Clinical UM Guideline


Subject:White Blood Cell Growth Factors
Guideline #:  CG-DRUG-16Current Effective Date:  05/11/2015
Status:RevisedLast Review Date:  05/07/2015

Description

White blood cell growth factors, also known as colony stimulating factors (CSF), are administered to enhance recovery of blood related functions in neutropenia (low white blood count) including febrile neutropenia (FN).  CSFs are also utilized to decrease the incidence and severity of infection associated with select disease-related and drug-related myelosuppression (inhibition of bone marrow function).

Granulocyte colony stimulating factors (G-CSF) are glycoproteins which exert major control over the reproduction and maturation of certain white blood cells, which include the following U.S. Food & Drug Administration (FDA) approved products:

Granulocyte-macrophage colony stimulating factor (GM-CSF) is a hematopoietic growth factor which stimulates proliferation and differentiation of hematopoietic progenitor cells.

Note:    For additional information please see the following document:

Clinical Indications

Medically Necessary:

Note:  See Definition section for definition of febrile neutropenia. 

  1. Filgrastim (Neupogen) or Filgrastim-sndz (Zarxio) is considered medically necessary when used for any of the following:
    1. Primary prophylaxis of febrile neutropenia (FN) in individuals with a risk of FN of 20% or greater based on chemotherapy regimen.
    2. Primary prophylaxis of developing FN is greater than or equal to 10% and less than 20% based on chemotherapy regimen and individuals have one or more of the following risk factors for FN:
      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. 
    3. Secondary prophylaxis of FN in 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.
    4. Adjunctive treatment of individuals with FN and high risk for infection-associated complications as demonstrated by any of the following:
      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.
    5. In an individual with acute lymphocytic leukemia (ALL) after completion of the first few days of initial induction chemotherapy or first post-remission course of chemotherapy; or
    6. 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;
      or
    7. Treatment of moderate to severe aplastic anemia; or
    8. Treatment of severe neutropenia in individuals with hairy cell leukemia; or
    9. In an individual with myelodysplastic syndromes (MDS) with severe neutropenia (absolute neutrophil count (ANC) less than or equal to 500 mm3 or experiencing recurrent infection; or
    10. In an individual receiving dose dense therapy (treatment given more frequently, such as every two weeks instead of every three weeks) for adjuvant treatment of breast cancer; or
    11. 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
    12. Treatment of (non-chemotherapy) drug-induced neutropenia; or
    13. Treatment of low neutrophil counts in individuals with glycogen storage disease type 1b; or
    14. Treatment for neutropenia associated with human immunodeficiency virus (HIV) infection and antiretroviral therapy; or
    15. In individuals receiving radiation therapy in the absence of chemotherapy if prolonged delays secondary to neutropenia are expected; or
    16. After accidental or intentional total body radiation of myelosuppressive doses (greater than 2 Grays [Gy]) (such as Hematopoietic Syndrome of Acute Radiation Syndrome); or
    17. After a hematopoietic progenitor stem cell transplant (HPCT/HSCT) for the following indications:
      • To promote myeloid reconstitution; or
      • When engraftment is delayed or has failed; or
    18. To mobilize progenitor cells into peripheral blood for collection by leukapheresis, as an adjunct to peripheral blood/hematopoietic stem cell transplantation (PBSCT/PHSCT); or
    19. Use as an alternate or adjunct to donor leukocyte infusions (DLI) in individuals with leukemic relapse after an allogeneic hematopoietic stem cell transplant.
  2. Pegfilgrastim (Neulasta) is considered medically necessary when used for any of the following:
    1. Primary prophylaxis of FN in individuals with a risk of FN of 20% or greater based on chemotherapy regimen.
    2. Primary prophylaxis of developing FN is greater than or equal to 10% and less than 20% based on chemotherapy regimen and individuals have one or more of the following risk factors for FN:
      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. 
    3. Secondary prophylaxis of FN in 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.
    4. Adjunctive treatment of individuals with FN and high risk for infection-associated complications as demonstrated by any of the following:
      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.
    5. In an individual with acute lymphocytic leukemia (ALL) after completion of the first few days of initial induction chemotherapy or first post-remission course of chemotherapy; or
    6. In an individual with myelodysplastic syndromes (MDS) with severe neutropenia (absolute neutrophil count (ANC) less than or equal to 500 mm3 or experiencing recurrent infection; or
    7. In an individual receiving dose dense therapy (treatment given more frequently, such as every two weeks instead of every three weeks) for adjuvant treatment of breast cancer; or
    8. After a hematopoietic progenitor stem cell transplant (HPCT/HSCT) for the following indications:
      • To promote myeloid reconstitution; or
      • When engraftment is delayed or has failed.
  3. Sargramostim (GM-CSF, Leukine) is considered medically necessary for individuals when any of the following are met:
    1. Primary prophylaxis of FN in individuals with a risk of FN of 20% or greater based on chemotherapy regimen.
    2. Primary prophylaxis of developing FN is greater than or equal to 10% and less than 20% based on chemotherapy regimen and individuals have one or more of the following risk factors for FN:
      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. 
    3. Secondary prophylaxis of FN in 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.
    4. Adjunctive treatment of individuals with FN and high risk for infection-associated complications as demonstrated by any of the following:
      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.
    5. In an individual receiving dose dense therapy (treatment given more frequently, such as every two weeks instead of every three weeks) for adjuvant treatment of breast cancer; or
    6. In an individual with acute lymphocytic leukemia (ALL) after completion of the first few days of initial induction chemotherapy or first post-remission course of chemotherapy; or
    7. For administration shortly after the completion of induction or repeat induction chemotherapy of acute myeloid leukemia (AML) for individuals over 55 years of age; or
    8. In an individual with myelodysplastic syndromes (MDS) with severe neutropenia (absolute neutrophil count (ANC) less than or equal to 500 mm3 or experiencing recurrent infection; or
    9. In individuals receiving radiation therapy in the absence of chemotherapy if prolonged delays secondary to neutropenia are expected; or
    10. After accidental or intentional total body radiation of myelosuppressive doses (greater than 2 Grays [Gy]) (such as Hematopoietic Syndrome of Acute Radiation Syndrome); or
    11. After a hematopoietic progenitor stem cell transplant (HPCT/HSCT) for the following indications:
      • To promote myeloid reconstitution; or
      • When engraftment is delayed or has failed; or
    12. To mobilize progenitor cells into peripheral blood for collection by leukapheresis, as an adjunct to peripheral blood/hematopoietic stem cell transplantation (PBSCT/PHSCT); or
  4. Tbo-Filgrastim (Granix) is considered medically necessary when used for any of the following:
    1. Primary prophylaxis of FN in individuals with a risk of FN of 20% or greater based on chemotherapy regimen.
    2. Primary prophylaxis of developing FN is greater than or equal to 10% and less than 20% based on chemotherapy regimen and individuals have one or more of the following risk factors for FN:
      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. 
    3. Secondary prophylaxis of FN in 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.
    4. Adjunctive treatment of individuals with FN and high risk for infection-associated complications as demonstrated by any of the following:
      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.

Not Medically Necessary:

The use of CSFs (filgrastim, filgrastim-sndz, pegfilgrastim, sargramostim and tbo-filgrastim) 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); or        
  7. For uses not meeting the criteria above.
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.

HCPCS 
J1442Injection, filgrastim (G-CSF), 1 microgram [Neupogen]
J1446Injection, tbo-filgrastim, 5 micrograms [Granix]
J2505Injection, pegfilgrastim, 6 mg [Neulasta]
J2820Injection, sargramostim (GM-CSF), 50 mcg [Leukine, Prokine]
J3490Unclassified drugs [when specified as filgrastim-sndz (Zarxio)]
Q5101Injection, Filgrastim (G-CSF), Biosimilar, 1 microgram [filgrastim-sndz (Zarxio)] (Note: code will be effective 07/01/2015)
S9537Home therapy; hematopoietic hormone injection therapy (e.g. erythropoietin, G-CSF, GM-CSF); per diem [when specified as G-CSF, GM-CSF]
  
ICD-9 Diagnosis[For dates of service prior to 10/01/2015]
 All diagnoses
  
ICD-10 Diagnosis[For dates of service on or after 10/01/2015]
 All diagnoses
  
Discussion/General Information

Filgrastim, Pegfilgrastim, Sargramostim:

Filgrastim, pegfilgrastim and sargramostim are recombinant colony-stimulating factors (CSFs) approved by the U.S. Food and Drug Administration (FDA) for stimulation, proliferation, differentiation of neutrophils, and end cell functional activation of hematopoietic cells.

The American Society of Clinical Oncology (ASCO) (Smith, 2006) Update of Recommendations for the Use of White Blood Cell Growth Factors: An Evidence-Based Clinical Practice Guideline was adapted for the oncologic indications in this document.  Additional non-FDA approved indications are based on expert consensus guidelines (National Comprehensive Cancer Network® [NCCN®] Clinical Practice Guidelines in Oncology and European Organisation for Research and Treatment of Cancer [EORTC; Aapro, 2011]), drug compendia and published peer reviewed literature as detailed in CG-DRUG-01 Off-Label Drug and Approved Orphan Drug Use.

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 38.3oC 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; NCCN, 2014).  The severity of neutropenia is related to the intensity and type of the chemotherapy regimen, individual-risk factors, and disease-related factors (NCCN, 2014; 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 individuals who are afebrile is not recommended (Smith, 2006).

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, 2013, 2014, 2015).

Pegfilgrastim (Neulasta) is not labeled for use in myeloid malignancies as it has not been studied for this indication.  According to the product information label (2014), the possibility pegfilgrastim acts as a growth factor for any tumor type, including myeloid malignancies and myelodysplasia, cannot be excluded.

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 CSFs have been introduced into clinical practice as additional supportive measures to reduce the likelihood of neutropenic complications due to chemotherapy in individuals who are at high risk.

The NCCN Clinical Practice Guidelines in Oncology for Myeloid Growth Factors (2014), ASCO (Smith, 2006) and EORTC (Aapro, 2011) recommend the assessment of risk for chemotherapy induced FN prior to initiating the first cycle of chemotherapy.  Factors in the evaluation include disease type, individual risk factors, the intent of treatment and the type of chemotherapeutic regimen.  The risk stratification includes high risk (greater than 20% risk of FN), intermediate risk (10-20% risk) and the low risk (less than 10% risk) groups.  NCCN recommends routine CSFs for primary prophylaxis of FN for individuals in the high risk group.  For individuals in the intermediate risk (10-20%), NCCN notes CSFs may be considered for primary prophylaxis when additional risk factors are present that would increase the individual's risk of FN (e.g., age greater than 65).  Routine use of CSF is not recommended as primary prophylaxis of FN when an individual is considered a low risk.  However, NCCN notes for low-risk individuals, "CSF may be considered if the individual is receiving curative or adjuvant therapy and is at significant risk for serious medical consequences of FN, including death."  Schnipper (2012) and colleagues reaffirmed the ASCO guidelines recommend "using white cell stimulating factors when the risk of febrile neutropenia, secondary to a recommended chemotherapy regimen is approximately 20% and equally effective treatment programs that do not require white cell stimulating factors are unavailable."  Independent clinical judgment based on the individual's clinical situation facilitates identifying the appropriate risk group.  After the initial treatment cycle and prior to each subsequent cycle, a risk categorization should be evaluated.  If FN or a dose-limiting neutropenic event occurred with the previous cycle of treatment with the same dose and schedule planned for the current cycle, the individual is now in the high risk group.  The use of white blood cell growth factors as prophylaxis is recommended 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, careful discussion to determine the risks and benefits of CSF use is recommended (NCCN, 2014).  

The EORTC guidelines (Aapro, 2011) note for dose dense (increased frequency) or dose-intense (increased dose) chemotherapy "multiple studies have confirmed that, because the time to neutrophil recovery is around 12 days, pegfilgrastim can be conveniently administered together with chemotherapy in patients receiving treatment at 14 days intervals."  The NCCN Clinical Guidelines for Myeloid Growth Factors (2014) note dose-dense regimens with CSF support "improved disease-free and/or overall survival compared to conventional chemotherapy."  In addition, specialty consensus opinion suggests white blood cell growth factors are used with dose dense chemotherapy regimens in the adjuvant setting to treat individuals with breast cancer.

Neutropenia also commonly occurs in individuals with human immunodeficiency virus (HIV) with 10% to 20% of individuals with early disease experiencing cytopenias and in 35% to 75% of individuals with advanced HIV (Kuritzkes, 2000).  Neutropenia, defined as an absolute neutrophil count (ANC) less than 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®, 2014) 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.

Radiation

In 2015, filgrastim received Supplemental Biologics License Application (sBLA) approval for use to increase survival in individuals acutely exposed to myelosuppressive doses of radiation (that is greater than 2 Gy).  The condition is also known as Hematopoietic Syndrome of Acute Radiation Syndrome.  The label includes a warning to avoid use of filgrastim with concurrent radiation therapy.  Available human data is based on information reported in anecdotal reports of accidental irradiation and the subsequent use of growth factors.  The specific dosing and timing of G-CSF infusions after exposure continue to be investigated in animal models.  Data from a randomized controlled non-human primate study were extrapolated to humans as this type of study in humans is not feasible.  Farese and colleagues (2013) reported a significant increase in survival by 38.3% over the 60 day in-life study for subjects treated with G-CSF compared to controls.

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, 2006) and the NCCN clinical practice guideline for myeloid growth factors in cancer treatment (2015).  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."

Filgrastim-sndz:
The FDA approved Zarxio (filgrastim-sndz) on March 6, 2015, as the first U.S. approved biosimilar product approved under the Biologics Price Competition and Innovation Act of 2009 (BCPI Act).  An abbreviated licensure pathway was created for "biological products shown to be "biosimilar" to or "interchangeable" with an FDA-licensed biological product, called the "reference product" (FDA, 2015).  Additional FDA (2015) information on biosimilar products include:

A biosimilar product is a biological product that is approved based on a showing that it is highly similar to an FDA-approved biological product, known as a reference product, and has no clinically meaningful differences in terms of safety and effectiveness from the reference product. Only minor differences in clinically inactive components are allowable in biosimilar products.

An interchangeable biological product is biosimilar to an FDA-approved reference product and meets additional standards for interchangeability.  An interchangeable biological product may be substituted for the reference product by a pharmacist without the intervention of the health care provider who prescribed the reference product.

Comparison studies were conducted between filgrastim-sndz and the filgrastim products approved in the U.S. and Europe. In addition, filgrastim-sndz was compared to the similar product licensed in Europe since 2009.  Results from the pharmacokinetic study demonstrated that filgrastim-sndz had bioequivalence with the reference product and ANC and CD34+ responses were equivalent.

Cioch and colleagues compared responses of filgrastim-sndz in 23 consecutive individuals who received an autologous hematopoietic stem cell transplant (AHSCT) at a single center.  Outcomes were compared to 23 controls that were transplanted and treated with filgrastim (Neupogen) prior to the biosimilar cohort.  There were no significant differences in the granulocyte recovery between the groups.  The mean number of days to ANC > 0.5 X 109/L in the biosimilar group was 13.0 ±4.0 days compared to the control group of 15.0 ± 5.6 days; p=0.11. The adverse events were similar in both groups.  However, there was 1 episode of neutropenic enterocolitis and sepsis in the biosimilar group. 

In a study involving 108 consecutive individuals treated with AHSCT, participants were randomized to a biosimilar or to the reference G-CSF (Neupogen) for stem cell mobilization.  A median of 1 apheresis was performed for both groups, and there was no significant difference in the amount of mobilized CD34+ cells into the peripheral blood or for the total number of CD34+ cells per kilogram of body weight.  All adverse events were comparable and mild-moderate in severity.  The authors concluded the efficacy and safety of biosimilar G-CSF was similar to the reference G-CSF (Neupogen) (Manko, 2014).

TBO-filgrastim:

In August 2012, the FDA approved tbo-filgrastim to reduce the severe neutropenia in individuals with non-myeloid malignancies receiving myelosuppressive anti-cancer drugs associated with a clinically significant incidence of febrile neutropenia.  Tbo-filgrastim is a recombinant methionyl human granulocyte colony-stimulating growth factor (r-metHuG-CSF) that binds to GCSF receptors and stimulates the growth of neutrophils.  Tbo-filgrastim is a biosimilar product to filgrastim (Neupogen) and is administered subcutaneously (del Giglio, 2008; Product Information Label, 2014).

A randomized, controlled, multinational phase III study involved 348 individuals with high-risk stage II, stage III or stage IV breast cancer who had not previously received treatment with chemotherapy.  Participants were randomized to tbo-filgrastim or placebo.  Treatment began one day after chemotherapy for at least five days and continued to achieve an ANC of greater than or equal to 10,000 x 106/L after nadir was reached, or until a maximum of 14 days of treatment.  The primary endpoint was duration of severe neutropenia (DSN) in cycle 1.  Tbo-filgrastim had a superior DSN compared to placebo with a significant reduction in DSN (1.1 days compared to 3.8 days, p<0.0001).  The mean DSN in cycle 1 was 1.1 days (range 0-5 days) for both tbo-filgrastim and filgrastim (Neupogen).  The median time to ANC recovery in cycle 1 was 8.0 days for both tbo-filgrastim and filgrastim (Neupogen) compared to 15 days in the placebo group.  The safety and effectiveness of tbo-filgrastim have not been established in individuals under 18 years of age.  The FDA has required post-approval studies of tbo-filgrastim to determine the safety and efficacy in the pediatric population (del Giglio, 2008; Product Information Label, 2014).

Warnings and Precautions:
Product information labels for filgrastim (Neupogen, 2015), filgrastim-sndz (Zarxio, 2015) and pegfilgrastim (Neulasta, 2014) include the following warnings and precautions:

Allergic Reactions
Serious allergic reactions, including anaphylaxis, have been reported.  The majority of reported events occurred upon initial exposure.  Allergic reactions, including anaphylaxis, in individuals receiving filgrastim can recur within days after the discontinuation of initial anti-allergic treatment.

Splenic Rupture
Splenic rupture, including fatal cases, has been reported following the administration of filgrastim products. Evaluate for an enlarged spleen or splenic rupture in individuals who report left upper abdominal or shoulder pain for an enlarged spleen or splenic rupture.

Acute Respiratory Distress Syndrome
Adult respiratory distress syndrome (ARDS) has been reported in individuals receiving filgrastim or pegfilgrastim. Evaluate individuals who develop fever and lung infiltrates or respiratory distress for ARDS.

Sickle Cell Disorders
Severe sickle cell crises can occur in individuals with sickle cell disorders receiving filgrastim or pegfilgrastim.

Pegfilgrastim includes an additional warning:
The On-body Injector for Neulasta uses acrylic adhesive. For individuals who have reactions to acrylic adhesives, use of this product may result in a significant reaction.

General information for filgrastim (Neupogen, 2015), filgrastim-sndz (Zarxio, 2015) and pegfilgrastim (Neulasta, 2014) include the following:

The safety and efficacy of growth factors given simultaneously with cytotoxic chemotherapy have not been established. Because of the potential sensitivity of rapidly dividing myeloid cells to cytotoxic chemotherapy:

The safety and efficacy of filgrastim have not been evaluated in individuals receiving concurrent radiation therapy. Simultaneous use of filgrastim with chemotherapy and radiation therapy should be avoided.

Additional information from product labels for filgrastim (Neupogen, 2015) and filgrastim-sndz (Zarxio, 2015) includes:

Pediatric Use
In a phase 3 study to assess the safety and efficacy of Neupogen in the treatment of severe chronic neutropenia (SCN), 120 individuals with a median age of 12 years were studied.  Of the 120 participants, 12 were infants (1 month to 2 years of age), 47 were children (2 to 12 years of age), and 9 were adolescents (12 to 16 years of age).  Additional information is available from a SCN postmarketing surveillance study, which includes long-term follow-up of individuals in the clinical studies and information from additional participants who entered directly into the postmarketing surveillance study.  Of the 531 participants in the surveillance study as of 31 December 1997, 32 were infants, 200 were children, and 68 were adolescents.

Children with congenital types of neutropenia (Kostmann's syndrome, congenital agranulocytosis, or Schwachman-Diamond syndrome) have developed cytogenetic abnormalities and have undergone transformation to myelodysplastic syndrome (MDS) and acute myelogenous leukemia (AML) while receiving chronic filgrastim treatment.  The relationship of these events to filgrastim administration is unknown.  Limited data from children who were followed in the phase 3 study for 1.5 years did not suggest alterations in sexual maturation or endocrine function.

Additional product information for pegfilgrastim (Neulasta, 2014) includes:

Pediatric Use
Safety and effectiveness of Neulasta in pediatric patients have not been established.  The adverse reaction profile and pharmacokinetics of pegfilgrastim were studied in 37 pediatric patients with sarcoma.  The mean (± standard deviation [SD]) systemic exposure (AUC0-inf ) of pegfilgrastim after subcutaneous administration at 100 mcg/kg was 22.0 (± 13.1) mcg•hr/mL in the 6 to11 years age group (n = 10), 29.3 (± 23.2) mcg•hr/mL in the 12 to21 years age group (n = 13), and 47.9 (± 22.5) mcg•hr/mL in the youngest age group (0 to5 years, n = 11).  The terminal elimination half-lives of the corresponding age groups were 20.2 (± 11.3) hours, 21.2 (± 16.0) hours, and 30.1 (± 38.2) hours, respectively.  The most common adverse reaction was bone pain.

The product information label for sargramostim (Leukine, 2013) includes the following warnings and precautions:

Pediatric Use
Benzyl alcohol is a constituent of liquid sargramostim and bacteriostatic water for injection diluents.  Benzyl alcohol has been reported to be associated with a fatal "Gasping Syndrome" in premature infants.  Liquid solutions containing benzyl alcohol (including liquid leukine) or lyophilized leukine reconstituted with bacteriostatic water for injection, USP (0.9% benzyl alcohol) should not be administered to neonates.

Fluid Retention
Edema, capillary leak syndrome, pleural and/or pericardial effusion have been reported in individuals after sargramostim administration.  Use with caution in individuals with preexisting fluid retention, pulmonary infiltrates or congestive heart failure.

Respiratory Symptoms
Sequestration of granulocytes in the pulmonary circulation has been documented following sargramostim infusion and dyspnea has been reported occasionally in individuals treated with sargramostim.  Use with caution in individuals with hypoxia or preexisting lung disease.

Cardiovascular Symptoms
Occasional transient supraventricular arrhythmia has been reported in uncontrolled studies during sargramostim administration, particularly with individuals with a previous history of cardiac arrhythmia.  Arrhythmias have been reversible after discontinuation of sargramostim.  Use with caution in individuals with preexisting cardiac disease.

Renal and Hepatic Dysfunction
In some individuals with preexisting renal or hepatic dysfunction enrolled in uncontrolled clinical trials, administration of sargramostim has induced elevation of serum creatinine or bilirubin and hepatic enzymes.  Dose reduction or interruption of sargramostim has resulted in a decrease to pretreatment levels.  Monitoring of renal and hepatic function in individuals displaying renal or hepatic dysfunction prior to initiation of treatment is recommended at least every other week during sargramostim administration.

General Precautions
Serous allergic or anaphylactic reactions have been reported.  If serious allergic or anaphylactic reaction occurs, sargramostim therapy should immediately be discontinued and appropriate therapy initiated.

A syndrome characterized by respiratory distress, hypoxia, flushing, hypotension, syncope, and/or tachycardia has been reported following the first administration of sargramostim in a particular cycle.  These signs have resolved with symptomatic treatment and usually do not recur with subsequent doses in the same cycle of treatment.

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.

The product information label for tbo-filgrastim (Granix, 2014) includes the following warnings and precautions:

Splenic Rupture
Splenic rupture, including fatal cases, can occur following administration of human granulocyte colony-stimulating factors.  In individuals who report upper abdominal or shoulder pain after receiving tbo-filgrastim, discontinue tbo-filgrastim and evaluate for an enlarged spleen or splenic rupture.

Acute Respiratory Distress Syndrome (ARDS)
Acute respiratory distress syndrome (ARDS) can occur in individuals receiving human granulocyte colony-stimulating factors.  Evaluate individuals who develop fever and lung infiltrates or respiratory distress after receiving tbo-filgrastim, for ARDS.  Discontinue tbo-filgrastim in individuals with ARDS.

Allergic Reactions
Serious allergic reactions including anaphylaxis can occur in individuals receiving human granulocyte colony-stimulating factors. Reactions can occur on initial exposure.  The administration of antihistamines‚ steroids‚ bronchodilators‚ and/or epinephrine may reduce the severity of the reactions.  Permanently discontinue tbo-filgrastim in individuals with serious allergic reactions.  Do not administer tbo-filgrastim to individuals with a history of serious allergic reactions to filgrastim or pegfilgrastim.

Use in Individuals with Sickle Cell Disease
Severe and sometimes fatal sickle cell crises can occur in individuals with sickle cell disease receiving human granulocyte colony-stimulating factors.  Consider the potential risks and benefits prior to the administration of human granulocyte colony-stimulating factors in individuals with sickle cell disease.  Discontinue tbo-filgrastim in individuals undergoing a sickle cell crisis.

Capillary Leak Syndrome
Capillary leak syndrome (CLS) can occur in individuals receiving human granulocyte colony-stimulating factors and is characterized by hypotension, hypoalbuminemia, edema and hemoconcentration.  Episodes vary in frequency, severity and may be life-threatening if treatment is delayed. Individuals who develop symptoms of capillary leak syndrome should be closely monitored and receive standard symptomatic treatment, which may include a need for intensive care.

Additional product information for tbo-filgrastim (Granix, 2014) includes:

Pediatric Use
The safety and effectiveness of tbo-filgrastim in children under 18 years of age have not been established.

Other Proposed Uses:

The use of sargramostim to induce remission in Crohn's disease has been proposed.  In a Cochrane review (Roth, 2011), data from three studies did not show any difference between sargramostim and placebo drug to induce remission or clinical improvement for individuals with active Crohn's disease.  The investigators recommended randomized controlled trials to research the effects of sargramostim on Crohn's disease.

Multiple phase I and phase II clinical trials are studying the safety and efficacy of sargramostim to treat malignant melanoma.  However, the published data have been primarily from smaller series that included a variety of additional immunomodulatory agents and outcomes were mixed.  Investigators have noted the outcomes from larger randomized phase III trials with longer follow-up are needed.  NCCN clinical practice guidelines (2015) for melanoma do not include treatment regimens which include sargramostim or neupogen.

There is moderate evidence from three separate systematic reviews which showed 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 (Carr, 2003; Cheng, 2007).

Based on encouraging data from phase II trials, a large randomized multicenter, placebo-controlled double-blind trial (AX200), investigated the use of G-CSF initiated ≤9 hours since onset of stroke symptoms. The primary and secondary endpoints of the trial were not met as G-CSF did improve the outcomes of stroke over those treated with placebo (Ringelstein, 2013).  The use of G-CSF continues to be investigated for off-label indications to evaluate efficacy and safety.

Definitions

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.

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.

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 self-care. Totally confined to bed or chair
5= Dead

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.

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.

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.

References

Peer Reviewed Publications:

  1. Aarts MJ, Peters FP, Mandigers CM, et al. Primary granulocyte colony-stimulating factor prophylaxis during the first two cycles only or throughout all chemotherapy cycles in patients with breast cancer at risk for febrile neutropenia. J Clin Oncol. 2013; 31(34):4290-4296.
  2. Cioch M., Jawniak D, Kotwica K, et al. Biosimilar granulocyte colony-stimulating factor is effective in reducing the duration of neutropenia after autologous peripheral blood stem cell transplantation. Transplant Proc. 2014; 46(8):2882-2884.
  3. Cooper KL, Madan J, Whyte S, et al. Granulocyte colony-stimulating factors for febrile neutropenia prophylaxis following chemotherapy: systematic review and meta-analysis. BMC Cancer. 2011; 11:404.
  4. Crawford J, Armitage J, Balducci L, et al. Myeloid growth factors. J Natl Compr Canc Netw. 2013; 11(10):1266-1290.
  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. del Giglio A, Eniu A, Ganea-Motan D, et al. XMO2 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.
  7. Farese AM, Brown CR, Smith CP, et al. The ability of filgrastim to mitigate mortality following LD50/60 total-body irradiation is administration time-dependent. Health Phys. 2014; 106(1):39-47.
  8. Farese AM, Cohen MV, Katz BP, et al. Filgrastim improves survival in lethally irradiated nonhuman primates. Radiat Res. 2013; 179(1):89-100.
  9. Freyer G, Jovenin N, Yazbek G, et al. Granocyte-colony stimulating factor (G-CSF) has significant efficacy as secondary prophylaxis of chemotherapy-induced neutropenia in patients with solid tumors: results of a prospective study. Anticancer Res. 2013; 33(1):301-307.
  10. Gatzemeier U, Ciuleanu T, Dediu M, et al.  XM02, the first biosimilar G-CSF, is safe and effective in reducing the duration of severe neutropenia and incidence of febrile neutropenia in patients with small cell or non-small cell lung cancer receiving platinum-based chemotherapy. J Thorac Oncol. 2009; 4(6):736-740.
  11. 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.
  12. 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; 30(2):256-260.
  13. Mac Nicholas R, Norris S. Review article: optimizing SVR and management of the haematological side effects of peginterferon/ribavirin antiviral therapy for HCV-the role of epoetin, G-CSF and novel agents. Aliment Pharmacol Ther. 2010; 31:929–937.
  14. Manko J, Walter-Croneck A, Jawniak D, et al. A clinical comparison of the efficacy and safety of biosimilar G-CSF and originator G-CSF in haematopoietic stem cell mobilization. Pharmacol Rep. 2014 66(2):239-242.
  15. Naeim A, Henk HJ, Becker L, et al. Pegfilgrastim prophylaxis is associated with a lower risk of hospitalization of cancer patients than filgrastim prophylaxis: a retrospective United States claims analysis of granulocyte colony-stimulating factors (G-CSF). BMC Cancer. 2013; 13:11.
  16. Ringelstein EB, Thijs V, Norrving B, et al.; AXIS 2 Investigators. Granulocyte colony-stimulating factor in patients with acute ischemic stroke: results of the AX200 for Ischemic Stroke trial. Blood. 2013; 44(10): 2681-2687.
  17. 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.
  18. Schmitt M, Publicover A, Orchard KH, et al. Biosimilar G-CSF based mobilization of peripheral blood hematopoietic stem cells for autologous and allogeneic stem cell transplantation. Theranostics. 2014; 4(3):280-289.
  19. 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.
  20. 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.
  21. Tandon P, Doucette K, Fassbender, K, et al. Granulocyte colony-stimulating factor for hepatitis C therapy-associated neutropenia: systematic review and economic evaluation. J Viral Hep. 2011; 18:e381-e393.
  22. Untch M, Fasching PA, Konecny GE, et al.; Arbeitsgemeinschaft Gynäkologische Onkologie PREPARE investigators. PREPARE trial: a randomized phase III trial comparing preoperative, dose-dense, dose-intensified chemotherapy with epirubicin, paclitaxel and CMF versus a standard-dosed epirubicin/cyclophosphamide followed by paclitaxel ± darbepoetin alfa in primary breast cancer-results at the time of surgery. Ann Oncol. 2011; 22(9):1988-1998.
  23. Untch M, von Minckwitz G, Konecny GE, et al.; Arbeitsgemeinschaft Gynäkologische Onkologie PREPARE investigators. PREPARE trial: a randomized phase III trial comparing preoperative, dose-dense, dose-intensified chemotherapy with epirubicin, paclitaxel, and CMF versus a standard-dosed epirubicin-cyclophosphamide followed by paclitaxel with or without darbepoetin alfa in primary breast cancer--outcome on prognosis. Ann Oncol. 2011; 22(9):1999-2006.
  24. Vogel CL, Wojtukiewicz MZ, Carroll RR, et al. First and subsequent cycle use of pegfilgrastim prevents febrile neutropenia in patients with breast cancer: a multicenter, double-blind, placebo-controlled phase III study. J Clin Oncol. 2005; 23:1178-1184.

Government Agency, Medical Society, and Other Authoritative Publications:

  1. Aapro MS, Bohlius J, Cameron DA, et al.; European Organisation for Research and Treatment of Cancer. 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 tumours. Eur J Cancer. 2011; 47(1):8-32.
  2. Bath PM, Sprigg N, England T. Colony stimulating factors (including erythropoietin, granulocyte colony stimulating factor and analogues) for stroke. Cochrane Database Syst Rev. 2013; (6):CD005207.
  3. 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.
  4. Carr R, Modi N, Dore C. G-CSF and GM-CSF for treating or preventing neonatal infections. Cochrane Database Sys Rev. 2003;(3):CD003066.
  5. Cesaro S, Nesi F, Tridello G, et al. A randomized, non-inferiority study comparing efficacy and safety of a single dose of pegfilgrastim versus daily filgrastim in pediatric patients after autologous peripheral blood stem cell transplant. PLoS One. 2013; 8(1):e53252.
  6. 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.
  7. Clark OA, Lyman G, Castro AA, et al. Colony stimulating factors for chemotherapy induced febrile neutropenia. Cochrane Database Sys Rev. 2003; (3):CD003039.
  8. Crawford J, Caserta C, Roila F; ESMO Guidelines Working Group. Hematopoietic growth factors: ESMO clinical practice guidelines for the applications. Ann Oncol. 2010; 21 Suppl 5:v248-v251.
  9. Dryden DM, Fassbender K, Doucette K, et al. Overview of Granulocyte-colony stimulating factor for antiviral-associated neutropenia. [Technology Overview number 48]. Ottawa: Canadian Agency for Drugs and Technologies in Health; 2008.
  10. Dryden DM, Fassbender K, Doucette K, et al. Granulocyte-colony stimulating factor for antiviral-associated neutropenia: systematic review and economic evaluation [Technology report number 115]. Ottawa:Canadian Agency for Drugs and Technologies in Health; 2008.
  11. Filgrastim. In: DrugPoints® System (electronic version). Truven Health Analytics, Greenwood Village, CO.  Updated January 24, 2014. Available at: http://www.micromedexsolutions.com. Accessed on February 24, 2015.
  12. Filgrastim; TBO-filgrastim Monograph. Lexicomp® Online, American Hospital Formulary Service® (AHFS®) Online, Hudson, Ohio, Lexi-Comp., Inc. Last revised March 28, 2014. Accessed on February 24, 2015.
  13. Flowers CR, Seidenfeld J, Bow EJ, et al. Antimicrobial prophylaxis and outpatient management of fever and neutropenia in adults treated for malignancy: American Society of Clinical Oncology clinical practice guideline. J Clin Oncol. 2013; 31(6):794-810.
  14. Ghany MG, Strader DB, Thomas DL, Seeff LB. Diagnosis, management and treatment of hepatitis C: an update. Hepatology. 2009; 49(4):1335-1374.
  15. Gralow JR, Barlow WE, Lew D, et al. A phase II study of docetaxel and vinorelbine plus filgrastim for HER-2 negative, stage IV breast cancer: SWOG S0102. Breast Cancer Res Treat. 2014; 143(2):351-358.
  16. Granix [Product Information]. North Wales, PA. Sicor Biotech UAB/Teva Pharmaceuticals; December 19, 2014. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2014/125294s035lbl.pdf. Accessed on April 5, 2015.
  17. Kaplan JE, Benson C, Holmes KH, et al.; Centers for Disease Control and Prevention (CDC), National Institutes of Health, HIV Medicine Association of the Infectious Diseases Society of America. Guidelines for prevention and treatment of opportunistic infections in HIV-infected adults and adolescents: recommendations from CDC, the National Institutes of Health, and the HIV Medicine Association of the Infectious Diseases Society of America. MMWR Recomm Rep. 2009; 58(RR-4):1-207.
  18. Leukine [Product Information]. Seattle, WA. Bayer HealthCare Pharmaceuticals; August 2013. Available at: http://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=c96afe62-f0cf-4d4b-b57d-194a8ec12389. Accessed on April 5, 2015.
  19. National Comprehensive Cancer Network (NCCN®) Drugs & Biologic Compendium® © 2015 National Comprehensive Cancer Network, Inc. For additional information visit the NCCN website: http://www.nccn.org. Accessed on February 24, 2015.
  20. National Comprehensive Cancer Network. Clinical Practice Guidelines in Oncology®. For additional information visit the NCCN website: http://www.nccn.org/index.asp. Accessed on April 5, 2015.
    • Acute myeloid leukemia. V.1.2015. Revised December 3, 2014.
    • Myeloid growth factors in cancer treatment. V.2.2014. Revised May 2, 2014.
    • Melanoma. V.3.2015. Revised March 11, 2015.
    • Older adult oncology. V.1.2015. Revised January 15, 2015.
  21. Neulasta[Product Information]. Thousand Oaks, CA. Amgen; December 23, 2014. Available at: http://pi.amgen.com/united_states/neulasta/neulasta_pi_hcp_english.pdf. Accessed on April 5, 2015.
  22. Neupogen [Product Information]. Thousand Oaks, CA. Amgen; March 30, 2015. Available at: http://pi.amgen.com/united_states/neupogen/neupogen_pi_hcp_english.pdf. Accessed on April 5, 2015.
  23. Pegfilgrastim. In: DrugPoints System (electronic version). Truven Health Analytics, Greenwood Village, CO. Updated January 27, 2015. Available at: http://www.micromedexsolutions.com. Accessed on February 24, 2015.
  24. Pegfilgrastim Monograph. Lexicomp® Online, American Hospital Formulary Service® (AHFS®) Online, Hudson, Ohio, Lexi-Comp., Inc. Last revised January 1, 2009. Accessed on February 24, 2015.
  25. Renner P, Milazzo S, Liu JP, et al. Primary prophylactic colony-stimulating factors for the prevention of chemotherapy-induced febrile neutropenia in breast cancer patients. Cochrane Database Syst Rev. 2012;(10):CD007913.
  26. Roth L, Macdonald JK, McDonald JW, Chande N. Sargramostim (GM-CSF) for induction of remission in Crohn's disease. Cochrane Database Syst Rev. 2011; (11):CD008538.
  27. Sargramostim. In: DrugPoints System (electronic version). Truven Health Analytics, Greenwood Village, CO. Updated December 10, 2014. Available at: http://www.micromedexsolutions.com. Accessed on February 24, 2015.
  28. Sargramostim Monograph. Lexicomp® Online, American Hospital Formulary Service® (AHFS®) Online, Hudson, Ohio, Lexi-Comp., Inc. Last revised December 1, 2008. Accessed on February 24, 2015.
  29. Schnipper LE, Smith TJ, Raghavan D, et al. American Society of Clinical Oncology identifies five key opportunities to improve care and reduce costs: the top five list for oncology. J Clin Oncol. 2012; 30(14):1715-1724.
  30. 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):3187-3205. Available at: http://www.jco.org/cgi/reprint/JCO.2006.06.4451v2.pdf. Accessed on April 5, 2015.
  31. Zarxio [Product Information]. Princeton, NJ. Sandoz Inc.; March 6, 2015. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/125553lbl.pdf. Accessed on April 5, 2015.
Websites for Additional Information
  1. American Cancer Society. Available at: http://www.cancer.org/. Accessed on April 5, 2015.
  2. National Cancer Institute. Available at: http://www.cancer.gov/. Accessed on April 5, 2015.
  3. U.S. Department of Health & Human Services. Acute Radiation Syndrome. Updated November 21, 2014. Available at: http://www.remm.nlm.gov/ars_summary.htm. Accessed on April 8, 2015.
Index

Colony Stimulating Factors (CSF)
Granix
Hematopoietic Stimulating Growth Factors
Leukine
Neulasta
Neupogen
Tbo-filgrastim
Zarxio

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.

History

Status

Date

Action

Revised05/07/2015Medical Policy & Technology Assessment Committee (MPTAC) review.
Revised05/06/2015Hematology/Oncology Subcommittee review.  Added filgrastim-sndz (Zarxio) to medically necessary indication I. Clarified primary prophylaxis criteria I-B; II-B; III-B; IV-B (removed "or equal to"). Clarified criterion I-P for radiation myelosuppression to align with new FDA approved indication.  Removed "autologous" from transplant criterion and standardized verbiage for criteria I-Q; II-H; III-K. Updated Discussion, References and Websites. Updated Coding section to include HCPCS changes effective 07/01/2015.
Reviewed05/15/2014MPTAC review.
Reviewed05/14/2014Hematology/Oncology Subcommittee review.  Updated Discussion, References and Websites.
 01/01/2014Updated Coding section with 01/01/2014 HCPCS changes; removed J1440, J1441 deleted 12/31/2013.  Changed name of Neutroval to Granix.
Revised05/09/2013MPTAC review.
Revised05/08/2013Hematology/Oncology Subcommittee review.  Clarified primary prophylaxis when FN risk is ≥ 10% and ≤ 20% based on chemotherapy regimen.  Clarified ANC unit (mm3) in Filgrastim criterion I.  Updated Description/Scope, Coding, Discussion, Definitions, References and Websites.
Revised11/08/2012MPTAC review.
Revised11/07/2012Hematology/Oncology Subcommittee review. Added medically necessary indication for tbo-filgrastim. Updated Description/Scope, Coding, Discussion, Definitions, References and Websites.
Revised05/10/2012MPTAC review.
Revised05/09/2012Hematology/Oncology Subcommittee review. Medically necessary indication for use in dose dense chemotherapy clarified, and will includes use of pegfilgrastim. Updated Discussion, References and Websites.
Reviewed05/19/2011MPTAC review.
Reviewed05/18/2011Hematology/Oncology Subcommittee review. Updated Discussion, Coding, References and Websites.
Revised05/13/2010MPTAC review.
Revised05/12/2010Hematology/Oncology Subcommittee review. Reformatted clinical indications. Restated medically necessary indication for prophylaxis of febrile neutropenia (FN). Deleted redundant not medically necessary FN indications. Added not medically necessary indication "For uses not meeting the above criteria." Updated Rationale, References and Websites.
Revised05/21/2009MPTAC review.
Revised05/20/2009Hematology/Oncology Subcommittee review. Deleted Place of Service section. Dosing table removed. Deletion of medically necessary indications for malignant melanoma, neonatal sepsis in infants with pre-eclampsia-associated neutropenia, and drug induced agranulocytosis. Added medically necessary indication for glycogen storage disease, hairy cell leukemia. Coding updated.
 10/01/2008Updated coding section with 10/01/2008 ICD-9 changes.
Reviewed05/15/2008MPTAC review.
Reviewed05/14/2008Hematology/Oncology Subcommittee review. Format changed to align indications with specific agents. Updated the off-label indications for filgrastim and sargramostim. Clarified the FDA labeled indications for sargramostim.
Revised05/17/2007MPTAC review.
Revised05/16/2007Hematology/Oncology Subcommittee review. Title changed from CSF to White Blood Cell Growth Factors. Removed clinical protocols information from Pediatric indications. Modified medical necessity statement for non-oncologic label and off-label indications. Dosing, references and coding updated.
New06/08/2006MPTAC. New Guideline including 2006 American Society of Clinical Oncology (ASCO) Updated recommendations. 
New06/07/2006Hematology/Oncology Subcommittee. New Guideline.
   
Pre-Merger Organizations

Last Review Date

Document Number

Title

Anthem, Inc.

 

 No document
Anthem BCBS

 

 No document
WellPoint Health Networks, Inc.

10/03/2005

Pharmacology ToolkitFilgrastim (Neupogen®, G-CSF)
 

01/03/2005

Pharmacology ToolkitNeulasta® (Pegfilgrastim)
 

10/03/2005

Pharmacology ToolkitSargramostim (Leukine®, Prokine®)