Allogeneic hematopoietic stem cells transplantation improves the survival of intermediate-risk acute myeloid leukemia patients aged less than 60 years

  • Ying Zhang
  • Yimin Zhang
  • Qi Chen
  • Gusheng Tang
  • Weiping Zhang
  • Jianmin Yang
  • Jianmin Wang
  • Xiaoxia HuEmail author
Original Article


The prognosis of acute myeloid leukemia (AML) with normal karyotype is further determined by specific genetic alterations. The optimal post-remission therapy (PRT) in younger patients within this group after first complete remission (CR1) remains to be determined. We report a retrospective evaluation of PRT approaches in 223 patients under the age of 60 years old with intermediate-risk AML in CR1. Patients receiving allogenic hematopoietic stem cell transplantation (alloHSCT) obtained improved overall survival (OS) than patients who treated with chemotherapy (5-year 61.6 ± 5.2% versus 41.1 ± 5.3%, p = 0.004). AlloHSCT led to fewer cases of relapse (hazard ratio [HR] 0.14, p < 0.001) and increased the relapse-free survival (RFS, HR 0.45, p < 0.001). With alloHSCT, the outcome of patients who reached negative minimal residual disease after 2 cycles of consolidation could be further improved with an increased OS of 66% and RFS of 61%. Nucleophosmin-1 (NPM1) mutation negative, CCAAT/enhancer binding protein alpha (CEBPA) double mutation negative, and FLT-3 internal tandem duplication negative (NPM1mut-negCEBPAdm-negFLT3-ITDneg) patients had a significantly longer RFS with alloHSCT. In conclusion, our results provide additional evidence that alloHSCT is preferential PRT in patients with intermediate-risk AML that are under the age of 60 years old in CR1.


Acute myeloid leukemia Intermediate risk Postremission therapy Allogeneic hematopoietic stem cell transplantation NPM1mut-negCEBPAdm-negFLT3-ITDneg 


Authors’ contribution

Y.Z. collected and reviewed patient information, analyzed and interpreted the data, and wrote the manuscript; Y.M.Z. and Q.C. performed the statistical analysis; G.T. performed the molecular analysis; W.Z. and J.Y. performed the diagnosis and treatment for patients; J.W. and X.H. designed the study, interpreted the data, and critically reviewed the manuscript. All authors reviewed and approved the manuscript.


This work was supported by the National Natural Science Foundation of China (NSFC; 81770160, 81470321, 81270567, 81530047). X.H. was sponsored by Municipal Human Resources Development Program for Outstanding Leaders in Medical Disciplines in Shanghai (2017BR012).

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards.

Informed consent

For this retrospective study, formal content is not required.

Supplementary material

277_2018_3584_MOESM1_ESM.pdf (461 kb)
Supplementary Table 1 (PDF 460 kb)


  1. 1.
    Dohner H, Estey EH, Amadori S, Appelbaum FR, Buchner T, Burnett AK, Dombret H, Fenaux P, Grimwade D, Larson RA, Lo-Coco F, Naoe T, Niederwieser D, Ossenkoppele GJ, Sanz MA, Sierra J, Tallman MS, Lowenberg B, Bloomfield CD (2010) Diagnosis and management of acute myeloid leukemia in adults: recommendations from an international expert panel, on behalf of the European LeukemiaNet. Blood 115(3):453–474CrossRefGoogle Scholar
  2. 2.
    Burnett AK, Russell NH, Hills RK, Hunter AE, Kjeldsen L, Yin J, Gibson BE, Wheatley K, Milligan D (2013) Optimization of chemotherapy for younger patients with acute myeloid leukemia: results of the medical research council AML15 trial. J Clin Oncol 31(27):3360–3368CrossRefGoogle Scholar
  3. 3.
    Weick JK, Kopecky KJ, Appelbaum FR, Head DR, Kingsbury LL, Balcerzak SP, Bickers JN, Hynes HE, Welborn JL, Simon SR, Grever M (1996) A randomized investigation of high-dose versus standard-dose cytosine arabinoside with daunorubicin in patients with previously untreated acute myeloid leukemia: a Southwest Oncology Group study. Blood 88(8):2841–2851PubMedGoogle Scholar
  4. 4.
    Kern W, Estey EH (2006) High-dose cytosine arabinoside in the treatment of acute myeloid leukemia: review of three randomized trials. Cancer 107(1):116–124CrossRefGoogle Scholar
  5. 5.
    Herr AL, Labopin M, Blaise D, Milpied N, Potter M, Michallet M, Heit W, Ferrara F, Esteve J, Arcese W, Ehninger G, Rowe JM, Kobbe G, Rosselet A, Bunjes D, Rio B, Brune M, Nagler A, Gorin NC, Frassoni F, Rocha V (2007) HLA-identical sibling allogeneic peripheral blood stem cell transplantation with reduced intensity conditioning compared to autologous peripheral blood stem cell transplantation for elderly patients with de novo acute myeloid leukemia. Leukemia 21(1):129–135CrossRefGoogle Scholar
  6. 6.
    Rollig C, Bornhauser M, Thiede C, Taube F, Kramer M, Mohr B, Aulitzky W, Bodenstein H, Tischler HJ, Stuhlmann R, Schuler U, Stolzel F, von Bonin M, Wandt H, Schafer-Eckart K, Schaich M, Ehninger G (2011) Long-term prognosis of acute myeloid leukemia according to the new genetic risk classification of the European LeukemiaNet recommendations: evaluation of the proposed reporting system. J Clin Oncol 29(20):2758–2765CrossRefGoogle Scholar
  7. 7.
    Devine SM, Owzar K, Blum W, Mulkey F, Stone RM, Hsu JW, Champlin RE, Chen YB, Vij R, Slack J, Soiffer RJ, Larson RA, Shea TC, Hars V, Sibley AB, Giralt S, Carter S, Horowitz MM, Linker C, Alyea EP (2015) Phase II study of allogeneic transplantation for older patients with acute myeloid leukemia in first complete remission using a reduced-intensity conditioning regimen: results from cancer and leukemia group B 100103 (alliance for clinical trials in oncology)/blood and marrow transplant clinical trial network 0502. J Clin Oncol 33(35):4167–4175CrossRefGoogle Scholar
  8. 8.
    Dohner H, Estey E, Grimwade D, Amadori S, Appelbaum FR, Buchner T, Dombret H, Ebert BL, Fenaux P, Larson RA, Levine RL, Lo-Coco F, Naoe T, Niederwieser D, Ossenkoppele GJ, Sanz M, Sierra J, Tallman MS, Tien HF, Wei AH, Lowenberg B, Bloomfield CD (2017) Diagnosis and management of AML in adults: 2017 ELN recommendations from an international expert panel. Blood 129(4):424–447CrossRefGoogle Scholar
  9. 9.
    Frohling S, Schlenk RF, Breitruck J, Benner A, Kreitmeier S, Tobis K, Dohner H, Dohner K, leukemia AMLSGUAm (2002) Prognostic significance of activating FLT3 mutations in younger adults (16 to 60 years) with acute myeloid leukemia and normal cytogenetics: a study of the AML Study Group Ulm. Blood 100(13):4372–4380CrossRefGoogle Scholar
  10. 10.
    Patel JP, Gonen M, Figueroa ME, Fernandez H, Sun Z, Racevskis J, Van Vlierberghe P, Dolgalev I, Thomas S, Aminova O, Huberman K, Cheng J, Viale A, Socci ND, Heguy A, Cherry A, Vance G, Higgins RR, Ketterling RP, Gallagher RE, Litzow M, van den Brink MR, Lazarus HM, Rowe JM, Luger S, Ferrando A, Paietta E, Tallman MS, Melnick A, Abdel-Wahab O, Levine RL (2012) Prognostic relevance of integrated genetic profiling in acute myeloid leukemia. N Engl J Med 366(12):1079–1089CrossRefGoogle Scholar
  11. 11.
    Ostronoff F, Othus M, Lazenby M, Estey E, Appelbaum FR, Evans A, Godwin J, Gilkes A, Kopecky KJ, Burnett A, List AF, Fang M, Oehler VG, Petersdorf SH, Pogosova-Agadjanyan EL, Radich JP, Willman CL, Meshinchi S, Stirewalt DL (2015) Prognostic significance of NPM1 mutations in the absence of FLT3-internal tandem duplication in older patients with acute myeloid leukemia: a SWOG and UK National Cancer Research Institute/Medical Research Council report. J Clin Oncol 33(10):1157–1164CrossRefGoogle Scholar
  12. 12.
    Estey E, Dohner H (2006) Acute myeloid leukaemia. Lancet 368(9550):1894–1907CrossRefGoogle Scholar
  13. 13.
    Schlenk RF, Dohner K, Krauter J, Frohling S, Corbacioglu A, Bullinger L, Habdank M, Spath D, Morgan M, Benner A, Schlegelberger B, Heil G, Ganser A, Dohner H, German-Austrian Acute Myeloid Leukemia Study G (2008) Mutations and treatment outcome in cytogenetically normal acute myeloid leukemia. N Engl J Med 358(18):1909–1918CrossRefGoogle Scholar
  14. 14.
    Baldus CD, Thiede C, Soucek S, Bloomfield CD, Thiel E, Ehninger G (2006) BAALC expression and FLT3 internal tandem duplication mutations in acute myeloid leukemia patients with normal cytogenetics: prognostic implications. J Clin Oncol 24(5):790–797CrossRefGoogle Scholar
  15. 15.
    Stirewalt DL, Kopecky KJ, Meshinchi S, Engel JH, Pogosova-Agadjanyan EL, Linsley J, Slovak ML, Willman CL, Radich JP (2006) Size of FLT3 internal tandem duplication has prognostic significance in patients with acute myeloid leukemia. Blood 107(9):3724–3726CrossRefGoogle Scholar
  16. 16.
    Cornelissen JJ, van Putten WL, Verdonck LF, Theobald M, Jacky E, Daenen SM, van Marwijk Kooy M, Wijermans P, Schouten H, Huijgens PC, van der Lelie H, Fey M, Ferrant A, Maertens J, Gratwohl A, Lowenberg B (2007) Results of a HOVON/SAKK donor versus no-donor analysis of myeloablative HLA-identical sibling stem cell transplantation in first remission acute myeloid leukemia in young and middle-aged adults: benefits for whom? Blood 109(9):3658–3666CrossRefGoogle Scholar
  17. 17.
    Rambaldi A, Grassi A, Masciulli A, Boschini C, Mico MC, Busca A, Bruno B, Cavattoni I, Santarone S, Raimondi R, Montanari M, Milone G, Chiusolo P, Pastore D, Guidi S, Patriarca F, Risitano AM, Saporiti G, Pini M, Terruzzi E, Arcese W, Marotta G, Carella AM, Nagler A, Russo D, Corradini P, Alessandrino EP, Torelli GF, Scime R, Mordini N, Oldani E, Marfisi RM, Bacigalupo A, Bosi A (2015) 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 16(15):1525–1536CrossRefGoogle Scholar
  18. 18.
    Ahn JS, Kim HJ, Kim YK, Jung SH, Yang DH, Lee JJ, Kim NY, Choi SH, Jung CW, Jang JH, Kim HJ, Moon JH, Sohn SK, Won JH, Kim SH, Kim DD (2016) Transplant outcomes of the triple-negative NPM1/FLT3-ITD/CEBPA mutation subgroup are equivalent to those of the favourable ELN risk group, but significantly better than the intermediate-I risk group after allogeneic transplant in normal-karyotype AML. Ann Hematol 95(4):625–635CrossRefGoogle Scholar
  19. 19.
    Heidrich K, Thiede C, Schafer-Eckart K, Schmitz N, Aulitzky WE, Kramer A, Rosler W, Hanel M, Einsele H, Baldus CD, Trappe RU, Stolzel F, Middeke JM, Rollig C, Taube F, Kramer M, Serve H, Berdel WE, Ehninger G, Bornhauser M, Schetelig J, Study Alliance L (2017) Allogeneic hematopoietic cell transplantation in intermediate risk acute myeloid leukemia negative for FLT3-ITD, NPM1- or biallelic CEBPA mutations. Ann Oncol 28(11):2793–2798PubMedGoogle Scholar
  20. 20.
    Boissel N, Renneville A, Biggio V, Philippe N, Thomas X, Cayuela JM, Terre C, Tigaud I, Castaigne S, Raffoux E, De Botton S, Fenaux P, Dombret H, Preudhomme C (2005) Prevalence, clinical profile, and prognosis of NPM mutations in AML with normal karyotype. Blood 106(10):3618–3620CrossRefGoogle Scholar
  21. 21.
    Thiede C, Steudel C, Mohr B, Schaich M, Schakel U, Platzbecker U, Wermke M, Bornhauser M, Ritter M, Neubauer A, Ehninger G, Illmer T (2002) Analysis of FLT3-activating mutations in 979 patients with acute myelogenous leukemia: association with FAB subtypes and identification of subgroups with poor prognosis. Blood 99(12):4326–4335CrossRefGoogle Scholar
  22. 22.
    Frohling S, Schlenk RF, Stolze I, Bihlmayr J, Benner A, Kreitmeier S, Tobis K, Dohner H, Dohner K (2004) CEBPA mutations in younger adults with acute myeloid leukemia and normal cytogenetics: prognostic relevance and analysis of cooperating mutations. J Clin Oncol 22(4):624–633CrossRefGoogle Scholar
  23. 23.
    Wang L, Gao L, Xu S, Gong S, Chen L, Lu S, Chen J, Qiu H, Xu X, Ni X, Song X, Zhang W, Yang J, Liu M, Hu X, Wang J (2013) FISH+CD34+CD38- cells detected in newly diagnosed acute myeloid leukemia patients can predict the clinical outcome. J Hematol Oncol 6(1):85CrossRefGoogle Scholar
  24. 24.
    Ringden O, Labopin M, Ehninger G, Niederwieser D, Olsson R, Basara N, Finke J, Schwerdtfeger R, Eder M, Bunjes D, Gorin NC, Mohty M, Rocha V (2009) Reduced intensity conditioning compared with myeloablative conditioning using unrelated donor transplants in patients with acute myeloid leukemia. J Clin Oncol 27(27):4570–4577CrossRefGoogle Scholar
  25. 25.
    Cornelissen JJ, Versluis J, Passweg JR, van Putten WL, Manz MG, Maertens J, Beverloo HB, Valk PJ, van Marwijk Kooy M, Wijermans PW, Schaafsma MR, Biemond BJ, Vekemans MC, Breems DA, Verdonck LF, Fey MF, Jongen-Lavrencic M, Janssen JJ, Huls G, Kuball J, Pabst T, Graux C, Schouten HC, Gratwohl A, Vellenga E, Ossenkoppele G, Lowenberg B (2015) Comparative therapeutic value of post-remission approaches in patients with acute myeloid leukemia aged 40-60 years. Leukemia 29(5):1041–1050CrossRefGoogle Scholar
  26. 26.
    Zhang WP, Wang ZW, Hu XX, Chen J, Yang D, Song XM, Gao L, Ni X, Chen L, Xia XX, Zhou H, Tang GS, Cheng H, Luo YR, Li HM, Yang JM, Wang JM (2018) Preconditioning with fludarabine, busulfan and cytarabine versus standard BuCy2 for patients with acute myeloid leukemia: a prospective, randomized phase II study. Bone Marrow Transplant.
  27. 27.
    Zhang WP, Yang D, Song XM, Ni X, Chen J, Chen L, Yang JM, Zhou H, Cheng H, Liu BH, Li HM, Wang JM (2013) Allogeneic peripheral blood stem cell transplantation is a promising and safe choice for the treatment of refractory/relapsed acute myelogenous leukemia, even with a higher leukemia burden. Biol Blood Marrow Transplant 19(4):653–660CrossRefGoogle Scholar
  28. 28.
    Lin DY (1997) Non-parametric inference for cumulative incidence functions in competing risks studies. Stat Med 16(8):901–910CrossRefGoogle Scholar
  29. 29.
    Zhu HH, Zhang XH, Qin YZ, Liu DH, Jiang H, Chen H, Jiang Q, Xu LP, Lu J, Han W, Bao L, Wang Y, Chen YH, Wang JZ, Wang FR, Lai YY, Chai JY, Wang LR, Liu YR, Liu KY, Jiang B, Huang XJ (2013) MRD-directed risk stratification treatment may improve outcomes of t(8;21) AML in the first complete remission: results from the AML05 multicenter trial. Blood 121(20):4056–4062CrossRefGoogle Scholar
  30. 30.
    Anderson JR, Cain KC, Gelber RD (1983) Analysis of survival by tumor response. J Clin Oncol 1(11):710–719. CrossRefPubMedGoogle Scholar
  31. 31.
    Cornelissen JJ, Blaise D (2016) Hematopoietic stem cell transplantation for patients with AML in first complete remission. Blood 127(1):62–70CrossRefGoogle Scholar
  32. 32.
    Gorin NC, Giebel S, Labopin M, Savani BN, Mohty M, Nagler A (2015) Autologous stem cell transplantation for adult acute leukemia in 2015: time to rethink? Present status and future prospects. Bone Marrow Transplant 50(12):1495–1502CrossRefGoogle Scholar
  33. 33.
    Gilleece MH, Labopin M, Yakoub-Agha I, Volin L, Socié G, Ljungman P, Huynh A, Deconinck E, Wu D, Bourhis JH, Cahn JY, Polge E, Mohty M, Savani BN, Nagler A. Measurable residual disease, conditioning regimen intensity and age predict outcome of allogeneic hematopoietic cell transplantation for acute myeloid leukemia in first remission:a registry analysis of 2292 patients by the Acute Leukemia Working Party European ociety of Blood and Marrow Transplantation. Am J Hematol 93(9):1142–1152Google Scholar
  34. 34.
    Vidriales MB, Perez-Lopez E, Pegenaute C, Castellanos M, Perez JJ, Chandia M, Diaz-Mediavilla J, Rayon C, de Las Heras N, Fernandez-Abellan P, Cabezudo M, de Coca AG, Alonso JM, Olivier C, Hernandez-Rivas JM, Montesinos P, Fernandez R, Garcia-Suarez J, Garcia M, Sayas MJ, Paiva B, Gonzalez M, Orfao A, San Miguel JF (2016) Minimal residual disease evaluation by flow cytometry is a complementary tool to cytogenetics for treatment decisions in acute myeloid leukaemia. Leuk Res 40:1–9CrossRefGoogle Scholar
  35. 35.
    Gorin NC, Labopin M, Pabst T, Remenyi P, Wu D, Huynh A, Volin L, Cahn JY, Yakoub-Agha I, Mercier M, Houhou M, Mohty M, Nagler A (2017) Unrelated matched versus autologous transplantation in adult patients with good and intermediate risk acute myelogenous leukemia in first molecular remission. Am J Hematol 92(12):1318–1323CrossRefGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Department of Hematology, Institute of HematologyChanghai HospitalShanghaiChina
  2. 2.Department of Health StatisticsSecond Military Medical UniversityShanghaiChina

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