Non-Transplant Therapy for Older Adults with Acute Myeloid Leukemia

Author: Mikkael A. Sekeres MD, MS1
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  • 1 From the Department of Hematology and Medical Oncology, The Cleveland Clinic Foundation, Cleveland, Ohio.

Acute myeloid leukemia is a disease of older adults, with a median age at diagnosis of 68 years. This group represents a high-risk population, because inherent disease characteristics predict for resistance to chemotherapy and advanced age is accompanied by high treatment-related mortality. Standard remission-induction and postremission therapy can result in a median disease-free survival of 10 months and rare long-term survival. Efforts to improve outcomes have not made a major impact on complete remission rates of 40% to 60%, or on overall survival. Newer therapies, divided into aggressive and nonaggressive approaches, focus on targeting the disease biology specific to older adults and on maximizing quality of life. Clinical trials should be considered at every stage of treatment in this group of patients.

Dr. Sekeres has consulted for Johnson & Johnson Pharmaceuticals and is on the Speaker's Bureau for Celgene and Pharmion.

Correspondence: Mikkael A. Sekeres, MD, MS, Assistant Professor of Medicine, Department of Hematology and Medical Oncology, The Cleveland Clinic Foundation, 9500 Euclid Avenue, Desk R35, Cleveland, OH 44195. E-mail: sekerem@ccf.org
  • 1.

    Estey EH. How I treat older patients with AML. Blood 2000;96:16701673.

  • 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;331:896903.

    • Search Google Scholar
    • Export Citation
  • 3.

    Rowe JM, Neuberg D, Friedenberg W et al.. A phase 3 study of three induction regimens and of priming with GM-CSF in older adults with acute myeloid leukemia: a trial by the Eastern Cooperative Oncology Group. Blood 2004;103:479485.

    • Search Google Scholar
    • Export Citation
  • 4.

    Stone RM, Berg DT, George SL et al.. Postremission therapy in older patients with de novo acute myeloid leukemia: a randomized trial comparing mitoxantrone/intermediate-dose cytarabine with standard-dose cytarabine (CALGB study 8923). Blood 2001;98:548553.

    • Search Google Scholar
    • Export Citation
  • 5.

    Stone RM. The difficult problem of acute myeloid leukemia in the older adult. CA Cancer J Clin 2002;52:363371.

  • 6.

    Jemal A, Murray T, Ward E et al.. Cancer statistics, 2005. CA Cancer J Clin 2005;55:1030.

  • 7.

    Surveillance, Epidemiology, and End Results (SEER) Program. SEER*Stat Database: Incidence - SEER 9 Regs Public-Use, Nov 2004 Sub (1973-2002), National Cancer Institute, DCCPS, Surveillance Research Program, Cancer Statistics Branch, released April 2005, based on the November 2004 submission. Available at: http://www.seer.cancer.gov. Accessed October 19, 2005.

    • Search Google Scholar
    • Export Citation
  • 8.

    United States Census Bureau. U.S. Interim projections by age, sex, race, and Hispanic origin. Available at: http://www.census.gov/ipc/www/usinterimproj. Accessed October 19, 2005.

    • Search Google Scholar
    • Export Citation
  • 9.

    Friedberg JW, Neuberg D, Stone RM et al.. Outcome in patients with myelodysplastic syndrome after autologous bone marrow transplantation for non-Hodgkin's lymphoma. J Clin Oncol 1999;17:31283135.

    • Search Google Scholar
    • Export Citation
  • 10.

    Guralnik JM, Eisenstaedt RS, Ferrucci L et al.. Prevalence of anemia in persons 65 years and older in the United States: evidence for a high rate of unexplained anemia. Blood 2004;104:22632268.

    • Search Google Scholar
    • Export Citation
  • 11.

    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;58:41734179.

    • Search Google Scholar
    • Export Citation
  • 12.

    Byrd JC, Mrozek K, Dodge RK et al.. Pretreatment cytogenetic abnormalities are predictive of induction success, cumulative incidence of relapse and overall survival in adult patients with denovo acute myeloid leukemia: results from CALGB 8461. Blood 2002;100:43254336.

    • Search Google Scholar
    • Export Citation
  • 13.

    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;92:23222333.

    • Search Google Scholar
    • Export Citation
  • 14.

    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;98:13121320.

    • Search Google Scholar
    • Export Citation
  • 15.

    Greenberg P, Cox C, LeBeau MM et al.. International scoring system for evaluating prognosis in myelodysplastic syndromes. Blood 1997;89:20792088.

  • 16.

    Farag S, Archer K, Mrózek K et al.. Pre-Treatment cytogenetics predict complete remission and long-term outcome in patients (Pts) 60 years with acute myeloid leukemia (AML): Results from Cancer and Leukemia Group B (CALGB) 8461 [abstract]. Blood 2004;104:568a.

    • Search Google Scholar
    • Export Citation
  • 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;89:33233329.

    • Search Google Scholar
    • Export Citation
  • 18.

    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;35:289296.

    • Search Google Scholar
    • Export Citation
  • 19.

    Estey E, Thall P, Beran M et al.. Effect of diagnosis (refractory anemia with excess blasts, refractory anemia with excess blasts in transformation, or acute myeloid leukemia [AML]) on outcome of AML-type chemotherapy. Blood 1997;90:29692977.

    • Search Google Scholar
    • Export Citation
  • 20.

    Head DR. Revised classification of acute myeloid leukemia. Leukemia 1996;10:18261831.

  • 21.

    Hiddemann W, Kern W, Schoch C et al.. Management of acute myeloid leukemia in elderly patients. J Clin Oncol 1999;17:35693576.

  • 22.

    Schaich M, Soucek S, Thiede C et al.. MDR1 and MRP1 gene expression are independent predictors for treatment outcome in adult acute myeloid leukaemia. Differences in anti-apoptotic and multidrug resistance phenotypes in elderly and young acute myeloid leukemia patients are related to the maturation of blast cells. Br J Haematol 2005;128:324332.

    • Search Google Scholar
    • Export Citation
  • 23.

    Suarez L, Vidriales MB, Moreno MJ et al.. Differences in anti-apoptotic and multidrug resistance phenotypes in elderly and young acute myeloid leukemia patients are related to the maturation of blast cells. Haematologica 2005;90:5459.

    • Search Google Scholar
    • Export Citation
  • 24.

    Keating S, Suciu S, de Witte T et al.. Prognostic factors of patients with acute myeloid leukemia (AML) allografted in first complete remission: an analysis of the EORTC-GIMEMA AML 8A trial. The European Organization for Research and Treatment of Cancer (EORTC) and the Gruppo Italiano Malattie Ematologiche Maligne dell' Adulto (GIMEMA) Leukemia Cooperative Groups. Bone Marrow Transplant 1996;17:9931001.

    • Search Google Scholar
    • Export Citation
  • 25.

    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;94:10861899.

    • Search Google Scholar
    • Export Citation
  • 26.

    Baer MR, George SL, Dodge RK et al.. Phase 3 study of the multidrug resistance modulator PSC-833 in previously untreated patients 60 years of age and older with acute myeloid leukemia: Cancer and Leukemia Group B Study 9720. Blood 2002;100:12241232.

    • Search Google Scholar
    • Export Citation
  • 27.

    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;91:36073615.

    • Search Google Scholar
    • Export Citation
  • 28.

    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;16:872881.

    • Search Google Scholar
    • Export Citation
  • 29.

    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;332:16711677.

    • Search Google Scholar
    • Export Citation
  • 30.

    DeLima M, Ghaddar H, Pierce S, Estey E. Treatment of newly-diagnosed acute myelogenous leukaemia in patients aged 80 years and above. Br J Haematol 1996;93:8995.

    • Search Google Scholar
    • Export Citation
  • 31.

    Lowenberg B, van Putten W, Theobald M et al.. Effect of priming with granulocyte colony-stimulating factor on the outcome of chemotherapy for acute myeloid leukemia. N Engl J Med 2003;349:743752.

    • Search Google Scholar
    • Export Citation
  • 32.

    Goldstone AH, Burnett AK, Wheatley K et al.. Attempts to improve treatment outcomes in acute myeloid leukemia (AML) in older patients: the results of the United Kingdom Medical Research Council AML11 trial. Blood 2001;98:13021311.

    • Search Google Scholar
    • Export Citation
  • 33.

    Stone RM, Berg DT, George SL et al.. Postremission therapy in older patients with de novo acute myeloid leukemia: a randomized trial comparing mitoxantrone and intermediate-dose cytarabine with standard-dose cytarabine. Blood 2001;98:548553.

    • Search Google Scholar
    • Export Citation
  • 34.

    Rubin EH, Andersen JW, Berg DT et al.. Risk factors for high-dose cytarabine neurotoxicity: an analysis of a cancer and leukemia group B trial in patients with acute myeloid leukemia. J Clin Oncol 1992;10:948953.

    • Search Google Scholar
    • Export Citation
  • 35.

    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;15:833839.

    • Search Google Scholar
    • Export Citation
  • 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;8:272279.

    • Search Google Scholar
    • Export Citation
  • 37.

    Sekeres MA, Stone RM, Zahrieh D et al.. Decision-making and quality of life in older adults with acute myeloid leukemia or advanced myelodysplastic syndrome. Leukemia 2004;18:809816.

    • Search Google Scholar
    • Export Citation
  • 38.

    Carey RW, Ribas-Mundo M, Ellison RR et al.. Comparative study of cytosine arabinoside therapy alone and combined with thioguanine, mercaptopurine, or daunorubicin in acute myelocytic leukemia. Cancer 1975;36:15601566.

    • Search Google Scholar
    • Export Citation
  • 39.

    Rai KR, Holland JF, Glidewell OJ et al.. Treatment of acute myelocytic leukemia: a study by cancer and leukemia group B. Blood 1981;58:12031212.

  • 40.

    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;78:25202526.

    • Search Google Scholar
    • Export Citation
  • 41.

    Sekeres M, Rybicki L, Sobecks R et al.. The Time interval from diagnosis of acute myeloid leukemia (AML) in older adults to start of remission induction therapy predicts survival [abstract]. Blood 2003;102:3257a.

    • Search Google Scholar
    • Export Citation
  • 42.

    van der Holt B, Lowenberg B, Burnett AK et al.. The value of the MDR1 reversal agent PSC-833 in addition to daunorubicin and cytarabine in the treatment of elderly patients with previously untreated acute myeloid leukemia (AML), in relation to MDR1 status at diagnosis. Blood 2005;106:26462654.

    • Search Google Scholar
    • Export Citation
  • 43.

    Marcucci G, Stock W, Dai G et al.. Phase I study of oblimersen sodium, an antisense to Bcl-2, in untreated older patients with acute myeloid leukemia: pharmacokinetics, pharmacodynamics, and clinical activity. J Clin Oncol 2005;23:34043411.

    • Search Google Scholar
    • Export Citation
  • 44.

    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;19:32443254.

    • Search Google Scholar
    • Export Citation
  • 45.

    Nabhan C, Rundhaugen LM, Riley MB et al.. Phase II pilot trial of gemtuzumab ozogamicin (GO) as first line therapy in acute myeloid leukemia patients age 65 or older. Leuk Res 2005;29:5357.

    • Search Google Scholar
    • Export Citation
  • 46.

    McSweeney PA, Niederwieser D, Shizuru JA et al.. Hematopoietic cell transplantation in older patients with hematologic malignancies: replacing high-dose cytotoxic therapy with graft-versus-tumor effects. Blood 2001;97:33903400.

    • Search Google Scholar
    • Export Citation
  • 47.

    Bertz H, Potthoff K, Finke J. Allogeneic stem-cell transplantation from related and unrelated donors in older patients with myeloid leukemia. J Clin Oncol 2003;21:14801484.

    • Search Google Scholar
    • Export Citation
  • 48.

    Wallen H, Gooley TA, Deeg HJ et al.. Ablative allogeneic hematopoietic cell transplantation in adults 60 years of age and older. J Clin Oncol 2005;23:34393446.

    • Search Google Scholar
    • Export Citation
  • 49.

    Alyea EP, Kim HT, Ho V et al.. Comparative outcome of nonmyeloablative and myeloablative allogeneic hematopoietic cell transplantation for patients older than 50 years of age. Blood 2005;105:18101814.

    • Search Google Scholar
    • Export Citation
  • 50.

    Lancet J, Gotlib J, Gojo I et al.. Tipifarnib (ZARNESTRATM in previously untreated poor-risk aml of the elderly: updated results of a multicenter Phase 2 trial. Blood 2004;104:874a.

    • Search Google Scholar
    • Export Citation
  • 51.

    Stone RM, DeAngelo DJ, Klimek V et al.. Patients with acute myeloid leukemia and an activating mutation in FLT3 respond to a small-molecule FLT3 tyrosine kinase inhibitor, PKC412. Blood 2005;105:5460.

    • Search Google Scholar
    • Export Citation
  • 52.

    Raffoux E, Chaibi P, Dombret H, Degos L. Valproic acid and all-trans retinoic acid for the treatment of elderly patients with acute myeloid leukemia. Haematologica 2005;90:986988.

    • Search Google Scholar
    • Export Citation
  • 53.

    Vey N, Dreyfus F, Guerci A et al.. Trisenox (arsenic trioxide) in patients with myelodysplastic syndromes (MDS): preliminary results of a phase I/II study [abstract]. ASH Annual Meeting Abstracts 2004;104:1433a.

    • Search Google Scholar
    • Export Citation
  • 54.

    Shadduck RK, Rossetti JM, Faroun Y et al.. AML induction therapy with outpatient azacitidine [abstract]. ASH Annual Meeting Abstracts 2004;104(11):1800a.

    • Search Google Scholar
    • Export Citation
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