Current Treatment Options in Oncology

, Volume 15, Issue 2, pp 171–186 | Cite as

Optimal Therapy for Adult Patients with Acute Myeloid Leukemia in First Complete Remission

Leukemia (JP Dutcher, Section Editor)

Opinion statement

Although it is absolutely clear that postremission therapy is currently necessary to obtain disease-free long-term survivorship for patients with acute myeloid leukemia (AML) in first complete remission (CR), it is not entirely clear what form that treatment should take. High-dose cytarabine is clearly effective and there definitely is a dose-response relationship for cytarabine and remission duration. High-dose cytarabine is effective for younger patients but not elderly patients. It is effective for patients with favorable cytogenetics but it is not clear whether it is effective for patients with intermediate or unfavorable cytogenetics. Furthermore, it is not clear what the most effective and least toxic dose and schedule of high-dose cytarabine is.


Acute myeloid leukemia High-dose cytarabine Cytogenetics Lenalidomide Clofarabine Interleukin-2 Stem cell transplantation 

References and Recommended Reading

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. 1.
    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.PubMedCrossRefGoogle Scholar
  2. 2.
    Bloomfield CD, Lawrence D, Byrd JC, et al. Frequency of prolonged remission duration after high-dose cytarabine intensification in acute myeloid leukemia varies by cytogenetic subtype. Cancer Res. 1998;58:4173–9.PubMedGoogle Scholar
  3. 3.
    Fukushima T, Urasaki Y, Yamaguchi M, et al. A randomized comparison of modified intermediate-dose Ara-C vs high-dose Ara-C in postremission therapy for acute myeloid leukemia. Anticancer Res. 2012;32:643–7.PubMedGoogle Scholar
  4. 4.
    Burnett AK, Russell NH, Hills RK, et al. Optimization of chemotherapy for younger patients with acute myeloid leukemia: results of the medical research council AML15 trial. J Clin Oncol. 2013;31:3360–8.PubMedCrossRefGoogle Scholar
  5. 5.
    Löwenberg B, Pabst T, Vellenga E, et al. Cytarabine dose for acute myeloid leukemia. N Engl J Med. 2011;364:1027–36.PubMedCrossRefGoogle Scholar
  6. 6.
    Hengeveld M, Suciu S, Karrasch M, et al. Intensive consolidation therapy compared with standard consolidation and maintenance therapy for adults with acute myeloid leukemia aged between 46 and 60 years: final results of the randomized phase III study (AML 8B) of the European Organization for Research and Treatment of Cancer (EORTC) and the Gruppo Italiano Malattie Ematologiche Maligne dell’Adulto (GIMEMA) leukemia cooperative groups. Ann Hematol. 2012;91:825–35.PubMedCrossRefPubMedCentralGoogle Scholar
  7. 7.
    Miyawaki S, Ohtake S, Fujisawa S, et al. A randomized comparison of 4 courses of standard-dose multi-agent chemotherapy vs 3 courses of high-dose cytarabine alone in postremission therapy for acute myeloid leukemia in adults. The JALSG AML201 study. Blood. 2011;117:2366–72.PubMedCrossRefGoogle Scholar
  8. 8.
    Thomas X, Elhamri M, Raffoux E, et al. Comparison of high-dose cytarabine and timed sequential chemotherapy as consolidation for younger adults with AML in first remission: the ALFA-9802 study. Blood. 2011;118:1754–62.PubMedCrossRefGoogle Scholar
  9. 9.
    Fopp M, Fey MF, Bacchi M, et al. Post-remission therapy of adult acute myeloid leukemia: one cycle of high-dose vs standard-dose cytarabine. Leukaemia Project Group of the Swiss Group for Clinical Cancer Research (SAKK). Ann Oncol. 1997;8:251–7.PubMedCrossRefGoogle Scholar
  10. 10.
    Schaich M, Rollig C, Soucek S, et al. Cytarabine dose of 36 g/m(2) compared with 12 g/m(2) within first consolidation in acute myeloid leukemia: results of patients enrolled onto the prospective randomized AML96 study. J Clin Oncol. 2011;29:2696–702.PubMedCrossRefGoogle Scholar
  11. 11.
    Moore JO, George SL, Dodge RK, et al. Sequential multi-agent chemotherapy is not superior to high-dose cytarabine alone as postremission intensification therapy for acute myeloid leukemia in adults under 60 years of age. Cancer and Leukemia Group B study 9222. Blood. 2005;105:3420–7.PubMedCrossRefPubMedCentralGoogle Scholar
  12. 12.
    Bradstock KF, Matthews JP, Lowenthal RM, et al. A randomized trial of high-vs conventional-dose cytarabine in consolidation chemotherapy for adult de novo acute myeloid leukemia in first remission after induction therapy containing high-dose cytarabine. Blood. 2005;105:481–8.PubMedCrossRefGoogle Scholar
  13. 13.
    Elonen E, Almqvist A, Hanninen A, et al. Comparison between four and eight cycles of intensive chemotherapy in adult myeloid leukemia: a randomized trial of the Finnish Leukemia Group. Leukemia. 1998;12:1041–8.PubMedCrossRefGoogle Scholar
  14. 14.
    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;339:1649–56.PubMedCrossRefGoogle Scholar
  15. 15.
    Messerer D, Engel J, Hasford J, et al. impact of different postremission strategies on quality of life in patients with acute myeloid leukemia. Haematologica. 2008;93:826–33.PubMedCrossRefGoogle Scholar
  16. 16.
    Visani G, Olivieri A, Malagola M, et al. Consolidation therapy for adult acute myeloid leukemia: a systematic analysis according to evidence based medicine. Leuk Lymphoma. 2006;47:1091–102.PubMedCrossRefGoogle Scholar
  17. 17.
    Wang J, Ouyang J, Zhou R, et al. Autologous hematopoietic stem cell transplantation for acute myeloid leukemia in first complete remission: a meta-analysis of randomized trials. Acta Haematol. 2010;124:61–71.PubMedCrossRefGoogle Scholar
  18. 18.
    Bug G, Koschmieder S, Krauter J, et al. 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. Ann Hematol. 2014;93:193–202.PubMedCrossRefGoogle Scholar
  19. 19.
    Schlenk RF, Pasquini MC, Pérez WS, et al. HLA-identical sibling allogeneic transplants vs chemotherapy in acute myelogenous leukemia with t(8;21) in first complete remission: collaborative study between the German AML Intergroup and CIBMTR. Biol Blood Marrow Transplant. 2008;14:187–96.PubMedCrossRefPubMedCentralGoogle Scholar
  20. 20.
    Koreth J, Schlenk R, Kopecky KJ, 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;301:2349–61.PubMedCrossRefPubMedCentralGoogle Scholar
  21. 21.
    Stelljes M, Beelen DW, Braess J, et al. Allogeneic transplantation as postremission therapy for cytogenetically high-risk acute myeloid leukemia: landmark analysis from a single prospective multicenter trial. Haematologica. 2011;96:972–9.PubMedCrossRefPubMedCentralGoogle Scholar
  22. 22.
    Pratcorona M, Brunet S, Nomdedéu J, et al. Favorable outcome of patients with acute myeloid leukemia harboring a low-allelic burden FLT3-ITD mutation and concomitant NPM1 mutation: relevance to postremission therapy. Blood. 2013;121:2734–8.PubMedCrossRefGoogle Scholar
  23. 23.
    Hu B, Vikas P, Mohty M, Savani BN. Allogeneic stem cell transplantation and targeted therapy for FLT3/ITD+ acute myeloid leukemia: an update. Expert Rev Hematol. 2013;7:301–15.Google Scholar
  24. 24.
    Farag SS, Maharry K, Zhang MJ, et al. Comparison of reduced-intensity hematopoietic cell transplantation with chemotherapy in patients age 60-70 years with acute myelogenous leukemia in first remission. Biol Blood Marrow Transplant. 2011;17:1796–803.PubMedCrossRefGoogle Scholar
  25. 25.
    Ustun C, Lazarus HM, Weisdorf D. To transplant or not: a dilemma for treatment of elderly AML patients in the twenty-first century. Bone Marrow Transplant. 2013;48:1497–505.PubMedCrossRefGoogle Scholar
  26. 26.
    Sproat L, Bolwell B, Rybicki L, et al. Effect of postremission chemotherapy preceding allogeneic hematopoietic cell transplant in patients with acute myeloid leukemia in first remission. Leuk Lymphoma. 2010;51:1699–704.PubMedCrossRefGoogle Scholar
  27. 27.
    Warlick ED, Paulson K, Brazauskas R, et al. Effect of postremission therapy before reduced-intensity conditioning allogeneic transplantation for acute myeloid leukemia in first complete remission. Biol Blood Marrow Transplant. 2013;20:202–8.Google Scholar
  28. 28.
    Wiernik PH, Holland JF, Glidewell O, et al. Is bone marrow transplantation the best treatment for a patient with acute nonlymphocytic leukemia in remission? 1980 [Personal communication].Google Scholar
  29. 29.••
    Burnett AK, Goldstone A, Hills RK, et al. Curability of patients with acute myeloid leukemia who did not undergo transplantation in first remission. J Clin Oncol. 2013;31:1293–301. The paper demonstrates that postponing transplantation until relapse is prudent.PubMedCrossRefGoogle Scholar
  30. 30.
    Stelljes M, Beelen DW, Braess J, et al. Allogeneic transplantation vs chemotherapy as postremission therapy for acute myeloid leukemia: a prospective matched pairs analysis. J Clin Oncol. 2014;2:158–60.Google Scholar
  31. 31.
    Peterson BA, Bloomfield CD. Prolonged maintained remissions of adult acute nonlymphocytic leukaemia. Lancet. 1977;2:158–60.Google Scholar
  32. 32.
    Büchner T, Urbanitz D, Hiddemann W, et al. Intensified induction and consolidation with or without maintenance chemotherapy for acute myeloid leukemia (AML): two multi-center studies of the German AML Cooperative Group. J Clin Oncol. 1985;3:1583–9.PubMedGoogle Scholar
  33. 33.
    Büchner T, Hiddemann W, Schaefer UW, et al. Combined effect of very early intensification and prolonged postremission chemotherapy in patients with AML. Leukemia. 1992;6 Suppl 4:68–70.Google Scholar
  34. 34.
    Büchner T, Hiddemann W, Wörmann B, et al. Long-term effects of prolonged maintenance and of very early intensification chemotherapy in AML: data from AMLCG. Leukemia. 1992;6 Suppl 2:68–71.Google Scholar
  35. 35.
    Büchner T, Hiddemann W, Wörmann B, et al. Acute myeloid leukemia in adults: is postconsolidation maintenance therapy necessary ? Int J Hematol. 2000;72:285–9.PubMedGoogle Scholar
  36. 36.
    Dutcher JP, Wiernik PH, Markus S, et al. Intensive maintenance therapy improves survival in adult acute nonlymphocytic leukemia: an eight-year follow-up. Leukemia. 1988;2:413–9.PubMedGoogle Scholar
  37. 37.
    Dutcher JP, Wiernik PH, Markus S, et al. 15 year follow-up of adult patients with acute myeloid leukemia: Study BCRC 7802. Proc XXV Congress Int Soc Hematology. 1994; [Abstract #48].Google Scholar
  38. 38.
    Urbanitz D, Büchner T, Pielken H, et al. Neuraminidase-treated allogeneic blasts for maintenance in acute myelogenous leukemia: results of a prospective randomized trial. Haematol Blood Transfus. 1987;30:64–8.PubMedGoogle Scholar
  39. 39.
    Baer MR. Is there a role for maintenance therapy in acute myeloid leukemia? Best Prac Res Clin Haematol. 2009;22:517–21.CrossRefGoogle Scholar
  40. 40.
    Rosenblat TL, Jurcic JG. Induction and postremission strategies in acute myeloid leukemia: state of the art and future directions. Hematol Oncol Clin North Am. 2011;25:1189–213.PubMedCrossRefGoogle Scholar
  41. 41.•
    Stone RM. Is it time to revisit standard postremission therapy? Best Pract Res Clin Haematol. 2012;25:437–41. A thoughtful discussion.PubMedCrossRefGoogle Scholar
  42. 42.
    Ganzel C, Douer D, Tallman MS. Postconsolidation maintenance and monitoring in patients with acute promyelocytic leukemia. J Nat Compr Cancer Netw. 2013;11:1512–21.Google Scholar
  43. 43.
    Tallman MS, Andersen JW, Schiffer CA, et al. All-trans retinoic acid in acute promyelocytic leukemia. N Engl J Med. 1997;337:1021–8.PubMedCrossRefGoogle Scholar
  44. 44.
    Wiernik PH, Dutcher JP, Todd M, et al. Polyethylene glycolated interleukin-2 as maintenance therapy for acute myelogenous leukemia in second remission. Am J Hematol. 1994;47:41–4.PubMedCrossRefGoogle Scholar
  45. 45.
    Meloni G, Vignetti M, Andrizzi C, et al. Interleukin-2 for the treatment of advanced acute myelogenous leukemia patients with limited disease: updated experience with 20 cases. Leuk Lymphoma. 1996;21:429–35.PubMedCrossRefGoogle Scholar
  46. 46.
    Meloni G, Trisolini SM, Capria S, et al. How long can we give interleukin-2? Clinical and immunologic evaluation of AML patients after 10 or more years of IL2 administration. Leukemia. 2002;16:2016–8.PubMedCrossRefGoogle Scholar
  47. 47.
    Speletas M, Ritis K, Bourikas G. Achievement and maintenance of complete remission in a patient with acute myelogenous leukemia after weekly administration of interleukin-2. Haematologica. 1996;81:346–8.PubMedGoogle Scholar
  48. 48.
    Maraninchi D, Vey N, Viens P, et al. A phase II study of interleukin-2 in 49 patients with relapsed or refractory acute leukemia. Leuk Lymphoma. 1998;31:343–9.PubMedGoogle Scholar
  49. 49.
    Cortes JE, Kantarjian HM, O’Brien S, et al. A pilot study of interleukin-2 for adult patients with acute myelogenous leukemia in first complete remission. Cancer. 1999;85:1506–13.PubMedCrossRefGoogle Scholar
  50. 50.
    Stein AS, O’Donnell MR, Slovak ML, et al. Interleukin-2 after autologous stem-cell transplantation for adult patients with acute myeloid leukemia in first complete remission. J Clin Oncol. 2003;21:615–23.PubMedCrossRefGoogle Scholar
  51. 51.
    Stone RM, DeAngelo DJ, Janosova A, et al. Low dose interleukin-2 following intensification therapy with high dose cytarabine for acute myelogenous leukemia in first complete remission. Am J Hematol. 2008;83:771–7.PubMedCrossRefGoogle Scholar
  52. 52.
    Baer MR, George SL, Caliguri MA, et al. Low-dose interleukin-2 immunotherapy does not improve outcome of patients age 60 years and older with acute myeloid leukemia in first complete remission: Cancer and Leukemia Group B study 9720. J Clin Oncol. 2008;26:4934–9.PubMedCrossRefPubMedCentralGoogle Scholar
  53. 53.
    Kolitz JE, George SL, Benson DM Jr, et al. Recombinant interleukin-2 in patients aged younger than 60 years with acute myeloid leukemia in first complete remission: results from Cancer and Leukemia Group B 19808. Cancer. 2014;120:1010–7.Google Scholar
  54. 54.
    Pautas C, Merabet F, Thomas X, et al. Randomized study of intensified anthracycline doses for induction and recombinant interleukin-2 for maintenance in patients with acute myeloid leukemia age 50 to 70 years: results of the ALFA-9801 study. J Clin Oncol. 2010;28:808–14.PubMedCrossRefGoogle Scholar
  55. 55.
    Buyse M, Squifflet P, Lange BJ, et al. Individual patient data meta-analysis of randomized trials evaluating IL-2 monotherapy as remission maintenance therapy in acute myeloid leukemia. Blood. 2011;117:7007–13.PubMedCrossRefPubMedCentralGoogle Scholar
  56. 56.
    Gutbrodt KL, Schliemann C, Giovannoni L, et al. Antibody-based delivery of interleukin-2 to neovascular has potent activity against acute myeloid leukemia. Sci Transl Med. 2013;5:201.CrossRefGoogle Scholar
  57. 57.
    Martner A, Thorén FB, Aurelius J, Hellstrand K. Immunotherapeutic strategies for relapse control in acute myeloid leukemia. Blood Rev. 2013;27:209–16.PubMedCrossRefGoogle Scholar
  58. 58.
    Brune M, Castaigne S, Catalano J, et al. Improved leukemia-free survival after postconsolidation immunotherapy with histamine dihydrochloride and interleukin-2 in acute myeloid leukemia: results of a randomized phase 3 trial. Blood. 2006;108:88–96.PubMedCrossRefGoogle Scholar
  59. 59.
    Buyse M, Michiels S, Squifflet P, et al. Leukemia-free survival as a surrogate end point for overall survival in the evaluation of maintenance therapy for patients with acute myeloid leukemia in complete remission. Haematologica. 2011;96:1106–12.PubMedCrossRefPubMedCentralGoogle Scholar
  60. 60.
    Berry SM, Broglio KR, Berry DA. Addressing the incremental benefit of histamine dihydrochloride when added to interleukin-2 in treating acute myeloid leukemia: a Bayesian meta-analysis. Cancer Invest. 2011;29:293–9.PubMedCrossRefGoogle Scholar
  61. 61.
    Thorén FB, Romero AI, Brune M, Hellstrand K. Histamine dihydrochloride and low-dose interleukin-2 as post-consolidation immunotherapy in acute myeloid leukemia. Expert Opin Biol Ther. 2009;9:1217–23.PubMedCrossRefGoogle Scholar
  62. 62.
    Romero AI, Thorén FB, Aurelius J, et al. Post-consolidation immunotherapy with histamine dihydrochloride and interleukin-2 in AML. Scand J Immunol. 2009;70:194–205.PubMedCrossRefGoogle Scholar
  63. 63.
    Martner A, Thorén FB, Aurelius J, et al. Immunotherapy with histamine dihydrochloride for the prevention of relapse in acute myeloid leukemia. Expert Rev Hematol. 2010;3:381–91.PubMedCrossRefGoogle Scholar
  64. 64.
    Yang LP, Perry CM. Histamine dihydrochloride: in the management of acute myeloid leukaemia. Drugs. 2011;71:109–22.PubMedCrossRefGoogle Scholar
  65. 65.
    Yang LP, Perry CM. Spotlight on histamine dihydrochloride in acute myeloid leukaemia. Drugs Aging. 2011;28:325–9.PubMedCrossRefGoogle Scholar
  66. 66.
    Aurelius J, Martner A, Brune M, et al. Remission maintenance in acute myeloid leukemia: impact of functional histamine H2 receptors expressed by leukemic cells. Haematologica. 2012;97:1904–8.PubMedCrossRefPubMedCentralGoogle Scholar
  67. 67.
    Levi JA, Wiernik PH. A comparative clinical trial of 5-azacitidine and guanazole in previously treated adults with acute nonlymphocytic leukemia. Cancer. 1976;38:36–41.PubMedCrossRefGoogle Scholar
  68. 68.
    Tawfik B, Sliesoraitis S, Lyerly S, et al. Efficacy of the hypomethylating agents as frontline, salvage, or consolidation therapy in adults with acute myeloid leukemia (AML). Ann Hematol. 2014;93:47–55.PubMedCrossRefGoogle Scholar
  69. 69.
    Burnett AK, Hills RK, Milligan D, et al. Identification of patients with acute myeloblastic leukemia who benefit from the addition of gemtuzumab ozogamicin: results of the MRC AML 15 trial. J Clin Oncol. 2011;29:369–77.PubMedCrossRefGoogle Scholar
  70. 70.
    Amadori S, Suciu S, Stasi R, et al. Sequential combination of gemtuzumab ozogamicin and standard chemotherapy in older patients with newly diagnosed acute myeloid leukemia: results of a randomized phase III trial by the EORTC and GIMEMA consortium (AML-17). J Clin Oncol. 2013;31:4424–30.PubMedCrossRefGoogle Scholar
  71. 71.
    Jacoby MA, Martin MG, Uy GL, et al. Phase I study of oral clofarabine consolidation in adults aged 60 and older with acute myeloid leukemia. Am J Hematol. 2014;89:487–92.Google Scholar
  72. 72.
    Claxton D, Erba HP, Faderl S, et al. Outpatient consolidation treatment with clofarabine in a phase 2 study of older adult patients with previously untreated acute myelogenous leukemia. Leuk Lymphoma. 2012;53:435–40.PubMedCrossRefGoogle Scholar
  73. 73.
    Chen Y, Borthakur G. Lenalidomide as a novel treatment of acute myeloid leukemia. Expert Opin Investig Drugs. 2013;22:389–97.PubMedCrossRefGoogle Scholar
  74. 74.
    Sockel K, Bornhaeuser M, Mischak-Weissinger E, et al. Lenalidomide maintenance after allogeneic HSCT seems to trigger acute graft-vs-host disease in patients with high-risk myelodysplastic syndromes or acute myeloid leukemia and del(5q): results of the LENAMAINT trial. Haematologica. 2012;97:e34–5.PubMedCrossRefPubMedCentralGoogle Scholar
  75. 75.
    Hourigan CS, McCarthy P, de Lima M. Back to the future! The evolving role of maintenance therapy after hematopoietic stem cell transplantation. Biol Blood Marrow Transplant. 2014;20:154–63.Google Scholar
  76. 76.
    Stone RM. Should the presence of minimal residual disease (MRD) in morphologic complete remission alter postremission strategy in AML? Best Pract Res Clin Haematol. 2011;24:509–14.PubMedCrossRefGoogle Scholar
  77. 77.••
    Freeman SD, Virgo P, Couzens S, et al. Prognostic relevance of treatment response measured by flow cytometric residual disease detection in older patients with acute myeloid leukemia. J Clin Oncol. 2013;31:4123–31. It is still not clear how to respond to the observation of minimal residual disease, but it is of paramount importance to study this question.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2014

Authors and Affiliations

  1. 1.Cancer Research Foundation of New YorkChappaquaUSA

Personalised recommendations