Intensified Daunorubicin in Induction Therapy and Autologous Peripheral Blood Stem Cell Transplantation in Postremission Therapy (Double-7 Protocol) for Adult Acute Myeloid Leukemia

Abstract

To investigate whether an intensified dose of daunorubicin (DNR) in induction therapy and autologous peripheral blood stem cell transplantation (PBSCT) in the postremission period are effective treatments, we used a Double-7 protocol to treat adult patients with de novo acute myeloid leukemia (excluding M0 and M3). Induction therapy consisted of 40 mg/m2 of DNR intravenous drip infusion for 7 days and 200 mg/m2 of ara-C by continuous infusion for 7 days (7 + 7 DC regimen). Patients who achieved complete remission (CR) were given high-dose chemotherapy with autologous PBSCT in postremission therapy. Of the 22 assessable patients, 16 attained CR (73%). Disease-free survival (DFS) and overall survival (OS) at 3 years were 61.2% and 48.1%, respectively. Nine of the CR patients underwent PBSCT without therapy-related mortality. Patients in a favorable cytogenetic group (n = 7) attained 100% CR and long-term survival (71.4% DFS and 85.7% OS at 3 years). Thus, intensified DNR administration of 280 mg/m2 (40 mg/m2 per day for 7 days) in induction therapy for adult patients younger than 60 years of age might be optimal or at least comparable with the new anthracyclines such as idarubicin. In addition, autologous PBSCT in postremission therapy might improve DFS and OS, at least for patients in a favorable cytogenetic group, such as those with a t(8;21) abnormality.Int J Hematol. 2002; 76: 436-445.

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

References

  1. 1.

    Appelbaum F, Rowe JM, Radich J, Dick JE. Acute myeloid leukemia.Hematology (Am Soc Hematol Educ Program). 2001: 62-86.

  2. 2.

    Lowenberg B, Downing J, Burnett A. Acute myeloid leukemia.N Engl J Med. 1999; 341: 1051–1062.

    Article  PubMed  CAS  Google Scholar 

  3. 3.

    Brenner M, Pinkel D. Cure of leukemia.Semin Hematol. 1999; 36: 73–83.

    PubMed  CAS  Google Scholar 

  4. 4.

    Bishop JF. The treatment of adult acute myeloid leukemia.Semin Oncol. 1997; 24: 57–69.

    PubMed  CAS  Google Scholar 

  5. 5.

    Ohno R. How high can we increase complete remission rate in adult acute myeloid leukemia?Int J Hematol. 2000; 72: 272–279.

    PubMed  CAS  Google Scholar 

  6. 6.

    Dillman RO, Davis RB, Green MR, et al. A comparative study of two different doses of cytarabine for acute myeloid leukemia: a phase III trial of Cancer and Leukemia Group B.Blood. 1991; 78: 2520–2526.

    PubMed  CAS  Google Scholar 

  7. 7.

    Bishop JF, Lowenthal RM, Josuna D, et al. Etoposide in acute non-lymphocytic leukemia.Blood. 1990; 75: 27–32.

    PubMed  CAS  Google Scholar 

  8. 8.

    Yates J, Glidewell P, Wiemik P, et al. Cytosine arabinoside with daunorubicin or adriamycin for therapy of acute myelocytic leukemia: a CALGB study.Blood. 1982; 60: 454–462.

    PubMed  CAS  Google Scholar 

  9. 9.

    Bermann E, Heller G, Santorsa J, et al. Results of a randomized trial comparing idarubicin and cytosine arabinoside with daunorubicin and cytosine arabinoside in adult patients with newly diagnosed acute myelogenous leukemia.Blood. 1991; 77: 1666–1674.

    Google Scholar 

  10. 10.

    Vogler WR, Velez-Garcia E, Weiner RS, et al. A phase III trial comparing idarubicin and daunorubicin in combination with cytarabine in acute myelogenous leukemia: a Southeastern Cancer Study Group Study.J Clin Oncol. 1992; 10: 1103–1111.

    Article  PubMed  CAS  Google Scholar 

  11. 11.

    Wiernik P, Banks PL, Case DC Jr, et al. Cytarabine plus idarubicin or daunorubicin as induction and consolidation therapy for previously untreated adult patients with acute myeloid leukemia.Blood. 1992; 79: 313–319.

    PubMed  CAS  Google Scholar 

  12. 12.

    Hansen OP, Pedersen-Bjergaard J, Ellegaard J, et al. Aclarubicin plus cytosine arabinoside versus daunorubicin plus cytosine arabinoside in previously untreated patients with acute myeloid leukemia: a Danish national phase III trial: the Danish Society of Hematology Study Group on AML, Denmark.Leukemia. 1991; 5: 510–516.

    PubMed  CAS  Google Scholar 

  13. 13.

    Arlin Z, Case D, Moore J, et al. Randomized multicenter trial of cytosinearabinoside with mitoxantrone or daunorubicin in previously untreated patients with acute nonlymphocytic leukemia (ANLL): Lederle Cooperative Group.Leukemia. 1990; 4: 177–183.

    PubMed  CAS  Google Scholar 

  14. 14.

    Usui N, Dobashi N, Kobayashi T, et al. Role of daunorubicin in the induction therapy for adult acute myeloid leukemia.J Clin Oncol. 1998; 16: 2086–2092.

    Article  PubMed  CAS  Google Scholar 

  15. 15.

    Creutzig U, Ritter J, Zimmermann M, et al. Idarubicin improves blast cell clearance during induction therapy in children with AML: results of study AML-BFM 93: AML-BFM Study Group.Leukemia. 2001; 15: 348–354.

    Article  PubMed  CAS  Google Scholar 

  16. 16.

    Champlin R, Gajewski J, Nimer S, et al. Postremission chemotherapy for adults with acute myelogenous leukemia: improved survival with high dose cytarabine and daunorubicin consolidation treatment.J Clin Oncol. 1990; 8: 1199–1206.

    Article  PubMed  CAS  Google Scholar 

  17. 17.

    Mayer RJ, Davis RB, Schiffer CA, et al. Intensive postremission chemotherapy in adults with acute myeloid leukemia.N Engl J Med. 1994; 331: 896–903.

    Article  PubMed  CAS  Google Scholar 

  18. 18.

    Kern W, Aul C, Maschmeyer G, et al. Superiority of high-dose over intermediate-dose cytosine arabinoside in the treatment of patients with high-risk acute myeloid leukemia: results of an age-adjusted prospective randomized comparison.Leukemia. 1998; 12: 1049–1055.

    Article  PubMed  CAS  Google Scholar 

  19. 19.

    Bloomfield C, Lawrence D, Byrd JC, et al. Frequency prolonged remission duration after high-dose cytarabine intensification in acute myeloid leukemia varies by cytogenetic subtype.Cancer Res. 1998; 58: 4173–4179.

    PubMed  CAS  Google Scholar 

  20. 20.

    Byrd J, Dodge RK, Carroll A, et al. Patients with t(8;21)(q22;q22) and acute myeloid leukemia have superior failure-free and overall survival when repetitive cycles of high-dose cytarabine are administered.J Clin Oncol. 1999; 17: 3767–3775.

    Article  PubMed  CAS  Google Scholar 

  21. 21.

    Zittoun R, Mandelli F, Willemze R, 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 delľAdulto (GIMEMA) Leukemia Cooperative Groups.N Engl J Med. 1995; 332: 217–223.

    Article  PubMed  CAS  Google Scholar 

  22. 22.

    Harousseau J-L, Cahn J-Y, Pignon B, et al. Comparison of autologous bone marrow transplantation and intensive chemotherapy as postremission therapy in adult acute myeloid leukemia.Blood. 1997; 90: 2978–2986.

    PubMed  CAS  Google Scholar 

  23. 23.

    Cassileth PA, Harrington DP, Appelbaum FR, et al. Chemotherapy compared with autologous or allogeneic bone marrow transplantation in the management of acute myeloid leukemia in first remission.N Engl J Med. 1998; 339: 1649–1659.

    Article  PubMed  CAS  Google Scholar 

  24. 24.

    Burnett AK, Goldstone AH, Stevens RM, et al. 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: UK Medical Research Council Adult and Children’s Leukaemia Working Parties.Lancet. 1998; 351: 700–708.

    Article  PubMed  CAS  Google Scholar 

  25. 25.

    Pavlovsky S, Fernandez I, Milone G, et al. Autologous peripheral blood progenitor cell transplantation mobilized with high-dose cytarabine in acute myeloid leukemia in first complete remission.Ann Oncol. 1998; 9: 151–157.

    Article  PubMed  CAS  Google Scholar 

  26. 26.

    Gorin NC. Autologous stem cell transplantation in acute myeloid leukemia.Blood. 1998; 92: 1073–1090.

    PubMed  CAS  Google Scholar 

  27. 27.

    Bennett JM, Catovsky D, Daniel MT, et al. Proposal for the classification of the acute leukaemias French-American-British (FAB) co-operative group.Br J Haematol. 1976; 33: 451–458.

    Article  PubMed  CAS  Google Scholar 

  28. 28.

    Bennett JM, Catovsky D, Daniel MT, et al. Proposal for the recognition of minimally differentiated acute myeloid leukaemia (AML-M0).Br J Haematol. 1991; 78: 325–329.

    Article  PubMed  CAS  Google Scholar 

  29. 29.

    Usui N, Dobashi N, Asai O, et al. Sequential administration of mitoxantrone and etoposide for adult acute myeloid leukemia [abstract].Proc Am Soc Clin Oncol. 2000; 19: 33a.

    Google Scholar 

  30. 30.

    Cheson BD, Cassileth PA, Head DR, et al. Report of the National Cancer Institute-sponsored workshop on definitions of diagnosis and response in acute myeloid leukemia.J Clin Oncol. 1990; 8: 813–819.

    Article  PubMed  CAS  Google Scholar 

  31. 31.

    Grimwade D, Walker H, Oliver F, et al. The importance of diagnostic cytogenetics on outcome in AML: analysis of 1,612 patients entered into the MRC AML 10 trial.Blood. 1998; 92: 2322–2333.

    PubMed  CAS  Google Scholar 

  32. 32.

    Slovak M, Kopecky KJ, Cassileth PA, 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: 4075–4083.

    PubMed  CAS  Google Scholar 

  33. 33.

    National Cancer Institute.Common Toxicity Criteria. Bethesda, MD: National Cancer Institute; 1999: 1–80.

  34. 34.

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

    Article  Google Scholar 

  35. 35.

    Dixon D, Simon R. Sample size considerations for studies comparing survival curves using historical controls.J Clin Epidemiol. 1998; 41: 1209–1213.

    Article  Google Scholar 

  36. 36.

    Peto R, Pike MC, Armitage P, et al. Design and analysis of randomized clinical trials requiring prolonged observation of each patient, II: analysis and examples.Br J Cancer. 1977; 35: 1–39.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  37. 37.

    Rowe J, Tallman M. Intensifying induction therapy in acute myeloid leukemia: has a new standard of care emerged?Blood. 1997; 90: 2121–2126.

    PubMed  PubMed Central  CAS  Google Scholar 

  38. 38.

    Rowe JM. What is the best induction regimen for acute myelogenous leukemia?Leukemia. 1998; 12(suppl): S16-S19.

    PubMed  CAS  Google Scholar 

  39. 39.

    Ohno R, Kobayashi T, Tanimoto M, et al. Randomized study of individualized induction therapy with or without vincristine, and of maintenance-intensification therapy between 4 or 12 courses in adult acute myeloid leukemia.Cancer. 1993; 71: 3888–3895.

    Article  PubMed  CAS  Google Scholar 

  40. 40.

    Kobayashi T, Miyawaki S, Tanimoto M, et al. Randomized trials between behenoyl cytarabine and cytarabine in combination induction and consolidation therapy, and with or without ubenimex after maintenance/intensification therapy in adult acute myeloid leukemia.J Clin Oncol. 1996; 14: 204–213.

    Article  PubMed  CAS  Google Scholar 

  41. 41.

    Cassileth PA, Lynch E, Hines JD, et al. Varying intensity of postremission therapy in acute myeloid leukemia.Blood. 1992; 79: 1924–1930.

    PubMed  CAS  Google Scholar 

  42. 42.

    Hewlett J, Kopecky KJ, Head D, et al. A prospective evaluation of the role of allogeneic marrow transplantation and low-dose monthly maintenance chemotherapy in the treatment of adult acute myelogenous leukemia (AML): a Southwest Oncology Group study.Leukemia. 1995; 9: 562–569.

    PubMed  CAS  Google Scholar 

  43. 43.

    Miyawaki S, Tanimoto M, Kobayashi T, et al. No beneficial effect from addition of etoposide to daunorubicin, cytarabine, and 6-mercaptopurine in individualized induction therapy of acute myeloid leukemia: the JALSG-AML 92 study: Japan Adult Leukemia Study Group.Int J Hematol. 1999; 70: 97–104.

    PubMed  CAS  Google Scholar 

  44. 44.

    Sievers E, Larson RA, Stadtmauer EA, et al. Efficacy and safety of gemtuzumab ozogamicin in patients with CD33-positive acute myeloid leukemia in first relapse.J Clin Oncol. 2001; 19: 3244–3254.

    Article  PubMed  CAS  Google Scholar 

  45. 45.

    Bishop JF, Matthews JP, Young GA, et al. A randomized study of high dose cytarabine in induction in acute myeloid leukemia.Blood. 1996; 87: 1710–1717.

    PubMed  CAS  Google Scholar 

Download references

Author information

Affiliations

Authors

Corresponding authors

Correspondence to Noriko Usui or Nobuaki Dobashi or Osamu Asai or Shingo Yano or Yuichi Yahagi or Takeshi Saito or Yuko Yamaguchi or Kinuyo Kasama or Yutaka Okawa or Naohiro Sekiguchi or Yutaka Takei or Katsuki Sugiyama or Yoji Ogasawara or Hiroko Ohtsubo or Ken Kaito or Masayuki Kobayashi.

About this article

Cite this article

Usui, N., Dobashi, N., Asai, O. et al. Intensified Daunorubicin in Induction Therapy and Autologous Peripheral Blood Stem Cell Transplantation in Postremission Therapy (Double-7 Protocol) for Adult Acute Myeloid Leukemia. Int J Hematol 76, 436–445 (2002). https://doi.org/10.1007/BF02982809

Download citation

Key words

  • Adult AML
  • Daunorubicin
  • Induction therapy
  • Auto-PBSCT
  • Double-7