The class of drugs known as granulocyte colony stimulating factors (G-CSFs) include: filgrastim (Neupogen®), filgrastim-sndz, (Zarxio®), filgrastim-aafi (Nivestym®), pegfilgrastim (Neulasta®) (Neulasta® Onpro®), pegfilgrastim-jmdb (Fulphila™), pegfilgrastim-cbqv (Udenyca™), pegfilgrastim-bmez (Ziextenzo™), pegfilgrastim-apgf (Nyvepria™), and tbo-filgrastim (Granix®).  Sargramostim (Leukine®) is a granulocyte-macrophage colony-stimulating factor (GM-CSF).

Febrile neutropenia (FN) is defined as a single temperature equal to or greater than 38.3°C, or a temperature equal to or greater than 38.0°C over 1 hour, and neutrophils less than 500/mcL.

G-CSFs are a blood growth factor that stimulates the bone marrow to produce more infection-fighting white blood cells known as neutrophils. These neutrophils are then released into the blood stream where they aid in fighting infection. When neutrophil levels drop and an individual becomes neutropenic, the body is less able to fight off infection. Individuals at high risk to develop these types of conditions may be clinically indicated for the administration of G-CSFs.

Note: Risk assessment for use of G-CSFs includes (not an all-inclusive list) disease type, chemotherapy regimen (high-dose, dose-dense, or standard-dose), risk factors, and treatment intent (curative/adjuvant vs. palliative). Independent clinical judgment should be exercised based on the individual’s situation.

Filgrastim (Neupogen) may be considered medically necessary for ANY of the following indications:

Food and Drug Administration (FDA) Indications

·         Individuals with nonmyeloid malignancies receiving myelosuppressive anticancer drug therapy associated with significant incidence of severe neutropenia with fever to decrease incidence of infection; or

·         Individuals with acute myeloid leukemia (AML) following induction or consolidation chemotherapy to reduce the time to neutrophil recovery and duration of fever; or

·         Individuals with nonmyeloid malignancies undergoing myeloablative chemotherapy followed by bone marrow transplantation (BMT) to reduce duration of neutropenia and neutropenia-related clinical sequelae; or

·         Individuals undergoing autologous peripheral blood progenitor cell collection and therapy for mobilization of hematopoietic progenitor cells into peripheral blood for collection by leukapheresis; or

·         For chronic administration in individuals with severe chronic neutropenia to reduce incidence and duration of sequelae of neutropenia in symptomatic individuals with congenital neutropenia, cyclic neutropenia, or idiopathic neutropenia; or

·         Individuals acutely exposed to myelosuppressive doses of radiation in hematopoietic acute radiation syndrome (H-ARS) to increase survival; or

National Comprehensive Cancer Network (NCCN) Recommendations

Acute Myeloid Leukemia (AML):

·         As treatment induction in individuals less than 60 years in age with intermediate or poor-risk disease in combination with fludarabine, high-dose cytarabine, and idarubicin; or

·         As a component of repeating the initial successful induction regimen if late relapse (greater than or equal to 12 months since induction); or

·         For relapsed or refractory disease in combination with ONE of the following:

o    Cladribine and cytarabine, with or without mitoxantrone or idarubicin: or

o    Fludarabine and cytarabine, with or without idarubicin; or

o    Clofarabine and cytarabine, with or without idarubicin; or

Management of Immunotherapy-Related Toxicities/CAR-T-Cell-Related Toxicities:

·         As additional supportive care for neutropenic individuals; or

Myelodysplastic Syndromes (MDS):

·         Treatment of lower risk* disease associated with symptomatic anemia, without del(5q) with or without other cytogenetic abnormalities, with serum erythropoietin levels less than or equal to 500 mU/mL, and ring sideroblasts greater than or equal to 15%:

o    In combination with an erythropoiesis-stimulating agent (ESA); or

o    In combination with lenalidomide and an ESA if no response to an ESA alone; or

·         Treatment of lower risk* disease associated with symptomatic anemia, without del(5q), with or without cytogenetic abnormalities, with serum erythropoietin levels less than or equal to 500 mU/mL, ring sideroblasts less than 15%, in combination with an ESA following no response or loss of response to an ESA alone; or

Myeloid Growth Factors:

·         Prophylaxis of chemotherapy-induced FN  or other dose-limiting neutropenic events in high-risk (greater than 20% overall risk of FN) individuals with solid tumors and nonmyeloid malignancies receiving treatment in the curative/adjuvant or palliative settings; or

·         Prophylaxis of chemotherapy-induced FN or other dose-limiting neutropenic events in intermediate-risk (10% to 20% overall risk of FN) individuals  with solid tumors and nonmyeloid malignancies receiving treatment in the curative/adjuvant or palliative settings who have one (1) or more of the following risk factors (see Table 1):

o    Prior chemotherapy or radiation therapy; or

o    Persistent neutropenia; or

o    Bone marrow involvement by tumor; or

o    Recent surgery and/or open wounds; or

o    Liver dysfunction (bilirubin greater than 2.0); or

o    Renal dysfunction (CrCl less than 50 mL/min); or

o    Age greater than 65 years receiving full chemotherapy dose intensity; or

·         As treatment of chemotherapy-induced FN in individuals who:

o    Have been receiving prophylactic filgrastim; or

o    Have not received prophylactic granulocyte colony-stimulating factors but who have one or more risk factors for an infection-associated complication (see Table 2):

§  Sepsis syndrome; or

§  Age greater than 65 years; or

§   Absolute Neutrophil Count (ANC) less than 100/mcL; or

§  Duration of neutropenia expected to be greater than 10 days; or

§  Pneumonia or other clinically documented infections; or

§  Invasive fungal infection; or

§  Hospitalization at the time of fever; or

§  Prior episode of febrile neutropenia; or

·         As treatment for individuals with radiation-induced myelosuppression following a radiological/nuclear incident in H-ARS; or

·         Used in hematopoietic cell transplant for:

o    Mobilization of hematopoietic progenitor cells in the autologous setting as a single agent, following combination chemotherapy, or in combination with sargramostim; or

o    Mobilization of hematopoietic progenitor cells in combination with plerixafor in the autologous setting for individuals with non-Hodgkin lymphoma or multiple myeloma; or

o    Mobilization of donor hematopoietic progenitor cells (preferred**) or for granulocyte transfusion in the allogeneic setting; or

o    As supportive care in the post-transplant setting.

Filgrastim-sndz (Zarxio) and filgrastim-aafi (Nivestym) may be considered medically necessary for ANY of the following:

FDA Indications

·         To decrease the incidence of infection as manifested by febrile neutropenia in individuals with nonmyeloid malignancies receiving myelosuppressive anti-cancer drugs associated with a significant incidence of severe neutropenia with fever; or

·        For individuals with AML following induction or consolidation chemotherapy to reduce the time to neutrophil recovery and duration of fever following treatments; or

·         For individuals with nonmyeloid malignancies undergoing myeloablative chemotherapy followed by BMT to reduce duration of neutropenia and neutropenia-related clinical sequelae; or

·         For individuals undergoing autologous peripheral blood progenitor cell collection and therapy for mobilization of hematopoietic progenitor cells into peripheral blood for collection by leukapheresis; or

·        For chronic administration in individuals with severe chronic neutropenia to reduce incidence and duration of sequelae of neutropenia in symptomatic individuals with congenital neutropenia, cyclic neutropenia, or idiopathic neutropenia.

Filgrastim-sndz (Zarxio) may be considered medically necessary for ANY of the following:

NCCN Recommendations

Management of Immunotherapy-Related Toxicities/CAR-T-Cell-Related Toxicities

·         As additional supportive care for neutropenic individuals; or

Myelodysplastic Syndromes (MDS):

·         Treatment of lower risk* disease associated with symptomatic anemia, without del(5q) with or without other cytogenetic abnormalities, with serum erythropoietin levels less than or equal to 500 mU/mL, and ring sideroblasts greater than or equal to 15%:

o    In combination with an erythropoiesis-stimulating agent (ESA); or

o    In combination with lenalidomide and an ESA if no response to an ESA alone; or

·         Treatment of lower risk* disease associated with symptomatic anemia, without del(5q), with or without cytogenetic abnormalities, with serum erythropoietin levels less than or equal to 500 mU/mL, ring sideroblasts less than 15%, in combination with an ESA following no response or loss of response to an ESA alone; or

Myeloid Growth Factors:

·         Prophylaxis of chemotherapy-induced FN or other dose-limiting neutropenic events in high-risk (greater than 20% overall risk of FN) individuals with solid tumors and nonmyeloid malignancies receiving treatment in the curative/adjuvant or palliative settings; or

·         Prophylaxis of chemotherapy-induced FN or other dose-limiting neutropenic events in intermediate-risk (10% to 20% overall risk of FN) individuals with solid tumors and nonmyeloid malignancies receiving treatment in the curative/adjuvant or palliative settings who have one or more of the following risk factors (see Table 1):

o    Prior chemotherapy or radiation therapy; or

o    Persistent neutropenia; or

o    Bone marrow involvement by tumor; or

o    Recent surgery and/or open wounds; or

o    Liver dysfunction (bilirubin greater than 2.0); or

o    Renal dysfunction (CrCl  less than 50 mL/min); or

o    Age greater than 65 years receiving full chemotherapy dose intensity; or

·         As treatment of chemotherapy-induced FN in individuals who:

o    Have been receiving prophylactic filgrastim-sndz (Zarxio); or   

o    Have not received prophylactic G-CSFs but who have one or more risk factors for an infection-associated complication (see Table 2):

§  Sepsis syndrome; or

§  Age greater than 65 years; or

§  ANC less than 100/mcL; or

§  Duration of neutropenia expected to be greater than 10 days; or

§  Pneumonia or other clinically documented infections; or

§  Invasive fungal infection; or

§  Hospitalization at the time of fever; or

§  Prior episode of febrile neutropenia; or; or

·         As treatment for individuals with radiation-induced myelosuppression following a radiological/nuclear incident in H-ARS; or

·         Used in hematopoietic cell transplant for:

o    Mobilization of hematopoietic progenitor cells in the autologous setting as a single agent, following combination chemotherapy, or in combination with sargramostim (Leukine); or

o    For mobilization of donor hematopoietic progenitor cells in combination with plerixafor (Mozobil) in the autologous setting for individuals with non-Hodgkin lymphoma or multiple myeloma; or

o    Mobilization of donor hematopoietic progenitor cells or for granulocyte transfusion in the allogenic setting; or

o     As supportive care in the post-transplant setting.

Filgrastim-aafi (Nivestym) may be considered medically necessary for ANY of the following:

NCCN Recommendations

Management of Immunotherapy-Related Toxicities/CAR-T-Cell-Related Toxicities

·         As additional supportive care for neutropenic individuals; or

Myeloid Growth Factors

·         Prophylaxis of chemotherapy-induced FN or other dose-limiting neutropenic events in high-risk (greater than 20% overall risk of FN) individuals with solid tumors and nonmyeloid malignancies receiving treatment in the curative/adjuvant or palliative settings; or

·         Prophylaxis of chemotherapy-induced FN or other dose-limiting neutropenic events in intermediate-risk (10% to 20% overall risk of FN) individuals with solid tumors and nonmyeloid malignancies receiving treatment in the curative/adjuvant or palliative settings who have one or more of the following risk factors (see Table 1):

o    Prior chemotherapy or radiation therapy; or

o    Persistent neutropenia; or

o    Bone marrow involvement by tumor; or

o    Recent surgery and/or open wounds; or

o    Liver dysfunction (bilirubin greater than 2.0); or

o    Renal dysfunction (CrCl  less than 50 mL/min); or

o    Age greater than 65 years receiving full chemotherapy dose intensity; or

·         As treatment of chemotherapy-induced FN in individuals who:

o    Have been receiving prophylactic filgrastim-sndz (Zarxio); or   

o    Have not received prophylactic G-CSFs but who have one or more risk factors for an infection-associated complication (see Table 2):

§  Sepsis syndrome; or

§  Age greater than 65 years; or

§  ANC less than 100/mcL; or

§  Duration of neutropenia expected to be greater than 10 days; or

§  Pneumonia or other clinically documented infections; or

§  Invasive fungal infection; or

§  Hospitalization at the time of fever; or

§  Prior episode of febrile neutropenia; or

·         As treatment for individuals with radiation-induced myelosuppression following a radiological/nuclear incident in H-ARS; or

·         Used in hematopoietic cell transplant for:

o    Mobilization of hematopoietic progenitor cells in the autologous setting as a single agent, following combination chemotherapy, or in combination with sargramostim (Leukine); or

o    For mobilization of donor hematopoietic progenitor cells in combination with plerixafor (Mozobil) in the autologous setting for individuals with non-Hodgkin lymphoma or multiple myeloma; or

o    Mobilization of donor hematopoietic progenitor cells or for granulocyte transfusion in the allogenic setting; or

o     As supportive care in the post-transplant setting.

Tbo-filgrastim (Granix) may be considered medically necessary for ANY of the following:

FDA Indication

·         To reduce the duration of severe neutropenia in adult and pediatric individuals one (1) month and older with nonmyeloid malignancies receiving myelosuppressive anti-cancer drugs associated with a clinically significant incidence of FN; or

NCCN Recommendations

Myelodysplastic Syndromes (MDS):

·         Treatment of lower risk* disease associated with symptomatic anemia, without del(5q) with or without other cytogenetic abnormalities, with serum erythropoietin levels less than or equal to 500 mU/mL, and ring sideroblasts greater than or equal to 15%:

o    In combination with an erythropoiesis-stimulating agent (ESA); or

o    In combination with lenalidomide and an ESA if no response to an ESA alone; or

·         Treatment of lower risk* disease associated with symptomatic anemia, without del(5q), with or without cytogenetic abnormalities, with serum erythropoietin levels less than or equal to 500 mU/mL, ring sideroblasts less than 15%, in combination with an ESA following no response or loss of response to an ESA alone; or

Myeloid Growth Factors:

·         Prophylaxis of chemotherapy-induced FN or other dose-limiting neutropenic events in high-risk (greater than 20% overall risk of FN) individuals with solid tumors and nonmyeloid malignancies receiving treatment in the curative/adjuvant or palliative settings; or

·         Prophylaxis of chemotherapy-induced FN or other dose-limiting neutropenic events in intermediate-risk (10% to 20% overall risk of FN) individuals with solid tumors and nonmyeloid malignancies receiving treatment in the curative/adjuvant or palliative settings who have one (1) or more of the following risk factors (see Table 1):

o    Prior chemotherapy or radiation therapy; or

o    Persistent neutropenia; or

o    Bone marrow involvement by tumor; or

o    Recent surgery and/or open wounds; or

o    Liver dysfunction (bilirubin greater than 2.0) ; or

o    Renal dysfunction (CrCl less than 50 mL/min) ; or

o    Age greater than 65 years receiving full chemotherapy dose intensity; or

·         Treatment of chemotherapy-induced FN in individuals who have been receiving prophylactic tbo-filgrastim (Granix); or

·         As treatment for individuals with radiation-induced myelosuppression following a radiological/nuclear incident in H-ARS; or

·         Used in hematopoietic cell transplant for:

o    Mobilization of hematopoietic progenitor cells in the autologous setting as a single agent, following combination chemotherapy; or

o    Mobilization of hematopoietic progenitor cells in combination with plerixafor (Mozobil) in the autologous setting for individuals with non-Hodgkin lymphoma or multiple myeloma; or

o    Mobilization of donor hematopoietic progenitor cells or for granulocyte transfusion in the allogeneic setting; or

o    Supportive care in the post-transplant setting.

Pegfilgrastim (Neulasta) and (Neulasta Onpro) may be considered medically necessary for ANY of the following:

FDA Indications

·         Individuals with nonmyeloid malignancies receiving myelosuppressive anticancer drugs associated with a clinically significant incidence of FN to decrease the incidence of infection; or

·         Individuals acutely exposed to myelosuppressive doses of radiation in H-ARS to increase survival;or

Other Compendia Supported Recommendations, Class 2b and Higher

·         For harvesting peripheral blood stem cells prior to autologous stem-cell transplantation.

Pegfilgrastim-jmdb (Fulphila), pegfilgrastim-bmez (Ziextenzo), pegfilgrastim-cbqv (Udencya), and pegfilgrastim-apgf (Nyvepria) may be considered medically necessary for ANY the following:

FDA Indications

·         To decrease the incidence of infection as manifested by febrile neutropenia in individuals with nonmyeloid malignancies receiving myelosuppressive anti-cancer drugs associated with a significant incidence of severe neutropenia with fever.

Note: Pegfilgrastim-jmdb (Fulphila), pegfilgrastim-bmez (Ziextenzo), pegfilgrastim-cbqv (Udencya), and pegfilgrastim-apgf (Nyvepria) are not indicated for the mobilization or peripheral blood progenitor cells for hematopoietic stem cell transplantation.

Pegfilgrastim (Neulasta, Neulasta OnPro), pegfilgrastim-bmez (Ziextenzo), pegfilgrastim-cbqv (Udencya), pegfilgrastim-apgf (Nyvepria), and pegfilgrastim-jmdb (Fulphila) may be considered medically necessary for ANY of the following:

NCCN Recommendations

Management of Neutropenia

·         As treatment for individuals with radiation-induced myelosuppression following a radiological/nuclear incident in H-ARS; or

Myeloid Growth Factors:

·         Prophylaxis of chemotherapy-induced FN or other dose-limiting neutropenic events in high-risk (greater than 20% overall risk of FN) individuals with solid tumors and nonmyeloid malignancies receiving treatment in the curative/adjuvant or palliative settings; or

·         Prophylaxis of chemotherapy-induced FN or other dose-limiting neutropenic events in intermediate-risk (10% to 20% overall risk of FN) individuals with solid tumors and nonmyeloid malignancies receiving treatment in the curative/adjuvant or palliative settings who have one (1) or more of the following risk factors (see Table 1):

o    Prior chemotherapy or radiation therapy; or

o    Persistent neutropenia; or

o    Bone marrow involvement by tumor; or

o    Recent surgery and/or open wounds; or

o    Liver dysfunction (bilirubin greater than 2.0) ; or

o    Renal dysfunction (CrCl less than 50 mL/min) ; or

o    Age greater than 65 years receiving full chemotherapy dose intensity; or

·         Used for supportive care in the post autologous hematopoietic cell transplant setting.

Sargramostim (Leukine) may be considered medically necessary for ANY of the following indications:

FDA Indications

·        Individuals 55 years and older with AML following induction chemotherapy to shorten time to neutrophil recovery and to reduce the incidence of severe and life-threatening infections and infections resulting in death; or

·         Adult individuals undergoing mobilization of hematopoietic progenitor cells into peripheral blood for collection by leukapheresis and autologous transplantation; or

·         Individuals 2 years of age or older for the acceleration of myeloid reconstitution following autologous bone marrow or peripheral blood progenitor cell transplantation; or

·         Individuals 2 years or age or older for the acceleration of myeloid reconstitution following allogeneic bone marrow transplantation; or

·         Individuals 2 years or age or older for treatment of delayed neutrophil recovery or graft failure after autologous or allogeneic bone marrow transplantation; or

·         Individuals acutely exposed to myelosuppressive doses of radiation in H-ARS  to increase survival; or

NCCN Recommendations

Management of Neutropenia

·         As treatment for individuals with radiation-induced myelosuppression following a radiological/nuclear incident in H-ARS; or

Myeloid Growth Factors:

·         Treatment of chemotherapy-induced FN in individuals who have not received prophylactic G-CSFs but who have one or more risk factors for an infection-associated complication (see Table 2):

o    Sepsis syndrome; or

o    Age greater than 65 years; or

o    ANC less than 100/mcL; or

o    Duration of neutropenia expected to be greater than 10 days; or

o    Pneumonia or other clinically documented infections; or

o    Invasive fungal infection; or

o    Hospitalization at the time of fever; or

o    Prior episode of febrile neutropenia; or

·         As treatment for individuals with radiation-induced myelosuppression following a radiological/nuclear incident in H-ARS; or

·         Used in hematopoietic cell transplant for the mobilization of hematopoietic progenitor cells in combination with filgrastim or biosimilars in the autologous setting; or

Other Compendia Supported Recommendations, Class 2b and Higher

·         To decrease the incidence of infection as manifested by febrile neutropenia in individuals with nonmyeloid malignancies receiving myelosuppressive anti-cancer drugs associated with a significant incidence of severe neutropenia with fever.

The use of G-CSFs are considered not medically necessary for ANY of the following:

·         For uses not meeting the criteria above; or

·        As prophylaxis for FN, except when criteria above are met; or

·         As treatment of neutropenia in individuals who are afebrile, except when criteria above are met; or

·         As adjunctive therapy in individuals with uncomplicated FN, defined as: fever less than ten (10) days duration, no evidence of pneumonia, cellulitis, abscess, sinusitis, hypotension, multi-organ dysfunction, or invasive fungal infection; and no uncontrolled malignancies; or

·         Chemo sensitization of myeloid leukemias; or

·         As prophylaxis for FN during concomitant chemotherapy and radiation therapy; or

·        Continued use if no response is seen within 28-42 days (individuals who have failed to respond within this time frame are considered non-responders).

NOTE: In addition to the above criteria, product specific dosage and/or frequency limits may apply in accordance with the U.S. Food and Drug Administration (FDA)-approved product prescribing information, national compendia, Centers for Medicare and Medicaid Services (CMS) and other peer reviewed resources or evidence-based guidelines. Highmark may deny, in full or in part, reimbursement for utilization that does not fall within the applicable dosage and/or frequency limits.

*Note: Lower risk defined as IPSS-R (Very Low, Low, Intermediate), IPSS (Low/Intermediate-1), and WPSS (Very Low, Low, Intermediate).

**Note: Language derived from National Comprehensive Cancer Network (NCCN) guidelines.

Note: Filgrastim (Neupogen), J1442, excludes biosimilar reference in its definition and should therefore be reported with code Q5101 or Q5110 to report the biosimilarity of filgrastim. Pegfilgrastim (Neulasta), J2505, excludes biosimilar reference in its definition and should therefore be reported with code Q5108, Q5111, or Q5120 to report the biosimilarity of pegfilgrastim.

The safety and efficacy of sargramostim (Leukine) have not been assessed in individuals with AML less than 55 years of age.

Liquid solutions containing benzyl alcohol (including liquid sargramostim or lyophilized Leukine reconstituted with bacteriostatic water for injection, USP (0.9% benzyl alcohol)) should not be administered to neonates.