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Current Opinion in Hematology:
doi: 10.1097/MOH.0b013e32834e3c6e
MYELOID BIOLOGY: Edited by David C. Dale

Twenty years of the colony-stimulating factors

Dale, David C.

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University of Washington, 1959 NE Pacific Street, Seattle, Washington, USA

Correspondence to David C. Dale, MD, Professor of Medicine, Campus Box 356422, 1959 NE Pacific Street, Seattle, WA 98195, USA. E-mail: dcdale@u.washington.edu

Twenty years ago the colony-stimulating factors (CSFs) were approved for use in the prevention of neutropenia – granulocyte colony-stimulating factor (G-CSF) to prevent chemotherapy-induced neutropenia and granulocyte-macrophage colony-stimulating factor (GM-CSF) to accelerate marrow recovery after bone marrow transplantation. This development was preceded by three decades of work – from the discovery of the CSFs, through the cloning of the genes for the hematopoietic growth factors, and scaling up production to make clinical uses feasible [1]. Two decades later it is easy to see their enormous impact on the care of our patients.

Twenty years ago, chemotherapy-induced neutropenia was the dose-limiting adverse effect of cancer chemotherapy, and it still is today. The difference is that the problem can now be better managed chiefly because of the potency of G-CSF to accelerate marrow recovery if given 1–3 days after the myelotoxic chemotherapy. After the initial pivotal trials, several years of research were needed to establish indications and guidelines for appropriate use, and these guidelines have needed regular updates to match changes in cancer treatment regimens [2–4]. A key concept now is that myeloid growth factor treatment should be determined based on patient-specific risk factors – the nature of the patient's underlying disease, the myelotoxicity of the planned chemotherapy and the health status and comorbidities of the patient [4]. Recent evidence from meta-analyses indicates that G-CSF can both prevent febrile neutropenia during the period of chemotherapy and facilitate more intense chemotherapy for better cancer treatment outcomes [5,6].

The use of the CSFs for the treatment of chronic neutropenia has had a parallel history. In the late 1980s, several small trials suggested that they might be of use as long-term therapies for neutropenia. A randomized trial of G-CSF for treatment of cyclic, congenital and idiopathic neutropenia then established its effectiveness to correct neutropenia and prevent infections in this population [7]. The Severe Chronic Neutropenia International Registry has prospectively followed the patients from the initial trials and additional patients to show the long-term effectiveness of this therapy [8]. This registry also provided the clinical information for an increasingly precise description of the rare hematological diseases causing severe chronic neutropenia and the discovery of the specific causal genetic defects.

One of the challenging issues with use of the CSFs is whether they can cause myelodysplasia or leukemia. Twenty years has not answered this question, because it is so difficult to study. With cancer chemotherapy, we know that many of the standard agents used are both myelotoxic and leukemogenic. Because the CSFs permit more intensive therapy, it might be expected that combining CSFs with more myelotoxic treatments would be associated with greater risk. This indeed was the finding in a recent study, the same study that showed that, overall, more intensive chemotherapy with CSF support promoted long-term survival [9]. In patients with severe chronic neutropenia, one patient group, those with severe congenital neutropenia, who are known to have an intrinsic risk of leukemia, had about a 20% risk of developing myelodysplasia (MDS) or acute myeloid leukemia (AML) with long-term G-CSF treatment [10]. Other patient groups showed no apparent risk of MDS or AML with long-term G-CSF therapy. Current evidence suggests that the risk of AML associated with CSF administration must be small, but it is difficult to envision how a definitive study will ever be conducted.

To be sure, many questions remain about the CSFs: appropriate use, cost benefits, combinations, adverse effects, alternatives and bio-similars. Nevertheless, twenty years after their introduction the CSFs have become an integral part of the practice of hematology and oncology.

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Acknowledgements

None.

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Conflicts of interest

D.C.D. is a consultant for Amgen, the manufacturer of G-CSF, and conducts research on neutropenia with the support of Amgen and the National Institutes of Health.

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REFERENCES

1. Metcalf D. Hematopoietic cytokines. Blood 2008; 111:485–491.

2. Smith TJ, Khatcheressian J, Lyman GH, et al. 2006 Update of recommendations for the use of white blood cell growth factors: an evidence-based clinical practice guideline. J Clin Oncol 2006; 24:3187–3205.

3. Crawford J, Armitage J, Balducci L, et al. Myeloid growth factors. J Natl Compr Canc Netw 2009; 1:64–83.

4. Aapro MS, Bohlius J, Cameron DA, et al. European Organisation for Research and Treatment of Cancer. 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; 47:8–32.

5. Kuderer NM, Dale DC, Crawford J, et al. 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; 25:3158–3167.

6. Lyman GH, Dale DC. Long-term outcomes of myeloid growth factor treatment. J Natl Compr Canc Netw 2011; 8:945–952.

7. Dale DC, Bonilla MA, Davis MW, et al. A randomized controlled phase III trial of recombinant human granulocyte colony-stimulating factor (Filgrastim) for treatment of severe chronic neutropenia. Blood 1993; 81:2496–2502.

8. Dale DC, Bolyard AA, Schwinzer BG, et al. The Severe Chronic Neutropenia International Registry: 10-year follow-up report. Support Cancer Ther 2006; 3:220–231.

9. Lyman GH, Dale DC, Wolff DA, et al. 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; 17:2914–2924.

10. Rosenberg PS, Zeidler C, Bolyard AA, et al. Stable long-term risk of leukaemia in patients with severe congenital neutropenia maintained on G-CSF therapy. Br J Haematol 2010; 150:196–199.

© 2012 Lippincott Williams & Wilkins, Inc.

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