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Copyright 2002
The Cleveland Clinic Foundation

Over the past 15 years, a new class of drugs has been 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 interleukin-11 (IL-11) 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. Because they are costly, and may have side effects, careful patient selection for their use is necessary, and only after a search for correctable causes for the cytopenia has been undertaken. All patients on chemotherapy whose blood count drops may, however, become eligible for the use of HGFs. Appropriate use for these agents is discussed in this chapter.

National guidelines published by the American Society of Clinical Oncology (ASCO) exist for G-CSF and GM-CSF,^1,2 and a joint American Society of Hematology (ASH)/ASCO guideline has been published for the use of EPO.^3,4

Definition

Pathophysiology

Signs and
Symptoms

Diagnosis

Therapy

Outcomes

References

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.

Hypoxia stimulates EPO production by the peritubular cells of the kidney. T-lymphocytes, endothelial cells, fibroblasts, and monocytes/macrophages are the source 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.⁵

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.⁵

The HGFs also have a role in potentiating the effect of mature cells. 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.⁵

Two different forms of thrombopoietin are 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, this HGF seems to stimulate the production of neutralizing antibodies, sometimes leading to an immune thrombocytopenic purpura-like state and even to an immune panhypoplasia.⁶ Use of EPO has also been associated with development of neutralizing antibodies, leading to pure red cell aplasia.⁷

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 (tiredness, dizziness, feeling cold, "I can hardly move my legs") are improved with a rise in hemoglobin (Hgb).

The growth of quality-of-life research has been an epiphenomenon of EPO's commercialization. For patients receiving chemotherapy, measuring the fatigue that led to the inability to juggle one's grandson on one's lap became the focus of scientific investigation. Measuring tools, such as the Functional Assessment of Cancer—Anemia (FACT-An) and the Linear Analog Self-Assessment—Anemia (LASA), appeared in the literature of oncology.³ Some of the other issues were: Should EPO begin simultaneously with chemotherapy? Should EPO be given once the falling Hgb hits 13 (gm/dl), 12, 11, 10, or 9? Should a patient's Hgb be allowed to rise with EPO to 12, 13, or 14? The role of iron in maintaining an EPO response was less deeply studied; should iron replacement be administered, and if so, should it be intravenous (IV) or oral? The practicing physician still does not know. For EPO, thrice-per-week dosing vs. once-per-week dosing was never compared head to head, but once-per-week dosing became a standard of care because it was easier.

A major dose-limiting side effect of chemotherapy is febrile neutropenia. The depth of neutropenia will depend on several factors, including previous radiation the patient may have received, the dose intensity of chemotherapy treatments, and any multiple co-morbidities. Fever is usually the first clinical symptom of infection. A patient on chemotherapy who presents with an absolute neutrophil count <500/µL (microliter) and is febrile to >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 can also lead to severe thrombocytopenia and increased bleeding risk. For leukemia patients, it was once thought that platelet transfusions should begin when the platelet count reaches 20,000/µL.⁸ Then, over the years, trials 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 in our institution usually involves frequent visits to receive platelet transfusions. IL-11 has not achieved the same success as EPO or G-CSF for the treatment of their respective cytopenias.

The results of the complete blood cell count, differential, and platelet count render the diagnoses of anemia, neutropenia, or thrombocytopenia; however, the proper work-up in patients is important, even for those on chemotherapy. Not every patient on chemotherapy becomes anemic because of the chemotherapy effect on marrow only, and the treating physician should not automatically prescribe exogenous erythropoietin. The following often should be checked: (1) stool guaiac status, to make sure that gastrointestinal bleeding is not starting; (2) peripheral smear, searching for the development of schistocytes, as one might see in disseminated intravascular coagulation; (3) Coombs' testing, especially in lymphoma or chronic lymphocytic leukemia (CLL) patients, to make sure immune hemolysis is not starting; (4) nutrient status, ie, iron, vitamin B12, and folate, to maintain normal levels as much as possible. In EPO-treated patients, replacing iron will often improve the EPO response.

THERAPY

When the decision has been made to treat with an HGF, one can use the ASCO guideline for GM-CSF or G-CSF² and the ASH/ASCO guideline for EPO.^3,4

For chemotherapy-associated anemia, the ASH/ASCO guideline comments on all these issues. The evidence in the medical literature was closely analyzed and, for chemotherapy-associated anemia, as the falling Hgb approaches 10 g/dL, initiating EPO prevents transfusions (one must treat about five patients in order to prevent one transfusion) and raises Hgb.^3,4 Usually EPO is given as either 150 U/Kg three times per week or 40,000 U every week. The newer form of EPO, darbepoietin (Aranesp) is given once every 2 weeks at a dose of 2.25 µg/Kg.

GM-CSF and G-CSF reduced the incidence of febrile neutropenia by approximately 50% in three major randomized studies in adults in which the incidence of febrile neutropenia was predicted to be greater than 40% in the control group.²

As for whether to initiate CSFs in afebrile vs. febrile neutropenia, the 2000 guideline states, "current evidence supports the recommendation that CSFs should not be routinely used for patients with neutropenia who are afebrile." Then, "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 is less than 500/µL, but clinical benefit has not consistently accompanied the decreased duration.²

A special comment should be made about therapy of anemia and neutropenia in patients with myelodysplastic syndrome (MDS). There is one randomized controlled trial comparing EPO with placebo in low-risk MDS⁹ Low-risk MDS is 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 of myelodysplasia patients. Also, EPO is more likely to be useful in non-transfused anemic patients as opposed to those who have already begun transfusions. The dose of EPO in this trial was 150 U/Kg three times per a week for 4 weeks, with the option of increasing to 300 U/Kg three times per a week after 1 month if there was no response.

The ASCO guidelines recommend using G-CSF or GM-CSF to increase the absolute neutrophil count of neutropenic patients with MDS, but data do not exist in the medical literature to 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 (PBPCs). Studies exist providing data that recipients engraft just as quickly with the use of cytokine-primed PBPCs as they do with bone marrow.¹⁰ Also, the duration of neutropenia for recipients of autologous and allogeneic BMT is shortened by the use of G-CSF or GM-CSF.¹⁰ EPO has little or no utility in the setting of BMT in reducing the need for red blood cell 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. The best the guideline can state is, "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 they may shorten its duration.

Side Effects of HGFs
Side effects with EPO are generally well tolerated. Diarrhea and fluid retention may occur. Hypertension may also occur, especially in patients with renal failure and underlying hypertension, who develop a good response with a rise in hematocrit. Seizures have been reported. A case of reversible EPO-dependent transformation of MDS to an acute monoblastic leukemia has been reported.¹¹

G-CSF is better tolerated than GM-CSF, which usually has a greater risk of fever, skin rash, and pericardial effusions. G-CSF has been associated with bone pain and spleen enlargement (and even rupture of the spleen). Other, 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.¹²

Thrombopoietin has been associated with the development of neutralizing antibodies to native thrombopoietin, and cases of immune thrombocytopenia have been documented.¹³

In the ASCO 2000 updated CSF guidelines,² each individual guideline is followed by a section called "Clinical Outcomes," which are helpful and insightful commentaries. For example, in the clinical outcomes after text on "Primary prophylaxis of febrile neutropenia," the authors make the point that "by design, primary prophylaxis results in unnecessary treatment of at least 50% of patients who should not have experienced febrile neutropenia on standard chemotherapy regimens."² After the text of "Guidelines for initiation and duration of CSF administration," the authors state that "the optimal timing and duration of CSF administration are still under investigation."²

Return to Medicine Index

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