Current Oncology Reports

, Volume 4, Issue 5, pp 403–409 | Cite as

Older adults with acute myeloid leukemia

  • Mikkael A. Sekeres
  • Richard Stone
Article

Abstract

Acute myeloid leukemia (AML) occurs most frequently in older adults, with a median age range from 65 to 70 years. Both the disease and its treatment are distinct from their counterparts in young patients. Herein we characterize the intrinsic biologic features of AML as it occurs in the older population, review currently available therapeutic approaches, and discuss therapeutic strategies in development.

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. 1.
    Heath C: Epidemiology and hereditary aspects of acute leukemia. In Neoplastic Disease of the Blood. Edited by Wiernik P, Canellos G, Dutcher J, Kyle R. New York: Churchill-Livingston; 1996:177.Google Scholar
  2. 2.
    Mayer RJ, Davis RB, Schiffer CA, et al.: Intensive postremission chemotherapy in adults with acute myeloid leukemia. Cancer and Leukemia Group B. N Engl J Med 1994, 331:896–903. The definitive study of 1088 patients with de novo AML that established high-dose ara-C as standard consolidation therapy for younger patients.PubMedCrossRefGoogle Scholar
  3. 3.
    Rubin EH, Andersen JW, Berg DT, et al.: Risk factors for highdose cytarabine neurotoxicity: an analysis of a cancer and leukemia group B trial in patients with acute myeloid leukemia. J Clin Oncol 1992, 10:948–953.PubMedGoogle Scholar
  4. 4.
    Smith GA, Damon LE, Rugo HS, et al.: High-dose cytarabine dose modification reduces the incidence of neurotoxicity in patients with renal insufficiency. J Clin Oncol 1997, 15:833–839.PubMedGoogle Scholar
  5. 5.
    Head DR: Revised classification of acute myeloid leukemia. Leukemia 1996, 10:1826–1831.PubMedGoogle Scholar
  6. 6.
    Hiddemann W, Kern W, Schoch C, et al.: Management of acute myeloid leukemia in elderly patients. J Clin Oncol 1999, 17:3569–3576.PubMedGoogle Scholar
  7. 7.
    Bauduer F, Ducout L, Dastugue N, et al.: De novo and secondary acute myeloid leukemia in patients over the age of 65: a review of fifty-six successive and unselected cases from a general hospital. Leuk Lymphoma 1999, 35:289–296.PubMedCrossRefGoogle Scholar
  8. 8.
    Burnett A: Tailoring the treatment of acute myeloid leukemia. Curr Opin Oncol 1999, 11:14–19.PubMedCrossRefGoogle Scholar
  9. 9.
    Hoyle CF, de Bastos M, Wheatley K, et al.: AML associated with previous cytotoxic therapy, MDS or myeloproliferative disorders: results from the MRC’s 9th AML trial. Br J Haematol 1989, 72:45–53.PubMedGoogle Scholar
  10. 10.
    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. The Medical Research Council Adult and Children’s Leukaemia Working Parties. Blood 1998, 92:2322–2333.PubMedGoogle Scholar
  11. 11.
    Silverman L: The myelodysplastic syndrome. In Cancer Medicine. Edited by Holland JF, Frei E III, Bast RC Jr, et al. Baltimore: Williams & Wilkins; 1996:2593–2615.Google Scholar
  12. 12.
    Economopoulos T, Stathakis N, Foudoulakis A, et al.: Myelodysplastic syndromes: analysis of 131 cases according to the FAB classification. Eur J Haematol 1987, 38:338–344.PubMedCrossRefGoogle Scholar
  13. 13.
    Greenberg P, Cox C, LeBeau MM, et al.: International scoring system for evaluating prognosis in myelodysplastic syndromes. Blood 1997, 89:2079–2088. This study establishes the International Prognostic Scoring System for predicting outcome in patients with myelodysplastic syndromes.PubMedGoogle Scholar
  14. 14.
    Cheson BD, Bennett JM, Kantarjian H, et al.: Report of an international working group to standardize response criteria for myelodysplastic syndromes. Blood 2000, 96:3671–3674.PubMedGoogle Scholar
  15. 15.
    Wijermans P, Lubbert M, Verhoef G, et al.: Low-dose 5-aza-2′-deoxycytidine, a DNA hypomethylating agent, for the treatment of high-risk myelodysplastic syndrome: a multicenter phase II study in elderly patients. J Clin Oncol 2000, 18:956–962.PubMedGoogle Scholar
  16. 16.
    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, 58:4173–4179. A cytogenetic analysis of CALGB 8525 that establishes cytogenetic risk groups that predict response to high-dose ara-C.PubMedGoogle Scholar
  17. 17.
    Leith CP, Kopecky KJ, Godwin J, et al.: Acute myeloid leukemia in the elderly: assessment of multidrug resistance (MDR1) and cytogenetics distinguishes biologic subgroups with remarkably distinct responses to standard chemotherapy. A Southwest Oncology Group study. Blood 1997, 89:3323–3329. This SWOG study determined the incidence of the MDR gene to be 71% in older adults.PubMedGoogle Scholar
  18. 18.
    Rossi G, Pelizzari AM, Bellotti D, et al.: Cytogenetic analogy between myelodysplastic syndrome and acute myeloid leukemia of elderly patients. Leukemia 2000, 14:636–641.PubMedCrossRefGoogle Scholar
  19. 19.
    Leith CP, Kopecky KJ, Chen IM, et al.: Frequency and clinical significance of the expression of the multidrug resistance proteins MDR1/P-glycoprotein, MRP1, and LRP in acute myeloid leukemia: a Southwest Oncology Group Study. Blood 1999, 94:1086–1099.PubMedGoogle Scholar
  20. 20.
    Legrand O, Simonin G, Beauchamp-Nicoud A, et al.: Simultaneous activity of MRP1 and Pgp is correlated with in vitro resistance to daunorubicin and with in vivo resistance in adult acute myeloid leukemia. Blood 1999, 94:1046–1056.PubMedGoogle Scholar
  21. 21.
    Zhu YM, Das-Gupta EP, Russell NH: Microsatellite instability and p53 mutations are associated with abnormal expression of the MSH2 gene in adult acute leukemia. Blood 1999, 94:733–740.PubMedGoogle Scholar
  22. 22.
    Rees JK, Gray RG, Swirsky D, Hayhoe FG: Principal results of the Medical Research Council’s 8th acute myeloid leukaemia trial. Lancet 1986, 2:1236–1241.PubMedCrossRefGoogle Scholar
  23. 23.
    Rees JK, Gray RG, Wheatley K: Dose intensification in acute myeloid leukaemia: greater effectiveness at lower cost. Principal report of the Medical Research Council’s AML9 study. MRC Leukaemia in Adults Working Party. Br J Haematol 1996, 94:89–98.PubMedCrossRefGoogle Scholar
  24. 24.
    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.PubMedGoogle Scholar
  25. 25.
    Buchner T, Urbanitz D, Hiddemann W, et al.: 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 1985, 3:1583–1589.PubMedGoogle Scholar
  26. 26.
    Preisler H, Davis RB, Kirshner J, et al.: Comparison of three remission induction regimens and two postinduction strategies for the treatment of acute nonlymphocytic leukemia: a Cancer and Leukemia Group B study. Blood 1987, 69:1441–1449.PubMedGoogle Scholar
  27. 27.
    Heil G, Hoelzer D, Sanz MA, et al.: A randomized, doubleblind, placebo-controlled, phase III study of filgrastim in remission induction and consolidation therapy for adults with de novo acute myeloid leukemia. The International Acute Myeloid Leukemia Study Group. Blood 1997, 90:4710–4718.PubMedGoogle Scholar
  28. 28.
    Godwin JE, Kopecky KJ, Head DR, et al.: A double-blind placebo-controlled trial of granulocyte colony-stimulating factor in elderly patients with previously untreated acute myeloid leukemia: a Southwest Oncology Group study (9031). Blood 1998, 91:3607–3615.PubMedGoogle Scholar
  29. 29.
    Lowenberg B, Suciu S, Archimbaud E, et al.: Use of recombinant GM-CSF during and after remission induction chemotherapy in patients aged 61 years and older with acute myeloid leukemia: final report of AML-11, a phase III randomized study of the Leukemia Cooperative Group of European Organisation for the Research and Treatment of Cancer and the Dutch Belgian Hemato-Oncology Cooperative Group. Blood 1997, 90:2952–2961.PubMedGoogle Scholar
  30. 30.
    Witz F, Sadoun A, Perrin MC, et al.: A placebo-controlled study of recombinant human granulocyte-macrophage colonystimulating factor administered during and after induction treatment for de novo acute myelogenous leukemia in elderly patients. Groupe Ouest Est Leucemies Aigues Myeloblastiques (GOELAM). Blood 1998, 91:2722–2730.PubMedGoogle Scholar
  31. 31.
    Stone RM, Berg DT, George SL, et al.: Post-remission therapy in older patients with de novo acute myeloid leukemia (AML): a randomized trial comparing mitoxantrone/intermediate dose cytarabine with standard dose cytarabine (CALGB study 8923). Blood 2001, 98:548–553.PubMedCrossRefGoogle Scholar
  32. 32.
    Stone RM, Berg DT, George SL, et al.: Granulocyte-macrophage colony-stimulating factor after initial chemotherapy for elderly patients with primary acute myelogenous leukemia. Cancer and Leukemia Group B. N Engl J Med 1995, 332:1671–1677.PubMedCrossRefGoogle Scholar
  33. 33.
    Stone R: Leukemia in the elderly. In Hematology 1999—American Society of Hematology Education Program Book. New Orleans, LA; 1999:510–516.Google Scholar
  34. 34.
    Estey EH: How I treat older patients with AML. Blood 2000, 96:1670–1673.PubMedGoogle Scholar
  35. 35.
    Lowenberg B, Zittoun R, Kerkhofs H, et al.: On the value of intensive remission-induction chemotherapy in elderly patients of 65+ years with acute myeloid leukemia: a randomized phase III study of the European Organization for Research and Treatment of Cancer Leukemia Group. J Clin Oncol 1989, 7:1268–1274. One of only two randomized trials comparing intensive induction chemotherapy with an anthracycline-based regimen to low-dose or no therapy.PubMedGoogle Scholar
  36. 36.
    Tilly H, Castaigne S, Bordessoule D, et al.: Low-dose cytarabine versus intensive chemotherapy in the treatment of acute nonlymphocytic leukemia in the elderly. J Clin Oncol 1990, 8:272–279. One of only two randomized trials comparing intensive induction chemotherapy with an anthracycline-based regimen to low-dose or no therapy.PubMedGoogle Scholar
  37. 37.
    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.PubMedGoogle Scholar
  38. 38.
    Wiernik PH, 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.PubMedGoogle Scholar
  39. 39.
    Reiffers J, Huguet F, Stoppa AM, et al.: A prospective randomized trial of idarubicin vs daunorubicin in combination chemotherapy for acute myelogenous leukemia of the age group 55 to 75. Leukemia 1996, 10:389–395.PubMedGoogle Scholar
  40. 40.
    Pignon B, Witz F, Desablens B, et al.: Treatment of acute myelogenous leukaemia in patients aged 50–65: idarubicin is more effective than zorubicin for remission induction and prolonged disease-free survival can be obtained using a unique consolidation course. The Goelam Group. Br J Haematol 1996, 94:333–341.PubMedCrossRefGoogle Scholar
  41. 41.
    Baer MR, Pixley LA, Ford LA, et al.: High-dose cytarabine and idarubicin induction produces a high complete remission (CR) rate in previously untreated de novo acute myeloid leukemia (AML) patients (Pts) > 60 years old [abstract]. Blood 2000, 96:322a.Google Scholar
  42. 42.
    Rowe J, Neuberg D, Friedenberg W, et al.: A phase III study of daunorubicin vs idarubicin vs mitoxantrone for older adult patients (>55 years) with acute myelogenous leukemia (AML): a study of the Eastern Cooperative Oncology Group (E3993) [abstract]. Blood 1998, 92:1284a.Google Scholar
  43. 43.
    AML Collaborative Group: A systematic collaborative overview of randomized trials comparing idarubicin with daunorubicin (or other anthracyclines) as induction therapy for acute myeloid leukaemia. Br J Haematol 1998, 103:100–109.CrossRefGoogle Scholar
  44. 44.
    Dombret H, Chastang C, Fenaux P, et al.: A controlled study of recombinant human granulocyte colony-stimulating factor in elderly patients after treatment for acute myelogenous leukemia. AML Cooperative Study Group. N Engl J Med 1995, 332:1678–1683.PubMedCrossRefGoogle Scholar
  45. 45.
    Rowe JM, Andersen JW, Mazza JJ, et al.: A randomized placebocontrolled phase III study of granulocyte-macrophage colony-stimulating factor in adult patients (> 55 to 70 years of age) with acute myelogenous leukemia: a study of the Eastern Cooperative Oncology Group (E1490). Blood 1995, 86:457–462.PubMedGoogle Scholar
  46. 46.
    Schiffer CA, Miller K, Larson RA, et al.: A double-blind, placebo-controlled trial of pegylated recombinant human megakaryocyte growth and development factor as an adjunct to induction and consolidation therapy for patients with acute myeloid leukemia. Blood 2000, 95:2530–2535.PubMedGoogle Scholar
  47. 47.
    Usuki K, Urabe A, Masaoka T, et al.: Efficacy of granulocyte colony-stimulating factor in the treatment of acute myelogenous leukaemia: a multicentre randomized study. Br J Haematol 2002, 116:103–112.PubMedCrossRefGoogle Scholar
  48. 48.
    Sauter C, Berchtold W, Fopp M, et al.: Acute myelogenous leukaemia: maintenance chemotherapy after early consolidation treatment does not prolong survival. Lancet 1984, 1:379–382.PubMedCrossRefGoogle Scholar
  49. 49.
    Cassileth PA, Begg CB, Bennett JM, et al.: A randomized study of the efficacy of consolidation therapy in adult acute nonlymphocytic leukemia. Blood 1984, 63:843–847.PubMedGoogle Scholar
  50. 50.
    Lowenberg B, Suciu S, Archimbaud E, et al.: Mitoxantrone versus daunorubicin in induction-consolidation chemotherapy —the value of low-dose cytarabine for maintenance of remission, and an assessment of prognostic factors in acute myeloid leukemia in the elderly: final report. European Organization for the Research and Treatment of Cancer and the Dutch-Belgian Hemato-Oncology Cooperative Hovon Group. J Clin Oncol 1998, 16:872–881.PubMedGoogle Scholar
  51. 51.
    Grimwade D, Walker H, Harrison G, et al.: The predictive value of hierarchical cytogenetic classification in older adults with acute myeloid leukemia (AML): analysis of 1065 patients entered into the United Kingdom Medical Research Council AML11 trial. Blood 2001, 98:1312–1320. This study of 1065 patients with de novo AML verifies cytogenetic risk groups in an older patient population.PubMedCrossRefGoogle Scholar
  52. 52.
    Ferrara F, Annunziata M, Martino B, et al.: Aggressive salvage treatment is not appropriate for the majority of elderly patients with acute myeloid leukemia relapsing from first complete remission [abstract]. Blood 2000, 96:324a.Google Scholar
  53. 53.
    Appelbaum FR, Rowe JM, Radich J, Dick JE: Acute myeloid leukemia. Hematology (Am Soc Hematol Educ Program) 2001 Jan:62–86.Google Scholar
  54. 54.
    Storb RF, Champlin R, Riddell SR, et al.: Non-myeloablative transplants for malignant disease. Hematology (Am Soc Hematol Educ Program) 2001 Jan:375–391.Google Scholar
  55. 55.
    Appelbaum FR: Antibody-targeted therapy for myeloid leukemia. Semin Hematol 1999, 36(suppl 6):2–8.PubMedGoogle Scholar
  56. 56.
    Sievers EL, Appelbaum FR, Spielberger RT, et al.: Selective ablation of acute myeloid leukemia using antibody-targeted chemotherapy: a phase I study of an anti-CD33 calicheamicin immunoconjugate. Blood 1999, 93:3678–3684.PubMedGoogle Scholar
  57. 57.
    Sievers EL, Larson RA, Stadtmauer EA, et al.: Efficacy and safety of Mylotarg (gemtuzumab ozogamicin) in patients with CD33-positive acute myeloid leukemia in first relapse. J Clin Oncol 2001, 19:3244–3254. A study of 142 patients with AML in first relapse, with a median age of 61 years. Remission was achieved in 30% of patients, with 16% achieving a complete response and 13% achieving a complete response with the exception of a platelet count of less than 100,000/mL.PubMedGoogle Scholar
  58. 58.
    Stone R, Murray C, Berg S, et al.: Low dose interleukin-2 following intensification therapy with high dose ara-c for acute myelogenous leukemia in first complete remission [abstract]. Proc Am Soc Hematol 1994, 84:302a.Google Scholar
  59. 59.
    Westers TM, Stam AGM, Scheper RJ, et al.: A23187/IL-4 cultured leukemic dendritic cells stimulate autologous T cellmediated apoptosis of acute myeloid leukemic blasts [abstract]. Blood 2001, 98:121a.Google Scholar
  60. 60.
    Chauncey TR, Rankin C, Anderson JE, et al.: A phase I study of induction chemotherapy for older patients with newly diagnosed acute myeloid leukemia (AML) using mitoxantrone, etoposide, and the MDR modulator PSC 833: Southwest Oncology Group study 9617. Leuk Res 2000, 24:567–574.PubMedCrossRefGoogle Scholar
  61. 61.
    Baer MR, George SL, Dodge RK, et al.: Phase III study of the multidrug resistance (MDR) modulator PSC-833 in previously untreated acute myeloid leukemia (AML) patients over 60 years old: correlation of outcome with functional MDR (CALGB Studies 9720 and 9760) [abstract]. Blood 2001, 98:461a.Google Scholar
  62. 62.
    List AF, Kopecky KJ, Willman CL, et al.: Benefit of cyclosporine modulation of drug resistance in patients with poor-risk acute myeloid leukemia: a Southwest Oncology Group study. Blood 2001, 98:3212–3220. This study demonstrates that MDR modulation with the use of cyclosporine can improve outcome.PubMedCrossRefGoogle Scholar
  63. 63.
    Kosugi H, Towatari M, Hatano S, et al.: Histone deacetylase inhibitors are the potent inducer/enhancer of differentiation in acute myeloid leukemia: a new approach to anti-leukemia therapy. Leukemia 1999, 13:1316–1324.PubMedCrossRefGoogle Scholar
  64. 64.
    Talpaz M, Silver RT, Druker BJ, et al.: Imatinib induces durable hematologic and cytogenetic responses in patients with accelerated phase chronic myeloid leukemia: results of a phase 2 study. Blood 2002, 99:1928–1937.PubMedCrossRefGoogle Scholar
  65. 65.
    Kantarjian H, Sawyers C, Hochhaus A, et al.: Hematologic and cytogenetic responses to imatinib mesylate in chronic myelogenous leukemia. N Engl J Med 2002, 346:645–652.PubMedCrossRefGoogle Scholar
  66. 66.
    Druker BJ, Sawyers CL, Kantarjian H, et al.: Activity of a specific inhibitor of the BCR-ABL tyrosine kinase in the blast crisis of chronic myeloid leukemia and acute lymphoblastic leukemia with the Philadelphia chromosome. N Engl J Med 2001, 344:1038–1042.PubMedCrossRefGoogle Scholar
  67. 67.
    Druker BJ, Talpaz M, Resta DJ, et al.: Efficacy and safety of a specific inhibitor of the BCR-ABL tyrosine kinase in chronic myeloid leukemia. N Engl J Med 2001, 344:1031–1037.PubMedCrossRefGoogle Scholar
  68. 68.
    Kiyoi H, Naoe T, Nakano Y, et al.: Prognostic implication of FLT3 and N-RAS gene mutations in acute myeloid leukemia. Blood 1999, 93:3074–3080.PubMedGoogle Scholar
  69. 69.
    Yokota S, Kiyoi H, Nakao M, et al.: Internal tandem duplication of the FLT3 gene is preferentially seen in acute myeloid leukemia and myelodysplastic syndrome among various hematological malignancies: a study on a large series of patients and cell lines. Leukemia 1997, 11:1605–1609.PubMedCrossRefGoogle Scholar
  70. 70.
    Stirewalt DL, Kopecky KJ, Meshinchi S, et al.: FLT3, RAS, and TP53 mutations in elderly patients with acute myeloid leukemia. Blood 2001, 97:3589–3595.PubMedCrossRefGoogle Scholar
  71. 71.
    Karp JE, Lancet JE, Kaufmann SH, et al.: Clinical and biologic activity of the farnesyltransferase inhibitor R115777 in adults with refractory and relapsed acute leukemias: a phase 1 clinical-laboratory correlative trial. Blood 2001, 97:3361–3369.PubMedCrossRefGoogle Scholar

Copyright information

© Current Science Inc 2002

Authors and Affiliations

  • Mikkael A. Sekeres
    • 1
  • Richard Stone
    • 1
  1. 1.Dana-Farber Cancer InstituteHarvard Medical SchoolBostonUSA

Personalised recommendations