Joseph Woong Kim, Nishith K. Singh, and Philip M. Arlen
BACKGROUND
■Hematologic toxicity (leukopenia, anemia, and thrombocytopenia) is the most common side effect of chemotherapy. It can lead to serious complications, such as neutropenic fever, which may require hospitalization.
■Hematopoietic growth factors are the regulatory molecules that stimulate the proliferation, differentiation, and survival of hematopoietic progenitor and stem cells. They were originally called colony-stimulating factors (CSFs) because of their role in colony formation in bone marrow cell cultures.
■Several hematopoietic growth factors are currently available for clinical use and are synthesized mainly by DNA recombinant technology.
■Recommendations in this chapter come primarily from the evidence-based clinical practice guidelines of the American Society of Clinical Oncology (ASCO), the National Comprehensive Cancer Network (NCCN), and the American Society of Hematology (ASH).
MYELOID GROWTH FACTORS
■Currently, two myeloid growth factors, filgrastim and pegfilgrastim, both of which are granulocyte colony–stimulating factors (G-CSF), have been approved by the U.S. Food and Drug Administration (FDA) for use in prevention of chemotherapy-induced neutropenia. Filgrastim is specific for production of neutrophils, but has immunomodulatory effects on lymphocytes, monocytes, and macrophages. Anti-inflammatory effects have also been described for G-CSF. Pegfilgrastim is a pegylated form of filgrastim and has a longer half-life ranging from 15 to 80 hours.
■Sargramostim is a granulocyte macrophage colony–stimulating factor (GM-CSF) that stimulates the production of monocytes and eosinophils, in addition to neutrophils, and prolongs their half-lives. It also enhances their function through activation of chemotaxis, phagocytosis, oxidative activity, and antibody-dependent cellular cytotoxicity. Its labeled clinical indication for its administration is to shorten the time to neutrophil recovery following induction chemotherapy in older adult patients with acute myelogenous leukemia and other various stem cell transplantation settings.
INDICATIONS
Primary Prophylaxis
CSFs are recommended for use with first- and subsequent-cycle chemotherapy to prevent febrile neutropenia (FN) when risk of FN is high (>20%). Although no nomogram exists to calculate this risk, factors to consider when determining a patient’s risk of FN include type of chemotherapy regimen (dose-dense therapy, high-dose therapy, standard-dose therapy), goal of therapy (palliative or curative), and a patient’s risk factors including
■Age above 65
■Poor performance status
■Extensive prior treatments, including large-port radiation
■Previous episodes of FN
■Cytopenia due to bone marrow involvement by tumor
■Advanced cancer
■Active infections or presence of open wounds
■Poor nutritional status
■Other serious comorbidities, or renal or liver dysfunction
Several placebo-controlled randomized controlled trials have shown that the prophylactic use of G-CSFs has been shown to reduce the incidence, length, and severity of chemotherapy-related neutropenia in various solid tumor types. Dose-dense chemotherapy regimens supported by G-CSF had shown superior clinical outcome compared to conventional chemotherapy in adjuvant treatment of node-positive breast cancer, and in elderly patients with aggressive lymphoma. Cochrane meta-analyses of 2,607 randomized lymphoma patients from 13 trials reported that G-CSF and GM-CSF as a prophylaxis reduced the risk of neutropenia, FN, and infection. However, there was no evidence that either G-CSF or GM-CSF provide a significant benefit in terms of tumor response, freedom from treatment failure, or overall survival.
Secondary Prophylaxis
The guidelines recommend administering CSFs to patients who had FN or dose-limiting neutropenic event that could otherwise impact planned dose of chemotherapy from a prior cycle of chemotherapy when no CSFs were given. Dose reduction and treatment delay are reasonable alternatives in the palliative setting.
Neutropenic Fever
Routine adjunctive use of CSFs for treatment of FN is not recommended. CSFs should be considered in patients with FN who are at high risk for infection-associated complications, or who have prognostic factors that are predictive of poor clinical outcomes. High-risk features include
■Age above 65
■Expected prolonged (more than 10 days)
■Profound (<100/µL) neutropenia
■Sepsis syndrome
■Hospitalization at the time of the development of fever
■Pneumonia
■Invasive fungal infection
■Uncontrolled primary disease
A multicenter randomized trial demonstrated that therapeutic G-CSF shortened hospital stay (median, 5 days versus 7 days; P = 0.015), antibiotic therapy (median, 5 days versus 6 days; P = 0.013), and duration of grade IV neutropenia (median, 2 days versus 3 days; P = 0.0004), in 210 solid tumor patients with FN, and at least one high-risk feature. Cochrane meta-analysis of 1,518 patients from 13 trials reported that therapeutic CSF was associated with shorter hospital stay, duration of neutropenia, but no improvement in overall survival.
Hematopoietic Stem Cell Transplantation
CSFs are used routinely to mobilize peripheral blood stem cells (PBSCs) and to shorten the duration of neutropenia after cytoreduction and autologous PBSC transplantation. Postautotransplantation use of CSFs has been associated with shorter duration of neutropenia and hospitalization, and reduced medical costs. In contrast, CSFs used after allogeneic transplantation have been reported to increase the risk of severe graft-versus-host disease and to reduce survival.
Leukemia and Myelodysplastic Syndromes
■In patients with acute myeloid leukemia (AML), CSFs can be used in two settings—(1) after completion of induction chemotherapy and (2) after completion of consolidation chemotherapy. Use of G-CSF shortly after completion of induction chemotherapy can lead to a modest decrease in neutropenia duration, but has not been shown to have a favorable effect on remission rate, duration, or survival. Use of G-CSF after completion of consolidation chemotherapy seems to have a more profound shortening of neutropenia duration and infection rate, with no effect on complete response duration or overall survival. Recent Cochrane meta-analysis including 5,256 AML patients in 19 trials reported that the addition of CSFs did not alter all-cause mortality in the short and long term. The administration of CSFs did not affect the occurrence of episodes of neutropenic fever, bacteremias, or invasive fungal infections. Currently, there are insufficient data to support the use of long-acting CSF (pegfilgrastim) in AML.
■In myelodysplastic syndrome (MDS), intermittent use of CSFs may be considered in patients with severe neutropenia complicated by recurrent infections. There are no data on the safety of long-term use.
■In acute lymphoblastic leukemia (ALL), CSFs are recommended after the completion of the initial induction or first postremission chemotherapy course to shorten the duration of neutropenia. Their effects on duration of hospitalization and acquisition of serious infections are less consistent.
SIDE EFFECTS
Bone pain is frequently encountered with the use of myeloid growth factors. Rarely, splenic rupture and severe thrombocytopenia have been reported. CSFs may cause a transient acute respiratory distress syndrome or inflammatory pleuritis and pericarditis, which are thought to be secondary to neutrophil influx or capillary leak syndrome. In patients with sickle cell disease, use of CSFs has led to severe sickle cell crisis, resulting in death in some cases. Concurrent use of CSFs with chemotherapy and radiation therapy should be avoided because of the potential sensitivity of rapidly dividing myeloid cells to cytotoxic chemotherapy. In addition, CSFs should be avoided in patients receiving concomitant chemoradiotherapy, particularly involving the mediastinum. This is because of the observation that patients receiving CSF support while being treated with concurrent chemoradiotherapy for lung cancers had more significant thrombocytopenia and increased pulmonary toxicities compared to patients in placebo arms. These findings suggested potential for an adverse interaction between mediastinal radiotherapy and CSF administration.
G-CSF
■In general, G-CSF is better tolerated than GM-CSF and is used more commonly.
■May rarely cause pathologic neutrophil infiltration (Sweet syndrome).
■Antibodies to growth factors have been detected with some preparations, but are not neutralizing.
■Fragmentary evidence has raised concerns for increased risk of late monosomy 7-associated MDS and AML in patients with aplastic anemia treated with long-term G-CSF.
GM-CSF
■May cause flulike symptoms, fever, and rash.
■There is in vitro evidence that GM-CSF may stimulate HIV replication; however, clinical studies have not shown adverse effects on viral load among patients on antiretroviral therapy.
■The liquid form of sargramostim was withdrawn from the market in January 2008 because of increased reports of syncope, which was not seen with the lyophilized formulation.
DOSING
■Recommended dosing of CSFs is listed in Table 34.1.
■In chemotherapy patients, a transient increase in neutrophil count is typically observed in the first 1 to 2 days after initiation of CSFs. Treatment should continue until post–nadir ANC reaches 10,000/mm3. Check complete blood count twice weekly.
■Pegfilgrastim should not be administered from 14 days before to 24 hours after myelosuppressive chemotherapy.
■Sargramostim is licensed for use after autologous or allogeneic bone marrow transplant and for AML.
ERYTHROPOIESIS-STIMULATING AGENTS
Erythropoiesis-stimulating agents (ESAs) are semisynthetic agents that simulate the effects of erythropoietin (EPO), an endogenous hormone produced by the kidneys. By binding to EPO receptors, ESAs stimulate the division and differentiation of committed erythroid progenitors in bone marrow. ESAs are manufactured by recombinant DNA technology and are available as epoetin-α and darbepoetin-α. Darbepoetin-α has a half-life around three times longer than that of epoetin-α; however, they are considered equivalent in terms of effectiveness and safety.
EFFECTS
■ESAs were first used to manage anemia in patients with chronic renal failure (CRF). Several randomized clinical trials have demonstrated that ESAs decrease blood transfusion requirements and improve quality of life in patients on hemodialysis.
■In cancer patients undergoing chemotherapy, ESAs have been shown to reduce the need for transfusions, but their effects on anemia symptoms and quality of life have not been proven.
■A growing body of evidence has raised serious concerns about the safety of ESAs.
Transfusion Requirements and Quality of Life
A recent systematic review summarized the results of 57 trials involving 9,353 cancer patients randomly assigned to receive ESA plus RBC transfusion or transfusion alone. This meta-analysis included patients who did and patients who did not receive concurrent antineoplastic therapy. Results showed a 36% reduction in transfusion requirement in those receiving ESA. Although there was a positive overall effect on quality of life, the report could not draw definite conclusions because of different parameters used by the various studies.
Survival, Mortality, and Disease Control
■Observational studies have suggested that anemia in cancer patients is associated with shorter survival and that increasing hemoglobin (Hb) levels may improve survival and tumor response in some cancers. Because radiation and some chemotherapy agents are dependent on tissue oxygenation for their effect, it was speculated that improving oxygen delivery by increasing Hb levels may optimize the effects of antineoplastic treatments. Based on this hypothesis, several randomized trials in head and neck, breast, non–small cell lung, lymphoid, and cervical cancers were conducted to evaluate the effect of ESAs on survival and disease control. Most of these studies were terminated prematurely because of earlier disease progression and increased mortality. A preliminary report of a study using ESAs in cancer patients not receiving chemotherapy showed no reduced need for blood transfusions; it did show increased mortality. Based on this report, the FDA released a black box safety alert in February 2007 warning against the use of ESAs for anemia in cancer patients not receiving chemotherapy. The FDA also recommended a minimum effective dose of ESAs that would gradually increase Hb levels sufficient to avoid transfusion, but not to exceed 12 g/dL. Most of the ESA trials had set a goal of Hb >12 g/dL; however, the risks of shortened survival and TTP have persisted even when ESAs are dosed to achieve Hb levels >12 g/dL. An updated meta-analysis of 53 RCTs and 13,933 cancer patients looked for mortality as the primary end point and found ESAs to be associated with significantly greater overall on-study mortality. In those with chemotherapy-induced anemia (n = 10,441), a statistically significant mortality change could not be demonstrated. Poor outcomes could not be consistently attributed to a single mechanism.
■It has been suggested that shorter TTP could be attributed to EPO receptor-positive tumors. However, currently available assays to detect EPO receptors are nonspecific and their validity has not been determined.
■In July 2007, the Centers for Medicare and Medicaid Services revised their national coverage guidelines to limit reimbursement of ESAs. Coverage of ESAs in cancer patients is now restricted to those receiving chemotherapy whose Hb level is ≤10 g/dL prior to initiation of ESA treatment.
■Increased mortality and adverse events have also been observed in CRF patients, which have led to lower Hb targets in this patient population.
INDICATIONS
ASCO and ASH Guidelines
In nonmyeloid cancers, ESAs should be considered as one of the many options in patients receiving chemotherapy whose anemia is symptomatic and chemotherapy related. The goals are avoidance of blood transfusions and possible symptomatic benefit. ESAs can be initiated if Hb falls below 10. For Hb levels between 10 and 12, use of ESAs should only be based on symptoms, clinical circumstances, and patient preference. If there is no response after 6 to 8 weeks with appropriate dose modification, treatment should be discontinued. Blood transfusion is a therapeutic option.
FDA-Approved Indications
ESAs are approved for chemotherapy-related anemia in nonmyeloid malignancies treated with palliative intent, CRF, HIV (zidovudine) therapy, and to reduce the need for blood transfusion in elective noncardiac and nonvascular surgeries.
Off-Label/Investigational Use
■There is evidence supporting the use of ESAs for anemia related to MDS. However, patients may require higher doses and response may be delayed. Predictors of response include low-risk MDS and low EPO levels (≤200 units/L). Combining ESAs and G-CSF in MDS patients has resulted in improved response rates.
■Other reported uses include multiple myeloma, non-Hodgkin lymphoma, chronic lymphocytic leukemia, β-thalassemia, radiation therapy, rheumatoid arthritis, paroxysmal nocturnal hemoglobulinuria, Castleman disease, congestive heart failure, critical illnesses, hepatitis C (in patients treated with interferon-α and ribarvirin), and blood-unit collection for autotransfusion.
DOSING
Recommended dosing and dose adjustments of ESAs in chemotherapy-induced anemia are listed in Table 34.1. After initiation or dose modification of ESAs, Hb should be monitored weekly until it stabilizes.
SIDE EFFECTS
■The most serious side effects of ESAs are thromboembolic events, defined as transient ischemic attack, stroke, pulmonary emboli, deep vein thrombosis, and myocardial infarction. A meta-analysis showed that thromboembolic events increased 67% in cancer patients; for a population with baseline risk of 20%, the number needed to harm would be 7.5 patients (95% CI 3.1 to 15.6). There is evidence for increased risk of thromboembolic events in CRF and surgical patients, especially with higher Hb targets. Preliminary analysis of a trial in spinal surgery patients given ESAs to decrease postsurgery transfusion requirements showed increased incidence of thromboembolic events in the ESA arm. Notably, patients received no prophylactic anticoagulants postoperatively.
■ESAs are contraindicated in uncontrolled hypertension, more commonly seen in CRF patients who receive IV ESAs.
■Other side effects include headache, fatigue, fever, rash, pruritis, hypersensitivity reactions, arthralgia and myalgia, nausea, seizures, and pure red-cell aplasia due to neutralizing antibodies to native EPO.
OTHER CONSIDERATIONS
■Iron supplementation should be considered in patients receiving ESAs, especially those with borderline iron stores, because iron deficiency can develop soon after initiation of ESAs and can adversely affect response to ESAs. Data from multiple controlled trials have shown that IV iron can enhance ESA efficacy and can reduce the required dose in cancer patients.
■Measuring serum EPO levels may help to identify patients more likely to respond to ESAs. Patients with baseline EPO levels ≤100 units/L are more likely to respond to ESAs than those with levels >100 units/L.
PLATELET GROWTH FACTORS
■Thrombocytopenia can be a life-threatening consequence of antineoplastic treatments. Platelet transfusions are required to prevent or mitigate hemorrhagic complications. Patients at high risk for bleeding or who experience delays in receiving planned chemotherapy include the following:
•Patients with poor bone marrow reserve or a history of bleeding
•Patients on treatment regimens highly toxic to bone marrow
•Patients with a potential bleeding site (e.g., necrotic tumor)
■Fortunately, iatrogenic thrombocytopenia that requires platelet transfusion or causes major bleeding is relatively uncommon, although occurrence tends to increase with cumulative cycles of chemotherapy that are toxic to hematopoietic progenitor cells. At present, formal guidelines for the use of thrombopoietic growth factors are under development.
■Although several thrombopoietic agents are in clinical development, oprelvekin is the only thrombocytopoietic agent FDA approved for clinical use in nonmyeloid malignancies with chemotherapy-induced anemia. Oprelvekin is a product of recombinant DNA technology and is nearly homologous with native IL-11. Oprelvekin stimulates megakaryocytopoiesis and thrombopoiesis, and has been shown to modestly shorten the duration of thrombocytopenia and reduce the need for platelet transfusions in patients who develop platelet counts <20 × 103 per µL after prior antineoplastic treatments. Oprelvekin is not indicated following myeloablative chemotherapy.
■Major side effects include fluid retention and atrial arrhythmias. Hypersensitivity reactions, including anaphylaxis, have also been reported. Table 34.1 provides the recommended dose of oprelvekin.
■Recombinant thrombopoietins (TPOs) are no longer being developed because of antibody production. TPO mimetics (TPO receptor agonists) are currently under investigation.
REVIEW QUESTIONS
1.Which of the following benefits of ESA has been consistently demonstrated in RCTs and meta-analyses?
a.Reduced requirement for blood transfusion
b.Decrease in symptoms related to anemia
c.Decreased mortality in cancer patients
d.Decreased cardiac complications related to anemia
e.Improved quality of life
2.Among the following clinical scenarios, which patient is the best candidate for ESA if the goal is to reduce the need for blood transfusions?
a.A 55-year-old female with stage II breast cancer on adjuvant chemotherapy with asymptomatic Hb of 10 g/dL.
b.A 60-year-old female with metastatic breast cancer on palliative chemotherapy with symptomatic anemia of Hb 8 g/dL.
c.A 55-year-old male with metastatic prostate cancer on palliative chemotherapy with asymptomatic anemia of Hb 9 g/dL.
d.A 50-year-old female with stage III breast cancer on dose dense adjuvant chemotherapy with asymptomatic Hb level of 10.5 g/dL.
e.None of the above.
3.Which of the following clinical cases LEAST justifies the use of G-CSF?
a.A 50-year-old male on the 12th cycle of FOLFIRI with bevacizumab for metastatic colon cancer presents with FN with ANC 220. He has no other complaints.
b.A 49-year-old female with stage II triple negative breast cancer is coming to receive cycle 3 of dose dense AC-T. A prior cycle without G-CSF support was complicated by prolonged FN.
c.A 40-year-old female with cervical cancer with history of extensive pelvic radiation presents with fever and ANC of 90. Otherwise, the patient has no complaints.
d.A 69-year-old male with metastatic non–small cell lung cancer presents on cycle 3 of cisplatin and vinorelbine presents with FN and increased productive cough and shortness of breath.
e.A 69-year-old male presenting to start induction chemotherapy with Docetaxel, cisplatin, and 5-fluorouracil for unresectable hypopharyngeal carcinoma.
4.Which of the following is the TRUE statement about the evidence concerning CSFs?
a.A dose-dense chemotherapy regimen supported by pegfilgrastim showed superior clinical benefit, compared with the regimen supported by filgrastim in elderly patients with aggressive lymphoma.
b.Meta-analysis of lymphoma clinical trials showed that CSF as a primary prophylaxis reduced the risk of neutropenia, FN and infection, but no benefit in overall survival.
c.Meta-analysis clinical trials of G-CSF for chemotherapy-induced FN showed that CSFs reduced the hospital stay, time to neutrophil recovery, and infection-related mortality.
d.ASCO 2006 update guideline recommends that the use of CSFs when the risk of FN is approximately 40%.
e.Meta-analysis of randomized controlled trials that evaluated the addition of CSFs during and following chemotherapy in patients with AML showed that CSF decreases the occurrence of bacteremia and invasive fungal infection but produces no difference in all-cause mortality.
Suggested Readings
1.Bohlius J, Herbst C, Reiser M, Schwarzer G, Engert A. Granulopoiesis-stimulating factors to prevent adverse effects in the treatment of malignant lymphoma. Cochrane Database Syst Rev. 2008;4:CD003189.
2.Bohlius J, Schmidlin K, Brillant C, et al. Erythropoietin or darbepoetin for patients with cancer: meta-analysis based on individual patient data. Cochrane Database Syst Rev. 2009;3:CD007303.
3.Caro JJ, Salas M, Ward A, Goss G. Anemia as an independent prognostic factor for survival in patients with cancer: a systemic, quantitative review. Cancer. 2001;91(12):2214-2221.
4.Clark OA, Lyman GH, Castro AA, Clark LG, Djulbegovic B. Colony-stimulating factors for chemotherapy-induced febrile neutropenia: a meta-analysis of randomized controlled trials. J Clin Oncol. 2005;23(18):4198-4214.
5.Cwirla SE, Balasubramanian P, Duffin DJ, et al. Peptide agonist of the thrombopoietin receptor as potent as the natural cytokine. Science. 1997;276(5319):1696-1699.
6.Elliott S, Busse L, Bass MB, et al. Anti-Epo receptor antibodies do not predict Epo receptor expression. Blood. 2006;107(5):1892-1895.
7.Gribben JG, Devereux S, Thomas NS, et al. Development of antibodies to unprotected glycosylation sites on recombinant human GM-CSF. Lancet. 1990;335(8687):434-437.
8.Gurion R, Belnik-Plitman Y, Gafter-Gvili A, et al. Colony-stimulating factors for prevention and treatment of infectious complications in patients with acute myelogenous leukemia. Cochrane Database Syst Rev. 2012;6:CD008238.
9.Henke M, Mattern D, Pepe M, et al. Do erythropoietin receptors on cancer cells explain unexpected clinical findings? J Clin Oncol. 2006;24(29):4708-4713.
10.Henry DH, Dahl NV, Auerbach M, Tchekmedyian S, Laufman LR. Intravenous ferric gluconate significantly improves response to epoetin alfa versus oral iron or no iron in anemic patients with cancer receiving chemotherapy. Oncologist. 2007;12(2):231-242.
11.Kuderer NM, Dale DC, Crawford J, Lyman GH. 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(21):3158-3167.
12.Ringdén O, Labopin M, Gorin N-C, et al. for the Acute Leukaemia Working Party of the European Group for Blood and Marrow Transplantation. Growth factor-associated graft-versus-host disease and mortality 10 years after allogeneic bone marrow transplantation. Br J Haematol. 2012;157: 220-229. doi: 10.1111/j.1365-2141.2012.09034.x
13.Rizzo JD, Brouwers M, Hurley P, et al. American Society of Hematology/American Society of Clinical Oncology clinical practice guideline update on the use of epoetin and darbepoetin in adult patients with cancer. Blood. 2010;116(20):4045-4059.
14.Seidenfeld J, Piper M, Bohlius J, et al. Comparative effectiveness of epoetin and darbepoetin for managing anemia in patients undergoing cancer treatment. In: Comparative Effectiveness Reviews, No. 3;2006.
15.Singh AK, Szczech L, Tang KL, et al. Correction of anemia with epoetin alfa in chronic kidney disease. N Engl J Med. 2006;355(20):2085-2098.
16.Smith RE Jr., Aapro MS, Ludwig H, et al. Darbepoetin alfa for the treatment of anemia in patients with active cancer not receiving chemotherapy or radiotherapy: results of a phase III, multicenter, randomized, double-blind, placebo-controlled study. J Clin Oncol.2008;26(7):1040-1050.
17.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(19):3187-3205.
18.Stasi R, Abruzzese E, Lanzetta G, Terzoli E, Amadori S. Darbepoetin alfa for the treatment of anemic patients with low- and intermediate-1-risk myelodysplastic syndromes. Ann Oncol. 2005;16(12):1921-1927.
19.Tepler I, Elias L, Smith JW II, et al. A randomized placebo-controlled trial of recombinant human interleukin-11 in cancer patients with severe thrombocytopenia due to chemotherapy. Blood. 1996;87(9):3607-3614.
20.Wright JR, Ung YC, Julian JA, et al. Randomized, double-blind, placebo-controlled trial of erythropoietin in non-small-cell lung cancer with disease-related anemia. J Clin Oncol. 2007;25(9):1027-1032.