The Washington Manual of Oncology, 3 Ed.

Growth Factor Support in Oncology

Melissa Rooney • Janelle Mann

 I. INTRODUCTION. Myelosuppression is one of the most common dose-limiting toxicities of cytotoxic agents. An understanding of hematopoiesis and the roles of growth factors can significantly improve complications of treatment. Hematopoiesis is the process of production multiplication and specialization of blood cells in the bone marrow. The proliferation and differentiation of the pluripotent stem cell to the myeloid and the lymphoid progenitors and the further differentiation of those to the mature circulating blood cells involve complex interaction of the stem cells, bone marrow stromal cells, and cytokines. The cytokines also activate the mature hematopoietic cells. Hematopoietic growth factors’ action and effect on cell lines are still not fully understood; however, some identified growth factors and potential therapeutic options are described later.

1. MYELOID GROWTH FACTORS
2. Granulocyte colony-stimulating factor (G-CSF)
3. Endogenous G-CSF. G-CSF is a glycoprotein secreted by monocytes, fibroblasts, and endothelial cells. It targets G-CSF receptors on myeloid precursor cells in the bone marrow, promotes the maturation of the granulocyte colony-forming unit to the polymorphonuclear leukocyte, and enhances neutrophil function.
4. Recombinant preparations (rHuG-CSF). Filgrastim (Neupogen and Granix) and pegfilgrastim (Neulasta) are the two currently available formulations of recombinant G-CSF in the United States. Filgrastim and pegfilgrastim function through the same mechanism of action promoting neutrophil proliferation, differentiation, and activation. Filgrastim has a half-life of 3.5 hours. Pegfilgrastim, which is a covalent conjugate of filgrastim and monomethoxypolyethylene glycol, has a prolonged half-life of 15 to 80 hours.
5. Recommended dose. The recommended dose of filgrastim is 5 µg/kg administered subcutaneously daily until an absolute neutrophil count (ANC) of 10,000/mm³ has been reached following a chemotherapy-induced nadir. When filgrastim is used following high-dose chemotherapy with autologous stem cell rescue, a higher dose of filgrastim of 10 µg/kg daily is recommended. When used in this setting, filgrastim should be continued until an ANC of 1,000/mm³ is reached on three consecutive days. The dose of filgrastim should then be reduced to 5 µg/kg subcutaneously daily until ANC remains >1,000/mm³ for three consecutive days at which therapy can be discontinued. When filgrastim is utilized in stem cell mobilization and collection prior to stem cell transplantation, filgrastim is administered at a dose of 10 µg/kg daily 4 days prior to apheresis and continued until the stem cell collection is complete. Of note, filgrastim should not be administered within 24 hours from the administration of cytotoxic chemotherapy because of the potential cellular toxicities to rapidly dividing myeloid cells. Filgrastim administration should also be avoided in patients receiving concurrent chemotherapy with radiation to the chest.

 Pegfilgrastim is administered at a dose of 6 mg given subcutaneously, one time 24 to 72 hours following the administration of chemotherapy, and at least 14 days prior to the initiation of subsequent doses of chemotherapy. The safety and efficacy of pegfilgrastim in the setting of concurrent chemotherapy and radiation have not been established. Pegfilgrastim is not currently indicated for stem cell mobilization (J Clin Oncol 2006;24:4451).

 Filgrastim and pegfilgrastim doses do not need to be adjusted for renal or hepatic function.

4. Adverse effects. The most common adverse reactions associated with the use of recombinant G-CSF include bone pain, fever, and injection-site reactions. Rare adverse reactions including splenic rupture, adult respiratory distress syndrome (ARDS), and alveolar hemorrhage have also been reported. In patients with sickle cell anemia, the use of recombinant G-CSF has been associated with severe and potentially fatal sickle cell crisis (Blood 2001;97:3998). Allergic reactions of varying severity are also described with the use of recombinant G-CSF.
5. Granulocyte–macrophage colony-stimulating factor (GM-CSF)
6. Endogenous GM-CSF. GM-CSF is a protein that stimulates stem cell precursors to produce all types of white blood cells including neutrophils, lymphocytes, eosinophils, basophils, and monocytes. GM-CSF also enhances neutrophil and monocyte/macrophage function.
7. Recombinant granulocyte–macrophage colony-stimulating factor (rHuGM-CSF). Sargramostim (Leukine) is the only rHuGM-CSF formulation available in the United States. Administration of rHuGM-CSF results in increased production, differentiation, and activation of neutrophils, eosinophils, monocytes, and macrophages. When administered subcutaneously, sargramostim has a half-life of 2.7 hours.
8. Recommended dose. The recommended dose of sargramostim is 250 µg/m²/day for all indicated treatment settings. Subcutaneous and intravenous dosing are available; however, subcutaneous dosing is the preferred route of administration. Sargramostim is indicated following induction chemotherapy for AML in adults ≥55 years old, engraftment failure or delay following bone marrow transplant, myeloid reconstitution following autologous or allogeneic bone marrow transplant, and stem cell mobilization. In the setting of primary prophylaxis of neutropenia in patients receiving chemotherapy, GM-CSF is administered off label, 24 to 72 hours after chemotherapy, and is discontinued once the ANC has recovered to 10,000/mm³ or the ANC is more than 1,500/mm³ for 3 days. GM-CSF is contraindicated 24 hours preceding and following chemotherapy and radiation therapy. Hepatic and renal function should be monitored closely during the administration of sargramostim.
9. Adverse effects. The most common adverse effects associated with sargramostim include fever, headaches, diarrhea, bone pain, myalgias, arthralgias, and injection-site reactions. Fluid retention manifested by edema, capillary leak syndrome, pleural effusion, and pericardial effusion have also been reported. Sargramostim is contraindicated in patients with myeloid blast counts exceeding 10% in the peripheral blood or bone marrow. Allergic reactions to sargramostim are uncommon, but severe anaphylactic reactions have been described. Sargramostim is contraindicated in patients with previous reactions to GM-CSF, other products derived from yeast, or any of the other ingredients used to make sargramostim. In addition, a rare constellation of symptoms consisting of respiratory distress, hypoxia, hypotension, flushing, and tachycardia may be seen following the first dose of sargramostim. The “first dose” reaction is treated with supportive care and does not typically recur with subsequent doses.
10. Clinical applications of myeloid growth factors. The current recommendations for the use of colony-stimulating factors are based on the 2005 American Society of Clinical Oncology (ASCO) clinical practice guidelines (J Clin Oncol 2006;24:3187).
11. Primary prophylaxis. An initial risk assessment for chemotherapy-induced neutropenic fever should be performed prior to the first cycle of chemotherapy. When performing a thorough risk assessment, factors including the patient’s underlying disease, planned chemotherapeutic drug regimen, treatment intent, and individual patient risk factors must be considered. Primary prophylaxis is recommended for chemotherapeutic regimens with a high risk (>20%) of inducing neutropenic fevers. A list of chemotherapeutic drug regimens associated with a >20% risk of neutropenic fevers are conveniently located in the NCCN guidelines on growth factor support. All dose-dense regimens require the use of growth factor support. In addition to considering the chemotherapeutic regimen, certain patient factors are known to predispose individuals to a higher rate of neutropenic fevers and include older age (>65 years old), poor performance status, poor nutritional status, prior chemotherapy or radiation, and comorbid conditions (renal dysfunction, liver dysfunction, recent infection, and recent surgery). In patients with high-risk features, primary prophylaxis may be considered in chemotherapeutic regimens with a risk of febrile neutropenia of less than 20%. Lastly, the treatment intent must be considered as growth factor support may avoid treatment delays in curative settings.
12. Secondary prophylaxis. For patients who experience a neutropenic complication from an earlier cycle of chemotherapy (for which primary prophylaxis was not administered), secondary prophylaxis with CSFs is recommended in situations in which dose reduction or delay may compromise disease-free survival, overall survival, or treatment outcomes.
13. Afebrile neutropenia. CSFs should not routinely be administered for afebrile patients with neutropenia.
14. Febrile neutropenia. The routine use of CSFs as an adjunct to antibiotic therapy in the setting of neutropenic fever is not currently recommended. The 2005 ASCO guidelines support the use of CSFs in patients with neutropenic fevers who are at high risk for infection-related complications (prolonged and profound neutropenia, age >65 years old, uncontrolled primary disease, pneumonia, hypotension, multiorgan dysfunction, invasive fungal infection, or development of fever during hospitalization). Additionally, the recently updated Infectious Disease Society of America (IDSA) guidelines from 2010 also do not recommend the routine use of CSFs as an adjunct to antibiotic therapy in neutropenic fever (Clin Infect Dis 2011;427).
15. Dose-dense/dose-intense regimens. Dose-dense/dose-intense regimens have been shown to increase disease-free and overall survival in the treatment of node-positive breast cancer, small cell lung cancer, and non-Hodgkin’s lymphoma. In those situations, it is appropriate to use CSFs to maintain the use of dose-dense/dose-intense chemotherapy regimen (J Clin Oncol 2006;24:3187).
16. Bone marrow transplant. CSFs are routinely used in conjunction with chemotherapy to mobilize peripheral stem cells. CSFs are recommended following autologous stem cell transplant, but not allogeneic stem cell transplant.
17. Acute myeloid leukemia (AML). The administration of CSFs following induction chemotherapy for AML can decrease the duration of neutropenia when begun shortly after chemotherapy; however, studies have not consistently shown a positive impact on the duration of hospitalization and incidence of severe infections. CSFs following induction chemotherapy in AML are considered reasonable, and may have the most benefit in patients over the age of 55 years old. In the setting of consolidative therapy for AML, CSFs are recommended following chemotherapy, as CSFs have convincingly been shown to decrease the incidence of infection and decrease hospitalization rates. There is also a more pronounced shortening of the duration of neutropenia following consolidative chemotherapy when compared with induction chemotherapy. There are currently no data surrounding the use of pegylated CSFs in patients with myeloid leukemias, and so their use in this setting is not recommended at this time. The use of CSFs for priming of leukemia cells is also not recommended.
18. Acute lymphoid leukemia (ALL). CSFs are recommended following the completion of induction or first postremission course of therapy as this has been shown to shorten the duration of neutropenia (<1,000/mm³) by approximately one week. Although G-CSF has been shown to shorten the duration of neutropenia, the data have not been consistent relating to G-CSFs’ effect on the duration of hospitalization, incidence of febrile neutropenia, or incidence of severe infections. G-CSF can be given concurrently with corticosteroids/antimetabolite therapies as the combination of drug therapies does not appear to prolong myelosuppression induced by chemotherapy.
19. Myelodysplastic syndromes. CSFs can increase ANC; however, there is no data supporting long-term continuous use. Intermittent administration may be considered in the subset of patients with severe neutropenia and recurrent infection.

 10. Concomitant chemoradiotherapy. CSFs should be avoided in patients receiving concurrent chemotherapy and radiation therapy, especially involving the mediastinum. CSF use can be considered in patients receiving radiation therapy alone, if prolonged treatment delays secondary to neutropenia are expected.

 III. ERYTHROID GROWTH FACTORS

1. Erythropoietin (EPO)
2. Endogenous EPO. EPO is a glycoprotein hormone that regulates red blood cell production by stimulating erythroid colony-forming units to proliferate and maturate, which is essential for erythroid cell maturation. Healthy individuals require 5 to 30 mU/mL of EPO to maintain a normal hemoglobin and hematocrit. Under normal circumstances, EPO increases in the setting of hypoxia or anemia. In patients receiving chemotherapy, inappropriately low and high concentrations of EPO can occur.
3. Recombinant erythropoietin (rHuEPO). Currently there are two preparations of recombinant EPO, erythropoiesis-stimulating agents (ESAs) available in the United States, epoetin alfa (Epogen and Procrit) and the hyperglycosylated recombinant EPO, darbepoetin alfa (Aranesp). ESAs exert their effect on erythroid progenitors, leading to induction, proliferation, and differentiation. This results in an increase in reticulocyte counts, followed by a rise in hematocrit and hemoglobin levels. Epoetin alfa has a half-life of approximately 16 to 67 hours when given subcutaneously compared with darbepoetin alfa that has a half-life of 24 to 144 hours for cancer patients.
4. Recommended dose. It is imperative to appropriately select patients for the use of ESA therapy given increased risks associated with the use of these products. On the basis of the 2010 ASCO/ASH guidelines and the FDA guidelines for ESA use, ESAs are recommended as a treatment option for chemotherapy-induced anemia and patients with an hgb≤10 g/dL (ASCO/ASH guidelines). In patients with a declining hemoglobin, ≤12 g/dL but ≥10 g/dL, initiation of ESA therapy should be determined by clinical circumstances. Patients must be enrolled in the FDA risk evaluation mitigation (REMS) program, APPRAISE, prior to initiating therapy.

 The recommended starting dose of epoetin is 150 U/kg subcutaneously three times weekly for 4 weeks, with a possible increase in dose level to 300 U/kg three times weekly for an additional 4 to 8 weeks in those who do not respond to the initial dose. An alternative weekly dosing regimen (40,000 U/week) based on common clinical practice may be considered, although this is supported by lower level evidence. Dose escalation to 60,000 U/week may also be considered in patients who do not respond to the initial dose. Darbepoetin alfa is also approved for the management of chemotherapy-induced anemia. The recommended starting dose for darbepoetin alfa is 2.25 µg/kg subcutaneously weekly or 500 µg subcutaneously once every 3 weeks. In the setting of inadequate response in hemoglobin (≤/5 1 g/dL increase and below 10 g/dL after initial 6 weeks), the dose should be increased to 4.5 µg/kg weekly. For the every 3-week regimen, there is no current recommendation to increase the dose.

 If the rate of hemoglobin increase is more than 1 g/dL in a 2-week period or hemoglobin reaches a level sufficient to avoid red blood cell transfusions, the dose of epoetin should be decreased by 25% and the dose of darbepoetin should be decreased by 40%.

 If the rise in hemoglobin is less than 1 g/dL at 8 weeks of treatment, the ESA should be discontinued, and an evaluation for iron deficiency and tumor progression should be considered.

 The dose of EPO should be withheld if hemoglobin exceeds a level sufficient to avoid red blood cell transfusion or 512 g/dL, and therapy can be restarted when the hemoglobin falls to 10 g/dL. When restarting epoetin alfa, reduce the previous dose by 25% and resume treatment with darbepoetin alfa with a 40% dose reduction.

4. Clinical indications. In patients with nonmyeloid malignancies, EPO is indicated for the treatment of anemia due to the effect of concomitantly administered chemotherapy. EPO therapy should be discontinued once chemotherapy is stopped, regardless of hemoglobin. The role of ESAs in anemia due to myelodysplastic syndrome is under debate, and ESAs are not currently FDA approved for these indications.
5. Adverse effects. Common adverse effects with EPO therapy include edema, high blood pressure, fever, headache, insomnia, rash, nausea, vomiting, injection-site reaction, arthralgia, myalgias, fatigue, cough, and dyspnea. Less commonly reported but potential adverse effects include chest pain, arrhythmia, diarrhea, seizure, and thromboembolic events. A rare but serious adverse event is antibody-mediated pure red cell aplasia (PRCA) leading to severe anemia. Patients who develop a loss of response to ESAs should be evaluated for PRCA, and these drugs should be discontinued. Additionally, iron deficiency is common during ESA administration, which is a result of the consumption of available iron stores and decline in transfusion rate.

 In 2007, the FDA required ESA therapy labeling changes to include a new black box warning. The black box warning indicates that ESAs can increase the risk of thromboembolic events, serious cardiovascular events, and death when administered to patients with a goal hemoglobin greater than 12 g/dL. Several studies have shown shortened time to tumor progression, specifically in patients with advanced breast, cervical, head and neck, lymphoid, and nonsmall cell lung cancer in patients receiving ESA therapy with a target hemoglobin ≥10 g/dL. (J Clin Oncol 2010:4996) Additionally, ESA therapy is no longer indicated for patients receiving myelosuppressive chemotherapy with curative intent owing to increased risk of thromboembolic events.

 As a requirement of the REMS program, access to these medications is restricted. Healthcare providers and hospitals must be enrolled in the ESA APPRISE Oncology Program to prescribe or dispense ESAs to patients with cancer.

 IV. PLATELET AND MEGAKARYOCYTIC GROWTH FACTORS

1. Thrombopoietin (TPO)
2. Endogenous TPO. TPO stimulates growth and maturation of megakaryocyte-erythroid progenitor cells into mature megakaryocytes. Normally 10¹¹ platelets are produced daily, with platelets having a lifespan of 8 to 9 days in circulation. TPO is produced in the liver primarily and is regulated through the TPO receptors available for binding on platelets (Transfusion 2002;42:321). In the setting of thrombocytopenia, TPO levels are high due to decreased production. Intermittent platelet transfusions in the thrombocytopenic patient may actually blunt the TPO response (N Engl J Med 1998;339:746).
3. TPO receptor agonist. The initial thrombopoietic agents were recombinant and pegylated human megakaryocyte growth factor. Although initially promising, development of antibodies against endogenous TPO resulted in refractory thrombocytopenia. Romiplostim (NPlate) and eltrombopag (Promacta) are synthetic second-generation platelet-stimulating agents that are currently FDA approved for the treatment of chronic idiopathic thrombocytopenia purpura (ITP), but may have a potential role for chemotherapy-induced thrombocytopenia. Second-generation agents are still under research and safety concerns still exist with these agents, including risk of thrombosis, rebound thrombocytopenia, and formation of bone marrow reticulin (Curr Opin Oncol 2008;20:690).
4. Oprelvekin (neumega). Interleukin (IL)-11 is a thrombopoietic growth factor that directly stimulates the proliferation of hematopoietic stem cells at various steps in the hematopoiesis process including the megakaryocyte progenitor cells, which induces megakaryocyte maturation resulting in increased platelet production. Oprelvekin, recombinant IL-11, was the first cytokine to reach the market with the indication of prevention of chemotherapy-induced thrombocytopenia. Early clinical trials in cancer patients have shown increased steady-state platelet counts and to reduce the risk of thrombocytopenia from chemotherapy (J Clin Oncol1997;15:3368). The dose is 50 µg/kg/day, given subcutaneously starting 24 hours after chemotherapy, until the postnadir platelet count is greater than 50,000/µL or 48 hours before beginning the next cycle of chemotherapy. Dose adjustments are recommended in patients with impaired renal function, CrCl
5. FUTURE DIRECTIONS. A better understanding of stem cell trafficking is essential to the development of newer agents that will potentiate the effects of the currently available CSFs. Newer EPO and TPO agonists are currently in development. Efforts are being made to develop oral, longer acting agents that could possibly be incorporated into the treatment of chemotherapy-induced anemia and thrombocytopenia.

SUGGESTED READINGS

Freifeld AG, Bow EJ, Sepkowitz KA, et al. Clinical practice guideline for the use of antimicrobial agents in neutropenic patients with cancer: 2010 Update by the Infectious Diseases Society of America. Clin Infect Dis 2011;52:427–431.

Levy B, Arnason JE, Bussel JB. The use of second-generation thrombopoietic agents for chemotherapy-induced thrombocytopenia. Curr Opin Oncol 2008;20:690–696.

Rizzo JD, Brouwers M, Hurley P, et al. American Soceity of Clinical Oncology/American Society of Hematology Clinical Practice Guideline Update on the Use of Epoetin and Darbepoetin in Adult Patients with Cancer. J Clin Oncol2010;28:4996–5010.

Smith TJ, Khatcheressian J, et al. Update of Recommendations for the Use of White Blood Cell Growth Factors: An Evidence-Based Clinical Practice Guidelines. J Clin Oncol 2006;24:3187–3205.