Description
People with certain cancers may be given drugs (chemotherapy) to treat their disease. A side effect of many chemotherapy drugs is destruction of or delay in making immune cells that fight infection. These cells are known as white blood cells, neutrophils, or granulocytes. Neutropenia means a lack of granulocytes (infection-fighting cells). People being treated for cancer may develop neutropenia and fever. When this happens, treatment with antibiotics in the hospital is often necessary in case there is a serious infection. In the 1980s scientists discovered a type of protein called granulocyte-colony stimulating factor (G-CSF) that could stimulate the body to make more granulocytes. It has become a standard practice to give G-CSF drugs in conjunction with certain types of chemotherapy likely to cause neutropenia. These agents can also be given as part of a bone marrow or stem cell transplant or to treat some rare conditions.

Policy  

NEUPOGEN (filgrastim)
GRANIX (tbo-filgrastim)
ZARXIO (filgrastim-sndz) 
NEULASTA (pegfilgrastim)
FULPHILA (pegfilgrastim-jmdp) 
UDENYCA (pegfilgrastim-cbqv) 
ZIEXTENZO (pegfilgrastim-bmez)
Nivestym (filgrastim-aafi)
Neupogen (filgrastim)
Nyvepria (pegfilgrastim-apgf)
Neulasta (pegfilgrastim)

Coverage of these drugs is provided when the criteria below is met and there has been a trial and failure of preferred therapy.

A.   INDICATIONS
The indications below, including FDA-approved indications and compendial uses, are considered a covered benefit, provided that all the approval criteria are met and the member has no exclusions to the prescribed therapy. 

FDA-Approved Indications

Neupogen 

• Cancer Patients Receiving Myelosuppressive Chemotherapy
  • Neupogen is indicated to decrease the incidence of infection, as manifested by febrileneutropenia, in patients with non-myeloid malignancies receiving myelosuppressive anti-cancer drugs associated with a significant incidence of severe neutropenia with fever.
• Patients With Acute Myeloid Leukemia Receiving Induction or Consolidation
  • Neupogen is indicated for reducing the time to neutrophil recovery and the duration of fever, following induction or consolidation chemotherapy treatment of adults with acute myeloid leukemia.
• Cancer Patients Receiving Bone Marrow Transplant
  • Neupogen is indicated to reduce the duration of neutropenia and neutropenia-related clinical sequelae, (e.g., febrile neutropenia) in patients with non-myeloid malignancies undergoing myeloablative chemotherapy followed by marrow transplantation.
• Patients Undergoing Peripheral Blood Progenitor Cell Collection and Therapy
  • Neupogen is indicated for the mobilization of hematopoietic progenitor cells into the peripheralblood for collection by leukapheresis.
• Patients With Severe Chronic Neutropenia
  • Neupogen is indicated for chronic administration to reduce the incidence and duration of sequelae of neutropenia (e.g., fever, infections, oropharyngealulcers) in symptomatic patients with congenital neutropenia, cyclic neutropenia, or idiopathic neutropenia.  

NEULASTA (pegfilgrastim)
FULPHILA (pegfilgrastim-jmdp) 
UDENYCA (pegfilgrastim-cbqv)
ZIEXTENZO (pegfilgrastim-bmez)
Nivestym (filgrastim-aafi)
Neupogen (filgrastim)
Nyvepria (pegfilgrastim-apgf)
Neulasta (pegfilgrastim)

I.  INDICATIONS 

The indications below including FDA-approved indications and compendial uses are considered a covered benefit provided that all the approval criteria are met and the member has no exclusions to the prescribed therapy.

A. FDA-Approved Indication

Neulasta
Neulasta is indicated to decrease the incidence of infection, as manifested by febrile neutropenia, in patients with non-myeloid malignancies receiving myelosuppressive anti-cancer drugs associated with a clinically significant incidence of febrile neutropenia.

Fulphila
Fulphila is indicated to decrease the incidence of infection, as manifested by febrile neutropenia, in patients with non-myeloid malignancies receiving myelosuppressive anti-cancer drugs associated with a clinically significant incidence of febrile neutropenia

Udenyca
Udenyca is indicated to decrease the incidence of infection, as manifested by febrile neutropenia, in patients with non-myeloid malignancies receiving myelosuppressive anti-cancer drugs associated with a clinically significant incidence of febrile neutropenia.

Ziextenzo
Ziextenzo  is indicated to decrease the incidence of infection, as manifested by febrile neutropenia, in patients with non-myeloid malignancies receiving myelosuppressive anti-cancer drugs associated with a clinically significant incidence of febrile neutropenia.

B. Compendial Use
Stem cell transplantation-related indications 

All other indications are considered experimental/investigational and are not a covered benefit.

Granix
Granix is indicated to reduce the duration of severe neutropenia in patients with non-myeloid malignancies receiving myelosuppressive anti-cancer drugs associated with a clinically significant incidence of febrile neutropenia. 

Zarxio 

• Cancer Patients Receiving Myelosuppressive Chemotherapy
  • Zarxio is indicated to decrease the incidence of infection, as manifested by febrile neutropenia, in patients with non-myeloid malignancies receiving myelosuppressive anti-cancer drugs associated with a significant incidence of severe neutropenia with fever.
• Patients With Acute Myeloid Leukemia Receiving Induction or Consolidation
  • Zarxio is indicated for reducing the time to neutrophil recovery and the duration of fever, following induction or consolidation chemotherapy treatment of adults with acute myeloid  leukemia.
• Cancer Patients Receiving Bone Marrow Transplant
  • Zarxio is indicated to reduce the duration of neutropenia and neutropenia-related clinical sequelae, (e.g., febrile neutropenia) in patients with non-myeloid malignancies undergoing myeloablative chemotherapy followed  by  marrow transplantation.
• Patients Undergoing Peripheral Blood Progenitor Cell Collection and Therapy
  • Zarxio is indicated for the mobilization of hematopoietic progenitor cells into the peripheral blood for collection by leukapheresis. 
• Patients With Severe Chronic Neutropenia
  • Zarxio is indicated for chronic administration to reduce the incidence and duration of sequelae of neutropenia (e.g., fever, infections, oropharyngeal ulcers) in symptomatic patients with congenital neutropenia, cyclic neutropenia, or idiopathic neutropenia.  

Compendial Uses (Neupogen/Granix/Zarxio)

• Treatment of chemotherapy-induced febrile neutropenia in patients with non-myeloid  malignancies
• Treatment of symptomatic anemia in patients with myelodysplastic syndromes (MDS), in combination with epoetin or darbepoetin
• Treatment of neutropenia in patients with MDS and recurrent or resistant infections
• Following chemotherapy for acute lymphocytic leukemia
• Leukemic relapse following allogeneic stem cell transplantation
• Agranulocytosis
• Aplastic anemia
• Neutropenia related to HIV/AIDS
• Neutropenia related to renal transplantation 

LEUKINE (sargramostim)

Coverage of this drug is provided when the criteria below is met and there has been a trial and failure of preferred therapy.  

A.   INDICATIONS 
The indications below including FDA-approved indications and compendial uses are considered a covered benefit provided that all the approval criteria are met and the member has no exclusions to the prescribed therapy. 

1. FDA-Approved Indications
   • Use Following Induction Chemotherapy  in Acute Myelogenous Leukemia
     • Leukine is indicated for use following induction chemotherapy in older adult patients with acute myelogenous leukemia to shorten time to neutrophil recovery and to reduce the incidence of severe and life-threatening infections and infections resulting in  death.
   • Use in Mobilization and Following Transplantation of Autologous Peripheral Blood Progenitor  Cells
     • Leukine is indicated for the mobilization of hematopoietic progenitor cells into peripheral blood for collection by leukapheresis. Mobilization allows for the collection of increased numbers of progenitor cells capable of engraftment as compared with collection without mobilization. After myeloablative chemotherapy, the transplantation of an increased number of progenitor cells can lead to more rapid engraftment, which may result in a decreased need for supportive care. Myeloid reconstitution is further accelerated by administration of Leukine following peripheral blood progenitor  cell transplantation.
   • Use in Myeloid Reconstitution After  Autologous  Bone Marrow Transplantation
     • Leukine is indicated for acceleration of myeloid recovery in patients with non-Hodgkin's lymphoma (NHL), acute lymphoblastic leukemia (ALL) and Hodgkin's disease undergoing autologous bone marrow  transplantation (BMT).
   • Use in Myeloid Reconstitution After Allogeneic Bone Marrow  Transplantation
     • Leukine is indicated for acceleration of myeloid recovery in patients undergoing allogeneic BMT from HLA-matched related donors.
   • Use in Bone Marrow Transplantation Failure or Engraftment Delay
     • Leukine is indicated in patients who have undergone allogeneic or autologous BMT in whom engraftment is delayed or has failed.
2. Compendial Uses
   • Prophylaxis and treatment  of chemotherapy-induced febrile neutropenia in non-myeloid malignancies
   • Treatment of neutropenia in patients with myelodysplastic syndromes  (MOS)
   • AML following consolidation chemotherapy
   • ALL following induction or consolidation chemotherapy
   • Agranulocytosis
   • Aplastic anemia
   • Neutropenia related to HIV/AIDS 

B.    REQUIRED DOCUMENTATION FOR ALL MEDICATIONS LISTED
The following documentation is required to initiate a prior authorization review:

Neutropenia In Cancer Patients Receiving Myelosuppressive Chemotherapy: Length of chemotherapy cycle, the days of the cycle on which chemotherapy will be administered, and the first day of the cycle on which the Neupogen/Granix/Zarxio will be administered (e.g., 14 day cycle, chemotherapy on day 1, Neupogen administered day 2) Myelodysplastic Syndrome:  Document the patient's serum erythropoietin level 

C.   CRITERIA FOR APPROVAL FOR ALL CSFs

1. Neutropenia In Cancer Patients Receiving Myelosuppressive Chemotherapy

• • Authorization of 6 months may be granted for members for prevention of febrile neutropenia when all of the following criteria are met:
  • • Member has a non-myeloid malignancy (refer to section 6. for the diagnosis of  ALL)
    • Member is currently receiving or will be receivingmyelosuppressive chemotherapy or radiotherapy
    • Neupogen/Granix/Zarxio will not be administered less than 24 hours before or after chemotherapy or radiotherapy
    • The member will not receive chemotherapy and radiotherapy concurrently 
  • Authorization of 6 months may be granted for members for the treatment of a current episode of febrile neutropenia when all of the following criteria are met:
    • Member has a non-myeloid malignancy (refer to section 6. for the diagnosis of ALL)
    • Member is currently receiving myelosuppressive chemotherapy or  radiotherapy
    • Neupogen/Granix/Zarxio will not be administeredless than 24 hours before or after chemotherapy or radiotherapy
    • Member did not receive pegylated G-CSF (e.g., Neulasta) for prevention of neutropenia during the current chemotherapy cycle

2. Acute Myeloid Leukemia (AML)
   • Authorization  of 6 months may be granted for members who are receiving treatment for AML. 
3. Stem Cell Transplantation-related Indications
   • Authorization of 6 months may be granted for members for any of the following indications:
   • Peripheral blood progenitor cell (PBPC) mobilization/collection prior to transplantation
   • Use following bone marrow transplantation or PBPC transplantation
   • Leukemic relapse after allogeneic stem cell transplantation
4. Severe Chronic Neutropenia
   • Authorization of 6 months may be granted for members with severe chronic neutropenia (congenital, cyclic, or idiopathic) with chronic absolute neutrophil count [ANC] less than or equal to 500 cells/mm^3
5. Myelodysplastic Syndromes (MDS)
   • Authorization of 6 months may be granted for members with MOS undergoing treatment for anemia who meet all of the following conditions:
     • The member has lower risk MOS (i.e., low or intermediate-1 risk  stratification)
     • The member has symptomatic anemia
     • Neupogen/Granix/Zarxio will be used with epoetin or darbepoetin
     • The serum erythropoietin level is less than, or equal to, 500 mU/ml
   • Authorization of 6 months may be granted for members with MOS who meet all of the following conditions:
     • The member is neutropenic
     • The member experiences recurrent or resistant infections
6. Acute Lymphocytic Leukemia (ALL)
   • Authorization of 6 months may be granted for members receiving treatment for ALL.
7. Other Indications
   • Authorization of 6 months may be granted for members with any of the following indications:
     • Agranulocytosis
     • Aplastic anemia
     • Neutropenia related to HIV/AIDS ANC less than or equal to 1,000 (cells/mm3) 
     • Neutropenia related to renal transplantation
   • Authorization of 1 month may be granted for members with any of the following indications:
     • Hematopoietic Acute Radiation Syndrome (H-ARS), (all filgrastim products, all pegfilgrastim products, sargramostim, and tbo-filgrastim): To increase survival in patients acutely exposed to myelosuppressive doses of radiation once weekly for 2 doses

All other indications are considered investigational and/or unproven and therefore considered NOT MEDICALLY NECESSARY and are not a covered benefit.   

D. CONTINUATION OF THERAPY
All members (including new members) requesting authorization for continuation of therapy must meet all initial authorization criteria. 

References

1. Smith TJ, Khatcheressian J, Lyman GH, et al. 2006 Update of Recommendations for the Use of White Blood Cell Growth Factors: An Evidence-Based Clinical Practice Guideline. J Clin Oncol 2006;24:3187-3205. © 2006 by American Society of Clinical Oncology.
2. American Society of Clinical Oncology. 1997 update of recommendations for the use of hematopoietic colony-stimulating factors: Evidence-based clinical practice guidelines. J Clin Oncol. 1997;15(10):3288.
3. Neulasta Prescribing Information. V13. Thousand Oaks, CA: Amgen; 2011. Available at: http://pi.amgen.com/united_states/neulasta/neulasta_pi_hcp_english.pdf Accessed March 2018.
4. Neupogen Prescribing Information. V24. Thousand Oaks, CA: Amgen; 2013. Available at:http://pi.amgen.com/united_states/neupogen/neupogen_pi_hcp_english.pdf Accessed March 2018.
5. Granix Prescribing Information. North Wales, PA: Cephalon (Teva); 2013. Available at: November 12, 2015 27, 2014.
6. Shi YK, Chen Q, Zhu YZ, et al. Pegylated filgrastim is comparable with filgrastim as support for commonly used chemotherapy regimens: a multicenter, randomized, crossover phase 3 study. Anti-Cancer Drugs 24:641-647.
7. Del Giglio A, Eniu A, et al. XM02 is superior to placebo and equivalent to Neupogen in reducing the duration of severe neutropenia and the incidence of febrile neutropenia in cycle 1 in breast cancer patients receiving docetaxel/doxorubicin chemotherapy. BMC Cancer 2008, 8:332. Available at: https://bmccancer.biomedcentral.com/articles/10.1186/1471-2407-8-332 Accessed March 2018.
8. Lubenau H, Bias P, et al. Pharmacokinetic and Pharmacodynamic Profile of New Biosimilar Filgrastim XM02 Equivalent to Marketed Filgrastim Neupogen. Biodrugs 2009; 23(1):43-51.
9. Heil G, Hoelzer D, et al. A Randomized, Double-Blind, Placebo-Controlled, Phase III Study of Filgrastim in Remission Induction and Consolidation Therapy for Adults With De Novo Acute Myeloid Leukemia. Blood 1997; 90:4710-4718.
10. Duhrsen U, Villeval JL, Boyd J, et al. Effects of recombinant human granulocyte colony-stimulating factor on hematopoietic progenitor cells in cancer patients. Blood 1988; 72:2074-2081.
11. Dale DC, Bonilla MA, Davis MW, et al. A randomized controlled phase III trial of recombinant human granulocyte colonystimulating factor (filgrastim) for treatment of severe chronic neutropenia. Blood 1993; 81:2496-2502.
12. Herbert KE, Gambell P, et al. Pegfilgrastim compared to filgrastim for cytokine-alone mobilization of autologous haematopoietic stem and progenitor cells. Bone Marrow Transplantation 2013; 48:351-356.
13. Ferrara F, Izzo T, et al. Comparison of fixed dose pegfilgrastim and daily filgrastim after autologous stem cell transplantation in patients with multiple myeloma autografted on an outpatient basis. Hematol Oncol 2011; 29:139-143.
14. Choosing Wisely: An initiative of the ABIM Foundation. American Society of Clinical Oncology: 10 Things Physicians and Patients Should Question. Available at  http://www.choosingwisely.org/doctor-patient-lists/american-society-of-clinicaloncology/ Accessed March 2018.
15. Bokemeyer C, et.al. Over and Under-Prophylaxis for chemotherapy-induced (febrile) Neutropenia Relative to Evidence-Based Guidelines is associated With Differences in Outcomes: Findings from the MONITOR-GCSF Study. Available at: https://www.ncbi.nlm.nih.gov/pubmed/28111718 Accessed March 2018. 
16. Neulasta [package insert]. Thousand Oaks, CA: Amgen Inc.; December 2017.
17. Fulphila [package insert]. Zurich, Switzerland: Mylan; June 2018.
18. Udenyca [package insert]. Redwood City, California: Coherus BioSciences, Inc: November 2018.
19. Micromedex Solutions [database online]. Ann Arbor, MI: Truven Health Analytics Inc. Updated periodically. www.micromedexsolutions.com [available with subscription]. Accessed June 15, 2018.
20. The NCCN Drugs & Biologics Compendium® © 2018 National Comprehensive Cancer Network, Inc. Available at: http://www.nccn.org. Accessed June 15, 2018.
21. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology: Myeloid Growth Factors. Version 1.2018. http://www.nccn.org/professionals/physican_gls/pdf/myeloid_growth.pdf. Accessed June 15, 2018.
22. Aapro MS, Bohlius J, Cameron DA, et al. 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. Eur J Cancer. 2011;47(1):8-32.
23. Smith TJ, Bohlke K, Lyman GH, et al. Recommendations for the use of white blood cell growth factors: American Society of Clinical Oncology Clinical Practice Guideline Update. J Clin Oncol. 2015;33(28):3199-3212.

Coding Section 

Procedure and diagnosis codes on Medical Policy documents are included only as a general reference tool for each policy. They may not be all-inclusive. 

This medical policy was developed through consideration of peer-reviewed medical literature generally recognized by the relevant medical community, U.S. FDA approval status, nationally accepted standards of medical practice and accepted standards of medical practice in this community, Blue Cross Blue Shield Association technology assessment program (TEC) and other nonaffiliated technology evaluation centers, reference to federal regulations, other plan medical policies, and accredited national guidelines.

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