Long-Term Outcomes of Myeloid Growth Factor Treatment

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Myeloid growth factors are used to reduce myelotoxicity and the risk of infection after cancer chemotherapy and in patients with chronic neutropenia. This article addresses the long-term benefits and risks associated with granulocyte colony-stimulating factor (G-CSF) therapy in both settings. A systematic review of randomized controlled trials recently reported long-term outcomes regarding the risk of second malignancies and overall survival. Based on these studies, the risk for acute myeloid leukemia (AML) associated with known carcinogenic agents, such as chemotherapy, could not be distinguished from any risk associated with growth factor support. However, the enhanced delivery of chemotherapy dose intensity enabled by the use of G-CSF in these studies was associated with a significant reduction in all-cause mortality. Although some reduction in treatment-related mortality with G-CSF support may occur, the observed improvement in long-term survival likely relates to better disease control with more-intense G-CSF–supported chemotherapy. Myeloid growth factors have also been shown to benefit patients with severe chronic neutropenia. Almost all patients with cyclic, congenital, or idiopathic neutropenia experience response to G-CSFs. Treatment is titrated to determine a dose that provides a safe elevation in neutrophil counts. Reports have shown that patients can be maintained for years at the same dose after adjusting for growth and development. In congenital neutropenia, the inherent risk of developing myelodysplastic syndromes or AML requires careful monitoring, including routine blood counts and annual bone marrow examinations.

Correspondence: Gary H. Lyman, MD, MPH, Duke University Medical Center and the Duke Cancer Institute, 2424 Erwin Road, Suite 205, Durham, NC 27705. E-mail: Gary.Lyman@Duke.edu
  • 1

    Kuderer NM, Dale DC, Crawford J. Impact of primary prophylaxis with granulocyte colony-stimulating factor on febrile neutropenia and mortality in adult cancer patients receiving chemotherapy: a systematic review. J Clin Oncol 2007;25:31583167.

    • Search Google Scholar
    • Export Citation
  • 2

    Wittman B, Horan J, Lyman GH. Prophylactic colony-stimulating factors in children receiving myelosuppressive chemotherapy: a meta-analysis of randomized controlled trials. Cancer Treat Rev 2006;32:289303.

    • Search Google Scholar
    • Export Citation
  • 3

    Aapro MS, Bohlius J, Cameron DA. 2010 update of EORTC guidelines for the use of granulocyte-colony stimulating factor to reduce the incidence of chemotherapy-induced febrile neutropenia in adult patients with lymphoproliferative disorders and solid tumours. Eur J Cancer 2011;47:832.

    • Search Google Scholar
    • Export Citation
  • 4

    Crawford J, Armitage J, Balducci L. NCCN Clinical Practice Guidelines in Oncology for Myeloid Growth Factors. J Natl Compr Canc Netw 2009;7:6483.

    • Search Google Scholar
    • Export Citation
  • 5

    Smith TJ, Khatcheressian J, Lyman GH. 2006 update of recommendations for the use of white blood cell growth factors: an evidence-based clinical practice guideline. J Clin Oncol 2006;24:31873205.

    • Search Google Scholar
    • Export Citation
  • 6

    Castro GA, Church A, Pechet L. Leukemia after chemotherapy of Hodgkin's disease. N Engl J Med 1973;289:103104.

  • 7

    Preisler HD, Lyman GH. Acute myelogenous leukemia subsequent to therapy for a different neoplasm: clinical features and response to therapy. Am J Hematol 1977;3:209218.

    • Search Google Scholar
    • Export Citation
  • 8

    Crump M, Tu D, Shepherd L. Risk of acute leukemia following epirubicin-based adjuvant chemotherapy: a report from the National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol 2003;21:30663071.

    • Search Google Scholar
    • Export Citation
  • 9

    Kalaycio M, Rybicki L, Pohlman B. Risk factors before autologous stem-cell transplantation for lymphoma predict for secondary myelodysplasia and acute myelogenous leukemia. J Clin Oncol 2006;24:36043610.

    • Search Google Scholar
    • Export Citation
  • 10

    Le Deley MC, Suzan F, Cutuli B. Anthracyclines, mitoxantrone, radiotherapy, and granulocyte colony-stimulating factor: risk factors for leukemia and myelodysplastic syndrome after breast cancer. J Clin Oncol 2007;25:292300.

    • Search Google Scholar
    • Export Citation
  • 11

    Leone G, Pagano L, Ben-Yehuda D. Therapy-related leukemia and myelodysplasia: susceptibility and incidence. Haematologica 2007;92:13891398.

  • 12

    Patt DA, Duan Z, Fang S. Acute myeloid leukemia after adjuvant breast cancer therapy in older women: understanding risk. J Clin Oncol 2007;25:38713876.

    • Search Google Scholar
    • Export Citation
  • 13

    Praga C, Bergh J, Bliss J. Risk of acute myeloid leukemia and myelodysplastic syndrome in trials of adjuvant epirubicin for early breast cancer: correlation with doses of epirubicin and cyclophosphamide. J Clin Oncol 2005; 23:41794191.

    • Search Google Scholar
    • Export Citation
  • 14

    Hershman D, Neugut AI, Jacobson JS. Acute myeloid leukemia or myelodysplastic syndrome following use of granulocyte colony-stimulating factors during breast cancer adjuvant chemotherapy. J Natl Cancer Inst 2007;99:196205.

    • Search Google Scholar
    • Export Citation
  • 15

    Relling MV, Boyett JM, Blanco JG. Granulocyte colony-stimulating factor and the risk of secondary myeloid malignancy after etoposide treatment. Blood 2003;101:38623867.

    • Search Google Scholar
    • Export Citation
  • 16

    Lyman GH, Dale DC, Wolff DA. Acute myeloid leukemia or myelodysplastic syndrome in randomized controlled clinical trials of cancer chemotherapy with granulocyte colony-stimulating factor: a systematic review. J Clin Oncol 2010;28:29142924.

    • Search Google Scholar
    • Export Citation
  • 17

    Clark OA, Lyman GH, Castro AA. Colony-stimulating factors for chemotherapy-induced febrile neutropenia: a meta-analysis of randomized controlled trials. J Clin Oncol 2005;23:41984214.

    • Search Google Scholar
    • Export Citation
  • 18

    Dale DC, Guerry D, Werwerka JR. Chronic neutropenia. Medicine 1979;58:128144.

  • 19

    Welte K, Zeidler C. Severe congenital neutropenia. Hematol Oncol Clin North Am 2009;23:307320.

  • 20

    Boxer L, Dale DC. Neutropenia: causes and consequences. Semin Hematol 2002;39:7581.

  • 21

    Dale DC, Hammond WP. Cyclic neutropenia: a clinical review. Blood Rev 1988;2:178185.

  • 22

    Horwitz M, Benson KF, Person RE. Mutations in ELA2, encoding neutrophil elastase, define a 21-day biological clock in cyclic haematopoiesis. Nat Genetics 1999;23:433436.

    • Search Google Scholar
    • Export Citation
  • 23

    Dale DC, Person RE, Bolyard AA. Mutations in the gene encoding neutrophil elastase in congenital and cyclic neutropenia. Blood 2000;96:23172322.

    • Search Google Scholar
    • Export Citation
  • 24

    Klein C, Grudzien M, Appaswamy G. HAX1 deficiency causes autosomal recessive severe congenital neutropenia (Kostmann disease). Nat Genet 2007;39:8692.

    • Search Google Scholar
    • Export Citation
  • 25

    Dale DC, Link DC. The many causes of severe congenital neutropenia. N Engl J Med 2009;360:35.

  • 26

    Papadaki HA, Pontikoglou C. Pathophysiologic mechanisms, clinical features and treatment of idiopathic neutropenia. Expert Rev Hematol 2008;12:217229.

    • Search Google Scholar
    • Export Citation
  • 27

    Jakubowski AA, Souza L, Kelly F. Effects of human granulocyte colony-stimulating factor in a patient with idiopathic neutropenia. N Engl J Med 1989;320:3842.

    • Search Google Scholar
    • Export Citation
  • 28

    Hammond WP, Price TH, Souza LM, Dale DC. Treatment of cyclic neutropenia with granulocyte colony stimulating factor. N Engl J Med 1989;320:13061311.

    • Search Google Scholar
    • Export Citation
  • 29

    Bonilla MA, Gillio AP, Ruggeiro M. Effects of recombinant human granulocyte colony-stimulating factor on neutropenia in patients with congenital agranulocytosis. N Engl J Med 1989;320:15741580.

    • Search Google Scholar
    • Export Citation
  • 30

    Welte K, Zeidler C, Reiter A. Differential effects of granulocyte-macrophage colony-stimulating factor and granulocyte colony-stimulating factor in children with severe congenital neutropenia. Blood 1990;75:10561063.

    • Search Google Scholar
    • Export Citation
  • 31

    Imashuku S, Tsuchida M, Sasaki M. Recombinant human granulocyte-colony-stimulating factor in the treatment of patients with chronic benign granulocytopenia and congenital agranulocytosis (Kostmann's syndrome). Acta Paediatr 1992;81:133136.

    • Search Google Scholar
    • Export Citation
  • 32

    Dale DC, Bonilla MA, Davis MW. A randomized controlled phase III trial of recombinant human granulocyte colony-stimulating factor (filgrastim) for treatment of severe chronic neutropenia. Blood 1993;81:24962502.

    • Search Google Scholar
    • Export Citation
  • 33

    Dale DC, Cottle TE, Fier CJ. Severe chronic neutropenia: treatment and follow-up of patients in the Severe Chronic Neutropenia International Registry. Am J Hematol 2003;72:8293.

    • Search Google Scholar
    • Export Citation
  • 34

    Dale DC, Bolyard AA, Schwinzer BG. The Severe Chronic Neutropenia International Registry: 10-year follow-up report. Support Cancer Ther 2006;3:220231.

    • Search Google Scholar
    • Export Citation
  • 35

    Wright DG, Kenney RF, Oette DH. Contrasting effects of recombinant human granulocyte-macrophage colony-stimulating factor (CSF) and granulocyte CSF treatment on the cycling of blood elements in childhood-onset cyclic neutropenia. Blood 1994;84:12571267.

    • Search Google Scholar
    • Export Citation
  • 36

    Mori PG, Pasino M, Dufour C. Recombinant human granulocyte-macrophage colony-stimulating factor (rhGM-CSF) and rhG-CSF in the treatment of a child with severe chronic neutropenia. Blood 1994;84:32443245.

    • Search Google Scholar
    • Export Citation
  • 37

    Jones E, Bolyard AA, Dale DC. Quality of life in patients receiving granulocyte colony stimulating factor for treatment of severe chronic neutropenia. JAMA 1993;270:11321133.

    • Search Google Scholar
    • Export Citation
  • 38

    Rosenberg PS, Alter BP, Bolyard AA. Severe Chronic Neutropenia International Registry. The incidence of leukemia and mortality from sepsis in patients with severe congenital neutropenia receiving long-term G-CSF therapy. Blood 2006;107:46284635.

    • Search Google Scholar
    • Export Citation
  • 39

    Rosenberg PS, Zeidler C, Bolyard AA. Stable long-term risk of leukaemia in patients with severe congenital neutropenia maintained on G-CSF therapy. Br J Haematol 2010;150:196199.

    • Search Google Scholar
    • Export Citation
  • 40

    Rosenberg PS, Alter BP, Link DC. Neutrophil elastase mutations and risk of leukaemia in severe congenital neutropenia. Br J Haematol 2008;140:210213.

    • Search Google Scholar
    • Export Citation
  • 41

    DiMeglio LA, Bolyard AA, Marrero TM. The risk of low bone mineral density with long-term G-CSF therapy for severe chronic neutropenia [abstract]. Blood 2010;16:Abstract 634.

    • Search Google Scholar
    • Export Citation
  • 42

    Boxer LA, Bolyard AA, Marrero TM. Outcomes of pregnancies for women with severe chronic neutropenia with or without G-CSF treatment [abstract]. Blood 2010;16:635636.

    • Search Google Scholar
    • Export Citation
  • 43

    Choi SW, Boxer LA, Pulsipher MA. Stem cell transplantation in patients with severe congenital neutropenia with evidence of leukemic transformation. Bone Marrow Transplant 2005;35:473477.

    • Search Google Scholar
    • Export Citation
  • 44

    Carlsson G, Winiarski J, Ljungman P. Hematopoietic stem cell transplantation in severe congenital neutropenia. Pediatr Blood Cancer 2011;56:444451.

    • Search Google Scholar
    • Export Citation
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