The class of drugs known as granulocyte colony stimulating factors (G-CSFs) include: filgrastim (Neupogen®), filgrastim-sndz, (Zarxio®), filgrastim-aafi (Nivestym®), filgrastim-ayow (Releuko) pegfilgrastim (Neulasta®) (Neulasta® Onpro®), pegfilgrastim-jmdb (Fulphila™), pegfilgrastim-cbqv (Udenyca™), pegfilgrastim-bmez (Ziextenzo™), pegfilgrastim-apgf (Nyvepria™), pegfilgrastim-fpgk (Stimufend®), pegfilgrastim-pbbk (Fylnetra®), tbo-filgrastim (Granix®) eflapegrastim-xnst (Rolvedon™) and efbemalenograstim alfa-vuxw (Ryzneuta®). 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.

Preferred Pegfilgrastim Products

Pegfilgrastim (Neulasta), pegfilgrastim-jmdb (Fulphila), pegfilgrastim-bmez (Ziextenzo) are the preferred G-CSF pegfilgrastim products for all Food and Drug Administration (FDA) approved indications.

Non- Preferred Pegfilgrastim Eflapegrastim, and Efbemalenograstim Products

In order for a request for a non-preferred product [pegfilgrastim-cbqv (Udenyca), pegfilgrastim-apgf (Nyvepria) ™) pegfilgrastim-fpgk (Stimufend), pegfilgrastim-pbbk (Fylnetra) eflapegrastim-xnst (Rolvedon) or efbemalenograstim alfa-vuxw (Ryzneuta)] to be approved the individual must have had an adequate therapeutic trial and experienced a documented drug therapy failure or intolerance to the preferred product(s) or the preferred product is contraindicated.

Adequate therapeutic trial is defined as three (3) months following the injection series at FDA or compendia based therapeutic doses of preferred product.

Preferred Filgrastim Products

Filgrastim-sndz (Zarxio) and filgrastim-aafi (Nivestym) are the preferred G-CSF filgrastim products for all Food and Drug Administration (FDA) approved indications.

Non- Preferred Filgrastim  Products

In order for a request for a non-preferred product [filgrastim (Neupogen), filgrastim-ayow (Releuko), and tbo-filgrastim (Granix)] to be approved the individual must have had an adequate therapeutic trial and experienced a documented drug therapy failure or intolerance to the preferred product(s) or the preferred product is contraindicated.

Adequate therapeutic trial is defined as three (3) months following the injection series at FDA or compendia based therapeutic doses of preferred product.

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

• For 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

Compendia Sources

Filgrastim (Neupogen) may be considered medically necessary for treatment of any of the current category 1, 2A, or 2B NCCN recommendations

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

• 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; or

Compendia Sources

Filgrastim-sndz (Zarxio) and filgrastim-aafi (Nivestym) may be considered medically necessary for treatment of any of the current category 1, 2A, or 2B NCCN recommendations.

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

• 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

Compendia Sources

Tbo-filgrastim (Granix) may be considered medically necessary for treatment of any of the current category 1, 2A, or 2B NCCN recommendations.

Filgrastim-ayow (Releuko) may be considered medically necessary for ANY of the following:

• Individuals with nonmyeloid malignancies receiving myelosuppressive anti- cancer drugs associated with a significant incidence of severe neutropenia with fever to reduce the incidence of infection‚ as manifested by febrile neutropenia; or
• For individuals with AML following induction or consolidation chemotherapy treatment to reduce the time to neutrophil recovery and the duration of fever; or
• For individuals with nonmyeloid malignancies undergoing myeloablative chemotherapy followed by BMT to reduce duration of neutropenia and neutropenia-related clinical sequelae; 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

Compendia Sources

Filgrastim-ayow (Releuko) may be considered medically necessary for treatment of any of the current category 1, 2A, or 2B NCCN recommendations.

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

• 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

Compendia Sources

Pegfilgrastim (Neulasta) and (Neulasta Onpro) may be considered medically necessary for treatment of any of the current category 1, 2A, or 2B NCCN recommendations; 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-apgf (Nyvepria) pegfilgrastim-pbbk (Fylnetra) eflapegrastim-xnst (Rolvedon) and efbemalenograstim alfa-vuxw (Ryzneuta) may be considered medically necessary for ANY the following:

• 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.

Compendia Sources

Pegfilgrastim biosimilars (Fulphila, Nyvepria, Fylnetra) eflapegrastim-xnst (Rolvedon) and efbemalenograstim alfa-vuxw (Ryzneuta) may be considered medically necessary for treatment of any of the current category 1, 2A, or 2B NCCN recommendations.

Note: Pegfilgrastim biosimilars (Fulphila, Ziextenzo, Nyvepria, Fylnetra), eflapegrastim-xnst (Rolvedon) and efbemalenograstim alfa-vuxw (Ryzneuta) are not indicated for the mobilization or peripheral blood progenitor cells for hematopoietic stem cell transplantation.

Pegfilrastim-cbqv  (Udenyca) pegfilgrastim-fgpk (Stimufend) and pegfilgrastim-bmez (Ziextenzo) may be considered medically necessary for ANY the following:

• 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

Compendia Sources

Pegfilrastim biosimilars (Udenyca, Stimufend, Ziextenzo) may be considered medically necessary for treatment of any of the current category 1, 2A, or 2B NCCN recommendations.

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

Compendia Sources

Sargramostim (Leukine) may be considered medically necessary for treatment of any of the current category 1, 2A, or 2B NCCN recommendations; 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: 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), J2506, 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.

The administration of G-CSFs is typically an outpatient procedure which is only eligible for coverage as an inpatient procedure in special circumstances, including, but not limited to, the presence of a co-morbid condition that would require monitoring in a more controlled environment such as the inpatient setting.