Medical PolicyMedical Policy
Policy Num: 05.001.043
Policy Name: Hematopoietic Colony-Stimulating Factors (CSFs)
Policy ID: [05.001.043] [Ac / L / M+ / P+ ] [0.00.00]
Last Review: October 24, 2024
Next Review: October 20, 2025
Related Policies: None
| Population Reference No. | Populations | Interventions | Comparators | Outcomes |
| 1 | Individuals · With cancer receiving cytotoxic antineoplastic therapy sufficient to adversely affect myelopoiesis | Intervention of interest are: · Hematopoetic Colony Factors (CSF) | Comparators of interest are: · Convetional therapy with out CSFs | Relevant Outcomes include: · Overall quality of life · Disease-specific survival · Overall survival · Treatment related morbidity |
There are several brands of short-acting colony stimulating factor (CSF) products on the market, including Neupogen (filgrastim), Zarxio (filgrastim-sndz), Nivestym (filgrastim-aafi), Granix (tbo-filgrastim) and Leukine (sargramostim). There is a lack of reliable evidence that any one brand of short-acting CSF is superior to other brands for medically necessary indications.
There are several brands of long-acting granulocyte colony stimulating factors (G-CSFs) on the market, including Neulasta (pegfilgrastim), Neulasta Onpro kit (pegfilgrastim), Nyvepria (pegfigrastim-apgf), Fulphila (pegfilgrastim-jmdb), Udenyca (pegfilgrastim-cbqv) and Ziextenzo (pegfilgrastim-bmez). There is a lack of reliable evidence that any one brand of long-acting G-CSF is superior to other brands for medically necessary indications.
The objective of this evidence-based review is to evaluate the role of Hematopoietic Colony-Stimulating Factors (CSFs) short and long active in cancer patients receiving cytotoxic antineoplastic therapy sufficient to adversely affect myelopoiesis and the integrity of the gastrointestinal mucosa are at risk for invasive infection due to colonizing bacteria or fungi that translocate across intestinal mucosal surfaces.
Trple S considers short-acting granulocyte colony stimulating factors (G-CSFs), medically necessary for prevention of neutropenia in persons with cancer receiving myelosuppressive chemotherapy when the following criteria are met:
I. The short-acting G-CSF will not be used in combination with other colony stimulating factors within any chemotherapy cycle; and
II. The member will not be receiving concurrent chemotherapy and radiation therapy; and
III. One of the following criteria is met
A. The short-acting G-CSF will be used for primary prophylaxis in individuals with a solid tumor or non-myeloid malignancies who have received, is currently receiving, or will be receiving myelosuppressive chemotherapy that is expected to result in:
1. 20% or higher incidence of febrile neutropenia (FN) (see Appendix); or
2. 10 - 19% risk of FN (see Appendix)
Note: In the absence of special circumstances, most commonly used regimens have risks of FN of less than 20 %. When available, alternative regimens offering equivalent efficacy, but not requiring CSF support, should be utilized (Smith et al, 2006).
B. The short-acting G-CSF will be used for secondary prophylaxis in members with solid tumors or non-myeloid malignancies who experienced a febrile neutropenic complication or a dose-limiting neutropenic event (a nadir or day of treatment count impacting the planned dose of chemotherapy) from a prior cycle of similar chemotherapy, with the same dose and schedule planned for the current cycle (for which primary prophylaxis was not received).
Note: Colony-stimulating factors should not be routinely used for afebrile neutropenia (Smith et al, 2006).
C. The short-acting G-CSF will be used for treatment of febrile neutropenia (FN).
Tripe S considers short-acting G-CSF products medically necessary for the following indications:
I. Acute Myeloid Leukemia
II. Agranulocytosis (non-chemotherapy drug-induced)
III. Aplastic anemia
IV. CAR T-cell-related toxicities: Supportive care for neutropenic persons with CAR T-cell-related toxicities
V. Chronic Myeloid Leukemia: Members with chronic myeloid leukemia (CML) for treatment of persistent neutropenia due to tyrosine kinase inhibitor therapy
VI. Glycogen Storage Disease (GSD) Type 1: Individuals with GSD Type 1 for treatment of low neutrophil counts
VII. Hairy Cell Leukemia: Members with hairy cell leukemia with neutropenic fever following chemotherapy
VIII. Hematopoietic Syndrome of Acute Radiation Syndrome - Treatment for radiation-induced myelosuppression following a radiological/nuclear incident
IX. Myelodysplastic syndrome (anemia or neutropenia)
X. Neutropenia related to HIV/AIDS
XI. Neutropenia related to renal transplantation
XII. Severe chronic neutropenia (congenital, cyclic, or idiopathic)
XIII. Stem cell transplantation-related indications.
Trple S considers long-acting granulocyte colony stimulating factors (G-CSFs), pegfilgrastim (Neulasta), pegfilgrastim-jmdb (Fulphila), Nyvepria (pegfilgrastim -apgf), pegfilgrastim-cbqv (Udenyca), and pegfilgrastim-bmez (Ziextenzo) medically necessary for prevention of neutropenia in persons with cancer receiving myelosuppressive chemotherapy when the following criteria are met:
I. The long-acting G-CSF will not be used in combination with other colony stimulating factors within any chemotherapy cycle; and
II. The member will not be receiving concurrent chemotherapy and radiation therapy; and
III. The requested medication will not be administered with weekly chemotherapy regimens; and
IV. One of the following criteria is met
A. The long-acting G-CSF will be used for primary prophylaxis in individuals with a solid tumor or non-myeloid malignancies who have received, is currently receiving, or will be receiving myelosuppressive chemotherapy that is expected to result in:
1. 20% or higher incidence of febrile neutropenia (FN) (see Appendix); or
2. 10 - 19% risk of FN (see Appendix)
Note: In the absence of special circumstances, most commonly used regimens have risks of FN of less than 20 %. When available, alternative regimens offering equivalent efficacy, but not requiring CSF support, should be utilized (Smith et al, 2006).
B. The long-acting G-CSF will be used for secondary prophylaxis in members with solid tumors or non-myeloid malignancies who experienced a febrile neutropenic complication or a dose-limiting neutropenic event (a nadir or day of treatment count impacting the planned dose of chemotherapy) from a prior cycle of similar chemotherapy, with the same dose and schedule planned for the current cycle (for which primary prophylaxis was not received).
Note: Colony-stimulating factors should not be routinely used for afebrile neutropenia (Smith et al, 2006).
C. The short-acting G-CSF will be used for treatment of febrile neutropenia (FN).
Triple S considers long-acting G-CSF products medically necessary for the following indications:
I. Chronic Myeloid Leukemia - Members with chronic myeloid Leukemia (CML) for treatment of persistent neutropenia due to tyrosine kinase inhibitor therapy
II. Hairy cell leukemia - Members with hairy cell leukemia with neutropenic fever following chemotherapy
III. Hematopoietic Syndrome of Acute Radiation Syndrome - Treatment for radiation-induced myelosuppression following a radiological/nuclear incident
IV. Stem cell transplantation-related indications.
Filgrastim (Neupogen®) is FDA approved for the following indications. (1) :
Filgrastim (Neupogen) is recommended by The NCCN Drugs and Biologics Compendium® for off-label use for the following indications:
Triple S considers continued treatment with short-acting G-CSF products and long-acting G-CSF products medically necessary for all members who meet all initial authorization criteria.
Dosing Limits
A. Quantity Limit (max daily dose) [NDC Unit]:
− Neupogen 300 mcg vial: 3 vials per 1 day
− Neupogen 300 mcg SingleJect: 3 syringes per 1 day
− Neupogen 480 mcg vial: 3 vials per 1 day
− Neupogen 480 mcg SingleJect: 3 syringes per 1 day
− Nivestym 300 mcg vial: 3 vials per 1 day
− Nivestym 300 mcg prefilled syringe: 3 syringes per 1 day
− Nivestym 480 mcg vial: 3 vials per 1 day
− Nivestym 480 mcg prefilled syringe: 3 syringes per 1 day
− Zarxio 300 mcg prefilled syringe: 3 syringes per 1 day
− Zarxio 480 mcg prefilled syringe: 3 syringes per 1 day
− Granix 300 mcg pre-filled syringe: 4 syringes per 1 day
− Granix 300 mcg single-dose vial: 4 vials per 1 day
− Granix 480 mcg pre-filled syringe: 3 syringes per 1 day
− Granix 480 mcg single-dose vial: 3 vials per 1 day
− Neulasta 6 mg prefilled syringe: 1 syringe per 14 days
− Fulphila 6 mg prefilled syringe: 1 syringe per 14 days
− Udenyca 6 mg prefilled syringe: 1 syringe per 14 days
− Ziextenzo 6 mg prefilled syringe: 1 syringe per 14 days
Dosage/Administration
Indication Dose BMT/PBPC/Radiation Indications 10 mcg/kg daily for up to 14 days
Congenital Neutropenia 6 mcg/kg twice daily
All other indications 5 mcg/kg daily for up to 14 days
Prophylactic use in patients with non-myeloid malignancy Patient who experienced a neutropenic complication from a prior cycle of the same chemotherapy
• 6 mg subcutaneously once per chemotherapy cycle and dosed no more frequently than every 14 days • For pediatric patients weighing <45 Kg
<10 kg = 0.1 mg/kg − 10-20 kg = 1.5 mg − 21-30 kg = 2.5 mg − 31-44 kg = 4 mg
Acute Radiation Exposure (Hematopoietic Subsyndrome of Acute Radiation Syndrome)
• 6 mg subcutaneously weekly x 2 doses
• For pediatric patients weighing
< 10 kg = 0.1 mg/kg − 10-20 kg = 1.5 mg − 21-30 kg = 2.5 mg − 31-44 kg = 4 mg
BMT failure or engraftment delay 6 mg subcutaneously for 1 dose only
Initial Approval Criteria short-acting colony stimulating factor (CSF)
Coverage is provided in the following conditions:
Bone marrow transplant (BMT) †/‡
Peripheral Blood Progenitor Cell (PBPC) mobilization and transplant 18,30,33,35-37 †/‡
Prophylactic use in patients with non-myeloid malignancy 1-4,5,6,8,9,11,12,14,16,27-29 †/‡
• Patient is undergoing myelosuppressive chemotherapy with an expected incidence offebrile neutropenia of 20% or greater §; OR
• Patient is undergoing myelosuppressive chemotherapy with an expected incidence offebrile neutropenia of 10% or greater§ AND one or more of the following co-morbidities:
− Elderly patients (age > 65) receiving full dose intensity chemotherapy
− History of recurrent febrile neutropenia from chemotherapy
− Extensive prior exposure to chemotherapy
− Previous exposure of pelvis, or other areas of large amounts of bone marrow, to radiation
− Pre-existing neutropenia (ANC ≤ 1000/mm3)
− Bone marrow involvement with tumor
− Patient has a condition that can potentially increase the risk of serious infection(i.e. HIV/AIDS with low CD4 counts)
− Recent surgery and/or open wounds
− Poor performance status − Renal dysfunction (creatinine clearance 2.0)
− Chronic immunosuppression in the post-transplant setting including organ transplant
Note: Dose-dense therapy, in general, requires growth factor support to maintain dose intensity and schedule. In the palliative setting, consideration should be given to dose reduction or change in regimen.
Treatment of chemotherapy-induced febrile neutropenia 1-4,5,6,8,9,11,12,14,16,27-29 ‡
• Patient has been on prophylactic therapy with filgrastim or tbo-filgrastim (Note: therapy should notbe used concomitantly with pegfilgrastim); OR
• Patient has not received prophylactic therapy with a granulocyte colony stimulatingfactor;
AND
Patient has one or more of the following risk factors for developing infectionrelated complications:
− Sepsis Syndrome
− Age >65
− Absolute neutrophil count [ANC] < 100/mcL
− Duration of neutropenia expected to be greater than 10 days
− Pneumonia or other clinically documented infections
− Invasive fungal infection
− Hospitalization at the time of fever
− Prior episode of febrile neutropenia
Patient who experienced a neutropenic complication from a prior cycle of the same chemotherapy 1-4,5,6,8,9,11,12,14,16,27-29
‡ Note: Dose-dense therapy, in general, requires growth factor support to maintain dose intensity and schedule. In the palliative setting, consideration should be given to dose reduction or change in regimen.
Acute Myeloid Leukemia (AML) patient following induction or consolidation chemotherapy 1- 4,7,13,35 †/‡
Bone Marrow Transplantation (BMT) failure or Engraftment Delay 5,6,25,26,30,33,35-37 †/‡
Severe chronic neutropenia 10 †/‡
• Patient must have an absolute neutrophil count (ANC) < 500/mm3; AND
• Patient must have a diagnosis of one of the following:
o Congenital neutropenia; OR
o Cyclic neutropenia; OR
o Idiopathic neutropenia
Myelodysplastic Syndrome 5 ‡
• Endogenous serum erythropoietin level of ≤500 mUnits/mL; AND
• Patient has lower risk disease (i.e., defined as IPSS-R [VeryLow, Low, Intermediate], IPSS [Low/Intermediate-1], WPSS [Very Low, Low, Intermediate]); AND
• Used for treatment of symptomatic anemia; AND
• Patient is receiving concurrent therapy with an Erythropoiesis Stimulating Agent(ESA) Patients acutely exposed to myelosuppressive doses of radiation (Hematopoietic Subsyndrome of Acute Radiation Syndrome) 1-4,17 †/‡ Management of CAR T-cell related Toxicity 5 ‡
• Patient has been receiving therapy with CAR T-cell therapy (e.g. tisangenleclecleucel (Kymriah), Axicabtagene Ciloleucel (Yescarta), etc.); AND
• Patient is experiencing neutropenia related to their therapy.
† FDA-labeled indication(s); ‡ Compendia recommended indication(s)
*Febrile neutropenia is defined as:
− a single temperature ≥38.3 °C orally or ≥38.0 °C over 1 hour; AND
− neutropenia: < 500 neutrophils/mcL or < 1,000 neutrophils/mcL and a predicted decline to ≤500 neutrophils/mcL over the next 48 hours
Initial Approval Criteria long-acting granulocyte colony stimulating factors (G-CSFs)
Universal Criteria
Prophylactic use in patients with non-myeloid malignancy †
• Patient is undergoing myelosuppressive chemotherapy with an expected incidence offebrile neutropenia* of 20% or greater §; OR
• Patient is undergoing myelosuppressive chemotherapy with an expected incidence of febrile neutropenia* of 10% or greater § AND one or more of the following co-morbidities:
− Age >65 receiving full dose intensity
− History of recurrent febrile neutropenia from chemotherapy − Extensive prior exposure to chemotherapy
− Previous exposure of pelvis, or other areas of large amounts of bone marrow, to radiation
− Persistent neutropenia (ANC ≤ 1000/mm3)
− Bone marrow involvement by tumor
− Patient has a condition that can potentially increase the risk of serious infection (i.e. HIV/AIDS with low CD4 counts)
− Recent surgery and/or open wounds
− Poor performance status
− Renal dysfunction (creatinine clearance 2.0)
− Chronic immunosuppression in the post-transplant setting, including organ transplant
Note: Dose-dense therapy, in general, requires growth factor support to maintain dose intensity and schedule. In the palliative setting, consideration should be given to dose reduction or change in regimen.
Patient who experienced a neutropenic complication from a prior cycle of the same chemotherapy §‡
Note: Dose-dense therapy, in general, requires growth factor support to maintain dose intensity and schedule. In the palliative setting, consideration should be given to dose reduction or change in regimen.
Patients acutely exposed to myelosuppressive doses of radiation (Hematopoietic Subsyndrome of Acute Radiation Syndrome) †
Bone marrow transplantation (BMT) failure or engraftment delay ‡
Peripheral blood progenitor cell (PBPC) mobilization and transplant ‡
† FDA-labeled indication(s); ‡ Compendia recommended indication(s)
. Renewal Criteria
Coverage for all other indications can be renewed based upon the following criteria:
• Patient continues to meet indication-specific relevant criteria such as concomitanttherapy requirements (not including prerequisite therapy), performance status, etc. identified in section III; AND • Absence of unacceptable toxicity from the drug. Examples of unacceptable toxicity include: splenic rupture, acute respiratory distress syndrome (ARDS), serious allergic reactions/anaphylaxis, sickle cell crisis, glomerulonephritis, leukocytosis, capillary leak syndrome, potential for tumor growth stimulation of malignant cells, aortitis, alveolar hemorrhage and hemoptysis, thrombocytopenia, cutaneous vasculitis etc.
In naïve patients first treatment of choice will be biosimilar Granix. In order to consider any other CSF-SA agents (Nivestym, Neupogen, Zarxio), patients must have documented previous use and therapeutic failure, intolerance or contraindication to biosimilar Granix.
BlueCard/National Account Issues
Requires authorization.
Benefits are determined by the group contract, member benefit booklet, and/or individual subscriber certificate in effect at the time services were rendered. Benefit products or negotiated coverages may have all or some of the services discussed in this medical policy excluded from their coverage.
CSF-SA: Patients first treatment of choice will be biosimilar Zarxio. In order to consider any other CSF-SA agents (Nivestym, Neupogen, Granix), patients must have documented previous use and therapeutic failure, intolerance or contraindication to biosimilar Zarxio.
CSF-LA: Fulphila is considered as preffered agent. In order to consider any other CSF-LA agents (Neulasta and Neulasta On Pro, Ziextenzo, Udenyca, Nyvepria or any other long-acting colony-stimulating factors) patients must have documented previous use and therapeutic failure, intolerance or contraindication to preffered agent.
Standard practice in protecting against chemotherapy-associated infection has been chemotherapy dose modification or dose delay, administration of progenitor-cell support, or selective use of prophylactic antibiotics. Chemotherapy associated neutropenic fever or infection has customarily involved treatment with intravenous antibiotics, usually accompanied by hospitalization. The hematopoietic colony-stimulating factors (CSFs) have been introduced into clinical practice as additional supportive measures that can reduce the likelihood of neutropenic complications due to chemotherapy.
Colony‐stimulating factors are glycoproteins which act on hematopoietic cells by binding to specific cell surface receptors and stimulating proliferation, differentiation commitment, and some end‐cell functional activation. Endogenous G‐CSF is a lineage specific colony‐stimulating factor which is produced by monocytes, fibroblasts, and endothelial cells. G‐CSF regulates the production of neutrophils within the bone marrow. G‐CSF is not species specific and has been shown to have minimal direct in vivo or in vitro effects on the production of hematopoietic cell types other than the neutrophil lineage.
The prophylactic use of colony‐stimulating factors (CSFs) can reduce the risk, severity, and duration of both severe neutropenia and febrile neutropenia. Despite these benefits, CSFs are not administered to all patients receiving myelosuppressive chemotherapy because of the costs associated with their routine use. The selective use of CSFs in members at increased risk for neutropenic complications may, however, enhance their cost‐effective use by directing treatment toward those patients who are most likely to benefit. The preventative use of CSF reduces the incidence, length and severity of chemotherapy-related neutropenia and may prevent life‐threatening complications. The definition of patients at high risk for severe or febrile neutropenia is outlined in ASCO guidelines referenced in this policy.
CSFs also have a place in therapy for many other types of neutropenia, bone marrow transplant, as well as for building up of white blood cells in peripheral blood progenitor cell (PBPC) transplantation. Post bone marrow transplant, the patient must recover their white blood cells for higher quality of life as they are often isolated due to their weakened immune system during the transplant process. Radiation therapy can also weaken the immune system substantially, causing neutropenia. The inherent mechanism of action of colony‐stimulating factors (CSFs) to “jump start” bone marrow into creating myeloid cells helps correct neutropenia in many of these cases.
Colony-stimulating factors are recommended in some situations, e.g., to reduce the likelihood of febrile neutropenia (FN) when the expected incidence is greater than 20 %; after documented FN in a prior chemotherapy cycle to avoid infectious complications and maintain dose-intensity in subsequent treatment cycles when chemotherapy dose-reduction is not appropriate; and after high-dose chemotherapy with autologous progenitor-cell transplantation. Colony-stimulating factors are also effective in the mobilization of peripheral-blood progenitor cells. Therapeutic initiation of CSFs in addition to antibiotics at the onset of FN should be reserved for patients at high risk for septic complications. Use of CSFs in patients with myelodysplastic syndromes may be reasonable if they are experiencing neutropenic infections. Administration of CSFs after initial chemotherapy for acute myeloid leukemia does not appear to be detrimental, but clinical benefit has been variable and caution is advised. Available data support use of CSFs in pediatric cancer patients similar to that recommended for adult patients. Colony-stimulating factors should not be used concurrently with chemotherapy and radiation, or to support increasing dose-dense chemotherapy regimens.
Colony-Stimulating Factors (CSFs) and Concomitant Chemotherapy and Radiation Therapy
The American Society of Clinical Oncology (ASCO) Clinical Practice Guideline Update (2015) states that "CSFs should be avoided in patients receiving concomitant chemotherapy and radiation therapy, particularly involving the mediastinum.
In the absence of chemotherapy, therapeutic use of CSFs may be considered in patients receiving radiation therapy alone if prolonged delays secondary to neutropenia are expected." (Type: evidence based. Evidence quality: high. Strength of recommendation: strong.)
Neupogen (filgrastim)
Neupogen (filgrastim) is a human granulocyte colony‐stimulating factor (G‐CSF), produced by recombinant DNA technology. Neupogen (filgrastim) has been approved by the FDA
I. To decrease the incidence of infection‚ as manifested by febrile neutropenia‚ in patients with nonmyeloid malignancies receiving myelosuppressive anticancer drugs associated with a significant incidence of severe neutropenia with fever;
II. Reducing the time to neutrophil recovery and the duration of fever following induction or consolidation chemotherapy treatment of adults with AML;
III. To reduce the duration of neutropenia and neutropenia‐related clinical sequelae (e.g., febrile neutropenia) in patients with nonmyeloid malignancies undergoing myeloablative chemotherapy followed by marrow transplantation;
IV. Mobilization of hematopoietic progenitor cells into the peripheral blood for collection by leukapheresis;
V. For chronic administration to reduce the incidence and duration of sequelae of neutropenia (e.g. fever‚infections‚oropharyngeal ulcers) in symptomatic patients with congenital neutropenia‚ cyclic neutropenia‚or idiopathic neutropenia; and
VI. To increase survival in patients acutely exposed to myelosuppressive doses of radiation (Hematopoietic Syndrome of Acute Radiation Syndrome).
1. To decrease the incidence of infection‚ as manifested by febrile neutropenia‚ in patients with nonmyeloid malignancies receiving myelosuppressive anticancer drugs associated with a significant incidence of severe neutropenia with fever;
2. Reducing the time to neutrophil recovery and the duration of fever following induction or consolidation chemotherapy treatment of adults with AML;
3. To reduce the duration of neutropenia and neutropenia‐related clinical sequelae (e.g., febrile neutropenia) in patients with nonmyeloid malignancies undergoing myeloablative chemotherapy followed by marrow transplantation;
4. Mobilization of hematopoietic progenitor cells into the peripheral blood for collection by leukapheresis;
5. For chronic administration to reduce the incidence and duration of sequelae of neutropenia (e.g. fever‚infections‚oropharyngeal ulcers) in symptomatic patients with congenital neutropenia‚ cyclic neutropenia‚or idiopathic neutropenia; and
6. To increase survival in patients acutely exposed to myelosuppressive doses of radiation (Hematopoietic Syndrome of Acute Radiation Syndrome).
Efficacy studies of Neupogen (filgrastim) could not be conducted in humans with acute radiation syndrome for ethical and feasibility reasons. Approval of this indication was based on efficacy studies conducted in animals and data supporting the use of Neupogen (filgrastim) for other approved indications.
Filgrastim is available as Neupogen 300mcg and 480mcg vials and as 300mcg and 480mcg prefilled syringes. In adult cancer patients receiving myelosuppressive chemotherapy or induction and consolidation therapy for acute myeloid leukemia, the U.S. Food and Drug Administration (FDA)-approved labeling recommends a starting dose of granulocyte-CSF (filgrastim, Neupogen) of 5 micrograms per kilogram per day (mcg/kg/day). Doses may be increased in increments of 5 mcg/kg for each chemotherapy cycle, according to the duration and severity of the absolute neutrophil count (ANC) nadir. In phase III clinical trials, effective doses were 4 to 8 mcg/kg/day. Neupogen (filgrastim) should not be administered earlier than 24 hours after cytotoxic chemotherapy or within 24 hours before chemotherapy. Administer Neupogen (filgrastim) daily for up to two weeks until the ANC has reached 10,000/cubic millimeter (mm³) after the expected chemotherapy-induced neutrophil nadir. Discontinue Neupogen (filgrastim) if the ANC surpasses 10,000/mm³ after the expected neutrophil nadir.
In adult cancer patients receiving bone marrow transplant, the recommended dose of Neupogen is 10 mcg/kg/day given as an intravenous infusion of 4 or 24 hours, or as a continuous 24-hour subcutaneous infusion. The first dose should be administered at least 24 hours after cytotoxic chemotherapy or after bone marrow infusion. The daily dose of Neupogen (filgrastim) is titrated against the absolute neutrophil count during the period of neutrophil recovery, according to the guidelines in the Prescribing Information.
The recommended dose of Neupogen for the mobilization of peripheral blood progenitor cells is 10 mcg/kg/day subcutaneously, either as a bolus or a continuous infusion, given for at least 4 days before the first leukapheresis procedure and continued until the last leukapheresis.
The recommended daily starting dose for congenital neutropenia is 6 mcg/kg twice-daily subcutaneously every day and for idiopathic or cyclic neutropenia is 5 mcg/kg as a single injection subcutaneously every day. Chronic daily administration is required to maintain clinical benefit. Absolute neutrophil count should not be used as the sole indication of efficacy. The dose should be individually adjusted based on the members’ clinical course as well as ANC.
The recommended dose of Neupogen for patients acutely exposed to myelosuppressive doses of radiation is 10 mcg/kg/day by subcutaneous injection. Administer as soon as possible after suspected or confirmed exposure to radiation doses greater than 2 gray (Gy).
Other than for peripheral blood progenitor cell re-infusion, CSFs should be administered subcutaneously or intravenously no earlier than 24 hours and preferably between 24 and 72 hours after the administration of cytotoxic chemotherapy to provide optimal neutrophil recovery. Therapy should be discontinued if the absolute neutrophil count surpasses 10,000/mm3 after the expected chemotherapy-induced nadir. Starting CSFs up to 5 days after peripheral blood progenitor cell re-infusion is reasonable based on available clinical data.
Neupogen (filgrastim) should not be utilized in the following:
• Routine use as prophylaxis in member/chemotherapy regimens without significant risk of febrile neutropenia or in members that are not receiving myelosuppressive chemotherapy.
• Members with known hypersensitivity to E coli‐derived proteins, filgrastim, or any component of the product.
Granix (tbo-filgrastim)
Granix (tbo-filgrastim) is a human granulocyte colony stimulating factor (G-CSF), produced by recombinant DMA technology. Granix (tbo-filtrastim) is indicated to decrease the duration of severe neutropenia in patients with non-myeloid malignancies receiving myelosuppressive anti-cancer drugs associated with clinically significant incidence of febrile neutropenia.
Tbo-filgrastim is available as Granix 300 mcg and 480 mcg prefilled syringes.
Febrile neutropenia prophylaxis, in non-myeloid malignancies following myelosuppressive chemotherapy: The usual starting dose of Granix (tbo-filgrastim) is 5 micrograms/kilogram (mcg/kg)/day administered as a subcutaneous injection. Granix (tbo-filgrastim) should not be administered earlier than 24 hours after cytotoxic chemotherapy or within 24 hours before chemotherapy. Administer Granix (tbo-filgrastim) daily until the expected neutrophil nadir is passed and the neutrophil count has recovered to the normal range. Monitor complete blood count (CPC) prior to chemotherapy and twice per week until recovery.
Granix (tbo-filgrastim) should not be used in the following:
• Routine use as prophylaxis in member/chemotherapy regimens without significant risk of febrile neutropenia or in members that are not receiving myelosuppressive chemotherapy.
• Members with known hypersensitivity to E. coli-derived proteins, tbo-filgrastim, or any component of the product.
Zarxio (filgrastim-sndz)
Zarxio (filgrastim‐sndz) is a human granulocyte colony‐stimulating factor (G‐CSF), produced by recombinant DNA technology.
Zarxio (filgrastim‐sndz) is approved by the FDA
I. To decrease the incidence of infection‚ as manifested by febrile neutropenia‚in patients with nonmyeloid malignancies receiving myelosuppressive anticancer drugs associated with a significant incidence of severe neutropenia with fever;
II. Reducing the time to neutrophil recovery and the duration of fever; following induction or consolidation chemotherapy treatment of adults with AML;
III. To reduce the duration of neutropenia and neutropenia‐related clinical sequelae (e.g., febrile neutropenia) in patients with nonmyeloid malignancies undergoing myeloablative chemotherapy followed by marrow transplantation;
IV. Mobilization of hematopoietic progenitor cells into the peripheral blood for collection by leukapheresis; and
V. For chronic administration to reduce the incidence and duration of sequelae of neutropenia (e.g. fever‚ infections‚ oropharyngeal ulcers) in symptomatic patients with congenital neutropenia‚ cyclic neutropenia‚ or idiopathic neutropenia.
1. To decrease the incidence of infection‚ as manifested by febrile neutropenia‚in patients with nonmyeloid malignancies receiving myelosuppressive anticancer drugs associated with a significant incidence of severe neutropenia with fever;
2. Reducing the time to neutrophil recovery and the duration of fever; following induction or consolidation chemotherapy treatment of adults with AML;
3. To reduce the duration of neutropenia and neutropenia‐related clinical sequelae (e.g., febrile neutropenia) in patients with nonmyeloid malignancies undergoing myeloablative chemotherapy followed by marrow transplantation;
4. Mobilization of hematopoietic progenitor cells into the peripheral blood for collection by leukapheresis; and
5. For chronic administration to reduce the incidence and duration of sequelae of neutropenia (e.g. fever‚ infections‚ oropharyngeal ulcers) in symptomatic patients with congenital neutropenia‚ cyclic neutropenia‚ or idiopathic neutropenia.
Filgrastim‐sndz is available as Zarxio 300mcg and 480mcg prefilled syringes.
Febrile Neutropenia Prophylaxis, in non‐myeloid malignancies following myelosuppressive chemotherapy: The usual starting dose of Zarxio (filgrastim‐sndz) is 5 micrograms/kilogram (mcg/kg)/day (rounded to the nearest vial size based on institution‐defined weight limits) administered as a single daily injection by SC bolus injection‚ by short IV infusion (15 to 30 minutes) ‚or by continuous SC or continuous IV infusion in cancer patients receiving myelosuppressive therapy. Doses may be increased in increments of 5 mcg/kg/day for each cycle according to the duration and severity of the ANC nadir. In phase III clinical trials, effective doses were 4 to 8 mcg/kg/day. Zarxio (filgrastim‐sndz) should not be administered earlier than 24 hours after cytotoxic chemotherapy or within 24 hours before chemotherapy. Administer Zarxio (filgrastim‐sndz) daily for up to two weeks until the ANC has reached 10,000/cubic millimeter (mm³ after the expected chemotherapy-induced neutrophil nadir. Discontinue Zarxio (filgrastim‐sndz) if the ANC surpasses 10,000/mm³ after the expected neutrophil nadir.
Febrile Neutropenia Prophylaxis, In members with acute myeloid leukemia receiving chemotherapy: The usual starting dose of Zarxio (filgrastim‐sndz) is 5 micrograms/kilogram (mcg/kg)/day (rounded to the nearest vial size based on institution‐defined weight limits) administered as a single daily injection by SC bolus injection‚by short IV infusion (15 to 30 minutes) ‚or by continuous SC or continuous IV infusion in cancer patients receiving myelosuppressive therapy. Doses may be increased in increments of 5 mcg/kg/day for each cycle according to the duration and severity of the ANC nadir. In phase III clinical trials, effective doses were 4 to 8 mcg/kg/day. Zarxio (filgrastim‐sndz) should not be administered earlier than 24 hours after cytotoxic chemotherapy or within 24 hours before chemotherapy. Administer filgrastim daily for up to two weeks until the ANC has reached 10,000/cubic millimeter (mm³ after the expected chemotherapy‐induced neutrophil nadir. Discontinue Zarxio (filgrastim‐sndz) if the ANC surpasses 10,000/mm³ after the expected neutrophil nadir.
Febrile Neutropenia Prophylaxis, In non‐myeloid malignancies following progenitor‐cell transplantation: In cancer members receiving myeloablative therapy with bone marrow transplant, a starting dose of 10 micrograms/kilogram/day (rounded to the nearest vial size based on institution‐defined weight limits) as an intravenous infusion of four or 24 hours is recommended with dose titration against the neutrophil response. Zarxio (filgrastimsndz) should be administered at least 24 hours after cytotoxic chemotherapy, and at least 24 hours after bone marrow infusion. The daily dose of Zarxio (filgrastim‐sndz) during the period of neutrophil recovery should be titrated against the ANC according to the instructions in the Prescribing Information.
Harvesting of peripheral blood stem cells: Zarxio (filgrastim‐sndz) 10 mcg/kg/day (rounded to the nearest vial size based on institution‐defined weight limits) SC as a bolus or continuous infusion, given at least four days before first leukapheresis and continued until the last leukapheresis.
Neutropenic disorder, chronic (Severe), Symptomatic: The recommended starting dose for congenital neutropenia is 6 mcg/kg (rounded to the nearest vial size based on institution‐defined weight limits) twice daily subcutaneously every day. The recommended starting dose for idiopathic or cyclic neutropenia is 5mcg/kg (rounded to the nearest vial size based on institution‐defined weight limits) as a single injection subcutaneously every day. Chronic daily administration is required to maintain clinical benefit. Absolute neutrophil count should not be used as the sole indication of efficacy. The dose should be individually adjusted based on the members’clinical course as well as ANC.
Zarxio (filgrastim‐sndz) should not be utilized in the following:
• Routine use as prophylaxis in member/chemotherapy regimens without significant risk of febrile neutropenia or in members that are not receiving myelosuppressive chemotherapy
• Members with known hypersensitivity to filgrastim or pegfilgrastim.
Nivestym (filgrastim-aafi)
On July 20, 2018, the U.S. FDA approved Nivestym (filgrastim-aafi) (Pfizer, Inc.), a biosimilar to Neupogen (filgrastim) (Amgen, Inc.), for all eligible indications of the referenced product; thus, Nivestym, a leukocyte growth factor, is approved for the same indications as Neupogen. The FDA approval was based on a review of a comprehensive data package and totality of evidence demonstrating a high degree of similarity of Nivestym compared to its reference product.
The National Comprehensive Cancer Network (NCCN) Drugs and Biologics Compendium (September 2018) had not made a recommendation for Nivestym (filgrastim-aafi).
Filgrastim-aafi is available for injection as 300 mcg/mL in a single-dose vial, and 480 mcg/1.6 mL single-dose vial. It is also available as a prefilled syringe for injection 300 mcg/0.5 mL, and 480 mcg/0.8 mL.
Note: Simultaneous use of filgrastim-aafi with chemotherapy and radiation therapy is not recommended and should be avoided (Pfizer, 2018).
Neulasta (pegfilgrastim)
Neulasta (pegfilgrastim) is a covalent conjugate of recombinant methionyl human G‐CSF (filgrastim) and monomethoxypolyethylene glycol. Both filgrastim and Neulasta (pegfilgrastim) are colony stimulating factors that act on hematopoietic cells by binding to specific cell surface receptors thereby stimulating proliferation, differentiation, commitment, and end cell functional activation.
Neulasta (pegfilgrastim), a long acting version of Neupogen (filgrastim), is administered once per chemotherapy cycle. It is approved by the FDA to decrease the incidence of infection, as manifested by FN, in patients with non-myeloid malignancies receiving myelosuppressive anti-cancer drugs associated with a clinically significant incidence of FN. Neulasta is also approved for use in patients acutely exposed to myelosuppressive doses of radiation (Hematopoietic Subsyndrome of Acute Radiation Syndrome). Neulasta is not labeled for use in myeloid malignancies -- leukemias and lymphomas -- because there is concern that it may stimulate the tumor cells to grow and it is not currently indicated for stem cell mobilization.
In patients with cancer receiving myelosuppressive chemotherapy, pegfilgrastim was evaluated in three randomized, double-blind, controlled studies. Studies 1 and 2 were active-controlled studies that employed doxorubicin 60 mg/m2 and docetaxel 75 mg/m2 administered every 21 days for up to 4 cycles for the treatment of metastatic breast cancer. Study 1 investigated the utility of a fixed dose of pegfilgrastim. Study 2 employed a weight-adjusted dose. In the absence of growth factor support, similar chemotherapy regimens have been reported to result in a 100% incidence of severe neutropenia (ANC < 0.5 x 109/L) with a mean duration of 5 to 7 days and a 30% to 40% incidence of febrile neutropenia. Based on the correlation between the duration of severe neutropenia and the incidence of febrile neutropenia found in studies with filgrastim, duration of severe neutropenia was chosen as the primary endpoint in both studies, and the efficacy of pegfilgrastim was demonstrated by establishing comparability to filgrastim-treated patients in the mean days of severe neutropenia. In Study 1, 157 patients were randomized to receive a single subcutaneous injection of pegfilgrastim (6 mg) on day 2 of each chemotherapy cycle or daily subcutaneous filgrastim (5 mcg/kg/day) beginning on day 2 of each chemotherapy cycle. In Study 2, 310 patients were randomized to receive a single subcutaneous injection of pegfilgrastim (100 mcg/kg) on day 2 or daily subcutaneous filgrastim (5 mcg/kg/day) beginning on day 2 of each chemotherapy cycle. Both studies met the major efficacy outcome measure of demonstrating that the mean days of severe neutropenia of pegfilgrastim-treated patients did not exceed that of filgrastim-treated patients by more than 1 day in cycle 1 of chemotherapy. The mean days of cycle 1 severe neutropenia in Study 1 were 1.8 days in the pegfilgrastim arm compared to 1.6 days in the filgrastim arm [difference in means 0.2 (95% CI -0.2, 0.6)] and in Study 2 were 1.7 days in the pegfilgrastim arm compared to 1.6 days in the Filgrastim arm [difference in means 0.1 (95% CI -0.2, 0.4)]. A secondary endpoint in both studies was days of severe neutropenia in cycles 2 through 4 with results similar to those for cycle 1.
Study 3 was a randomized, double-blind, placebo-controlled study that employed docetaxel 100 mg/m2 administered every 21 days for up to 4 cycles for the treatment of metastatic or non-metastatic breast cancer. In this study, 928 patients were randomized to receive a single subcutaneous injection of pegfilgrastim (6 mg) or placebo on day 2 of each chemotherapy cycle. Study 3 met the major trial outcome measure of demonstrating that the incidence of febrile neutropenia (defined as temperature ≥ 38.2°C and ANC ≤ 0.5 x109/L) was lower for pegfilgrastim-treated patients as compared to placebo-treated patients (1% versus 17%, respectively, p < 0.001). The incidence of hospitalizations (1% versus 14%) and IV anti-infective use (2% versus 10%) for the treatment of febrile neutropenia was also lower in the pegfilgrastim-treated patients compared to the placebo-treated patients.
Study 4 was a multicenter, randomized, open-label study to evaluate the efficacy, safety, and pharmacokinetics of pegfilgrastim in pediatric and young adult patients with sarcoma. Patients with sarcoma receiving chemotherapy age 0 to 21 years were eligible. Patients were randomized to receive subcutaneous pegfilgrastim as a single dose of 100 mcg/kg (n= 37) or subcutaneous filgrastim at a dose 5 mcg/kg/day (n=6) following myelosuppressive chemotherapy. Recovery of neutrophil counts was similar in the pegfilgrastim and filgrastim groups. The most common adverse reaction reported was bone pain.
Efficacy studies of Neulasta (pegfilgrastim) could not be conducted in humans with acute radiation syndrome for ethical and feasibility reasons. Approval of this indication was based on efficacy studies conducted in animals and data supporting the use Neulasta’s (pegfilgrastim) effect on severe neutropenia in patients with cancer receiving myelosuppressive chemotherapy.
According to the FDA-approved labeling, the recommended dose of Neulasta for febrile neutropenia prophylaxis is a single subcutaneous injection of 6 mg, administered once per chemotherapy cycle. According to the labeling, Neulasta should not be administered in the period between 14 days before and 24 hours after administration of cytotoxic chemotherapy. Neulasta cannot be given more than once per chemotherapy cycle and cannot be given more often than every 14 days. Therefore, Neulasta (pegfilgrastim) should not be utilized in myelosuppressive chemotherapy regimens that are administered more frequently than every two weeks.
The recommended dose for hematopoietic subsyndrome of acute radiation syndrome is two doses of 6 mg each, administered subcutaneous injection one week apart. For dosing in pediatric patients, please refer to Full Prescribing Information. Administer the first dose as soon as possible after suspected or confirmed exposure to radiation doses greater than 2 gray (Gy). Administer the second dose one week after the first dose.
A healthcare provider must fill the On‐body Injector with Neulasta using the prefilled syringe and then apply the On‐body Injector for Neulasta to the patient’ skin (abdomen or back of arm). The back of the arm may only be used if there is a caregiver available to monitor the status of the On‐body Injector for Neulasta. Approximately 27 hours after the On‐body Injector for Neulasta is applied to the patient’ skin, Neulasta will be delivered over approximately 45 minutes. A healthcare provider may initiate administration with the On‐body Injector for Neulasta on the same day as the administration of cytotoxic chemotherapy, as long as the On‐body Injector for Neulasta delivers Neulasta no less than 24 hours after administration of cytotoxic chemotherapy. Refer to the Healthcare Provider Instructions for Use for the On‐body Injector for Neulasta for full administration information.
Per NCCN, there are insufficient data to support dose and schedule of weekly regimens of Neulasta or chemotherapy schedules less than two weeks and these cannot be recommended.
It is not recommending to split the Neulasta (pegfilgrastim) dose (to achieve <6mg dosing) due to inconformities in the pegylated mixture leading to the possibility of inaccurate dosing and increased drug wastage/cost. The 6mg formulation is not intended to be utilized in this manner by the manufacturer and these dosing strategies are not FDA approved. Alternative white blood cell colony stimulating factor formulations should be utilized when the 6mg Neulasta (pegfilgrastim) dose is viewed as supratherapeutic by the prescribing oncologist.
Neulasta (pegfilgrastim) should not be used in the following:
• Members with known hypersensitivity to E coli‐derived proteins, pegfilgrastim, or any component of the product.
• Use in myeloid malignancies (AML, CML, etc.) or Myelodysplastic Syndrome (MDS).
• Should not be used in infants, children, and smaller adolescents weighing less than 45 kg—pegfilgrastim is not FDA approved for pediatric use.
• Routine use as prophylaxis in members/chemotherapy regimens without significant risk of febrile neutropenia or in members that are not receiving myelosuppressive chemotherapy.
• Partial doses (utilizing a portion of the 6mg dose for multiple or partial doses).
• Treatment of neutropenia or febrile neutropenia (only approved for prophylaxis).
NCCN guidelines on myeloid growth factors state that administration of pegfilgrastim next day or up to 3 to 4 days following chemotherapy is preferred; however, the panel agreed that same-day administration of pegfilgrastim may be considered under certain circumstances, defined as administration of pegfilgrastim on the day during which patients receive chemotherapy. NCCN panelists stated that same-day administration is done for logistical reasons and to minimize burdens on long-distance patients. NCCN guidelines note that clinical trials both in support of and against same-day pegfilgrastim have been published. The guidelines explain that the original rationale for not giving same-day CSF was the potential for increased neutropenia resulting from CSF stimulation of myeloid progenitors at the time of cytotoxic chemotherapy. The guidelines cited a direct comparison (citing Kaufman, et al.), where pegfilgrastim was administered either same-day or next-day in women with breast cancer receiving chemotherapy. Febrile neutropenia was observed in 33 percent of patients treated in the same-day group compared with only 11 percent of patients in the next-day group. The NCCN guidelines observed that a similar trend was seen in a prospective randomized double-blind trial of patients receiving chemotherapy for NHL where same-day pegfilgrastim was associated with enhanced myelosuppression and no reduction of leukopenia was seen. However, despite longer duration of grade 4 neutropenia in the same-day group, there was no increase in the overall incidence of neutropenia and the increased duration did not meet the non-inferiority margin. The guidelines noted that, while this study recommends administration of pegfilgrastim 24 hours after chemotherapy, it was acknowledged that same-day administration may be an acceptable alternative for some patients.
NCCN guidelines also described a retrospective review by Vance, et al. of same-day pegfilgrastim in patients with breast cancer receiving chemotherapy and no increased neutropenia was observed. The guidelines also identified a retrospective study of 159 patients with a variety of tumor types and chemotherapy regimens showing a similar incidence of myelosuppressive adverse events when comparing the two groups. A double-blind phase II study in patients with non-small cell lung cancer treated with chemotherapy showed no increase in neutropenia nor any adverse events in patients receiving same-day pegfilgrastim compared to patients receiving next-day pegfilgrastim treatment. The benefit of same-day pegfilgrastim was also observed in patients with non-small cell lung cancer treated with weekly chemotherapy regimens. Same day pegfilgrastim in these patients was shown to be beneficial not only from a safety perspective but also from a logistical one where next-day pegfilgrastim would have compromised the weeily chemotherapy schedule. Anotehr study in pateints with lung cancer showed an unexpected low rate of severe neutropenia (only 2 patients per group) suggesting that same-day filgrastim is a reasonable option. More recent retrospective studies in patients with gynecologic malignancies demonstrated the safety and efficacy of pegfilgrastim administered within 24 hours of chemotherapy.
Micromedex DrugDex compendium states that the use of pegfilgrastim in the period between 14 days before and 24 hours after chemotherapy is not recommended. It states that pegfilgrastim administered once on the same day as chemotherapy was shown to be noninferior to pegfilgrastim administered once 24 hours after chemotherapy for the duration of grade 4 neutropenia after the first cycle of chemotherapy in patients with breast cancer and non-Hodgkin lymphoma; however, the duration of grade 4 neutropenia was longer and the incidence of febrile neutropenia was higher with same-day compared with next-day administration. The Compendium cited a study by Burris, et al. that compared data on severe (grade 4) neutropenia duration and febrile neutropenia incidence in patients receiving chemotherapy with pegfilgrastim administered the same day or 24 hours after chemotherapy. Burris, et al. noted that these were similar, randomized, double-blind phase II noninferiority studies of patients with lymphoma or non-small-cell lung (NSCLC), breast, or ovarian cancer. Each study was analyzed separately. The primary end point in each study was cycle-1 severe neutropenia duration. Approximately 90 patients per study were to be randomly assigned at a ratio of 1:1 to receive pegfilgrastim 6 mg once per cycle on the day of chemotherapy or the day after (with placebo on the alternate day). The authors found that, in four studies, 272 patients received chemotherapy and one or more doses of pegfilgrastim (133 same day, 139 next day). Three studies (breast, lymphoma, NSCLC) enrolled an adequate number of patients for analysis. However, in the NSCLC study, the neutropenic rate was lower than expected (only two patients per arm experienced grade 4 neutropenia). In the breast cancer study, the mean cycle-1 severe neutropenia duration was 1.2 days (95% confidence limit [CL], 0.7 to 1.6) longer in the same-day compared with the next-day group (mean, 2.6 v 1.4 days). In the lymphoma study, the mean cycle-1 severe neutropenia duration was 0.9 days (95% CL, 0.3 to 1.4) longer in the same-day compared with the next-day group (mean, 2.1 v 1.2 days). In the breast and lymphoma studies, the absolute neutrophil count profile for same-day patients was earlier, deeper, and longer compared with that for next-day patients, although the results indicate that same-day administration was statistically noninferior to next-day administration according to neutropenia duration. The authors concluded that, for or patients receiving pegfilgrastim with chemotherapy, pegfilgrastim administered 24 hours after chemotherapy completion is recommended.
An UpToDate review of the use of granulocyte colony stimulating factors in adult patients with chemotherapy-induced neutropenia (Larson, 2014) stated: "Because of the potential sensitivity of rapidly dividing myeloid cells to cytotoxic chemotherapy, growth factors should be discontinued several days before the next chemotherapy treatment and they should not be given on the same day as chemotherapy. Experience from clinical trials indicates that myelosuppression is more profound if the myeloid growth factors were given immediately prior to or on the same day as the chemotherapy. For the same reason, growth factors should not be given concurrently with radiation therapy directed at portals containing active marrow."
Hematological side effects (e.g., anemia, neutropenia, and thrombocytopenia) of combination therapy with pegylated (PEG)-interferon alfa and ribavirin are commonly encountered during antiviral therapy for chronic hepatitis C (HCV) (Collantes and Younossi, 2005). An important consequence of these side effects is dose modification of PEG-interferon alfa, ribavirin, or both. The FDA-approved product labeling of both peginterferon preparations (alfa-2a and alfa-2b) recommend dose reduction for patients with neutrophils counts less than 750 cells/mm3 and drug discontinuation for those with counts less than 500 cells/mm3. However, there has been concern that such dose modifications will diminish the effectiveness of optimal treatment regimen for HCV and may have a negative impact on sustained virological response.
Collantes and Younossi (2005) note that the clinical implications of neutropenia or thrombocytopenia are less clear than for anemia; nevertheless, severe infection and bleeding are uncommon. Dose adjustments effectively treat these hematological side effects, but the resulting sub-optimal dosing and potential impact on virological response are major concerns. Recent attempts to maximize adherence to the optimal treatment regimen have used hematopoietic growth factors rather than dose adjustment to treat side effects. Research on growth factor support has focused on anemia and neutropenia. Erythropoietin and darbepoetin alfa are erythropoietic growth factors that effectively increase hemoglobin while maintaining the optimal ribavirin dose and improving patients' quality of life (see CPB 0195 - Erythropoiesis Stimulating Agents or CPB 0195m - Erythropoiesis Stimulating Agents [Medicare]).
CSFs should not be used for routine prophylaxis in member/chemotherapy regimens without significant risk of febrile neutropenia or in members that are not receiving myelosuppressive chemotherapy. They should also not be used in persons with hypersensitivity to the product or its components or to E. coli derived proteins.
Investigators have examined the potential for adjunctive use of the granulocyte colony stimulating factor (G-CSF) filgrastim to improve clinical outcomes in persons with chronic hepatitis C. Early clinical studies found that routine co-administration of filgrastim failed to significantly enhance the sustained virologic response to interferon-based therapies in hepatitis C (Gronbaek et al, 2002; Van Thiel et al, 1995). Clinical studies are needed to assess the effectiveness of G-CSF to treat chemotherapy induced neutropenia in hepatitis C.
Collantes and Younossi (2005) concluded that, although filgrastim shows tremendous promise for managing hematological side effects of combination therapy for HCV, and potentially enhancing adherence, further research is needed to clarify the safety, effectiveness, and cost-effectiveness of growth factors in the management of patients with chronic HCV. Ong and Younossi (2004) reached similar conclusions, noting that the impact of growth factors on sustained virological response and their cost-effectiveness in patients with chronic HCV need further assessment.
The Canadian Agency for Drugs and Technologies in Health (Dryden et al, 2008) released a report on G-CSF for antiviral-associated neutropenia. A systematic review was used to evaluate the effect of treatment with G-CSF compared with that of interferon dose reduction to control neutropenia. It was not superior to interferon dose reduction. While G-CSF may enable patients to stay on or resume optimal antiviral therapy, the evidence is weak. The mild adverse effects respond to simple treatments that alleviate symptoms. The report concluded that it is unclear if the use of G-CSF compared with dose reduction improves sustained virological response in patients with hepatitis C and neutropenia.
Early research is examining the potential for G-CSF to enhance myocardial function in myocardial infarction (MI). In a prospective, randomized, double-blinded, placebo-controlled phase II clinical trial, Engelmann et al (2006) compared the effects of G-CSF on the improvement of MI in patients undergoing delayed percutaneous coronary intervention (PCI) for ST-segment elevation MI (STEMI). A total of 44 patients with late re-vascularized subacute STEMI were treated either with G-CSF or placebo over 5 days after successful PCI. Primary end points were change of global and regional MI from baseline (1 week after PCI) to 3 months after PCI evaluated by magnetic resonance imaging (MRI). Secondary end points consisted of characterization of mobilized stem cell populations, assessment of safety parameters up to 12 months including 6-month angiography, as well as myocardial perfusion evaluated by MRI. Global myocardial function from baseline (1 week after PCI) to 3 months improved in both groups, but G-CSF was not superior to placebo. A slight but non-significant improvement of regional function occurred in both groups. Granulocyte-CSF resulted in mobilization of endothelial progenitor cell populations and was well-tolerated with a similar rate of target lesion re-vascularization from in-stent re-stenosis. In both groups major adverse cardiovascular events occurred in a comparable frequency; G-CSF resulted in significant improvement of myocardial perfusion 1 week and 1 month after PCI. The authors concluded that G-CSF treatment after PCI in subacute STEMI is feasible and relatively safe. However, patients do not benefit from G-CSF when PCI is performed late. They noted that as a result of its phase II character, this trial is limited by its small sample size. These investigators stated that further research should focus on immediate administration of G-CSF in early re-vascularized MI and on larger multi-center studies examining clinical outcomes.
In a meta-analysis, Abdel-Latif and colleagues (2008) examined the effects of G-CSF therapy for cardiac repair after acute MI. These investigators searched Medline, Embase, Science Citation Index, CINAHL, and the Cochrane Central database of controlled clinical trials for randomized controlled trials of G-CSF therapy in patients with acute MI. They conducted a fixed-effects meta-analysis across 8 eligible studies (n = 385 patients). Compared with controls, G-CSF therapy increased LV ejection fraction (EF) by 1.09 %, increased LV scar size by 0.22 %, decreased LV end-diastolic volume by 4.26 ml, and decreased LV end-systolic volume by 2.50 ml. None of these effects was statistically significant. The risk of death, recurrent MI, and in-stent re-stenosis was similar in G-CSF-treated patients and controls. Subgroup analysis revealed a modest but statistically significant increase in EF (4.73 %, p < 0.0001) with G-CSF therapy in studies that enrolled patients with mean EF less than 50 % at baseline. Subgroup analysis also showed a significant increase in EF (4.65 %, p < 0.0001) when G-CSF was administered relatively early (less than or equal to 37 hours) after the acute event. The authors concluded that G-CSF therapy in unselected patients with acute MI appears safe but does not provide an overall benefit. Subgroup analyses suggested that G-CSF therapy may be salutary in acute MI patients with LV dysfunction and when started early. They stated that larger randomized studies are needed to evaluate the potential benefits of early G-CSF therapy in acute MI patients with LV dysfunction. This is in agreement with the findings of Zohlnhöfer et al (2008) who reported that available evidence does not support a beneficial effect of G-CSF in patients with acute MI after re-perfusion.
Beohar et al (2010) stated that cytokine therapy including G-CSF and granulocyte-macrophage colony stimulating factor (GM-CSF) promises to provide a non-invasive treatment option for ischemic heart disease. Cytokines are thought to influence angiogenesis directly via effects on endothelial cells or indirectly through progenitor cell-based mechanisms or by activating the expression of other angiogenic agents. Several cytokines mobilize progenitor cells from the bone marrow or are involved in the homing of mobilized cells to ischemic tissue. The recruited cells contribute to myocardial regeneration both as a structural component of the regenerating tissue and by secreting angiogenic or anti-apoptotic factors, including cytokines. To date, randomized controlled trials (RCTs) have not reproduced the efficacy observed in pre-clinical and small-scale clinical investigations. Nevertheless, the list of promising cytokines continues to grow, and combinations of cytokines, with or without concurrent progenitor cell therapy, warrant further investigation. In particular, the authors stated that the mechanism of action and potential inflammatory sequelae associated with GM-CSF must be better understood and controlled before larger human trials can be considered.
A Cochrane review found insufficient evidence to support the use of G-CSF for treating stroke (Bath and Sprigg, 2006). The investigators found that G-CSF was associated with a non-significant reduction in combined death and dependency in 2 small trials (n = 46 subjects), although there was substantial heterogeneity in this result. These investigators concluded that there was insufficient evidence to support the use of G-CSF in the treatment of patients with recurrent stroke.
In a Cochrane review, Cheng et al (2007) examined the role of G-CSF as an adjunct to antibiotics in the treatment of pneumonia in non-neutropenic adults. The investigators found that, when, combined with antibiotics, G-CSF appears to be a safe treatment for people with pneumonia, but it does not appear to reduce mortality. The authors concluded that currently there is no evidence to support the routine use of G-CSF in the treatment of pneumonia. They noted that studies in which G-CSF is administered prophylactically or earlier in therapy may be of interest.
Felty syndrome (FS) is a rare but severe subset of sero-positive rheumatoid arthritis (RA) complicated by granulocytopenia and splenomegaly; occurring in less than 1 % of patients with RA. The granulocytopenia in FS may improve when RA is treated with second-line medications such as gold, methotrexate, and corticosteroids. Moreover, G-CSF has been studied in the treatment of patients with FS.
Stanworth and co-workers (1998) prospectively monitored the use of G-CSF in 8 FS patients with recurrent infections or who required joint surgery. Significant side effects were documented in 5, including nausea, malaise, generalized joint pains, and in 1 patient, a vasculitic skin rash. In 2 patient’s treatments had to be stopped, and in these cases G-CSF had been started at full vial dosage (300 micrograms/ml filgrastim or 263 micrograms/ml lenograstim) alternate days or daily. Treatment with G-CSF was continued in 3 patients by re-starting at a lower dose, and changing the proprietary formulation. Treatment with G-CSF increased the neutrophil count, decreased severe infection, and allowed surgery to be performed. A combined clinical and laboratory index suggested that long-term treatment (up to 3.5 years) did not exacerbate the arthritis. Once on established treatment, it may be possible to use smaller weekly doses of G-CSF to maintain the same clinical benefit. One of the 3 patients whose FS was associated with a large granular T-cell lymphocytosis showed a reduction in this subset of lymphocytes during G-CSF treatment.
Balint and Balint (2004) noted that over 95 % of FS patients are positive for rheumatoid factor, 47 to 100 % are positive for anti-nuclear antibody (ANA), and 78 % of patients have the HLA-DR4*0401 antigen. Some 30 % of FS patients have large granular lymphocyte expansion. Large granular lymphocyte expansion associated with uncomplicated RA is immunogenetically and phenotypically very similar to but clinically different from FS. Neutropenia of FS can be effectively treated with disease-modifying anti-rheumatic drugs, the widest experience being with methotrexate. Furthermore, results of treatment with G-CSF are encouraging. Splenectomy results in immediate improvement of neutropenia in 80 % of the patients, but the rate of infection decreases to a lesser degree.
In a phase I study, Sato et al (2008) examined the feasibility and safety of immuno-embolization with GM-CSF; sargramostim for malignant liver tumors, predominantly hepatic metastases from patients with primary uveal melanoma. A total of 39 patients with surgically unresectable malignant liver tumors, including 34 patients with primary uveal melanoma, were enrolled. Hepatic artery embolization accompanied an infusion of dose-escalated GM-CSF (25 to 2,000 microg) given every 4 weeks. Primary end points included dose-limiting toxicity and maximum tolerated dose (MTD). Patients who completed 2 cycles of treatments were monitored for hepatic anti-tumor response. Survival rates of patients were also monitored. Maximum tolerated dose was not reached up to the dose level of 2,000 microg, and there were no treatment-related deaths. A total of 31 assessable patients with uveal melanoma demonstrated 2 complete responses, 8 partial responses, and 10 occurrences of stable disease in their hepatic metastases. The median overall survival of intent-to-treat patients who had metastatic uveal melanoma was 14.4 months. Multi-variate analyses indicated that female sex, high doses of GM-CSF (greater than or equal to 1,500 microg), and regression of hepatic metastases (complete and partial responses) were correlated to longer overall survival. Moreover, high doses of GM-CSF were associated with prolonged progression-free survival in extra-hepatic sites. The authors concluded that immuno-embolization with GM-CSF is safe and feasible in patients with hepatic metastasis from primary uveal melanoma. Encouraging preliminary efficacy and safety results warrant additional clinical study in metastatic uveal melanoma.
Daud et al (2008) conducted a prospective trial in patients with high-risk (stage III B/C, IV), resected melanoma, with GM-CSF 125 microg/m(2)/d administered for 14 days every 28 days. Patients underwent clinical restaging every 4 cycles, with dendritic cells (DCs) analysis performed at baseline and at 2, 4, 8, and 12 weeks. Of 42 patients enrolled, 39 were assessable for clinical outcome and DC analysis. Median overall survival was 65 months (95 % confidence interval [CI]: 43 to 67 months) and recurrence-free survival was 5.6 months (95 % CI: 3 to 11 months). Treatment with GM-CSF caused an increase in mature DCs, first identified after 2 weeks of treatment, normalizing by 4 weeks. Patients with decreased DCs at baseline had significant increases in DC number and function compared with those with "normal" parameters at baseline. No change was observed in the number of myeloid-derived suppressor cells (MDSCs). Early recurrence (less than 90 days) correlated with a decreased effect of GM-CSF on host DCs, compared with late or no (evidence of) recurrence. The authors concluded that GM-CSF treatment was associated with a transient increase in mature DCs, but not MDSCs. Greater increase of DCs was associated with remission or delayed recurrence. The prolonged overall survival observed warrants further exploration.
In a phase I study, Lutzky et al (2009) evaluated the safety and tolerability of adjuvant treatment with subcutaneous GM-CSF administered in combination with escalating doses of thalidomide in patients with surgically resected stage II (T4), III, or IV melanoma at high risk for recurrence. Adjuvant treatment included GM-CSF 125 microg/m2 subcutaneously for 14 days and thalidomide at an initial dose of 50 mg/d, escalated in cohorts of 3 to 6 patients each to a maximum of 400 mg/day followed by 14 days of rest. Treatment was continued for up to 1 year in the absence of disease progression. Of 19 patients treated, the most common toxicities were grade 1/2 constipation (68 %), fatigue (58 %), neuropathy (42 %), bone and joint pain (37 %), and dyspnea, dizziness, injection site skin reaction, and somnolence (32 % each). Thrombotic events in 3 of 19 patients (16 %), including 1 treatment-related death, were the most serious adverse events and were thought to be due to thalidomide. With a median follow-up of 945 days (2.6 years), 8 (42 %) patients were alive, including 1 with disease and 7 without evidence of disease. Treatment with GM-CSF plus thalidomide for patients with resected high-risk melanoma was associated with a high incidence of thrombotic events. Because life-threatening events are unacceptable in the adjuvant setting, up-front anti-thrombotic prophylaxis will be necessary for further evaluation of GM-CSF plus thalidomide as a viable regimen in this patient group.
In a phase I-II study, Urba and colleagues (2008) evaluated the safety, clinical activity and immunogenicity of an immunotherapy developed from human prostate cancer cell lines (PC-3 and LNCaP) modified to secrete GM-CSF. Patients with non-castrate prostate cancer with biochemical (prostate specific antigen) recurrence following prostatectomy or radiation therapy and no radiological evidence of metastasis were enrolled in the study (n = 19). They were injected with an initial dose of 5 x 10(8) cells followed by 12 bi-weekly administrations of 1 x 10(8) cells. The adverse event profile, prostate specific antigen (PSA) response, changes in PSA kinetics and immunogenicity were assessed. Immunotherapy was well-tolerated with no serious treatment related adverse events and no autoimmune reactions. A negative deflection in PSA slope was observed in 84 % of patients after treatment with a significant increase in median PSA doubling time from 28.7 weeks before treatment to 57.1 weeks after treatment (p = 0.0095). Median time to PSA progression was 9.7 months. Immunoblot analysis of patient serum demonstrated new or enhanced production of PC-3 or LNCaP reactive antibodies in 15 of 19 (79 %) patients after immunotherapy. Induction of antibody responses reactive against PC-3 in general, and to the PC-3 associated filamin-B protein specifically, were positively associated with treatment associated changes in PSA kinetics. The authors concluded that GM-CSF secreting cellular immunotherapy has a favorable toxicity profile with signals of clinical and immunological activity against hormone naïve prostate cancer. An association between immune response and PSA changes was observed. Phase 3 trials in patients with advanced, metastatic, hormone refractory prostate cancer are under way.
In an open-label, multi-center, dose-escalation study, Higano and associates (2008) assessed multiple dose levels of immunotherapy in patients with metastatic hormone-refractory prostate cancer (HRPC). The immunotherapy, based on the GVAX (prostate cancer vaccine) platform, consisted of 2 allogeneic prostate-carcinoma cell lines modified to secrete GM-CSF. Dose levels ranged from 100 x 10(6) cells q28d x 6 to 500 x 10(6) cells prime/300 x 10(6) cells boost q14d x 11. Endpoints included safety, immunogenicity, overall survival, radiologic response, PSA kinetics, and serum GM-CSF pharmacokinetics. A total of 80 men, median age of 69 years (range of 49 to 90 years), were treated. The most common adverse effect was injection-site erythema. Overall, the immunotherapy was well-tolerated. A maximal tolerated dose was not established. The median survival time was 35.0 months in the high-dose group, 20.0 months in the mid-dose, group, and 23.1 months in the low-dose group. Prostate specific antigen stabilization occurred in 15 (19 %) patients, and a greater than 50 % decline in PSA was seen in 1 patient. The proportion of patients who generated an antibody response to 1 or both cell lines increased with dose and included 10 of 23 (43 %) in the low-dose group, 13 of 18 (72 %) in the mid-dose group, and 16 of 18 (89 %) in the high-dose group (p = 0.002; Cochran-Armitage trend test). The authors concluded that this immunotherapy was well-tolerated; immunogenicity and overall survival varied by dose. They also noted that 2 phases III clinical trials in patients with metastatic HRPC are underway.
Si et al (2009) examined the effects of combined cryoablation and GM-CSF treatment for metastatic hormone refractory prostate cancer. A total of 12 patients with metastatic hormone refractory prostate cancer were treated by combining cryoablation and GM-CSF administration. Besides PSA measurements, peripheral blood mononuclear cells were also obtained; the frequency of tumor-specific T cells was tested ex vivo in an interferon-gamma enzyme-linked immunospot assay after stimulating with autologous prostate cancer-derived protein lysates. To assess cytolytic activity, T cells were co-incubated with LNCaP or renal cancer cells (GRC-1), and release of cytosolic adenylate kinase was measured by a luciferase assay. The median PSA decline percentage was 69.4 % (range of 30.5 % to 92.5 %) and the median time to the nadir PSA was 4 months after therapy (range of 3 to 6 months). The median time to disease progress was 18 months, and 1 patient obtained a 92.5 % PSA decline and a greater than 50 % reduction of lung disease and survived 31 months. Four or 8 weeks after treatment, the tumor-specific T-cell responses were increased in peripheral blood mononuclear cell. The cytolytic activity against LNCaP was also increased significantly whereas no response was found against GRC-1. It seemed that there was no direct correlation between the degree of T-cell response and decline in PSA. The authors suggested that combined cryoablation with GM-CSF treatment may be an alternative approach for metastatic hormone refractory prostate cancer.
Amato and colleagues (2009) evaluated the effectiveness of GM-CSF in combination with thalidomide on PSA reduction in hormone-naïve prostate carcinoma (HNPC) patients with rising PSA levels after definitive local treatment. Patients (n = 21) with evidence of progression demonstrated by 3 consecutive rises in PSA and no evidence of radiographic involvement were treated on a chronic dosing schedule with GM-CSF. They received 250 microg/m2 (maximum 500 microg) 3 times a week by subcutaneous injection, with injections at least 24 hours apart. Thalidomide administration began concurrently with an initial dose of 100 mg daily for 7 consecutive days. During week 2 to 4, the dose was escalated every 7 days by 100 mg per individual tolerance to a maximum of 400 mg. The maximum tolerated dose of thalidomide was continued without interruption. Prostate specific antigen, testosterone, and routine laboratory parameters were measured every 6 weeks. One patient was not evaluable because of non-compliance. For the 20 evaluable patients, baseline PSA levels ranged from 1.3 to 61.0 ng/ml. A total of 19 patients left the study at 3.0 to 33.3 months, secondary to individual tolerance, progressive disease, or development of a second primary tumor. One patient continues to receive therapy at 33.8 months. Two patients did not respond to the therapy. For the 18 patients who did respond, the median reduction in PSA level was 59 % (range of 26 % to 89 %), and the median duration of response was 11 months (range of 4.5 to 36 months). Grades 1-2 toxicity included peripheral neuropathy, fatigue, skin rash, and constipation. One patient had deep-vein thrombosis/pulmonary embolism. The authors concluded that GM-CSF plus thalidomide can be administered successfully with encouraging anti-tumor activity and reversible toxicity. This may represent an alternative to hormonal therapy.
Battiwalla and McCarthy (2009) noted that the cytokine G-CSF stimulates myeloid progenitors and is routinely used to accelerate neutrophil recovery in the treatment of hematological malignancy and blood or marrow transplantation. Despite significant reductions in the frequency and duration of FN episodes, infections and the length of hospitalization, filgrastim has never been conclusively proven to produce a survival benefit in allogeneic hematopoietic stem cell transplantation (HSCT) and is considered a supportive measure. These investigators analyzed the conflicting evidence and appraised the utility of G-CSF in allogeneic HSCT. They concluded that G-CSF administration following allogeneic HSCT needs to take into consideration the impact on immune reconstitution, risk of leukemic progression in patients with chromosome 7 abnormalities and the absence of proven benefit in patients receiving marrow or peripheral blood progenitors as the stem cell source. The authors also noted that although there is conflicting evidence whether the administration of G-CSF post allogeneic transplant worsens survival, there is no apparent benefit.
In a single-blind, multi-center, RCT, Carr and associates (2009) examined if GM-CSF administered as prophylaxis to pre-term neonates at high-risk of neutropenia would reduce sepsis, mortality, and morbidity. A total of 280 neonates of below or equal to 31 weeks' gestation and below the 10th centile for birth weight were randomized within 72 hrs of birth to receive GM-CSF 10 microg/kg per day subcutaneously for 5 days or standard management. From recruitment to day 28, a detailed daily clinical record form was completed by the treating clinicians. Primary outcome was sepsis-free survival to 14 days from trial entry. Analysis was by intention-to-treat. Neutrophil counts after trial entry rose significantly more rapidly in infants treated with GM-CSF than in control infants during the first 11 days (difference between neutrophil count slopes 0.34 x 10(9)/L/day; 95 % CI: 0.12 to 0.56). There was no significant difference in sepsis-free survival for all infants (93 of 139 treated infants, 105 of 141 control infants; difference -8 %, 95 % CI: -18 to 3). A meta-analysis of this trial and previous published prophylactic trials showed no survival benefit. The authors concluded that early post-natal prophylactic GM-CSF corrects neutropenia but does not reduce sepsis or improve survival and short-term outcomes in extremely pre-term neonates.
In a meta-analysis, Bo et al (2011) examined the effects of G-CSF or GM-CSF therapy in non-neutropenic patients with sepsis. A systematic literature search of Medline, Embase and Cochrane Central Register of Controlled Trials was conducted using specific search terms. A manual review of references was also performed. Eligible studies were RCTs that compared G-CSF or GM-CSF therapy with placebo for the treatment of sepsis in adults. Main outcome measures were all-cause mortality at 14 days and 28 days after initiation of G-CSF or GM-CSF therapy, in-hospital mortality, reversal rate from infection, and adverse events. A total of 12 RCTs with 2,380 patients were identified. In regard to 14-day mortality, a total of 9 death events occurred among 71 patients (12.7 %) in the treatment group compared with 13 events among 67 patients (19.4 %) in the placebo groups. Meta-analysis showed there was no significant difference in 28-day mortality when G-CSF or GM-CSF were compared with placebo (relative risks (RR) = 0.93, 95 % CI: 0.79 to 1.11, p = 0.44; p for heterogeneity = 0.31, I2 = 15 %). Compared with placebo, G-CSF or GM-CSF therapy did not significantly reduce in-hospital mortality (RR = 0.97, 95 % CI: 0.69 to 1.36, p = 0.86; p for heterogeneity = 0.80, I2 = 0 %). However, G-CSF or GM-CSF therapy significantly increased the reversal rate from infection (RR = 1.34, 95 % CI: 1.11 to 1.62, p = 0.002; p for heterogeneity = 0.47, I2 = 0 %). No significant difference was observed in adverse events between groups (RR = 0.93, 95 % CI: 0.70 to 1.23, p = 0.62; p for heterogeneity = 0.03, I2 = 58 %). Sensitivity analysis by excluding one trial did not significantly change the results of adverse events (RR = 1.05, 95 % CI: 0.84 to 1.32, p = 0.44; p for heterogeneity = 0.17, I2 = 36 %). The authors concluded that there is no current evidence supporting the routine use of G-CSF or GM-CSF in patients with sepsis. They stated that large prospective multi-center clinical trials investigating monocytic HLA-DR (mHLA-DR)-guided G-CSF or GM-CSF therapy in patients with sepsis-associated immunosuppression are needed.
Granulocyte-CSF is used to mobilize CD34+ hematopoietic stem cells from the bone marrow to the peripheral blood. In a pilot study, Nefussy et al (2010) examined the use cell subsets induced by G-CSF to slow down disease progression in patients with amyotrophic lateral sclerosis (ALS). Patients with definite or probable ALS were assigned in a double-blind manner to receive G-CSF or placebo every 3 months for 1 year. The primary outcome measure was the functional decline, measured by the revised ALS Functional Rating Scale, Revised (ALSFRS-R) score. Secondary outcome measures included vital capacity, manual muscle strength, compound muscle action potential amplitudes, neurophysiological index, and McGill single item quality of life score (QoL). A total of 39 patients were enrolled. Seventeen patients who received G-CSF and 18 who received placebo were evaluated. Granulocyte-CSF was effective in mobilizing CD34+ to blood. The outcome measures used showed no statistically significant benefit, although there was a trend of slowing disease progression following 2 G-CSF treatments, as shown by lower slopes of ALSFRS-R and QoL in the first 6 treatment months. The treatment had no major side-effects. The authors concluded that G-CSF administration in ALS patients caused successful mobilization of autologous bone marrow cells, but was not effective in slowing down disease deterioration.
In a Cochrane review, Minton et al (2010) evaluated the effectiveness of drugs for the management of cancer-related fatigue (CRF). These investigators searched the Cochrane Central Register of Controlled Trials (from Issue 2 2007) MEDLINE and EMBASE from January 2007 to October 2009 and a selection of cancer journals. They searched references of identified articles and contacted authors to obtain unreported data. Studies were included in the review if they meet the following criteria:
I. assessed drug therapy for the management of CRF compared to placebo, usual care or a non-pharmacological intervention,
II. RCTs, and
III. adult patients with a clinical diagnosis of cancer.
1. assessed drug therapy for the management of CRF compared to placebo, usual care or a non-pharmacological intervention,
2. RCTs, and
3. adult patients with a clinical diagnosis of cancer.
Two review authors independently assessed trial quality and extracted data. Meta-analyses were performed on different drug classes using continuous variable data. A total of 50 studies met the inclusion criteria; and 6 additional studies were identified since the original review. Only 31 of these studies involving 7,104 participants were judged to have used a sufficiently robust measure of fatigue and thus were deemed suitable for detailed analysis. The drugs were still analyzed by class (anti-depressants, hemopoietic growth factors, progestational steroids, as well as psychostimulants). Methylphenidate showed a small but significant improvement in fatigue over placebo (Z = 2.83; p = 0.005). Since the publication of the original review increased safety concerns have been raised regarding erythropoietin and this can not now be recommended in practice. The authors concluded that there is increasing evidence that psychostimulant trials provide evidence for improvement in CRF at a clinically meaningful level. There is still a requirement for a large scale RCT of methylphenidate to confirm the preliminary results. There are new safety data that indicates that the hemopoietic growth factors are associated with increased adverse outcomes. These drugs can no longer be recommended in the treatment of CRF.
In a multi-center RCT, Korzenik et al (2005) investigated the effectiveness of sargramostim in treating Crohn's disease. A total of 124 patients with moderate-to-severe active Crohn's disease were randomly assigned to receive 6 µg of sargramostim per kilogram of body weight per day or placebo subcutaneously for 56 days using a 2:1 ratio. The primary end point was a clinical response, defined by a decrease from baseline of at least 70 points in the Crohn's Disease Activity Index (CDAI) at the end of treatment (day 57). Other end points included changes in disease severity and the health-related quality of life and adverse events. There was no significant difference in the rate of the primary end point of a clinical response defined by a decrease of at least 70 points in the CDAI score on day 57 between the sargramostim and placebo groups (54 % versus 44 %, p = 0.28). However, significantly more patients in the sargramostim group than in the placebo group reached the secondary end points of a clinical response defined by a decrease from baseline of at least 100 points in the CDAI score on day 57 (48 % versus 26 %, p = 0.01) and of remission, defined by a CDAI score of 150 points or less on day 57 (40 % versus 19 %, p = 0.01). The rates of either type of clinical response and of remission were significantly higher in the sargramostim group than in the placebo group on day 29 of treatment and 30 days after treatment. The sargramostim group also had significant improvements in the quality of life. Mild-to-moderate injection-site reactions and bone pain were more common in the sargramostim group, and 3 patients in this group had serious adverse events possibly or probably related to treatment. These investigators concluded that although this study was negative for the primary end point, findings for the secondary end points suggested that sargramostim therapy decreased disease severity and improved the quality of life in patients with active Crohn's disease. The authors noted that the role of GM-CSF in the biology of Crohn’s disease remains to be defined.
Tbo-filgrastim, a short-acting, synthetic form of G-CSF, is a biologic response modifier that binds to stem cells in bone marrow and stimulates the production of neutrophils. On August 29, 2012, the FDA approved the use of tbo-filgrastim (Neutroval) to reduce the duration of severe neutropenia in patients with non-myeloid malignancies receiving myelosuppressive anti-cancer drugs associated with a clinically significant incidence of febrile neutropenia. Tbo-filgrastim was evaluated in a clinical study of 348 adult patients with advanced breast cancer receiving treatment with the anti-cancer drugs doxorubicin and docetaxel. Patients were randomly assigned to receive tbo-filgrastim, a placebo, or a non-U.S.-approved filgrastim product, a drug that also stimulates neutrophil production by the bone marrow. The effectiveness of tbo-filgrastim was determined based on study results that showed that patients receiving tbo-filgrastim recovered from severe neutropenia in 1.1 days compared with 3.8 days in those receiving the placebo.
In a Cochrane review, Moazzami and associates (2013) assessed the effects of stem cell mobilization following G-CSF therapy in patients with acute MI. These investigators searched CENTRAL (The Cochrane Library Issue 4, 2010), MEDLINE (1950 to week 3 of November 2010), EMBASE (1980 to week 48 of 2010), BIOSIS Previews (1969 to November 30, 2010), ISI Science Citation Index Expanded (1970 to December 4, 2010) and ISI Conference Proceedings Citation Index - Science (1990 to December 4, 2010). These researchers also checked reference lists of articles. They included RCTS involving participants with a clinical diagnosis of acute MI who were randomly allocated to the subcutaneous administration of G-CSF through a daily dose of 2.5, 5 or 10 microgram/kg for 4 to 6 days or placebo. No age or other restrictions were applied for the selection of patients. Two authors independently selected trials, assessed trials for eligibility and methodological quality, and extracted data regarding the clinical efficacy and adverse outcomes. Disagreements were resolved by the third author. These investigators included 7 trials reported in 30 references in the review (354 participants). In all trials, G-CSF was compared with placebo preparations. Dosage of G-CSF varied among studies, ranging from 2.5 to 10 microgram/kg/day. Regarding overall risk of bias, data regarding the generation of randomization sequence and incomplete outcome data were at a low-risk of bias; however, data regarding binding of personnel were not conclusive. The rate of mortality was not different between the 2 groups (RR 0.64, 95 % CI: 0.15 to 2.80, p = 0.55). Regarding safety, the limited amount of evidence is inadequate to reach any conclusions regarding the safety of G-CSF therapy. Moreover, the results did not show any beneficial effects of G-CSF in patients with acute MI regarding left ventricular function parameters, including left ventricular ejection fraction (RR 3.41, 95 % CI: -0.61 to 7.44, p = 0.1), end systolic volume (RR -1.35, 95 % CI: -4.68 to 1.99, p = 0.43) and end diastolic volume (RR -4.08, 95 % CI: -8.28 to 0.12, p = 0.06). It should also be noted that the study was limited since the trials included lacked long enough follow-up durations. The authors concluded that limited evidence from small trials suggested a lack of benefit of G-CSF therapy in patients with acute MI. Moreover, they stated that since data of the risk of bias regarding blinding of personnel were not conclusive, larger RCTs with appropriate power calculations and longer follow-up durations are needed to address current uncertainties regarding the clinical effectiveness and therapy-related adverse events of G-CSF treatment.
In a Cochrane review, Bath and colleagues (2013) evaluated
I. the safety and effectiveness of CSFs in people with acute or subacute ischemic or hemorrhagic stroke, and
II. the effect of CSFs on circulating stem and blood cell counts.
1. the safety and effectiveness of CSFs in people with acute or subacute ischemic or hemorrhagic stroke, and
2. the effect of CSFs on circulating stem and blood cell counts.
These investigators searched the Cochrane Stroke Group Trials Register (last searched September 2012), the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2012, Issue 4), MEDLINE (1985 to September 2012), EMBASE (1985 to September 2012) and Science Citation Index (1985 to September 2012). In an attempt to identify further published, unpublished and ongoing trials, these researchers contacted manufacturers and principal investigators of trials (last contacted April 2012). They also searched reference lists of relevant articles and reviews. They included RCTs recruiting people with acute or subacute ischemic or hemorrhagic stroke. Colony-stimulating factors included stem cell factor (SCF), erythropoietin (EPO), G-CSF, GM-CSF, macrophage-colony stimulating factor (M-CSF, CSF-1), thrombopoietin (TPO), or analogs of these. The primary outcome was functional outcome at the end of the trial. Secondary outcomes included safety at the end of treatment, death at the end of follow-up, infarct volume and hematology measures. Two review authors independently extracted data and assessed trial quality; they contacted study authors for additional information. These investigators included a total of 11 studies involving 1,275 participants. In 3 trials (n = 782), EPO therapy was associated with a significant increase in death by the end of the trial (odds ratio (OR) 1.98, 9 5% CI: 1.19 to 3.3, p = 0.009) and a non-significant increase in serious adverse events. Erythropoietin significantly increased the red cell count with no effect on platelet or white cell count, or infarct volume. Two small trials of carbamylated EPO have been completed but have yet to be reported. These researchers included 8 small trials (n = 548) of G-CSF. Granulocyte-CSF was associated with a non-significant reduction in early impairment (mean difference (MD) -0.4, 95 % CI: -1.82 to 1.01, p = 0.58); but had no effect on functional outcome at the end of the trial. Granulocyte-CSF significantly elevated the white cell count and the CD34+ cell count, but had no effect on infarct volume. Further trials of G-CSF are ongoing. The authors concluded that there are significant safety concerns regarding EPO therapy for stroke. It is too early to know whether other CSFs improve functional outcome.
Poole and colleagues (2013) stated that many patients with peripheral artery disease (PAD) have walking impairment despite therapy. Experimental studies in animals demonstrated improved perfusion in ischemic hind limb after mobilization of bone marrow progenitor cells (PCs), but whether this is effective in patients with PAD is unknown. These researchers examined if therapy with GM-CSF improves exercise capacity in patients with intermittent claudication. In a phase II, double-blind, placebo-controlled study, 159 patients (median [SD] age, 64 [8] years; 87 % male, 37 % with diabetes) with intermittent claudication were enrolled at medical centers affiliated with Emory University in Atlanta, Georgia, between January 2010 and July 2012. Participants were randomized (1:1) to receive 4 weeks of subcutaneous injections of GM-CSF (leukine), 500 μg/day 3 times a week, or placebo. Both groups were encouraged to walk to claudication daily. The primary outcome was peak treadmill walking time (PWT) at 3 months. Secondary outcomes were PWT at 6 months and changes in circulating PC levels, ankle brachial index (ABI), and walking impairment questionnaire (WIQ) and 36-item Short-Form Health Survey (SF-36) scores. Of the 159 patients randomized, 80 were assigned to the GM-CSF group. The mean (SD) PWT at 3 months increased in the GM-CSF group from 296 (151) seconds to 405 (248) seconds (mean change, 109 seconds [95 % CI: 67 to 151]) and in the placebo group from 308 (161) seconds to 376 (182) seconds (change of 56 seconds [95 % CI: 14 to 98]), but this difference was not significant (mean difference in change in PWT, 53 seconds [95 % CI: -6 to 112], p = 0.08). At 3 months, compared with placebo, GM-CSF improved the physical functioning subscore of the SF-36 questionnaire by 11.4 (95 % CI: 6.7 to 16.1) versus 4.8 (95 % CI: -0.1 to 9.6), with a mean difference in change for GM-CSF versus placebo of 7.5 (95 % CI: 1.0 to 14.0; p = 0.03). Similarly, the distance score of the WIQ improved by 12.5 (95 % CI: 6.4 to 18.7) versus 4.8 (95 % CI: -0.2 to 9.8) with GM-CSF compared with placebo (mean difference in change, 7.9 [95 % CI: 0.2 to 15.7], p = 0.047). There were no significant differences in the ABI, WIQ distance and speed scores, claudication onset time, or mental or physical component scores of the SF-36 between the groups. The authors concluded that therapy with GM-CSF 3 times a week did not improve treadmill walking performance at the 3-month follow-up. The improvements in some secondary outcomes with GM-CSF suggested that it may warrant further study in patients with claudication. In addition, further investigation is needed to investigate the variability of responsiveness to GM-CSF and its clinical significance.
Siristatidis et al (2013) noted that GM-CSF is a cytokine/growth factor produced by epithelial cells that exerts embryotrophic effects during the early stages of embryo development. These investigators performed a systematic review, and 6 studies that were performed in humans undergoing assisted reproduction technologies (ART) were located. They examined if embryo culture media supplementation with GM-CSF could improve success rates. As the type of studies and the outcome parameters investigated were heterogeneous, these researchers decided not to perform a meta-analysis. Most of the studies had a trend favoring the supplementation with GM-CSF, when outcomes were measured in terms of increased percentage of good-quality embryos reaching the blastocyst stage, improved hatching initiation and number of cells in the blastocyst, and reduction of cell death. However, no statistically significant differences were found in implantation and pregnancy rates in all apart from 1 large multi-center trial, which reported favorable outcomes, in terms of implantation and live birth rates. The authors proposed properly conducted and adequately powered RCTs to further validate and extrapolate the current findings with the live birth rate to be the primary outcome measure.
In a Cochrane review, Cruciani et al (2013) examined the effects of adjunctive G-CSF compared with placebo or no growth factor added to usual care on rates of infection, cure and wound healing in people with diabetes who have a foot infection. These investigators searched the Cochrane Wounds Group Specialised Register (searched March 14, 2013); the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2013, Issue 2); Ovid MEDLINE (1948 to week 1 of March 2013); Ovid EMBASE (1974 to March 13, 2013); Ovid MEDLINE (In-Process March 13,2013); and EBSCO CINAHL (1982 to February 28, 2013). Randomized controlled trials that evaluated the effect of adding G-CSF to usual care in people with a diabetic foot infection were included for analysis. Three review authors independently assessed trial eligibility, methodological quality and extracted data. They reported RR or, for continuous outcomes, MD, with 95 % CI. In the case of low or no heterogeneity these researchers pooled studies using a fixed-effect model. They identified and included 5 eligible trials with a total of 167 patients. The investigators administered various G-CSF preparations, at different doses and for different durations of time. Adding G-CSF did not significantly affect the likelihood of resolution of infection or wound healing, but it was associated with a significantly reduced likelihood of lower extremity surgical interventions (RR 0.38; 95 % CI: 0.21 to 0.70), including amputation (RR 0.41; 95 % CI: 0.18 to 0.95). Moreover, providing G-CSF reduced the duration of hospital stay (MD -1.40 days; 95 % CI: -2.27 to -0.53 days), but did not significantly affect the duration of systemic antibiotic therapy (MD -0.27 days; 95 % CI: -1.30 to 0.77 days). The authors concluded that the available evidence is limited, but suggests that adjunctive G-CSF treatment in people with a diabetic foot infection, including infected ulcers, does not appear to increase the likelihood of resolution of infection or healing of the foot ulcer. However, it does appear to reduce the need for surgical interventions, especially amputations, and the duration of hospitalization. Clinicians might consider adding G-CSF to the usual treatment of diabetic foot infections, especially in patients with a limb-threatening infection, but it is not clear which patients might benefit.
In a phase I/II clinical trial, Saberi et al (2014) examined the effect of spinal cord injury (SCI) severity on the neurological outcomes, after neuroprotective treatment for SCI with G-CSF. A total of 74 consecutive patients with SCI of at least 6 months duration, with stable neurological status in the last 3 months having informed consent, for the treatment were included in the study. All the patients had undergone at least 3 months of standard rehabilitation. Patients were assessed by American Spinal Injury Association (ASIA) scale, Spinal Cord Independence Measure (SCIM) III, and International Association of Neurorestoratology-Spinal Cord Injury Functional Rating Scale (IANR-SCIFRS) just before intervention and periodically until 6 months after subcutaneous administration of 5 g/kg per day of G-CSF for 7 consecutive days. Multiple linear regression models, was performed for statistical evaluation of lesion completeness and level of injury on changes in ASIA motor, light touch, pinprick, IANR-SCIFRS, and SCIM III scores, as a phase I/II, comparative study. The study consisted of 52 motor complete, and 22 motor incomplete SCI patients. There was not any significant difference regarding age and sex, chronicity, and level of SCI between the 2 groups. Motor incomplete patients had significantly more improvement in ASIA motor score compared to the motor complete patients (7.68 scores, p < 0.001) also they had significant improvement in light touch (6.42 scores, p = 0.003) and pin-prick sensory scores (4.89 scores, p = 0.011). Therefore, G-CSF administration in motor incomplete SCIs is associated with significantly higher motor improvement, and also the higher the initial ASIA Impairment Scale (AIS) grade, the less would be the final AIS change, and incomplete cases are more welcome into the future studies. The clinical value of G-CSF in patients with chronic spinal cord injuries need to be further investigated in phase III clinical studies.
Chung et al (2014) investigated the effects of G-CSF on glial scar formation after SCI in rats and compared the therapeutic effects between G-CSF and GM-CSF to evaluate G-CSF as a potential substitute for GM-CSF in clinical application. Rats were randomly assigned to 1 of 4 groups:
I. a sham-operated group (Group 1),
II. an SCI group without treatment (Group 2),
III. an SCI group treated with G-CSF (Group 3), and
IV. an SCI group treated with GM-CSF (Group 4).
1. a sham-operated group (Group 1),
2. an SCI group without treatment (Group 2),
3. an SCI group treated with G-CSF (Group 3), and
4. an SCI group treated with GM-CSF (Group 4).
Granulocyte-colony stimulating factor and GM-CSF were administered via intra-peritoneal injection immediately after SCI. The effects of G-CSF and GM-CSF on functional recovery, glial scar formation, and axonal regeneration were evaluated and compared. The rats in Groups 3 and 4 showed better functional recovery and more decreased cavity sizes than those in Group 2 (p < 0.05). Both G-CSF and GM-CSF suppressed intensive expression of glial fibrillary acidic protein around the cavity at 4 weeks and reduced the expression of chondroitin sulfate proteoglycans (p < 0.05). Also, early administration of G-CSF and GM-CSF protected axon fibers from destructive injury and facilitated axonal regeneration. There were no significant differences in comparisons of functional recovery, glial scar formation, and axonal regeneration between G-CSF and GM-CSF. The authors concluded that G-CSF suppressed glial scar formation after SCI in rats, possibly by restricting the expression of glial fibrillary acidic protein and chondroitin sulfate proteoglycans, which might facilitate functional recovery from SCI. They stated that GM-CSF and G-CSF had similar effects on glial scar formation and functional recovery after SCI, suggesting that G-CSF can potentially be substituted for GM-CSF in the treatment of SCI. The findings from this animal study need to be validated in well-designed human trials.
Fulphila (pegfilgrastim-jmdp)
On June 4, 2018 the FDA approved Fulphila (pegfilgrastim-jmdb) as the first biosimilar to Neulasta (pegfilgrastim) to decrease the chance of infection as suggested by febrile neutropenia (fever, often with other signs of infection, associated with an abnormally low number of infection-fighting white blood cells), in patients with non-myeloid (non-bone marrow) cancer who are receiving myelosuppressive chemotherapy that has a clinically significant incidence of febrile neutropenia.
A biosimilar is a biological product that is highly similar to and has no clinically meaningful differences from an existing FDA-approved reference product. The FDA’s approval of Fulphila is based on review of evidence that included extensive structural and functional characterization, animal study data, human pharmacokinetic and pharmacodynamic data, clinical immunogenicity data, and other clinical safety and effectiveness data that demonstrates Fulphila is biosimilar to Neulasta. Fulphila has been approved as a biosimilar, not as an interchangeable product.
Pegfilgrastim-jmdb (Fulphila) is a covalent conjugate of recombinant methionyl human G-CSF and monomethoxypolyethylene glycol. As with filgrastim (Neupogen) and pegfilgrastim (Neulasta), pegfilgrastim-jmdb is a colony-stimulating factor that acts on hematopoietic cells by binding to specific cell surface receptors, thereby stimulating proliferation, differentiation, commitment, and end cell functional activation.
The recommended dosage of Fulphila is a single subcutaneous injection of 6 mg administered once per chemotherapy cycle. For dosing in pediatric patients weighing less than 45 kg, please refer to Full Prescribing Information. Fulphila should not be administered between 14 days before and 24 hours after administration of cytotoxic chemotherapy. Fulphila is administered subcutaneously via a single-dose prefilled syringe for manual use.
Fulphila is contraindicated in patients with a history of serious allergic reactions to pegfilgrastim products or filgrastim products and patients on Fulphila therapy should be closely monitored for the following potential adverse reactions:
• Splenic rupture, including fatal cases, can occur following the administration of pegfilgrastim products. Evaluate for an enlarged spleen or splenic rupture in patients who report left upper abdominal or shoulder pain after receiving Fulphila.
• Acute respiratory distress syndrome (ARDS) can occur in patients receiving pegfilgrastim products. Evaluate patients who develop fever and lung infiltrates or respiratory distress after receiving Fulphila, for ARDS. Discontinue Fulphila in patients with ARDS.
• Severe and sometimes fatal sickle cell crises can occur in patients with sickle cell disorders receiving pegfilgrastim products.
• Glomerulonephritis has occurred in patients receiving pegfilgrastim products. The diagnoses were based upon azotemia, hematuria (microscopic and macroscopic), proteinuria, and renal biopsy. Generally, events of glomerulonephritis resolved after dose reduction or discontinuation of pegfilgrastim products. If glomerulonephritis is suspected, evaluate for cause. If causality is likely, consider dose-reduction or interruption of Fulphila.
• Leukocytosis or White blood cell (WBC) counts of 100 x 109/L or greater have been observed in patients receiving pegfilgrastim products. Monitoring of complete blood count (CBC) during therapy with Fulphila is recommended.
• Capillary Leak Syndrome has been reported after G-CSF administration, including pegfilgrastim products, and is characterized by hypotension, hypoalbuminemia, edema and hemoconcentration. Episodes vary in frequency, severity and may be life-threatening if treatment is delayed. Patients who develop symptoms of capillary leak syndrome should be closely monitored and receive standard symptomatic treatment, which may include a need for intensive care.
• Potential for Tumor Growth Stimulatory Effects on Malignant Cells.
Pegfilgrastim was evaluated in three randomized, double-blind, controlled studies. Studies 1 and 2 were active-controlled studies that employed doxorubicin 60 mg/m2 and docetaxel 75 mg/m2 administered every 21 days for up to 4 cycles for the treatment of metastatic breast cancer. Study 1 investigated the utility of a fixed dose of pegfilgrastim. Study 2 employed a weight-adjusted dose. In the absence of growth factor support, similar chemotherapy regimens have been reported to result in a 100% incidence of severe neutropenia (ANC < 0.5 x 109/L) with a mean duration of 5 to 7 days and a 30% to 40% incidence of febrile neutropenia. Based on the correlation between the duration of severe neutropenia and the incidence of febrile neutropenia found in studies with filgrastim, duration of severe neutropenia was chosen as the primary endpoint in both studies, and the efficacy of pegfilgrastim was demonstrated by establishing comparability to filgrastim-treated patients in the mean days of severe neutropenia.
In Study 1, 157 patients were randomized to receive a single subcutaneous injection of pegfilgrastim (6 mg) on day 2 of each chemotherapy cycle or daily subcutaneous filgrastim (5 mcg/kg/day) beginning on day 2 of each chemotherapy cycle. In Study 2, 310 patients were randomized to receive a single subcutaneous injection of pegfilgrastim (100 mcg/kg) on day 2 or daily subcutaneous filgrastim (5 mcg/kg/day) beginning on day 2 of each chemotherapy cycle.
Both studies met the major efficacy outcome measure of demonstrating that the mean days of severe neutropenia of pegfilgrastim-treated patients did not exceed that of filgrastim-treated patients by more than 1 day in cycle 1 of chemotherapy. The mean days of cycle 1 severe neutropenia in Study 1 were 1.8 days in the pegfilgrastim arm compared to 1.6 days in the filgrastim arm [difference in means 0.2 (95% CI -0.2, 0.6)] and in Study 2 were 1.7 days in the pegfilgrastim arm compared to 1.6 days in the filgrastim arm [difference in means 0.1 (95% CI -0.2, 0.4)].
A secondary endpoint in both studies was days of severe neutropenia in cycles 2 through 4 with results similar to those for cycle 1.
Study 3 was a randomized, double-blind, placebo-controlled study that employed docetaxel 100 mg/m2 administered every 21 days for up to 4 cycles for the treatment of metastatic or non-metastatic breast cancer. In this study, 928 patients were randomized to receive a single subcutaneous injection of pegfilgrastim (6 mg) or placebo on day 2 of each chemotherapy cycle. Study 3 met the major trial outcome measure of demonstrating that the incidence of febrile neutropenia (defined as temperature ≥ 38.2°C and ANC ≤ 0.5 x109/L) was lower for pegfilgrastim-treated patients as compared to placebo-treated patients (1% versus 17%, respectively, p < 0.001). The incidence of hospitalizations (1% versus 14%) and IV anti-infective use (2% versus 10%) for the treatment of febrile neutropenia was also lower in the pegfilgrastim-treated patients compared to the placebo-treated patients.
Study 4 was a multicenter, randomized, open-label study to evaluate the efficacy, safety, and pharmacokinetics of pegfilgrastim in pediatric and young adult patients with sarcoma. Patients with sarcoma receiving chemotherapy age 0 to 21 years were eligible. Patients were randomized to receive subcutaneous pegfilgrastim as a single-dose of 100 mcg/kg (n = 37) or subcutaneous filgrastim at a dose 5 mcg/kg/day (n = 6) following myelosuppressive chemotherapy. Recovery of neutrophil counts was similar in the pegfilgrastim and filgrastim groups. The most common adverse reaction reported was bone pain.
Udenyca (pegfilgrastim-cbqv)
On November 02, 2018, the U.S. FDA approved Udenyca (pegfilgrastim-cbqv), formerly CHS-1701, a PEGylated growth colony-stimulating factor and the second biosimilar to Neulasta, for patients with cancer receiving myelosuppressive chemotherapy. The FDA approved indication for Udenyca is a leukocyte growth factor indicated to decrease the incidence of infection, as manifested by febrile neutropenia, in patients with non-myeloid malignancies receiving myelosuppressive anti-cancer drugs associated with a clinically significant incidence of febrile neutropenia.
Pegfilgrastim-cbqv is a covalent conjugate of recombinant methionyl human G-CSF and monomethoxypolyethylene glycol. Recombinant methionyl human G-CSF is obtained from the bacterial fermentation of a strain of E coli transformed with a genetically engineered plasmid containing the human G-CSF gene. As with pegfilgrastim (Neulasta) and pegfilgrastim-jmdb (Fulphila), pegfilgrastim-cbqv is a colony-stimulating factors that act on hematopoietic cells by binding to specific cell surface receptors, thereby stimulating proliferation, differentiation, commitment, and end cell functional activation.
The approval of Udenyca was supported by a comprehensive analytical similarity package, as well as pharmacokinetic, pharmacodynamic and immunogenicity studies, including over 600 healthy subjects.
Udenyca is not indicated for the mobilization of peripheral blood progenitor cells for hematopoietic stem cell transplantation and is contraidicated in patients with a history of serious allergic reaction to human granulocyte colony-stimulating factors such as pegfilgrastim or filgrastim products. Warnings and precautions for Udenyca include evaluating patients who report left upper abdominal or shoulder pain for an enlarged spleen or splenic rupture, evaluating patients who develop fever, lung infiltrates, or respiratory distress and discontinuing treatment in patients with Acute respiratory distress syndrome (ARDS). In the event of serious allergic reactions, including anaphylaxis, permanently discontinue Udenyca. Fatal sickle cell crises have occurred. If glomerulonephritis develops, consider dose-reduction or interruption of Udenyca if causality is likely. The most common adverse reactions (≥ 5% difference in incidence compared to placebo) are bone pain and pain in extremity.
m) is a human granulocyte colony stimulating factor (G-CSF), produced by recombinant DMA technology. Granix (tbo-filtrastim) is indicated to decrease the duration of severe neutropenia in patients with non-myeloid malignancies receiving myelosuppressive anti-cancer drugs associated with clinically significant incidence of febrile neutropenia.
Tbo-filgrastim is available as Granix 300 mcg and 480 mcg prefilled syringes.
Febrile neutropenia prophylaxis, in non-myeloid malignancies following myelosuppressive chemotherapy: The usual starting dose of Granix (tbo-filgrastim) is 5 micrograms/kilogram (mcg/kg)/day administered as a subcutaneous injection. Granix (tbo-filgrastim) should not be administered earlier than 24 hours after cytotoxic chemotherapy or within 24 hours before chemotherapy. Administer Granix (tbo-filgrastim) daily until the expected neutrophil nadir is passed and the neutrophil count has recovered to the normal range. Monitor complete blood count (CPC) prior to chemotherapy and twice per week until recovery.
Granix (tbo-filgrastim) should not be used in the following:
• Routine use as prophylaxis in member/chemotherapy regimens without significant risk of febrile neutropenia or in members that are not receiving myelosuppressive chemotherapy.
• Members with known hypersensitivity to E. coli-derived proteins, tbo-filgrastim, or any component of the product. Udenyca (pegfilgrastim-cbqv)
• On November 02, 2018, the U.S. FDA approved Udenyca (pegfilgrastim-cbqv), formerly CHS-1701, a PEGylated growth colony-stimulating factor and the second biosimilar to Neulasta, for patients with cancer receiving myelosuppressive chemotherapy. The FDA approved indication for Udenyca is a leukocyte growth factor indicated to decrease the incidence of infection, as manifested by febrile neutropenia, in patients with non-myeloid malignancies receiving myelosuppressive anti-cancer drugs associated with a clinically significant incidence of febrile neutropenia.
• Pegfilgrastim-cbqv is a covalent conjugate of recombinant methionyl human G-CSF and monomethoxypolyethylene glycol. Recombinant methionyl human G-CSF is obtained from the bacterial fermentation of a strain of E coli transformed with a genetically engineered plasmid containing the human G-CSF gene. As with pegfilgrastim (Neulasta) and pegfilgrastim-jmdb (Fulphila), pegfilgrastim-cbqv is a colony-stimulating factors that act on hematopoietic cells by binding to specific cell surface receptors, thereby stimulating proliferation, differentiation, commitment, and end cell functional activation.
• The approval of Udenyca was supported by a comprehensive analytical similarity package, as well as pharmacokinetic, pharmacodynamic and immunogenicity studies, including over 600 healthy subjects.
• Udenyca is not indicated for the mobilization of peripheral blood progenitor cells for hematopoietic stem cell transplantation and is contraidicated in patients with a history of serious allergic reaction to human granulocyte colony-stimulating factors such as pegfilgrastim or filgrastim products. Warnings and precautions for Udenyca include evaluating patients who report left upper abdominal or shoulder pain for an enlarged spleen or splenic rupture, evaluating patients who develop fever, lung infiltrates, or respiratory distress and discontinuing treatment in patients with Acute respiratory distress syndrome (ARDS). In the event of serious allergic reactions, including anaphylaxis, permanently discontinue Udenyca. Fatal sickle cell crises have occurred. If glomerulonephritis develops, consider dose-reduction or interruption of Udenyca if causality is likely. The most common adverse reactions (≥ 5% difference in incidence compared to placebo) are bone pain and pain in extremity.
Ziextenzo (pegfilgrastim-bmez)
• On November 04, 2019, the U.S. FDA approved Ziextenzo (pegfilgrastim-bmez), a third biosimilar referencing Neulasta (pegfilgrastim). Ziextenzo is a leukocyte growth factor indicated to decrease the incidence of infection, as manifested by febrile neutropenia, in patients with non-myeloid malignancies receiving myelosuppressive anti-cancer drugs associated with a clinically significant incidence of febrile neutropenia. Ziextenzo is not indicated for the mobilization of peripheral blood progenitor cells for hematopoietic stem cell transplantation. Biosimilar means that the biological product is approved based on data demonstrating that it is highly similar to an FDA-approved biological product, known as a reference product, and that there are no clinically meaningful differences between the biosimilar product and the reference product. Biosimilarity of Ziextenzo has been demonstrated for the condition(s) of use (e.g., indication(s), dosing regimen(s)), strength(s), dosage form(s), and route(s) of administration described in its Full Prescribing Information.
• The FDA approval of Ziextenzo was based on results from three randomized, double-blind, controlled studies in patients with cancer receiving myelosuppressive chemotherapy. Studies 1 and 2 were active-controlled studies that employed doxorubicin 60 mg/m2 and docetaxel 75 mg/m2 administered every 21 days for up to 4 cycles for the treatment of metastatic breast cancer. Study 1 investigated the utility of a fixed dose of pegfilgrastim. Study 2 employed a weight-adjusted dose. In the absence of growth factor support, similar chemotherapy regimens have been reported to result in a 100% incidence of severe neutropenia (ANC < 0.5 x 109 /L) with a mean duration of 5 to 7 days and a 30% to 40% incidence of febrile neutropenia. Based on the correlation between the duration of severe neutropenia and the incidence of febrile neutropenia found in studies with filgrastim, duration of severe neutropenia was chosen as the primary endpoint in both studies, and the efficacy of pegfilgrastim was demonstrated by establishing comparability to filgrastim-treated patients in the mean days of severe neutropenia. In Study 1, 157 patients were randomized to receive a single subcutaneous injection of pegfilgrastim (6 mg) on day 2 of each chemotherapy cycle or daily subcutaneous filgrastim (5 mcg/kg/day) beginning on day 2 of each chemotherapy cycle. In Study 2, 310 patients were randomized to receive a single subcutaneous injection of pegfilgrastim (100 mcg/kg) on day 2 or daily subcutaneous filgrastim (5 mcg/kg/day) beginning on day 2 of each chemotherapy cycle.
• Both studies met the major efficacy outcome measure of demonstrating that the mean days of severe neutropenia of pegfilgrastim-treated patients did not exceed that of filgrastim-treated patients by more than 1 day in cycle 1 of chemotherapy. The mean days of cycle 1 severe neutropenia in Study 1 were 1.8 days in the pegfilgrastim arm compared to 1.6 days in the filgrastim arm [difference in means 0.2 (95% CI -0.2, 0.6)] and in Study 2 were 1.7 days in the pegfilgrastim arm compared to 1.6 days in the filgrastim arm [difference in means 0.1 (95% CI - 0.2, 0.4)]. A secondary endpoint in both studies was days of severe neutropenia in cycles 2 through 4 with results similar to those for cycle 1.
• Study 3 was a randomized, double-blind, placebo-controlled study that employed docetaxel 100 mg/m2 administered every 21 days for up to 4 cycles for the treatment of metastatic or non-metastatic breast cancer. In this study, 928 patients were randomized to receive a single subcutaneous injection of pegfilgrastim (6 mg) or placebo on day 2 of each chemotherapy cycle. Study 3 met the major trial outcome measure of demonstrating that the incidence of febrile neutropenia (defined as temperature ≥ 38.2°C and ANC ≤ 0.5 x 109 /L) was lower for pegfilgrastim-treated patients as compared to placebo-treated patients (1% versus 17%, respectively, p < 0.001). The incidence of hospitalizations (1% versus 14%) and IV anti-infective use (2% versus 10%) for the treatment of febrile neutropenia was also lower in the pegfilgrastim-treated patients compared to the placebo- treated patients.
• Study 4 was a multicenter, randomized, open-label study to evaluate the efficacy, safety, and pharmacokinetics of pegfilgrastim in pediatric and young adult patients with sarcoma. Patients with sarcoma receiving chemotherapy age 0 to 21 years were eligible. Patients were randomized to receive subcutaneous pegfilgrastim as a single-dose of 100 mcg/kg (n = 37) or subcutaneous filgrastim at a dose 5 mcg/kg/day (n = 6) following myelosuppressive chemotherapy. Recovery of neutrophil counts was similar in the pegfilgrastim and filgrastim groups. The most common adverse reaction reported was bone pain.
• Most common adverse reactions (≥ 5% difference in incidence compared to placebo) reported in the clinical studies were bone pain and pain in extremity.
Nyvepria (pegfilgrastim-apgf)
On June 10, 2020, the U.S. FDA approved a fourth biosimilar to Neulasta called Nyvepria (pegfilgrastim-apgf), a PEGylated growth colony-stimulating factor. Nyvepria is a leukocyte growth factor indicated to decrease the incidence of infection, as manifested by febrile neutropenia, in patients with non-myeloid malignancies receiving myelosuppressive anti-cancer drugs associated with a clinically significant incidence of febrile neutropenia. The FDA approval was based on the review of a totality of evidence demonstrating a high degree of similarity of Nyvepria to its reference product.
Pegfilgrastim was evaluated in three randomized, double-blind, controlled studies. Studies 1 and 2 were active-controlled studies that employed doxorubicin 60 mg/m2 and docetaxel 75 mg/m2 administered every 21 days for up to 4 cycles for the treatment of metastatic breast cancer. Study 1 investigated the utility of a fixed dose of pegfilgrastim. Study 2 employed a weight-adjusted dose. In the absence of growth factor support, similar chemotherapy regimens have been reported to result in a 100% incidence of severe neutropenia (ANC <0.5 x 109/ L) with a mean duration of 5 to 7 days and a 30% to 40% incidence of febrile neutropenia. Based on the correlation between the duration of severe neutropenia and the incidence of febrile neutropenia found in studies with filgrastim, duration of severe neutropenia was chosen as the primary endpoint in both studies, and the efficacy of pegfilgrastim was demonstrated by establishing comparability to filgrastim-treated patients in the mean days of severe neutropenia. In Study 1, 157 patients were randomized to receive a single subcutaneous injection of pegfilgrastim (6 mg) on day 2 of each chemotherapy cycle or daily subcutaneous filgrastim (5 mcg/kg/day) beginning on day 2 of each chemotherapy cycle. In Study 2, 310 patients were randomized to receive a single subcutaneous injection of pegfilgrastim (100 mcg/kg) on day 2 or daily subcutaneous filgrastim (5 mcg/kg/day) beginning on day 2 of each chemotherapy cycle. Both studies met the major efficacy outcome measure of demonstrating that the mean days of severe neutropenia of pegfilgrastim-treated patients did not exceed that of filgrastim-treated patients by more than 1 day in cycle 1 of chemotherapy. The mean days of cycle 1 severe neutropenia in Study 1 were 1.8 days in the pegfilgrastim arm compared to 1.6 days in the filgrastim arm [difference in means 0.2 (95% CI -0.2, 0.6)] and in Study 2 were 1.7 days in the pegfilgrastim arm compared to 1.6 days in the filgrastim arm [difference in means 0.1 (95% CI -0.2, 0.4)]. A secondary endpoint in both studies was days of severe neutropenia in cycles 2 through 4 with results similar to those for cycle 1.
Study 3 was a randomized, double-blind, placebo-controlled study that employed docetaxel 100 mg/m2 administered every 21 days for up to 4 cycles for the treatment of metastatic or non-metastatic breast cancer. In this study, 928 patients were randomized to receive a single subcutaneous injection of pegfilgrastim (6 mg) or placebo on day 2 of each chemotherapy cycle. Study 3 met the major trial outcome measure of demonstrating that the incidence of febrile neutropenia (defined as temperature ≥38.2°C and ANC ≤0.5 x 109 /L) was lower for pegfilgrastim-treated patients as compared to placebo-treated patients (1% versus 17%, respectively, p < 0.001). The incidence of hospitalizations (1% versus 14%) and IV anti-infective use (2% versus 10%) for the treatment of febrile neutropenia was also lower in the pegfilgrastim-treated patients compared to the placebo-treated patients.
Study 4 was a multicenter, randomized, open-label study to evaluate the efficacy, safety, and pharmacokinetics of pegfilgrastim in pediatric and young adult patients with sarcoma. Patients with sarcoma receiving chemotherapy age 0 to 21 years were eligible. Patients were randomized to receive subcutaneous pegfilgrastim as a single dose of 100 mcg/kg (n = 37) or subcutaneous filgrastim at a dose 5 mcg/kg/day (n = 6) following myelosuppressive chemotherapy. Recovery of neutrophil counts was similar in the pegfilgrastim and filgrastim groups. The most common adverse reaction reported was bone pain.
Fulphila (pegfilgrastim-jmdb) is a leukocyte growth factor indicated to decrease the incidence of infection, as manifested by febrile neutropenia, in patients with non-myeloid malignancies receiving myelosuppressive anti-cancer drugs associated with a clinically significant incidence of febrile neutropenia.
Leukine (sargramostim) is a recombinant human granulocyte-macrophage colony stimulating factor indicated for use following induction chemotherapy in older adult patients with acute myelogenous leukemia (AML) to shorten time to neutrophil recovery and to reduce the incidence of severe and life-threatening infection and infections resulting in death; the mobilization of hematopoietic progenitor cells into peripheral blood for collection by leukapheresis; the acceleration of myeloid recovery in patients with non-Hodgkin’s lymphoma (NHL), acute lymphoblastic leukemia (ALL) and Hodgkin’s disease undergoing autologous bone marrow transplantation (BMT); the acceleration of myeloid recovery in patients undergoing allogenic BMT from HLA-matched related donors; for patients who have undergone allogeneic or autologous BMT in whom engraftment is delayed or has failed; and to increase survival in adult and pediatric patients from birth to 17 years of age acutely exposed to myelosuppressive doses of radiation (Hematopoietic Syndrome of Acute Radiation Syndrome).
Neulasta (pegfilgrastim) is a leukocyte growth factor indicated to decrease the incidence of infection, as manifested by febrile neutropenia, in patients with non-myeloid malignancies receiving myelosuppressive anti-cancer drugs associated with a clinically significant incidence of febrile neutropenia; and to increase survival in patients acutely exposed to myelosuppressive doses of radiation (Hematopoietic Subsyndrome of Acute Radiation Syndrome). Neulasta is not indicated for the mobilization of peripheral blood progenitor cells for hematopoietic stem cell transplantation.
Neupogen (filgrastim) is a leukocyte growth factor indicated to decrease the incidence of infection, as manifested by febrile neutropenia, in patients with nonmyeloid malignancies receiving myelosuppressive anti-cancer drugs associated with a significant incidence of severe neutropenia with fever; reduce the time to neutrophil recovery and the duration of fever, following induction or consolidation chemotherapy treatment of patients with AML; reduce the duration of neutropenia and neutropenia-related clinical sequelae, e.g., febrile neutropenia, in patients with nonmyeloid malignancies undergoing myeloablative chemotherapy followed by BMT; mobilize autologous hematopoietic progenitor cells into the peripheral blood for collection by leukapheresis; reduce the incidence and duration of sequelae of severe neutropenia (e.g., fever, infections, oropharyngeal ulcers) in symptomatic patients with congenital neutropenia, cyclic neutropenia or idiopathic neutropenia; and to increase survival in patients acutely exposed to myelosuppressive doses of radiation (Hematopoietic Syndrome of Acute Radiation Syndrome).
Nivestym (filgrastim-aafi) is a leukocyte growth factor indicated to decrease the incidence of infection, as manifested by febrile neutropenia, in patients with nonmyeloid malignancies receiving myelosuppressive anti-cancer drugs associated with a significant incidence of severe neutropenia with fever; reduce the time to neutrophil recovery and the duration of fever following induction or consolidation chemotherapy treatment of patients with AML; reduce the duration of neutropenia and neutropenia-related clinical sequelae, e.g., febrile neutropenia, in patients with nonmyeloid malignancies undergoing myeloablative chemotherapy followed by BMT; mobilize autologous hematopoietic progenitor cells into the peripheral blood for collection by leukapheresis; and to reduce the incidence and duration of sequelae of severe neutropenia (e.g., fever, infections, oropharyngeal ulcers) in symptomatic patients with congenital neutropenia, cyclic neutropenia, or idiopathic neutropenia.
Granix (tbo-filgrastim) is a leukocyte growth factor indicated for reduction in the duration of severe neutropenia in patients with non-myeloid malignancies receiving myelosuppressive anti-cancer drugs associated with a clinically significant incidence of febrile neutropenia.
Udenyca (pegfilgrastim-cbqv) is a leukocyte growth factor indicated to decrease the incidence of infection, as manifested by febrile neutropenia, in patients with non-myeloid malignancies receiving myelosuppressive anti-cancer drugs associated with a clinically significant incidence of febrile neutropenia.
Zarxio (filgrastim-sndz) is a leukocyte growth factor indicated to decrease the incidence of infection, as manifested by febrile neutropenia, in patients with nonmyeloid malignancies receiving myelosuppressive anti-cancer drugs associated with a significant incidence of severe neutropenia with fever; reduce the time to neutrophil recovery and the duration of fever, following induction or consolidation chemotherapy treatment of patients with AML; reduce the duration of neutropenia and neutropenia-related clinical sequelae, e.g., febrile neutropenia, in patients with nonmyeloid malignancies undergoing myeloablative chemotherapy followed by BMT; mobilize autologous hematopoietic progenitor cells into the peripheral blood for collection by leukapheresis; and to reduce the incidence and duration of sequelae of severe neutropenia (e.g., fever, infections, oropharyngeal ulcers) in symptomatic patients with congenital neutropenia, cyclic neutropenia, or idiopathic neutropenia.
Ziextenzo (pegfilgrastim-bmez) is a leukocyte growth factor indicated to decrease the incidence of infection, as manifested by febrile neutropenia, in patients with non-myeloid malignancies receiving myelosuppressive anti-cancer drugs associated with a clinically significant incidence of febrile neutropenia.
A biosimilar product is a biologic product that is approved based on demonstrating that it is highly similar to an FDA‐approved biologic product, known as a reference product, and has no clinically meaningful differences in terms of safety and effectiveness from the reference product. Only minor differences in clinically inactive components are allowable in biosimilar products.
Promotion of greater diversity and inclusion in clinical research of historically marginalized groups (e.g., People of Color [African-American, Asian, Black, Latino and Native American]; LGBTQIA (Lesbian, Gay, Bisexual, Transgender, Queer, Intersex, Asexual); Women; and People with Disabilities [Physical and Invisible]) allows policy populations to be more reflective of and findings more applicable to our diverse members. While we also strive to use inclusive language related to these groups in our policies, use of gender-specific nouns (e.g., women, men, sisters, etc.) will continue when reflective of language used in publications describing study populations.
Population Reference No. 1
Patients with profound prolonged neutropenia are at particularly high risk for serious infections; profound prolonged neutropenia is most likely to occur in the pre-engraftment phase of hematopoietic cell transplantation (HCT; particularly allogeneic) and in patients undergoing induction chemotherapy for acute leukemia.
Because neutropenic patients are unable to mount robust inflammatory responses, serious infection can occur with minimal symptoms and signs. In such patients, fever is often the only sign of infection. Infections in neutropenic patients can progress rapidly, leading to hypotension and/or other life-threatening complications. It is critical to recognize neutropenic fever early and to initiate empiric systemic antibacterial therapy promptly in order to avoid progression to a sepsis syndrome and possibly death.
Guidelines have been developed for the management of fever in neutropenic patients with cancer, including hematopoietic cell transplant recipients.
White blood cell growth factors, also known as colony stimulating factors (CSF), are administered to enhance recovery of blood related functions in neutropenia (low white blood count) including febrile neutropenia (FN). CSFs are also utilized to decrease the incidence and severity of infection associated with select disease-related and drug-related myelosuppression (inhibition of bone marrow function).
Granulocyte colony stimulating factors (G-CSF) are glycoproteins which exert major control over the reproduction and maturation of certain white blood cells, which include the following U.S. Food &
Drug Administration (FDA) approved products:
• Filgrastim (Neupogen®, Amgen, Thousand Oaks, CA)
• Pegfilgrastim (Neulasta® and Neulasta® OnPro®, Amgen, Thousand Oaks, CA)
• Pegfilgrastim-bmez (Ziextenzo™, Sandoz, Princeton, NJ)
• Pegfilgrastim-cbqv (Udenyca™, Coherus BioSciences, Redwood City, CA)
• Pegfilgrastim-jmdb (Fulphila™, Mylan, Rockford, IL)
• Filgrastim-aafi (Nivestym™, Pfizer, Lake Forest, IL)
• Filgrastim-sndz (Zarxio®, Sandoz, Princeton, NJ)
• Tbo-filgrastim (Granix®, Sicor Biotech UAB/Teva Pharmaceuticals, North Wales, PA)
Granulocyte-macrophage colony stimulating factor (GM-CSF) is a hematopoietic growth factor which
stimulates proliferation and differentiation of hematopoietic progenitor cells.
• Sargramostim (Leukine®, Bayer Healthcare Pharmaceuticals, Seattle, WA)
The evidence is sufficient to determine the impact of the technology results in a meaningful improvement in the net health outcome.
| Population Reference No. 1 Policy Statement | [X] MedicallyNecessary | [ ] Investigational |
| Table: Selected Chemotherapy Regimens with an Incidence of Febrile Neutropenia 20% or greater | |
| Cancer Histology | Regimen |
| Acute Lymphoblastic Leukemia (ALL) | Select ALL regimens as directed by treatment protocol (see NCCN guidelines) |
| Bladder Cancer | Dose dense MVAC (methotrexate, vinblastine, doxorubicin, cisplatin) |
| | CBDCa/Pac (carboplatin, paclitaxel) |
| Bone Cancer | VAI (vincristine, doxorubicin or dactinomycin, ifosfamide) |
| VDC-IE (vincristine, doxorubicin or dactinomycin, and cyclophosphamide alternating with ifosfamide and etoposide) | |
| VIDE (vincristine, ifosfamide, doxorubicin or dactinomycin, etoposide) | |
| Cisplatin/doxorubicin | |
| VDC (cyclophosphamide, vincristine, doxorubicin or dactinomycin | |
| Breast Cancer | Docetaxel + trastuzumab |
| | Dose-dense AC (doxorubicin, cyclophosphamide) + paclitaxel (or dose dense paclitaxel) |
| | TAC (docetaxel, doxorubicin, cyclophosphamide) |
| | AT (doxorubicin, docetaxel) |
| | Doc (docetaxel) |
| | TC (docetaxel, cyclophosphamide) |
| | TCH (docetaxel, carboplatin, trastuzumab) |
| Colorectal Cancer | FOLFOXIRI (Fluorouracil, leucovorin, oxaliplatin, irinotecan) |
| Esophageal and Gastric Cancers | Docetaxel/cisplatin/fluorouracil |
| Head and Neck Squamous Cell Carcinoma | TPF (docetaxel, cisplatin, 5-fluorouracil) |
| Hodgkin Lymphoma | Brentuximab vedotin + AVD (doxorubicin, vinblastine, dacarbazine) |
| | Escalated BEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, prednisone) |
| Kidney Cancer | Doxorubicin/gemcitabine |
| Melanoma | Dacarbazine-based combination with IL-2, interferon alpha (dacarbazine, cisplatin, vinblastine, IL-2, interferon alfa) |
| Multiple myeloma | DT-PACE (dexamethasone/ thalidomide / cisplatin / doxorubicin / cyclophoaphamide / etoposide) + bortezomib (VTD-PACE) |
| DT-PACE (dexamethasone / thalidomide / cisplatin / doxorubicin / cyclophoaphamide/etoposide) | |
| Non-Hodgkin's Lymphoma | Dose-adjusted EPOCH (etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin) |
| | ICE (ifosfamide, carboplatin, etoposide) |
| | Dose-dense CHOP-14 (cyclophosphamide, doxorubicin, vincristine, prednisone) + rituximab |
| | MINE (mesna, ifosfamide, mitoxantrone, etoposide) |
| | DHAP (dexamethasone, cisplatin, cytarabine) |
| | ESHAP (etoposide, methylprednisolone, cisplatin, cytarabine (Ara-C)) |
| | HyperCVAD + rituximab (cyclophosphamide, vincristine, doxorubicin, dexamethasone + rituximab) |
| | VAPEC-B (vincristine, doxorubicin, prednisolone, etoposide, cyclophosphamide, bleomycin) |
| Ovarian Cancer | Topotecan |
| | Docetaxel |
| Pancreatic Cancer | FOLFIRINOX (fluorouracil, leucovorin, irinotecan, oxaliplatin) |
| Soft Tissue Sarcoma | MAID (mesna, doxorubicin, ifosfamide, dacarbazine) |
| | Doxorubicin |
| | Ifosfamide/doxorubicin |
| Small Cell Lung Cancer | Top (topotecan) |
| | CAV (cyclophosphamide, doxorubicin, vincristine) |
| Testicular cancer | VelP (vinblastine, ifosfamide, cisplatin) |
| | VIP (etoposide, ifosfamide, cisplatin) |
| | TIP (paclitaxel, ifosfamide, cisplatin) |
Source: Smith et al, 2006; NCCN Hematopoietic Growth Factors, 2020.
American Society of Clinical Oncology (ASCO)
American Society of Clinical Oncology (ASCO) published guidelines in 2015 entitled, “Recommendations for the Use of WBC Growth Factors: American Society of Clinical Oncology Clinical Practice Guideline Update.” 41 The ASCO guidelines provide direction as to how colony-stimulating factors (CSFs) should be used in people with cancer. Recommendations include:
Primary prophylaxis with a CSF starting with the first cycle and continuing through subsequent cycles of chemotherapy is recommended in patients who have an approximately 20% or higher risk for febrile neutropenia based on patient-, diseaseand treatment-related factors. Primary CSF prophylaxis should also be administered in patients receiving dose dense chemotherapy when considered appropriate. Consideration should be given to alternative, equally effective, and safe chemotherapy regimens not requiring CSF support when available. (Type: evidence based, benefits outweigh harms. Evidence quality: high. Strength of recommendation: strong.)
Secondary prophylaxis with a CSF is recommended for patients who experienced a neutropenic complication from a prior cycle of chemotherapy (for which primary prophylaxis was not received), in which a reduced dose or treatment delay may compromise disease-free or overall survival or treatment outcome. In many clinical situations, dose reduction or delay may be a reasonable alternative. (Type: evidence based, benefits outweigh harms. Evidence quality: high. Strength of recommendation: strong.)
CSFs should not be routinely used for patients with neutropenia who are afebrile. (Type: evidence based, benefits outweigh harms. Evidence quality: high. Strength of recommendation: strong.)
CSFs should not be routinely used as adjunctive treatment with antibiotic therapy for patients with fever and neutropenia. However, CSFs should be considered in patients with fever and neutropenia who are at high risk for infection-associated complications or who have prognostic factors predictive of poor clinical outcomes. (Type: evidence based, benefits outweigh harms. Evidence quality: high. Strength of recommendation: strong.)
Dose-dense regimens with CSF support should only be used if supported by convincing efficacy data or within an appropriately designed clinical trial. Efficacy data support the use of dose-dense chemotherapy in the adjuvant treatment of high-risk breast cancer and the use of high-dose intensity methotrexate, vinblastine, doxorubicin, and cisplatin in urothelial cancer. There are limited and conflicting data on the value of dose-dense regimens with CSF support in non-Hodgkin lymphoma, and it cannot routinely be recommended at this time. (Type: evidence based, benefits outweigh harms. Evidence quality: high for breast cancer and lymphoma; intermediate for urothelial cancer. Strength of recommendation: strong for breast cancer and lymphoma; moderate for urothelial cancer.)
CSFs may be used alone, after chemotherapy, or in combination with plerixafor to mobilize peripheral-blood progenitor cells. Choice of mobilization strategy depends in part on type of cancer and type of transplantation. (Type: evidence based, benefits outweigh harms. Evidence quality: strong. Strength of recommendation: high.)
CSFs should be administered after autologous stem-cell transplantation to reduce the duration of severe neutropenia. (Type: evidence based, benefits outweigh harms. Evidence quality: high. Strength of recommendation: strong.) CSFs may be administered after allogeneic stem-cell transplantation to reduce the duration of severe neutropenia. (Type: evidence based. Evidence quality: low. Strength of recommendation: weak).
Prophylactic CSFs for patients with diffuse aggressive lymphoma age ≥ 65 years treated with curative chemotherapy (cyclophosphamide, doxorubicin, vincristine, prednisone, and rituximab) should be considered, particularly in the presence of comorbidities. (Type: evidence based, benefits outweigh harms. Evidence quality: intermediate. Strength of recommendation: moderate.)
The use of CSFs in pediatric patients will almost always be guided by clinical protocols. As in adults, the use of CSFs is reasonable as primary prophylaxis for pediatric patients with a high likelihood of febrile neutropenia. Similarly, the use of CSFs for secondary prophylaxis or for therapy should be limited to high-risk patients. (Type: evidence based, benefits outweigh harms. Evidence quality: high. Strength of recommendation: strong.)
For pediatric indications in which dose-intense chemotherapy is known to have a survival benefit, such as Ewing sarcoma, CSFs should be used to enable the administration of these regimens. (Type: evidence based, benefits outweigh harms. Evidence quality: high. Strength of recommendation: strong.)
CSFs should not be used in pediatric patients with nonrelapsed acute lymphoblastic leukemia or nonrelapsed acute myeloid leukemia who do not have an infection. (Type: informal consensus. Evidence quality: intermediate. Strength of recommendation: moderate.)
Pegfilgrastim, filgrastim, tbo-filgrastim, and filgrastim-sndz (and other biosimilars, as they become available) can be used for the prevention of treatment-related febrile neutropenia. The choice of agent depends on convenience, cost, and clinical situation. There have been no additional data comparing granulocyte CSFs and granulocyte-macrophage CSFs since the 2006 update; therefore, there is no change in the recommendation regarding their therapeutic equivalency. (Type: evidence based, benefits outweigh harms. Evidence quality: high. Strength of recommendation: strong.)
Current recommendations for the management of patients exposed to lethal doses of total-body radiotherapy, but not doses high enough to lead to certain death resulting from injury to other organs, include the prompt administration of CSFs or pegylated granulocyte CSFs. (Type: formal consensus [by others], benefits outweigh harms. Evidence quality: intermediate. Strength of recommendation: moderate.)
European Organisation for Research and Treatment of Cancer (EORTC)
The European Organisation for Research and Treatment of Cancer (EORTC) published clinical practice guidelines in 2011 entitled, “2010 update of EORTC guidelines for the use of granulocyte-colony stimulating factor to reduce the incidence of chemotherapy-induced febrile neutropenia in adult patients with lymphoproliferative disorders and solid tumors.” 44 The EORTC guidelines provide direction on the use of colony-stimulating factors for prevention of chemotherapy-induced febrile neutropenia (FN) in patients with cancer. Recommendations are graded on a scale of A-D, based on levels of evidence applied by the EORTC Guidelines Working Party. Levels of evidence are as follows: I = evidence obtained from meta-analysis of multiple, well-designed, controlled studies or from high-power randomized, controlled clinical trials; II = Evidence obtained from at least one well-designed experimental study or low-power randomized, controlled clinical trial; III = Evidence obtained from well-designed, quasi-experimental studies such as non-randomised, controlled single-group, pre-post, cohort, time or matched case-control series; IV = studies such as comparative and correlational descriptive and case studies; and V = evidence obtained from case reports and clinical examples. Grading recommendations are as follows: A = evidence of type I or consistent findings from multiple studies of types II, III or IV; B = evidence of types II, III or IV and findings are generally consistent; C = evidence of types II, III or IV but findings are inconsistent; and D = little or no systematic empirical evidence. Recommendations include:
Recommendation 1: patient-related risk factors for increased incidence of FN o Patient-related risk factors should be evaluated in the overall assessment of FN risk before administering each cycle of chemotherapy. Particular consideration should be given to the elevated risk of FN for elderly patients (aged 65 and over). Other adverse risk factors that may influence FN risk include: advanced stage of disease; experience of previous episode(s) of FN; lack of G-CSF use and absence of antibiotic prophylaxis. However, please note that the indiscriminate use of antibiotic prophylaxis for patients undergoing treatment for solid tumours or lymphoma is not recommended either by this working party or the EORTC Infectious Disease Group. Recommendation grade: B.
Recommendation 2: chemotherapy regimens associated with increased risk of FN o Consideration should be given to the elevated risk of FN when using certain chemotherapy regimens. Recommendation grade: A/B (depending on the evidence for each chemotherapy regimen). For the list of identified chemotherapy regimens, reference Table 5. It should be noted that this list is not comprehensive and there may be other drugs or regimens associated with an increased risk of FN.
Recommendation 3: G-CSF to support chemotherapy o In situations where dose-dense or dose-intense chemotherapy strategies have survival benefits, prophylactic G-CSF should be used as a supportive treatment. Recommendation grade: A. o If reductions in chemotherapy dose intensity or density are known to be associated with a poor prognosis, primary GCSF prophylaxis should be used to maintain chemotherapy. Examples of this could be when the patient is receiving adjuvant or potentially curative treatment or when the treatment intent is to prolong survival. Recommendation grade A. Where treatment intent is palliative, use of less myelosuppressive chemotherapy or dose/schedule modification should be considered. Recommendation grade: B.
Recommendation 4: impact of the overall FN risk on G-CSF use o The risk of complications related to FN should be assessed individually for each patient at the beginning of each cycle. When assessing FN risk, the clinician should take into account patient-related risk factors (recommendation 1), the chemotherapy regimen and associated complications (recommendations 2 and 3) and treatment intent (recommendation 3). Prophylactic G-CSF is recommended when there is a P20% overall risk of FN. When chemotherapy regimens associated with an FN risk of 10–20%, particular attention should be given to the assessment of patient characteristics that may increase the overall risk of FN. Recommendation grade: A.
Recommendation 5: G-CSF in patients with existing FN o Treatment with G-CSF for patients with solid tumours and malignant lymphoma and ongoing FN is indicated only in special situations. These are limited to those patients who are not responding to appropriate antibiotic management and who are developing life-threatening infectious complications (such as severe sepsis or septic shock). Recommendation grade: B.
Recommendation 6: choice of formulation o Filgrastim, lenograstim and pegfilgrastim have clinical efficacy and we recommend the use of any of these agents, according to current administration guidelines, to prevent FN and FN-related complications, where indicated. Filgrastim biosimilars are now also a treatment option in Europe. Recommendation grade: A.
Medicare coverage for outpatient (Part B) drugs is outlined in the Medicare Benefit Policy Manual (Pub. 100-2), Chapter 15, §50 Drugs and Biologicals. In addition, National Coverage Determination (NCD), Local Coverage Determinations (LCDs) and Local Coverage Articles (LCAs) may exist and compliance with these policies is required where applicable. They can be found at: http://www.cms.gov/medicare-coverage-database/search/advanced-search.aspx. Additional indications may be covered at the discretion of the health plan.
Medicare Part B Covered Diagnosis Codes (applicable to existing NCD/LCD/LCA):
Jurisdiction(s): N NCD/LCD Document (s): A57789 https://www.cms.gov/medicare-coverage-database/search/document-id-searchresults.aspx?DocID=A57789&bc=gAAAAAAAAAAA&
| Codes | Number | Description |
| CPT |
| |
| HCPCS | J1442 | filgrastim (G-CSF) 1 mcg |
| | J1447 | Injection, tbo-filgrastim, 1 mcg |
| J2506 | Injection, pegfilgrastim, excludes biosimilar, 0.5 mg | |
| | Q5101 | Injection, filgrastim-sndz, (Zarxio), 1 mcg |
| | Q5110 | Injection, filgrastim-aafi, biosimilar, (Nivestym), 1 mcg |
| | Q5108 | Injection, pegfilgrastim-jmdb, biosimilar, (Fulphila), 0.5 mg |
| | Q5111 | Injection, pegfilgrastim-cbqv, biosimilar, (Udenyca), 0.5 mg |
| | Q5120 | Injection, pegfilgrastim-bmez, biosimilar, (ZIEXTENZO), 0.5 mg |
| Q5122 | Injection, pegfilgrastim-apgf, biosimilar, (Nyvepria), 0.5 mg | |
| ICD-10-CM | C92.00 | Acute myeloblastic leukemia, not having achieved remission |
| | C92.02 | Acute myeloblastic leukemia, in relapse |
| | C92.50 | Acute myelomonocytic leukemia, not having achieved remission |
| | C92.52 | Acute myelomonocytic leukemia, in relapse |
| | C92.60 | Acute myeloid leukemia with 11q23-abnormality not having achieved remission |
| | C92.62 | Acute myeloid leukemia with 11q23-abnormality in relapse |
| | C92.A0 | Acute myeloid leukemia with multilineage dysplasia, not having achieved remission |
| | C92.A2 | Acute myeloid leukemia with multilineage dysplasia, in relapse |
| | C93.00 | Acute monoblastic/monocytic leukemia, not having achieved remission |
| | C93.02 | Acute monoblastic/monocytic leukemia, in relapse |
| | C93.10 | Chronic myelomonocytic leukemia not having achieved remission |
| | C94.00 | Acute erythroid leukemia, not having achieved remission |
| | C94.02 | Acute erythroid leukemia, in relapse |
| | C94.20 | Acute megakaryoblastic leukemia not having achieved remission |
| | C94.22 | Acute megakaryoblastic leukemia, in relapse |
| | D46.0 | Refractory anemia without ring sideroblasts, so stated |
| | D46.1 | Refractory anemia with ring sideroblasts |
| | D46.20 | Refractory anemia with excess of blasts, unspecified |
| | D46.21 | Refractory anemia with excess of blasts 1 |
| | D46.4 | Refractory anemia, unspecified |
| | D46.9 | Myelodysplastic syndrome, unspecified |
| | D46.A | Refractory cytopenia with multilineage dysplasia |
| | D46.B | Refractory cytopenia with multilineage dysplasia and ring sideroblasts |
| | D46.Z | Other myelodysplastic syndromes |
| | D61.810-D61.818 | Pancytopenia |
| | D70.0 | Congenital agranulocytosis |
| | D70.1 | Agranulocytosis secondary to cancer chemotherapy |
| | D70.2 | Other drug-induced agranulocytosis |
| | D70.3 | Neutropenia due to infection |
| | D70.4 | Cyclic neutropenia |
| | D70.9 | Neutropenia, unspecified |
| | T45.1X5A | Adverse effect of antineoplastic and immunosuppressive drugs |
| | T66.XXXA-T66.XXXS | Radiation sickness, unspecified |
| | W88.1XXA-W88.1XXS | Exposure to radioactive isotopes |
| | W88.8XXA-W88.8XXS | Exposure to other ionizing radiation |
| | Z41.8 | Encounter for other procedures for purposes other than remedying health state |
| | Z48.290 | Encounter for aftercare following bone marrow transplant |
| | Z51.11 | Encounter for antineoplastic chemotherapy |
| | Z51.12 | Encounter for antineoplastic immunotherapy |
| | Z51.89 | Encounter for other specified aftercare |
| | Z52.001 | Unspecified donor, stem cells |
| | Z52.011 | Autologous donor, stem cells |
| | Z52.091 | Other blood donor, stem cells |
| | Z76.89 | Persons encountering health services in other specified circumstances |
| | Z94.81 | Bone marrow transplant status |
| | Z94.84 | Stem cells transplant status |
| | Z79.899 | Other long term (current) drug therapy |
| Type of Service | | |
| Place of Service | | |
SOME MODIFIRES
| Date | Action | Description |
|---|---|---|
| 10/24/2024 | Policy Review | Policy revieweed and approved by the Providers Advisory Committee. No Changes |
| 4/12/2024 | Code updated | Code J2506 added to table list. |
| 10/26/2023 | Policy Review | Policy revieweed by the Providers Advisory Committee. No Changes |
| 9/20/2023 | Changes in preferred agent determination. | CSF-LA products: Neulasta, Neulasta OnPro to be removed as preferred agents effective 10/01/2023. |
| 7/14/2023 | Changes in preferred agent determination. | Due to limitations in market availability of Ziextenzo it was removed as a preferred agent. Fulphila is then defined as preferred agent in addition to Neulasta and Neulasta On Pro. Inclusion language added to the policy. |
| 12/29/2022 | Preferred agent determination | CSF-SA: Zarxio defined as preferred product for all population that comply with medical necessity criteria. Removed language referred to naive individuals. CSF-LA: Neulasta, Neulasta OnPro and Ziextenzo are considered as covered agents. Fulphila, Udenyca, Nyvepria or any other long-acting colony-stimulating factors are not considered for coverage. |
| 11/09/2022 | Annual Review | Reviewed by the Providers Advisory Committee. Deleted HCPCS code J2505 eff 1/01/2022 No changes No changes in policy statement. |
| 11/10/2021 | Annual Review | Policy revieweed by the Providers Advisory Committee. No changes. |
| 08/01/2021 | Policy Review | Biosimilar Zarxio was added as a preffered agent at Benefit application section of the policy. No changes in policy statement. |
| 1/04/2021 | New Policy | Hematopoietic Colony-Stimulating Factors (CSFs) |