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Annals of Hematology

, Volume 93, Issue 2, pp 193–202 | Cite as

Long-term results of a prospective randomized trial evaluating G-CSF priming in intensive induction chemotherapy followed by autologous stem cell transplantation in elderly patients with acute myeloid leukemia

  • Gesine Bug
  • Steffen Koschmieder
  • Juergen Krauter
  • Michael Heuser
  • Felicitas Thol
  • Stefanie Wiebe
  • Wolf-Karsten Hofmann
  • Stefan A. Klein
  • Gerd Wegener
  • Gudrun Göhring
  • Wolfgang Heit
  • Dieter Hoelzer
  • Arnold Ganser
  • Oliver G. OttmannEmail author
Original Article

Abstract

Few studies have evaluated granulocyte colony-stimulating factor (G-CSF) priming in elderly patients with intensively treated acute myeloid leukemia (AML), and no data are available for genetically defined AML subgroups. We provide long-term results (median follow-up 7.6 years) of a randomized trial in which 183 patients (median age 67 years) received G-CSF prior to (G-CSF priming) or after two cycles of induction chemotherapy. CR rates with G-CSF priming and G-CSF post-chemotherapy were comparable (57 vs. 67 %, p = 0.153), with overall survival (OS) probabilities of 14 vs. 17 % at 10 years. Induction mortality was significantly higher with G-CSF priming (23 vs. 10 %, p = 0.015), primarily in normal karyotype (NK) AML. In this subgroup, a trend for better relapse-free survival (RFS) was observed with G-CSF priming (44 vs. 22 % at 10 years, p = 0.074) but did not translate into an OS benefit. G-CSF priming had no impact on AML with FLT3-ITD and NPM mutations and did not improve outcome in patients with adverse cytogenetics. In a landmark analysis, late consolidation with autologous stem cell transplantation or a second consolidation cycle significantly improved RFS compared with one consolidation cycle (21.0 vs. 12.8 months, p = 0.046). Future studies on G-CSF priming should be restricted to NK AML and used only in post-remission therapy.

Keywords

Acute myeloid leukemia G-CSF priming Monosomal karyotype FLT3-ITD Autologous stem cell transplantation 

Notes

Acknowledgments

The authors would like to thank Caroline Zander, Gabriele Samson, and Emilia Januschewski for the excellent data management. This study was supported by an unrestricted grant from Amgen GmbH and Pfizer GmbH by the Deutsche Krebshilfe e.V (grant no. 109003) and grant no. DJCLS R 10/22 from the Deutsche-José-Carreras Leukämie-Stiftung e.V (DJCLS). OGO holds an endowed professorship of the DJCLS.

Conflict of interest

The authors declare no conflict of interest.

Informed consent

Informed consent was obtained from all patients for being included in the study.

Supplementary material

277_2013_1873_MOESM1_ESM.doc (38 kb)
Supplemental figure 1 Consort diagram of the trial. (DOC 37 kb)

References

  1. 1.
    Rowe JM, Tallman MS (2010) How I treat acute myeloid leukemia. Blood 116:3147–3156PubMedCrossRefGoogle Scholar
  2. 2.
    Bhalla K, Birkhofer M, Arlin Z, Grant S, Lutzky J, Graham G (1988) Effect of recombinant GM-CSF on the metabolism of cytosine arabinoside in normal and leukemic human bone marrow cells. Leukemia 2:810–813PubMedGoogle Scholar
  3. 3.
    Miyauchi J, Kelleher CA, Wang C, Minkin S, McCulloch EA (1989) Growth factors influence the sensitivity of leukemic stem cells to cytosine arabinoside in culture. Blood 73:1272–1278PubMedGoogle Scholar
  4. 4.
    Smith MA, Singer CR, Pallister CJ, Smith JG (1995) The effect of haemopoietic growth factors on the cell cycle of AML progenitors and their sensitivity to cytosine arabinoside in vitro. Br J Haematol 90:767–773PubMedCrossRefGoogle Scholar
  5. 5.
    Braess J, Voss S, Jahns-Streubel G, Schoch C, Haferlach T, Kern W et al (2000) The pharmacodynamic basis for the increased antileukaemic efficacy of cytosine arabinoside-based treatment regimens in acute myeloid leukaemia with a high proliferative activity. Br J Haematol 110:170–179PubMedCrossRefGoogle Scholar
  6. 6.
    Beekman R, Touw IP (2010) G-CSF and its receptor in myeloid malignancy. Blood 115:5131–5136PubMedCrossRefGoogle Scholar
  7. 7.
    Saito Y, Uchida N, Tanaka S, Suzuki N, Tomizawa-Murasawa M, Sone A et al (2010) Induction of cell cycle entry eliminates human leukemia stem cells in a mouse model of AML. Nat Biotechnol 28:275–280PubMedGoogle Scholar
  8. 8.
    Ottmann OG, Bug G, Krauter J (2007) Current status of growth factors in the treatment of acute myeloid and lymphoblastic leukemia. Semin Hematol 44:183–192PubMedCrossRefGoogle Scholar
  9. 9.
    Heuser M, Zapf A, Morgan M, Krauter J, Ganser A (2011) Myeloid growth factors in acute myeloid leukemia: systematic review of randomized controlled trials. Ann Hematol 90:273–281PubMedCrossRefGoogle Scholar
  10. 10.
    Estey EH, Thall PF, Pierce S, Cortes J, Beran M, Kantarjian H et al (1999) Randomized phase II study of fludarabine + cytosine arabinoside + idarubicin +/− all-trans retinoic acid +/− granulocyte colony-stimulating factor in poor prognosis newly diagnosed acute myeloid leukemia and myelodysplastic syndrome. Blood 93:2478–2484PubMedGoogle Scholar
  11. 11.
    Amadori S, Suciu S, Jehn U, Stasi R, Thomas X, Marie JP et al (2005) Use of glycosylated recombinant human G-CSF (lenograstim) during and/or after induction chemotherapy in patients 61 years of age and older with acute myeloid leukemia: final results of AML-13, a randomized phase-3 study. Blood 106:27–34PubMedCrossRefGoogle Scholar
  12. 12.
    Ohno R, Naoe T, Kanamaru A, Yoshida M, Hiraoka A, Kobayashi T et al (1994) A double-blind controlled study of granulocyte colony-stimulating factor started two days before induction chemotherapy in refractory acute myeloid leukemia. Kohseisho Leukemia Study Group. Blood 83:2086–2092PubMedGoogle Scholar
  13. 13.
    Löwenberg B, van Putten W, Theobald M, Gmur J, Verdonck L, Sonneveld P et al (2003) Effect of priming with granulocyte colony-stimulating factor on the outcome of chemotherapy for acute myeloid leukemia. N Engl J Med 349:743–752PubMedCrossRefGoogle Scholar
  14. 14.
    Buchner T, Berdel WE, Hiddemann W (2004) Priming with granulocyte colony-stimulating factor—relation to high-dose cytarabine in acute myeloid leukemia. N Engl J Med 350:2215–2216PubMedCrossRefGoogle Scholar
  15. 15.
    Milligan DW, Wheatley K, Littlewood T, Craig JI, Burnett AK (2006) Fludarabine and cytosine are less effective than standard ADE chemotherapy in high-risk acute myeloid leukemia, and addition of G-CSF and ATRA are not beneficial: results of the MRC AML-HR randomized trial. Blood 107:4614–4622PubMedCrossRefGoogle Scholar
  16. 16.
    Pabst T, Vellenga E, van Putten W, Schouten HC, Graux C, Vekemans MC et al (2012) Favorable effect of priming with granulocyte colony-stimulating factor in remission induction of acute myeloid leukemia restricted to dose escalation of cytarabine. Blood 119:5367–5373PubMedCrossRefGoogle Scholar
  17. 17.
    Mitelman F (1995) An international system for human cytogenetic nomenclature. S. Karger, BaselGoogle Scholar
  18. 18.
    Breems DA, Van Putten WL, De Greef GE, Van Zelderen-Bhola SL, Gerssen-Schoorl KB, Mellink CH et al (2008) Monosomal karyotype in acute myeloid leukemia: a better indicator of poor prognosis than a complex karyotype. J Clin Oncol 20082(6):4791–4797CrossRefGoogle Scholar
  19. 19.
    Dohner K, Schlenk RF, Habdank M, Scholl C, Rucker FG, Corbacioglu A et al (2005) Mutant nucleophosmin (NPM1) predicts favorable prognosis in younger adults with acute myeloid leukemia and normal cytogenetics: interaction with other gene mutations. Blood 106:3740–3746PubMedCrossRefGoogle Scholar
  20. 20.
    Frohling S, Schlenk RF, Breitruck J, Benner A, Kreitmeier S, Tobis K et al (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 100:4372–4380PubMedCrossRefGoogle Scholar
  21. 21.
    Dohner H, Estey EH, Amadori S, Appelbaum FR, Buchner T, Burnett AK et al (2010) Diagnosis and management of acute myeloid leukemia in adults: recommendations from an international expert panel, on behalf of the European LeukemiaNet. Blood 115:453–474PubMedCrossRefGoogle Scholar
  22. 22.
    Cheson BD, Cassileth PA, Head DR, Schiffer CA, Bennett JM, Bloomfield CD et al (1990) Report of the National Cancer Institute-sponsored workshop on definitions of diagnosis and response in acute myeloid leukemia. J Clin Oncol 8:813–819PubMedGoogle Scholar
  23. 23.
    Kaplan E, Meier P (1958) Nonparametric estimation of from incomplete observations. J Am Stat Assoc 53:457–481CrossRefGoogle Scholar
  24. 24.
    Krug U, Rollig C, Koschmieder A, Heinecke A, Sauerland MC, Schaich M et al (2010) Complete remission and early death after intensive chemotherapy in patients aged 60 years or older with acute myeloid leukaemia: a web-based application for prediction of outcomes. Lancet 376:2000–2008PubMedCrossRefGoogle Scholar
  25. 25.
    Gurion R, Belnik-Plitman Y, Gafter-Gvili A, Paul M, Vidal L, Ben-Bassat I et al (2012) Colony-stimulating factors for prevention and treatment of infectious complications in patients with acute myelogenous leukemia. Cochrane Database Syst Rev 6, CD008238PubMedGoogle Scholar
  26. 26.
    Thomas X, Raffoux E, Botton S, Pautas C, Arnaud P, de Revel T et al (2007) Effect of priming with granulocyte-macrophage colony-stimulating factor in younger adults with newly diagnosed acute myeloid leukemia: a trial by the Acute Leukemia French Association (ALFA) Group. Leukemia 21:453–461PubMedCrossRefGoogle Scholar
  27. 27.
    Cahn JY, Labopin M, Mandelli F, Goldstone AH, Eberhardt K, Reiffers J et al (1995) Autologous bone marrow transplantation for first remission acute myeloblastic leukemia in patients older than 50 years: a retrospective analysis of the European Bone Marrow Transplant Group. Blood 85:575–579PubMedGoogle Scholar
  28. 28.
    Olivieri A, Capelli D, Montanari M, Brunori M, Massidda D, Poloni A et al (2001) Very low toxicity and good quality of life in 48 elderly patients autotransplanted for hematological malignancies: a single center experience. Bone Marrow Transplant 27:1189–1195PubMedCrossRefGoogle Scholar
  29. 29.
    Ferrara F, Venditti A, Carellajr AM, Cantore N, Buccisano F, Tamburini A et al (2002) Autologous stem-cell transplantation for patients with acute myeloid leukemia aged over 60 years. Eur J Haematol 69:200–204PubMedCrossRefGoogle Scholar
  30. 30.
    Oriol A, Ribera JM, Esteve J, Guardia R, Brunet S, Bueno J et al (2004) Feasibility and results of autologous stem cell transplantation in de novo acute myeloid leukemia in patients over 60-years-old. Results of the CETLAM AML-99 protocol. Haematologica 89:791–800PubMedGoogle Scholar
  31. 31.
    Ferrara F, Palmieri S, Annunziata M, Viola A, Pocali B, Califano C et al (2004) Continuous infusion idarubicin and oral busulfan as conditioning for patients with acute myeloid leukemia aged over 60 years undergoing autologous stem cell transplantation. Bone Marrow Transplant 34:573–576PubMedCrossRefGoogle Scholar
  32. 32.
    Thomas X, Suciu S, Rio B, Leone G, Broccia G, Fillet G et al (2007) Autologous stem cell transplantation after complete remission and first consolidation in acute myeloid leukemia patients aged 61–70 years: results of the prospective EORTC-GIMEMA AML-13 study. Haematologica 92:389–396PubMedCrossRefGoogle Scholar
  33. 33.
    Perrot A, Luquet I, Pigneux A, Mugneret F, Delaunay J, Harousseau JL et al (2011) Dismal prognostic value of monosomal karyotype in elderly patients with acute myeloid leukemia: a GOELAMS study of 186 patients with unfavorable cytogenetic abnormalities. Blood 118:679–685PubMedCrossRefGoogle Scholar
  34. 34.
    Medeiros BC, Othus M, Fang M, Roulston D, Appelbaum FR (2010) Prognostic impact of monosomal karyotype in young adult and elderly acute myeloid leukemia: the Southwest Oncology Group (SWOG) experience. Blood 116:2224–2228PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2013

Authors and Affiliations

  • Gesine Bug
    • 1
  • Steffen Koschmieder
    • 2
  • Juergen Krauter
    • 3
  • Michael Heuser
    • 3
  • Felicitas Thol
    • 3
  • Stefanie Wiebe
    • 4
  • Wolf-Karsten Hofmann
    • 5
  • Stefan A. Klein
    • 5
  • Gerd Wegener
    • 3
  • Gudrun Göhring
    • 6
  • Wolfgang Heit
    • 7
  • Dieter Hoelzer
    • 1
  • Arnold Ganser
    • 3
  • Oliver G. Ottmann
    • 1
    • 8
    Email author
  1. 1.Department of Medicine II, Hematology/OncologyUniversity Hospital FrankfurtFrankfurtGermany
  2. 2.Department of Medicine IV, Oncology, Hematology and Stem Cell TransplantationUniversity Hospital of RWTH AachenAachenGermany
  3. 3.Department of Hematology, Hemostasis, Oncology and Stem Cell TransplantationMedical School HannoverHannoverGermany
  4. 4.Medizinische Klinik AUniversitätsklinikum MünsterMünsterGermany
  5. 5.Department of Hematology and OncologyMedical Faculty Mannheim of the University of HeidelbergMannheimGermany
  6. 6.Institute of PathologyMedical School HannoverHannoverGermany
  7. 7.Medizinische KlinikEvangelisches Krankenhaus Essen-WerdenEssen-WerdenGermany
  8. 8.Medizinische Klinik II, Abteilung Hämatologie und OnkologieUniversitätsklinikum FrankfurtFrankfurtGermany

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