tang B, et al. Better outcomes of modified myeloablative conditioning without antithymocyte globulin versus myeloablative conditioning in cord blood transplantation for hematological malignancies: a retrospective (development) and a prospective (validation) study. Int J Cancer. 2018;143:699–708.CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Horwitz ME, Morris A, Gasparetto C, Sullivan K, Long G, Chute J, et al. Myeloablative intravenous busulfan/fludarabine conditioning does not facilitate reliable engraftment of dual umbilical cord blood grafts in adult recipients. Biol Blood Marrow Transplant. 2008;14:591–4.CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Sobecks RM, Rybicki L, Yurch M, Kalaycio M, Dean R, Andresen S, et al. Intravenous compared with oral busulfan as preparation for allogeneic hematopoietic progenitor cell transplantation for AML and MDS. Bone Marrow Transplant. 2012;47:633–8.CrossRefPubMedGoogle Scholar
  23. 23.
    Yamamoto H, Uchida N, Matsuno N, Kon A, Nishida A, Ota H, et al. I.v. BU/fludarabine plus melphalan or TBI in unrelated cord blood transplantation for high-risk hematological diseases. Bone Marrow Transplant. 2015;50:607–9.CrossRefPubMedGoogle Scholar
  24. 24.
    Ryu SG, Lee JH, Choi SJ, Lee JH, Lee YS, Seol M, et al. Randomized comparison of four-times-daily versus once-daily intravenous busulfan in conditioning therapy for hematopoietic cell transplantation. Biol Blood Marrow Transplant. 2007;13:1095–105.CrossRefPubMedGoogle Scholar
  25. 25.
    Pasquini MC, Le-Rademacher J, Zhu X, Artz A, DiPersio J, Fernandez HF, et al. Intravenous busulfan-based myeloablative conditioning regimens prior to hematopoietic cell transplantation for hematologic malignancies. Biol Blood Marrow Transplant. 2016;22:1424–30.CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Benadiba J, Ansari M, Krajinovic M, Vachon MF, Duval M, Teira P, et al. Pharmacokinetics-adapted Busulfan-based myeloablative conditioning before unrelated umbilical cord blood transplantation for myeloid malignancies in children. PLoS One. 2018;13:e0193862.CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Danylesko I, Shimoni A, Nagler A. Treosulfan-based conditioning before hematopoietic SCT: more than a BU look-alike. Bone Marrow Transplant. 2012;47:5–14.CrossRefPubMedGoogle Scholar
  28. 28.
    de Koning C, Langenhorst J, van Kesteren C, Lindemans CA, Huitema ADR, Nierkens S, et al. Innate immune recovery predicts CD4+ T cell reconstitution after hematopoietic cell transplantation. Biol Blood Marrow Transplant. 2018;25:819–26.CrossRefPubMedGoogle Scholar
  29. 29.
    Holmes HM, Des Bordes JK, Kebriaei P, Yennu S, Champlin RE, Giralt S, et al. Optimal screening for geriatric assessment in older allogeneic hematopoietic cell transplantation candidates. J Geriatr Oncol. 2014;5:422–30.CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Japanese Society of Hematology 2019

Authors and Affiliations

  • Takanori Ohta
    • 1
    Email author
  • Yasuhiro Sugio
    • 1
  • Hiroshi Imanaga
    • 1
  • Seidou Oku
    • 1
  • Yuju Ohno
    • 1
  1. 1.Department of Internal MedicineKitakyushu Municipal Medical CenterKitakyushuJapan

Personalised recommendations