Growth Factors in Leukemia

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  • 1 From the Division of Hematology and Oncology, Northwestern University Feinberg School of Medicine, Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, Illinois.

The role of myeloid growth factors, such as granulocyte colony-stimulating factor and granulocyte-macrophage colony-stimulating factor, in the management of acute myeloid and acute lymphoblastic leukemias has been evaluated extensively in multiple clinical trials. Growth factors have been given before, concurrently, or sequentially with chemotherapy with the goal of reducing the duration of neutropenia and consequently the incidence and severity of infections, and improving the rate of remissions and overall survival. They also have been studied as chemotherapy-sensitizing agents in an effort to recruit dormant myeloid stem cells into the sensitive phase of the cycle. Additionally, growth factors, shown to stimulate proliferation and differentiation of leukemia cells in vitro, were evaluated as monotherapy in patients with acute leukemia. Most studies show modest improvement in the duration of the neutropenia, which does not consistently correlate with the severity of infection, rate or duration of remissions, or disease-free and overall survival. Attempts to enhance the chemosensitivity of the leukemic cells and decrease drug resistance failed to improve the rate of remission and survival in several large series. However, more recent reports suggested an improved outcome in younger patients with acute myeloid leukemia with normal karyotype. Several anecdotal case reports have shown that growth factor monotherapy can induce a complete remission in patients with acute leukemia. Data from the published clinical trials do not seem to support emergence of drug-resistant leukemia, worsening toxicity, and bone marrow failure with growth factor administration.

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Correspondence: Olga Frankfurt, MD, Division of Hematology and Oncology, Northwestern University Feinberg School of Medicine, Robert H. Lurie Comprehensive Cancer Center of Northwestern University, 676 North St. Clair Street, Suite 850, Chicago, IL 60611. E-mail: o-frankfurt@northwestern.edu
  • 1.

    Welte K, Gabrilove J, Bronchud MH. Filgrastim (r-metHuG-CSF): the first 10 years. Blood 1996;88:19071929.

  • 2.

    Spiekermann K, Roesler J, Emmendoerffer A. Functional features of neutrophils induced by G-CSF and GM-CSF treatment: differential effects and clinical implications. Leukemia 1997;11:466478.

    • Search Google Scholar
    • Export Citation
  • 3.

    Lieschke GJ, Grail D, Hodgson G. Mice lacking granulocyte colony-stimulating factor have chronic neutropenia, granulocyte and macrophage progenitor cell deficiency, and impaired neutrophil mobilization. Blood 1994;84:17371746.

    • Search Google Scholar
    • Export Citation
  • 4.

    Lieschke GJ, Stanley E, Grail D. Mice lacking both macrophage- and granulocyte-macrophage colony-stimulating factor have macrophages and coexistent osteopetrosis and severe lung disease. Blood 1994;84:2735.

    • Search Google Scholar
    • Export Citation
  • 5.

    Lane SW, Crawford J, Kenealy M. Pegfilgrastim compared to granulocyte colony stimulating Ffctor (G-CSf) with hyper-CVAD chemotherapy regimen for aggressive lymphoid malignancy [abstract]. Blood 2005;106. Abstract 4274.

    • Search Google Scholar
    • Export Citation
  • 6.

    Crawford J, Ozer H, Stoller R. Reduction by granulocyte colony-stimulating factor of fever and neutropenia induced by chemotherapy in patients with small-cell lung cancer. N Engl J Med 1991;325:164170.

    • Search Google Scholar
    • Export Citation
  • 7.

    Ohno R, Tomonaga M, Kobayashi T. Effect of granulocyte colony-stimulating factor after intensive induction therapy in relapsed or refractory acute leukemia. N Engl J Med 1990;323:871877.

    • Search Google Scholar
    • Export Citation
  • 8.

    Stone RM, Berg DT, George SL. 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
  • 9.

    Dombret H, Chastang C, Fenaux P. 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;332:16781683.

    • Search Google Scholar
    • Export Citation
  • 10.

    Rowe JM, Andersen JW, Mazza JJ. A randomized placebo-controlled 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;86:457462.

    • Search Google Scholar
    • Export Citation
  • 11.

    Maslak PG, Weiss MA, Berman E. Granulocyte colony-stimulating factor following chemotherapy in elderly patients with newly diagnosed acute myelogenous leukemia. Leukemia 1996;10:3239.

    • Search Google Scholar
    • Export Citation
  • 12.

    Heil G, Hoelzer D, Sanz MA. A randomized, double-blind, 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;90:47104718.

    • Search Google Scholar
    • Export Citation
  • 13.

    Godwin JE, Kopecky KJ, Head DR. 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
  • 14.

    Harousseau JL, Witz B, Lioure B. Granulocyte colony-stimulating factor after intensive consolidation chemotherapy in acute myeloid leukemia: results of a randomized trial of the Groupe Ouest-Est Leucemies Aigues Myeloblastiques. J Clin Oncol 2000;18:780787.

    • Search Google Scholar
    • Export Citation
  • 15.

    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
  • 16.

    Usuki K, Urabe A, Masaoka T. Efficacy of granulocyte colony-stimulating factor in the treatment of acute myelogenous leukaemia: a multicentre randomized study. Br J Haematol 2002;116:103112.

    • Search Google Scholar
    • Export Citation
  • 17.

    Moore JO, Dodge RK, Amrein PC. Granulocyte-colony stimulating factor (filgrastim) accelerates granulocyte recovery after intensive postremission chemotherapy for acute myeloid leukemia with aziridinyl benzoquinone and mitoxantrone: Cancer and Leukemia Group B study 9022. Blood 1997;89:780788.

    • Search Google Scholar
    • Export Citation
  • 18.

    Estey EH. Growth factors in acute myeloid leukaemia. Best Pract Res Clin Haematol 2001;14:175187.

  • 19.

    Bennett CL, Stinson TJ, Tallman MS. Economic analysis of a randomized placebo-controlled phase III study of granulocyte macrophage colony stimulating factor in adult patients (> 55 to 70 years of age) with acute myelogenous leukemia. Eastern Cooperative Oncology Group (E1490). Ann Oncol 1999;10:177182.

    • Search Google Scholar
    • Export Citation
  • 20.

    Lu Z, Luo R, Erder H. Cost impact of filgrastim as an adjunct to chemotherapy for patients with acute myeloid leukemia [abstract]. Blood 1996;88(suppl 1):209a.

    • Search Google Scholar
    • Export Citation
  • 21.

    Woronoff-Lemsi M, Demoly P, Arveux P. Cost-effectiveness analysis of GOELEM SA3, a randomized placebo-controlled protocol of GM-CSF for elderly patients with acute myeloid leukemia [abstract]. Blood 1997;90(suppl 1):72a.

    • Search Google Scholar
    • Export Citation
  • 22.

    Bennett CL, Hynes D, Godwin J. Economic analysis of granulocyte colony stimulating factor as adjunct therapy for older patients with acute myelogenous leukemia (AML): estimates from a Southwest Oncology Group clinical trial. Cancer Invest 2001;19:603610.

    • Search Google Scholar
    • Export Citation
  • 23.

    Pui CH, Bovett JM, Hughes WT. Human granulocyte colony-stimulating factor after induction chemotherapy in children with acute lymphoblastic leukemia. N Engl J Med 1997;336:17811787.

    • Search Google Scholar
    • Export Citation
  • 24.

    Lowenberg B, Downing JR, Burnett A. Acute myeloid leukemia. N Engl J Med 1999;341:10511062.

  • 25.

    Schiffer CA. Hematopoietic growth factors and the future of therapeutic research on acute myeloid leukemia. N Engl J Med 2003;349:727729.

    • Search Google Scholar
    • Export Citation
  • 26.

    Hiddemann W, Kiehl M, Zuhlsdorf M. Granulocyte-macrophage colony-stimulating factor and interleukin-3 enhance the incorporation of cytosine arabinoside into the DNA of leukemic blasts and the cytotoxic effect on clonogenic cells from patients with acute myeloid leukemia. Semin Oncol 1992:19(suppl 4):3137.

    • Search Google Scholar
    • Export Citation
  • 27.

    Miyauchi J, Kelleher CA, Wang C. Growth factors influence the sensitivity of leukemic stem cells to cytosine arabinoside in culture. Blood 1989;73:12721278.

    • Search Google Scholar
    • Export Citation
  • 28.

    Cannistra SA, DiCarlo J, Groshek P. Simultaneous administration of granulocyte-macrophage colony-stimulating factor and cytosine arabinoside for the treatment of relapsed acute myeloid leukemia. Leukemia 1991;5:230238.

    • Search Google Scholar
    • Export Citation
  • 29.

    Lowenberg B, Touw IP. Hematopoietic growth factors and their receptors in acute leukemia. Blood 1993;81:281292.

  • 30.

    Rutella S, Bonanno G, Procoli A. Granulocyte colony-stimulating factor enhances the in vitro cytotoxicity of gemtuzumab ozogamicin against acute myeloid leukemia cell lines and primary blast cells. Exp Hematol 2006;34:5465.

    • Search Google Scholar
    • Export Citation
  • 31.

    Lowenberg B, van Putten W, Theobald M. 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.

    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
  • 33.

    Lofgren C, Paul C, Astrom M. Granulocyte-macrophage colony-stimulating factor to increase efficacy of mitoxantrone, etoposide and cytarabine in previously untreated elderly patients with acute myeloid leukaemia: a Swedish multicentre randomized trial. Br J Haematol 2004;124:474480.

    • Search Google Scholar
    • Export Citation
  • 34.

    Thomas X, Raffoux E, De Botton S. Effect of priming with granulocyte-macrophage colony-stimulating factor (GM-CSF) in younger adults with newly diagnosed acute myeloid leukemia (AML): a trial by the Acute Leukemia French Association (ALFA) group [abstract]. Blood 2005;106:530a. Abstract 1862.

    • Search Google Scholar
    • Export Citation
  • 35.

    Thomas X, Fenaux P, Dombret H. Granulocyte-macrophage colony-stimulating factor (GM-CSF) to increase efficacy of intensive sequential chemotherapy with etoposide, mitoxantrone and cytarabine (EMA) in previously treated acute myeloid leukemia: a multicenter randomized placebo-controlled trial (EMA91 Trial). Leukemia 1999;13:12141220.

    • Search Google Scholar
    • Export Citation
  • 36.

    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
  • 37.

    Takamatsu Y, Miyamoto T, Iwasaki H. Remission induction by granulocyte colony-stimulating factor in hypoplastic acute myelogenous leukemia complicated by infection. A case report and review of the literature. Acta Haematol 1998;99:224230.

    • Search Google Scholar
    • Export Citation
  • 38.

    Ferrara F, Di Noto R, Viola A. Complete remission in acute myeloid leukaemia with t(8;21) following treatment with G-CSF: flow cytometric analysis of in vivo and in vitro effects on cell maturation. Br J Haematol 1999;106:520523.

    • Search Google Scholar
    • Export Citation
  • 39.

    Nimubona S, Grulois I, Bernard M. Complete remission in hypoplastic acute myeloid leukemia induced by G-CSF without chemotherapy: report on three cases. Leukemia 2002;16:18711873.

    • Search Google Scholar
    • Export Citation
  • 40.

    Piccaluga PP, Martinelli G, Malagola M. Complete remission in acute myeloid leukemia with granulocyte-colony stimulating factor without chemotherapy. Report of cytogenetic remission of a t(9;11)(p22q23) positive AML patient and review of literature [e-case]. Haematologica 2003;88:ECR28.

    • Search Google Scholar
    • Export Citation
  • 41.

    Faderl S, Thall PF, Kantarjian HM. Caspase 2 and caspase 3 as predictors of complete remission and survival in adults with acute lymphoblastic leukemia. Clin Cancer Res 1999;5:40414047.

    • Search Google Scholar
    • Export Citation
  • 42.

    Faderl S, Harris D, Van Q. Granulocyte-macrophage colony-stimulating factor (GM-CSF) induces antiapoptotic and proapoptotic signals in acute myeloid leukemia. Blood 2003;102:630637.

    • Search Google Scholar
    • Export Citation
  • 43.

    Ohno R, Tomonaga M, Ohshima T. A randomized controlled study of granulocyte colony stimulating factor after intensive induction and consolidation therapy in patients with acute lymphoblastic leukemia. Japan Adult Leukemia Study Group. Int J Hematol 1993;58:7381.

    • Search Google Scholar
    • Export Citation
  • 44.

    Larson RA, Dodge RK, Linker CA. A randomized controlled trial of filgrastim during remission induction and consolidation chemotherapy for adults with acute lymphoblastic leukemia: CALGB study 9111. Blood 1998;92:15561564.

    • Search Google Scholar
    • Export Citation
  • 45.

    Thomas X, Boiron JM, Huguet F. Efficacy of granulocyte and granulocyte-macrophage colony-stimulating factors in the induction treatment of adult acute lymphoblastic leukemia: a multicenter randomized study. Hematol J 2004;5:384394.

    • Search Google Scholar
    • Export Citation
  • 46.

    Ottmann OG, Hoelzer D, Gracien E. Concomitant granulocyte colony-stimulating factor and induction chemoradiotherapy in adult acute lymphoblastic leukemia: a randomized phase III trial. Blood 1995;86:444450.

    • Search Google Scholar
    • Export Citation
  • 47.

    Alvarado Ibarra ML, Borbolla Escoboza JR, Lopez-Hernandez MA. Neutrophil recovery time and adverse effects in acute leukemia patients treated with intensive chemotherapy and concomitant G or GM-CSF. Rev Invest Clin 1999;51:7780.

    • Search Google Scholar
    • Export Citation
  • 48.

    Tsuchiya H, Adachi N, Asou N. Responses to granulocyte colony-stimulating factor (G-CSF) and granulocyte-macrophage CSF in Ph1-positive acute lymphoblastic leukemia with myeloid surface markers. Blood 1991;77:411413.

    • Search Google Scholar
    • Export Citation
  • 49.

    Jenkins CS, Ozer H, Parker JC. Mobilization of calla-positive lymphoblasts during treatment with granulocyte colony-stimulating factor [abstract]. Blood 1992;80:2944.

    • Search Google Scholar
    • Export Citation
  • 50.

    Shimoda K, Okamura S, Harada N. Granulocyte colony-stimulating factor receptors on human acute leukemia: biphenotypic leukemic cells possess granulocyte colony-stimulating factor receptors. Cancer Res 1992;52:30523055.

    • Search Google Scholar
    • Export Citation
  • 51.

    Shinjo K, Takeshita A, Ohnishi K, Ohno R. Granulocyte colony-stimulating factor receptor at various differentiation stages of normal and leukemic hematopoietic cells. Leuk Lymphoma 1997;25:3746.

    • Search Google Scholar
    • Export Citation
  • 52.

    Welte K, Reiter A, Mempel K. A randomized phase-III study of the efficacy of granulocyte colony-stimulating factor in children with high-risk acute lymphoblastic leukemia. Berlin-Frankfurt-Munster Study Group. Blood 1996;87:31433150.

    • Search Google Scholar
    • Export Citation
  • 53.

    Geissler K, Koller E, Hubmann E. Granulocyte colony-stimulating factor as an adjunct to induction chemotherapy for adult acute lymphoblastic leukemia—a randomized phase-III study. Blood 1997;90:590596.

    • Search Google Scholar
    • Export Citation
  • 54.

    Heil G, Chadid L, Hoelzer D. GM-CSF in a double-blind randomized, placebo controlled trial in therapy of adult patients with de novo acute myeloid leukemia (AML). Leukemia 1995;9:39.

    • Search Google Scholar
    • Export Citation
  • 55.

    Zittoun R, Suciu S, Mandelli F. Granulocyte-macrophage colony-stimulating factor associated with induction treatment of acute myelogenous leukemia: a randomized trial by the European Organization for Research and Treatment of Cancer Leukemia Cooperative Group. J Clin Oncol 1996;14:21502159.

    • Search Google Scholar
    • Export Citation
  • 56.

    Witz F, Sadoun A, Perrin MC. A placebo-controlled study of recombinant human granulocyte-macrophage colony-stimulating 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;91:27222730.

    • Search Google Scholar
    • Export Citation
  • 57.

    Hast R, Hellstrom-Lindberg E, Ohm L. No benefit from adding GM-CSF to induction chemotherapy in transforming myelodysplastic syndromes: better outcome in patients with less proliferative disease. Leukemia 2003;17:18271833.

    • Search Google Scholar
    • Export Citation
  • 58.

    Amadori S, Suciu S, Jehn U. Use of glycosylated recombinant human G-CSF (lenograstim) during and/or after induction chemotherapy in patients 61 years of age and older with acute myeloid leukemia: final results of AML-13, a randomized phase-III study. Blood 2005;106:2734.

    • Search Google Scholar
    • Export Citation
  • 59.

    Bradstock K, Matthews J, Young G. Effects of glycosylated recombinant human granulocyte colony-stimulating factor after high-dose cytarabine-based induction chemotherapy for adult acute myeloid leukaemia. Leukemia 2001;15:13311338.

    • Search Google Scholar
    • Export Citation
  • 60.

    Ifrah N, Witz F, Jouet JP. Intensive short term therapy with granulocyte-macrophage-colony stimulating factor support, similar to therapy for acute myeloblastic leukemia, does not improve overall results for adults with acute lymphoblastic leukemia. GOELAMS Group. Cancer 1999;86:14961505.

    • Search Google Scholar
    • Export Citation
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