Chapter 43: Indications for Growth Factors in Hematology-Oncology

Epidemiology

Febrile neutropenia is a major dose-limiting toxicity of chemotherapy. Studies have demonstrated that selective use of colony-stimulating factors (CSFs) in patients at high-risk for complications of neutropenia can enhance cost-effectiveness by reducing the risk, severity and duration of febrile neutropenia

NCI Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0 Neutrophil Count Decreased³

WHO Toxicity Criteria

Examples of Regimens with >20% Risk of Febrile Neutropenia²

Treatment Overview

NCCN Guidelines^® (V.1.2013)² and ASCO Guidelines (2006 Update)⁵ recommend routine use of CSFs support for patients at high risk (defined >20%) of developing febrile neutropenia who are receiving treatment with curative intent, adjuvant therapy, or treatment expected to prolong survival or to improve quality of life (QOL)^2,5

ASCO Guidelines also recommends CSFs for:

• Patients with diffuse aggressive lymphomas aged ≥65 years treated with curative chemotherapy (CHOP or more aggressive regimens)

• Patients exposed to lethal doses of total-body irradiation (TBI) (CSFs or pegylated G-CSF)⁵

NCCN Guidelines (V.1.2013) also recommend evaluation of patients for the use of myeloid growth factors before every cycle of cytotoxic chemotherapy

• If febrile neutropenia or a dose-limiting neutropenic event previously occurred during chemotherapy without CSFs use, the guidelines recommend considering CSFs use during repeated treatment cycles

• If fever with neutropenia or a dose-limiting neutropenic event occurred during prior chemotherapy in spite of appropriate CSFs use, the guidelines recommend considering decreasing the dosages of myelosuppressive treatment, or changing the treatment regimen

The chemotherapy regimens given as examples increase a patient's risk of developing febrile neutropenia. Additional risk factors to be considered when evaluating a patient's overall risk of febrile neutropenia include:

• Age (>65 years)

• Previous chemotherapy or radiation therapy

• Preexisting neutropenia or bone marrow involvement with tumor

• Preexisting conditions including:

  • Neutropenia

  • Infection/open wounds

  • Recent surgery

• Poor performance status

• Poor renal function

• Liver dysfunction, most notably elevated bilirubin

Preparations

1. Filgrastim (granulocyte-colony stimulating factor, G-CSF)

2. Pegfilgrastim (pegylated G-CSF)

3. Sargramostim (granulocyte macrophage-colony stimulating factor, GM-CSF)

NCI Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0 Febrile Neutropenia³

Radiation Therapy Oncology Group (RTOG) Cooperative Group Common Toxicity Criteria⁴

Regimen: Filgrastim (G-CSF, NEUPOGEN^®)

Patients with cancer receiving myelosuppressive chemotherapy:

Filgrastim 5 mcg/kg per day; administer by subcutaneous or intravenous injection or by subcutaneous or intravenous infusion beginning 1–3 days after completion of chemotherapy and continuing until ANC reaches 10,000/mm³ or clinically sufficient neutrophil count is achieved after nadir

Notes:

• Calculated doses may be rounded to use the most economical combination of available products (commercial vials and syringes contain either 300 mcg or 480 mcg

• FDA-approved labeling indicates subcutaneous or intravenous administration for up to 2 weeks after expected chemotherapy-induced ANC nadir)

• It is recommended not to use filgrastim within 24 hours before or 24 hours after chemotherapy administration

Dose Adjustment:

• Dosages may be increased in increments of 5 mcg/kg per dose for each chemotherapy cycle, according to the duration and severity of the ANC nadir

Patients with cancer receiving bone marrow/peripheral blood cell transplants (BMT/PBPCT):

Filgrastim 10 mcg/kg per day; administer by intravenous infusion over 4 or 24 hours or as a continuous 24-hour subcutaneous infusion

Note: Administer at least 24 hours after cytotoxic chemotherapy, and at least 24 hours after bone marrow infusion

Dosage Adjustment:

• When ANC >1000/mm³ for 3 consecutive days, reduce dose to 5 mcg/kg per day

• If ANC remains >1000/mm³ for 3 more consecutive days, discontinue G-CSF

• If ANC decreases to <1000/mm³, resume at 5 mcg/kg per day

• If ANC decreases to <1000/mm³ at any time during administration of 5 mcg/kg per day, increase G-CSF dosage to 10 mcg/kg per day and follow dose adjustment guidelines

Peripheral blood progenitor cells (PBPCs) collection:

Filgrastim 10 mcg/kg/day; administer by subcutaneous injection or continuous infusion

Notes:

• The optimal timing and duration of growth factor stimulation have not been determined

• Administration is recommended to begin 4 days before the first leukapheresis and continued until the last leukapheresis

Severe chronic neutropenia (SCN):

Congenital neutropenia

Filgrastim 6 mcg/kg per dose; administer by subcutaneous injection twice daily, continually

Idiopathic or cyclic neutropenia

Filgrastim 5 mcg/kg per day; administer by subcutaneous injection, continually

Notes:

• Chronic daily administration is needed to maintain clinical benefit

• ANC should not be used as the sole indication of efficacy

  • Dosages should be individually adjusted based on a patient's clinical course as well as ANC

• In a postmarketing surveillance study, median daily doses were 6 mcg/kg (congenital neutropenia), 2.1 mcg/kg (cyclic neutropenia), and 1.2 mcg/kg (idiopathic neutropenia). In rare instances patients with congenital neutropenia have required dosages ≥100 mcg/kg per day

Notes on dosing:

• The recommendations listed apply only to adult patients

• Doses for obese patients should be calculated on actual body weight, including morbidly obese patients

• Do not empirically reduce doses in elderly patients because of patient age

Preparation for intravenous administration:

• Filgrastim may be diluted in 5% dextrose injection (D5W) to a concentration within the range of 5–15 mcg/mL

  • Dilution to concentrations <5 mcg/mL is not recommended

• The diluted product must be protected from adsorption to container and administration set surfaces by adding albumin (human) to the vehicle solution (D5W) to a final concentration of 2 mg/mL BEFORE adding filgrastim

• Do not dilute filgrastim with sodium chloride-containing solutions

  • Admixture in saline solutions may cause precipitation

• The needle cover of prefilled syringes contains dry natural rubber (a latex derivative), which may cause allergic reactions in sensitive individuals

Efficacy

• In a phase III placebo-controlled trial of patients with small cell lung cancer, filgrastim use reduced the incidence of febrile neutropenia after chemotherapy by 36% (76% vs. 40%, P <0.001)

• An increase in ANC is seen approximately 24 hours after beginning filgrastim administration

• A 50% decrease in circulating neutrophils occurs within 1–2 days after discontinuing filgrastim use, which returns to pretreatment levels within 4–7 days

• In patients with AML receiving induction chemotherapy, filgrastim use reduced the median time to ANC recovery by 5 days (P <0.0001), the median duration of fever by 1.5 days (P = 0.009), and resulted in a statistically significant reduction in duration of intravenous antibiotic use and hospitalization

• In patients with AML receiving consolidation therapy, filgrastim significantly reduced the incidence of severe neutropenia, time to neutrophil recovery, the incidence and duration of fever, and the duration of intravenous antibiotic use and hospitalization

• After BMT, patients who received filgrastim support had a statistically significant reduction in the median number of days of severe neutropenia (21.5 vs. 10 days) and in the number of days of febrile neutropenia (13.5 vs. 5 days)

• In mobilized PBPCs, both CFU-GM and CD34+ cells were increased by more than 10-fold from baseline on day 5, and remained increased with leukapheresis. During engraftment, filgrastim-treated patients had significantly fewer days of platelet transfusion (median 6 vs. 10 days), fewer days of RBC transfusion (median 2 vs. 3 days), and significantly shorter time to recover a sustained ANC ≥500/mm³

• In 120 patients with severe chronic neutropenia, filgrastim treatment resulted in significant benefits in the incidence and duration of infection, fever, antibiotic use, and oropharyngeal ulcers⁶

Adverse Events

Indications

Patients with neoplastic diseases

• Use after myelosuppressive chemotherapy to reduce the incidence of febrile neutropenia

• Patients with acute myeloid leukemia receiving induction or consolidation chemotherapy

BMT

• Peripheral blood progenitor cell (PBPC) collection

Patients with non-neoplastic diseases

Severe chronic neutropenia⁶

Therapy Monitoring

1. During G-CSF therapy after cytotoxic chemotherapy: CBC with differential, before chemotherapy and twice weekly

2. After BMT: CBC with differential at least 3 times per week

3. During initiation of therapy for severe chronic neutropenia: CBC with differential twice weekly for the first 4 weeks and for 2 weeks following dose adjustment, then monthly if ANC is stable during the first year of treatment. Thereafter, regular CBC evaluation is recommended as clinically indicated and at least quarterly

4. PRBC collection: ANC after 4 days of G-CSF, and consider dose modifications if WBC is >100,000/mm³

Notes

1. The manufacturer recommends against CSF use 24 hours before or after cytotoxic chemotherapy, as well as simultaneous CSF use with chemotherapy and radiation

2. Patients must be instructed to report abdominal or shoulder tip pain, prompting evaluation for splenomegaly or splenic rupture, especially healthy donors receiving filgrastim for mobilization of PBPC

3. Patients must be instructed to report symptoms associated with respiratory distress, prompting evaluation for acute respiratory distress syndrome (ARDS)

4. Use with caution in patients with sickle cell disease; sickle cell crises have been reported following therapy. Only physicians qualified by specialized training or experience in the treatment of patients with sickle cell disorders should prescribe filgrastim for such patients, and only after careful consideration of the potential risks and benefits

5. Safety has not been established in patients with chronic myeloid leukemia (CML) or myelodysplastic syndromes (MDS), in patients receiving chemotherapy associated with delayed myelosuppression, or those receiving mitomycin or myelosuppressive doses of antimetabolites such as fluorouracil

6. In all clinical studies of the use of G-CSF for PBPC collection, G-CSF was administered after reinfusion of the collected cells

7. G-CSF is contraindicated in patients with a hypersensitivity to Escherichia coli–derived proteins, filgrastim, or any component of the formulation (sorbitol, polysorbate 80)

8. Patients should be referred to the “Information for Patients and Caregivers” portion of product labeling which provides information about neutrophils, neutropenia, safety, and efficacy. If home administration is desired, a puncture-resistant container for the disposal of used syringes and needles should be provided⁶

Regimen: Pegfilgrastim (Pegylated G-CSF, Neulasta^®)

Patients with cancers receiving myelosuppressive chemotherapy:

Pegfilgrastim 6 mg; administer subcutaneously once per chemotherapy cycle

Notes:

• A 6 mg fixed dose is recommended for adult patients whose body weight is ≥45 kg

• Administer doses at least 24 hours after cytotoxic chemotherapy is completed and at least 14 days before the next administration of cytotoxic chemotherapy

• Recommended injection sites are outer upper arm, abdomen >2 inches from the umbilicus, the front of the middle thighs, and upper outer area of the buttocks

Indications

Patients with neoplastic diseases:

To reduce the incidence of febrile neutropenia after myelosuppressive chemotherapy in patients with non-myeloid malignancies, NCCN Guidelines^® (V.1.2013) recommend routine use of CSF support as primary prophylaxis for patients at high risk (defined >20%) and consideration of CSF support in patients at intermediate risk (10–20%) of developing febrile neutropenia who are receiving treatment with curative intent, adjuvant therapy, or treatment expected to prolong survival or improve QOL²

NCCN Guidelines^® (V.1.2013) also recommend:

1. Evaluation of patients for the use of myeloid growth factors before each cycle of cytotoxic chemotherapy

2. If febrile neutropenia or dose-limiting neutropenia occurred in cycles with no CSF support, consider using a CSF

3. If febrile neutropenia or dose-limiting neutropenia occurred during a cycle in which a CSF was used, consider decreasing the dose/dosage of the myelosuppressive drugs in use or a change in the antineoplastic treatment regimen

ASCO Guidelines also recommend CSF support for:

1. Patients aged ≥65 years with diffuse aggressive lymphomas treated with curative chemotherapy (CHOP or more aggressive regimens)

2. Patients exposed to lethal doses of TBI⁵

Therapy Monitoring

Recommended only with regard to patient's hematologic status and ability to tolerate myelosuppressive chemotherapy⁷

Efficacy

• In a phase III trial in patients with breast cancer (Stages II–IV) who received combination chemotherapy with doxorubicin 60 mg/m² and docetaxel 75 mg/m², the efficacy of pegfilgrastim was similar to that of filgrastim based on the duration of severe neutropenia (1.8 days vs. 1.6 days) and the incidence of febrile neutropenia (13% vs. 20%)^7,8

• Pegfilgrastim is primarily eliminated by neutrophil receptor binding. Consequently, pegfilgrastim concentrations decline rapidly at the onset of neutrophil recovery⁷

• In two randomized controlled trials, pegfilgrastim was similar to filgrastim in the number of days of severe neutropenia during cycles 2–4 of chemotherapy⁷

• In a placebo-controlled trial, pegfilgrastim was found to lower the incidence of febrile neutropenia compared to placebo (1% vs. 17% P <0.001), decrease hospitalizations (1% vs. 14%), and decrease anti-infective use (2% vs. 10%)⁷

Adverse Events

Notes

1. Safety and efficacy have not been established for PBPC mobilization

2. Allergic reactions including anaphylaxis, skin rash, generalized erythema, flushing, and urticaria have been reported. In rare cases, allergic reactions including anaphylaxis recurred within days after initial anti-allergic treatment was discontinued. Patients should report flushing, dizziness, rash, and any signs or symptoms of infection

3. Patients must be instructed to report upper left abdominal or shoulder tip pain, prompting evaluation for splenomegaly or splenic rupture

4. Patients must be instructed to report symptoms of respiratory distress including shortness of breath, prompting evaluation for acute respiratory distress syndrome

5. Use with caution in patients with sickle cell disease; sickle cell crises have been reported following therapy with filgrastim, the active component of pegfilgrastim. Only physicians qualified by specialized training or experience in the treatment of patients with sickle cell disorders should administer pegfilgrastim

6. The needle cover of prefilled syringes contains dry natural rubber (a latex derivative), which may cause allergic reactions in sensitive individuals

7. The G-CSF receptor through which pegfilgrastim and filgrastim act has been found on tumor cell lines. The possibility that pegfilgrastim acts as a growth factor for any tumor type, including myeloid malignancies and myelodysplasia, diseases for which pegfilgrastim is not approved, cannot be excluded⁷

Regimen: Sargramostim (GM-CSF, Leukine^®)

Following induction chemotherapy in AML (adults):

Sargramostim 250 mcg/m² per day; administer by intravenous infusion over 4 hours until ANC >1500/mm³ for 3 consecutive days or a maximum of 42 days is reached

Notes:

• Start therapy on day 11 of cycle or 4 days after completion of induction chemotherapy if the bone marrow on day 10 is hypoblastic with <5% blasts

• This regimen may be repeated if a second cycle of induction chemotherapy is needed

• Interrupt or reduce the dose by half if ANC is >20,000 cells/mm³

• Discontinue immediately if leukemia regrows

Mobilization of peripheral blood progenitor cells (PBPCs):

Sargramostim 250 mcg/m² per day; administer by intravenous infusion over 24 hours or by subcutaneous injection once daily throughout the entire course of PBPC collection

Note:

Reduce dose by 50% if WBC >50,000 cells/mm³

Following transplantation of autologous PBPCs:

Sargramostim 250 mcg/m² per day; administer by intravenous infusion over 24 hours or by subcutaneous injection once daily beginning immediately after the infusion of PBPCs and continuing until ANC >1500 cells/mm³ for 3 consecutive days

Myeloid reconstitution after autologous or allogeneic BMT:

Sargramostim 250 mcg/m² per day; administer by intravenous infusion over 2 hours beginning 2–4 hours after bone marrow infusion and ≥24 hours after the last dose of chemotherapy or radiation therapy. Patients should not receive sargramostim until the postmarrow infusion ANC is <500 cells/mm³. Continue therapy until ANC >1500 cells/mm³ for 3 consecutive days

Notes:

1. If blast cells appear or progression of the underlying disease occurs, discontinue use immediately

2. Interrupt or reduce the dosage by half if ANC is >20,000 cells/mm³

BMT failure or engraftment delay:

Sargramostim 250 mcg/m² per day; administer by intravenous infusion over 2 hours for 14 consecutive days

Notes:

• If engraftment has not occurred within 7 days after completing sargramostim therapy, repeat the course of Sargramostim 250 mcg/m² per day by intravenous infusion over 2 hours for 14 consecutive days

• If engraftment has not occurred within 7 days after completing a second course of sargramostim, administer Sargramostim 500 mcg/m² per day by intravenous infusion over 2 hours for 14 consecutive days. If there is still no improvement, it is unlikely that further dose escalation will be beneficial

• If blast cells appear or progression of the underlying disease occurs, discontinue use immediately

Notes on dosing:

• If a severe adverse reaction occurs, temporarily reduce the sargramostim dosage by 50% or temporarily interrupt administration until the reaction abates

• Doses recommended are for adult patients

• Doses for obese patients should be calculated on actual body weight, including use in morbidly obese patients

• Do not empirically reduce doses in elderly patients because of patient age

Preparation of solution:

Sargramostim for intravenous infusion must be diluted with 0.9% sodium chloride injection (0.9% NS). If the final concentration of sargramostim is less than 10 mcg/mL, albumin (human) must be added to the vehicle solution (0.9% NS) to produce a final albumin concentration of 0.1% BEFORE adding sargramostim to prevent sargramostim adsorption to the product container and administration set tubing

• To produce a vehicle solution with an albumin concentration of 0.1% suitable for diluting sargramostim:

  Add 1 mL 5% albumin (human) to 49 mL 0.9% NS, or

  Add 0.2 mL 25% albumin (human) to 49.8 mL 0.9% NS

When administered by subcutaneous injection, sargramostim should be used without further dilution

Efficacy

• After AML 7+3 induction therapy consisting of daunorubicin 60 mg/m² per day for 3 consecutive days plus cytarabine 100 mg/m² per day for 7 consecutive days, sargramostim significantly shortened the duration of neutropenia compared to placebo⁹ (ANC <500/mm³ by 4 days, ANC <1000/mm³ by 7 days), decreased the incidence of grades III–V infection (10% vs. 36%, respectively) and death from infection (6% vs. 15%, respectively), and significantly shortened the time to neutrophil recovery¹⁰

• A retrospective review of PBPC collections from patients with cancer treated with sargramostim 250 mcg/m² per day showed significantly higher numbers of granulocyte-macrophage colony-forming units (CFU-GM) than those collected without mobilization (11.41 × 10⁴ CFU-GM/kg vs. 0.96 × 10⁴ CFU-GM/kg, respectively)⁹

• In a historical controlled study of patients with lymphoma or myeloid leukemia who experienced BMT failure or engraftment delay, patients who received sargramostim with autologous transplantation achieved a median survival of 474 days versus 161 days for historical controls who had not received GM-CSF⁹

• Similarly, after failure of allogeneic hematopoietic progenitor cell transplantation, the median survival was 97 days in a group of patients who received sargramostim versus 35 days for the historical control patients who had not received GM-CSF⁹

Indications

1. Following induction chemotherapy in AML

2. Mobilization of PBPCs for collection and myeloid reconstitution after autologous PBPC transplantation

3. Myeloid reconstitution after autologous or allogeneic BMT

4. BMT failure or engraftment delays⁹

Therapy Monitoring

CBC with differential twice weekly during therapy. Monitoring of renal and hepatic function is recommended at least biweekly in patients displaying renal or hepatic dysfunction prior to initiation of treatment. Body weight and hydration status should be carefully monitored during administration. Interrupt therapy or reduce dose by half for excessive leukocytosis as defined by manufacturer: ANC >20,000 cells/mm³ or WBC >50,000 cells/mm³

Notes

1. Use with caution in patients with:

   1. Pre-existing cardiac disease

   2. Hypoxia, lung disease, or pulmonary symptoms

   3. Fluid retention

   4. Renal or hepatic impairment

   5. Rapid increase in peripheral blood counts

2. Use with caution in children

3. Discontinue GM-CSF immediately if blast cells appear after bone marrow infusion. It is possible that GM-CSF may act as a growth factor for tumor cells; use caution with patients with any malignancy with myeloid characteristics

4. Contraindications

   1. Patients with known hypersensitivity to GM-CSF, yeast-derived products, or any component of the sargramostim formulations, including:

      1. Mannitol, sucrose, tromethamine in both liquid and lyophilized formulations

      2. Benzyl alcohol in the liquid formulation (do not administer to neonates, infants, pregnant women, and nursing mothers, as benzyl alcohol may cause “Gasping Syndrome”)

   2. Concomitant sargramostim use with cytotoxic chemotherapy and radiation therapy

      1. Commence administering sargramostim at least 24 hours after completing myelosuppressive chemotherapy or radiation therapy, and discontinue use at least 24 hours before resuming myelosuppressive chemotherapy or radiation therapy administration

   3. Patients with >10% leukemic myeloid blasts in the bone marrow or peripheral blood

5. Efficacy of GM-CSF has not been assessed in AML patients <55 years of age⁹

Adverse Events

Epidemiology

Preparations

1. Epoetin alfa (Procrit^®, Epogen^®)

2. Darbepoetin alfa (Aranesp^®)

Treatment Overview^4,5,6,7

• In patients with cancer, use erythropoiesis-stimulating agents (ESAs) only for treatment of anemia associated with myelosuppressive chemotherapy

• ESAs are not indicated for patients receiving myelosuppressive therapy when the anticipated outcome is cure

• ESAs are not indicated for use in treating anemia associated with hormonal agents, therapeutic biologic products, or radiotherapy, unless a patient is also receiving myelosuppressive chemotherapy concomitantly

• Discontinue ESAs following the completion of a chemotherapy course (no plan to resume treatment)

• ESA use has not been demonstrated to improve symptoms of anemia, quality of life, fatigue, or patient well-being in controlled clinical trials

• Patients should be instructed to read the manufacturer supplied “Medication Guide and Patient Instructions for Use” and should be informed that this is not a disclosure of all possible side effects

  • According to the manufacturers' product information, “patients should be informed of the increased risks of mortality, serious cardiovascular events, thromboembolic reactions, stroke, and tumor progression”

• The possibility that ESAs can act as a growth factor for any tumor type, particularly myeloid malignancies, cannot be excluded. ESAs shortened overall survival and/or increased the risk of tumor progression or recurrence in some clinical studies in patients with breast, non–small cell lung, head and neck, lymphoid, and cervical cancers.^4,5,6,7 To decrease these risks, as well as the risk of serious cardio- and thrombo-vascular events, use the lowest dose needed to avoid red blood cell transfusion^2,3,4,5

• Blood pressure in patients with a history of hypertension or cardiovascular disease should be carefully monitored and controlled prior to initiation and during treatment with ESAs

• Epoetin alpha increases the reticulocyte count within 10 days of initiation, followed by increases in the RBC count, Hgb, and Hct, usually within 2–6 weeks

• A lack of response or failure to maintain a hemoglobin response with ESAs within the recommended dosing range may be due to deficiencies of folic acid, iron, or vitamin B₁₂, which should be excluded or corrected. Baseline and periodic monitoring of iron, total iron-binding capacity, transferrin saturation (≥20%), ferritin (≥100 ng/mL), folate, and vitamin B₁₂ levels are recommended

• Iron supplementation should be instituted as necessary to provide for increased requirements during ESA therapy

• In a prospective, randomized trial of 157 patients with cancer- or chemotherapy-related anemia, patients were randomly assigned to receive:

  1. No iron

  2. Ferrous sulfate 325 mg orally twice daily

  3. Iron dextran 100 mg intravenously at each weekly visit until the calculated dose for iron replacement was reached

     • The first 3 doses required a 25-mg iron dextran test dose administered by intravenous injection over 1–2 minutes, followed by:

     • Iron dextran 75 mg as a short intravenous infusion

     • A test dose was not given if allergic reactions had not occurred during the first 3 weekly doses

  4. Total dose infusion (TDI) of iron dextran calculated to achieve a desired hemoglobin concentration

     • Methylprednisolone 125 mg/dose was given before and after iron dextran to ameliorate arthralgias and myalgias associated with this method of iron administration

     • Iron dextran was given as a 25-mg test dose by intravenous injection over 1–2 minutes. If the test dose was tolerated, it was followed after a 1-hour observation period with:

     • Iron Dextran diluted in 500 mL 0.9% sodium chloride injection administered at a rate of 175 mL/h

     • Iron dextran TDI was calculated as follows for patients with body weight >15 kg:

       

• Mean increases in Hgb levels were 0.9 g/dL, 1.5 g/dL, 2.5 g/dL, and 2.4 g/dL for the no iron, oral ferrous sulfate, weekly iron dextran, and TDI iron dextran groups, respectively. The percentage of patients who had a Hgb response was also significantly better (P <0.01) in both groups given iron dextran (68%) than patients who received oral therapy (36%), or no iron therapy (25%)

• Pure red blood cell aplasia (PRCA) has been reported in a limited number of patients. If a patient shows evidence of PRCA (severe anemia and low reticulocyte count), withhold treatment and evaluate patient for neutralizing antibodies to erythropoietin, contact Amgen (1-800-772-6436) to perform assays for binding and neutralizing antibodies. If PRCA is detected, do not restart or switch to any other ESA^2,4,5,6

• There have been rare reports of potentially serious allergic reactions to ESAs

• Contraindications to ESA therapy are uncontrolled hypertension PRCA that begins after ESA treatment, and serious allergic reactions to ESAs.

• If home use is prescribed for a patient, the patient should be thoroughly instructed in the importance of proper disposal and cautioned against reusing needles, syringes, or drug product. A puncture-resistant container should be available for the disposal of used syringes and needles, and guidance provided on disposal of full containers

Regimen: Epoetin Alfa (Epogen^®, Procrit^®)

In patients with non-myeloid malignancies where anemia is due to the effect of myelosuppressive chemotherapy, and, after initiating epoetin therapy, there are planned at least two additional months of chemotherapy:

• Therapy should not be initiated if Hgb ≥10 g/dL

• ESA treatment should target the lowest Hgb level that will avoid RBC transfusion

• ESA therapy is not indicated for patients receiving chemotherapy with curative intent

Adult cancer patients receiving myelosuppressive chemotherapy³:

Epoetin alfa 40,000 units; administer by subcutaneous injection once weekly^✫, or

Epoetin alfa 150 units/kg; administer by subcutaneous injection 3 times per week

Note: NCCN Guidelines^® list alternative regimens with extended dosing intervals²:

Epoetin alfa 80,000 Units; administer by subcutaneous injection every 2 weeks or

Epoetin alfa 120,000 Units; administer by subcutaneous injection every 3 weeks

Pediatric patients (ages 5–18 years) with cancer who are receiving myelosuppressive chemotherapy:

Epoetin alfa 600 Units/kg; administer by intravenous injection once weekly (maximum weekly dose = 40,000 Units)

Treatment Modifications

• Reduce epoetin alfa dose by 25% when Hgb reaches a level needed to avoid transfusion or Hgb increases >1 g/dL during any 2-week period

• Hold dose if Hgb exceeds a level needed to avoid transfusion. Resume epoetin alfa use at 25% less than the dose previously administered when Hgb approaches a level at which transfusions may be required

• Increase epoetin alfa dose if Hgb increase is ≤1 g after 4 weeks of therapy without RBC transfusion:

• For adults patients with cancer increase doses to either 60,000 units by subcutaneous injection weekly, or

• 300 units/kg three times weekly

• For pediatric patients with cancer increase doses to 900 units/kg by intravenous injection (maximum weekly dose = 60,000 units)

• Discontinue epoetin alfa if Hgb response after 8 weeks of use is <1 g/dL, or transfusion is still required

• Discontinue epoetin alfa following completion of a chemotherapy course

Therapy Monitoring

Until a maintenance dose is established and after any dose adjustment: Monitor Hgb weekly until the hemoglobin level is stable and sufficient to minimize the need for RBC transfusion

After Hgb stabilizes: Monitor Hgb at regular intervals

Monitor iron, folate, and vitamin B₁₂ status before and during treatment. Supplementation is recommended if serum ferritin <100 mcg/L or serum transferrin saturation <20%, or folate or vitamin B₁₂ are less than the range of normal concentrations

Efficacy

• Among anemic patients with cancer receiving epoetin alfa or placebo concomitantly with chemotherapy, 14% vs. 28%, respectively, required transfusion support during weeks 5–16 after starting ESA treatment (59/344 were receiving cisplatin-containing regimens)⁵

• In a randomized, placebo-controlled study in patients with anemia who received chemotherapy, epoetin alfa was shown to significantly reduce transfusion requirements (24.7% vs. 39.5%, P = 0.0057) and raise Hgb levels (2.2 g/dL vs. 0.5 g/dL, P = 0.001)²

• A double-blind, placebo-controlled, randomized, phase III study found patients who received darbepoetin alfa 2.25 mcg/kg per week required fewer transfusions (27% vs. 52%, P <0.001) than patients receiving placebo²

Indications

Patients with neoplastic diseases

• Anemia from concomitantly administered chemotherapy for non-myeloid, metastatic malignancies receiving chemotherapy for a minimum of 2 months

• In addition to the FDA-approved indications, ASCO/ASH 2007 guidelines recognize ESA use in low-risk myelodysplasia⁹

Patients with non-neoplastic diseases

• Anemia from chronic kidney disease (CKD)

• Zidovudine-related anemia in HIV patients

• Reduction of allogeneic blood transfusion in patients who receive elective, noncardiac, nonvascular surgery

Adverse Events

Notes

1. Epoetin alpha increases the risk of seizures in patients with CKD. Patients should be monitored closely and contact their prescriber for new-onset seizures, premonitory symptoms, or change in seizure frequency.

2. Epoetin alfa is contraindicated in patients with hypersensitivity to any component of the formulation:

   Epogen® and Procrit®

   • Single-dose vials containing preservative-free epoetin alfa 2000, 3000, 4000 or 10,000 units/mL also contain the following excipients: albumin (human), sodium citrate, sodium chloride, and citric acid in water for injection, USP

   • Single-dose vials containing preservative-free epoetin alfa 40,000 units/mL also contain albumin (human), sodium phosphate monobasic monohydrate, sodium phosphate dibasic anhydrate, sodium citrate, sodium chloride, and citric acid in water for injection, USP

   • Multi-dose vials containing 10,000 units/mL or 20,000 units/mL of epoetin alfa also contain albumin (human), sodium citrate, sodium chloride, ± citric acid, and 1% benzyl alcohol as preservative in water for injection, USP

3. Patients with uncontrolled hypertension should not receive epoetin alfa

4. Epoetin alfa should be discontinued after completion of a course of chemotherapy

5. ESA therapy increased the risks for myocardial infarction, stroke, congestive heart failure and fatal thrombotic events (1.1% in patients with cancer participating in clinical trials). An increase in Hgb >1 g/dL over 2 weeks may contribute to these risks

6. Multi-dose vials contain benzyl alcohol, which is contraindicated in neonates, infants, pregnant women, and nursing mothers, as it may cause “Gasping Syndrome”

Regimen: Darbepoetin Alfa (ARANESP®)

In adult patients with metastatic, nonmyeloid malignancies receiving myelosuppressive chemotherapy:

• Therapy should not be initiated if Hgb is ≥10 g/dL

• ESA treatment should target the lowest Hgb level that will avoid RBC transfusion

• ESA therapy is not indicated for patients receiving chemotherapy with curative intent

Patients with cancer who are receiving myelosuppressive chemotherapy:

Darbepoetin 2.25 mcg/kg; administer by subcutaneous injection, once weekly, or

Darbepoetin alfa 500 mcg; administer by subcutaneous injection, once every 3 weeks

NCCN guidelines list alternative dosing schedules for consideration:

Darbepoetin 100 mcg weekly

Darbepoetin 200 mcg biweekly

Darbepoetin 300 mcg every three weeks

Notes:

• NCCN Guidelines^® include alternative fixed dose schedules for consideration:²

  • Darbepoetin alfa 100 mcg; administer by subcutaneous injection, once weekly, or

  • Darbepoetin alfa 200 mcg; administer by subcutaneous injection, once every 2 weeks, or

  • Darbepoetin alfa 300 mcg; administer by subcutaneous injection, once every 3 weeks

• For patients who receive weekly darbepoetin, if Hgb increases <1 g/dL and remains <10 g/dL after 6 weeks of therapy, increase the darbepoetin dosage to 4.5 mcg/kg per week

• If Hgb increases >1 g/dL in a 2-week period or Hgb reaches a level needed to avoid transfusion, reduce the dosage by 40% of dose previously administered

• If Hgb exceeds a level needed to avoid transfusion, hold therapy until Hgb approaches a level where transfusion may be required, then reinitiate at a dosage decreased by 40% from the dose previously administered

• Discontinue darbepoetin following completion of a chemotherapy course, or, if after 8 weeks of therapy there is no response as measured by Hgb levels or if transfusions are still required

Therapy Monitoring⁴

Until a maintenance dose established and after any dose adjustment: Monitor Hgb weekly until hemoglobin is stable and sufficient to minimize the need for RBC transfusion

After Hgb stabilized: Monitor Hgb at regular intervals

Monitor iron, folate, and vitamin B₁₂ status before and during treatment. Supplementation is recommended if serum ferritin <100 mcg/L or serum transferrin saturation <20%, or folate or vitamin B₁₂ are less than the range of normal concentrations

Indications⁴

Patients with neoplastic diseases

Anemia from concomitantly administered chemotherapy that is expected to continue for a minimum of 2 months (non-curative intent) in patients with metastatic, nonmyeloid malignancies

Patients with non-neoplastic diseases

Anemia associated with chronic renal failure, including patients on dialysis and patients not on dialysis

Efficacy

Darbepoetin once weekly dosing was studied in advanced lung cancer patients (both SCLC and NSCLC) with Hgb values <11g/dL who were receiving platinum containing chemotherapy regimens. At 12 weeks, a significantly lower proportion of patients who received darbepoetin vs. placebo required a RBC transfusion (26% vs. 50%, respectively)⁴

Efficacy of darbepoetin 500 mcg administered once every 3 weeks versus 2.25 mcg/kg weekly was studied in patients with a Hgb <11g/dL undergoing cytotoxic chemotherapy. Seventy-two percent of patients required dose reductions in the every-3-weeks group whereas 77% required dose reductions in the once weekly group. Twenty-three percent of patients in the once-every-3-weeks group required RBC transfusion and 28% of the weekly group required RBC transfusion^4,10

Adverse Events

Notes

Epidemiology

Preparations

Oprelvekin (Neumega^®)

Regimen: Oprelvekin (Recombinant Human Interleukin-11 [rhil-11] NEUMEGA®)

Therapy Monitoring³

1. Platelet counts: Monitor during the time of the expected nadir and until adequate recovery has occurred. Discontinue oprelvekin when postnadir platelet counts are ≥50,000/mm³

2. Fluid and electrolytes: Monitor especially in patients receiving chronic diuretic therapy. In clinical trials, 2 patients died from severe hypokalemia after high-dose ifosfamide and use of daily diuretics. A CBC should be obtained prior to chemotherapy and at regular intervals during oprelvekin therapy

Notes³

1. Not indicated after myeloablative chemotherapy. In a phase II trial of women who received myeloablative chemotherapy and autologous bone marrow transplant, the incidence of platelet transfusions and time to neutrophil and platelet engraftment were similar between patients who received oprelvekin or placebo. The incidence of adverse events was increased with oprelvekin use

2. Severe or fatal adverse reaction reported postmarketing in BMT setting: Fluid retention that may lead to pulmonary edema, capillary leak syndrome, peripheral edema, dyspnea on exertion, atrial arrhythmias, exacerbation of pre-existing pleural effusion, and papilledema

3. Safety and efficacy for oprelvekin use has also not been established in the following settings:

   1. Agents that cause delayed myelosuppression such as nitrosoureas or mitomycin

   2. Myelosuppressive regimens of >5 days' duration

   3. Chronic administration

   4. Children

4. Use with caution in patients who have a history of atrial arrhythmia or CHF, in patients at risk of developing fluid retention or CHF, patients receiving aggressive hydration, and in patients whose clinical condition can be exacerbated by fluid retention

5. Patients with a history of stroke or TIA may be at increased risk for nervous system events

6. Oprelvekin is contraindicated in patients with a history of hypersensitivity to the drug or any component of the formulation, including: glycine, dibasic sodium phosphate heptahydrate, monobasic sodium phosphate monohydrate, and water for injection

Indications

Prevention of severe thrombocytopenia (platelet count ≤20,000/mm³) and the reduction of the need for platelet transfusion in adult patients who are at high risk for thrombocytopenia after myelosuppressive chemotherapy for non-myeloid malignancies

Efficacy³

1. In a randomized placebo-controlled trial of 93 patients with various nonmyeloid malignancies who had recovered from an episode of severe chemotherapy-induced thrombocytopenia (platelet counts ≤20,000/mm³), the number of patients who required platelet transfusions was significantly less for patients who received oprelvekin (50 mcg/kg per day) than for patients who received placebo (72% versus 93%, respectively; P <0.05)

2. Oprelvekin should be reserved for patients who experienced therapy-limiting thrombocytopenia; it is not recommended for routine primary prophylaxis against thrombocytopenia

3. Platelet increases are seen within 5–9 days. After cessation of treatment, platelet counts continue to increase for up to 7 days, then return toward baseline within 14 days

Adverse Events

Dosage

Patients with cancer receiving myelosuppressive chemotherapy:

Oprelvekin 50 mcg/kg per day; administer by subcutaneous injection, beginning 6–24 hours after completion of chemotherapy until platelet count is ≥50,000/mm³ or for a maximum of 21 days

Notes:

• Product concentration after reconstitution is 5 mg/mL

• Do not round doses

• Administer oprelvekin for a maximum of 21 days for up to 6 cycles

• Discontinue oprelvekin at least 2 days before starting myelosuppressive chemotherapy

• Administer subcutaneously in the abdomen, thighs, hips, or upper arms

• In renal impairment (creatinine clearance <30 mL/min [<0.5 mL/s]), reduce dosage to 25 mcg/kg per day

• Recommended dosage in obese adults does not differ from the standard adult dose of 50 mcg/kg per day, which is based on actual body weight. The maximum patient weight treated with oprelvekin in clinical trials was 147 kg