Colony Stimulating Factor Agents Form

Overview Clinical criteria Overview Coding Document history References This document addresses the use of white blood cell growth factors, also known as colony stimulating factors (CSF). There are two types of CSFs, granulocyte and granulocyte-macrophage. Granulocyte colony stimulating factors (G-CSF) are glycoproteins which exert major control over the reproduction and maturation of certain white blood cells. Granulocyte-macrophage colony stimulating factor (GM-CSF) is a hematopoietic growth factor that stimulates proliferation and differentiation of hematopoietic progenitor cells.
The following agents are included in the class. • G-CSF:
o Granix (tbo-filgrastim) o Neulasta Onpro/Neulasta (pegfilgrastim) and Biosimilars  Fulphila (pegfilgrastim- jmdb)  Fylnetra (pegfilgrastim-pbbk)  Nyvepria (pegfilgrastim-apgf)  Stimufend (pegfilgrastim-fpgk)  Udenyca (pegfilgrastim-cbqv)  Ziextenzo (pegfilgrastim-bmez) o Neupogen (filgrastim) and Biosimilars  Nivestym (filgrastim-aafi)  Releuko (filgrastim-ayow)  Zarxio (filgrastim-sndz) o Rolvedon (eflapegrastim-xnst) o Ryzneuta (efbemalenograstim alfa-vuxw)
• GM-CSF o Leukine (sargramostim) Ryzneuta (efbemalenograstim-alfa) Ryzneuta is a leukocyte growth factor FDA indicated to decrease the incidence of infection, as manifested by febrile neutropenia, in adult patients with non-myeloid malignancies receiving myelosuppressive anti-cancer drugs associated with a clinically significant incidence of febrile neutropenia. Ryzneuta is not indicated for the mobilization of peripheral blood progenitor cells for hematopoietic stem cell transplantation. Rolvedon (eflapegrastim-xnst) Rolvedon is a nonbiosimilar long-acting hematopoietic growth factor consisting of a recombinant human granulocyte-colony stimulating factor (rhG-CSF) analog conjugated to a human IgG4Fc fragment. The addition of the Fc fragment extend the drug’s half-life, which has been used in other marketed biologics (e.g. etanercept). Rolvedon is indicated to decrease the incidence of infection, as manifested by febrile neutropenia, in adult patients with non-myeloid malignancies receiving myelosuppressive anti-cancer drugs associated with clinically significant incidence of febrile neutropenia. Rolvedon is not indicated for the mobilization of peripheral blood progenitor cells for hematopoietic stem cell transplantation.
Primary prophylaxis of chemotherapy-induced febrile neutropenia 1

Neutropenia with fever (febrile neutropenia [FN]) is a serious consequence of myelosuppressive chemotherapy that usually results in hospitalization and the need for intravenous antibiotics (Lyman 2014). FN may result in dose reductions, delays, or even discontinuation of chemotherapy, which, in turn, may compromise patient outcomes. It is important to identify which patients are at high risk for developing FN so that patients can receive optimal chemotherapy while their risk for FN is appropriately managed. There are many factors that need to be evaluated to determine a patient’s risk of developing FN, which includes type of chemotherapy regimen, type of cancer being treated, and other patient-specific risk factors.
A review of the literature was performed to gain a comprehensive and updated understanding of FN risk associated with chemotherapy regimens and patient-specific FN risk factors. Studies that have analyzed FN risk factors, often have several limitations, including their retrospective nature and small sample sizes. Our assessment of the following patient risk factors and chemotherapy regimens (see appendix below) is after a review of published literature and guidelines from the American Society of Clinical Oncology (ASCO) and National Comprehensive Cancer Network (NCCN).
The patient risk factors for the development of febrile neutropenia include:
• Age greater than 65 years (Lyman 2014; Aagaard 2018); OR • Poor performance status (Eastern Cooperative Oncology Group 3 or 4) or HIV infection (in particular, those with low CD4 counts (≤ 450/µL)) but chemotherapy still indicated (Lyman 2014); OR • Prior radiation therapy (within previous 1 year) (Terbuch 2018) (Fujiwara 2017) (Shigeta 2015); OR • Bone marrow involvement by tumor producing cytopenias (Lyman 2014); OR • Persistent neutropenia (absolute neutrophil count [ANC] less than 1500mm3) (Lyman 2014); OR • Poor renal function (glomerular filtration rate [GFR] less than 60mL/min) (Lyman 2014; Aagaard 2018); OR • Liver dysfunction (liver function tests at least 2X upper limit of normal or bilirubin > 2.0 mg/dL) (Lyman 2014; Aagaard 2018); OR • Recent surgery performed as part of cancer management within previous 30 days (not to include a procedure such as port placement, drain placement, IVC filter, etc.) (Lyman 2014; Aagaard 2018); OR • History of active infection within previous 60 days (Lyman 2014; Aagaard 2018); OR • Current open wound and chemotherapy cannot be delayed (Lyman 2014; Aagaard 2018). Zynteglo (betibeglogene autotemcel) Gene Therapy Before administration of Zynteglo, hematopoietic stem cells are mobilized with granulocyte colony-stimulating factor and plerixafor, and cells are collected by apheresis. In clinical trials, up to two mobilization cycles (separated by at least 2 weeks) were performed, determined by the need to reach the cumulated target collection number needed for beti-cel manufacture or manufacturing and for rescue cells cryopreserved and stored on site. Prior to apheresis, transfusions are recommended to obtain 8 hemoglobin levels of at least 11 g per deciliter; this hemoglobin level is recommended to be maintained during mobilization and apheresis to suppress stress erythropoiesis. Other uses Use of G-CSF agents in damaged myocardium The use of G-CSF has been proposed as an adjunct to standard therapies to promote mobilization of stem cells and progenitor cells from the bone marrow into the circulating blood to improve repair of the damaged myocardium. The benefits of G-CSF in other fields, such as oncology, has led to research assessing the potential of G-CSF in repairing myocardial tissue and improving clinical outcomes in those with damaged hearts. To date, the published evidence regarding the safety and efficacy of G-CSF has been lacking.
Consider as additional supportive care for neutropenic patients The use of G-CSF has been suggested in the NCCN guidelines as a 2A recommendation in supportive care for Grade 1 fever in those using CAR T-cell therapy to prevent progression of cytokine release syndrome (CRS). At this time, there is a lack of published evidence regarding safety and efficacy for this use. A small retrospective analysis in diffuse large B-cell lymphoma members using G- CSF during CAR-T therapy (Gaut 2019) showed no difference in the incidence and severity of infection or incidence of developing CRS between those who received G-CSF and those that did not.
Wilms Tumor (favorable history) The use of G-CSF has been suggested for use as supportive care in Wilms Tumor (nephroblastoma) after doses of myelosuppressive agents after courses of cyclophosphamide and etoposide and cyclophosphamide, doxorubicin, and vincristine in Regimen M and Regimen I. NCCN currently does not provide any literature support for this use. Definitions and Measures
Absolute neutrophil count (ANC): A measure of the number of neutrophils (a type of white blood cell) in the blood. Acute Radiation Syndrome (ARS): Also known as radiation sickness. 2

Adjuvant or adjunctive treatment: Treatment given after the primary treatment to increase the chances of a cure and may include chemotherapy, radiation, hormone or biological therapy. Febrile neutropenia: Febrile neutropenia can occur as a result of severe neutropenia; defined as the occurrence of fever (greater than or equal to 38.3oC for more than 1 hour) in association with an ANC less than 0.5 x 109/L or ANC less than 1.0 x 109/L and a predicted decline to less than or equal to 0.5 x 109/L over the subsequent 48 hours. ECOG or Eastern Cooperative Oncology Group Performance Status: A scale and criteria used by doctors and researchers to assess how an individual’s disease is progressing, assess how the disease affects the daily living abilities of the individual, and determine appropriate treatment and prognosis. This scale may also be referred to as the WHO (World Health Organization) or Zubrod score which is based on the following scale: • • • • • • 0 = Fully active, able to carry on all pre-disease performance without restriction 1 = Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature, for example, light house work, office work 2 = Ambulatory and capable of all self-care but unable to carry out any work activities. Up and about more than 50% of waking hours 3 = Capable of only limited self-care, confined to bed or chair more than 50% of waking hours 4 = Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair 5 = Dead Neutropenia: A decrease in the number of neutrophils (white blood cells that respond quickly to infection) in the blood. Neutrophils less than 1,500/mm3 is considered to be neutropenic and at risk for infection. Neutrophils fewer than 500 cells/mm3 is considered at high risk of infection. Neutrophil: A type of white blood cell that helps fight infection. Primary prophylaxis: Prevention of febrile neutropenia with the first cycle of a specified chemotherapy regimen. Secondary prophylaxis: Prevention of febrile neutropenia given with the second and/or subsequent cycle of a given regimen of chemotherapy for individuals who had a neutropenic complication from the preceding cycle of chemotherapy and there is no plan to reduce the dose intensity. Clinical Criteria When a drug is being reviewed for coverage under a member’s medical benefit plan or is otherwise subject to clinical review (including prior authorization), the following criteria will be used to determine whether the drug meets any applicable medical necessity requirements for the intended/prescribed purpose.
Rolvedon (eflapegrastim-xnst) Requests for Rolvedon (eflapegrastim-xnst) may be approved if the following criteria are met: I. II. Individual with nonmyeloid malignancy is using for primary prophylaxis of Febrile Neutropenia (FN); AND Individual has a risk of FN of 20% or greater based on chemotherapy regimen (NCCN 2A) (see Appendix, Table 1); OR III. IV. Individual with nonmyeloid malignancy is using for primary prophylaxis of FN; AND Individual has a risk of developing FN is greater than or equal to 10% and less than 20% based on chemotherapy regimen (see Appendix, Table 1) and individuals have any of the following risk factors for FN: A. Age greater than 65 years (Lyman 2014; Aagaard 2018); OR B. Poor performance status (Eastern Cooperative Oncology Group 3 or 4) or HIV infection (in particular, those with low CD4 counts (≤ 450/µL)) but chemotherapy still indicated (Lyman 2014); OR C. Prior radiation therapy (within previous 1 year) (Terbuch 2018) (Fujiwara 2017) (Shigeta 2015); OR D. Bone marrow involvement by tumor producing cytopenias (Lyman 2014); OR E. Persistent neutropenia (absolute neutrophil count [ANC] less than 1500mm3) (Lyman 2014); OR F. Poor renal function (glomerular filtration rate [GFR] less than 60mL/min) (Lyman 2014; Aagaard 2018); OR G. Liver dysfunction (liver function tests at least 2X upper limit of normal or bilirubin > 2.0 mg/dL) (Lyman 2014) (Aagaard 2018); OR H. Recent surgery performed as part of cancer management within previous 30 days (not to include a procedure such as port placement, drain placement, IVC filter, etc.) (Lyman 2014; Aagaard 2018); OR I. History of active infection within previous 60 days (Lyman 2014; Aagaard 2018); OR 3

OR V. VI. OR VII. VIII. IX. J. Current open wound and chemotherapy cannot be delayed (Lyman 2014; Aagaard 2018). Individual with nonmyeloid malignancy is using for secondary prophylaxis of FN; AND Individual has experienced a neutropenic complication from a prior cycle of chemotherapy (for which prophylaxis was not received), in which a reduced dose may compromise disease-free or overall survival or treatment outcome (NCCN 2A);
Individual is using as adjunctive treatment for FN; AND Individual has not received prophylactic therapy with pegfilgrastim (NCCN 2A); AND Individual has a high risk for infection-associated complications as demonstrated by any of the following: A. Expected prolonged (greater than 10 days) and profound (less than 0.1 x 109/L) neutropenia; OR B. Age greater than 65 years; OR C. Pneumonia or other clinically documented infections; OR D. Hypotension and multi organ dysfunction (sepsis syndrome); OR E. F. Prior episode of febrile neutropenia; OR G. Hospitalized at the time of the development of fever.
Invasive fungal infection; OR Ryzneuta (efbemalenograstim alfa-vuxw) Requests for Ryzneuta (efbemalenograstim alfa-vuxw) may be approved if the following criteria are met: I. II. Individual with nonmyeloid malignancy is using for primary prophylaxis of Febrile Neutropenia (FN); AND Individual has a risk of FN of 20% or greater based on chemotherapy regimen (NCCN 2A) (see Appendix, Table 1); OR III. IV. OR V. VI. OR VII. VIII. IX. Individual with nonmyeloid malignancy is using for primary prophylaxis of FN; AND Individual has a risk of developing FN is greater than or equal to 10% and less than 20% based on chemotherapy regimen (see Appendix, Table 1) and individuals have any of the following risk factors for FN: A. Age greater than 65 years (Lyman 2014; Aagaard 2018); OR B. Poor performance status (Eastern Cooperative Oncology Group 3 or 4) or HIV infection (in particular, those with low CD4 counts (≤ 450/µL)) but chemotherapy still indicated (Lyman 2014); OR C. Prior radiation therapy (within previous 1 year) (Terbuch 2018) (Fujiwara 2017) (Shigeta 2015); OR D. Bone marrow involvement by tumor producing cytopenias (Lyman 2014); OR E. Persistent neutropenia (absolute neutrophil count [ANC] less than 1500mm3) (Lyman 2014); OR F. Poor renal function (glomerular filtration rate [GFR] less than 60mL/min) (Lyman 2014; Aagaard 2018); OR G. Liver dysfunction (liver function tests at least 2X upper limit of normal or bilirubin > 2.0 mg/dL) (Lyman 2014) (Aagaard 2018); OR H. Recent surgery performed as part of cancer management within previous 30 days (not to include a procedure such as port placement, drain placement, IVC filter, etc.) (Lyman 2014; Aagaard 2018); OR I. History of active infection within previous 60 days (Lyman 2014; Aagaard 2018); OR J. Current open wound and chemotherapy cannot be delayed (Lyman 2014; Aagaard 2018). Individual with nonmyeloid malignancy is using for secondary prophylaxis of FN; AND Individual has experienced a neutropenic complication from a prior cycle of chemotherapy (for which prophylaxis was not received), in which a reduced dose may compromise disease-free or overall survival or treatment outcome (NCCN 2A);
Individual is using as adjunctive treatment for FN; AND Individual has not received prophylactic therapy with pegfilgrastim (NCCN 2A); AND Individual has a high risk for infection-associated complications as demonstrated by any of the following: A. Expected prolonged (greater than 10 days) and profound (less than 0.1 x 109/L) neutropenia; OR B. Age greater than 65 years; OR C. Pneumonia or other clinically documented infections; OR D. Hypotension and multi organ dysfunction (sepsis syndrome); OR E. F. Prior episode of febrile neutropenia; OR G. Hospitalized at the time of the development of fever. Invasive fungal infection; OR 4

Neulasta/Neulasta Onpro (pegfilgrastim), Fulphila (pegfilgrastim-jmdb), Fylnetra (pegfilgrastim-pbbk), Nyvepria (pegfilgrastim- apgf), Stimufend (pegfilgrastim-fpgk), Udenyca (pegfilgrastim-cbqv), or Ziextenzo (pegfilgrastim-bmez) Requests for Neulasta (pegfilgrastim), Fulphila (pegfilgrastim-jmdb), Fylnetra (pegfilgrastim-pbbk), Nyvepria (pegfilgrastim-apgf), Udencya (pegfilgrastim-cbqv), or Ziextnzo (pegfilgrastim-bmez) may be approved if the following criteria are met: I. II. Individual with nonmyeloid malignancy is using for primary prophylaxis of Febrile Neutropenia (FN); AND Individual has a risk of FN of 20% or greater based on chemotherapy regimen (see Appendix, Table 1); OR III. IV.

OR

V. VI. OR VII. VIII. IX. OR X. OR XI. OR XII. OR XIII. OR XIV. XV. Individual with nonmyeloid malignancy is using for primary prophylaxis of FN; AND Individual’s risk of developing FN is greater than or equal to 10% and less than 20% based on chemotherapy regimen (see Appendix, Table 1) and individual has any of the following risk factors for FN: A. Age greater than 65 years (Lyman 2014; Aagaard 2018); OR B. Poor performance status (Eastern Cooperative Oncology Group 3 or 4) or HIV infection (in particular, those with low CD4 counts (≤ 450/µL)) but chemotherapy still indicated (Lyman 2014); OR C. Prior radiation therapy (within previous 1 year) (Terbuch 2018) (Fujiwara 2017) (Shigeta 2015); OR D. Bone marrow involvement by tumor producing cytopenias (Lyman 2014); OR E. Persistent neutropenia (absolute neutrophil count [ANC] less than 1500mm3) (Lyman 2014); OR F. Poor renal function (glomerular filtration rate [GFR] less than 60mL/min) (Lyman 2014; Aagaard 2018); OR G. Liver dysfunction (liver function tests at least 2X upper limit of normal or bilirubin > 2.0 mg/dL) (Lyman 2014) (Aagaard 2018); OR H. Recent surgery performed as part of cancer management within previous 30 days (not to include a procedure such as port placement, drain placement, IVC filter, etc) (Lyman 2014; Aagaard 2018); OR I. History of active infection within previous 60 days (Lyman 2014; Aagaard 2018); OR J. Current open wound and chemotherapy cannot be delayed (Lyman 2014; Aagaard 2018); Individual with nonmyeloid malignancy is using for secondary prophylaxis of FN; AND Individual has experienced a neutropenic complication from a prior cycle of chemotherapy (for which prophylaxis was not received), in which a reduced dose may compromise disease-free or overall survival or treatment outcome (NCCN 2A);
Individual is using as adjunctive treatment for FN; AND Individual has not received prophylactic therapy with pegfilgrastim (NCCN 2A); AND Individual has a high risk for infection-associated complications as demonstrated by any of the following: A. Expected prolonged (greater than 10 days) and profound (less than 0.1 x 109/L) neutropenia; OR B. Age greater than 65 years; OR C. Pneumonia or other clinically documented infections; OR D. Hypotension and multi organ dysfunction (sepsis syndrome); OR E. F. Prior episode of febrile neutropenia; OR G. Hospitalized at the time of the development of fever;
Invasive fungal infection; OR Individual is receiving dose dense therapy (treatment given more frequently, such as every 2 weeks instead of every 3 weeks) for adjuvant treatment of breast cancer (ASCO Smith 2015);
Individual is using after accidental or intentional total body radiation of myelosuppressive doses (greater than 2 Grays [Gy]) (such as Hematopoietic Syndrome of Acute Radiation Syndrome);
Individual is using after a hematopoietic progenitor stem cell transplant (HPCT/HSCT) to promote myeloid reconstitution OR when engraftment is delayed or has failed (NCCN 2A);
Individual is using for treatment for hematopoietic cell mobilization for autologous donors in combination with plerixafor (NCCN 2A);
Individual is using for Wilms Tumor (Nephroblastoma) (NCCN 2A); AND Using with Regimen M and Regimen I for one of the following courses: 5

A. Cyclophosphamide and etoposide; OR B. Cyclophosphamide, doxorubicin, and vincristine;
OR XVI. Individual is using for autologous hematopoietic stem cell (HSC) mobilization as part of the development of an FDA-approved ex vivo gene therapy (e.g. Zynteglo (betibeglogene autoemcel)).
Neupogen (filgrastim), Nivestym (filgrastim-aafi), Releuko (filgrastim-ayow), or Zarxio (filgrastim-sndz)
Requests for Neupogen (filgrastim), Nivestym (filgrastim-aafi), Releuko (filgrastim-ayow), or Zarxio (filgrastim-sndz) may be approved if the following criteria are met: I. II. Individual with nonmyeloid malignancy is using for primary prophylaxis of FN; AND Individual has a risk of FN of 20% or greater based on chemotherapy regimen (see Appendix, Table 1);

OR

III. IV.

OR

V. VI. OR VII. VIII. IX. X. OR XI. XII. OR XIII. Individual with nonmyeloid malignancy is using for primary prophylaxis of FN; AND Individual’s risk of developing FN is greater than or equal to 10% and less than 20% based on chemotherapy regimen (see Appendix, Table 1) and individual has any risk factors for FN: A. Age greater than 65 years (Lyman 2014; Aagaard 2018); OR B. Poor performance status (Eastern Cooperative Oncology Group 3 or 4) or HIV infection (in particular, those with low CD4 counts (≤ 450/µL) but chemotherapy still indicated (Lyman 2014); OR C. Prior radiation therapy (within previous 1 year) (Terbuch 2018) (Fujiwara 2017) (Shigeta 2015); OR D. Bone marrow involvement by tumor producing cytopenias (Lyman 2014); OR E. Persistent neutropenia (absolute neutrophil count [ANC] less than 1500mm3) (Lyman 2014); OR F. Poor renal function (glomerular filtration rate [GFR] less than 60mL/min) (Lyman 2014) (Aagaard 2018); OR G. Liver dysfunction (liver function tests at least 2X upper limit of normal or bilirubin > 2.0 mg/dL) (Lyman 2014; Aagaard 2018); OR H. Recent surgery performed as part of cancer management within previous 30 days (not to include a procedure such as port placement, drain placement, IVC filter, etc) (Lyman 2014; Aagaard 2018); OR I. History of active infection within previous 60 days (Lyman 2014; Aagaard 2018); OR J. Current open wound and chemotherapy cannot be delayed (Lyman 2014; Aagaard 2018); Individual with nonmyeloid malignancy is using for secondary prophylaxis of FN; AND Individual has experienced a neutropenic complication from a prior cycle of chemotherapy (for which prophylaxis was not received), in which a reduced dose may compromise disease-free or overall survival or treatment outcome (NCCN 2A);
Individual is using as adjunctive treatment for FN (NCCN 2A); AND Individual has been on prophylactic therapy with filgrastim;
OR
Individual has not received prophylactic therapy with a granulocyte colony stimulating factor (NCCN Guidelines Myeloid Growth Factors); AND Individual has a high risk for infection-associated complications as demonstrated by any of the following (NCCN 2A): A. Expected prolonged (greater than 10 days) and profound (less than 0.1 x 109/L) neutropenia; OR B. Age greater than 65 years; OR C. Pneumonia or other clinically documented infections; OR D. Hypotension and multi organ dysfunction (sepsis syndrome); OR E. F. Prior episode of febrile neutropenia; OR G. Hospitalized at the time of the development of fever;
Invasive fungal infection; OR Individual is 18 years of age or older and has a diagnosis of acute myeloid leukemia (AML); AND Individual is using shortly after the completion of induction or repeat induction chemotherapy, or after the completion of consolidation chemotherapy for AML;
Individual has a diagnosis of hairy cell leukemia with severe neutropenia (AHFS, NCCN Guidelines Hairy Cell Leukemia);
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OR XIV. XV. OR XVI. XVII. OR XVIII. OR XIX. OR XX. OR XXI. XXII. OR XXIII. OR XXIV. OR XXV. OR XXVI. OR XXVII. OR XXVIII. OR XXIX. OR XXX. XXXI. OR XXXII. Individual has a diagnosis of myelodysplastic syndrome (MDS) (NCCN 2A); AND Individual has severe neutropenia (ANC less than or equal to 500mm3) or experiencing recurrent or resistant infections;
Individual has a diagnosis of myelodysplastic syndrome with ring sideroblasts (MDS-RS) or MDS/MPN-RS-T; AND Individual is using in combination with Reblozyl;
Individual is receiving dose dense therapy (treatment given more frequently, such as every 2 weeks instead of every 3 weeks) for adjuvant treatment of breast cancer (ASCO Smith 2015);
Individual is using for chronic administration to reduce the incidence and duration of sequelae of neutropenia (for example, fever, infections, oropharyngeal ulcers) in symptomatic individuals with congenital neutropenia, cyclic neutropenia, or idiopathic neutropenia;
Individual is using for the treatment of (non-chemotherapy) drug-induced neutropenia (AHFS);
Individual is less than 21 years of age and is diagnosed with glycogen storage disease type 1b; AND Individual is using for the treatment of low neutrophil counts (AHFS); Individual is using for the treatment of neutropenia associated with human immunodeficiency virus infection and antiretroviral therapy (AHFS);
Individual is using after accidental or intentional total body radiation of myelosuppressive doses (greater than 2 Grays [Gy]) (such as Hematopoietic Syndrome of Acute Radiation Syndrome);
Individual is using after a hematopoietic progenitor stem cell transplant (HPCT/HSCT) to promote myeloid reconstitution or when engraftment is delayed or has failed (NCCN 2A);
Individual is using to mobilize progenitor cells into peripheral blood for collection by leukapheresis, as an adjunct to peripheral blood/hematopoietic stem cell transplantation (PBSCT/PHSCT);
Individual is using as an alternate or adjunct to donor leukocyte infusions (DLI) in those with leukemic relapse after an allogenic hematopoietic stem cell transplant (DrugPoints B Iia);
Individual is using to reduce the duration of neutropenia and neutropenia related clinical sequelae in those with nonmyeloid malignancies undergoing myeloblative chemotherapy followed by bone marrow transplant (BMT);
Individual is using for treatment for hematopoietic cell mobilization for autologous donors in combination with plerixafor (NCCN 2A);
Individual is using for Wilms Tumor (Nephroblastoma) (NCCN 2A); AND Using with Regimen M and Regimen I for one of the following courses: A. Cyclophosphamide and etoposide; OR B. Cyclophosphamide, doxorubicin, and vincristine; Individual is using for autologous hematopoietic stem cell (HSC) mobilization as part of the development of an FDA-approved ex vivo gene therapy (e.g. Zynteglo (betibeglogene autoemcel)) (NCCN 2A);
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OR XXXIII. Individual is using for hematopoietic cell mobilization for autologous donors in combination with Aphexda (motixafortide) (Aphexda Label). Leukine (Sargramostim) Requests for Leukine (sargramostim) may be approved if the following criteria are met: I. II. III. Individual is using as adjunctive treatment for FN: AND Individual has not previously received prophylactic granulocyte colony-stimulating factors (NCCN 2A); AND Individual has a high risk for infection-associated complications as demonstrated by any of the following (NCCN 2A): A. Expected prolonged (greater than 10 days) and profound (less than 0.1 x 109/L) neutropenia; OR B. Age greater than 65 years; OR C. Pneumonia or other clinically documented infections; OR D. Hypotension and multi organ dysfunction (sepsis syndrome); OR E. F. Prior episode of febrile neutropenia; OR G. Hospitalized at the time of the development of fever;
Invasive fungal infection; OR OR IV. OR V. VI. VII. OR VIII. IX. OR X. XI. OR XII. XIII. OR XIV. XV. OR XVI. OR XVII. XVIII. XIX. XX. OR XXI. XXII. Individual is receiving dose dense therapy (treatment given more frequently, such as every 2 weeks instead of every 3 weeks) for adjuvant treatment of breast cancer (ASCO Smith 2015);
Individual has a diagnosis of acute myeloid leukemia (AML); AND Individual is 55 years and older; AND Individual is using shortly after the completion of induction or repeat induction chemotherapy of AML;
Individual has a diagnosis of myelodysplastic syndrome (MDS); AND Individual has severe neutropenia (ANC less than or equal to 500mm3) or experiencing recurrent or resistant infections (NCCN Guidelines Myelodysplastic Syndromes; AHFS);
Individual is 18 years or older; AND Individual is using for the mobilization of hematopoietic progenitor cells into peripheral blood for collection by leukapheresis and autologous transplantation;
Individual is 2 years of age and older; AND Individual is using for the acceleration of myeloid reconstitution following autologous or allogenic bone marrow transplantation or peripheral blood progenitor cell transplantation;
Individual is 2 years of age and older; AND Individual is using for the treatment of delayed neutrophil recovery or graft failure after autologous or allogenic bone marrow transplantation;
Individual is using to increase survival in adult and pediatric individuals (from birth to 17 years of age) acutely exposed to myelosuppressive doses of radiation (such as Hematopoietic Syndrome of Acute Radiation Syndrome (H-ARS));
Individual is 18 years of age or younger; AND Individual is diagnosed with relapsed/refractory high-risk neuroblastoma; AND Individual is using in combination with dinutuximab (Unituxin), 13-cis-retinoic acid (i.e. isotretinoin) and with or without interleukin-2 (IL-2) (i.e. aldesleukin); AND Individual achieved a partial response to first-line multi-agent, multi-modality therapy (i.e. induction combination chemotherapy, or myeloablative consolidation chemotherapy followed by autologous stem cell transplant);
Individual is diagnosed with relapsed/refractory high-risk neuroblastoma; AND Individual is using in combination with Danyelza (naxitamab-gqgk). 8

Granix (Tbo-Filgrastim) Requests for Granix (Tbo-Filgrastim) may be approved if the following criteria are met: I. II. Individual with non-myeloid malignancy is using for primary prophylaxis of Febrile Neutropenia (FN); AND Individual has a risk of FN of 20% or greater based on chemotherapy regimen (see Appendix, Table 1); OR III. IV. OR V. VI. OR VII. VIII. IX. X. OR XI. OR XII. XIII. OR XIV. XV. OR XVI. Individual with nonmyeloid malignancy is using for primary prophylaxis of FN; AND Individual’s risk of developing FN is greater than or equal to 10% and less than 20% based on chemotherapy regimen (see Appendix, Table 1) and individual has any risk factors for FN: Age greater than 65 years (Lyman 2014; Aagaard 2018); OR A. B. Poor performance status (Eastern Cooperative Oncology Group 3 or 4) or HIV infection (in particular, those with low CD4 counts (≤ 450/µL)) but chemotherapy still indicated (Lyman 2014); OR C. Prior radiation therapy (within previous 1 year) (Terbuch 2018) (Fujiwara 2017) (Shigeta 2015); OR D. Bone marrow involvement by tumor producing cytopenias (Lyman 2014); OR E. Persistent neutropenia (absolute neutrophil count [ANC] less than 1500mm3) (Lyman 2014); OR F. Poor renal function (glomerular filtration rate [GFR] less than 60mL/min) (Lyman 2014; Aagaard 2018); OR G. Liver dysfunction (liver function tests at least 2X upper limit of normal or bilirubin > 2.0 mg/dL) (Lyman 2014; Aagaard 2018); OR H. Recent surgery performed as part of cancer management within previous 30 days (not to include a procedure such as port placement, drain placement, IVC filter, etc.) (Lyman 2014; Aagaard 2018); OR I. History of active infection within previous 60 days (Lyman 2014; Aagaard 2018); OR J. Current open wound and chemotherapy cannot be delayed (Lyman 2014; Aagaard 2018); Individual with nonmyeloid malignancy is using for secondary prophylaxis of FN; AND Individual has experienced a neutropenic complication from a prior cycle of chemotherapy (for which prophylaxis was not received), in which a reduced dose may compromise disease-free or overall survival or treatment outcome (NCCN 2A);
Individual is using as an adjunctive treatment for FN; AND Individual was previously using Granix (tbo-filgrastim) prophylactically (NCCN 2A);
OR Individual has not received prophylactic therapy with a granulocyte colony stimulating factor (NCCN Guidelines Myeloid Growth Factors); AND Individual has a high risk for infection-associated complications as demonstrated by any of the following:
A. Expected prolonged (greater than 10 days) and profound (less than 0.1 x 109/L) neutropenia (NCCN 2A);OR B. Age greater than 65 years; OR C. Pneumonia or other clinically documented infections; OR D. Hypotension and multi organ dysfunction (sepsis syndrome); OR E. F. Prior episode of febrile neutropenia; OR G. Hospitalized at the time of the development of fever;
Invasive fungal infection; OR Individual is using after a hematopoietic progenitor stem cell transplant (HPCT/HSCT) to promote myeloid reconstitution or when engraftment is delayed or has failed (NCCN 2A); Individual has a diagnosis of myelodysplastic syndrome (MDS); AND Individual has severe neutropenia (ANC less than or equal to 500mm3) or experiencing recurrent or resistant infections (NCCN 2A);
Individual has a diagnosis of myelodysplastic syndrome with ring sideroblasts (MDS-RS) or MDS/MPN-RS-T; AND Individual is using in combination with Reblozyl;
Individual is using to mobilize progenitor cells into peripheral blood for collection by leukapheresis, as an adjunct to peripheral blood/hematopoietic stem cell transplantation (PBSCT/PHSCT) (AHFS); 9

OR XVII. OR XVIII. OR XIX. Individual is using for treatment for hematopoietic cell mobilization for autologous donors in combination with plerixafor (NCCN 2A);
Individual is using for autologous hematopoietic stem cell (HSC) mobilization as part of the development of an FDA-approved ex vivo gene therapy (e.g. Zynteglo (betibeglogene autoemcel)); Individual is using for hematopoietic cell mobilization for autologous donors in combination with Aphexda (motixafortide) (Aphexda Label).
Colony Stimulating Factors (filgrastim and their biosimilars, pegfilgrastim and their biosimilars, sargramostim, and tbo-filgrastim) may not be approved for any of the following: I. II. III. IV. V. VI. VII. Individual is using as prophylaxis for febrile neutropenia, except when above criteria are met; OR Individual using as treatment for neutropenia in those who are afebrile, except when above criteria are met; OR Individual is using as adjunctive therapy in those with uncomplicated febrile neutropenia, defined as a fever less than 10 days duration, no evidence of pneumonia, cellulitis, abscess, sinusitis, hypotension, multi-organ dysfunction, or invasive fungal infection, and no uncontrolled malignancies; OR Individual is using for chemosensitization of myeloid leukemias; OR Individual is using for prophylaxis of FN during concomitant chemotherapy and radiation therapy; OR Individual is continuing use if no response is seen within 28-42 days (individuals who have failed to respond within this time frame are considered non-responders); OR Individual is using as a technique to increase the numbers of circulating hematopoietic stem cells as treatment of damaged myocardium. Step Therapy Note: When a white blood cell growth factor, also known as a colony stimulating factor (CSF) is deemed approvable based on the clinical criteria above, the benefit plan may have additional criteria requiring the use of a preferred1 agent or agents. Non-Preferred Long-acting (pegfilgrastim) Colony Stimulating Factor (CSF) Agents Step Therapy A list of long-acting preferred white blood cell growth factors is available here. Requests for a non-preferred Long-acting CSF agent may be approved when the following criteria are met: I. Individual has had a trial and inadequate response or intolerance to one preferred Long-acting CSF agent. Non-Preferred Short-acting (filgrastim) Colony Stimulating Factor (CSF) Agents Step Therapy A list of short-acting preferred white blood cell growth factors is available here. Requests for a non-preferred Short-acting CSF agent may be approved when the following criteria are met: I. Individual has had a trial and inadequate response or intolerance to one preferred Short-acting CSF agent:

 OR

II. The preferred agent is not FDA-approved for the prescribed indication and the requested non-preferred agent is. 1Preferred, as used herein, refers to agents that were deemed to be clinically comparable to other agents in the same class or disease category but are preferred based upon clinical evidence and cost effectiveness. Coding The following codes for treatments and procedures applicable to this document are included below for informational purposes. Inclusion or exclusion of a procedure, diagnosis or device code(s) does not constitute or imply member coverage or provider reimbursement policy. Please refer to the member’s contract benefits in effect at the time of service to determine coverage or non-coverage of these services as it applies to an individual member. CPT
10

96377 HCPCS Q5122 Q5120 J1442 J1447 J2506 J2820 Q5101 Q5108 Q5110 Q5111 Q5125 J1449 Q5127 Q5130 J3490 J3590 Application of on-body injector (includes cannula insertion) for timed subcutaneous injection [Neulasta OnPro injector] Injection, pegfilgrastim-apgf, biosimilar, (Nyvepria), 0.5 mg
Injection, pegfilgrastim-bmez, biosimilar, (Ziextenzo), 0.5 mg Injection, filgrastim (G-CSF), excludes biosimilars, 1 microgram [Neupogen] Injection, tbo-filgrastim, 1 microgram [Granix] Injection, pegfilgrastim, excludes biosimilar, 0.5 mg Injection, sargramostim (GM-CSF), 50 mcg [Leukine, Prokine] Injection, filgrastim-sndz, biosimilar, (Zarxio), 1 microgram Injection, pegfilgrastim-jmdb, biosimilar, (Fulphila), 0.5 mg Injection, filgrastim-aafi, biosimilar, (Nivestym), 1 microgram Injection, pegfilgrastim-cbqv, biosimilar, (Udenyca), 0.5 mg Injection, filgrastim-ayow, biosimilar, (Releuko), 1 microgram [Releuko] Injection, eflapegrastim-xnst, 0.1 mg [Rolvedon] Injection, pegfilgrastim-fpgk (11ylnetra11), biosimilar, 0.5 mg [Stimufend] Injection, pegfilgrastim-pbbk (11ylnetra), biosimilar, 0.5 mg [Fylnetra] Unclassified drugs (when specified as [Ryzneuta] (efbemalenograstim alfa-vuxw)) Unclassified biologics (when specified as [Ryzneuta] (efbemalenograstim alfa-vuxw)) ICD-10 Diagnosis All diagnoses Document History Revised: 12/11/2023