Medical 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:     September 25, 2025
Next Review:     September 20, 2026

Related Policies: None

Hematopoietic Colony-Stimulating Factors (CSFs)

SUMMARY

Hematopoietic Colony-Stimulating Factors (CSFs) are biologic agents used to stimulate the production of neutrophils and reduce the incidence of febrile neutropenia in patients undergoing cytotoxic chemotherapy. Their use has been shown to decrease hospitalization rates, treatment-related complications, and improve patient quality of life. Multiple CSFs are available, including filgrastim, pegfilgrastim, and tbo-filgrastim, as well as biosimilars.

Several brands of short-acting colony-stimulating factors (CSFs) are available, including Neupogen® (filgrastim), Zarxio® (filgrastim-sndz), Nivestym® (filgrastim-aafi), Granix® (tbo-filgrastim), and Leukine® (sargramostim). There is no reliable evidence that any one short-acting CSF brand is superior to another for medically necessary indications. Long-acting granulocyte colony-stimulating factors (G-CSFs) include Neulasta® (pegfilgrastim), Neulasta Onpro® kit (pegfilgrastim), Nyvepria® (pegfilgrastim-apgf), Fulphila® (pegfilgrastim-jmdb), Udenyca® (pegfilgrastim-cbqv), and Ziextenzo® (pegfilgrastim-bmez). Evidence similarly shows no clinically meaningful differences in efficacy or safety between available pegfilgrastim products.

OBJECTIVE

The objective of this evidence-based review is to evaluate the role of short- and long-acting CSFs in cancer patients receiving cytotoxic chemotherapy regimens associated with clinically significant myelosuppression. These patients are at risk for febrile neutropenia (FN) and invasive infection due to bacterial or fungal translocation across compromised mucosal barriers.

POLICY STATEMENTS

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 is FDA approved for the following indications. (1) :

• Hematopoietic cell transplantation - as single agent therapy in autologous peripheral stem cell mobilization
• Management of neutropenia - as prophylaxis for febrile neutropenia in non-myeloid malignancies following myelosuppressive chemotherapy associated with a significant incidence of severe neutropenia with fever, to reduce duration of neutropenia and related clinical sequelae in patients with non-myeloid malignancies following bone marrow transplant, as prophylaxis for febrile neutropenia for acute myeloid leukemia following induction or consolidation chemotherapy, to treat severe chronic neutropenia, and to treat hematopoietic syndrome of acute radiation syndrome
• Management of neutropenia - for individuals under 18 years of age, as prophylaxis for febrile neutropenia in non-myeloid malignancies following myelosuppressive chemotherapy associated with a significant incidence of severe neutropenia with fever, to treat severe chronic neutropenia, and to treat hematopoietic syndrome of acute radiation syndrome

Filgrastim is recommended by The NCCN Drugs and Biologics Compendium^® for off-label use for the following indications:

• Acute myeloid leukemia - intensive induction therapy as part of an alternative non-anthracycline-containing regimen in patients whose anthracycline dose has been exceeded or who have cardiac issues but are still able to receive aggressive therapy
• Acute myeloid leukemia - intensive induction therapy in combination with fludarabine, high-dose cytarabine, and idarubicin plus gemtuzumab in patients with favorable-risk AML (CBF-AML, NPM1-mutated/FLT3 wild-type AML, in-frame bZIP mutation in CEBPA)
• Acute myeloid leukemia - intensive induction therapy in combination with Fludarabine, high-dose cytarabine, and idarubicin; Fludarabine, high-dose cytarabine, and idarubicin with gemtuzumab ozogamicin; or Fludarabine, high-dose cytarabine, and idarubicin with venetoclax for patients with intermediate risk AML
• Acute myeloid leukemia - intensive induction therapy in combination with Fludarabine, high-dose cytarabine, and idarubicin or Fludarabine, high-dose cytarabine, and idarubicin with venetoclax in patients with poor risk AML with or without TP53 mutation or del17p abnormality
• Acute myeloid leukemia - as a component of repeating the initial successful induction regimen if late relapse (≥12 months since induction regimen)
• Acute myeloid leukemia - in combination with cladribine and cytarabine, with or without mitoxantrone or idarubicin; or in combination with fludarabine and cytarabine, with or without idarubicin for relapsed/refractory disease
• Hematopoietic cell transplantation – as a single agent or in combination with plerixafor, cyclophosphamide with or without plerixafor, or disease-specific chemotherapy with or without plerixafor for autologous peripheral stem cell mobilization and as single agent therapy for allogeneic peripheral stem cell mobilization
• Hematopoietic cell transplantation - in combination with plerixafor as additional therapy for insufficient collection of stem cells following treatment with filgrastim or a filgrastim biosimilar alone or with disease-specific chemotherapy
• Immunotherapy-related toxicities - as additional supportive care for neutropenic patients treated with CAR T-cell therapy
• Management of neutropenia - as treatment for chemotherapy-induced febrile neutropenia in patients receiving prophylactic filgrastim or filgrastim biosimilars or in patients at risk for an infection-associated complication
• Management of neutropenia - as prophylaxis for chemotherapy-induced febrile neutropenia or other dose-limiting neutropenic events in patients with solid tumors and non-myeloid malignancies receiving treatment in the curative/adjuvant or palliative settings and are at high-risk (>20% overall risk of febrile neutropenia), intermediate-risk (10% to 20% overall risk of febrile neutropenia) and have 1 or more risk factors, or low-risk (<10% overall risk of febrile neutropenia) and has 2 or more risk factors
• Myelodysplastic syndromes-associated anemia - in combination with an erythropoiesis-stimulating agent for the treatment of lower risk disease associated with symptomatic anemia, without del(5q), with serum erythropoietin ≤ 500 mU/mL, and ring sideroblasts ≥ 15% or ≥ 5% with an SF3B1 mutation
• Myelodysplastic syndromes-associated anemia - in combination with an erythropoiesis-stimulating agent for the treatment of lower risk disease associated with symptomatic anemia, without del(5q), with serum erythropoietin ≤ 500 mU/mL, and ring sideroblasts < 15% or < 5% with an SF3B1 mutation following no response (despite adequate iron stores) or erythroid response followed by loss of response to an erythropoiesis-stimulating agent alone
• Wilms tumor (nephroblastoma) - administered with regimen M and regimen I for courses of cyclophosphamide and etoposide, and cyclophosphamide, doxorubicin, and vincristine

POLICY GUIDELINES

NCCN Guidelines (2025) recommend CSFs for patients at high risk of febrile neutropenia and in selected intermediate-risk scenarios.
 

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]: 
−    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.

The first treatment of choice will be biosimilar Zarxio.  In order to consider any other CSF-SA agents (Granix), patients must have appropriate clinical documentation. 

BENEFIT APPLICATION

BlueCard/National Account Issues

Prior authorization may be required to ensure use in appropriate clinical settings.

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.

Medicaid Vital Coverage Guidance

Pursuant to ASES Normative Letter 18-0813, Filgastrim products are covered under the Pharmacy Benefit (Part D) in accordance with the applicable Pharmacy Benefit Manager (PBM) coverage and formulary guidelines. However, in instances where an Oncologist provider elects to utilize the Buy and Bill process, these agents may be eligible for coverage under the Medical Benefit (Part B), according to this policy.

Triple-S Preferred Drugs Determination

CSF-SA: Patients first treatment of choice will be biosimilar Zarxio. In order to consider any other CSF-SA agents (Granix), patients must have documented previous use and therapeutic failure, intolerance or contraindication to biosimilar Zarxio. The following agents are not considered for coverage on commercial : Nivestym, Nypozi and Neupogen.  Neupogen is covered under medical benefit only for hematologist oncologist as per ASES normarive letter 18-0813.

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. 

BACKGROUND

CSFs are recombinant glycoproteins that regulate neutrophil production, maturation, and function. Clinical trials and real-world evidence have demonstrated their efficacy in reducing febrile neutropenia incidence, hospitalization, and mortality. The introduction of biosimilars has expanded access and reduced costs.

REGULATORY STATUS

FDA-approved products include:
 
Filgrastim (Neupogen®) and biosimilars (e.g., Zarxio®, Nivestym®, Releuko®, Nypozi®).
 
Pegfilgrastim (Neulasta®) and biosimilars (e.g., Fulphila®, Udenyca®, Stimufend®, Fylnetra®, Nyvepria®).
 
Tbo-filgrastim (Granix®).

All products are approved for reducing the incidence of infection, as manifested by febrile neutropenia, in patients with non-myeloid malignancies receiving myelosuppressive chemotherapy.

RATIONALE

Evidence supports the use of CSFs in preventing chemotherapy-induced febrile neutropenia, with demonstrated reductions in infection-related morbidity, mortality, and healthcare utilization. The use of biosimilars provides a clinically equivalent but more cost-effective option.

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.

SUPPLEMENTAL INFORMATION

International guidelines (ASCO, ESMO, NCCN) consistently endorse CSFs for high-risk patients.
 
Comparative effectiveness studies confirm similar outcomes between reference biologics and biosimilars.

Source: Smith et al, 2006; NCCN Hematopoietic Growth Factors, 2020.

PRACTICE GUIDELINES AND POSITION STATEMENTS

ASCO Guidelines (2022, 2023 updates): Recommend G-CSF prophylaxis for patients at high risk of febrile neutropenia (≥20%) and selectively for intermediate risk (10–19%) with additional risk factors.

NCCN Guidelines (2025, Hematopoietic Growth Factors): Reaffirm prophylactic G-CSF use in alignment with ASCO, with no evidence favoring one product over another.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 NATIONAL COVERAGE

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&

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APPLICABLE MODIFIERS

SOME MODIFIRES

POLICY HISTORY