International Journal of Hematology

, Volume 107, Issue 4, pp 468–477 | Cite as

Prospective randomization of post-remission therapy comparing autologous peripheral blood stem cell transplantation versus high-dose cytarabine consolidation for acute myelogenous leukemia in first remission

  • Toshihiro Miyamoto
  • Koji Nagafuji
  • Tomoaki Fujisaki
  • Naoyuki Uchida
  • Kosei Matsue
  • Hideho Henzan
  • Ryosuke Ogawa
  • Ken Takase
  • Takatoshi Aoki
  • Michihiro Hidaka
  • Takanori Teshima
  • Shuichi Taniguchi
  • Koichi Akashi
  • Mine Harada
  • For the Japan Study Group for Cell Therapy and Transplantation (JSCT)
Original Article


We prospectively compared outcomes of autologous stem cell transplantation (ASCT) versus high-dose cytarabine (HiDAC) consolidation as post-remission therapy for favorable- and intermediate-risk acute myelogenous leukemia (AML) in first complete remission (CR1). Two-hundred-forty patients under 65 years with AML-M1, M2, M4, or M5 subtypes were enrolled. After induction, 153 patients did not undergo randomization, while the remaining 87 who achieved CR1 were prospectively randomized to HiDAC (n = 45) or ASCT arm (n = 42). In the HiDAC arm, 43 patients completed three cycles of HiDAC, whereas in ASCT arm 22 patients completed two cycles of consolidation consisting of intermediate-dose cytarabine plus mitoxantrone or etoposide followed by ASCT. The three-year disease-free survival (DFS) rate was 41% in HiDAC and 55% in ASCT arm (p = 0.25). Three-year overall survival (OS) rates were 77 and 68% (p = 0.67). Incidence of relapse was 54 and 41% (p = 0.22). There was no significant difference in nonrelapse mortality between two arms (p = 0.88). Patients in the ASCT arm tended to have higher DFS rates and lower relapse rates than patients in HiDAC; however, there was no significant improvement in OS in patients with favorable- and intermediate-risk AML in CR1. Patients with AML are not benefited by the intensified chemotherapy represented by ASCT.


AML Post-remission ASCT HiDAC 



We thank the medical and nursing staff working on the JSCT for providing patient information. This work was supported by a Grant from the Regional Medicine Research Foundation (Tochigi, Japan). This work was also supported by a Grant-in-Aid for Scientific Research (no. 16H05340 to T.M.) and Grant-in-Aid for Scientific Research on Innovative Areas “Stem Cell Aging and Disease” (no. 25115002 to T.M.).

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest. T.M., K.N., and M.H. designed this study, collected clinical information, and wrote the manuscript. S.T, K.T, G.Y, S.Y, H.H, K.K, K.O, T.A., H.I, H.H, T.T, and K.A contributed to the collection of clinical information. All authors read and approved the final manuscript.


  1. 1.
    Mrozek K, Marcucci G, Nicolet D, Maharry KS, Becker H, Whitman SP, et al. Prognostic significance of the European LeukemiaNet standardized system for reporting cytogenetic and molecular alterations in adults with acute myeloid leukemia. J Clin Oncol. 2012;30(36):4515–23.CrossRefPubMedPubMedCentralGoogle Scholar
  2. 2.
    Schlenk RF. Post-remission therapy for acute myeloid leukemia. Haematologica. 2014;99(11):1663–70.CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    Slovak ML, Kopecky KJ, Cassileth PA, Harrington DH, Theil KS, Mohamed A, et al. Karyotypic analysis predicts outcome of preremission and postremission therapy in adult acute myeloid leukemia: a Southwest Oncology Group/Eastern Cooperative Oncology Group Study. Blood. 2000;96(13):4075–83.PubMedGoogle Scholar
  4. 4.
    Bloomfield CD, Lawrence D, Byrd JC, Carroll A, Pettenati MJ, Tantravahi R, et al. Frequency of prolonged remission duration after high-dose cytarabine intensification in acute myeloid leukemia varies by cytogenetic subtype. Cancer Res. 1998;58(18):4173–9.PubMedGoogle Scholar
  5. 5.
    O’Donnel MR, Tallman MS, Abboud CN, Altman JK, Appelbaum FR, Bhatt V, et al. NCCN clinical practice guidelines in oncology. AML. NCCN guidelines version 3.  2017. Accessed 13 Dec 2017.
  6. 6.
    Dohner H, Estey E, Grimwade D, Amadori S, Appelbaum FR, Buchner T, et al. Diagnosis and management of AML in adults: 2017 ELN recommendations from an international expert panel. Blood. 2017;129(4):424–47.CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Miyawaki S. JSH guideline for tumors of hematopoietic and lymphoid tissues: leukemia 1. Acute myeloid leukemia (AML). Int J Hematol. 2017;106(3):310–25.CrossRefPubMedGoogle Scholar
  8. 8.
    Koreth J, Schlenk R, Kopecky KJ, Honda S, Sierra J, Djulbegovic BJ, et al. Allogeneic stem cell transplantation for acute myeloid leukemia in first complete remission: systematic review and meta-analysis of prospective clinical trials. JAMA. 2009;301(22):2349–61.CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Burnett AK, Wheatley K, Goldstone AH, Stevens RF, Hann IM, Rees JH, et al. The value of allogeneic bone marrow transplant in patients with acute myeloid leukaemia at differing risk of relapse: results of the UK MRC AML 10 trial. Br J Haematol. 2002;118(2):385–400.CrossRefPubMedGoogle Scholar
  10. 10.
    Zittoun RA, Mandelli F, Willemze R, de Witte T, Labar B, Resegotti L, et al. Autologous or allogeneic bone marrow transplantation compared with intensive chemotherapy in acute myelogenous leukemia. European Organization for Research and Treatment of Cancer (EORTC) and the Gruppo Italiano Malattie Ematologiche Maligne dell’Adulto (GIMEMA) Leukemia Cooperative Groups. N Engl J Med. 1995;332(4):217–23.CrossRefPubMedGoogle Scholar
  11. 11.
    Suciu S, Mandelli F, de Witte T, Zittoun R, Gallo E, Labar B, et al. Allogeneic compared with autologous stem cell transplantation in the treatment of patients younger than 46 years with acute myeloid leukemia (AML) in first complete remission (CR1): an intention-to-treat analysis of the EORTC/GIMEMAAML-10 trial. Blood. 2003;102(4):1232–40.CrossRefPubMedGoogle Scholar
  12. 12.
    Vellenga E, van Putten W, Ossenkoppele GJ, Verdonck LF, Theobald M, Cornelissen JJ, et al. Autologous peripheral blood stem cell transplantation for acute myeloid leukemia. Blood. 2011;118(23):6037–42.CrossRefPubMedGoogle Scholar
  13. 13.
    Zuckerman T, Beyar-Katz O, Rowe JM. Should autotransplantation in acute myeloid leukemia in first complete remission be revisited? Curr Opin Hematol. 2016;23(2):88–94.CrossRefPubMedGoogle Scholar
  14. 14.
    Gorin NC, Labopin M, Frassoni F, Milpied N, Attal M, Blaise D, et al. Identical outcome after autologous or allogeneic genoidentical hematopoietic stem-cell transplantation in first remission of acute myelocytic leukemia carrying inversion 16 or t(8;21): a retrospective study from the European Cooperative Group for Blood and Marrow Transplantation. J Clin Oncol. 2008;26(19):3183–8.CrossRefPubMedGoogle Scholar
  15. 15.
    Kuwatsuka Y, Miyamura K, Suzuki R, Kasai M, Maruta A, Ogawa H, et al. Hematopoietic stem cell transplantation for core binding factor acute myeloid leukemia: t(8;21) and inv(16) represent different clinical outcomes. Blood. 2009;113(9):2096–103.CrossRefPubMedGoogle Scholar
  16. 16.
    Usuki K, Kurosawa S, Uchida N, Yakushiji K, Waki F, Matsuishi E, et al. Comparison of autologous hematopoietic cell transplantation and chemotherapy as postremission treatment in non-M3 acute myeloid leukemia in first complete remission. Clin Lymphoma Myeloma Leuk. 2012;12(6):444–51.CrossRefPubMedGoogle Scholar
  17. 17.
    Saraceni F, Bruno B, Lemoli RM, Meloni G, Arcese W, Falda M, et al. Autologous stem cell transplantation is still a valid option in good- and intermediate-risk AML: a GITMO survey on 809 patients autografted in first complete remission. Bone Marrow Transpl. 2017;52(1):163–6.CrossRefGoogle Scholar
  18. 18.
    Harada M, Akashi K, Hayashi S, Eto T, Takamatsu Y, Teshima T, et al. Granulocyte colony-stimulating factor-combined marrow-ablative chemotherapy and autologous blood cell transplantation for the treatment of patients with acute myelogenous leukemia in first remission. The Fukouka Bone Marrow Transplant Group. Int J Hematol. 1997;66(3):297–301.CrossRefPubMedGoogle Scholar
  19. 19.
    Gondo H, Harada M, Miyamoto T, Takenaka K, Tanimoto K, Mizuno S, et al. Autologous peripheral blood stem cell transplantation for acute myelogenous leukemia. Bone Marrow Transpl. 1997;20(10):821–6.CrossRefGoogle Scholar
  20. 20.
    Eto T, Takase K, Miyamoto T, Ohno Y, Kamimura T, Nagafuji K, et al. Autologous peripheral blood stem cell transplantation with granulocyte colony-stimulating factor combined conditioning regimen as a postremission therapy for acute myelogenous leukemia in first complete remission. Int J Hematol. 2013;98(2):186–96.CrossRefPubMedGoogle Scholar
  21. 21.
    Yoshimoto G, Nagafuji K, Miyamoto T, Kinukawa N, Takase K, Eto T, et al. FLT3 mutations in normal karyotype acute myeloid leukemia in first complete remission treated with autologous peripheral blood stem cell transplantation. Bone Marrow Transplant. 2005;36(11):977–83.CrossRefPubMedGoogle Scholar
  22. 22.
    Cornelissen JJ, Gratwohl A, Schlenk RF, Sierra J, Bornhauser M, Juliusson G, et al. The European LeukemiaNet AML Working Party consensus statement on allogeneic HSCT for patients with AML in remission: an integrated-risk adapted approach. Nat Rev Clin Oncol. 2012;9(10):579–90.CrossRefPubMedGoogle Scholar
  23. 23.
    Paschka P, Dohner K. Core-binding factor acute myeloid leukemia: can we improve on HiDAC consolidation? Hematol Am Soc Hematol Educ Program. 2013;2013:209–19.Google Scholar
  24. 24.
    Jourdan E, Boissel N, Chevret S, Delabesse E, Renneville A, Cornillet P, et al. Prospective evaluation of gene mutations and minimal residual disease in patients with core binding factor acute myeloid leukemia. Blood. 2013;121(12):2213–23.CrossRefPubMedGoogle Scholar
  25. 25.
    Boissel N, Leroy H, Brethon B, Philippe N, de Botton S, Auvrignon A, et al. Incidence and prognostic impact of c-Kit, FLT3, and Ras gene mutations in core binding factor acute myeloid leukemia (CBF-AML). Leukemia. 2006;20(6):965–70.CrossRefPubMedGoogle Scholar
  26. 26.
    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.CrossRefPubMedGoogle Scholar
  27. 27.
    Shima T, Miyamoto T, Kikushige Y, Yuda J, Tochigi T, Yoshimoto G, et al. The ordered acquisition of Class II and Class I mutations directs formation of human t(8;21) acute myelogenous leukemia stem cell. Exp Hematol. 2014;42(11):955 e1–5–965 e1–5.CrossRefGoogle Scholar
  28. 28.
    Boissel N, Renneville A, Leguay T, Lefebvre PC, Recher C, Lecerf T, et al. Dasatinib in high-risk core binding factor acute myeloid leukemia in first complete remission: a French Acute Myeloid Leukemia Intergroup trial. Haematologica. 2015;100(6):780–5.CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    Hospital MA, Prebet T, Bertoli S, Thomas X, Tavernier E, Braun T, et al. Core-binding factor acute myeloid leukemia in first relapse: a retrospective study from the French AML Intergroup. Blood. 2014;124(8):1312–9.CrossRefPubMedGoogle Scholar
  30. 30.
    Ustun C, Marcucci G. Emerging diagnostic and therapeutic approaches in core binding factor acute myeloid leukaemia. Curr Opin Hematol. 2015;22(2):85–91.CrossRefPubMedGoogle Scholar
  31. 31.
    Burnett AK, Russell NH, Hills RK, Kell J, Freeman S, Kjeldsen L, et al. Addition of gemtuzumab ozogamicin to induction chemotherapy improves survival in older patients with acute myeloid leukemia. J Clin Oncol. 2012;30(32):3924–31.CrossRefPubMedGoogle Scholar
  32. 32.
    Odenike OM, Alkan S, Sher D, Godwin JE, Huo D, Brandt SJ, et al. Histone deacetylase inhibitor romidepsin has differential activity in core binding factor acute myeloid leukemia. Clin Cancer Res. 2008;14(21):7095–101.CrossRefPubMedPubMedCentralGoogle Scholar
  33. 33.
    Bots M, Verbrugge I, Martin BP, Salmon JM, Ghisi M, Baker A, et al. Differentiation therapy for the treatment of t(8, 21) acute myeloid leukemia using histone deacetylase inhibitors. Blood. 2014;123(9):1341–52.CrossRefPubMedPubMedCentralGoogle Scholar
  34. 34.
    Perl AE, Altman JK, Cortes J, Smith C, Litzow M, Baer MR, et al. Selective inhibition of FLT3 by gilteritinib in relapsed or refractory acute myeloid leukaemia: a multicentre, first-in-human, open-label, phase 1–2 study. Lancet Oncol. 2017;18(8):1061–75.CrossRefPubMedGoogle Scholar
  35. 35.
    Papaemmanuil E, Gerstung M, Bullinger L, Gaidzik VI, Paschka P, Roberts ND, et al. Genomic classification and prognosis in acute myeloid leukemia. N Engl J Med. 2016;374(23):2209–21.CrossRefPubMedPubMedCentralGoogle Scholar
  36. 36.
    Kumar CC. Genetic abnormalities and challenges in the treatment of acute myeloid leukemia. Genes Cancer. 2011;2(2):95–107.CrossRefPubMedPubMedCentralGoogle Scholar
  37. 37.
    Stone RM, Mandrekar SJ, Sanford BL, Laumann K, Geyer S, Bloomfield CD, et al. Midostaurin plus chemotherapy for acute myeloid leukemia with a FLT3 mutation. N Engl J Med. 2017;377(5):454–64.CrossRefPubMedPubMedCentralGoogle Scholar
  38. 38.
    Stein EM, DiNardo CD, Pollyea DA, Fathi AT, Roboz GJ, Altman JK, et al. Enasidenib in mutant IDH2 relapsed or refractory acute myeloid leukemia. Blood. 2017;130(6):722–31.CrossRefPubMedPubMedCentralGoogle Scholar
  39. 39.
    The Leukemia & Lymphoma Society. Study seeks new AML therapies. Cancer Discov. 2016;6(12):1297–8.Google Scholar
  40. 40.
    Hanekamp D, Cloos J, Schuurhuis GJ. Leukemic stem cells: identification and clinical application. Int J Hematol. 2017;105(5):549–57.CrossRefPubMedGoogle Scholar

Copyright information

© The Japanese Society of Hematology 2017

Authors and Affiliations

  • Toshihiro Miyamoto
    • 1
  • Koji Nagafuji
    • 2
  • Tomoaki Fujisaki
    • 3
  • Naoyuki Uchida
    • 4
  • Kosei Matsue
    • 5
  • Hideho Henzan
    • 6
  • Ryosuke Ogawa
    • 7
  • Ken Takase
    • 8
  • Takatoshi Aoki
    • 9
  • Michihiro Hidaka
    • 10
  • Takanori Teshima
    • 11
  • Shuichi Taniguchi
    • 4
  • Koichi Akashi
    • 1
  • Mine Harada
    • 12
  • For the Japan Study Group for Cell Therapy and Transplantation (JSCT)
  1. 1.Department of Medicine and Biosystemic ScienceKyushu University Graduate School of Medical ScienceFukuokaJapan
  2. 2.Department of HematologyKurume University HospitalKurumeJapan
  3. 3.Department of HematologyMatsuyama Red Cross HospitalMatsuyamaJapan
  4. 4.Department of HematologyToranomon HospitalTokyoJapan
  5. 5.Department of HematologyKameda Medical CenterKamogawaJapan
  6. 6.Department of HematologyHamanomachi HospitalFukuokaJapan
  7. 7.Department of HematologyJapan Community Health Care Organization Kyushu HospitalKita-KyushuJapan
  8. 8.Department of HematologyNational Kyushu Medical CenterFukuokaJapan
  9. 9.Department of HematologyHarasanshin HospitalFukuokaJapan
  10. 10.Department of Internal Medicine, National Hospital OrganizationKumamoto Medical CenterKumamotoJapan
  11. 11.Department of HematologyHokkaido University HospitalSapporoJapan
  12. 12.Medical Center for Karatsu-Higashimatsuura Medical AssociationKaratsuJapan

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