The Bethesda Handbook of Clinical Oncology

Philip M. Arlen and Andreas Niethammer

BACKGROUND

Hematologic toxicity (leukopenia, anemia, and thrombocytopenia) is the most common side effect of chemotherapy and large field radiotherapy. Further, cytopenia is inherent to stem cell transplantation. 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), 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. The labeled clinical indication is for use 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 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 patient’s risk factors including the following:

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

Neutropenia

HIV-infected patient

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 2607 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 experienced febrile neutropenia or dose-limiting neutropenic event in a prior cycle of chemotherapy when no CSFs were given and a repeat of which episode could impact the next planned dose of chemotherapy . Dose reduction and treatment delay, however, are reasonable alternatives, especially in the palliative setting.

Neutropenic Fever

Routine adjunctive use of CSFs for 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 the following:

Age above 65

Expected prolonged (more than 10 days)

Profound (<100/mcl) neutropenia

Sepsis syndrome

Being hospitalized at the time of the development of fever

Pneumonia

Invasive fungal infection

Uncontrolled primary disease

A multicenter randomized trial demonstrated that therapeutic G-CSF shortens hospital stay (median, 5 days versus 7 days; P = 0.015), antibiotic therapy (median, 5 days versus 6 days; P = 0.013), duration of grade 4 neutropenia (median, 2 days versus 3 days; P = 0.0004) in 210 solid tumor patients with febrile neutropenia, and at least one high-risk feature. Cochrane meta-analysis of 1518 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 cell (PBSC) and to shorten the duration of neutropenia after cytoreduction and autologous PBSC transplantation. Post auto-transplantation 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.

For mobilization of stem cells before harvesting from the healthy donor or the patient before autologous stem cell transplant, different protocols exist.

Mobilizing stem cells typically involves daily injections of filgrastim with the most common adverse events being bone pain and allergic reactions. While initially there was a concern about secondary leukemia in subjects having received G-CSF, large studies show no increase in incidence. Severe side effects are rare with less than 1% of donors experiencing such toxicity. In a review by the National Marrow Donor Program, among >23,000 subjects having donated peripheral stem cells, 4 fatalities were observed and 37 severe adverse events. The incidence of hematologic malignancies in follow up (n=12) did not exceed the expected incidence in the adjusted general population. (Halter et al).

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 shown to have favorable effect on remission rate, duration, or survival. Use of G-CSF after completion of consolidation chemotherapy seems to have a more profound beneficial effect on the duration of neutropenia and the rate of serious infections. However, no effect on complete response duration or overall survival can be observed. Indeed, a recent Cochrane meta-analysis including 5256 AML patients in 19 trials reported that the addition of CSFs did not alter all-cause mortality in the short and long term. In this meta-analysis, the administration of CSFs did not affect the occurrence of episodes of neutropenic fever, bacteremias, or invasive fungal infections. Thus, currently, there are insufficient data to support the use of CSF for leukemia priming effects. Likewise, insufficient data exist 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 post-remission chemotherapy course to shorten the duration of neutropenia. Their effect 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 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.

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 the increased reports of syncope, which was not seen with the lyophilized formulation.

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.

DOSING

In chemotherapy patients, 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.

TABLE 34.1Growth Factors for Transplant or Nonmyeloid Cancer Patients Only: FDA-approved Dosing and Indications

Drug	Dosing	Indications
Filgrastim (Neupogen)	5 μg/kg SC daily 24 h after completion of chemotherapy until ANC reaches 2,000 to 3,000/mm³ 10 μg/kg SC daily at least 4 d before the first leukapheresis; continue until the last leukapheresis	Myelosuppressive chemotherapy PBSC mobilization
Pegfilgrastim (Neulasta)	Single 6-mg fixed dose SC 24 h after completion of chemotherapy	Myelosuppressive chemotherapy
Sargramostim (Leukine)	250 μg/mm² i.v. daily until ANC reaches 1,500/mm³ for 3 consecutive days; reduce dose by 50% if ANC increases to >20,000/mm³	Auto/allo BMT, after AML induction chemotherapy
Epoetin alfa (Epogen; Procrit)	Start at 150 U/kg SC TIW or 40,000 U SC weekly	Chemotherapy-induced anemia
	Escalate dose to 300 U/kg TIW or 60,000 U SC weekly if Hb rises <1 gm/dL in 4 wks and remains below 10 gm/dl, no reduction in transfusion requirements or rise in Hb after 8 wk (for TIW dosing)
	Reduce dose by 25% when Hb reaches level needed to avoid transfusion or Hb rises >1 g/dL in 2 wk
	n Hold when Hb rises to a level where transfusions may be required; resume at 25% below previous dose when Hb reaches level where transfusion may be required
Darbepoetin alfa (Aranesp)	Start at 2.25 mcg/kg SC weekly or 500 mcg SC Q3W Escalate dose to 4.5 mcg/kg if Hb rises >1 g/dL after 6 wk Reduce dose by 40% of previous dose when Hb reaches level needed to avoid transfusion or Hb rises >1 g/dL in 2 wk Hold if Hb exceeds a level needed to avoid a blood transfusion. Resume at 40% below previous dose.	Chemotherapy-induced anemia
Oprelvekin (Neumega)	50 mcg/kg SC daily; start 6 to 24 h after completion of chemotherapy and continue until post-nadir platelet count is >50,000/mm³	Nonmyeloablative chemotherapy-induced thrombocytopenia

AML, acute myeloid leukemia; ANC, absolute neutrophil count; auto/allo BMT, autologous/allogeneic bone marrow transplant; d, days; ESA, erythropoiesis-stimulating agent; FDA, U.S. Food and Drug Administration; h, hours; Hb, hemoglobin; i.v., intravenously; PBSC, peripheral blood stem cell; Q3W, every 3 weeks; SC, subcutaneously; TIW, three times per week; wk, weeks.

2015 American Society of Clinical Oncology (ASCO) Clinical Practice Guidelines on the Use of Hematopoietic Colony-stimulating Factors (CSFs)

Key points include the following:

Patients with a greater than 20% risk of febrile neutropenia, primary prophylaxis with CSF with first and subsequent cycles of chemotherapy is recommended. Regimens that do not require CSF and are equally effective should be considered as well.

Patients with a neutropenic complication from a previous cycle of chemotherapy (without primary prophylaxis) and reduction or delay in treatment would alter outcome/survival, CSF is recommended for secondary prophylaxis. However, a reduction/delay may be reasonable in many.

Adjunctive treatment of CSFs with antibiotics should not be routinely used for patients with febrile neutropenia. However, patients with febrile neutropenia who are considered at risk for poor outcomes or infection-related complications may be considered for adjunctive treatment with CSFs.

In order to mobilize peripheral-blood progenitor cells, CSFs may be used with plerixafor, after chemotherapy, or alone.

To lessen the duration of severe neutropenia, CSFs should be given after autologous stem-cell transplants.

To lessen the duration of severe neutropenia, CSFs may be given after allogeneic stem-cell transplants. Since the 2006 update, reports of increased risk of grade 2 to 4 graft-versus-host disease with CSF use after allogeneic transplantation have not been confirmed.

Patients aged 65 or older, particularly those with comorbidities, with aggressive forms of diffuse lymphoma treated with curative chemotherapy should be considered for CSF prophylaxis.

Pediatric patients—CSFs for primary prophylaxis is considered reasonable in patients at high risk for febrile neutropenia. Secondary prophylaxis should be limited to patients who are at high risk.

CSFs should be used in pediatric patients to facilitate dose-intense chemotherapy regimens that are known to have survival benefits (Ewing sarcoma).

The guidelines do not recommend using CSFs in nonrelapsed acute myeloid leukemia or nonrelapsed acute lymphocytic leukemia in pediatric patients without infection.

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 alfa and darbepoetin alfa. Darbepoetin alfa has a half-life around three times longer than that of epoetin alfa; 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 the 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 the differing 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 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, however, 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 or lower 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 non-myeloid 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 non-myeloid malignancies treated with palliative intent, CRF, HIV (zidovudine) therapy, and to reduce the need for blood transfusion in elective non-cardiac 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 U/L). Combining ESAs and G-CSF in MDS patients has resulted in improved response rates.

Other indications include multiple myeloma, non-Hodgkin’s lymphoma, chronic lymphocytic leukemia, beta thalassemia, radiation therapy, rheumatoid arthritis, paroxysmal nocturnal hemoglobinuria, Castleman’s disease, congestive heart failure, critical illnesses, hepatitis C (in patients treated with interferon-alfa and ribavirin), and blood-unit collection for auto-transfusion.

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 post-surgery 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 i.v. ESAs.

Other side effects include headache, fatigue, fever, rash, pruritus, 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 I.V. 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 U/L are more likely to respond to ESAs than those with levels 100 U/L.

PLATELET GROWTH FACTORS

Thrombocytopenia can be a life-threatening consequence of antineoplastic treatments. Platelet transfusions are required to prevent or mitigate hemorrhagic complications. Due to the short life span of thrombocytes, transfusion necessity may arise as frequently as on a weekly bases. 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 non-myeloid 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 X103 per mcL 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.