Therapy for Older AML Patients: The Role of Novel Agents and Allogeneic Stem Cell Transplant

View More View Less
  • a From the Department of Hematologic Malignancies, H. Lee Moffitt Cancer Center & Research Institute, Tampa, Florida, and Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas M. D. Anderson Cancer Center, Houston, Texas.

The development of novel therapeutics in acute myeloid leukemia (AML) is driven by the need to improve efficacy and reduce toxicity. Clearly, elderly patients with AML represent a highly heterogeneous group, based on a wide array of disease- and patient-specific characteristics. Therefore, novel treatment strategies aimed at overcoming specific biologic modifiers of disease resistance will be paramount to successful therapy for some, whereas in others, the ability to administer a low-toxicity regimen on a chronic basis to achieve disease control may prove beneficial, perhaps even in the absence of complete responses. In addition, identifying genomic and proteomic expression patterns using an individual's unique neoplastic clone will likely optimize the ability to predict responders to novel therapies and identify new and relevant therapeutic targets. The development of reduced-intensity preparative regimens for allogeneic transplants has allowed physicians and patients to explore the option of long-term disease control. The risk–benefit ratio for this procedure will depend on the disease state, patient performance status, and comorbidities. However, current results underscore that age alone should no longer be a contraindication for allogeneic transplant with curative intent in these patients, and long-term disease control with good quality of life is possible and can be expected. Future trials combining the novel therapies described in this article and novel transplant technologies should allow more elderly patients with AML or myelodysplastic syndromes to experience long and productive lives.

If the inline PDF is not rendering correctly, you can download the PDF file here.

Correspondence: Jeffrey E. Lancet, MD, Department of Hematologic Malignancies, H. Lee Moffitt Cancer Center & Research Institute, 12902 Magnolia Drive, SRB-4th floor, Tampa, FL 33612. E-mail: Jeffrey.Lancet@moffitt.org
  • 1.

    Surveillance, Epidemiology, and End Results (SEER) Program. Acute myeloid leukemia incidence for 2000-2004. National Cancer Institute, DCCPS, Surveillance Research Program, Cancer Statistics Branch. 2007. Available at: www.seer.cancer.gov. Accessed September 8, 2008.

    • Search Google Scholar
    • Export Citation
  • 2.

    Appelbaum FR, Gundacker H, Head DR. Age and acute myeloid leukemia. Blood 2006;107:34813485.

  • 3.

    Farag SS, Archer KJ, Mrozek K. Pretreatment cytogenetics add to other prognostic factors predicting complete remission and long-term outcome in patients 60 years of age or older with acute myeloid leukemia: results from Cancer and Leukemia Group B 8461. Blood 2006;108:6373.

    • Search Google Scholar
    • Export Citation
  • 4.

    Frohling S, Schlenk RF, Kayser S. Cytogenetics and age are major determinants of outcome in intensively treated acute myeloid leukemia patients older than 60 years: results from AMLSG trial AML HD98-B. Blood 2006;108:32803288.

    • Search Google Scholar
    • Export Citation
  • 5.

    Grimwade D, Walker H, Harrison G. 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
  • 6.

    Leith CP, Kopecky KJ, Godwin J. 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
  • 7.

    Leith CP, Kopecky KJ, Chen IM. 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;94:10861099.

    • Search Google Scholar
    • Export Citation
  • 8.

    Mahadevan D, List AF. Targeting the multidrug resistance-1 transporter in AML: molecular regulation and therapeutic strategies. Blood 2004;104:19401951.

    • Search Google Scholar
    • Export Citation
  • 9.

    Kantarjian H, O Brien S, Cortes J. Results of intensive chemotherapy in 998 patients age 65 years or older with acute myeloid leukemia or high-risk myelodysplastic syndrome: predictive prognostic models for outcome. Cancer 2006;106:10901098.

    • Search Google Scholar
    • Export Citation
  • 10.

    Goldstone AH, Burnett AK, Wheatley K. 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
  • 11.

    Lowenberg B, Suciu S, Archimbaud E. 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
  • 12.

    Lowenberg B, Suciu S, Archimbaud E. 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;90:29522961.

    • Search Google Scholar
    • Export Citation
  • 13.

    Rowe JM, Neuberg D, Friedenberg W. 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
  • 14.

    Stone RM, Berg DT, George SL. Granulocyte-macrophage colony-stimulating factor after initial chemotherapy for elderly patients with primary acute myelogenous leukemia. N Engl J Med 1995;332:16711677.

    • Search Google Scholar
    • Export Citation
  • 15.

    Schoch C, Kern W, Schnittger S. The influence of age on prognosis of de novo acute myeloid leukemia differs according to cytogenetic subgroups. Haematologica 2004;89:10821090.

    • Search Google Scholar
    • Export Citation
  • 16.

    Cripe LD, Li X, Litzow M. A randomized, placebo-controlled, double blind trial of the MDR modulator, zosuquidar, during conventional induction and post-remission therapy for pts > 60 years of age with newly diagnosed acute myeloid leukemia (AML) or high-risk myelodysplastic syndrome (HR-MDS): ECOG 3999 [abstract]. Blood 2006;108:Abstract 423.

    • Search Google Scholar
    • Export Citation
  • 17.

    Lancet J, Baer MR, Cripe LD. Phase I/II pharmacodynamic study of the P-glycoprotein (Pgp) inhibitor zosuquidar administered by continuous infusion (CIV) with daunorubicin (DNR) and cytarabine (ARA-C) as primary therapy in older patients with acute myeloid leukemia (AML) [abstract]. Blood 2006;108:Abstract 422.

    • Search Google Scholar
    • Export Citation
  • 18.

    Burnett AK, Baccarani M, Johnson P. Clofarabine in previously untreated elderly (> 65 yrs) AML patients with an unfavourable cytogenetic profile who are considered unfit for standard intensive chemotherapy [abstract]. J Clin Oncol 2006;24:Abstract 6513.

    • Search Google Scholar
    • Export Citation
  • 19.

    Giles F, Rizzieri D, Karp J. Cloretazine (VNP40101M), a novel sulfonylhydrazine alkylating agent, in patients age 60 years or older with previously untreated acute myeloid leukemia. J Clin Oncol 2007;25:2531.

    • Search Google Scholar
    • Export Citation
  • 20.

    Kantarjian H, Oki Y, Garcia-Manero G. Results of a randomized study of 3 schedules of low-dose decitabine in higher-risk myelodysplastic syndrome and chronic myelomonocytic leukemia. Blood 2007;109:5257.

    • Search Google Scholar
    • Export Citation
  • 21.

    Silverman LR, Demakos EP, Peterson BL. randomized controlled trial of azacitidine in patients with the myelodysplastic syndrome: a study of the Cancer and Leukemia Group B. J Clin Oncol. 2002;20:24292440.

    • Search Google Scholar
    • Export Citation
  • 22.

    Lubbert M, Ruter B, Claus R. Continued low-dose decitabine (DAC) is an active first-line treatment in all cytogenetic subgroups of older AML patients: results of the FR00331 multicenter phase II study [abstract]. Blood 2007;110:Abstract 300.

    • Search Google Scholar
    • Export Citation
  • 23.

    Garcia-Manero G, Kantarjian HM, Sanchez-Gonzalez B. Phase 1/2 study of the combination of 5-aza-2'-deoxycytidine with valproic acid in patients with leukemia. Blood 2006;108:32713279.

    • Search Google Scholar
    • Export Citation
  • 24.

    Blum W, Klisovic RB, Hackanson B. Phase I study of decitabine alone or in combination with valproic acid in acute myeloid leukemia. J Clin Oncol 2007;25:38843891.

    • Search Google Scholar
    • Export Citation
  • 25.

    Garcia-Manero G, Yang AS, Klimek V. Phase I/II study of MGCD0103, an oral isotype-selective histone deacetylase (HDAC) inhibitor, in combination with 5-azacitidine in higher-risk myelodysplastic syndrome (MDS) and acute myelogenous leukemia (AML) [abstract]. Blood 2007;110:Abstract 444.

    • Search Google Scholar
    • Export Citation
  • 26.

    Grovdal M, Khan R, Aggerholm A. Maintenance treatment with azacytidine for patients with high risk myelodysplastic syndromes or acute myeloid leukaemia in complete remission after intensive chemotherapy [abstract]. Blood 2007;110:Abstract 818.

    • Search Google Scholar
    • Export Citation
  • 27.

    Lancet JE, Gojo I, Gotlib J. A phase II study of the farnesyltransferase inhibitor tipifarnib in poor-risk and elderly patients with previously untreated acute myelogenous leukemia. Blood 2007;109:13871394.

    • Search Google Scholar
    • Export Citation
  • 28.

    Harousseau JL, Martinelli G, Jedrzejczak WW. A randomized phase 3 study of tipifarnib compared to best supportive care (including hydroxyurea) in the treatment of newly diagnosed acute myeloid leukemia (AML) in patients 70 years or older [abstract]. Blood 2007;110:Abstract 439.

    • Search Google Scholar
    • Export Citation
  • 29.

    Raponi M, Lancet JE, Fan H. A 2-gene classifier for predicting response to the farnesyltransferase inhibitor tipifarnib in acute myeloid leukemia. Blood 2008;111:25892596.

    • Search Google Scholar
    • Export Citation
  • 30.

    Karp JE, Smith BD, Gojo I. Phase II trial of tipifarnib as maintenance therapy in first complete remission in adults with acute myelogenous leukemia and poor-risk features. Clin Cancer Res 2008;14:30773082.

    • Search Google Scholar
    • Export Citation
  • 31.

    Gilliland DG, Griffin JD. The roles of FLT3 in hematopoiesis and leukemia. Blood 2002;100:15321542.

  • 32.

    DeAngelo DJ, Stone RM, Heaney ML. Phase 1 clinical results with tandutinib (MLN518), a novel FLT3 antagonist, in patients with acute myelogenous leukemia or high-risk myelodysplastic syndrome: safety, pharmacokinetics, and pharmacodynamics. Blood 2006;108:36743681.

    • Search Google Scholar
    • Export Citation
  • 33.

    Knapper S, Burnett AK, Littlewood T. A phase 2 trial of the FLT3 inhibitor lestaurtinib (CEP701) as first-line treatment for older patients with acute myeloid leukemia not considered fit for intensive chemotherapy. Blood 2006;108:32623270.

    • Search Google Scholar
    • Export Citation
  • 34.

    Stone RM, DeAngelo DJ, Klimek V. 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
  • 35.

    DeAngelo DJ, Amrein PC, Kovacsovics TJ. Phase 1/2 study of tandutinib (MLN518) plus standard induction chemotherapy in newly diagnosed acute myelogenous leukemia (AML) [abstract]. Blood 2006;108:Abstract 158.

    • Search Google Scholar
    • Export Citation
  • 36.

    Stone RM, Fischer T, Paquette R. Phase IB study of PKC412, an oral FLT3 kinase inhibitor, in sequential and simultaneous combinations with daunorubicin and cytarabine (DA) induction and high-dose cytarabine consolidation in newly diagnosed adult patients (pts) with acute myeloid leukemia (AML) under age 61 [abstract]. Blood 2006;108:Abstract 157.

    • Search Google Scholar
    • Export Citation
  • 37.

    Stone RM, Klimek V, DeAngelo DJ. PKC412, an oral FLT3 inhibitor, has activity in mutant FLT3 acute myeloid leukemia (AML): a phase II clinical trial [abstract]. Blood 2002;100:Abstract 86a.

    • Search Google Scholar
    • Export Citation
  • 38.

    Larson RA, Sievers EL, Stadtmauer EA. Final report of the efficacy and safety of gemtuzumab ozogamicin (Mylotarg) in patients with CD33-positive acute myeloid leukemia in first recurrence. Cancer 2005;104:14421452.

    • Search Google Scholar
    • Export Citation
  • 39.

    Taksin AL, Legrand O, Raffoux E. High efficacy and safety profile of fractionated doses of Mylotarg as induction therapy in patients with relapsed acute myeloblastic leukemia: a prospective study of the alfa group. Leukemia 2006;21:6671.

    • Search Google Scholar
    • Export Citation
  • 40.

    Amadori S, Suciu S, Willemze R. Sequential administration of gemtuzumab ozogamicin and conventional chemotherapy as first line therapy in elderly patients with acute myeloid leukemia: a phase II study (AML-15) of the EORTC and GIMEMA leukemia groups. Haematologica 2004;89:950956.

    • Search Google Scholar
    • Export Citation
  • 41.

    Estey EH, Thall PF, Giles FJ. Gemtuzumab ozogamicin with or without interleukin 11 in patients 65 years of age or older with untreated acute myeloid leukemia and high-risk myelodysplastic syndrome: comparison with idarubicin plus continuous-infusion, high-dose cytosine arabinoside. Blood 2002;99:43434349.

    • Search Google Scholar
    • Export Citation
  • 42.

    Fianchi L, Pagano L, Leoni F. Gemtuzumab ozogamicin, citosine arabinoside, G-CSF combination (G-AraMy) in the treatment of elderly patients with poor-prognosis acute myeloid leukemia. Ann Oncol 2008;19:128134.

    • Search Google Scholar
    • Export Citation
  • 43.

    Harousseau JL, Recher CFR, Vey N. Gentuzumab-ozogamicin (GO) plus idarubicin (I) and cytarabine (C) as induction treatment for elderly patients with poor-risk cytogenetics acute myeloid leukemia (AML) [abstract]. Blood 2007;110:Abstract 1839.

    • Search Google Scholar
    • Export Citation
  • 44.

    Piccaluga PP, Martinelli G, Rondoni M. First experience with gemtuzumab ozogamicin plus cytarabine as continuous infusion for elderly acute myeloid leukaemia patients. Leuk Res 2004;28:987990.

    • Search Google Scholar
    • Export Citation
  • 45.

    Armitage J. Bone marrow transplantation. N Engl J Med 1994;330:827838.

  • 46.

    Loberiza F. Report on the state of the art in blood and marrow transplantation. Part 1 of the IBMTR/ABMTR summary slides with guide. IBMTR/ABMTR Newsletter 2003;10:710.

    • Search Google Scholar
    • Export Citation
  • 47.

    Frassoni F, Labopin M, Arcese W. The outcome of allogeneic hematopoietic stem cell transplantation (HSCT) for AML 1CR is significantly worse after 35 years. Implication for reducing the intensity of the conditioning regimen. Report of the acute leukemia working party of EBMT [abstract]. Blood 2000;96:Abstract 393a.

    • Search Google Scholar
    • Export Citation
  • 48.

    Ringden O, Horowitz M, Gale R. Outcome after allogeneic bone marrow transplant for leukemia in older adults. JAMA 1993;270:5760.

  • 49.

    Gale R, Bortin M, Van Bekkum D. Risk factors for acute graft versus host disease Br J Haematol 1987;67:397400.

  • 50.

    Ferrara J, Deeg H. Graft versus host disease. N Engl J Med 1991;324:667674.

  • 51.

    Horowitz M, Loberiza F, Bredeson C, Nugent M. Transplant registries: guiding clinical decisions and improving outcomes. Oncology 2001:15:649659.

    • Search Google Scholar
    • Export Citation
  • 52.

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

    • Search Google Scholar
    • Export Citation
  • 53.

    Ditschkowski M, Elmaagacli AH, Trenschel R. Myeloablative allogeneic hematopoietic stem cell transplantation in elderly patients. Clin Transplant 2006;20:127131.

    • Search Google Scholar
    • Export Citation
  • 54.

    Giralt S, Estey E, Albitar M. Engraftment of allogeneic hematopoietic progenitor cells with purine analog-containing chemotherapy: harnessing graft versus-leukemia without myeloablative therapy. Blood 1997;89:45314536.

    • Search Google Scholar
    • Export Citation
  • 55.

    Slavin S, Nagler A, Naparstak E. Nonmyeloablative stem cell transplantation and cell therapy as an alternative to conventional bone marrow transplantation with lethal cytoreduction for the treatment of malignant and non malignant hematologic diseases. Blood 1998;91:756763.

    • Search Google Scholar
    • Export Citation
  • 56.

    Khouri I, Keating MJ, Korbling M. Transplant lite: induction of graft vs malignancy using fludarabine based nonablative chemotherapy and allogeneic progenitor-cell transplantation as treatment for lymphoid malignancies. J Clin Oncol 1998;16:28172824.

    • Search Google Scholar
    • Export Citation
  • 57.

    Champlin R, Khouri I, Kornblau J. Reinventing bone marrow transplantation. Nonmyeloablative preparative regimens and induction of graft versus malignancy effect. Oncology 1999;13:621626.

    • Search Google Scholar
    • Export Citation
  • 58.

    McSweeney P, Niederwieser D, Shizuru J. 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
  • 59.

    Kiss TL, Sabry W, Lazarus HM, Lipton JH. Blood and marrow transplantation in elderly acute myeloid leukemia patients-older certainly is not better. Bone Marrow Transplant 2007;40:405415.

    • Search Google Scholar
    • Export Citation
  • 60.

    Center for International Blood & Marrow Transplant Research. Summary Slides. Available at: www.cibmtr.org/SERVICES/Observational_Research/Summary_Slides. Accessed September 8, 2008.

    • Search Google Scholar
    • Export Citation
  • 61.

    Wong R, Giralt S, Martin T. Reduced intensity conditioning for unrelated donor hematopoietic stem cell transplantation as treatment for myeloid malignancies in patients older than 55 years. Blood 2003;102:30523059.

    • Search Google Scholar
    • Export Citation
  • 62.

    de Lima M, Anagnostopoulos A, Munsell M. Nonablative versus reduced intensity conditioning regimens in the treatment of acute myeloid leukemia and high risk myelodysplastic syndrome: dose is relevant for long term disease control after allogeneic hematopoietic stem cell transplantation. Blood 2004;104:865872.

    • Search Google Scholar
    • Export Citation
  • 63.

    Gupta V, Daly A, Lipton J. Nonmyeloablative stem cell transplantation for myelodysplastic syndrome or acute myeloid leukemia in patients 60 years or older. Biol Blood Marrow Transplant 2005;11:764772.

    • Search Google Scholar
    • Export Citation
  • 64.

    Tauro S, Craddock C, Peggs K. Allogeneic stem cell transplantation using a reduced intensity conditioning regimen has the capacity to produce durable remissions and ling term disease free survival in patients with high risk acute myeloid leukemia and myelodysplasia. J Clin Oncol 2005;23:93879393.

    • Search Google Scholar
    • Export Citation
  • 65.

    Aoudjhane M, Labopin M, Gorin NC. Comparative outcome of reduced intensity and myeloablative conditioning regimen in HLA identical sibling allogeneic hematopoietic stem cell transplantation for patients older than 50 years with acute myeloblastic leukemia: a retrospective survey from the acute leukemia working party of the European group for blood and marrow transplantation. Leukemia 2005;19:23042312.

    • Search Google Scholar
    • Export Citation
  • 66.

    Hegenbart U, Nierderwieser D, Sandmaier BM. Treatment for acute myelogenous leukemia by low dose TBI based conditioning and hematopoietic cell transplantation from related and unrelated donors. J Clin Oncol 2006;24:444453.

    • Search Google Scholar
    • Export Citation
  • 67.

    Popat U, Heslop HE, Durett A. Outcome of reduced intensity allogeneic hematopoietic stem cell transplantation using antilymphocyte antibodies in patients with high risk acute myeloid leukemia. Bone Marrow Transplant 2006;37:547552.

    • Search Google Scholar
    • Export Citation
  • 68.

    Kroger N, Shimoni A, Zabelina T. Reduced toxicity conditioning with treosulfan, fludarabine and ATG as preparative regimen for allogeneic stem cell transplantation in elderly patients with secondary acute myeloid leukemia or myelodysplastic syndrome. Bone Marrow Transplant 2006;37:339344.

    • Search Google Scholar
    • Export Citation
  • 69.

    Estey E, de Lima M, Tibes R. Prospective feasibility analysis of reduced intensity conditioning regimens for hematopoietic stem cell transplantation in elderly patients with acute myeloid leukemia and high risk myelodysplastic syndrome. Blood 2007;109:13951400.

    • Search Google Scholar
    • Export Citation
  • 70.

    Shimoni A, Kroger N, Zabelina T. Hematopoietic stem cell transplantation from unrelated donors in elderly patients (age > 55 years) with hematologic malignancies: older age is no longer a contraindication when using reduced intensity conditioning. Leukemia 2005;19:712.

    • Search Google Scholar
    • Export Citation
  • 71.

    Falda M, Busca A, Baldi I. Nonmyeloablative allogeneic stem cell transplantation in elderly patients with hematological malignancies: results from the GITMO (Gruppo Italiano Trapianto Midollo Osseo) multicenter prospective trial. Am J Hematol 2007;82:863866.

    • Search Google Scholar
    • Export Citation
  • 72.

    Sorror M, Storer B, Sandmaier B. Hematopoietic cell transplantation comorbidity index and Karnofsky performance status are independent predictors of morbidity and mortality after allogeneic nonmyeloablative hematopoietic cell transplantation. Cancer 2008;112;19922001.

    • Search Google Scholar
    • Export Citation
  • 73.

    Majhail N, Brunstein C, Tomblyn M. Reduced intensity allogeneic transplant in patients older than 55 years of age. Unrelated umbilical cord blood is safe and effective for patients without a matched related donor. Biol Blood Marrow Trans 2008;14:282289.

    • Search Google Scholar
    • Export Citation
All Time Past Year Past 30 Days
Abstract Views 0 0 0
Full Text Views 73 59 2
PDF Downloads 41 38 1
EPUB Downloads 0 0 0