Granulocyte colony stimulating factors (G-CSF), filgrastim (e.g., Neupogen^®, Amgen, Thousand Oaks, CA) and pegfilgrastim (e.g., Neulasta^®, Amgen, Thousand Oaks, CA) and granulocyte-macrophage colony stimulating factor (GM-CSF), sargramostim (e.g., Leukine^®, Bayer Healthcare Pharmaceuticals, Seattle, WA) are glycoproteins which exert major control over the reproduction and maturation of certain white blood cells. These factors, also known as white blood cell growth factors, are administered to enhance recovery of hematopoietic (blood related) functions in neutropenia (low white blood count), or to decrease the incidence and severity of infection associated with drug-related myelosuppression (inhibition of bone marrow function).

Medically Necessary:

1. The granulocyte colony stimulating factors (G-CSF) filgrastim (Neupogen), pegfilgrastim (Neulasta) and granulocyte-macrophage colony stimulating factor (GM-CSF) sargramostim (Leukine)are considered medically necessary for use in individuals with cancer in any of the following indications:
   1. Primary Prophylaxis- For the prevention of febrile neutropenia (FN) in individuals
      1. when the risk of FN is 20% or greater based on chemotherapy regimen; OR
      2. when the risk of developing febrile neutropenia (FN) is less than 20% based on chemotherapy and any of the following risk factors are present:
         1. Age greater than 65 years; or
         2. Poor performance status; or
         3. Previous episodes of FN; or
         4. History of previous chemotherapy or radiation therapy; or
         5. After completion of combined chemoradiotherapy; or
         6. Bone marrow involvement by tumor producing cytopenias; or
         7. Preexisting neutropenia; or
         8. Poor nutritional status; or
         9. Poor renal function; or
         10. Liver dysfunction (i.e., elevated bilirubin); or
         11. The presence of open wounds or active infections; or
         12. Recent surgery (generally within the past 12 weeks); or
         13. Advanced cancer; or
         14. Other serious comorbidities. 
   2. Secondary Prophylaxis - For individuals who experienced a neutropenic complication from a prior cycle of chemotherapy (for which primary prophylaxis was not received), in which a reduced dose may compromise disease-free or overall survival or treatment outcome.
   3. Adjunctive Treatment
      1. Febrile Neutropenic Individuals - who are at high risk for infection-associated complications, or have any of the following prognostic factors predictive of clinical deterioration:
         1. Expected prolonged (greater than 10 days) and profound (less than 0.1 x 10⁹/L) neutropenia; or
         2. Age greater than 65 years; or
         3. Uncontrolled primary disease; or
         4. Pneumonia; or
         5. Hypotension and multi organ dysfunction (sepsis syndrome); or
         6. Invasive fungal infection; or
         7. Hospitalized at the time of the development of fever.
      2. After autologous hematopoietic stem cell transplant (HSCT)
      3. Acute Lymphocytic Leukemia (ALL) - after completion of the first few days of initial induction chemotherapy or first post-remission course of chemotherapy.
      4. Myelodysplastic Syndromes (MDS) - with severe neutropenia (absolute neutrophils count (ANC) less than or equal to 500mcL or experiencing recurrent infection.
2. The use of filgrastim (Neupogen) or sargramostim (Leukine) is considered medically necessary for individuals when any of the following are met:
   1. Use for Dose Dense Therapy- Dose-dense regimens (treatment given more frequently, such as every two weeks instead of every three weeks), specifically in the treatment of node positive breast cancer, small cell lung cancer and diffuse aggressive non-Hodgkin's lymphoma.
   2. Use as Adjunct to Peripheral Blood Progenitor Cell (PBPC) Transplantation- Administration of CSFs to mobilize progenitor cells into peripheral blood often in conjunction with chemotherapy, for collection by leukapheresis.
   3. Use in Individuals receiving Radiation Therapy - Individuals receiving radiation therapy in the absence of chemotherapy if prolonged delays secondary to neutropenia are expected.
   4. Use for Radiation Injury - CSF use for the accidental or intentional total body radiation of 3 to 10 Grays (Gy).
3. The use of filgrastim (Neupogen) is considered medically necessary for individuals when any of the following are met:
   1. Chronic administration to reduce the incidence and duration of sequelae of neutropenia (e.g., fever, infections, oropharyngeal ulcers) in symptomatic individuals with congenital neutropenia, cyclic neutropenia, or idiopathic neutropenia; or
   2. Treatment of low neutrophil counts in individuals with glycogen storage disease type 1b; or
   3. Treatment of moderate to severe aplastic anemia ; or
   4. Treatment for neutropenia associated with human immunodeficiency virus (HIV) infection and antiretroviral therapy ; or
   5. Treatment of drug-induced neutropenia ; or
   6. Treatment of severe neutropenia in individuals with hairy cell leukemia; or
   7. Use as an alternate or adjunct to donor leukocyte infusions in individuals with leukemic relapse after an allogeneic stem cell transplant; or
   8. Use in adult individuals with acute myeloid leukemia (AML,) shortly after the completion of induction or repeat induction chemotherapy or after the completion of consolidation chemotherapy for AML.

IV.  The use of sargramostim (Leukine) is considered medically necessary for individuals when any of the following are met:

1. Use in myeloid reconstitution after allogeneic bone marrow transplantation from HLA-matched related donors (MRD);
2. Use in individuals who have undergone allogeneic or autologous bone marrow transplantation in whom engraftment is delayed or has failed;
3. For administration shortly after the completion of induction or repeat induction chemotherapy of acute myeloid leukemia (AML) for individuals over 55 years of age.

Not Medically Necessary:

The use of CSFs (filgrastim, pegfilgrastim and sargramostim) is considered not medically necessary for any of the following:

1. As prophylaxis for FN, except when criteria above are met; or
2. As treatment of neutropenia in individuals who are afebrile, except when criteria above are met; or
3. As adjunctive therapy in individuals with uncomplicated febrile neutropenia, defined as: 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
4. Chemo sensitization of myeloid leukemias; or
5. As prophylaxis for FN during concomitant chemotherapy and radiation therapy or
6. 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);        
7. For uses not meeting the criteria above.

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.

Filgrastim, pegfilgrastim and sargramostim are approved by the U.S. Food and Drug Administration (FDA) for the indications listed above. The American Society of Clinical Oncology (ASCO) 2006 Update of Recommendations for the Use of White Blood Cell Growth Factors: An Evidence-Based Clinical Practice Guideline (Smith, 2006) was adapted for the oncologic indications in this document. Additional non-FDA approved indications are based on expert consensus guidelines, drug compendia and published peer reviewed literature as detailed in CG-DRUG-01 Off-Label Drug and Approved Orphan Drug Use.

According to ASCO, no guideline recommendation can be made regarding the equivalency of the two colony-stimulating agents, G-CSF (filgrastim) and GM-CSF (sargramostim). There is currently no data available to support preferential use of filgrastim or pegfilgrastim in the treatment of febrile neutropenia. Similarly, there is no currently available data to support preferential use of filgrastim or sargramostim in the treatment of AML, mobilization of progenitor cells, or following autologous or allogeneic bone marrow transplant (Smith, 2006). Further trials are recommended to study the comparative clinical activity, toxicity, and cost effectiveness of G-CSF and GM-CSF.

The currently available agents differ in their pharmacokinetic properties. Both sargramostim and filgrastim can be administered intravenously (IV) or subcutaneously (SC), whereas pegfilgrastim is administered only SC. Pegfilgrastim is a pegylated form of filgrastim developed to allow for less frequent dosing. Although the two agents have the same mechanism of action, pegfilgrastim has reduced renal clearance and prolonged persistence in vivo compared to filgrastim (Product Information Labels, 2006; 2008).

Pegfilgrastim (Neulasta) is not labeled for use in myeloid malignancies as it has not been studied for this indication. According to the product insert, the possibility pegfilgrastim acts as a growth factor for any tumor type, including myeloid malignancies and myelodysplasia cannot be excluded(2010).

Per ASCO (Smith, 2006), the individuals are at high risk for febrile neutropenia based on:

• Age
• Medical history
• Disease characteristics
• Myelotoxicity of the chemotherapy regimen

Standard practice in protecting against chemotherapy-associated infection has been chemotherapy dose modification or dose delay, administration of progenitor-cell support, or selective use of prophylactic antibiotics. Chemotherapy associated neutropenic fever or infection has customarily involved treatment with intravenous antibiotics, usually accompanied by hospitalization. The hematopoietic colony-stimulating factors (CSFs) have been introduced into clinical practice as additional supportive measures to reduce the likelihood of neutropenic complications due to chemotherapy.

Neutropenia, a decreased number of neutrophils (white blood cells which fight infection) in the blood is commonly caused by chemotherapy, and often results in hospitalization. Neutropenia occurs when myelosuppressive chemotherapeutic treatments reduce the neutrophil counts. The risk of infection increases as the absolute neutrophil count (ANC) drops below 1,000/microL (Crawford, 2004; Dale, 2002). Febrile neutropenia can occur as a result of severe neutropenia. Febrile neutropenia is defined as the occurrence of fever (greater than 38.2^oC for more than 1 hour) in association with an ANC less than 0.5 x 10⁹/L, but some studies have used an ANC less than 1.0 x 10⁹/L as the threshold (Dale, 2002). The severity of neutropenia is related to the intensity of the chemotherapy regimen, individual-risk factors (per Smith, including age), and disease-related factors (Ozer, 2000; Smith, 2006). Colony stimulating factors (CSFs) are used to prevent severe neutropenia, reduce the duration of neutropenia, prevent febrile neutropenia, and infection-related complications in individuals with cancer. The routine use of CSFs in neutropenic patients who are afebrile is not recommended (Smith, 2006). The National Comprehensive Cancer Network^® (NCCN^®) Clinical Practice Guidelines in Oncology™ on Myeloid Growth Factors (2011) recommends the use of white blood cell growth factors as prophylaxis for individuals considered at high-risk for febrile neutropenia, regardless if the treatment is intended to be curative, to prolong survival or to manage symptoms. In all risk categories, low-, intermediate- and high-risk for chemotherapy-induced neutropenia or other neutropenic-related events that may compromise or delay treatment, NCCN recommends careful discussion to determine the risks and benefits of CSF use. For low-risk individuals (less than 10%) risk, NCCN recommends "routine use of CSF should be considered if the individual is receiving curative or adjuvant therapy and is at significant risk for serious medical consequences of febrile neutropenia, including death."

Neutropenia also commonly occurs in individuals with human immunodeficiency virus (HIV) with 10% to 20% of individuals with early disease experiencing cytopenias and 35% to 75% of individuals with advanced HIV (Kuritzkes, 2000). Neutropenia, defined as an absolute neutrophil count [ANC] <1000 x 10⁹/L may be resulting from multiple factors in individuals with HIV. Additionally, neutropenia may be compounded by frontline treatment that may have myelosuppressive effects. Granulocyte colony stimulating factors have been used in individuals with HIV to stimulate granulopoiesis and increase circulating lymphocyte counts (Kuritzkes, 2000).

The American Hospital Formulary Service^® (AHFS^®, 2011) notes filgrastim has been used effectively to treat neutropenia in a small number of individuals receiving myelosuppressive drugs for nonmalignant conditions. Additionally, the AHFS notes filgrastim has been used to increase neutrophil counts for severe neutropenia in individuals with hairy cell leukemia.

There is moderate evidence from 3 separate systematic reviews supporting that CSFs should not be used routinely for the prevention or treatment of non-chemotherapy induced infection, specifically, neonatal infection, and diabetic foot infections or as an adjunct to antibiotics in treating non-neutropenic adults with pneumonia (Cheng, 2004).

ASCO recommendations for the management of individuals exposed to lethal doses of total body radiotherapy or accidental total body radiation include the administration of CSFs or pegylated G-CSF. The recommendation is based on observation of cases in the Radiation Emergency Assistance Center Training Site in the Radiation Accident Registry Center (REAC/TS registry). Twenty-five of 28 individuals experienced enhanced neutrophil recovery with the use of hematopoietic growth factors after accidental radiation exposures (Smith, 2006).

The use of CSFs in conjunction with concomitant use of radiation and chemotherapy is not recommended by ASCO. Smith and colleagues (2006) stated, "in the absence of chemotherapy, therapeutic use of CSFs may be considered in individuals receiving radiation therapy alone if prolonged delays secondary to neutropenia are expected."

Multiple phase I and phase II clinical trials are studying the safety and efficacy of sargramostim to treat malignant melanoma. However, the trials have been primarily smaller series that included a variety of additional immunomodulatory agents and outcomes were mixed. Investigators have noted the outcomes from larger randomized phase 3 trials with longer followup are needed.

The product label warns of the risk of cytogenetic abnormalities. Transformation to MDS and AML has been observed in individuals with congenital neutropenia on chronic treatment with filgrastim. The safety and efficacy of filgrastim use in neonates and individuals with autoimmune neutropenia of infancy have not been established (Product Information Label, 2006).

The product labels for both pegfilgrastim and filgrastim (2010; 2006) warn splenic ruptures, including fatal cases, have been reported following the administration of pegfilgrastim and its parent compound, filgrastim. Adult respiratory distress syndrome (ARDS) has also been reported in neutropenic individuals with sepsis, who also received filgrastim and pegfilgrastim. Safety and efficacy of pegfilgrastim for peripheral blood progenitor cell (PBPC) mobilization has not been evaluated in adequate and well-controlled studies. Pegfilgrastim should not be used for PBPC mobilization. The use of pegfilgrastim has not been studied in individuals receiving radiation therapy (Product Information Label, 2010).

Safety and effectiveness of sargramostim use in pediatric individuals have not been established; however, available safety data indicate that sargramostim does not exhibit any greater toxicity in pediatric cases than in adults (Product Information Label, 2008).

Adjuvant therapy: Treatment given after the primary treatment to increase the chances of a cure and may include chemotherapy, radiation, hormone, or biological therapy.

Advanced cancer: Cancer in which the disease has spread from where it started (the primary site) to other parts of the body.

Chemotherapy: Medical treatment of a disease, particularly cancer, with drugs or other chemicals.

ECOG Performance Status: A scale used to determine the individual's level of functioning.

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, e.g., light house work, office work
2= Ambulatory and capable of all selfcare but unable to carry out any work activities. Up and about more than 50% of waking hours
3= Capable of only limited selfcare, confined to bed or chair more than 50% of waking hours
4= Completely disabled. Cannot carry on any selfcare. Totally confined to bed or chair
5= Dead

Karnofsky Score: A measure of the individual's overall physical health, judged by their level of activity. The score is based on the following scale:

100%    Normal, no complaints, no signs of disease
90%      Capable of normal activity, few symptoms or signs of disease
80%      Normal activity with some difficulty, some symptoms or signs
70%      Caring for self, not capable of normal activity or work
60%      Requiring some help; can take care of most personal requirements
50%      Requires help often, requires frequent medical care
40%      Disabled, requires special care and help
30%      Severely disabled, hospital admission indicated but no risk of death
20%      Very ill, urgently requiring admission, requires supportive measures or treatment
10%      Moribund, rapidly progressive fatal disease processes
  0%        Death

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.

Peer Reviewed Publications:

1. Bohlius J, Reiser M, Schwarzer G, Engert A. Granulopoiesis-stimulating factors to prevent adverse effects in the treatment of malignant lymphoma. Cochrane Database Syst Rev. 2004; (3):CD003189.
2. Carr R, Modi N, Dore C. G-CSF and GM-CSF for treating or preventing neonatal infections. Cochrane Database Sys Rev. 2003; (3):CD003066.
3. Cheng AC, Stephens DP, Currie BJ. Granulocyte-colony stimulating factor (G-CSF) as an adjunct to antibiotics in the treatment of pneumonia in adults. Cochrane Database Syst Rev. 2007; (2):CD004400.
4. Clark OA, Lyman G, Castro AA, et al. Colony stimulating factors for chemotherapy induced febrile neutropenia. Cochrane Database Sys Rev. 2003; (3):CD003039.
5. Crawford J, Dale DC, Lyman GH. Chemotherapy-induced neutropenia: risks, consequences, and new directions for its management. Cancer. 2004; 100(2):228-237.
6. Dale DC. Colony-stimulating factors for the management of neutropenia in cancer patients. Drugs. 2002; 62 (Suppl 1):1-15.
7. Kirkwood JM, Lee S, Moschos SJ, et al. Immunogenicity and antitumor effects of vaccination with peptide vaccine +/- granulocyte-monocyte colony-stimulating factor and/or IFN-{alpha}2b in advanced metastatic melanoma: Eastern Cooperative Oncology Group Phase II Trial E1696. Clin Cancer Res. 2009; 15(4):1443 - 1451.
8. Kuritzkes DR. Neutropenia, neutrophil dysfunction, and bacterial infection in patients with human immunodeficiency virus disease: the role of granulocyte colony-stimulating factor. Clin Infect Dis. 2000; 52(3):298-303.
9. Mohan P, Brocklehurst P. Granulocyte transfusions for neonates with confirmed or suspected sepsis and neutropaenia. Cochrane Database Syst Rev. 2003; (4):CD003956.
10. Ozer H, Armitage JO, Bennett CL, et al. American Society of Clinical Oncology Growth Factors Expert Panel. 2000 update of recommendations for the use of hematopoietic colony-stimulating factors: evidence-based, clinical practice guidelines. J Clin Oncol. 2000; 18(20):3558-3585.
11. Sasse EC, Sasse AD, Brandalise SR, et al. Colony stimulating factors for prevention of myelosuppressive therapy induced febrile neutropenia in children with acute lymphoblastic leukaemia. Cochrane Database Syst Rev. 2005; (3):CD004139.
12. Slingluff CL Jr, Petroni GR, Olson WC, et al. Effect of granulocyte/macrophage colony-stimulating factor on circulating CD8+ and CD4+ T-cell responses to a multipeptide melanoma vaccine: outcome of a multicenter randomized trial. Clin Cancer Res. 2009; 15(22):7036-7044.
13. Smith TJ, Khatcheressian J , Lyman G, 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(19):1-19. Available at: http://www.jco.org/cgi/reprint/JCO.2006.06.4451v2.pdf. Accessed on February 7, 2011.
14. Spitler LE, Weber RW, Allen RE, et al. Recombinant human granulocyte-macrophage colony-stimulating factor (GM-CSF, sargramostim) administered for 3 years as adjuvant therapy of stages II (T4), III, and IV melanoma. J Immunother. 2009; 32(6):632-637.

Government Agency, Medical Society, and Other Authoritative Publications:

1. American Hospital Formulary Service^® (AHFS). AHFS Drug Information 2011^®. Bethesda, MD: American Society of Health-System Pharmacists^®, 2011.
2. Filgrastim (systemic). In: DrugPoints^® System [Internet database]. Greenwood Village, CO: Thomson Healthcare. Updated May 10, 2010. Available at: http://www.thomsonhc.com. Accessed on February 7, 2011.
3. Leukine [Product Information]. Seattle, WA. Bayer HealthCare Pharmaceuticals; April 4, 2008. Available at: http://berlex.bayerhealthcare.com/html/products/pi/Leukine_PI.pdf. Accessed on February 7, 2011.
4. National Comprehensive Cancer Network (NCCN). Clinical Practice Guidelines in Oncology™: Myeloid Growth Factors in cancer treatment. V.2.2011. Revised March 4, 2011. For additional information: http://www.nccn.org/index.asp. Accessed on February 7, 2011.
5. Neulasta^® [Product Information]. Thousand Oaks, CA. Amgen; February 17, 2010. Available at: http://pi.amgen.com/united_states/neulasta/neulasta_pi_hcp_english.pdf. Accessed on February 7, 2011.
6. Neupogen^® [Product Information]. Thousand Oaks, CA. Amgen; October 25, 2006. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2006/103353s5086LBL.pdf. Accessed on February 7, 2011.
7. Pegfilgrastim (systemic). In: DrugPoints System [Internet database]. Greenwood Village, CO: Thomson Healthcare. Updated August 18, 2010. Available at: http://www.thomsonhc.com. Accessed on February 7, 2011.
8. Sargramostim (systemic). IN: DrugPoints System [Internet database]. Greenwood Village, CO: Thomson Healthcare. Updated March 18, 2010. Available at: http://www.thomsonhc.com. Accessed on February 7, 2011.

1. American Cancer Society. http://www.orgsites.com/ga/acs/. Accessed on February 7, 2011. 

Colony Stimulating Factors (CSF)
Hematopietic Stimulating Growth Factors
Leukine
Neulasta
Neupogen

The use of specific product names is illustrative only. It is not intended to be a recommendation of one product over another, and is not intended to represent a complete listing of all products available.