The Role of Myeloid Growth Factors in Acute Leukemia

Myeloid growth factors granulocyte-colony stimulating and granulocyte macrophage colony-stimulating factors have been extensively studied in acute leukemias. Whether administered before, during, or after chemotherapy for acute myeloid leukemia and acute lymphoblastic leukemia, these agents reduce the duration of neutropenia and seem to be safe and well tolerated. Despite consistently showing a shorter duration of neutropenia, multiple, prospective, randomized trials have documented only modest benefits in terms of reduction in the incidence and severity of infections, without substantial gains or impact in complete remission, overall survival, and disease-free survival rates. Growth factors have also been used to recruit quiescent leukemia cells into the S-phase of the cell cycle to increase their susceptibility to chemotherapy with the goal to reduce relapse and resistance. Randomized trials evaluating this priming strategy have consistently shown improvement in disease- or event-free survival in the intermediate-risk group of patients with acute myeloid leukemia, but no overall survival benefit. This article focuses on the clinical experience with these agents as adjuncts to the treatment of acute leukemias.

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Correspondence: Martha Wadleigh, MD, Dana-Farber Cancer Institute, 44 Binney Street, Boston, MA 02115.E-mail: Martha_Wadleigh@DFCI.Harvard.edu

References

  • 1

    SmithTJKhatcheressianJLymanGH. 2006 update of recommendations for the use of white blood cell growth factors: an evidence-based clinical practice guideline. J Clin Oncol2006;24:31873205.

    • Search Google Scholar
    • Export Citation
  • 2

    BaerMRGeorgeSLDodgeRK. 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. Blood2002;100:12241232.

    • Search Google Scholar
    • Export Citation
  • 3

    StoneRMBergDTGeorgeSL. Granulocyte-macrophage colony-stimulating factor after initial chemotherapy for elderly patients with primary acute myelogenous leukemia. Cancer and Leukemia Group B. N Engl J Med1995;332:16711677.

    • Search Google Scholar
    • Export Citation
  • 4

    LowenbergBBoogaertsMADaenenSM. Value of different modalities of granulocyte-macrophage colony-stimulating factor applied during or after induction therapy of acute myeloid leukemia. J Clin Oncol1997;15:34963506.

    • Search Google Scholar
    • Export Citation
  • 5

    LowenbergBSuciuSArchimbaudE. 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. Blood1997;90:29522961.

    • Search Google Scholar
    • Export Citation
  • 6

    RoweJMAndersenJWMazzaJJ. 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). Blood1995;86:457462.

    • Search Google Scholar
    • Export Citation
  • 7

    ZittounRSuciuSMandelliF. 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 Oncol1996;14:21502159.

    • Search Google Scholar
    • Export Citation
  • 8

    AmadoriSSuciuSJehnU. 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-3 study. Blood2005;106:2734.

    • Search Google Scholar
    • Export Citation
  • 9

    GoldstoneAHBurnettAKWheatleyK. Attempts to improve treatment outcomes in acute myeloid leukemia (AML) in older patients: the results of the United Kingdom Medical Research Council AML11 trial. Blood2001;98:13021311.

    • Search Google Scholar
    • Export Citation
  • 10

    HeilGHoelzerDSanzMA. 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. Blood1997;90:47104718.

    • Search Google Scholar
    • Export Citation
  • 11

    GodwinJEKopeckyKJHeadDR. 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). Blood1998;91:36073615.

    • Search Google Scholar
    • Export Citation
  • 12

    DombretHChastangCFenauxP. 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 Med1995;332:16781683.

    • Search Google Scholar
    • Export Citation
  • 13

    BradstockKMatthewsJYoungG. Effects of glycosylated recombinant human granulocyte colony-stimulating factor after high-dose cytarabine-based induction chemotherapy for adult acute myeloid leukaemia. Leukemia2001;15:13311338.

    • Search Google Scholar
    • Export Citation
  • 14

    BennettCLStinsonTJLaverJH. Cost analyses of adjunct colony stimulating factors for acute leukemia: can they improve clinical decision making. Leuk Lymphoma2000;37:6570.

    • Search Google Scholar
    • Export Citation
  • 15

    Uyl-de GrootCALowenbergBVellengaE. Cost-effectiveness and quality-of-life assessment of GM-CSF as an adjunct to intensive remission induction chemotherapy in elderly patients with acute myeloid leukemia. Br J Haematol1998;100:629636.

    • Search Google Scholar
    • Export Citation
  • 16

    WitzFSadounAPerrinMC. 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). Blood1998;91:27222730.

    • Search Google Scholar
    • Export Citation
  • 17

    EsteyEHThallPFPierceS. Randomized phase II study of fludarabine + cytosine arabinoside + idarubicin +/– all-trans retinoic acid +/– granulocyte colony-stimulating factor in poor prognosis newly diagnosed acute myeloid leukemia and myelodysplastic syndrome. Blood1999;93:24782484.

    • Search Google Scholar
    • Export Citation
  • 18

    HarousseauJLWitzBLioureB. 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 Oncol2000;18:780787.

    • Search Google Scholar
    • Export Citation
  • 19

    CannistraSAGroshekPGriffinJD. Granulocyte-macrophage colony-stimulating factor enhances the cytotoxic effects of cytosine arabinoside in acute myeloblastic leukemia and in the myeloid blast crisis phase of chronic myeloid leukemia. Leukemia1989;3:328334.

    • Search Google Scholar
    • Export Citation
  • 20

    HiddemannWKiehlMZuhlsdorfM. 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 Oncol1992;19(2 Suppl 4):3137.

    • Search Google Scholar
    • Export Citation
  • 21

    BhallaKHolladayCArlinZ. Treatment with interleukin-3 plus granulocyte-macrophage colony-stimulating factors improves the selectivity of Ara-C in vitro against acute myeloid leukemia blasts. Blood1991;78:26742679.

    • Search Google Scholar
    • Export Citation
  • 22

    VellengaEYoungDCWagnerK. The effects of GM-CSF and G-CSF in promoting growth of clonogenic cells in acute myeloblastic leukemia. Blood1987;69:17711776.

    • Search Google Scholar
    • Export Citation
  • 23

    CannistraSADiCarloJGroshekP. Simultaneous administration of granulocyte-macrophage colony-stimulating factor and cytosine arabinoside for the treatment of relapsed acute myeloid leukemia. Leukemia1991;5:230238.

    • Search Google Scholar
    • Export Citation
  • 24

    FrenettePSDesforgesJFSchenkeinDP. Granulocyte-macrophage colony stimulating factor (GM-CSF) priming in the treatment of elderly patients with acute myelogenous leukemia. Am J Hematol1995;49:4855.

    • Search Google Scholar
    • Export Citation
  • 25

    RoweJMNeubergDFriedenbergW. 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. Blood2004;103:479485.

    • Search Google Scholar
    • Export Citation
  • 26

    RossiHAO’DonnellJSarcinelliF. Granulocyte-macrophage colony-stimulating factor (GM-CSF) priming with successive concomitant low-dose Ara-C for elderly patients with secondary/refractory acute myeloid leukemia or advanced myelodysplastic syndrome. Leukemia2002;16:310315.

    • Search Google Scholar
    • Export Citation
  • 27

    HofmannWKHeilGZanderC. Intensive chemotherapy with idarubicin, cytarabine, etoposide, and G-CSF priming in patients with advanced myelodysplastic syndrome and high-risk acute myeloid leukemia. Ann Hematol2004;83:498503.

    • Search Google Scholar
    • Export Citation
  • 28

    HeilGChadidLHoelzerD. GM-CSF in a double-blind randomized, placebo controlled trial in therapy of adult patients with de novo acute myeloid leukemia (AML). Leukemia1995;9:39.

    • Search Google Scholar
    • Export Citation
  • 29

    HastRHellstrom-LindbergEOhmL. No benefit from adding GM-CSF to induction chemotherapy in transforming myelodysplastic syndromes: better outcome in patients with less proliferative disease. Leukemia2003;17:18271833.

    • Search Google Scholar
    • Export Citation
  • 30

    ThomasXFenauxPDombretH. 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). Leukemia1999;13:12141220.

    • Search Google Scholar
    • Export Citation
  • 31

    LowenbergBvan PuttenWTheobaldM. Effect of priming with granulocyte colony-stimulating factor on the outcome of chemotherapy for acute myeloid leukemia. N Engl J Med2003;349:743752.

    • Search Google Scholar
    • Export Citation
  • 32

    ThomasXRaffouxEBottonS. Effect of priming with granulocyte-macrophage colony-stimulating factor in younger adults with newly diagnosed acute myeloid leukemia: a trial by the Acute Leukemia French Association (ALFA) Group. Leukemia2007;21:453461.

    • Search Google Scholar
    • Export Citation
  • 33

    KernWAulCMaschmeyerG. Granulocyte colony-stimulating factor shortens duration of critical neutropenia and prolongs disease-free survival after sequential high-dose cytosine arabinoside and mitoxantrone (S-HAM) salvage therapy for refractory and relapsed acute myeloid leukemia. German AML Cooperative Group. Ann Hematol1998;77:115122.

    • Search Google Scholar
    • Export Citation
  • 34

    HiddemannWKernWHeineckeA. Priming with G-CSF in acute myeloid leukemia: preliminary data of the AMLCG. Ann Hematol2004;83(Suppl 1):S5354.

    • Search Google Scholar
    • Export Citation
  • 35

    OhnoRTomonagaMOhshimaT. 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 Hematol1993;58:7381.

    • Search Google Scholar
    • Export Citation
  • 36

    LarsonRADodgeRKLinkerCA. A randomized controlled trial of filgrastim during remission induction and consolidation chemotherapy for adults with acute lymphoblastic leukemia: CALGB study 9111. Blood1998;92:15561564.

    • Search Google Scholar
    • Export Citation
  • 37

    WeiserMAO’BrienSThomasDA. Comparison of two different schedules of granulocyte-colony-stimulating factor during treatment for acute lymphocytic leukemia with a hyper-CVAD (cyclophosphamide, doxorubicin, vincristine, and dexamethasone) regimen. Cancer2002;94:285291.

    • Search Google Scholar
    • Export Citation
  • 38

    HofmannWKSeipeltGLangenhanS. Prospective randomized trial to evaluate two delayed granulocyte colony stimulating factor administration schedules after high-dose cytarabine therapy in adult patients with acute lymphoblastic leukemia. Ann Hematol2002;81:570574.

    • Search Google Scholar
    • Export Citation
  • 39

    BassanRLeredeTDi BonaE. Granulocyte colony-stimulating factor (G-CSF, filgrastim) after or during an intensive remission induction therapy for adult acute lymphoblastic leukaemia: effects, role of patient pretreatment characteristics, and costs. Leuk Lymphoma1997;26:153161.

    • Search Google Scholar
    • Export Citation
  • 40

    HolowieckiJGiebelSKrzemienS. G-CSF administered in time-sequenced setting during remission induction and consolidation therapy of adult acute lymphoblastic leukemia has beneficial influence on early recovery and possibly improves long-term outcome: a randomized multicenter study. Leuk Lymphoma2002;43:315325.

    • Search Google Scholar
    • Export Citation
  • 41

    GeisslerKKollerEHubmannE. Granulocyte colony-stimulating factor as an adjunct to induction chemotherapy for adult acute lymphoblastic leukemia—a randomized phase-III study. Blood1997;90:590596.

    • Search Google Scholar
    • Export Citation
  • 42

    OttmannOGHoelzerDGracienE. Concomitant granulocyte colony-stimulating factor and induction chemoradiotherapy in adult acute lymphoblastic leukemia: a randomized phase III trial. Blood1995;86:444450.

    • Search Google Scholar
    • Export Citation
  • 43

    KantarjianHMEsteyEHO’BrienS. Intensive chemotherapy with mitoxantrone and high-dose cytosine arabinoside followed by granulocyte-macrophage colony-stimulating factor in the treatment of patients with acute lymphocytic leukemia. Blood1992;79:876881.

    • Search Google Scholar
    • Export Citation
  • 44

    PapamichaelDAndrewsTOwenD. Intensive chemotherapy for adult acute lymphoblastic leukaemia given with or without granulocyte-macrophage colony stimulating factor. Ann Hematol1996;73:259263.

    • Search Google Scholar
    • Export Citation
  • 45

    IfrahNWitzFJouetJP. 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. Cancer1999;86:14961505.

    • Search Google Scholar
    • Export Citation

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