Effective Date:

a)    This policy will apply to all services performed on or after the above revision date which will become the new effective date.

b)    For all services referred to in this policy that were performed before the revision date, contact customer service for the rules that would apply.

The white blood cell stimulating medications (hematopoietic colony-stimulating factors – CSFs) have been introduced into clinical practice as additional supportive measures that can reduce the likelihood of complications related to low white blood count and infections during chemotherapy. The medications are Granix, Neupogen, Leukine, Prokine, and Neulasta.

CSFs are recommended in certain cases such as when the chemotherapy is expected to reduce certain blood counts below safe levels.

Granulocyte colony-stimulating factor (G-CSF; Filgrastim [Neupogen]), recombinant granulocyte colony-stimulating factor (tbo-filgrastim [Granix], Zarxio, Nivestym, and granulocyte-macrophage colony-stimulating factor (GM-CSF; sargramostim [Leukine, Prokine]) are considered medically necessary in adult and pediatric members with cancer for any of the following indications:

1. Primary prophylaxis in previously untreated adult and pediatric members with non-myeloid malignancies receiving established myelosuppressive chemotherapy that is expected to result in a 20 % or greater incidence of severe febrile neutropenia.

Chemotherapeutic an agent in which myelosuppression is the dose-limiting adverse effect include, but are not limited to the following:

• Busulfan
• Etoposide
• Mitomycin
• Carboplatin
• Floxuridine
• Mitoxantrone
• Carmustine
• Flourouracil
• Paclitaxel
• Cladribine
• Fludarabine
• Plicamycin
• Chlorambucil
• Hydroxyurea
• Procarbazine
• Cyclophosphamide
• Ifosfamide
• Teniposide
• Cytarabine
• Lomustine
• Thioguanine
• Dacarbazine
• Mechlorethamine
• Thiotepa
• Dactinomycin
• Melphanan
• Vinblastine
• Daunorubicin
• Mercaptopurine
• Vincristine
• Doxorubicin
• Methotrexate
• Vinorelbine.
1. Primary prophylaxis in members receiving a relatively non-myelosuppressive chemotherapy who are at increased risk for chemotherapy-induced infectious complications because of bone marrow compromise or comorbidity, including any of the following (not an all-inclusive list):

1. Pre-existing neutropenia due to disease; or
2. Extensive prior chemotherapy; or
3. Previous irradiation to the pelvis or other areas containing large amounts of bone marrow; or
4. History of recurrent febrile neutropenia while receiving earlier chemotherapy of similar or lesser dose-intensity; or
5. Conditions potentially enhancing the risk of serious infection, e.g., poor performance status and more advanced cancer decreased immune function, open wounds, or already-active tissue infections.
1. Adjunctive use with antibiotics in high-risk, febrile, neutropenic members who have any of the following prognostic factors that are predictive of clinical deterioration:
   1. Profound (absolute neutrophil count less than 100/mL) neutropenia; or
   2. Uncontrolled primary disease; or
   3. Pneumonia; or
   4. Hypotension; or
   5. Multi-organ dysfunction (sepsis syndrome); or
   6. Invasive fungal infection.
2. Use in settings where clinical research demonstrates that dose-intensive therapy not requiring progenitor-cell support produces improvement in disease control, when these therapies are expected to produce significant rates of febrile neutropenia (e.g., in more than 40 % of individuals);
3. For administration shortly after the completion of induction of acute myeloid leukemia (AML) therapy in members over 55 years of age, to achieve modest decreases in the duration of neutropenia or for members of any age, after the completion of consolidation chemotherapy for AML;
4. In acute lymphoblastic leukemia (ALL), for administration after completion of the first few days of chemotherapy of the initial induction or first post-remission course;
5. Reduction in the duration of neutropenia and neutropenia-related infectious complications in members with non-myeloid malignancies undergoing myeloablative chemotherapy followed by autologous or allogeneic bone marrow transplantation (BMT);
6. Mobilization of autologous or donor hematopoietic progenitor cells into the peripheral blood for collection by leukapheresis in order to increase the number of circulating peripheral-blood progenitor-cells (PBPC) collected for engraftment for allogeneic peripheral stem cell transplantation;
7. Assisting in the recovery of members who experience delayed or inadequate neutrophil engraftment following progenitor-cell transplantation by speeding hematopoietic reconstitution following BMT or PBPC transplantation;
8. Chronic administration to reduce the incidence and duration of sequelae of neutropenia (e.g., fever, infections, oropharyngeal ulcers) in symptomatic members with congenital neutropenia, cyclic neutropenia, or idiopathic neutropenia;
9. Intermittent use in members with myelodysplastic syndromes who have less than 15 % blasts in their bone marrow or are experiencing recurrent neutropenic infections;
10. Members with advanced HIV infection and neutropenia (absolute neutrophil count less than 1 x 109/L) to allow scheduled dosing of myelosuppressive anti-retroviral medication (e.g., zidovudine and ganciclovir).

Neulasta and pegfilgrastim biosimilars:

Neulasta (pegfilgrastim) and pegrilgrastim biosimilar products (6mg per chemotherapy cycle, not in the period 14 days before and 24 hours after chemotherapy administration) is considered medically necessary as an alternative to Neupogen (filgrastim) for members:

·         As primary prophylaxis, to decrease the incidence of infection, as manifested by febrile neutropenia, in patients with non-myeloid malignancies, prior to a myelosuppressive chemotherapy regimen with 17% or greater chance of inducing febrile neutropenia;

·         As secondary prophylaxis, to decrease the incidence of infection, as manifested by febrile neutropenia, in patients with non-myeloid malignancies following a myelosuppressive chemotherapy regimen less than 17% chance of inducing febrile neutropenia, who have exhibited an episode of febrile neutropenia during a prior chemotherapy cycle of the same drug regimen;

·         As primary prophylaxis, to decrease the incidence of infection, as manifested by febrile neutropenia, in patients with non-myeloid malignancies, prior to a myelosuppressive chemotherapy regimen with less than 17% chance of inducing febrile neutropenia, in patients with high risk for infection (i.e., prior myelosuppressive chemotherapy or radiotherapy resulting in bone marrow compromise, cytopenia due to tumor involvement of bone marrow, preexisting neutropenia)

Pegfilgrastim is considered experimental and investigational for any other use.

Codes Used In This BI:

J1442             Filgrastim (Neupogen) 1mcg

J1446             Tbo-filgrastim (Granix) (code deleted 1/1/16)

J1447             Tbo-filgrastim, 1mcg (Granix)

J2820             Sargramostim (Prokine, Leukine)

J2505             Pegfilgrastim, (Neulasta) 6mg (Prefilled syringe for manual inject or Onpro Kit)

J2506             Pegfilgrastim, (Neulasta) excludes biosimilar, 0.5mg

Q5101            Injection, filgrastim-sndz, biosimilar, (Zarxio), 1mcg

Q5108            Injection, pegfilgrastim-jmdb, biosimilar, (fulphila) 0.5mg

Q5110            Injection, filgrastim-aafi, biosimilar, (Nivestym), 1mcg

Q5111            Injection, pegfilgrastim-cbqv, biosimilar, (Udenyca)

Q5120            Injection, pegfilgrastim-bmez, biosimilar (Ziextenzo), 0.5mg

96372             Therapeutic/prophylactic injection (specific substance/drug); subcut or IM

96377             Application of on-body injector (includes cannula insertion) for timed subcut injection

CSFs are considered experimental and investigational for any of the following:

1. Routine use in most chemotherapy regimens as prophylaxis;
2. Neutropenic members who are afebrile;
3. Use as adjunctive therapy to antibiotics in members with uncomplicated febrile neutropenia, which is defined as follows: fever less than 11 days duration, no evidence of pneumonia cellulites, abscess, sinusitis, hypotension, multi-organ dysfunction, or invasive fungal infection; and no uncontrolled malignancies;
4. Administration prior to or concurrent with chemotherapy for AML;
5. Use in relapsed or refractory AML or ALL;
6. Chemosensitization of myeloid leukemias;
7. Treatment of aplastic anemia;
8. Use to increase the dose-intensity or schedule of cytotoxic chemotherapy beyond established dosage range for these regimens;
9. Use in members receiving concomitant chemotherapy and radiation therapy;
10. Use either before and/or concurrently with chemotherapy for “priming” effects;
11. Continued use if no response is seen within 28-42 days (members who have failed to respond within this time frame are considered non-responders).

1.    Stem Cell Growth Factors, Granulocyte Colony Stimulating Factor (Filgrastim), Arkansas Blue Cross Blue Shield Coverage Policy at: http://www.arkbluecross.com/members/ex_report.asp?ID=1997081

2.    Stem Cell Growth Factors, Granulocyte Macrophage Colony Stimulating Factor (Sargramostim), Arkansas Blue Cross Blue Shield Coverage Policy at: http://www.arkbluecross.com/members/ex_report.asp?ID=1997082

3.    Use of Hematopoietic Colony-Stimulating Factors: Evidence-Based, Practice Guidelines; American Society of Clinical Oncology at: http://www.asco.org/ac/1,1003,_12-002032-00_18-0011412-00_19-0011413-00_20-001,00.asp

4.    Hubel K, Engert A. Clinical applications of granulocyte colony-stimulating factor: An update and summary. Ann Hematol. 2003; 82(4):207-213.

5.    Dale D. Current management of chemotherapy-induced neutropenia: The role of colony-stimulating factors. Semin Oncol. 2003; 30(4 Suppl 13):3-9.

6.    Pagliuca A, Carrington PA, Pettengell R, et al. Guidelines on the use of colony-stimulating factors in haematological malignancies. Br J Haematol. 2003; 123(1):22-33.

7.    Appelbaum FR. Use of granulocyte colony-stimulating factor following hematopoietic cell transplantation: Does haste make waste? J Clin Oncol. 2004; 22(3):390-391.

8.    Ringden O, Labopin M, Gorin NC, et al. Treatment with granulocyte colony-stimulating factor after allogeneic bone marrow transplantation for acute leukemia increases the risk of graft-versus-host disease and death: A study from the Acute Leukemia Working Party of the European Group for Blood and Marrow Transplantation. J Clin Oncol. 2004; 22(3):416-423.

9.    Arora M, Burns LJ, Barker JN, et al. Randomized comparison of granulocyte colony-stimulating factor versus granulocyte-macrophage colony-stimulating factor plus intensive chemotherapy for peripheral blood stem cell mobilization and autologous transplantation in multiple myeloma. Biol Blood Marrow Transplant. 2004; 10(6):395-404.

10. Granix Package Insert. Cephalon, Inc. (Teva); February 2014.

Addendum:

Effective 07/01/2018: Added HCPCS code J2505 to the Claim Statement and Codes Used in This BI.  Administration of J2505 can use either 96372 or 96377.

Effective 01/01/2020: Updated policy to include HCPCs for Zarxio, and Nivestym (previously covered but codes not listed in policy).

Effective 05/01/2020: Updated policy to include HCPCs for fulphila and udenyca; added coverage for Ziextenzo.

Effective 07/01/2020: Updated Ziextenzo code (Q5120).

Effective 01/01/2022: Updated Neulasta code (J2506)