Skip to main content
SpringerLink
Log in

Risk-adapted induction and consolidation therapy in adults with de novo AML aged ≤ 60 years: results of a prospective multicenter trial

  • Original Article
  • Published:
Annals of Hematology Aims and scope Submit manuscript

Abstract

We treated 305 de novo acute myeloid leukemia (AML) patients aged ≤60 years with risk-adapted therapy. Patients with CBF leukemias or normal karyotype and good response to induction I [≤5% bone marrow (BM) blasts on day 15] were considered standard risk (SR), all others as high risk (HR). Patients with t(15;17) were excluded. Chemotherapy comprised double induction followed by early consolidation. As late consolidation, SR patients received high-dose cytarabine/daunorubicin (AraC/DNR). SR patients with normal karyotype were allotransplanted from HLA-matched siblings. HR patients were allotransplanted or if no sibling donor was available autotransplanted with peripheral blood progenitor cells (PBSC) harvested after early consolidation. 89% of the SR and 60% of the HR patients achieved CR. The continuous complete remission (CCR) rate at 80 months (median follow-up: 48 months) was 48% for SR and 32% for HR. The CCR rate was 54% for t(8;21), 47% for normal karyotype, and 33% for inv(16) patients. In the HR group, the CCR rate did not differ significantly for patients with bad response to IVA-I, unfavorable karyotype, or both. Forty-five HR patients were autotransplanted (n=20) or allotransplanted (n=25). The probability of CCR was 44% for autotransplantation vs 33% for allotransplantation. In conclusion, our risk-adapted strategy produced encouraging results in SR patients. Early response to therapy is a strong prognostic factor that predicts the probability of CR and long-term outcome.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8

Similar content being viewed by others

References

  1. Russell NH (1997) Biology of acute leukaemia. Lancet 349:118–122

    Article  CAS  PubMed  Google Scholar 

  2. Estey E, Kantarjian H, Keating M (2000) Therapy for acute myeloid leukemia. In: Hoffman R, Benz EJJ, Shatttil SJ, Furie B, Cohen HJ, Silberstein LE, McGlave P (eds) Hematology: basic principles and practice. Churchill Livingstone, New York, pp 1025–1042

  3. Löwenberg B, Downing JR, Burnett A (1999) Acute myeloid leukemia. N Engl J Med 341:1051–1062

    CAS  PubMed  Google Scholar 

  4. Mayer RJ, Davis RB, Schiffer CA, Berg DT, Powell BL, Schulman P, Omura GA, Moore JO, McIntyre OR, Frei III E (1994) Intensive postremission chemotherapy in adults with acute myeloid leukemia. N Engl J Med 331:896–903

    PubMed  Google Scholar 

  5. Bloomfield CD, Lawrence D, Byrd JC, Carroll A, Pettenati MJ, Tantravahi R, Patil SR, Davey FR, Berg DT, Schiffer CA, Arthur DC, Mayer RJ (1998) Frequency of prolonged remission duration after high-dose cytarabine intensification in acute myeloid leukemia varies by cytogenetic subtype. Cancer Res 58:4173–4179

    CAS  PubMed  Google Scholar 

  6. Burnett AK, Goldstone AH, Stevens RMF, Hann IM, Rees JKH, Gray RG, Wheatley K (1998) Randomised comparison of addition of autologous bone-marrow transplantation to intensive chemotherapy for acute myeloid leukaemia in first remission: results of MRC AML 10 trial. Lancet 351:700–708

    Article  CAS  PubMed  Google Scholar 

  7. Grimwade D, Walker H, Oliver F, Wheatley K, Harrison C, Harrison G, Rees J, Hann I, Stevens R, Burnett A, Goldstone A (1998) The importance of diagnostic cytogenetics on outcome in AML: analysis of 1,612 patients entered into the MRC AML 10 Trial. Blood 92:2322–2333

    CAS  PubMed  Google Scholar 

  8. Slovak ML, Kopecky KJ, Cassileth PA, Harrington DH, Theil KS, Mohamed A, Paietta E, Willman CL, Head DR, Rowe JM, Forman SJ, Appelbaum FR (2000) Karyotypic analysis predicts outcome of preremission and postremission therapy in adult acute myeloid leukemia: a Southwest Oncology Group/Eastern Cooperative Oncology Group Study. Blood 96:4075–4083

    CAS  PubMed  Google Scholar 

  9. Byrd JC, Mrozek K, Dodge RK, Carroll AJ, Edwards CG, Arthur DC, Pettenati MJ, Patil SR, Rao KW, Watson MS, Koduru PR, Moore JO, Stone RM, Mayer RJ, Feldman EJ, Davey FR, Schiffer CA, Larson RA, Bloomfield CD (2002) Pretreatment cytogenetic abnormalities are predictive of induction success, cumulative incidence of relapse, and overall survival in adult patients with de novo acute myeloid leukemia: results from Cancer and Leukemia Group B (CALGB 8461). Blood 100:4325–4336

    Article  CAS  PubMed  Google Scholar 

  10. Keating MJ, Smith TL, Kantarjian H, Cork A, Walters R, Trujillo JM, McCredie KB, Gehan EA, Freireich EJ (1988) Cytogenetic pattern in acute myelogenous leukemia: a major reproducible determinant of outcome. Leukemia 2:403–412

    CAS  PubMed  Google Scholar 

  11. Keating MJ, Smith TL, Gehan EA, McCredie KB, Bodey GP, Spitzer G, Hersh E, Gutterman J, Freireich EJ (1980) Factors related to length of complete remission in adult acute leukemia. Cancer 45:2017–2029

    CAS  PubMed  Google Scholar 

  12. Anderlini P, Ghaddar HM, Smith TL, Pierce S, Kantarjian HM, O’Brien S, Keating MJ, Freireich EJ, Estey EH (1996) Factors predicting complete remission and subsequent disease-free survival after a second course of induction therapy in patients with acute myelogenous leukemia resistant to the first. Leukemia 10:964–969

    CAS  PubMed  Google Scholar 

  13. Heil G, Mitrou PS, Hoelzer D, Freund M, Link H, Ehninger G, Steinke B, Öhl S, Wandt H, Fackler-Schwalbe E, Schlimok G, Lösch A, Quei er W, Löffler B, Gaus W, Högel J, Heimpel H, Kurrle E (1995) High-dose cytosine arabinoside and daunorubicin postremission therapy in adults with de novo acute myeloid leukemia: long term follow-up of a prospective multicenter trial. Ann Hematol 71:219–225

    Article  CAS  PubMed  Google Scholar 

  14. Heil G, Chadid L, Hoelzer D, Seipelt G, Mitrou P, Huber C, Kolbe K, Mertelsmann R, Lindemann A, Frisch J, Nicolay U, Gaus W, Heimpel H (1995) GM-CSF in a double-blind randomized, placebo controlled trial in therapy of adult patients with de-novo acute myeloid leukemia (AML). Leukemia 5:3–9

    Google Scholar 

  15. Fenaux P, Le Deley MC, Castaigne S, Archimbaud E, Chomienne C, Link H, Guerci A, Duarte M, Daniel MT, Bowen D, Huebner G, Bauters F, Fegueux N, Fey M, Sanz M, Löwenberg B, Maloisel F, Auzanneau G, Sadoun A, Gardin C, Bastion Y, Ganser A, Jacky E, Dombret H, Chastang C, Degos L, the European APL 91 Group (1993) Effect of all trans retinoic acid in newly diagnosed acute promyelocytic leukemia. Results of a multicenter randomized trial. Blood 82:3241–3249

    CAS  PubMed  Google Scholar 

  16. Büchner T, Hiddemann W, Wörmann B, Loffler H, Gassmann W, Haferlach T, Fonatsch C, Haase D, Schoch C, Hossfeld D, Lengfelder E, Aul C, Heyll A, Maschmeyer G, Ludwig WD, Sauerland MC, Heinecke A (1999) Double induction strategy for acute myeloid leukemia: the effect of high-dose cytarabine with mitoxantrone instead of standard-dose cytarabine with daunorubicin and 6-thioguanine: a randomized trial by the German AML Cooperative Group. Blood 93:4116–4124

    CAS  PubMed  Google Scholar 

  17. Cheson BD, Cassileth PA, Head DR, Schiffer CA, Bennett JM, Bloomfield CD, Brunning R, Gale RP, Grever MR, Keating MJ, Sawitzki A, Stass S, Weinstein H, Woods WG (1990) Report of the National Cancer Institute-sponsored workshop on definitions of diagnosis and response in acute myeloid leukemia. J Clin Oncol 8:813–819

    CAS  PubMed  Google Scholar 

  18. Kaplan EL, Meier P (1958) Nonparametric estimation from incomplete observations. J Am Stat Assoc 53:457–481

    Google Scholar 

  19. Büchner T, Urbanitz D, Hiddemann W, Ruehl H, Ludwig WD, Fischer J, Aul HC, Vaupel HA, Kuse R, Zeile G, Nowrousian MA, Koenig HJ, Walter M, Wendt FC, Sodomann H, Hossfeld DK, von Paleske A, Loeffler H, Gassmann W, Hellriegel KP, Fuelle HH, Luncksen C, Emmerich B, Pralle H, Pees HW, Pfreundschuh M, Bartels H, Koeppen KM, Schwerdtfeger R, Donhuijsen-Ant R, Mainzer K, Bonfert B, Koeppler H, Zurborn KH, Ranft K, Thiel E, Heinecke A (1985) Intensified induction and consolidation with or without maintenance chemotherapy for acute myeloid leukemia (AML): two multicenter studies of the German AML Cooperative Group. J Clin Oncol 3:1583–1589

    CAS  PubMed  Google Scholar 

  20. Arlin ZA, Ahmed T, Mittelman A, Feldman E, Mehta R, Weinstein P, Rieber E, Sullivan P, Baskind P (1987) A new regiment of amsacrine with high-dose cytarabine is safe and effective therapy for acute leukemia. J Clin Oncol 5:371–375

    CAS  PubMed  Google Scholar 

  21. Wheatley K, Burnett AK, Goldstone AH, Gray RG, Hann IM, Harrison CJ, Rees JK, Stevens RF, Walker H (1999) A simple, robust, validated and highly predictive index for the determination of risk-directed therapy in acute myeloid leukaemia derived from the MRC AML 10 trial. United Kingdom Medical Research Council’s Adult and Childhood Leukaemia Working Parties. Br J Haematol 107:69–79

    CAS  PubMed  Google Scholar 

  22. Bloomfield CD, Lawrence D, Arthur DC, Berg TD, Schiffer CA, Mayer RJ (1994) Curative impact of intensification with high-dose cytarabine (HiDAC) in acute myeloid leukemia (AML) varies by cytogenetic group (abstract). Blood 84 [Suppl 1]:111a

  23. Schoch C, Haase D, Haferlach T, Gudat H, Buchner T, Freund M, Link H, Lengfelder E, Wandt H, Sauerland MC, Loffler H, Fonatsch C (1996) Fifty-one patients with acute myeloid leukemia and translocation t(8;21)(q22;q22): an additional deletion in 9q is an adverse prognostic factor. Leukemia 10:1288–1295

    CAS  PubMed  Google Scholar 

  24. Sanz MA, Martin G, Rayon C, Esteve J, Gonzalez M, Diaz-Mediavilla J, Bolufer P, Barragan E, Terol MJ, Gonzalez JD, Colomer D, Chillon C, Rivas C, Gomez T, Ribera JM, Bornstein R, Roman J, Calasanz MJ, Arias J, Alvarez C, Ramos F, Deben G (1999) A modified AIDA protocol with anthracycline-based consolidation results in high antileukemic efficacy and reduced toxicity in newly diagnosed PML/RARalpha-positive acute promyelocytic leukemia. PETHEMA group. Blood 94:3015–3021

    CAS  PubMed  Google Scholar 

  25. Nguyen S, Leblanc T, Fenaux P, Witz F, Blaise D, Pigneux A, Thomas X, Rigal-Huguet F, Lioure B, Auvrignon A, Fiere D, Reiffers J, Castaigne S, Leverger G, Harousseau JL, Socie G, Dombret H (2002) A white blood cell index as the main prognostic factor in t(8;21) acute myeloid leukemia (AML): a survey of 161 cases from the French AML Intergroup. Blood 99:3517–3523

    Article  CAS  PubMed  Google Scholar 

  26. Schlenk R, Döhner K, Krauter J, Schaich M, Döhner H, Ehninger G, Heil G (2002) White blood cell count with a cut-off value of 26x 109/l predicts relapse and survival in t(8;21) positive acute myeloid leukemia: meta-analysis of the German AML-Intergroup. Blood 100 [Suppl 1]:343a

  27. Kern W, Haferlach T, Schoch C, Loffler H, Gassmann W, Heinecke A, Sauerland MC, Berdel W, Buchner T, Hiddemann W (2003) Early blast clearance by remission induction therapy is a major independent prognostic factor for both achievement of complete remission and long-term outcome in acute myeloid leukemia: data from the German AML Cooperative Group (AMLCG) 1992 Trial. Blood 101:64–70

    Article  CAS  PubMed  Google Scholar 

  28. Liso V, Albano F, Pastore D, Carluccio P, Mele G, Lamacchia M, Mestice A, Specchia G (2000) Bone marrow aspirate on the 14th day of induction treatment as a prognostic tool in de novo adult acute myeloid leukemia. Haematologica 85:1285–1290

    CAS  PubMed  Google Scholar 

  29. Heil G, Hoelzer D, Sanz MA, Lechner K, Yin JAL, Papa G, Noens L, Szer J, Ganser A, O‘Brien C, Matcham J, Barge A (1997) A randomized, double-blind, placebo-controlled, phase III study of filgrastim in remission induction and consolidation therapy for adults with de novo acute myeloid leukemia. Blood 90:4710–4718

    CAS  PubMed  Google Scholar 

Download references

Acknowledgement

The authors are indebted to I. Schäfer and N. Papendorf for their help in preparing the manuscript and C. Demirezen for her secretarial support.

Author information

Authors and Affiliations

  1. Department of Hematology, Hemostaseology and Oncology, Hannover Medical School, University of Hannover, Carl-Neuberg-Str. 1, 30625, Hannover, Germany

    G. Heil, J. Krauter & A. Ganser

  2. University of Ulm, Ulm, Germany

    A. Raghavachar & L. Bergmann

  3. University of Frankfurt, Frankfurt, Germany

    D. Hoelzer

  4. University of Hamburg, Hamburg, Germany

    W. Fiedler

  5. University of Freiburg, Freiburg, Germany

    M. Lübbert

  6. University of Gent, Gent, Belgium

    L. Noens

  7. Zentralklinikum Augsburg, Augsburg, Germany

    G. Schlimok

  8. Charité, Universitätsklinikum Berlin, CVK, Berlin, Germany

    R. Arnold

  9. Krankenhaus Siloah, Hannover, Germany

    H. Kirchner

Authors
  1. G. Heil
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. J. Krauter
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. A. Raghavachar
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. L. Bergmann
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. D. Hoelzer
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. W. Fiedler
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. M. Lübbert
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. L. Noens
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. G. Schlimok
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. R. Arnold
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. H. Kirchner
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. A. Ganser
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to G. Heil.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Heil, G., Krauter, J., Raghavachar, A. et al. Risk-adapted induction and consolidation therapy in adults with de novo AML aged ≤ 60 years: results of a prospective multicenter trial. Ann Hematol 83, 336–344 (2004). https://doi.org/10.1007/s00277-004-0853-z

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00277-004-0853-z

Keywords

Search

Navigation