Colony-stimulating factors are glycoproteins that act on hematopoietic cells by binding to specific cell surface receptors and stimulating proliferation, differentiation commitment, and a degree of end-cell functional activation. Granulocyte colony-stimulating factor (G-CSF), produced by monocytes, fibroblasts, and endothelial cells, regulates the production of neutrophils within the bone marrow and affects neutrophil progenitor proliferation.[1,2] While G-CSF is relatively lineage-specific, granulocyte-macrophage colonystimulating factor (GM-CSF) functions at earlier stages of lineage commitment, regulating the expansion and maturation of primitive hematopoietic progenitors. The GM-CSF cell receptor is expressed on granulocyte, erythrocyte, megakaryocyte, and macrophage progenitor cells. GM-CSF principally affects proliferation, differentiation, and activation of granulocytes and macrophages by inducing partially committed progenitor cells to divide and differentiate in the granulocyte-macrophage pathways. GM-CSF also plays a vital role in hematopoiesis by enhancing numerous functional activities of mature effector cells (eg, neutrophils, monocytes, macrophages, dendritic cells) involved in antigen presentation and cell-mediated immunity.[4-7] G-CSF regulates both basal and neutrophil production and increased production and release of neutrophils from the marrow in response to infection. GM-CSF mediates its action on the neutrophil lineage through its effects on phagocytic accessory cells and its synergy with G-CSF. G-CSF and GM-CSF differ somewhat in the number and composition of peripheral blood progenitor cells (PBPCs) and effector cells mobilized to the peripheral blood. Filgrastim, Pegfilgrastim, and Sargramostim
Filgrastim (Neupogen) is a human G-CSF produced by recombinant DNA technology. It is indicated for the treatment of patients with severe, chronic neutropenia; receiving myelosuppressive chemotherapy or bone marrow transplant; undergoing PBPC collection and therapy; and for acute myelogenous leukemia (AML) patients receiving induction or consolidation chemotherapy. Pegfilgrastim (Neulasta) is a covalent conjugate of filgrastim and polyethylene glycol indicated for decreasing the incidence of infection in patients receiving myelosuppressive chemotherapy for nonmyeloid malignancies. Sargramostim (Leukine), a human GM-CSF produced by recombinant DNA technology in a yeast (Saccharomyces cerevisiae) expression system, was initially approved in the setting of bone marrow transplant. Although not labeled for chemotherapy-induced neutropenia, it has been demonstrated to increase the rate of neutrophil recovery following chemotherapy,[12,13] and is included in the American Society of Clinical Oncology's (ASCO) evidence-based clinical practice guidelines for this use. Among current clinical indications, sargramostim is given to shorten the duration of neutropenia following induction chemotherapy in older adults with AML; for myeloid reconstitution after autologous or allogeneic bone marrow transplantation (BMT); and for BMT failure or engraftment delay, to mobilize autologous PBPCs following transplantation. Emerging Data From Colony-Stimulating Factor Trials
G-CSF facilitates adherence to full dose intensity in both standard and doseintensified regimens. G-CSF support during combination chemotherapy (cisplatin, doxorubicin, cyclophosphamide [Cytoxan, Neosar]) to treat advanced or recurrent endometrial cancer allowed patients to remain on therapy for an average of 7 months, with no dose-limiting neutropenia. Once-per-cycle dosing of pegfilgrastim (pegylated recombinant filgrastim), a longer-acting version of G-CSF, has been evaluated in clinical trials using myelosuppressive chemotherapy in breast cancer, and has been demonstrated comparable in safety and efficacy to filgrastim for decreasing the duration of severe neutropenia after chemotherapy in patients with nonmyeloid malignancy.[18,19] An additional beneficial action of adjuvant G-CSF in premenopausal, nodepositive breast cancer patients has recently been proposed. G-CSF in this setting, in addition to stimulating blood stem cells, may activate and repopulate dormant breast cancer stem cells (personal communication, K. Altundag, 2004). The activated breast cancer stem cells may then become chemosensitive to various cell cycle-specific chemotherapeutic agents. Both G-CSF and GM-CSF play important roles in modern cancer treatment, and new data regarding their uses have the potential to impact the practice of oncology. Researchers are exploring new avenues of investigation to determine the antitumor potential of both of these agents. Data supporting the use of G-CSF as an antitumor agent have been largely anecdotal or retrospective. G-CSF may be useful in selected AML patients who are not candidates for traditional treatments, and complete remissions have been reported with G-CSF alone in the treatment of AML. A short course of G-CSF (300 mg/d for 13 days) resulted in complete hematologic remission in a patient with acute undifferentiated leukemia. Two further relapses in this patient were also successfully treated with G-CSF. The patient died 50 months after starting G-CSF therapy from progressive neutropenia, anemia, thrombocytopenia, and acute leukemia, despite reinstitution of G-CSF therapy. Leukemic cells from AML patients with the t(8;21) translocation undergo neutrophilic differentiation following in vitro exposure to G-CSF. A second patient with t(8;21) (q22;q22) karyotype AML achieved a complete remission when treated with G-CSF (10 μg/kg for 14 days), in the absence of cytotoxic chemotherapy. A third case report describes a patient who achieved cytogenetic remission after 14 days treatment with G-CSF (lenograstim 3 mg/kg/d). Peripheral blood and bone marrow aspirate were normal in this patient following treatment, and the t(9;11) + 8 clone was no longer detectable. No serious adverse events have been observed in the approximately 16 case reports of complete response achieved with G-CSF treatment of patients with AML. The mechanism by which G-CSF is able to induce leukemia remission is unknown. Among hypotheses are a direct effect of G-CSF on AML blast cells, degradation of AML1-ETO (an oncoprotein that blocks G-CSF-mediated cell differentiation in t(8;21) AML), the activation of STAT (signal transducers and activators of transcription) pathways on myeloid leukemic cells, and induction of leukemic cell apoptosis.[21,25-28] The role of G-CSF and GM-CSF in hematopoietic recovery and control of disease in patients with chemosensitive gynecologic cancer has been assessed in one trial. Thirty-seven ovarian cancer patients and 34 breast cancer patients were treated with high-dose chemotherapy (carboplatin [Paraplatin], etoposide, and melphalan [Alkeran]), and then randomly assigned to receive either 5 mg/kg of G-CSF or GM-CSF until day 13 after PBPC transplantation. Significantly higher T-cell counts were observed in G-CSF-treated patients during early and late posttransplant follow-up, and patients who received G-CSF showed a significantly longer median time to progression. Data supporting the use of GM-CSF (sargramostim), either alone or in combination with chemotherapy, continue to emerge. The articles in this supplement examine the role of this key cytokine in a variety of clinical settings, based on presentations from the ASCO 40th Annual Meeting, held June 5-8, 2004, in New Orleans. GM-CSF Use in AML
Successful treatment of AML requires the control of bone marrow and systemic disease and specific treatment of central nervous system disease, if present. The cornerstone of this strategy includes systemically administered combination chemotherapy, which poses a particular problem for some patient populations (for example, the induction mortality rate is especially high among older adults with AML).[30,31] Extending survival in this group of patients is therefore an area of active clinical research, and cytokines continue to be used to prime AML blasts to the cytotoxic actions of chemotherapy. Response rate, overall survival, and relapsefree survival are improved in elderly, high-risk patients with AML and myelodysplastic syndrome when G-CSF priming precedes intensive chemotherapy. In this supplement, Eric Winer et al report a trial of GM-CSF used to enhance the cytoreductive effects of low-dose cytarabine in elderly patients with AML and myelodysplastic syndrome who were intolerant of conventional induction chemotherapy. Colony-Stimulating Factors in Melanoma
The outcome of therapy for metastasized melanoma remains poor. Biochemotherapy- combination chemotherapy and biotherapy-appears to have a higher response rate than single-agent or combination regimens.[33-36] Patients with metastatic melanoma have been treated with paclitaxel and dacarbazine, with G-CSF added to allow escalated doses while limiting toxicity.[37,38] A recent phase II trial demonstrated that initial starting doses of paclitaxel and dacarbazine, in combination, could be elevated from 135 and 800 mg/m2, respectively, to 250 and 1,000 mg/m2 when G-CSF was included to limit myelosuppression in patients with advanced malignant melanoma. One of the most potentially important activities of GM-CSF in the setting of malignant melanoma is its ability to activate macrophages, causing them to become cytotoxic for human melanoma cells at doses low enough to avoid the toxicity associated with interleukin-2 (IL-2), a cytokine commonly used in treatment.[40- 42] GM-CSF may provide an antitumor effect that prolongs disease-free and overall survival in patients with stage III/IV melanoma who are clinically diseasefree,[ 40] and investigation of GM-CSF for the treatment of advanced malignant melanoma remains active.[43-45] To take advantage of the different functions but complementary actions of GM-CSF and IL-2, E. George Elias et al conducted a phase II trial of this combination as adjuvant treatment of cutaneous melanoma in high-risk patients. Continuing this theme, John Fruehauf and colleagues performed a pilot study of the DVS regimen (docetaxel [Taxotere], vinorelbine [Navelbine], sargramostim) for the treatment of patients with stage IV melanoma, either following initial biochemotherapy or as first-line treatment. Results of both of these trials are reported within. GM-CSF in Breast and Female Genital Tract Cancer
Reported in this supplement, Christian Kurbacher and colleagues conducted a trial in which the safety and efficacy of chronic, low-dose, salvage GM-CSF were evaluated in heavily pretreated patients with chemotherapy-refractory carcinomas of the breast or female genital tract cancer. Their findings imply that GM-CSF has a pleiotropic effect in these tumors by both activating the dendritic cell-mediated antitumor response and directly inducing growth arrest by stimulating intratumoral GM-CSF receptors. Conclusion
Both G-CSF and GM-CSF are cytokines with a crucial role as a component of different combination regimens used for the immunotherapy or biochemotherapy of malignancies. As results from the clinical trials reported in this supplement suggest, GM-CSF may well have clinical benefits beyond enhancing neutrophil recovery. While encouraging, these results must be augmented by further study of the immunologic function of GM-CSF and its therapeutic applications in the treatment of cancer. Many research questions remain regarding specific immune modulation with this agent, including an optimal dosing schedule and its combination with other agents and the specific mechanism of effect. Future clinical trials exploring the extent to which the addition of GM-CSF to current anticancer therapies can improve outcomes and produce less toxicity will help to answer these questions.
Dr. Disis has received grants and/or research support from 3M Pharmaceuticals and GlaxoSmithKline. She has served as a consultant to Dendreon Corporation, Protiva, Merck, and Thereon.
1. Welte K, Bonilla MA, Gillio AP, et al: Recombinant human G-CSF: Effects on hematopoiesis in normal and cyclophosphamide treated primates. J Exp Med 165:941-948, 1987.
2. Duhrsen U, Villeval JL, Boyd J, et al: Effects of recombinant human granulocyte colonystimulating factor on hematopoietic progenitor cells in cancer patients. Blood 72:2074-2081, 1988.
3. Barreda DR, Hanington PC, Belosevic M: Regulation of myeloid development and function by colony stimulating factors. Dev Comp Immunol 28:509-514, 2004.
4. DiPersio JF, Hedvat C, Ford CF, et al: Characterization of the soluble human granulocytemacrophage colony stimulating factor receptor complex. J Biol Chem 266:279-286, 1991.
5. Park LS, Friend D, Gillis S, et al: Characterization of the cell surface receptor for human granulocyte/macrophage colony stimulating factor. Exp Med 164:251-262, 1986.
6. Santiago-Schwarz F, Divaris N, Kay C, et al: Mechanisms of tumor necrosis factor-granulocytemacrophage colony stimulating factor-induced dendritic cell development. Blood 82:3019-3028, 1993.
7. Armitage JO: Emerging applications of recombinant human granulocyte-macrophage colonystimulating factor. Blood 92:4491-4508, 1998.
8. Glaspy JA: Hematopoietic management in oncology practice. Part 1. Myeloid growth factors. Oncology (Huntingt) 17:1593-1603, 2003.
9. Gazitt Y: Comparison between granulocyte colony-stimulating factor and granulocyte-macrophage colony-stimulating factor in the mobilization of peripheral blood stem cells. Curr Opin Hematol 9:190-198, 2002.
10. Neupogen (filgrastim) prescribing information, 2002.
11. Neulasta (pegfilgrastim) prescribing information, 2002.
12. Jones SE, Schottstaedt MW, Duncan LA, et al: Randomized double-blind prospective trial to evaluate the effects of sargramostim versus placebo in a moderate-dose fluorouracil, doxorubicin, and cyclophosphamide adjuvant chemotherapy program for stage II and III breast cancer. J Clin Oncol 14:2976-2983, 1996.
13. Beveridge RA, Miller JA, Kales AN, et al: A comparison of efficacy of sargramostim (yeastderived RhuGM-CSF) and filgrastim (bacteria-derived RhuG-CSF) in the therapeutic setting of chemotherapy-induced myelosuppression. Cancer Invest 16:366-373, 1998.
14. Ozer H, Armitage JO, Bennett CL, et al: 2000 update of recommendations for the use of hematopoietic colony-stimulating factors: Evidence-based, clinical practice guidelines. American Society of Clinical Oncology Growth Factors Expert Panel. J Clin Oncol 18:3558-3585, 2000.
15. Leukine (sargramostim) prescribing information, 2003.
16. Frasci G: Treatment of breast cancer with chemotherapy in combination with filgrastim: Approaches to improving therapeutic outcome. Drugs 62(suppl 1):17-31, 2002.
17. Hall DJ, Martin DA, Kincaid K: Filgrastim support during combination chemotherapy using cisplatin, doxorubicin, and cyclophosphamide to treat advanced or recurrent endometrial cancer: A clinical study and literature review. Eur J Gynaecol Oncol 24:481-489, 2003.
18. Wolf T, Densmore JJ: Pegfilgrastim use during chemotherapy: Current and future applications. Curr Hematol Rep 3:419-423, 2004.
19. Crawford J: Once-per-cycle pegfilgrastim (Neulasta) for the management of chemotherapyinduced neutropenia. Semin Oncol 30(suppl 13):24-30, 2003.
20. Altundag K, Altundag O, Elkiran ET, et al: Addition of granulocyte-colony stimulating factor (G-CSF) to adjuvant treatment may increase survival in patients with operable breast cancer: Interaction of G-CSF with dormant micrometastatic breast cancer cells. Med Hypotheses 63:56-58, 2004.
21. Xavier L, Cunha M, Goncalves C, et al: Hematological remission and long term hematological control of acute myeloblastic leukemia induced and maintained by granulocyte-colony stimulating factor (G-CSF) therapy. Leuk Lymphoma 12:2137-2142, 2003.
22. Löwenberg B, Touw IP: Hematopoietic growth factors and their receptors in acute leukemia. Blood 81:281-292, 1993.
23. Ferrara F, Schiavone EM, Palmieri S, et al: Complete remission induced by G-CSF in a patient with acute myeloid leukemia with t(8;21)(q22;q22). Hematol J 4:218-221, 2003.
24. Piccaluga PP, Martinelli G, Malagola M, et al: 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. Haematologica 88:ECR28, 2003.
25. DaSilva N, Meyer-Monard S, Meno ML, et al: Functional G-CSF pathways in t(8;21) leukemic cells allow for differentiation and degradation of AML1-ETO. Hematol J 1:316-328, 2000.
26. DaSilva N, Meyer-Monard S, Meno ML, et al: G-CSF activates STAT pathways in Kasumi-1 myeloid leukemic cells with the t(8;21 translocation: Basis for potential therapeutic efficacy. Cytokines Cell Mol Ther 3:75-80, 1997.
27. Muroi K, Hatake K, Yoshida M, et al: Remission induction in acute myeloid leukemia by granulocyte colony-stimulating factor: Differentiation or apoptosis? Leuk Lymphoma 20:355-356, 1996.
28. Fujiwara H, Arma N, Matsushita K, et al: Granulocyte-colony stimulating factor induces differentiation and apoptosis of CD2, CD7 positive hybrid leukemia cells in vivo and ex vivo. Leuk Res 21:735-741, 1997.
29. Pierelli L, Perillo A, Ferrandina G, et al: The role of growth factor administration and T-cell recovery after peripheral blood progenitor cell transplantation in the treatment of solid tumors: Results from a randomized comparison of G-CSF and GM-CSF. Transfusion 41:1577-1585, 2001.
30. Bow EJ, Sutherland JA, Kilpatrick MG, et al: Therapy of untreated acute myeloid leukemia in the elderly: Remission-induction using a non-cytarabine-containing regimen of mitoxantrone plus etoposide. J Clin Oncol 14:1345-52, 1996.
31. Amadori S, Suciu S, Willemze R, et al: Sequential administration of gemtuzumab ozogamicin and conventional chemotherapy as first line therapy in elederly patients with acute myeloid leukemia: A phase II study (AML-15) of the EORTC and GIMEMA leukemia groups. Haematologica 89:950- 956, 2004.
32. Hofmann WK, Heil G, Zander C, et al: Intensive chemotherapy with idarubicin, cytarabine, etoposide, and G-CSF priming in patients with advanced myelodysplastic syndrome and high-risk acute myeloid leukemia. Ann Hematol 83:498-503, 2004.
33. Legha SS: Durable complete responses in metastatic melanoma treated with interleukin-2 in combination with interferon alpha and chemotherapy. Semin Oncol 24:S39-S43, 1997.
34. Legha SS, Ring S, Eton O, et al: Development of a biochemotherapy regimen with concurrent administration of cisplatin, vinblastine, dacarbazine, interferon alfa, and interleukin-2 for patients with metastatic melanoma. J Clin Oncol 16:1752-1759, 1998.
35. Richards JM, Mehta N, Ramming K, et al: Sequential chemoimmunotherapy in the treatment of metastatic melanoma. J Clin Oncol 10:1338-1343, 1992.
36. Richards JM, Gale D, Mehta N, et al: Combination of chemotherapy with interleukin-2 and interferon alfa for the treatment of metastatic melanoma. J Clin Oncol 17:651-657, 1999.
37. Einzig AI, Wiernik PH, Wadler S, et al: Phase I study of paclitaxel (Taxol) and granulocyte colony stimulating factor (G-CSF) in patients with unresectable malignancy. Invest New Drugs 16:29- 36, 1998.
38. Buter J, Sleijfer DT, Willemse PH, et al: Dose escalation of dacarbazine combined with interferon alpha-2a, G-CSF and ondansetron in patients with metastatic melanoma. Anticancer Res 14:1325-1328, 1994.
39. Feun LG, Savaraj N, Hurley J, et al: Phase II trial of paclitaxel and dacarbazine with filgrastim administration in advanced malignant melanoma. Cancer Invest 20:357-361, 2002.
40. Spitler LE, Grossbard ML, Ernstoff MS, et al: Adjuvant therapy of stage III and IV malignant melanoma using granulocyte-macrophage colony-stimulating factor. J Clin Oncol 18:1614-1621, 2000.
41. Grabstein KH, Urdal DL, Tushinski RJ, et al: Induction of macrophage tumoricidal activity by granulocyte-macrophage colony-stimulating factor. Science 232:506-508, 1986.
42. Thomassen MJ, Barna BP, Rankin D, et al: Differential effect of recombinant granulocyte macrophage colony-stimulating factor on human monocytes and alveolar macrophages. Cancer Res 49:4086-4089, 1989.
43. Smith JW, Kurt RA, Baher AG, et al: Immune effects of escalating doses of granulocytemacrophage colony-stimulating factor added to a fixed, low-dose, inpatient interleukin-2 regimen: A randomized phase I trial in patients with metastatic melanoma and renal cell carcinoma. J Immunother 26:130-138, 2003.
44. Groenewegen G, Bloem A, De Gast GC: Phase I/II study of sequential chemoimmunotherapy (SCIT) for metastatic melanoma: Outpatient treatment with dacarbazine, granulocyte-macrophage colony-stimulating factor, low-dose interleukin-2, and interferon-alpha. Cancer Immunol Immunother 51:630-636, 2002.
45. O'Day SJ, Boasberg PD, Piro L, et al: Maintenance biotherapy for metastatic melanoma with interleukin-2 and granulocyte macrophage-colony stimulating factor improves survival for patients responding to induction concurrent biochemotherapy. Clin Cancer Res 8:2775-2781, 2002.