Over the past 25 years, a new class of drugs has become available to boost marrow function: the hematopoietic growth factors (HGFs). These growth factors are a major triumph for recombinant technology. Available HGFs are erythropoietin (EPO) to increase red blood cell (RBC) production, granulocyte colony-stimulating factor (G-CSF) and granulocyte-macrophage colony-stimulating factor (GM-CSF) to increase granulocyte production, and thrombopoietin agonists to increase platelet numbers. Other HGFs in clinical trials for which published data exist are stem cell factor, macrophage CSF (M-CSF), IL-3, and thrombopoietin (TPO). Because these HGFs are costly and may have side effects, careful patient selection is necessary for their use and requires completion of a search for correctable causes for the cytopenia. However, all patients on chemotherapy whose blood count drops may become eligible for the use of HGFs. Appropriate use for these agents is discussed in this chapter.

National guidelines for G-CSF and GM-CSF have been published by the American Society of Clinical Oncology (ASCO)¹ and a joint American Society of Hematology (ASH)-ASCO guideline has been published for the use of EPO.² These guidelines have been regularly updated.

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Definition

The HGFs are chemicals, generally cytokines and interleukins, that interact with developing immature marrow cells and lead to greater numbers of red cells, white cells, or platelets or combinations of these. The locations of the genes responsible for the HGFs are known: chromosome 7 for EPO; the long arm of chromosome 5 for GM-CSF, IL-3, M-CSF, and the M-CSF receptor; and chromosome 17 for G-CSF.

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Pathophysiology

Hypoxia stimulates EPO production by the peritubular cells of the kidney. T lymphocytes, endothelial cells, fibroblasts, the liver, and monocytes-macrophages are the sources of the other HGFs. Various stimuli lead to increased levels of these growth factors. For example, endotoxin causes monocytes to release G-CSF and GM-CSF. Tumor necrosis factor alpha and IL-1, both formed and released by activated monocytes, stimulate endothelial cells and fibroblasts to produce greater amounts of GM-CSF and G-CSF.³

These cytokines interact with specific receptors on target cells. EPO binds to EPO receptors on committed RBC precursors; GM-CSF and IL-3 bind to receptors on early granulocyte precursors; and G-CSF binds to receptors on slightly more mature, committed granulocyte precursors.³ TPO interacts with megakaryocytes and stimulates their numbers and ability to produce greater numbers of platelets.

The HGFs also have a role in potentiating the effects of mature cells. Both GM-CSF and G-CSF increase the functionality of granulocytes, such as in killing microbes and tumor cells. GM-CSF inhibits neutrophil migration; G-CSF does not.³

Two different forms of TPO were used in clinical trials: a native molecule and a pegylated truncated form. Both are potent stimulators of thrombopoiesis and increase platelet numbers quickly after chemotherapy. However, these HGF forms seem to stimulate the production of neutralizing antibodies, sometimes leading to an immune thrombocytopenic purpura-like state and even to an immune panhypoplasia.⁴ This has led to the development of TPO mimetics, and two are commercially available. Use of EPO has also been associated with the development of neutralizing antibodies, leading to pure red cell aplasia.⁵

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Signs and Symptoms

HGFs owe their success to their alleviation of cytopenia. Renal failure patients on dialysis were universally anemic before the advent of commercial EPO and required transfusions. The signs and symptoms of anemia (e.g., tiredness, dizziness, feeling cold, “I can hardly move my legs”) are improved with an increase in the hemoglobin (Hgb) level.

The growth of quality-of-life research has been an epiphenomenon of the commercialization of EPOs. For a patient undergoing chemotherapy, measuring the associated debilitating fatigue became the focus of scientific investigation. Measuring tools, such as the Functional Assessment of Cancer-Anemia (FACT-An) and the Linear Analogue Self-Assessment—Anemia (LASA), were developed.² Other issues included the following:

• Should EPO begin simultaneously with chemotherapy?
• Should EPO be given once the falling Hgb level reaches 13, 12, 11, 10, or 9 g/dL?
• Should a patient’s Hgb level be allowed to rise with EPO to 12, 13, or 14 g/dL?
• Should iron replacement be administered and, if so, should it be IV or oral? (The role of iron in maintaining an EPO response has been studied.)

During the years leading up to 2007, there came to be increasing concern about tumor progression and shorter survival in EPO-treated cancer patients and a greater frequency of venous thromboembolic disease in EPO-treated subjects if the Hgb rose much above 10 g/dL. These data led the FDA to revise labeling contraindicating EPO for use in the adjuvant settings or in cancer patients not undergoing chemotherapy or radiation therapy. Also, Medicare and Medicaid will not reimburse for the use of EPO unless the Hgb is below 10 g/dL, and its use is only recommended to continue until the Hgb rises to >10 g/dL and “to avoid the need for transfusion.” Historically, EPO was given three times weekly, then once-weekly. Newer forms of long acting EPO led to every 2-or3-week dosing.

A major dose-limiting side effect of chemotherapy is febrile neutropenia. The degree of neutropenia will depend on several factors, including previous radiation the patient may have received, the dose intensity of chemotherapy treatments, and any comorbidities. Fever is usually the first clinical symptom of infection. A patient on chemotherapy who presents with an absolute neutrophil count lower than 500/µL and is febrile (>38° C) is usually admitted to the hospital for at least 2 days of IV antibiotics, until it is certain that initial blood cultures are negative. The prophylactic use of G-CSF or GM-CSF is more beneficial than using these HGFs at the point of febrile neutropenia.

Chemotherapy also can lead to severe thrombocytopenia and increased bleeding risk. For leukemia patients, it was believed that platelet transfusions should begin when the platelet count reaches 20,000/µL.⁶ Since then, trials have demonstrated that, in the absence of ongoing disseminated intravascular coagulation or fever, the platelet transfusion trigger could drop to 10,000/µL. The outpatient management of these patients usually involves frequent visits to receive platelet transfusions. Presently, TPO mimetics have not been shown to abrogate the duration of thrombocytopenia secondary to chemotherapy. Their use is only FDA approved to improve the thrombocytopenia of immune thrombocytopenic purpura (ITP).

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Diagnosis

The results of the complete blood cell count, differential, and platelet count indicate anemia, neutropenia, or thrombocytopenia; however, the proper workup in patients is important, even for those on chemotherapy. Not every patient on chemotherapy becomes anemic because of the chemotherapeutic effect on marrow, and the treating physician should not automatically prescribe exogenous erythropoietin. The following often should be checked:

• stool guaiac status, to ensure that gastrointestinal bleeding is not starting;
• peripheral smear, to search for the development of schistocytes, as might be seen in disseminated intravascular coagulation;
• Coombs’ testing, especially in lymphoma or chronic lymphocytic leukemia (CLL) patients, to ensure that immune hemolysis is not starting;
• nutrient status (i.e., iron, vitamin B12, and folate levels), to maintain normal levels as much as possible.

In EPO-treated patients, replacing iron in patients who are also iron deficient will often improve the EPO response.

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Treatment

When the decision has been made to treat with an HGF, the ASCO guidelines for GM-CSF or G-CSF¹ and the ASH/ASCO guidelines for EPO² can be used. For chemotherapy-associated anemia, the ASH/ASCO guidelines have recommendations. Evidence in the medical literature was closely analyzed and, for chemotherapy-associated anemia, as the falling Hgb level approaches 10 g/dL, initiating EPO prevents transfusions (approximately five patients must be treated to prevent one transfusion) and raises the Hgb level.² Historically, EPO was administered at 150 U/kg three times weekly or 40,000 U once weekly. The newer form of EPO, darbepoetin alfa (Aranesp), is administered once every 2 weeks at 2.25 µg/kg.

Use of GM-CSF and G-CSF has reduced the incidence of febrile neutropenia by approximately 50% in three major randomized studies in adults in whom the incidence of febrile neutropenia was predicted to be greater than 40% in the control group.⁷ As for whether to initiate CSFs in afebrile versus febrile neutropenia patients, the 2006 guideline¹ states that “current evidence supports the recommendation that CSFs should not be routinely used for patients with neutropenia who are afebrile,” and “the collective results [of the eight trials] provide strong and consistent support for the recommendation that CSFs should not be routinely used as adjunct therapy for the treatment of uncomplicated fever and neutropenia.” The eight trials have consistently shown a decrease in the duration of neutropenia when the neutropenia level is less than 500/µL, but clinical benefit has not consistently accompanied the decreased duration.

A special comment should be made about the treatment of anemia and neutropenia in patients with myelodysplastic syndrome (MDS). One randomized controlled trial has compared EPO with placebo in low-risk MDS patients.⁸ Low-risk MDS was defined as refractory anemia only, not refractory anemia with ringed sideroblasts or refractory anemia with excess blasts. In this trial, EPO was beneficial in raising the hemoglobin levels of patients with MDS. Also, EPO is more likely to be useful in nontransfused anemic patients as opposed to those who have already begun transfusions. The dosage of EPO in this trial was 150 U/kg three times weekly for 4 weeks, with the option of increasing to 300 U/kg three times weekly after 1 month if there is no response. The ASCO guidelines recommend using G-CSF or GM-CSF to increase the absolute neutrophil count of neutropenic patients with MDS, but little data in the medical literature support the routine, long-term, continuous use of G-CSF or GM-CSF in this setting.

G-CSF and GM-CSF have a special role in the setting of bone marrow transplantation (BMT). First, these cytokines may be given to normal donors to enhance the circulating pool of peripheral blood progenitor cells; studies have indicated that recipients engraft just as quickly with the use of cytokine-primed peripheral blood progenitor cells as they do with bone marrow.⁹ Also, the duration of neutropenia for those undergoing autologous and allogeneic BMT is shortened by the use of G-CSF or GM-CSF. EPO has little or no use in the setting of BMT to reduce the need for RBC transfusion.

In leukemic patients, CSFs have been used to prime patients, theoretically lining up blasts in the same cell phase so that chemotherapy will be more effective. According to the guideline, the use of CSFs as primers for chemotherapy might enhance response rates and disease-free survival. In leukemic patients, CSFs do not reverse the severe neutropenia but may shorten its duration.

TPO mimetics (romiplostim and eltrombopag) have demonstrated efficacy in raising platelet counts in ITP patients. They have been used in both pre and postsplenectomy patients. Romiplostim¹⁰ is administered subcutaneously weekly and eltrombopag¹¹ is orally administered daily.

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Side Effects

Side effects with EPO are generally well tolerated. Diarrhea and fluid retention may occur. Hypertension also may occur, especially in patients with renal failure and underlying hypertension, who develop a good response with a rise in the hematocrit level. Seizures have been reported. A case of reversible EPO-dependent transformation of MDS to an acute monoblastic leukemia also has been reported.¹²

As noted previously, there are increasing data suggesting increased risk of venous thromboembolism in patients on EPO, especially myeloma patients receiving immunomodulatory drugs (IMID), such as thalidomide and lenalidomide. Also, in vitro data suggest tumor cells have EPO receptors that, when activated by EPO, can lead to increased tumor growth. Some epidemiologic data demonstrate decreased survival in cancer patients receiving EPO for anemia but who are not receiving concomitant chemotherapy or radiation therapy.

G-CSF is better tolerated than GM-CSF, which usually has greater risks of fever, skin rash, and pericardial effusions. G-CSF has been associated with bone pain and spleen enlargement, even rupture of the spleen. More unusual side effects of G-CSF include pyogenic infections, leukocytoclastic vasculitis, interstitial pneumonitis, acute gouty arthritis, Sweet’s syndrome, stroke, acute iritis, and anaphylaxis.¹³

Thrombopoietin has been associated with the development of neutralizing antibodies to native TPO. Cases of immune thrombocytopenia have been documented.¹⁴ The TPO mimetics are well tolerated but have demonstrated the ability to cause bone marrow fibrosis, which is reversible. Also, worsening of thrombocytopenia occurs when their use is stopped.

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Summary

• Available hematopoietic growth factors include EPO to increase red blood cell production, G-CSF and GM-CSF to increase granulocyte production, and TPO mimetics to increase platelet numbers.
• HGFs are used primarily in the setting of renal failure, chemotherapy-induced cytopenias, bone marrow failure syndromes, and ITP.
• Colony-stimulating factors should not be used routinely as adjunct therapy for uncomplicated fever and neutropenia. Trials have consistently shown a decrease in the duration of neutropenia when the neutropenia level is less than 500/µL, but clinical benefit has not consistently accompanied the decreased duration.

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Suggested Readings

• Anderlini P, Champlin RE. Biologic and molecular effects of granulocyte colony-stimulating factor in healthy individuals: recent findings and current challenges [published online ahead of print December 5, 2007]. Blood 2008; 111:1767–1772. doi:10.1182/blood-2007-07-097543
• Kaushansky K. Lineage-specific hematopoietic growth factors. N Engl J Med 2006; 354:2034–2045.
• Lyman G, Dale DC. Hematopoietic growth factors in oncology. In: Rosen ST, ed. Cancer Treatment and Re-search. New York, NY: Springer Science; 2011.
• Neunert C, Lim W, Crowther M, Cohen A, Solberg L Jr, Crowther MA. The American Society of Hematology 2011 evidence-based practice guideline for immune thrombocytopenia [published online ahead of print February 16, 2011]. Blood 2011; 117:4190–4207. doi:10.1182/blood-2010-08-302984

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