Aetna Hematopoietic Colony-Stimulating Factors (CSFs) Form
This procedure is not covered
Background for this Policy
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 that can reduce the likelihood of neutropenic complications due to chemotherapy.
Colony‐stimulating factors are glycoproteins which act on hematopoietic cells by binding to specific cell surface receptors and stimulating proliferation, differentiation commitment, and some end‐cell functional activation. Endogenous G‐CSF is a lineage specific colony‐stimulating factor which is produced by monocytes, fibroblasts, and endothelial cells. G‐CSF regulates the production of neutrophils within the bone marrow. G‐CSF is not species specific and has been shown to have minimal direct in vivo or in vitro effects on the production of hematopoietic cell types other than the neutrophil lineage.
The prophylactic use of colony‐stimulating factors (CSFs) can reduce the risk, severity, and duration of both severe neutropenia and febrile neutropenia. Despite these benefits, CSFs are not administered to all patients receiving myelosuppressive chemotherapy because of the costs associated with their routine use. The selective use of CSFs in members at increased risk for neutropenic complications may, however, enhance their cost‐effective use by directing treatment toward those patients who are most likely to benefit. The preventative use of CSF reduces the incidence, length and severity of chemotherapy-related neutropenia and may prevent life‐threatening complications. The definition of patients at high risk for severe or febrile neutropenia is outlined in ASCO guidelines referenced in this policy.
CSFs also have a place in therapy for many other types of neutropenia, bone marrow transplant, as well as for building up of white blood cells in peripheral blood progenitor cell (PBPC) transplantation. Post bone marrow transplant, the patient must recover their white blood cells for higher quality of life as they are often isolated due to their weakened immune system during the transplant process. Radiation therapy can also weaken the immune system substantially, causing neutropenia. The inherent mechanism of action of colony‐stimulating factors (CSFs) to "jump start" bone marrow into creating myeloid cells helps correct neutropenia in many of these cases.
Colony-stimulating factors are recommended in some situations, e.g., to reduce the likelihood of febrile neutropenia (FN) when the expected incidence is greater than 20 %; after documented FN in a prior chemotherapy cycle to avoid infectious complications and maintain dose-intensity in subsequent treatment cycles when chemotherapy dose-reduction is not appropriate; and after high-dose chemotherapy with autologous progenitor-cell transplantation. Colony-stimulating factors are also effective in the mobilization of peripheral-blood progenitor cells. Therapeutic initiation of CSFs in addition to antibiotics at the onset of FN should be reserved for patients at high risk for septic complications. Use of CSFs in patients with myelodysplastic syndromes may be reasonable if they are experiencing neutropenic infections. Administration of CSFs after initial chemotherapy for acute myeloid leukemia does not appear to be detrimental, but clinical benefit has been variable and caution is advised. Available data support use of CSFs in pediatric cancer patients similar to that recommended for adult patients. Colony-stimulating factors should not be used concurrently with chemotherapy and radiation, or to support increasing dose-dense chemotherapy regimens.
Colony-Stimulating Factors (CSFs) and Concomitant Chemotherapy and Radiation Therapy
The
American Society of Clinical Oncology (ASCO) Clinical Practice Guideline Update(2015) states that "CSFs should be avoided in patients receiving concomitant chemotherapy and radiation therapy, particularly involving the mediastinum.
In the absence of chemotherapy, therapeutic use of CSFs may be considered in patients receiving radiation therapy alone if prolonged delays secondary to neutropenia are expected." (Type: evidence based. Evidence quality: high. Strength of recommendation: strong.)
Neupogen (filgrastim)
U.S. Food and Drug Administration (FDA)-Approved Indications
Patients with Cancer Receiving Myelosuppressive Chemotherapy
Neupogen is indicated to decrease the incidence of infection‚ as manifested by febrile neutropenia‚ in patients with non-myeloid malignancies receiving myelosuppressive anti-cancer drugs associated with a significant incidence of severe neutropenia with fever.
Patients With Acute Myeloid Leukemia Receiving Induction or Consolidation Chemotherapy
Neupogen is indicated for reducing the time to neutrophil recovery and the duration of fever, following induction or consolidation chemotherapy treatment of patients with acute myeloid leukemia (AML).
Patients with Cancer Undergoing Bone Marrow Transplantation
Neupogen is indicated to reduce the duration of neutropenia and neutropenia-related clinical sequelae‚ (e.g., febrile neutropenia) in patients with non-myeloid malignancies undergoing myeloablative chemotherapy followed by marrow transplantation.
Patients Undergoing Autologous Peripheral Blood Progenitor Cell Collection and Therapy
Neupogen is indicated for the mobilization of autologous hematopoietic progenitor cells into the peripheral blood for collection by leukapheresis.
Patients With Severe Chronic Neutropenia
Neupogen is indicated for chronic administration to reduce the incidence and duration of sequelae of neutropenia (e.g.‚ fever‚ infections‚ oropharyngeal ulcers) in symptomatic patients with congenital neutropenia‚ cyclic neutropenia‚ or idiopathic neutropenia.
Patients Acutely Exposed to Myelosuppressive Doses of Radiation (Hematopoietic Syndrome of Acute Radiation Syndrome)
Neupogen is indicated to increase survival in patients acutely exposed to myelosuppressive doses of radiation (Hematopoietic Syndrome of Acute Radiation Syndrome).
Neupogen (filgrastim) is a human granulocyte colony‐stimulating factor (G‐CSF), produced by recombinant DNA technology. Neupogen (filgrastim) has been approved by the FDA:Efficacy studies of Neupogen (filgrastim) could not be conducted in humans with acute radiation syndrome for ethical and feasibility reasons. Approval of this indication was based on efficacy studies conducted in animals and data supporting the use of Neupogen (filgrastim) for other approved indications.
Filgrastim is available as Neupogen 300mcg and 480mcg vials and as 300mcg and 480mcg prefilled syringes. In adult cancer patients receiving myelosuppressive chemotherapy or induction and consolidation therapy for acute myeloid leukemia, the U.S. Food and Drug Administration (FDA)-approved labeling recommends a starting dose of granulocyte-CSF (filgrastim, Neupogen) of 5 micrograms per kilogram per day (mcg/kg/day). Doses may be increased in increments of 5 mcg/kg for each chemotherapy cycle, according to the duration and severity of the absolute neutrophil count (ANC) nadir. In phase III clinical trials, effective doses were 4 to 8 mcg/kg/day. Neupogen (filgrastim) should not be administered earlier than 24 hours after cytotoxic chemotherapy or within 24 hours before chemotherapy. Administer Neupogen (filgrastim) daily for up to two weeks until the ANC has reached 10,000/cubic millimeter (mm³) after the expected chemotherapy-induced neutrophil nadir. Discontinue Neupogen (filgrastim) if the ANC surpasses 10,000/mm³ after the expected neutrophil nadir.
In adult cancer patients receiving bone marrow transplant, the recommended dose of Neupogen is 10 mcg/kg/day given as an intravenous infusion of 4 or 24 hours, or as a continuous 24-hour subcutaneous infusion. The first dose should be administered at least 24 hours after cytotoxic chemotherapy or after bone marrow infusion. The daily dose of Neupogen (filgrastim) is titrated against the absolute neutrophil count during the period of neutrophil recovery, according to the guidelines in the Prescribing Information.
The recommended dose of Neupogen for the mobilization of peripheral blood progenitor cells is 10 mcg/kg/day subcutaneously, either as a bolus or a continuous infusion, given for at least 4 days before the first leukapheresis procedure and continued until the last leukapheresis.
The recommended daily starting dose for congenital neutropenia is 6 mcg/kg twice-daily subcutaneously every day and for idiopathic or cyclic neutropenia is 5 mcg/kg as a single injection subcutaneously every day. Chronic daily administration is required to maintain clinical benefit. Absolute neutrophil count should not be used as the sole indication of efficacy. The dose should be individually adjusted based on the members’ clinical course as well as ANC.
The recommended dose of Neupogen for patients acutely exposed to myelosuppressive doses of radiation is 10 mcg/kg/day by subcutaneous injection. Administer as soon as possible after suspected or confirmed exposure to radiation doses greater than 2 gray (Gy).
Other than for peripheral blood progenitor cell re-infusion, CSFs should be administered subcutaneously or intravenously no earlier than 24 hours and preferably between 24 and 72 hours after the administration of cytotoxic chemotherapy to provide optimal neutrophil recovery. Therapy should be discontinued if the absolute neutrophil count surpasses 10,000/mm
3after the expected chemotherapy-induced nadir. Starting CSFs up to 5 days after peripheral blood progenitor cell re-infusion is reasonable based on available clinical data.
Neupogen (filgrastim) should not be utilized in the following:
Nivestym (filgrastim-aafi)
U.S. Food and Drug Administration (FDA)-Approved Indications
Patients with Cancer Receiving Myelosuppressive Chemotherapy
Nivestym is indicated to decrease the incidence of infection‚ as manifested by febrile neutropenia‚ in patients with non-myeloid malignancies receiving myelosuppressive anti-cancer drugs associated with a significant incidence of severe neutropenia with fever.
Patients With Acute Myeloid Leukemia Receiving Induction or Consolidation Chemotherapy
Nivestym is indicated for reducing the time to neutrophil recovery and the duration of fever, following induction or consolidation chemotherapy treatment of patients with acute myeloid leukemia (AML).
Patients with Cancer Undergoing Bone Marrow Transplantation (BMT)
Nivestym is indicated to reduce the duration of neutropenia and neutropenia-related clinical sequelae‚ (e.g., febrile neutropenia) in patients with non-myeloid malignancies undergoing myeloablative chemotherapy followed by bone marrow transplantation.
Patients Undergoing Autologous Peripheral Blood Progenitor Cell Collection and Therapy
Nivestym is indicated for the mobilization of autologous hematopoietic progenitor cells into the peripheral blood for collection by leukapheresis.
Patients With Severe Chronic Neutropenia
Nivestym is indicated for chronic administration to reduce the incidence and duration of sequelae of neutropenia (e.g.‚ fever‚ infections‚ oropharyngeal ulcers) in symptomatic patients with congenital neutropenia‚ cyclic neutropenia‚ or idiopathic neutropenia.
On July 20, 2018, the U.S. FDA approved Nivestym (filgrastim-aafi) (Pfizer, Inc.), a biosimilar to Neupogen (filgrastim) (Amgen, Inc.), for all eligible indications of the referenced product; thus, Nivestym, a leukocyte growth factor, is approved for the same indications as Neupogen. The FDA approval was based on a review of a comprehensive data package and totality of evidence demonstrating a high degree of similarity of Nivestym compared to its reference product.
Filgrastim-aafi is available for injection as 300 mcg/mL in a single-dose vial, and 480 mcg/1.6 mL single-dose vial. It is also available as a prefilled syringe for injection 300 mcg/0.5 mL, and 480 mcg/0.8 mL.
Note: Simultaneous use of filgrastim-aafi with chemotherapy and radiation therapy is not recommended and should be avoided (Pfizer, 2018).
Releuko (filgrastim-ayow)
U.S. Food and Drug Administration (FDA)-Approved Indications
Patients with Cancer Receiving Myelosuppressive Chemotherapy
Releuko is indicated to decrease the incidence of infection‚ as manifested by febrile neutropenia‚ in patients with non-myeloid malignancies receiving myelosuppressive anti-cancer drugs associated with a significant incidence of severe neutropenia with fever.
Patients With Acute Myeloid Leukemia Receiving Induction or Consolidation Chemotherapy
Releuko is indicated for reducing the time to neutrophil recovery and the duration of fever, following induction or consolidation chemotherapy treatment of patients with acute myeloid leukemia (AML).
Patients with Cancer Undergoing Bone Marrow Transplantation
Releuko is indicated to reduce the duration of neutropenia and neutropenia-related clinical sequelae‚ (e.g., febrile neutropenia) in patients with non-myeloid malignancies undergoing myeloablative chemotherapy followed by bone marrow transplantation.
Patients With Severe Chronic Neutropenia
Releuko is indicated for chronic administration to reduce the incidence and duration of sequelae of severe neutropenia (e.g.‚ fever‚ infections‚ oropharyngeal ulcers) in symptomatic patients with congenital neutropenia‚ cyclic neutropenia‚ or idiopathic neutropenia.
On January 25, 2022, the U.S. Food and Drug Administration (FDA) approved Releuko (filgrastim-ayow), a biosimilar referencing Neupogen. Releuko was developed by Amneal Pharmaceuticals Inc. in collaboration with Kashiv BioSciences, LLC. Releuko is a granulocyte colony-stimulating factor (G-CSF) which regulates the production, maturation, and activation of neutrophils (white blood cells). The FDA approval was based on supporting data from multiple studies consisting of different populations which demonstrated a high degree similarity of Releuko in comparison to its referenced biosimilar product, Neupogen (Amneal Pharmaceuticals, 2022b; FDA, 2022).
Filgrastim-ayow is availabe as Releuko in the following formulations (Kashiv BioSciences, 2022b):
Zarxio
(filgrastim-sndz)U.S. Food and Drug Administration (FDA)-Approved Indications
Patients with Cancer Receiving Myelosuppressive Chemotherapy
Zarxio is indicated to decrease the incidence of infection‚ as manifested by febrile neutropenia‚ in patients with non-myeloid malignancies receiving myelosuppressive anti-cancer drugs associated with a significant incidence of severe neutropenia with fever.
Patients With Acute Myeloid Leukemia Receiving Induction or Consolidation Chemotherapy
Zarxio is indicated for reducing the time to neutrophil recovery and the duration of fever, following induction or consolidation chemotherapy treatment of adults patients with acute myeloid leukemia (AML).
Patients with Cancer Undergoing Bone Marrow Transplantation
Zarxio is indicated to reduce the duration of neutropenia and neutropenia-related clinical sequelae‚ (e.g., febrile neutropenia) in patients with non-myeloid malignancies undergoing myeloablative chemotherapy followed by bone marrow transplantation.
Patients Undergoing Autologous Peripheral Blood Progenitor Cell Collection and Therapy
Zarxio is indicated for the mobilization of autologous hematopoietic progenitor cells into the peripheral blood for collection by leukapheresis.
Patients With Severe Chronic Neutropenia
Zarxio is indicated for chronic administration to reduce the incidence and duration of sequelae of neutropenia (e.g.‚ fever‚ infections‚ oropharyngeal ulcers) in symptomatic patients with congenital neutropenia‚ cyclic neutropenia‚ or idiopathic neutropenia.
Zarxio (filgrastim‐sndz) is a human granulocyte colony‐stimulating factor (G‐CSF), produced by recombinant DNA technology.
Zarxio (filgrastim‐sndz) is approved by the FDAFilgrastim‐sndz is available as Zarxio 300mcg and 480mcg prefilled syringes.
Febrile Neutropenia Prophylaxis, In non‐myeloid malignancies following myelosuppressive chemotherapy: The usual starting dose of Zarxio (filgrastim‐sndz) is 5 micrograms/kilogram (mcg/kg)/day (rounded to the nearest vial size based on institution‐defined weight limits) administered as a single daily injection by SC bolus injection‚ by short IV infusion (15 to 30 minutes)‚or by continuous SC or continuous IV infusion in cancer patients receiving myelosuppressive therapy. Doses may be increased in increments of 5 mcg/kg/day for each cycle according to the duration and severity of the ANC nadir. In phase III clinical trials, effective doses were 4 to 8 mcg/kg/day. Zarxio (filgrastim‐sndz) should not be administered earlier than 24 hours after cytotoxic chemotherapy or within 24 hours before chemotherapy. Administer Zarxio (filgrastim‐sndz) daily for up to two weeks until the ANC has reached 10,000/cubic millimeter (mm³ after the expected chemotherapy-induced neutrophil nadir. Discontinue Zarxio (filgrastim‐sndz) if the ANC surpasses 10,000/mm³ after the expected neutrophil nadir.
Febrile Neutropenia Prophylaxis, In members with acute myeloid leukemia receiving chemotherapy: The usual starting dose of Zarxio (filgrastim‐sndz) is 5 micrograms/kilogram (mcg/kg)/day (rounded to the nearest vial size based on institution‐defined weight limits) administered as a single daily injection by SC bolus injection‚by short IV infusion (15 to 30 minutes)‚or by continuous SC or continuous IV infusion in cancer patients receiving myelosuppressive therapy. Doses may be increased in increments of 5 mcg/kg/day for each cycle according to the duration and severity of the ANC nadir. In phase III clinical trials, effective doses were 4 to 8 mcg/kg/day. Zarxio (filgrastim‐sndz) should not be administered earlier than 24 hours after cytotoxic chemotherapy or within 24 hours before chemotherapy. Administer filgrastim daily for up to two weeks until the ANC has reached 10,000/cubic millimeter (mm³ after the expected chemotherapy‐induced neutrophil nadir. Discontinue Zarxio (filgrastim‐sndz) if the ANC surpasses 10,000/mm³ after the expected neutrophil nadir.
Febrile Neutropenia Prophylaxis, In non‐myeloid malignancies following progenitor‐cell transplantation: In cancer members receiving myeloablative therapy with bone marrow transplant, a starting dose of 10 micrograms/kilogram/day (rounded to the nearest vial size based on institution‐defined weight limits) as an intravenous infusion of four or 24 hours is recommended with dose titration against the neutrophil response. Zarxio (filgrastimsndz) should be administered at least 24 hours after cytotoxic chemotherapy, and at least 24 hours after bone marrow infusion. The daily dose of Zarxio (filgrastim‐sndz) during the period of neutrophil recovery should be titrated against the ANC according to the instructions in the Prescribing Information.
Harvesting of peripheral blood stem cells: Zarxio (filgrastim‐sndz) 10 mcg/kg/day (rounded to the nearest vial size based on institution‐defined weight limits) SC as a bolus or continuous infusion, given at least four days before first leukapheresis and continued until the last leukapheresis.
Neutropenic disorder, chronic (Severe), Symptomatic: The recommended starting dose for congenital neutropenia is 6 mcg/kg (rounded to the nearest vial size based on institution‐defined weight limits) twice daily subcutaneously every day. The recommended starting dose for idiopathic or cyclic neutropenia is 5mcg/kg (rounded to the nearest vial size based on institution‐defined weight limits) as a single injection subcutaneously every day. Chronic daily administration is required to maintain clinical benefit. Absolute neutrophil count should not be used as the sole indication of efficacy.The dose should be individually adjusted based on the members’clinical course as well as ANC.
Zarxio (filgrastim‐sndz) should not be utilized in the following:
Granix (
tbo-filgrastim)U.S. Food and Drug Administration (FDA)-Approved Indications
Granix (tbo-filgrastim) is a human granulocyte colony stimulating factor (G-CSF), produced by recombinant DMA technology. Granix (tbo-filtrastim) is indicated to decrease the duration of severe neutropenia in patients with non-myeloid malignancies receiving myelosuppressive anti-cancer drugs associated with clinically significant incidence of febrile neutropenia.
Tbo-filgrastim is available as Granix 300 mcg and 480 mcg prefilled syringes.
Febrile neutropenia prophylaxis, in non-myeloid malignancies following myelosuppressive chemotherapy: The usual starting dose of Granix (tbo-filgrastim) is 5 micrograms/kilogram (mcg/kg)/day administered as a subcutaneous injection. Granix (tbo-filgrastim) should not be administered earlier than 24 hours after cytotoxic chemotherapy or within 24 hours before chemotherapy. Administer Granix (tbo-filgrastim) daily until the expected neutrophil nadir is passed and the neutrophil count has recovered to the normal range. Monitor complete blood count (CPC) prior to chemotherapy and twice per week until recovery.
Granix (tbo-filgrastim) should not be used in the following:
Compendial Uses for Neupogen (filgrastim), Nivestym (filgrastim-aafi), Releuko (filgrastim-ayow), Zarxio (filgrastim-sndz), and Granix (tbo-filgrastim)
Leukine (sargramostim)
U.S. Food and Drug Administration (FDA)-Approved Indications
Acute Myeloid Leukemia Following Induction Chemotherapy
Leukine is indicated to shorten time to neutrophil recovery and to reduce the incidence of severe, life-threatening, or fatal infections following induction chemotherapy in adult patients 55 years and older with acute myeloid leukemia (AML).
Autologous Peripheral Blood Progenitor Cells Mobilization and Collection
Leukine is indicated in adult patients with cancer undergoing autologous hematopoietic stem cell transplantation for the mobilization of hematopoietic progenitor cells into peripheral blood for collection by leukapheresis.
Autologous Peripheral Blood Progenitor Cell and Bone Marrow Transplantation
Leukine is indicated for acceleration of myeloid reconstitution following autologous peripheral blood progenitor cell (PBPC) or bone marrow transplantation in adult and pediatric patients 2 years of age and older with non-Hodgkin's lymphoma (NHL), acute lymphoblastic leukemia (ALL) and Hodgkin's lymphoma (HL).
Allogeneic Bone Marrow Transplantation (BMT)
Leukine is indicated for the acceleration of myeloid reconstitution in adult and pediatric patients 2 years of age and older undergoing allogeneic BMT from human leukocyte antigens (HLA)-matched related donors.
Allogenic or Autologous Bone Marrow Transplantation: Treatment of Delayed Neutrophil Recovery or Graft Failure
Leukine is indicated for the treatment of adult and pediatric patients 2 years and older who have undergone allogeneic or autologous BMT in whom neutrophil recovery is delayed or failed.
Acute Exposure to Myelosuppressive Doses of Radiation (H-ARS)
Leukine is indicated to increase survival in adult and pediatric patients from birth to 17 years of age acutely exposed to myelosuppressive doses of radiation (Hematopoietic Syndrome of Acute Radiation Syndrome [H-ARS]).
Compendial Uses
Leukine (sargramostim) is a recombinant human granulocyte‐macrophage colony stimulating factor (rhu GM‐CSF) produced by recombinant DNA technology in a yeast (S. cerevisiae) expression system. GM‐CSF is a hematopoietic growth factor which stimulates proliferation and differentiation of hematopoietic progenitor cells. Leukine (sargramostim) is a glycoprotein of 127 amino acids characterized by three primary molecular species having molecular masses of 19,500, 16,800 and 15,500 daltons. The amino acid sequence of Leukine (sargramostim) differs from the natural human GM‐CSF by a substitution of leucine at position 23, and the carbohydrate moiety may be different from the native protein. The liquid Leukine (sargramostim) presentation is formulated as a sterile, preserved (1.1% benzyl alcohol), injectable solution (500 mcg/mL) in a vial. Biological potency is expressed in International Units (IU) as tested against the WHO First International Reference Standard.
GM‐CSF is a protein secreted by macrophages, T cells, mast cells, endothelial cells, and fibroblasts. It functions as a white blood cell growth factor and stimulates stem cells to produce granulocytes and monocytes. Prophylaxis of febrile neutropenia in cancer members‐the incidence of febrile neutropenia in patients receiving chemotherapy varies based on the regimen.
Sargramostim is available as Leukine 500mcg single dose vials and as lyophilized Leukine powder in vials containing 250 mcg. The recommended dosage for granulocyte-macrophage-CSF (sargramostim, Leukine) is 250 mcg/m2/day for all clinical settings.
For myeloid reconstitution of allogeneic, HLA‐matched related donors, two to four hours after bone marrow infusion (allogeneic) and not less than 24 hours after the last dose of chemo‐ or radiotherapy, administer Leukine (sargramostim) 250 micrograms/square meter/day intravenously over two hours. Continue therapy until the ANC is greater than 1500 cells/cubic millimeter for three consecutive days. In the event of a severe adverse reaction, the dose may be reduced by 50% or discontinued temporarily. If the ANC exceeds 20,000 cells/cubic millimeter, interrupt therapy or reduce the dose by 50%. Do not administer sargramostim until the post marrow infusion absolute neutrophil count is less than 500 cells/cubic millimeter. Discontinue sargramostim immediately if blast cells appear or disease progression occurs. Continuous intravenous infusions appear to be superior to both intravenous bolus injections and short intravenous infusions (Herrmann et al, 1989a; Rifkin et al, 1988). In some studies, daily intravenous bolus injections have not been effective in producing leukocytosis. It is possible that WBC CSF increases the risk of GvHD when given following allogeneic bone marrow or PBSC transplant.
For myeloid reconstitution in non‐Hodgkin's lymphoma, Hodgkin's disease, and acute lymphoblastic lymphoma, two to four hours after bone marrow infusion (autologous) and not less than 24 hours after the last dose of chemo‐ or radiotherapy, administer Leukine (sargramostim) 250 micrograms/square meter/day intravenously over two hours. Continue therapy until the ANC is greater than 1500 cells/cubic millimeter for three consecutive days. In the event of a severe adverse reaction, the dose may be reduced by 50% or discontinued temporarily. If the ANC exceeds 20,000 cells/cubic millimeter, interrupt therapy or reduce the dose by 50%. Do not administer sargramostim until the post marrow infusion absolute neutrophil count is less than 500 cells/cubic millimeter. Discontinue sargramostim immediately if blast cells appear or disease progression occurs. Continuous intravenous infusions appear to be superior to both intravenous bolus injections and short intravenous infusions (Herrmann et al, 1989a; Rifkin et al, 1988). In some studies, daily intravenous bolus injections have not been effective in producing leukocytosis.
For delay or failure of myeloid engraftment, administer Leukine (sargramostim) 250 micrograms/square meter (mcg/m (2)/day as a two‐hour intravenous (IV) infusion for 14 days. If engraftment has not occurred after seven days off therapy, the dose can be repeated. If engraftment has still not occurred after another seven days off therapy, a third course of 500mcg/m (2)/day IV for 14 days may be given. Further dose escalation is unlikely to be beneficial. Reduce the dose by 50% or temporarily discontinue if a severe reaction occurs (respiratory distress, hypoxia, flushing, hypotension, syncope, and/or tachycardia). If the ANC exceeds 20,000 cells/cubic millimeter (mm (3), hold Leukine (sargramostim) therapy and reduce the dose by 50%. Discontinue immediately if blast cells appear or if disease progression occurs. It is possible that WBC CSF increases the risk of GvHD when given following allogeneic bone marrow or pbsc transplant.
For febrile neutropenia prophylaxis in acute myelogenous leukemia, if on day ten (from the start of chemotherapy) the bone marrow is hypoplastic with less than 5% blasts, administer Leukine (sargramostim) 250 microgram/square meter/day intravenously beginning on or about day 11 or four days following the completion of induction chemotherapy for AML. Continue Leukine (sargramostim) until the ANC is greater than 1500 cells/cubic millimeter for three consecutive days or a maximum of 42 days. If a second cycle of induction chemotherapy is required, administer Leukine (sargramostim) approximately four days following the completion of chemotherapy if the bone marrow is hypoplastic with less than 5% blasts. Discontinue Leukine (sargramostim) immediately if leukemic regrowth occurs. In the event of a severe adverse reaction, the dose may be reduced by 50% or discontinued temporarily. If the ANC exceeds 20,000 cells/cubic millimeter, interrupt therapy or reduce the dose by 50%. Continuous intravenous infusions appear to be superior to both intravenous bolus injections and short intravenous infusions. Twice daily subcutaneous administration of sargramostim was more effective than a daily two‐hour intravenous infusion.
Harvesting of peripheral blood stem cells: Administer Leukine (sargramostim) 250 micrograms/square meter/day as a 24‐hour intravenous infusion or subcutaneously once daily. Continue dosing through the period of peripheral blood progenitor cell (PBPC) collection. Although the optimal schedule for collection of PBPC has not been established, PBPC collection in clinical trials has usually started on day five and performed daily until the specified targets were attained. Reduce the dose of Leukine (sargramostim) by 50% if the white blood cell count is greater than 50,000 cells/cubic millimeter. Consider other mobilization therapy if adequate numbers of progenitor cells are not collected.
Peripheral blood stem cell graft, autologous, myeloid reconstitution following transplant in members mobilized with granulocyte macrophage colony stimulating factor: 250 mcg/m(2)/day IV over 24 hr or subcutaneously once daily; begin immediately following peripheral blood progenitor cell infusion and continue until the absolute neutrophil count is greater than 1500 cells/mm(3) for three consecutive days.
Febrile neutropenia prophylaxis, in non‐myeloid malignancies following myelosuppressive chemotherapy: 250 mcg/m
2/day administered intravenously or subcutaneously once daily for up to 14 days, although optimal dosing has not been defined.
Treatment of severe febrile neutropenia: The recommended dose is 250 mcg/m
2/day, administered intravenously or subcutaneously once daily until neutrophil recovery, although optimal dosing has not been defined.
Neutropenia in myelodysplastic syndromes: In members with myelodysplastic syndrome, increases in granulocyte counts, monocyte counts, and reticulocyte counts were reported with Leukine (sargramostim) in intravenous doses of 15 to 480 micrograms/square meter (mcg/m(2)/day. Sargramostim was administered as a one‐hour or four‐hour infusion daily for seven days, or as a 12‐hour infusion for 14 days. Sargramostim has also been given subcutaneously. Detectable increases in these blood counts were observed with the lowest doses; however, the largest response occurred in members treated with 240 to 480 mcg/m
2/day, although optimal dosing has not been defined.
Dose Adjustments
No recommendation can be made regarding the equivalency of Neupogen (filgrastim) and Leukine (sargramostim).
The liquid sargramostim formulation has been reintroduced into the United States market after an upward trend of reports of adverse effects, including syncope (with or without documented hypotension), which coincided with a change in the liquid sargramostim formulation to include edetate disodium (EDTA). The EDTA has since been removed from the currently available formulation.
Leukine should not be used in the following:
Neulasta (pegfilgrastim)
U.S. Food and Drug Administration (FDA)-Approved Indications
Patients with Cancer Receiving Myelosuppressive Chemotherapy
Neulasta is indicated to decrease the incidence of infection, as manifested by febrile neutropenia, in patients with non-myeloid malignancies receiving myelosuppressive anti-cancer drugs associated with a clinically significant incidence of febrile neutropenia.
Hematopoietic Subsyndrome of Acute Radiation Syndrome
Neulasta is indicated to increase survival in patients acutely exposed to myelosuppressive doses of radiation (Hematopoietic Subsyndrome of Acute Radiation Syndrome).
Neulasta (pegfilgrastim) is a covalent conjugate of recombinant methionyl human G‐CSF (filgrastim) and monomethoxypolyethylene glycol. Both filgrastim and Neulasta (pegfilgrastim) are colony stimulating factors that act on hematopoietic cells by binding to specific cell surface receptors thereby stimulating proliferation, differentiation, commitment, and end cell functional activation.
Neulasta (pegfilgrastim), a long acting version of Neupogen (filgrastim), is administered once per chemotherapy cycle. It is approved by the FDA to decrease the incidence of infection, as manifested by FN, in patients with non-myeloid malignancies receiving myelosuppressive anti-cancer drugs associated with a clinically significant incidence of FN. Neulasta is also approved for use in patients acutely exposed to myelosuppressive doses of radiation (Hematopoietic Subsyndrome of Acute Radiation Syndrome). Neulasta is not labeled for use in myeloid malignancies -- leukemias and lymphomas -- because there is concern that it may stimulate the tumor cells to grow and it is not currently indicated for stem cell mobilization.
In patients with cancer receiving myelosuppressive chemotherapy, pegfilgrastim was evaluated in three randomized, double-blind, controlled studies. Studies 1 and 2 were active-controlled studies that employed doxorubicin 60 mg/m
2and docetaxel 75 mg/m
2administered every 21 days for up to 4 cycles for the treatment of metastatic breast cancer. Study 1 investigated the utility of a fixed dose of pegfilgrastim. Study 2 employed a weight-adjusted dose. In the absence of growth factor support, similar chemotherapy regimens have been reported to result in a 100% incidence of severe neutropenia (ANC < 0.5 x 10
9/L) with a mean duration of 5 to 7 days and a 30% to 40% incidence of febrile neutropenia. Based on the correlation between the duration of severe neutropenia and the incidence of febrile neutropenia found in studies with filgrastim, duration of severe neutropenia was chosen as the primary endpoint in both studies, and the efficacy of pegfilgrastim was demonstrated by establishing comparability to filgrastim-treated patients in the mean days of severe neutropenia. In Study 1, 157 patients were randomized to receive a single subcutaneous injection of pegfilgrastim (6 mg) on day 2 of each chemotherapy cycle or daily subcutaneous filgrastim (5 mcg/kg/day) beginning on day 2 of each chemotherapy cycle. In Study 2, 310 patients were randomized to receive a single subcutaneous injection of pegfilgrastim (100 mcg/kg) on day 2 or daily subcutaneous filgrastim (5 mcg/kg/day) beginning on day 2 of each chemotherapy cycle. Both studies met the major efficacy outcome measure of demonstrating that the mean days of severe neutropenia of pegfilgrastim-treated patients did not exceed that of filgrastim-treated patients by more than 1 day in cycle 1 of chemotherapy. The mean days of cycle 1 severe neutropenia in Study 1 were 1.8 days in the pegfilgrastim arm compared to 1.6 days in the filgrastim arm [difference in means 0.2 (95% CI -0.2, 0.6)] and in Study 2 were 1.7 days in the pegfilgrastim arm compared to 1.6 days in the Filgrastim arm [difference in means 0.1 (95% CI -0.2, 0.4)]. A secondary endpoint in both studies was days of severe neutropenia in cycles 2 through 4 with results similar to those for cycle 1.
Study 3 was a randomized, double-blind, placebo-controlled study that employed docetaxel 100 mg/m
2administered every 21 days for up to 4 cycles for the treatment of metastatic or non-metastatic breast cancer. In this study, 928 patients were randomized to receive a single subcutaneous injection of pegfilgrastim (6 mg) or placebo on day 2 of each chemotherapy cycle. Study 3 met the major trial outcome measure of demonstrating that the incidence of febrile neutropenia (defined as temperature ≥ 38.2°C and ANC ≤ 0.5 x10
9/L) was lower for pegfilgrastim-treated patients as compared to placebo-treated patients (1% versus 17%, respectively, p < 0.001). The incidence of hospitalizations (1% versus 14%) and IV anti-infective use (2% versus 10%) for the treatment of febrile neutropenia was also lower in the pegfilgrastim-treated patients compared to the placebo-treated patients.
Study 4 was a multicenter, randomized, open-label study to evaluate the efficacy, safety, and pharmacokinetics of pegfilgrastim in pediatric and young adult patients with sarcoma. Patients with sarcoma receiving chemotherapy age 0 to 21 years were eligible. Patients were randomized to receive subcutaneous pegfilgrastim as a single dose of 100 mcg/kg (n= 37) or subcutaneous filgrastim at a dose 5 mcg/kg/day (n=6) following myelosuppressive chemotherapy. Recovery of neutrophil counts was similar in the pegfilgrastim and filgrastim groups. The most common adverse reaction reported was bone pain.
Efficacy studies of Neulasta (pegfilgrastim) could not be conducted in humans with acute radiation syndrome for ethical and feasibility reasons. Approval of this indication was based on efficacy studies conducted in animals and data supporting the use Neulasta’s (pegfilgrastim) effect on severe neutropenia in patients with cancer receiving myelosuppressive chemotherapy.
According to the FDA-approved labeling, the recommended dose of Neulasta for febrile neutropenia prophylaxis is a single subcutaneous injection of 6 mg, administered once per chemotherapy cycle. According to the labeling, Neulasta should not be administered in the period between 14 days before and 24 hours after administration of cytotoxic chemotherapy. Neulasta cannot be given more than once per chemotherapy cycle and cannot be given more often than every 14 days. Therefore, Neulasta (pegfilgrastim) should not be utilized in myelosuppressive chemotherapy regimens that are administered more frequently than every two weeks.
The recommended dose for hematopoietic subsyndrome of acute radiation syndrome is two doses of 6 mg each, administered subcutaneous injection one week apart. For dosing in pediatric patients, please refer to Full Prescribing Information. Administer the first dose as soon as possible after suspected or confirmed exposure to radiation doses greater than 2 gray (Gy). Administer the second dose one week after the first dose.
A healthcare provider must fill the On‐body Injector with Neulasta using the prefilled syringe and then apply the On‐body Injector for Neulasta to the patient’ skin (abdomen or back of arm). The back of the arm may only be used if there is a caregiver available to monitor the status of the On‐body Injector for Neulasta. Approximately 27 hours after the On‐body Injector for Neulasta is applied to the patient’ skin, Neulasta will be delivered over approximately 45 minutes. A healthcare provider may initiate administration with the On‐body Injector for Neulasta on the same day as the administration of cytotoxic chemotherapy, as long as the On‐body Injector for Neulasta delivers Neulasta no less than 24 hours after administration of cytotoxic chemotherapy. Refer to the Healthcare Provider Instructions for Use for the On‐body Injector for Neulasta for full administration information.
It is not recommend to split the Neulasta (pegfilgrastim) dose (to achieve <6mg dosing) due to inconformities in the pegylated mixture leading to the possibility of inaccurate dosing and increased drug wastage/cost. The 6mg formulation is not intended to be utilized in this manner by the manufacturer and these dosing strategies are not FDA approved. Alternative white blood cell colony stimulating factor formulations should be utilized when the 6mg Neulasta (pegfilgrastim) dose is viewed as supratherapeutic by the prescribing oncologist.
Neulasta (pegfilgrastim) should not be used in the following:
NCCN guidelines on myeloid growth factors state that administration of pegfilgrastim next day or up to 3 to 4 days following chemotherapy is preferred; however the panel agreed that same-day administration of pegfilgrastim may be considered under certain circumstances, defined as administration of pegfilgrastim on the day during which patients receive chemotherapy. NCCN panelists stated that same-day administration is done for logistical reasons and to minimize burdens on long-distance patients. NCCN guidelines note that clinical trials both in support of and against same-day pegfilgrastim have been published. The guidelines explain that the original rationale for not giving same-day CSF was the potential for increased neutropenia resulting from CSF stimulation of myeloid progenitors at the time of cytotoxic chemotherapy. The guidelines cited a direct comparison (citing Kaufman, et al.), where pegfilgrastim was administered either same-day or next-day in women with breast cancer receiving chemotherapy. Febrile neutropenia was observed in 33 percent of patients treated in the same-day group compared with only 11 percent of patients in the next-day group. The NCCN guidelines observed that a similar trend was seen in a prospective randomized double-blind trial of patients receiving chemotherapy for NHL where same-day pegfilgrastim was associated with enhanced myelosuppression and no reduction of leukopenia was seen. However, despite longer duration of grade 4 neutropenia in the same-day group, there was no increase in the overall incidence of neutropenia and the increased duration did not meet the non-inferiority margin. The guidelines noted that, while this study recommends administration of pegfilgrastim 24 hours after chemotherapy, it was acknowledged that same-day administration may be an acceptable alternative for some patients.
NCCN guidelines also described a retrospective review by Vance, et al. of same-day pegfilgrastim in patients with breast cancer receiving chemotherapy and no increased neutropenia was observed. The guidelines also identified a retrospective study of 159 patients with a variety of tumor types and chemotherapy regimens showing a similar incidence of myelosuppressive adverse events when comparing the two groups. A double-blind phase II study in patients with non-small cell lung cancer treated with chemotherapy showed no increase in neutropenia nor any adverse events in patients receiving same-day pegfilgrastim compared to patients receiving next-day pegfilgrastim treatment. The benefit of same-day pegfilgrastim was also observed in patients with non-small cell lung cancer treated with weekly chemotherapy regimens. Same day pegfilgrastim in these patients was shown to be beneficial not only from a safety perspective but also from a logistical one where next-day pegfilgrastim would have compromised the weeily chemotherapy schedule. Anotehr study in pateints with lung cancer showed an unexpected low rate of severe neutropenia (only 2 patients per group) suggesting that same-day filgrastim is a reasonable option. More recent retrospective studies in patients with gynecologic malignancies demonstrated the safety and efficacy of pegfilgrastim administered within 24 hours of chemotherapy.
Micromedex DrugDex compendium states that the use of pegfilgrastim in the period between 14 days before and 24 hours after chemotherapy is not recommended. It states that pegfilgrastim administered once on the same day as chemotherapy was shown to be noninferior to pegfilgrastim administered once 24 hours after chemotherapy for the duration of grade 4 neutropenia after the first cycle of chemotherapy in patients with breast cancer and non-Hodgkin lymphoma; however, the duration of grade 4 neutropenia was longer and the incidence of febrile neutropenia was higher with same-day compared with next-day administration. The Compendium cited a study by Burris, et al. that compared data on severe (grade 4) neutropenia duration and febrile neutropenia incidence in patients receiving chemotherapy with pegfilgrastim administered the same day or 24 hours after chemotherapy. Burris, et al. noted that these were similar, randomized, double-blind phase II noninferiority studies of patients with lymphoma or non-small-cell lung (NSCLC), breast, or ovarian cancer. Each study was analyzed separately. The primary end point in each study was cycle-1 severe neutropenia duration. Approximately 90 patients per study were to be randomly assigned at a ratio of 1:1 to receive pegfilgrastim 6 mg once per cycle on the day of chemotherapy or the day after (with placebo on the alternate day). The authors found that, in four studies, 272 patients received chemotherapy and one or more doses of pegfilgrastim (133 same day, 139 next day). Three studies (breast, lymphoma, NSCLC) enrolled an adequate number of patients for analysis. However, in the NSCLC study, the neutropenic rate was lower than expected (only two patients per arm experienced grade 4 neutropenia). In the breast cancer study, the mean cycle-1 severe neutropenia duration was 1.2 days (95% confidence limit [CL], 0.7 to 1.6) longer in the same-day compared with the next-day group (mean, 2.6 v 1.4 days). In the lymphoma study, the mean cycle-1 severe neutropenia duration was 0.9 days (95% CL, 0.3 to 1.4) longer in the same-day compared with the next-day group (mean, 2.1 v 1.2 days). In the breast and lymphoma studies, the absolute neutrophil count profile for same-day patients was earlier, deeper, and longer compared with that for next-day patients, although the results indicate that same-day administration was statistically noninferior to next-day administration according to neutropenia duration. The authors concluded that, for or patients receiving pegfilgrastim with chemotherapy, pegfilgrastim administered 24 hours after chemotherapy completion is recommended.
An UpToDate review of the use of granulocyte colony stimulating factors in adult patients with chemotherapy-induced neutropenia (Larson, 2023) stated: "Because of the potential sensitivity of rapidly dividing myeloid cells to cytotoxic chemotherapy, growth factors should be discontinued several days before the next chemotherapy treatment and they should not be given on the same day as chemotherapy. Experience from clinical trials indicates that myelosuppression is more profound if the myeloid growth factors were given immediately prior to or on the same day as the chemotherapy. For the same reason, growth factors should not be given concurrently with radiation therapy directed at portals containing active marrow."
Hematological side effects (e.g., anemia, neutropenia, and thrombocytopenia) of combination therapy with pegylated (PEG)-interferon alfa and ribavirin are commonly encountered during antiviral therapy for chronic hepatitis C (HCV) (Collantes and Younossi, 2005). An important consequence of these side effects is dose modification of PEG-interferon alfa, ribavirin, or both. The FDA-approved product labeling of both peginterferon preparations (alfa-2a and alfa-2b) recommend dose reduction for patients with neutrophils counts less than 750 cells/mm
3and drug discontinuation for those with counts less than 500 cells/mm
3. However, there has been concern that such dose modifications will diminish the effectiveness of optimal treatment regimen for HCV and may have a negative impact on sustained virological response.
Collantes and Younossi (2005) note that the clinical implications of neutropenia or thrombocytopenia are less clear than for anemia; nevertheless, severe infection and bleeding are uncommon. Dose adjustments effectively treat these hematological side effects, but the resulting sub-optimal dosing and potential impact on virological response are major concerns. Recent attempts to maximize adherence to the optimal treatment regimen have used hematopoietic growth factors rather than dose adjustment to treat side effects. Research on growth factor support has focused on anemia and neutropenia. Erythropoietin and darbepoetin alfa are erythropoietic growth factors that effectively increase hemoglobin while maintaining the optimal ribavirin dose and improving patients' quality of life (see
CPB 0195 - Erythropoiesis Stimulating Agentsor
CPB 0195m - Erythropoiesis Stimulating Agents [Medicare]).
CSFs should not be used for routine prophylaxis in member/chemotherapy regimens without significant risk of febrile neutropenia or in members that are not receiving myelosuppressive chemotherapy. They should also not be used in persons with hypersensitivity to the product or its components or to E. coli derived proteins.
Investigators have examined the potential for adjunctive use of the granulocyte colony stimulating factor (G-CSF) filgrastim to improve clinical outcomes in persons with chronic hepatitis C. Early clinical studies found that routine co-administration of filgrastim failed to significantly enhance the sustained virologic response to interferon-based therapies in hepatitis C (Gronbaek et al, 2002; Van Thiel et al, 1995). Clinical studies are needed to assess the effectiveness of G-CSF to treat chemotherapy induced neutropenia in hepatitis C.
Collantes and Younossi (2005) concluded that, although filgrastim shows tremendous promise for managing hematological side effects of combination therapy for HCV, and potentially enhancing adherence, further research is needed to clarify the safety, effectiveness, and cost-effectiveness of growth factors in the management of patients with chronic HCV. Ong and Younossi (2004) reached similar conclusions, noting that the impact of growth factors on sustained virological response and their cost-effectiveness in patients with chronic HCV need further assessment.
The Canadian Agency for Drugs and Technologies in Health (Dryden et al, 2008) released a report on G-CSF for antiviral-associated neutropenia. A systematic review was used to evaluate the effect of treatment with G-CSF compared with that of interferon dose reduction to control neutropenia. It was not superior to interferon dose reduction. While G-CSF may enable patients to stay on or resume optimal antiviral therapy, the evidence is weak. The mild adverse effects respond to simple treatments that alleviate symptoms. The report concluded that it is unclear if the use of G-CSF compared with dose reduction improves sustained virological response in patients with hepatitis C and neutropenia.
Early research is examining the potential for G-CSF to enhance myocardial function in myocardial infarction (MI). In a prospective, randomized, double-blinded, placebo-controlled phase II clinical trial, Engelmann et al (2006) compared the effects of G-CSF on the improvement of MI in patients undergoing delayed percutaneous coronary intervention (PCI) for ST-segment elevation MI (STEMI). A total of 44 patients with late re-vascularized subacute STEMI were treated either with G-CSF or placebo over 5 days after successful PCI. Primary end points were change of global and regional MI from baseline (1 week after PCI) to 3 months after PCI evaluated by magnetic resonance imaging (MRI). Secondary end points consisted of characterization of mobilized stem cell populations, assessment of safety parameters up to 12 months including 6-month angiography, as well as myocardial perfusion evaluated by MRI. Global myocardial function from baseline (1 week after PCI) to 3 months improved in both groups, but G-CSF was not superior to placebo. A slight but non-significant improvement of regional function occurred in both groups. Granulocyte-CSF resulted in mobilization of endothelial progenitor cell populations and was well-tolerated with a similar rate of target lesion re-vascularization from in-stent re-stenosis. In both groups major adverse cardiovascular events occurred in a comparable frequency; G-CSF resulted in significant improvement of myocardial perfusion 1 week and 1 month after PCI. The authors concluded that G-CSF treatment after PCI in subacute STEMI is feasible and relatively safe. However, patients do not benefit from G-CSF when PCI is performed late. They noted that as a result of its phase II character, this trial is limited by its small sample size. These investigators stated that further research should focus on immediate administration of G-CSF in early re-vascularized MI and on larger multi-center studies examining clinical outcomes.
In a meta-analysis, Abdel-Latif and colleagues (2008) examined the effects of G-CSF therapy for cardiac repair after acute MI. These investigators searched Medline, Embase, Science Citation Index, CINAHL, and the Cochrane Central database of controlled clinical trials for randomized controlled trials of G-CSF therapy in patients with acute MI. They conducted a fixed-effects meta-analysis across 8 eligible studies (n = 385 patients). Compared with controls, G-CSF therapy increased LV ejection fraction (EF) by 1.09 %, increased LV scar size by 0.22 %, decreased LV end-diastolic volume by 4.26 ml, and decreased LV end-systolic volume by 2.50 ml. None of these effects was statistically significant. The risk of death, recurrent MI, and in-stent re-stenosis was similar in G-CSF-treated patients and controls. Subgroup analysis revealed a modest but statistically significant increase in EF (4.73 %, p < 0.0001) with G-CSF therapy in studies that enrolled patients with mean EF less than 50 % at baseline. Subgroup analysis also showed a significant increase in EF (4.65 %, p < 0.0001) when G-CSF was administered relatively early (less than or equal to 37 hours) after the acute event. The authors concluded that G-CSF therapy in unselected patients with acute MI appears safe but does not provide an overall benefit. Subgroup analyses suggested that G-CSF therapy may be salutary in acute MI patients with LV dysfunction and when started early. They stated that larger randomized studies are needed to evaluate the potential benefits of early G-CSF therapy in acute MI patients with LV dysfunction. This is in agreement with the findings of Zohlnhöfer et al (2008) who reported that available evidence does not support a beneficial effect of G-CSF in patients with acute MI after re-perfusion.
Beohar et al (2010) stated that cytokine therapy including G-CSF and granulocyte-macrophage colony stimulating factor (GM-CSF) promises to provide a non-invasive treatment option for ischemic heart disease. Cytokines are thought to influence angiogenesis directly via effects on endothelial cells or indirectly through progenitor cell-based mechanisms or by activating the expression of other angiogenic agents. Several cytokines mobilize progenitor cells from the bone marrow or are involved in the homing of mobilized cells to ischemic tissue. The recruited cells contribute to myocardial regeneration both as a structural component of the regenerating tissue and by secreting angiogenic or anti-apoptotic factors, including cytokines. To date, randomized controlled trials (RCTs) have not reproduced the efficacy observed in pre-clinical and small-scale clinical investigations. Nevertheless, the list of promising cytokines continues to grow, and combinations of cytokines, with or without concurrent progenitor cell therapy, warrant further investigation. In particular, the authors stated that the mechanism of action and potential inflammatory sequelae associated with GM-CSF must be better understood and controlled before larger human trials can be considered.
A Cochrane review found insufficient evidence to support the use of G-CSF for treating stroke (Bath and Sprigg, 2006). The investigators found that G-CSF was associated with a non-significant reduction in combined death and dependency in 2 small trials (n = 46 subjects), although there was substantial heterogeneity in this result. These investigators concluded that there was insufficient evidence to support the use of G-CSF in the treatment of patients with recurrent stroke.
In a Cochrane review, Cheng et al (2007) examined the role of G-CSF as an adjunct to antibiotics in the treatment of pneumonia in non-neutropenic adults. The investigators found that, when, combined with antibiotics, G-CSF appears to be a safe treatment for people with pneumonia, but it does not appear to reduce mortality. The authors concluded that currently there is no evidence to support the routine use of G-CSF in the treatment of pneumonia. They noted that studies in which G-CSF is administered prophylactically or earlier in therapy may be of interest.
Felty syndrome (FS) is a rare but severe subset of sero-positive rheumatoid arthritis (RA) complicated by granulocytopenia and splenomegaly; occurring in less than 1 % of patients with RA. The granulocytopenia in FS may improve when RA is treated with second-line medications such as gold, methotrexate, and corticosteroids. Moreover, G-CSF has been studied in the treatment of patients with FS.
Stanworth and co-workers (1998) prospectively monitored the use of G-CSF in 8 FS patients with recurrent infections or who required joint surgery. Significant side effects were documented in 5, including nausea, malaise, generalized joint pains, and in 1 patient, a vasculitic skin rash. In 2 patients treatment had to be stopped, and in these cases G-CSF had been started at full vial dosage (300 micrograms/ml filgrastim or 263 micrograms/ml lenograstim) alternate days or daily. Treatment with G-CSF was continued in 3 patients by re-starting at a lower dose, and changing the proprietary formulation. Treatment with G-CSF increased the neutrophil count, decreased severe infection, and allowed surgery to be performed. A combined clinical and laboratory index suggested that long-term treatment (up to 3.5 years) did not exacerbate the arthritis. Once on established treatment, it may be possible to use smaller weekly doses of G-CSF to maintain the same clinical benefit. One of the 3 patients whose FS was associated with a large granular T-cell lymphocytosis showed a reduction in this subset of lymphocytes during G-CSF treatment.
Balint and Balint (2004) noted that over 95 % of FS patients are positive for rheumatoid factor, 47 to 100 % are positive for anti-nuclear antibody (ANA), and 78 % of patients have the HLA-DR4*0401 antigen. Some 30 % of FS patients have large granular lymphocyte expansion. Large granular lymphocyte expansion associated with uncomplicated RA is immunogenetically and phenotypically very similar to but clinically different from FS. Neutropenia of FS can be effectively treated with disease-modifying anti-rheumatic drugs, the widest experience being with methotrexate. Furthermore, results of treatment with G-CSF are encouraging. Splenectomy results in immediate improvement of neutropenia in 80 % of the patients, but the rate of infection decreases to a lesser degree.
In a phase I study, Sato et al (2008) examined the feasibility and safety of immuno-embolization with GM-CSF; sargramostim for malignant liver tumors, predominantly hepatic metastases from patients with primary uveal melanoma. A total of 39 patients with surgically unresectable malignant liver tumors, including 34 patients with primary uveal melanoma, were enrolled. Hepatic artery embolization accompanied an infusion of dose-escalated GM-CSF (25 to 2,000 microg) given every 4 weeks. Primary end points included dose-limiting toxicity and maximum tolerated dose (MTD). Patients who completed 2 cycles of treatments were monitored for hepatic anti-tumor response. Survival rates of patients were also monitored. Maximum tolerated dose was not reached up to the dose level of 2,000 microg, and there were no treatment-related deaths. A total of 31 assessable patients with uveal melanoma demonstrated 2 complete responses, 8 partial responses, and 10 occurrences of stable disease in their hepatic metastases. The median overall survival of intent-to-treat patients who had metastatic uveal melanoma was 14.4 months. Multi-variate analyses indicated that female sex, high doses of GM-CSF (greater than or equal to 1,500 microg), and regression of hepatic metastases (complete and partial responses) were correlated to longer overall survival. Moreover, high doses of GM-CSF were associated with prolonged progression-free survival in extra-hepatic sites. The authors concluded that immuno-embolization with GM-CSF is safe and feasible in patients with hepatic metastasis from primary uveal melanoma. Encouraging preliminary efficacy and safety results warrant additional clinical study in metastatic uveal melanoma.
Daud et al (2008) conducted a prospective trial in patients with high-risk (stage III B/C, IV), resected melanoma, with GM-CSF 125 microg/m(2)/d administered for 14 days every 28 days. Patients underwent clinical restaging every 4 cycles, with dendritic cells (DCs) analysis performed at baseline and at 2, 4, 8, and 12 weeks. Of 42 patients enrolled, 39 were assessable for clinical outcome and DC analysis. Median overall survival was 65 months (95 % confidence interval [CI]: 43 to 67 months) and recurrence-free survival was 5.6 months (95 % CI: 3 to 11 months). Treatment with GM-CSF caused an increase in mature DCs, first identified after 2 weeks of treatment, normalizing by 4 weeks. Patients with decreased DCs at baseline had significant increases in DC number and function compared with those with "normal" parameters at baseline. No change was observed in the number of myeloid-derived suppressor cells (MDSCs). Early recurrence (less than 90 days) correlated with a decreased effect of GM-CSF on host DCs, compared with late or no (evidence of) recurrence. The authors concluded that GM-CSF treatment was associated with a transient increase in mature DCs, but not MDSCs. Greater increase of DCs was associated with remission or delayed recurrence. The prolonged overall survival observed warrants further exploration.
In a phase I study, Lutzky et al (2009) evaluated the safety and tolerability of adjuvant treatment with subcutaneous GM-CSF administered in combination with escalating doses of thalidomide in patients with surgically resected stage II (T4), III, or IV melanoma at high risk for recurrence. Adjuvant treatment included GM-CSF 125 microg/m
2subcutaneously for 14 days and thalidomide at an initial dose of 50 mg/d, escalated in cohorts of 3 to 6 patients each to a maximum of 400 mg/day followed by 14 days of rest. Treatment was continued for up to 1 year in the absence of disease progression. Of 19 patients treated, the most common toxicities were grade 1/2 constipation (68 %), fatigue (58 %), neuropathy (42 %), bone and joint pain (37 %), and dyspnea, dizziness, injection site skin reaction, and somnolence (32 % each). Thrombotic events in 3 of 19 patients (16 %), including 1 treatment-related death, were the most serious adverse events and were thought to be due to thalidomide. With a median follow-up of 945 days (2.6 years), 8 (42 %) patients were alive, including 1 with disease and 7 without evidence of disease. Treatment with GM-CSF plus thalidomide for patients with resected high-risk melanoma was associated with a high incidence of thrombotic events. Because life-threatening events are unacceptable in the adjuvant setting, up-front anti-thrombotic prophylaxis will be necessary for further evaluation of GM-CSF plus thalidomide as a viable regimen in this patient group.
In a phase I-II study, Urba and colleagues (2008) evaluated the safety, clinical activity and immunogenicity of an immunotherapy developed from human prostate cancer cell lines (PC-3 and LNCaP) modified to secrete GM-CSF. Patients with non-castrate prostate cancer with biochemical (prostate specific antigen) recurrence following prostatectomy or radiation therapy and no radiological evidence of metastasis were enrolled in the study (n = 19). They were injected with an initial dose of 5 x 10(8) cells followed by 12 bi-weekly administrations of 1 x 10(8) cells. The adverse event profile, prostate specific antigen (PSA) response, changes in PSA kinetics and immunogenicity were assessed. Immunotherapy was well-tolerated with no serious treatment related adverse events and no autoimmune reactions. A negative deflection in PSA slope was observed in 84 % of patients after treatment with a significant increase in median PSA doubling time from 28.7 weeks before treatment to 57.1 weeks after treatment (p = 0.0095). Median time to PSA progression was 9.7 months. Immunoblot analysis of patient serum demonstrated new or enhanced production of PC-3 or LNCaP reactive antibodies in 15 of 19 (79 %) patients after immunotherapy. Induction of antibody responses reactive against PC-3 in general, and to the PC-3 associated filamin-B protein specifically, were positively associated with treatment associated changes in PSA kinetics. The authors concluded that GM-CSF secreting cellular immunotherapy has a favorable toxicity profile with signals of clinical and immunological activity against hormone naïve prostate cancer. An association between immune response and PSA changes was observed. Phase 3 trials in patients with advanced, metastatic, hormone refractory prostate cancer are under way.
In an open-label, multi-center, dose-escalation study, Higano and associates (2008) assessed multiple dose levels of immunotherapy in patients with metastatic hormone-refractory prostate cancer (HRPC). The immunotherapy, based on the GVAX (prostate cancer vaccine) platform, consisted of 2 allogeneic prostate-carcinoma cell lines modified to secrete GM-CSF. Dose levels ranged from 100 x 10(6) cells q28d x 6 to 500 x 10(6) cells prime/300 x 10(6) cells boost q14d x 11. Endpoints included safety, immunogenicity, overall survival, radiologic response, PSA kinetics, and serum GM-CSF pharmacokinetics. A total of 80 men, median age of 69 years (range of 49 to 90 years), were treated. The most common adverse effect was injection-site erythema. Overall, the immunotherapy was well-tolerated. A maximal tolerated dose was not established. The median survival time was 35.0 months in the high-dose group, 20.0 months in the mid-dose, group, and 23.1 months in the low-dose group. Prostate specific antigen stabilization occurred in 15 (19 %) patients, and a greater than 50 % decline in PSA was seen in 1 patient. The proportion of patients who generated an antibody response to 1 or both cell lines increased with dose and included 10 of 23 (43 %) in the low-dose group, 13 of 18 (72 %) in the mid-dose group, and 16 of 18 (89 %) in the high-dose group (p = 0.002; Cochran-Armitage trend test). The authors concluded that this immunotherapy was well-tolerated; immunogenicity and overall survival varied by dose. They also noted that 2 phase III clinical trials in patients with metastatic HRPC are underway.
Si et al (2009) examined the effects of combined cryoablation and GM-CSF treatment for metastatic hormone refractory prostate cancer. A total of 12 patients with metastatic hormone refractory prostate cancer were treated by combining cryoablation and GM-CSF administration. Besides PSA measurements, peripheral blood mononuclear cells were also obtained; the frequency of tumor-specific T cells was tested ex vivo in an interferon-gamma enzyme-linked immunospot assay after stimulating with autologous prostate cancer-derived protein lysates. To assess cytolytic activity, T cells were co-incubated with LNCaP or renal cancer cells (GRC-1), and release of cytosolic adenylate kinase was measured by a luciferase assay. The median PSA decline percentage was 69.4 % (range of 30.5 % to 92.5 %) and the median time to the nadir PSA was 4 months after therapy (range of 3 to 6 months). The median time to disease progress was 18 months, and 1 patient obtained a 92.5 % PSA decline and a greater than 50 % reduction of lung disease and survived 31 months. Four or 8 weeks after treatment, the tumor-specific T-cell responses were increased in peripheral blood mononuclear cell. The cytolytic activity against LNCaP was also increased significantly whereas no response was found against GRC-1. It seemed that there was no direct correlation between the degree of T-cell response and decline in PSA. The authors suggested that combined cryoablation with GM-CSF treatment may be an alternative approach for metastatic hormone refractory prostate cancer.
Amato and colleagues (2009) evaluated the effectiveness of GM-CSF in combination with thalidomide on PSA reduction in hormone-naïve prostate carcinoma (HNPC) patients with rising PSA levels after definitive local treatment. Patients (n = 21) with evidence of progression demonstrated by 3 consecutive rises in PSA and no evidence of radiographic involvement were treated on a chronic dosing schedule with GM-CSF. They received 250 microg/m
2(maximum 500 microg) 3 times a week by subcutaneous injection, with injections at least 24 hours apart. Thalidomide administration began concurrently with an initial dose of 100 mg daily for 7 consecutive days. During week 2 to 4, the dose was escalated every 7 days by 100 mg per individual tolerance to a maximum of 400 mg. The maximum tolerated dose of thalidomide was continued without interruption. Prostate specific antigen, testosterone, and routine laboratory parameters were measured every 6 weeks. One patient was not evaluable because of non-compliance. For the 20 evaluable patients, baseline PSA levels ranged from 1.3 to 61.0 ng/ml. A total of 19 patients left the study at 3.0 to 33.3 months, secondary to individual tolerance, progressive disease, or development of a second primary tumor. One patient continues to receive therapy at 33.8 months. Two patients did not respond to the therapy. For the 18 patients who did respond, the median reduction in PSA level was 59 % (range of 26 % to 89 %), and the median duration of response was 11 months (range of 4.5 to 36 months). Grades 1-2 toxicity included peripheral neuropathy, fatigue, skin rash, and constipation. One patient had deep-vein thrombosis/pulmonary embolism. The authors concluded that GM-CSF plus thalidomide can be administered successfully with encouraging anti-tumor activity and reversible toxicity. This may represent an alternative to hormonal therapy.
Battiwalla and McCarthy (2009) noted that the cytokine G-CSF stimulates myeloid progenitors and is routinely used to accelerate neutrophil recovery in the treatment of hematological malignancy and blood or marrow transplantation. Despite significant reductions in the frequency and duration of FN episodes, infections and the length of hospitalization, filgrastim has never been conclusively proven to produce a survival benefit in allogeneic hematopoietic stem cell transplantation (HSCT) and is considered a supportive measure. These investigators analyzed the conflicting evidence and appraised the utility of G-CSF in allogeneic HSCT. They concluded that G-CSF administration following allogeneic HSCT needs to take into consideration the impact on immune reconstitution, risk of leukemic progression in patients with chromosome 7 abnormalities and the absence of proven benefit in patients receiving marrow or peripheral blood progenitors as the stem cell source. The authors also noted that although there is conflicting evidence whether the administration of G-CSF post allogeneic transplant worsens survival, there is no apparent benefit.
In a single-blind, multi-center, RCT, Carr and associates (2009) examined if GM-CSF administered as prophylaxis to pre-term neonates at high-risk of neutropenia would reduce sepsis, mortality, and morbidity. A total of 280 neonates of below or equal to 31 weeks' gestation and below the 10th centile for birth weight were randomized within 72 hrs of birth to receive GM-CSF 10 microg/kg per day subcutaneously for 5 days or standard management. From recruitment to day 28, a detailed daily clinical record form was completed by the treating clinicians. Primary outcome was sepsis-free survival to 14 days from trial entry. Analysis was by intention-to-treat. Neutrophil counts after trial entry rose significantly more rapidly in infants treated with GM-CSF than in control infants during the first 11 days (difference between neutrophil count slopes 0.34 x 10(9)/L/day; 95 % CI: 0.12 to 0.56). There was no significant difference in sepsis-free survival for all infants (93 of 139 treated infants, 105 of 141 control infants; difference -8 %, 95 % CI: -18 to 3). A meta-analysis of this trial and previous published prophylactic trials showed no survival benefit. The authors concluded that early post-natal prophylactic GM-CSF corrects neutropenia but does not reduce sepsis or improve survival and short-term outcomes in extremely pre-term neonates.
In a meta-analysis, Bo et al (2011) examined the effects of G-CSF or GM-CSF therapy in non-neutropenic patients with sepsis. A systematic literature search of Medline, Embase and Cochrane Central Register of Controlled Trials was conducted using specific search terms. A manual review of references was also performed. Eligible studies were RCTs that compared G-CSF or GM-CSF therapy with placebo for the treatment of sepsis in adults. Main outcome measures were all-cause mortality at 14 days and 28 days after initiation of G-CSF or GM-CSF therapy, in-hospital mortality, reversal rate from infection, and adverse events. A total of 12 RCTs with 2,380 patients were identified. In regard to 14-day mortality, a total of 9 death events occurred among 71 patients (12.7 %) in the treatment group compared with 13 events among 67 patients (19.4 %) in the placebo groups. Meta-analysis showed there was no significant difference in 28-day mortality when G-CSF or GM-CSF were compared with placebo (relative risks (RR) = 0.93, 95 % CI: 0.79 to 1.11, p = 0.44; p for heterogeneity = 0.31, I2 = 15 %). Compared with placebo, G-CSF or GM-CSF therapy did not significantly reduce in-hospital mortality (RR = 0.97, 95 % CI: 0.69 to 1.36, p = 0.86; p for heterogeneity = 0.80, I2 = 0 %). However, G-CSF or GM-CSF therapy significantly increased the reversal rate from infection (RR = 1.34, 95 % CI: 1.11 to 1.62, p = 0.002; p for heterogeneity = 0.47, I2 = 0 %). No significant difference was observed in adverse events between groups (RR = 0.93, 95 % CI: 0.70 to 1.23, p = 0.62; p for heterogeneity = 0.03, I2 = 58 %). Sensitivity analysis by excluding one trial did not significantly change the results of adverse events (RR = 1.05, 95 % CI: 0.84 to 1.32, p = 0.44; p for heterogeneity = 0.17, I2 = 36 %). The authors concluded that there is no current evidence supporting the routine use of G-CSF or GM-CSF in patients with sepsis. They stated that large prospective multi-center clinical trials investigating monocytic HLA-DR (mHLA-DR)-guided G-CSF or GM-CSF therapy in patients with sepsis-associated immunosuppression are needed.
Granulocyte-CSF is used to mobilize CD34+ hematopoietic stem cells from the bone marrow to the peripheral blood. In a pilot study, Nefussy et al (2010) examined the use cell subsets induced by G-CSF to slow down disease progression in patients with amyotrophic lateral sclerosis (ALS). Patients with definite or probable ALS were assigned in a double-blind manner to receive G-CSF or placebo every 3 months for 1 year. The primary outcome measure was the functional decline, measured by the revised ALS Functional Rating Scale, Revised (ALSFRS-R) score. Secondary outcome measures included vital capacity, manual muscle strength, compound muscle action potential amplitudes, neurophysiological index, and McGill single item quality of life score (QoL). A total of 39 patients were enrolled. Seventeen patients who received G-CSF and 18 who received placebo were evaluated. Granulocyte-CSF was effective in mobilizing CD34+ to blood. The outcome measures used showed no statistically significant benefit, although there was a trend of slowing disease progression following 2 G-CSF treatments, as shown by lower slopes of ALSFRS-R and QoL in the first 6 treatment months. The treatment had no major side-effects. The authors concluded that G-CSF administration in ALS patients caused successful mobilization of autologous bone marrow cells, but was not effective in slowing down disease deterioration.
In a Cochrane review, Minton et al (2010) evaluated the effectiveness of drugs for the management of cancer-related fatigue (CRF). These investigators searched the Cochrane Central Register of Controlled Trials (from Issue 2 2007) MEDLINE and EMBASE from January 2007 to October 2009 and a selection of cancer journals. They searched references of identified articles and contacted authors to obtain unreported data. Studies were included in the review if they meet the following criteria:Two review authors independently assessed trial quality and extracted data. Meta-analyses were performed on different drug classes using continuous variable data. A total of 50 studies met the inclusion criteria; and 6 additional studies were identified since the original review. Only 31 of these studies involving 7,104 participants were judged to have used a sufficiently robust measure of fatigue and thus were deemed suitable for detailed analysis. The drugs were still analyzed by class (anti-depressants, hemopoietic growth factors, progestational steroids, as well as psychostimulants). Methylphenidate showed a small but significant improvement in fatigue over placebo (Z = 2.83; p = 0.005). Since the publication of the original review increased safety concerns have been raised regarding erythropoietin and this can not now be recommended in practice. The authors concluded that there is increasing evidence that psychostimulant trials provide evidence for improvement in CRF at a clinically meaningful level. There is still a requirement for a large scale RCT of methylphenidate to confirm the preliminary results. There are new safety data that indicates that the hemopoietic growth factors are associated with increased adverse outcomes. These drugs can no longer be recommended in the treatment of CRF.
In a multi-center RCT, Korzenik et al (2005) investigated the effectiveness of sargramostim in treating Crohn's disease. A total of 124 patients with moderate-to-severe active Crohn's disease were randomly assigned to receive 6 µg of sargramostim per kilogram of body weight per day or placebo subcutaneously for 56 days using a 2:1 ratio. The primary end point was a clinical response, defined by a decrease from baseline of at least 70 points in the Crohn's Disease Activity Index (CDAI) at the end of treatment (day 57). Other end points included changes in disease severity and the health-related quality of life and adverse events. There was no significant difference in the rate of the primary end point of a clinical response defined by a decrease of at least 70 points in the CDAI score on day 57 between the sargramostim and placebo groups (54 % versus 44 %, p = 0.28). However, significantly more patients in the sargramostim group than in the placebo group reached the secondary end points of a clinical response defined by a decrease from baseline of at least 100 points in the CDAI score on day 57 (48 % versus 26 %, p = 0.01) and of remission, defined by a CDAI score of 150 points or less on day 57 (40 % versus 19 %, p = 0.01). The rates of either type of clinical response and of remission were significantly higher in the sargramostim group than in the placebo group on day 29 of treatment and 30 days after treatment. The sargramostim group also had significant improvements in the quality of life. Mild-to-moderate injection-site reactions and bone pain were more common in the sargramostim group, and 3 patients in this group had serious adverse events possibly or probably related to treatment. These investigators concluded that although this study was negative for the primary end point, findings for the secondary end points suggested that sargramostim therapy decreased disease severity and improved the quality of life in patients with active Crohn's disease. The authors noted that the role of GM-CSF in the biology of Crohn’s disease remains to be defined.
Tbo-filgrastim, a short-acting, synthetic form of G-CSF, is a biologic response modifier that binds to stem cells in bone marrow and stimulates the production of neutrophils. On August 29, 2012, the FDA approved the use of tbo-filgrastim (Neutroval) to reduce the duration of severe neutropenia in patients with non-myeloid malignancies receiving myelosuppressive anti-cancer drugs associated with a clinically significant incidence of febrile neutropenia. Tbo-filgrastim was evaluated in a clinical study of 348 adult patients with advanced breast cancer receiving treatment with the anti-cancer drugs doxorubicin and docetaxel. Patients were randomly assigned to receive tbo-filgrastim, a placebo, or a non-U.S.-approved filgrastim product, a drug that also stimulates neutrophil production by the bone marrow. The effectiveness of tbo-filgrastim was determined based on study results that showed that patients receiving tbo-filgrastim recovered from severe neutropenia in 1.1 days compared with 3.8 days in those receiving the placebo.
In a Cochrane review, Moazzami and associates (2013) assessed the effects of stem cell mobilization following G-CSF therapy in patients with acute MI. These investigators searched CENTRAL (The Cochrane Library Issue 4, 2010), MEDLINE (1950 to week 3 of November 2010), EMBASE (1980 to week 48 of 2010), BIOSIS Previews (1969 to November 30, 2010), ISI Science Citation Index Expanded (1970 to December 4, 2010) and ISI Conference Proceedings Citation Index - Science (1990 to December 4, 2010). These researchers also checked reference lists of articles. They included RCTS involving participants with a clinical diagnosis of acute MI who were randomly allocated to the subcutaneous administration of G-CSF through a daily dose of 2.5, 5 or 10 microgram/kg for 4 to 6 days or placebo. No age or other restrictions were applied for the selection of patients. Two authors independently selected trials, assessed trials for eligibility and methodological quality, and extracted data regarding the clinical efficacy and adverse outcomes. Disagreements were resolved by the third author. These investigators included 7 trials reported in 30 references in the review (354 participants). In all trials, G-CSF was compared with placebo preparations. Dosage of G-CSF varied among studies, ranging from 2.5 to 10 microgram/kg/day. Regarding overall risk of bias, data regarding the generation of randomization sequence and incomplete outcome data were at a low-risk of bias; however, data regarding binding of personnel were not conclusive. The rate of mortality was not different between the 2 groups (RR 0.64, 95 % CI: 0.15 to 2.80, p = 0.55). Regarding safety, the limited amount of evidence is inadequate to reach any conclusions regarding the safety of G-CSF therapy. Moreover, the results did not show any beneficial effects of G-CSF in patients with acute MI regarding left ventricular function parameters, including left ventricular ejection fraction (RR 3.41, 95 % CI: -0.61 to 7.44, p = 0.1), end systolic volume (RR -1.35, 95 % CI: -4.68 to 1.99, p = 0.43) and end diastolic volume (RR -4.08, 95 % CI: -8.28 to 0.12, p = 0.06). It should also be noted that the study was limited since the trials included lacked long enough follow-up durations. The authors concluded that limited evidence from small trials suggested a lack of benefit of G-CSF therapy in patients with acute MI. Moreover, they stated that since data of the risk of bias regarding blinding of personnel were not conclusive, larger RCTs with appropriate power calculations and longer follow-up durations are needed to address current uncertainties regarding the clinical effectiveness and therapy-related adverse events of G-CSF treatment.
In a Cochrane review, Bath and colleagues (2013) evaluatedThese investigators searched the Cochrane Stroke Group Trials Register (last searched September 2012), the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2012, Issue 4), MEDLINE (1985 to September 2012), EMBASE (1985 to September 2012) and Science Citation Index (1985 to September 2012). In an attempt to identify further published, unpublished and ongoing trials, these researchers contacted manufacturers and principal investigators of trials (last contacted April 2012). They also searched reference lists of relevant articles and reviews. They included RCTs recruiting people with acute or subacute ischemic or hemorrhagic stroke. Colony-stimulating factors included stem cell factor (SCF), erythropoietin (EPO), G-CSF, GM-CSF, macrophage-colony stimulating factor (M-CSF, CSF-1), thrombopoietin (TPO), or analogs of these. The primary outcome was functional outcome at the end of the trial. Secondary outcomes included safety at the end of treatment, death at the end of follow-up, infarct volume and hematology measures. Two review authors independently extracted data and assessed trial quality; they contacted study authors for additional information. These investigators included a total of 11 studies involving 1,275 participants. In 3 trials (n = 782), EPO therapy was associated with a significant increase in death by the end of the trial (odds ratio (OR) 1.98, 9 5% CI: 1.19 to 3.3, p = 0.009) and a non-significant increase in serious adverse events. Erythropoietin significantly increased the red cell count with no effect on platelet or white cell count, or infarct volume. Two small trials of carbamylated EPO have been completed but have yet to be reported. These researchers included 8 small trials (n = 548) of G-CSF. Granulocyte-CSF was associated with a non-significant reduction in early impairment (mean difference (MD) -0.4, 95 % CI: -1.82 to 1.01, p = 0.58); but had no effect on functional outcome at the end of the trial. Granulocyte-CSF significantly elevated the white cell count and the CD34+ cell count, but had no effect on infarct volume. Further trials of G-CSF are ongoing. The authors concluded that there are significant safety concerns regarding EPO therapy for stroke. It is too early to know whether other CSFs improve functional outcome.
Poole and colleagues (2013) stated that many patients with peripheral artery disease (PAD) have walking impairment despite therapy. Experimental studies in animals demonstrated improved perfusion in ischemic hind limb after mobilization of bone marrow progenitor cells (PCs), but whether this is effective in patients with PAD is unknown. These researchers examined if therapy with GM-CSF improves exercise capacity in patients with intermittent claudication. In a phase II, double-blind, placebo-controlled study, 159 patients (median [SD] age, 64 [8] years; 87 % male, 37 % with diabetes) with intermittent claudication were enrolled at medical centers affiliated with Emory University in Atlanta, Georgia, between January 2010 and July 2012. Participants were randomized (1:1) to receive 4 weeks of subcutaneous injections of GM-CSF (leukine), 500 μg/day 3 times a week, or placebo. Both groups were encouraged to walk to claudication daily. The primary outcome was peak treadmill walking time (PWT) at 3 months. Secondary outcomes were PWT at 6 months and changes in circulating PC levels, ankle brachial index (ABI), and walking impairment questionnaire (WIQ) and 36-item Short-Form Health Survey (SF-36) scores. Of the 159 patients randomized, 80 were assigned to the GM-CSF group. The mean (SD) PWT at 3 months increased in the GM-CSF group from 296 (151) seconds to 405 (248) seconds (mean change, 109 seconds [95 % CI: 67 to 151]) and in the placebo group from 308 (161) seconds to 376 (182) seconds (change of 56 seconds [95 % CI: 14 to 98]), but this difference was not significant (mean difference in change in PWT, 53 seconds [95 % CI: -6 to 112], p = 0.08). At 3 months, compared with placebo, GM-CSF improved the physical functioning subscore of the SF-36 questionnaire by 11.4 (95 % CI: 6.7 to 16.1) versus 4.8 (95 % CI: -0.1 to 9.6), with a mean difference in change for GM-CSF versus placebo of 7.5 (95 % CI: 1.0 to 14.0; p = 0.03). Similarly, the distance score of the WIQ improved by 12.5 (95 % CI: 6.4 to 18.7) versus 4.8 (95 % CI: -0.2 to 9.8) with GM-CSF compared with placebo (mean difference in change, 7.9 [95 % CI: 0.2 to 15.7], p = 0.047). There were no significant differences in the ABI, WIQ distance and speed scores, claudication onset time, or mental or physical component scores of the SF-36 between the groups. The authors concluded that therapy with GM-CSF 3 times a week did not improve treadmill walking performance at the 3-month follow-up. The improvements in some secondary outcomes with GM-CSF suggested that it may warrant further study in patients with claudication. In addition, further investigation is needed to investigate the variability of responsiveness to GM-CSF and its clinical significance.
Siristatidis et al (2013) noted that GM-CSF is a cytokine/growth factor produced by epithelial cells that exerts embryotrophic effects during the early stages of embryo development. These investigators performed a systematic review, and 6 studies that were performed in humans undergoing assisted reproduction technologies (ART) were located. They examined if embryo culture media supplementation with GM-CSF could improve success rates. As the type of studies and the outcome parameters investigated were heterogeneous, these researchers decided not to perform a meta-analysis. Most of the studies had a trend favoring the supplementation with GM-CSF, when outcomes were measured in terms of increased percentage of good-quality embryos reaching the blastocyst stage, improved hatching initiation and number of cells in the blastocyst, and reduction of cell death. However, no statistically significant differences were found in implantation and pregnancy rates in all apart from 1 large multi-center trial, which reported favorable outcomes, in terms of implantation and live birth rates. The authors proposed properly conducted and adequately powered RCTs to further validate and extrapolate the current findings with the live birth rate to be the primary outcome measure.
In a Cochrane review, Cruciani et al (2013) examined the effects of adjunctive G-CSF compared with placebo or no growth factor added to usual care on rates of infection, cure and wound healing in people with diabetes who have a foot infection. These investigators searched the Cochrane Wounds Group Specialised Register (searched March 14, 2013); the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2013, Issue 2); Ovid MEDLINE (1948 to week 1 of March 2013); Ovid EMBASE (1974 to March 13, 2013); Ovid MEDLINE (In-Process March 13,2013); and EBSCO CINAHL (1982 to February 28, 2013). Randomized controlled trials that evaluated the effect of adding G-CSF to usual care in people with a diabetic foot infection were included for analysis. Three review authors independently assessed trial eligibility, methodological quality and extracted data. They reported RR or, for continuous outcomes, MD, with 95 % CI. In the case of low or no heterogeneity these researchers pooled studies using a fixed-effect model. They identified and included 5 eligible trials with a total of 167 patients. The investigators administered various G-CSF preparations, at different doses and for different durations of time. Adding G-CSF did not significantly affect the likelihood of resolution of infection or wound healing, but it was associated with a significantly reduced likelihood of lower extremity surgical interventions (RR 0.38; 95 % CI: 0.21 to 0.70), including amputation (RR 0.41; 95 % CI: 0.18 to 0.95). Moreover, providing G-CSF reduced the duration of hospital stay (MD -1.40 days; 95 % CI: -2.27 to -0.53 days), but did not significantly affect the duration of systemic antibiotic therapy (MD -0.27 days; 95 % CI: -1.30 to 0.77 days). The authors concluded that the available evidence is limited, but suggests that adjunctive G-CSF treatment in people with a diabetic foot infection, including infected ulcers, does not appear to increase the likelihood of resolution of infection or healing of the foot ulcer. However, it does appear to reduce the need for surgical interventions, especially amputations, and the duration of hospitalization. Clinicians might consider adding G-CSF to the usual treatment of diabetic foot infections, especially in patients with a limb-threatening infection, but it is not clear which patients might benefit.
In a phase I/II clinical trial, Saberi et al (2014) examined the effect of spinal cord injury (SCI) severity on the neurological outcomes, after neuroprotective treatment for SCI with G-CSF. A total of 74 consecutive patients with SCI of at least 6 months duration, with stable neurological status in the last 3 months having informed consent, for the treatment were included in the study. All the patients had undergone at least 3 months of standard rehabilitation. Patients were assessed by American Spinal Injury Association (ASIA) scale, Spinal Cord Independence Measure (SCIM) III, and International Association of Neurorestoratology-Spinal Cord Injury Functional Rating Scale (IANR-SCIFRS) just before intervention and periodically until 6 months after subcutaneous administration of 5 g/kg per day of G-CSF for 7 consecutive days. Multiple linear regression models, was performed for statistical evaluation of lesion completeness and level of injury on changes in ASIA motor, light touch, pinprick, IANR-SCIFRS, and SCIM III scores, as a phase I/II, comparative study. The study consisted of 52 motor complete, and 22 motor incomplete SCI patients. There was not any significant difference regarding age and sex, chronicity, and level of SCI between the 2 groups. Motor incomplete patients had significantly more improvement in ASIA motor score compared to the motor complete patients (7.68 scores, p < 0.001) also they had significant improvement in light touch (6.42 scores, p = 0.003) and pin-prick sensory scores (4.89 scores, p = 0.011). Therefore, G-CSF administration in motor incomplete SCIs is associated with significantly higher motor improvement, and also the higher the initial ASIA Impairment Scale (AIS) grade, the less would be the final AIS change, and incomplete cases are more welcome into the future studies. The clinical value of G-CSF in patients with chronic spinal cord injuries need to be further investigated in phase III clinical studies.
Chung et al (2014) investigated the effects of G-CSF on glial scar formation after SCI in rats and compared the therapeutic effects between G-CSF and GM-CSF to evaluate G-CSF as a potential substitute for GM-CSF in clinical application. Rats were randomly assigned to 1 of 4 groups:Granulocyte-colony stimulating factor and GM-CSF were administered via intra-peritoneal injection immediately after SCI. The effects of G-CSF and GM-CSF on functional recovery, glial scar formation, and axonal regeneration were evaluated and compared. The rats in Groups 3 and 4 showed better functional recovery and more decreased cavity sizes than those in Group 2 (p < 0.05). Both G-CSF and GM-CSF suppressed intensive expression of glial fibrillary acidic protein around the cavity at 4 weeks and reduced the expression of chondroitin sulfate proteoglycans (p < 0.05). Also, early administration of G-CSF and GM-CSF protected axon fibers from destructive injury and facilitated axonal regeneration. There were no significant differences in comparisons of functional recovery, glial scar formation, and axonal regeneration between G-CSF and GM-CSF. The authors concluded that G-CSF suppressed glial scar formation after SCI in rats, possibly by restricting the expression of glial fibrillary acidic protein and chondroitin sulfate proteoglycans, which might facilitate functional recovery from SCI. They stated that GM-CSF and G-CSF had similar effects on glial scar formation and functional recovery after SCI, suggesting that G-CSF can potentially be substituted for GM-CSF in the treatment of SCI. The findings from this animal study need to be validated in well-designed human trials.
Fulphila (
pegfilgrastim-jmdp)
U.S. Food and Drug Administration (FDA)-Approved Indications
Patients with Cancer Receiving Myelosuppressive Chemotherapy
Fulphila is indicated to decrease the incidence of infection, as manifested by febrile neutropenia, in patients with non-myeloid malignancies receiving myelosuppressive anti-cancer drugs associated with a clinically significant incidence of febrile neutropenia.
On June 4, 2018 the FDA approved Fulphila (pegfilgrastim-jmdb) as the first biosimilar to Neulasta (pegfilgrastim) to decrease the chance of infection as suggested by febrile neutropenia (fever, often with other signs of infection, associated with an abnormally low number of infection-fighting white blood cells), in patients with non-myeloid (non-bone marrow) cancer who are receiving myelosuppressive chemotherapy that has a clinically significant incidence of febrile neutropenia.
A biosimilar is a biological product that is highly similar to and has no clinically meaningful differences from an existing FDA-approved reference product. The FDA’s approval of Fulphila is based on review of evidence that included extensive structural and functional characterization, animal study data, human pharmacokinetic and pharmacodynamic data, clinical immunogenicity data, and other clinical safety and effectiveness data that demonstrates Fulphila is biosimilar to Neulasta. Fulphila has been approved as a biosimilar, not as an interchangeable product.
Pegfilgrastim-jmdb (Fulphila) is a covalent conjugate of recombinant methionyl human G-CSF and monomethoxypolyethylene glycol. As with filgrastim (Neupogen) and pegfilgrastim (Neulasta), pegfilgrastim-jmdb is a colony-stimulating factor that acts on hematopoietic cells by binding to specific cell surface receptors, thereby stimulating proliferation, differentiation, commitment, and end cell functional activation.
The recommended dosage of Fulphila is a single subcutaneous injection of 6 mg administered once per chemotherapy cycle. For dosing in pediatric patients weighing less than 45 kg, please refer to Full Prescribing Information. Fulphila should not be administered between 14 days before and 24 hours after administration of cytotoxic chemotherapy. Fulphila is administered subcutaneously via a single-dose prefilled syringe for manual use.
Fulphila is contraindicated in patients with a history of serious allergic reactions to pegfilgrastim products or filgrastim products and patients on Fulphila therapy should be closely monitored for the following potential adverse reactions:
Pegfilgrastim was evaluated in three randomized, double-blind, controlled studies. Studies 1 and 2 were active-controlled studies that employed doxorubicin 60 mg/m
2and docetaxel 75 mg/m
2administered every 21 days for up to 4 cycles for the treatment of metastatic breast cancer. Study 1 investigated the utility of a fixed dose of pegfilgrastim. Study 2 employed a weight-adjusted dose. In the absence of growth factor support, similar chemotherapy regimens have been reported to result in a 100% incidence of severe neutropenia (ANC < 0.5 x 10
9/L) with a mean duration of 5 to 7 days and a 30% to 40% incidence of febrile neutropenia. Based on the correlation between the duration of severe neutropenia and the incidence of febrile neutropenia found in studies with filgrastim, duration of severe neutropenia was chosen as the primary endpoint in both studies, and the efficacy of pegfilgrastim was demonstrated by establishing comparability to filgrastim-treated patients in the mean days of severe neutropenia.
In Study 1, 157 patients were randomized to receive a single subcutaneous injection of pegfilgrastim (6 mg) on day 2 of each chemotherapy cycle or daily subcutaneous filgrastim (5 mcg/kg/day) beginning on day 2 of each chemotherapy cycle. In Study 2, 310 patients were randomized to receive a single subcutaneous injection of pegfilgrastim (100 mcg/kg) on day 2 or daily subcutaneous filgrastim (5 mcg/kg/day) beginning on day 2 of each chemotherapy cycle.
Both studies met the major efficacy outcome measure of demonstrating that the mean days of severe neutropenia of pegfilgrastim-treated patients did not exceed that of filgrastim-treated patients by more than 1 day in cycle 1 of chemotherapy. The mean days of cycle 1 severe neutropenia in Study 1 were 1.8 days in the pegfilgrastim arm compared to 1.6 days in the filgrastim arm [difference in means 0.2 (95% CI -0.2, 0.6)] and in Study 2 were 1.7 days in the pegfilgrastim arm compared to 1.6 days in the filgrastim arm [difference in means 0.1 (95% CI -0.2, 0.4)].
A secondary endpoint in both studies was days of severe neutropenia in cycles 2 through 4 with results similar to those for cycle 1.
Study 3 was a randomized, double-blind, placebo-controlled study that employed docetaxel 100 mg/m
2administered every 21 days for up to 4 cycles for the treatment of metastatic or non-metastatic breast cancer. In this study, 928 patients were randomized to receive a single subcutaneous injection of pegfilgrastim (6 mg) or placebo on day 2 of each chemotherapy cycle. Study 3 met the major trial outcome measure of demonstrating that the incidence of febrile neutropenia (defined as temperature ≥ 38.2°C and ANC ≤ 0.5 x10
9/L) was lower for pegfilgrastim-treated patients as compared to placebo-treated patients (1% versus 17%, respectively, p < 0.001). The incidence of hospitalizations (1% versus 14%) and IV anti-infective use (2% versus 10%) for the treatment of febrile neutropenia was also lower in the pegfilgrastim-treated patients compared to the placebo-treated patients.
Study 4 was a multicenter, randomized, open-label study to evaluate the efficacy, safety, and pharmacokinetics of pegfilgrastim in pediatric and young adult patients with sarcoma. Patients with sarcoma receiving chemotherapy age 0 to 21 years were eligible. Patients were randomized to receive subcutaneous pegfilgrastim as a single-dose of 100 mcg/kg (n = 37) or subcutaneous filgrastim at a dose 5 mcg/kg/day (n = 6) following myelosuppressive chemotherapy. Recovery of neutrophil counts was similar in the pegfilgrastim and filgrastim groups. The most common adverse reaction reported was bone pain.
Fylnetra (pegfilgrastim-pbbk)
U.S. Food and Drug Administration (FDA)-Approved Indications
Patients with Cancer Receiving Myelosuppressive Chemotherapy
Fylnetra is indicated to decrease the incidence of infection, as manifested by febrile neutropenia, in patients with non-myeloid malignancies receiving myelosuppressive anti-cancer drugs associated with a clinically significant incidence of febrile neutropenia.
On May 27, 2022, the U.S. Food and Drug Administration (FDA) approved Fylnetra (pegfilgrastim-pbbk), a biosimilar referencing Neulasta. Fylnetra was developed by Amneal Pharmaceuticals, Inc. in collaboration with Kashiv Biosciences, LLC. Fylnetra is a leukocyte growth factor to reduce the incidence of febrile neutropenia in patients with non-myeloid malignancies who are receiving myelosuppressive chemotherapy (Amneal Pharmaceuticals, 2022a). The FDA approval was based on supporting data from studies referencing Neulasta (pegfilgrastim). Fylnetra is the fifth pegfilgrastim biosimilar approved by the FDA after pegfilgrastim-apgf (Nyvepria; Hospira), pegfilgrastim-bmez (Ziextenzo; Sandoz), pegfilgrastim-cbqv (Udenyca; Coherus Biosciences), and pegfilgrastim-jmdb (Fulphila; Mylan).
Pegfilgrastim-pbbk is available as Fylnetra and is supplied for subcutaneous injection as 6 mg/0.6 mL solution in a single-dose prefilled syringe for manual use only (Kashiv BioSciences, 2022a).
Nyvepria (pegfilgrastim-apgf)
U.S. Food and Drug Administration (FDA)-Approved Indications
Patients with Cancer Receiving Myelosuppressive Chemotherapy
Nyvepria is indicated to decrease the incidence of infection, as manifested by febrile neutropenia, in patients with non-myeloid malignancies receiving myelosuppressive anti-cancer drugs associated with a clinically significant incidence of febrile neutropenia.
On June 10, 2020, the U.S. FDA approved a fourth biosimilar to Neulasta called Nyvepria (pegfilgrastim-apgf), a PEGylated growth colony-stimulating factor. Nyvepria is a leukocyte growth factor indicated to decrease the incidence of infection, as manifested by febrile neutropenia, in patients with non-myeloid malignancies receiving myelosuppressive anti-cancer drugs associated with a clinically significant incidence of febrile neutropenia. The FDA approval was based on the review of a totality of evidence demonstrating a high degree of similarity of Nyvepria to its reference product.
Pegfilgrastim was evaluated in three randomized, double-blind, controlled studies. Studies 1 and 2 were active-controlled studies that employed doxorubicin 60 mg/m
2and docetaxel 75 mg/m
2administered every 21 days for up to 4 cycles for the treatment of metastatic breast cancer. Study 1 investigated the utility of a fixed dose of pegfilgrastim. Study 2 employed a weight-adjusted dose. In the absence of growth factor support, similar chemotherapy regimens have been reported to result in a 100% incidence of severe neutropenia (ANC <0.5 x 10
9/ L) with a mean duration of 5 to 7 days and a 30% to 40% incidence of febrile neutropenia. Based on the correlation between the duration of severe neutropenia and the incidence of febrile neutropenia found in studies with filgrastim, duration of severe neutropenia was chosen as the primary endpoint in both studies, and the efficacy of pegfilgrastim was demonstrated by establishing comparability to filgrastim-treated patients in the mean days of severe neutropenia. In Study 1, 157 patients were randomized to receive a single subcutaneous injection of pegfilgrastim (6 mg) on day 2 of each chemotherapy cycle or daily subcutaneous filgrastim (5 mcg/kg/day) beginning on day 2 of each chemotherapy cycle. In Study 2, 310 patients were randomized to receive a single subcutaneous injection of pegfilgrastim (100 mcg/kg) on day 2 or daily subcutaneous filgrastim (5 mcg/kg/day) beginning on day 2 of each chemotherapy cycle. Both studies met the major efficacy outcome measure of demonstrating that the mean days of severe neutropenia of pegfilgrastim-treated patients did not exceed that of filgrastim-treated patients by more than 1 day in cycle 1 of chemotherapy. The mean days of cycle 1 severe neutropenia in Study 1 were 1.8 days in the pegfilgrastim arm compared to 1.6 days in the filgrastim arm [difference in means 0.2 (95% CI -0.2, 0.6)] and in Study 2 were 1.7 days in the pegfilgrastim arm compared to 1.6 days in the filgrastim arm [difference in means 0.1 (95% CI -0.2, 0.4)]. A secondary endpoint in both studies was days of severe neutropenia in cycles 2 through 4 with results similar to those for cycle 1.
Study 3 was a randomized, double-blind, placebo-controlled study that employed docetaxel 100 mg/m
2administered every 21 days for up to 4 cycles for the treatment of metastatic or non-metastatic breast cancer. In this study, 928 patients were randomized to receive a single subcutaneous injection of pegfilgrastim (6 mg) or placebo on day 2 of each chemotherapy cycle. Study 3 met the major trial outcome measure of demonstrating that the incidence of febrile neutropenia (defined as temperature ≥38.2°C and ANC ≤0.5 x 10
9/L) was lower for pegfilgrastim-treated patients as compared to placebo-treated patients (1% versus 17%, respectively, p < 0.001). The incidence of hospitalizations (1% versus 14%) and IV anti-infective use (2% versus 10%) for the treatment of febrile neutropenia was also lower in the pegfilgrastim-treated patients compared to the placebo-treated patients.
Study 4 was a multicenter, randomized, open-label study to evaluate the efficacy, safety, and pharmacokinetics of pegfilgrastim in pediatric and young adult patients with sarcoma. Patients with sarcoma receiving chemotherapy age 0 to 21 years were eligible. Patients were randomized to receive subcutaneous pegfilgrastim as a single dose of 100 mcg/kg (n = 37) or subcutaneous filgrastim at a dose 5 mcg/kg/day (n = 6) following myelosuppressive chemotherapy. Recovery of neutrophil counts was similar in the pegfilgrastim and filgrastim groups. The most common adverse reaction reported was bone pain.
Stimufend (pegfilgrastim-fpgk)
U.S. Food and Drug Administration (FDA)-Approved Indications
Patients with Cancer Receiving Myelosuppressive Chemotherapy
Stimufend is indicated to decrease the incidence of infection, as manifested by febrile neutropenia, in patients with non-myeloid malignancies receiving myelosuppressive anti-cancer drugs associated with a clinically significant incidence of febrile neutropenia.
On September 6, 2022, the U.S. Food and Drug Administration (FDA) approved Stimufend (pegfilgrastim-fpgk), a biosimilar referencing Neulasta. Stimufend was developed by Fresenius Kabi and is a leukocyte growth factor indicated to decrease the incidence of infection, as manifested by febrile neutropenia, in patients with non-myeloid malignancies receiving myelosuppressive anti-cancer drugs associated with a clinially significant incidence of febrile neutropenia. The FDA approval was established on a review of a comprehensive data package and aggregate evidence that demonstrated a high degree of similarity referencing Neulasta (pegfilgrastim) and with no clinically meaningful differences in safety and immunogenicity observed. Additionally, Stimufend marks the sixth pegfilgrastim biosimilar to receive a regulatory approval.
Pegfilgrastim-fpgk is available as Stimufend and supplied for subcutaneous injection as 6 mg/0.6 mL solution in a single-dose pre-filled syringe for manual use only.
Udenyca (pegfilgrastim-cbqv)
U.S. Food and Drug Administration (FDA)-Approved Indications
Patients with Cancer Receiving Myelosuppressive Chemotherapy
Udenyca is indicated to decrease the incidence of infection, as manifested by febrile neutropenia, in patients with non-myeloid malignancies receiving myelosuppressive anti-cancer drugs associated with a clinically significant incidence of febrile neutropenia.
Hematopoietic Subsyndrome of Acute Radiation Syndrome
Udenyca is indicated to increase survival in patients acutely exposed to myelosuppressive doses of radiation.
On November 02, 2018, the U.S. FDA approved Udenyca (pegfilgrastim-cbqv), formerly CHS-1701, a PEGylated growth colony-stimulating factor and the second biosimilar to Neulasta, for patients with cancer receiving myelosuppressive chemotherapy. The FDA approved indication for Udenyca is a leukocyte growth factor indicated to decrease the incidence of infection, as manifested by febrile neutropenia, in patients with non-myeloid malignancies receiving myelosuppressive anti-cancer drugs associated with a clinically significant incidence of febrile neutropenia.
Pegfilgrastim-cbqv is a covalent conjugate of recombinant methionyl human G-CSF and monomethoxypolyethylene glycol. Recombinant methionyl human G-CSF is obtained from the bacterial fermentation of a strain of E coli transformed with a genetically engineered plasmid containing the human G-CSF gene. As with pegfilgrastim (Neulasta) and pegfilgrastim-jmdb (Fulphila), pegfilgrastim-cbqv is a colony-stimulating factors that act on hematopoietic cells by binding to specific cell surface receptors, thereby stimulating proliferation, differentiation, commitment, and end cell functional activation.
The approval of Udenyca was supported by a comprehensive analytical similarity package, as well as pharmacokinetic, pharmacodynamic and immunogenicity studies, including over 600 healthy subjects.
Udenyca is not indicated for the mobilization of peripheral blood progenitor cells for hematopoietic stem cell transplantation and is contraidicated in patients with a history of serious allergic reaction to human granulocyte colony-stimulating factors such as pegfilgrastim or filgrastim products. Warnings and precautions for Udenyca include evaluating patients who report left upper abdominal or shoulder pain for an enlarged spleen or splenic rupture, evaluating patients who develop fever, lung infiltrates, or respiratory distress and discontinuing treatment in patients with Acute respiratory distress syndrome (ARDS). In the event of serious allergic reactions, including anaphylaxis, permanently discontinue Udenyca. Fatal sickle cell crises have occurred. If glomerulonephritis develops, consider dose-reduction or interruption of Udenyca if causality is likely. The most common adverse reactions (≥ 5% difference in incidence compared to placebo) are bone pain and pain in extremity.
Ziextenzo (pegfilgrastim-bmez)
U.S. Food and Drug Administration (FDA)-Approved Indications
Patients with Cancer Receiving Myelosuppressive Chemotherapy
Ziextenzo is indicated to decrease the incidence of infection, as manifested by febrile neutropenia, in patients with non-myeloid malignancies receiving myelosuppressive anti-cancer drugs associated with a clinically significant incidence of febrile neutropenia.
Compendial Uses for Neulasta (pegfilgrastim), Fulphila (pegfilgrastim-jmdp), Fylnetra (pegfilgrastim-pbbk), Nyvepria (pegilgrastim-apgf), Stimufend (pegfilgrastim-fpqk), Udenyca (pegfilgrastim-cbqv), and Ziextenzo (pegfilgrastim-bmez)
On November 04, 2019, the U.S. FDA approved Ziextenzo (pegfilgrastim-bmez), a third biosimilar referencing Neulasta (pegfilgrastim). Ziextenzo is a leukocyte growth factor indicated to decrease the incidence of infection, as manifested by febrile neutropenia, in patients with non-myeloid malignancies receiving myelosuppressive anti-cancer drugs associated with a clinically significant incidence of febrile neutropenia. Ziextenzo is not indicated for the mobilization of peripheral blood progenitor cells for hematopoietic stem cell transplantation. Biosimilar means that the biological product is approved based on data demonstrating that it is highly similar to an FDA-approved biological product, known as a reference product, and that there are no clinically meaningful differences between the biosimilar product and the reference product. Biosimilarity of Ziextenzo has been demonstrated for the condition(s) of use (e.g., indication(s), dosing regimen(s)), strength(s), dosage form(s), and route(s) of administration described in its Full Prescribing Information.
The FDA approval of Ziextenzo was based on results from three randomized, double-blind, controlled studies in patients with cancer receiving myelosuppressive chemotherapy. Studies 1 and 2 were active-controlled studies that employed doxorubicin 60 mg/m2 and docetaxel 75 mg/m2 administered every 21 days for up to 4 cycles for the treatment of metastatic breast cancer. Study 1 investigated the utility of a fixed dose of pegfilgrastim. Study 2 employed a weight-adjusted dose. In the absence of growth factor support, similar chemotherapy regimens have been reported to result in a 100% incidence of severe neutropenia (ANC < 0.5 x 109 /L) with a mean duration of 5 to 7 days and a 30% to 40% incidence of febrile neutropenia. Based on the correlation between the duration of severe neutropenia and the incidence of febrile neutropenia found in studies with filgrastim, duration of severe neutropenia was chosen as the primary endpoint in both studies, and the efficacy of pegfilgrastim was demonstrated by establishing comparability to filgrastim-treated patients in the mean days of severe neutropenia. In Study 1, 157 patients were randomized to receive a single subcutaneous injection of pegfilgrastim (6 mg) on day 2 of each chemotherapy cycle or daily subcutaneous filgrastim (5 mcg/kg/day) beginning on day 2 of each chemotherapy cycle. In Study 2, 310 patients were randomized to receive a single subcutaneous injection of pegfilgrastim (100 mcg/kg) on day 2 or daily subcutaneous filgrastim (5 mcg/kg/day) beginning on day 2 of each chemotherapy cycle.
Both studies met the major efficacy outcome measure of demonstrating that the mean days of severe neutropenia of pegfilgrastim-treated patients did not exceed that of filgrastim-treated patients by more than 1 day in cycle 1 of chemotherapy. The mean days of cycle 1 severe neutropenia in Study 1 were 1.8 days in the pegfilgrastim arm compared to 1.6 days in the filgrastim arm [difference in means 0.2 (95% CI -0.2, 0.6)] and in Study 2 were 1.7 days in the pegfilgrastim arm compared to 1.6 days in the filgrastim arm [difference in means 0.1 (95% CI - 0.2, 0.4)]. A secondary endpoint in both studies was days of severe neutropenia in cycles 2 through 4 with results similar to those for cycle 1.
Study 3 was a randomized, double-blind, placebo-controlled study that employed docetaxel 100 mg/m2 administered every 21 days for up to 4 cycles for the treatment of metastatic or non-metastatic breast cancer. In this study, 928 patients were randomized to receive a single subcutaneous injection of pegfilgrastim (6 mg) or placebo on day 2 of each chemotherapy cycle. Study 3 met the major trial outcome measure of demonstrating that the incidence of febrile neutropenia (defined as temperature ≥ 38.2°C and ANC ≤ 0.5 x 109 /L) was lower for pegfilgrastim-treated patients as compared to placebo-treated patients (1% versus 17%, respectively, p < 0.001). The incidence of hospitalizations (1% versus 14%) and IV anti-infective use (2% versus 10%) for the treatment of febrile neutropenia was also lower in the pegfilgrastim-treated patients compared to the placebo- treated patients.
Study 4 was a multicenter, randomized, open-label study to evaluate the efficacy, safety, and pharmacokinetics of pegfilgrastim in pediatric and young adult patients with sarcoma. Patients with sarcoma receiving chemotherapy age 0 to 21 years were eligible. Patients were randomized to receive subcutaneous pegfilgrastim as a single-dose of 100 mcg/kg (n = 37) or subcutaneous filgrastim at a dose 5 mcg/kg/day (n = 6) following myelosuppressive chemotherapy. Recovery of neutrophil counts was similar in the pegfilgrastim and filgrastim groups. The most common adverse reaction reported was bone pain.
Most common adverse reactions (≥ 5% difference in incidence compared to placebo) reported in the clinical studies were bone pain and pain in extremity.
Rolvedon (eflapegrastim-xnst)
U.S. Food and Drug Administration (FDA)-Approved Indications
Rolvedon is indicated to decrease the incidence of infection, as manifested by febrile neutropenia, in adult patients with non-myeloid malignancies receiving myelosuppressive anti-cancer drugs associated with clinically significant incidence of febrile neutropenia.
Compendial Uses
Eflapegrastim-xnst is available as Rolvedon (Spectrum Pharmaceuticals, Inc.) and is a long-acting recombinant human granulocyte-colony stimulating factor (G-CSF) that consists of a recombinant human G-CSF analog conjugated to a human IgG4 Fc fragment via a single polyethylene glycol linker. Rolvedon mediates its effect by binding to G-CSF receptors on myeloid progenitor cells and neutrophils, prompting signaling pathways that manage cell differentiation, proliferation, migration and survival (Spectrum Pharmaceuticals, 2022a).
Per the prescribing information, Rolvedon is contraindicated in patients with a history of serious allergic reactions to human granulocyte colony-stimulating factors such as eflapegrastim, pegfilgrastim or filgrastim products.
Per the prescribing information, Rolvedon carries the following warnings and precautions:
The most common adverse reactions (≥20%) are fatigue, nausea, diarrhea, bone pain, headache, pyrexia, anemia, rash, myalgia, arthralgia, and back pain (Spectrum Pharmaceuticals, 2022a).
On September 9, 2022, the U.S. Food and Drug Administration (FDA) approved Rolvedon (eflapegrastim-xnst) injection to decrease the incidence of infection, as manifested by febrile neutropenia, in adult patients with non-myeloid malignancies receiving myelosuppressive anti-cancer drugs associated with clinically significant incidence of febrile neutropenia. The FDA approval was based on supporting data from two identically designed pivotal Phase 3, randomized, open-label, noninferiority clinical trials, ADVANCE and RECOVER, evaluating the safety and efficacy of Rolvedon (Spectrum Pharmaceuticals, 2022b).
In the ADVANCE study, Schwartzberg and colleagues (2020) evaluated the safety and efficacy of Rolvedon (eflapegrastim-xnst) compared to pegfilgrastim for reducing the risk of chemotherapy-induced neutropenia. Patients with early-stage breast cancer were randomized 1:1 to fixed-dose Rolvedon 13.2 mg (3.6 mg G-CSF) (n = 196) or standard pegfilgrastim (6 mg G-CSF) (n = 210) following standard docetaxel plus cyclophosphamide chemotherapy for 4 cycles. The primary endpoint was to demonstrate the noninferiority of eflapegrastim compared with pegfilgrastim in mean duration of severe neutropenia (DSN; grade 4) in cycle 1. Secondary endpoints consisted of DSN in cycles 2-4, as well those assessed in each cycle which included time-to-absolute neutrophil count (ANC) recovery (time-from-chemotherapy administration to ANC ≥ 1.5 x 109 per L after the expected nadir), depth of ANC nadir (lowest ANC value), incidence of febrile neutropenia (FN; ANC < 1.0 x 109 per L and either temperature > 38.3º C or two consecutive readings ≥38.0º C over 2 hours), incidence of neutropenic complications (anti-infective use and/or hospitalizations), relative dose intensity (RDI), and safety (overall adverse event [AE] rates; AEs of special interest: musculoskeletal-related, splenic rupture, leukocytosis, and anaphylaxis). The incidence of cycle 1 severe neutropenia was 16% (n = 31) for Rolvedon compared to 24% (n = 51) for pegfilgrastim, reducing the relative risk by 35% (p = 0.034). The difference in mean cycle 1 DSN (-0.148 day) satisfied the primary endpoint of noninferiority (p < 0.0001) and also displayed statistical superiority for Rolvedon (p = 0.013). Noninferiority was sustained for the duration of treatment (all cycles, p < 0.0001), Additionally, secondary efficacy endpoints and safety results were similar for study arms. The investigators concluded that the results displayed noninferiority and comparable safety for Rolvedon at a lower G-CSF dose versus pegfilgrastim.
In the RECOVER study, Cobb and colleagues (2020), evaluated the safety and efficacy of Rolvedon (eflapegrastim-xnst) compared to pegfilgrastim for reducing the risk of chemotherapy-induced neutropenia. Patients with stage I to IIIA early-stage breast cancer (ESBC) were randomized 1:1 to fixed-dose Rolvedon 13.2 mg (3.6 mg G-CSF) (n = 118) or pegfilgrastim (6 mg G-CSF) ( n = 119) given one day after standard docetaxel/cyclophosphamide (TC) therapy for four cycles. The primary endpoint was to demonstrate noninferiority (NI) of Rolvedon compared to pegfilgrastim in mean duration of severe neutropenia (DSN; grade 4) in cycle 1. Secondary endpoints consisted of DSN in cycles 2-4, as well those assessed in each cycle which included time-to-ANC recovery (time-from-chemotherapy administration to ANC ≥1.5 × 109/L after the expected nadir); depth of ANC nadir (lowest ANC value); incidence of febrile neutropenia (FN; ANC <1.0 × 109/L and either temperature >38.3°C or two consecutive readings ≥38.0°C over 2 hours); incidence of neutropenic complications (antiinfective use and/or hospitalizations); relative dose intensity (RDI); and safety. The incidence of severe neutropenia was 20.3% (n = 24) for Rolvedon and 23.5% (n = 28) for pegfilgrastim. The DSN of Rolvedon in cycle 1 was noninferior to pegfilgrastim with a mean difference of -0.074 days (NI p-value < 0.0001). Noninferiority was sustained throughout the four treatment cycles (p < 0.0001 in all cycles). Other efficacy endpoints results were similar between treatment arms . The investigators concluded that the results displayed noninferior efficacy and comparable safety for Rolvedon, at a lower G-CSF dose, versus pegfilgrastim.
Acute-On-Chronic Liver Failure
Chavez-Tapia et al (2015) stated that acute-on-chronic liver failure (ACLF) is associated with increased short- and long-term mortality. Animal models of liver failure have demonstrated that G-CSF accelerated the liver regeneration process and improved survival. However, clinical evidence regarding the use of G-CSF in ACLF remains scarce. These researchers evaluated the benefits and harms of G-CSF in patients with ACLF. An electronic search was made in the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE and LILACS up to November 2013. Randomized clinical trials comparing the use of any regimen of G-CSF against placebo or no intervention in patients with ACLF were included. Primary outcomes included overall mortality, mortality due multi-organ failure, and adverse events. Relative risk and mean difference were used; 2 trials involving 102 patients were included. A significant reduction in short-term overall mortality was observed in patients receiving G-CSF compared to controls (RR 0.56; 95 % CI: 0.39 to 0.80); G-CSF failed to reduce mortality secondary to gastro-intestinal bleeding (RR 1.45; 95 % CI: 0.50 to 4.27). Adverse effects reported included: fever, rash, herpes zoster, headache and nausea. The authors concluded that the use of G-CSF for the treatment of patients with ACLF significantly reduced short-term mortality. They noted that while the evidence is still limited, the apparent benefit observed on short-term mortality, mild adverse effects and lack of an alternative therapy made the use of G-CSF in ACLF patients a reasonable alternative when liver transplantation is contraindicated or unavailable. This clinical value of G-CSF in the treatment of ACLF has to be further investigated.
Furthermore, an UpToDate review on "Acute liver failure in adults: Management and prognosis" (Goldberg, Chopra, and Rubin, 2023) listed G-CSF as an experimental approach. It stated that "Granulocyte colony-stimulating factor (G-CSF) has been studied for the treatment of acute-on-chronic liver failure (ACLF). The theory behind the approach is that mobilization of bone marrow-derived stem cells with G-CSF may promote hepatic regeneration. In a randomized trial with 47 patients with ACLF, 23 were assigned to receive G-CSF 5 mcg/kg subcutaneously daily for 5 days and then every 3 days for a total of 12 doses, and 24 were assigned to receive placebo. None of the patients had decompensated liver disease prior to the onset of ACLF. Patients treated with G-CSF had a higher actuarial probability of survival at 60 days than those treated with placebo (66 versus 26 %) and were less likely to develop hepato-renal syndrome (19 versus 71 %), hepatic encephalopathy (19 versus 66 %), or sepsis (14 versus 41 %). None of the patients who survived underwent emergent liver transplantation".
Luteinized Unruptured Follicle Syndrome
Shibata et al (2016) stated that luteinized unruptured follicle (LUF) syndrome is one of the intractable ovulation disorders that are commonly observed during cycles of treatment with ovulation inducers, for which no effective therapy other than assisted reproductive technology is available. These researchers examined if G-CSF could prevent the onset of LUF syndrome. They analyzed the effects of G-CSF in 68 infertile women with LUF syndrome who received ovulation induction (clomiphene + human chorionic gonadotropin [hCG] therapy or follicle-stimulating hormone + hCG therapy); G-CSF (lenograstim, 100 μg) was administered subcutaneously. Onsets of LUF syndrome were compared between the cycle during which G-CSF was given in combination with the ovulation inducer (i.e., the G-CSF treatment cycle) and the subsequent cycle during which only the ovulation inducer was given (i.e., the G-CSF non-treatment control cycle). The results showed that LUF syndrome recurred in only 3 cycles during the G-CSF treatment cycle (4.4 % [3/68 cycles]), whereas LUF syndrome recurred in 13 cycles during the subsequent G-CSF non-treatment control cycle (19.1 % [13/68 cycles]). The additional use of G-CSF significantly prevented the onset of LUF syndrome during ovulation induction (p = 0.013, McNemar test). No serious adverse reactions because of the administration of G-CSF were observed. The authors concluded that these findings indicated that G-CSF may become a useful therapy for LUF syndrome. These preliminary findings need to be validated by well-designed studies.
Recurrent Miscarriage and Implantation Failure
Cavalcante et al (2015) stated that the use of G-CSF has been proposed to improve pregnancy outcomes in reproductive medicine. These investigators performed a systematic review of the current use of G-CSF in patients who have difficulty conceiving and maintaining pregnancy. Two electronic databases (PubMed/ Medline and Scopus) were searched. Study selection, data extraction and quality assessment were performed in duplicate. The subject codes used were granulocyte colony-stimulating factor, G-CSF, recurrent miscarriage, IVF failure, and endometrium. The search of electronic databases resulted in 215 citations (PubMed/ Medline: 139 and Scopus: 76), of which 38 were present in both databases. Of the remaining 177 publications, 7 studies were included in the present review. The authors concluded that treatment with G-CSF is a novel proposal for immune therapy in patients with recurrent miscarriage and implantation failure following cycles of IVF. However, they stated that a larger number of well-designed studies are needed for this treatment to be established.
Prevention of Infections in Persons Receiving Myelotoxic Chemotherapy
In a Cochrane review, Skoetz and colleagues (2015) compared the safety and effectiveness of GM-CSF with antibiotics in cancer patients receiving myelotoxic chemotherapy. These investigators searched the Cochrane Library, Medline, Embase, databases of ongoing trials, and conference proceedings of the ASCO and the American Society of Hematology (ASH) (1980 to December 2015). They included both full-text and abstract publications; 2 review authors independently screened search results. These researchers included RCTs comparing prophylaxis with GM-CSF versus antibiotics for the prevention of infection in cancer patients of all ages receiving chemotherapy. All study arms had to receive identical chemotherapy regimens and other supportive care. The authors included full-text, abstracts, and unpublished data if sufficient information on study design, participant characteristics, interventions and outcomes was available. They excluded cross-over trials, quasi-randomized trials and post-hoc retrospective trials. Two review authors independently screened the results of the search strategies, extracted data, assessed risk of bias, and analyzed data according to standard Cochrane methods. They did final interpretation together with an experienced clinician. In this updated review, these investigators included no new RCTs. They included 2 trials in the review, 1 with 40 breast cancer patients receiving high-dose chemotherapy (HDC) and G-CSF compared to antibiotics, a second one evaluating 155 patients with small-cell lung cancer receiving GM-CSF or antibiotics. These researchers judged the overall risk of bias as high in the G-CSF trial, as neither patients nor physicians were blinded and not all included patients were analyzed as randomized (7 out of 40 patients). The authors considered the overall risk of bias in the GM-CSF to be moderate, because of the risk of performance bias (neither patients nor personnel were blinded), but low risk of selection and attrition bias. For the trial comparing G-CSF to antibiotics, all-cause mortality was not reported. There was no evidence of a difference for infection-related mortality, with zero events in each arm. Microbiologically or clinically documented infections, severe infections, quality of life, and adverse events were not reported. There was no evidence of a difference in frequency of FN (RR 1.22; 95 % CI: 0.53 to 2.84). The quality of the evidence for the 2 reported outcomes, infection-related mortality and frequency of FN, was very low, due to the low number of patients evaluated (high imprecision) and the high risk of bias. There was no evidence of a difference in terms of median survival time in the trial comparing GM-CSF and antibiotics. Two-year survival times were 6 % (0 to 12 %) in both arms (high imprecision, low quality of evidence). There were 4 toxic deaths in the GM-CSF arm and 3in the antibiotics arm (3.8 %), without evidence of a difference (RR 1.32; 95 % CI: 0.30 to 5.69; p = 0.71; low quality of evidence). There were 28 % grade III or IV infections in the GM-CSF arm and 18 % in the antibiotics arm, without any evidence of a difference (RR 1.55; 95 % CI: 0.86 to 2.80; p = 0.15, low quality of evidence). There were 5 episodes out of 360 cycles of grade IV infections in the GM-CSF arm and 3 episodes out of 334 cycles in the cotrimoxazole arm (0.8 %), with no evidence of a difference (RR 1.55; 95 % CI: 0.37 to 6.42; p = 0.55; low quality of evidence). There was no significant difference between the 2 arms for non-hematological toxicities like diarrhea, stomatitis, infections, neurologic, respiratory, or cardiac adverse events. Grade III and IV thrombopenia occurred significantly more frequently in the GM-CSF arm (60.8 %) compared to the antibiotics arm (28.9 %); (RR 2.10; 95 % CI: 1.41 to 3.12; p = 0.0002; low quality of evidence). Neither infection-related mortality, incidence of febrile neutropenia, nor quality of life were reported in this trial. The authors concluded that as they only found 2 small trials with 195 patients altogether, no conclusion for clinical practice is possible. They stated that more trials are needed to evaluate the benefits and harms of GM-CSF compared to antibiotics for infection prevention in cancer patients receiving chemotherapy.
Scleroderma
In a pilot study, Giuggioli and colleagues (2006) examined the effectiveness of G-CSF in the treatment of non-healing skin lesions in systemic sclerosis (SSc) patients. A total of 26 SSc patients (23 females and 3 males, aged 54 +/- 13.6 years) with skin ulcers were enrolled in this trial. Prior to the treatment with G-CSF, all ulcers failed to heal with conventional therapies carried out for a period of 1 to 5 years. All patients were treated with 5 ug/kg G-CSF subcutaneously for 5 days. Healing time, quality of wounds, visual analog scale (VAS) and Health assessment questionnaire disability index (HAQ-DI) were used to evaluate the effectiveness of the treatment. An improvement of skin ulcers was observed in 24/26 patients; in particular, 22/26 wounds completely healed, 2/26 showed a partial healing. In only 2 patients, skin ulcers did not change during the 6-month follow-up. The quality of life improved as showed by VAS (from 88 +/- 13 to 55 +/- 28; p < 0.0001) and HAQ-DI (from 2.12 +/- 0.45 to 1.28 +/- 0.30; p < 0.0001). The eradication of pathogens from the infected ulcers was also observed in 12/12 patients; while no adverse side effects related to G-CSF were recorded. The authors concluded that the findings of this study suggested that G-CSF may be useful in the treatment of scleroderma skin ulcers refractory to conventional treatments. These preliminary findings need to be validated by well-designed studies.
Furthermore, an UpToDate review on "Juvenile systemic sclerosis (scleroderma): Assessment and approaches to treatment" (Zulian, 2023) does not mention G-CSF and GM-CSF as therapeutic options.
Mobilization of Donor Hematopoietic Progenitor Cells for Allogeneic Transplantation
Schmitt et al (2016) stated that biosimilars of the granulocyte colony stimulating factor (G-CSF) filgrastim were approved by the European Medicines Agency (EMA) for registered indications of the originator G-CSF, including prevention and treatment of neutropenia, as well as mobilization of peripheral blood stem cells in 2008. Nevertheless, there is still an ongoing debate regarding the quality, efficacy and safety of biosimilar G-CSF. This article was a meta-analysis of clinical studies on the use of biosimilar G-CSF for mobilization and transplantation of hematopoietic stem cells as available in public databases. All data sets were weighted for the number of patients and parameters and then subjected to statistical meta-analysis employing the Mann-Whitney U-test followed by the Hodges-Lehmann estimator to assess differences between biosimilar and originator G-SCF. A total of 1,892 individuals, mostly with hematological malignancies but also including 351 healthy donors have been successfully mobilized for autologous or allogeneic stem cell transplantation using biosimilar G-CSF (Zarzio(TM): 1,239 individuals; ratiograstim (TM)/tevagrastim (TM): 653 individuals). A total of 740 patients with multiple myeloma, 491 with non-Hodgkin's lymphoma (NHL), 150 with Hodgkin's lymphoma (HL) and other diseases were included in this meta-analysis, as well as 161 siblings and 190 volunteer unrelated donors. For biosimilar and originator G-CSF, bioequivalence was observed for the yield of CD34+ stem cells as well as for the engraftment of the transplants. The authors concluded that biosimilar G-CSF has equivalent effects and safety as originator G-CSF.
Harada et al (2016) reported that from January 2012 to September 2015, a total of 49 patients received biosimilar filgrastim (BF) after allogeneic bone marrow transplantation (BMT, n = 31) or peripheral stem cell transplantation (PBSCT, n = 18) in their institution. To evaluate the clinical impact of BF on transplant outcomes of these patients, these researchers compared hematological recovery, overall survival (OS), disease-free survival (DFS), transplantation-related mortality (TRM), cumulative incidence of relapse (CIR), and acute and chronic graft-versus-host disease (GVHD) with those of control patients who received originator filgrastim (OF) after BMT (n = 31) or PBSCT (n = 18). All cases were randomly selected from a clinical database in our institution. In both the BMT and PBSCT settings, neutrophil recovery (17 versus 19 days in BMT; 13 versus 15 days in PBSCT) and platelet recovery (27 versus 31 days in BMT; 17 versus 28 days in PBSCT) were essentially the same between BF and OF. They were also comparable in terms of OS, DFS, TRM, CIR, and the incidence of acute GVHD and chronic GVHD. On multi-variate analysis, the use of BF in both BMT and PBSCT was not a significant factor for adverse transplant outcomes. Although BF significantly reduced filgrastim costs in both BMT and PBSCT, total hospitalization costs were not significantly different between BF and OF.
Hematopoietic Support Following Hematopoietic Stem Cell Transplantation
A multi-national "Guidelines for Preventing Infectious Complications among Hematopoietic Cell Transplant Recipients" (Tomblyn et al, 2009) stated that "Growth factors (e.g., granulocyte-macrophage–CSF [GM-CSF] and G-CSF) shorten the duration of neutropenia after HCT and may slightly reduce the risk of infection, but have not been shown to reduce mortality. Therefore, the routine use of growth factors after HCT is controversial and no recommendation for their use can be made".
Furthermore, an UpToDate review on "Hematopoietic support after hematopoietic cell transplantation" (Negrin, 2023) states that "For selected patients undergoing allogeneic HCT, we suggest administration of G-CSF or GM-CSF; this includes patients who undergo non-myeloablative conditioning, receive an umbilical cord graft, are treated with post-transplant cyclophosphamide, or experience slow hematologic reconstitution. For others, we generally do not incorporate a CSF, given controversial data regarding adverse effects".
Gupta et al (2021) noted that G-CSFs have been used post-HSCT for earlier neutrophil engraftment. The use of G-CSFs, and their effect on other post-HSCT outcomes remains debatable. In a systematic review and meta-analysis, these investigators searched PubMed, Embase, Cochrane library, Google Scholar, and IndMed using a pre-defined search strategy. They included RCTs and non-randomized studies (NRSs) reporting data on G-CSF administration post-HSCT, published in the English language from their inception until January 31, 2021. The primary outcome of this systematic review and meta-analysis was to evaluate the time to neutrophil engraftment (NE). The secondary outcomes were probability of NE, time to platelet engraftment (PE), the incidence of GVHD, duration of hospital stay (HS), and OS. A total of 14 studies were extracted (n = 9,850), of which 5 were RCTs, and 9 were NRSs. As per Egger's test, publication bias was not present for any outcome. After meta-analysis, these researchers found that the duration of NE favoring G-CSF arm from RCTs was -0.94 days (SMD) [(95 % CI: -1.38 to -0.51); I2 = 35%], and from NRSs -1.2 days (SMD) [(95 % CI: -1.43 to -0.96); I2 = 74 %]. For the outcome of GVHD, the RR of incidence for chronic GVHD and overall GVHD were not significant for the RCTs, and these were 1.11 (RR) [(95 % CI: 1.00 to 1.22); I2 = 43 %] and 1.10 (RR) [(95 % CI: 1.03 to 1.18); I2 = 48%], respectively, for NRSs. There was no difference in the incidence of GVHD (acute or chronic) in both arms. No significant difference was observed between the 2 arms for the outcomes of PE, HS, and OS. For NE, there was a marginal benefit of around one day with the use of G-CSF. The use of G-CSF did not alter time to PE, the incidence of GVHD, HS, and OS in either arm. These researchers stated that the justification for G-CSF administration post-HSCT to achieve a benefit of one day for NE is debatable; and the clinical and economic relevance is questionable.
The authors stated that the limitations of this study were that these researchers could not analyze all the outcomes post-HSCT. They did not include the studies in languages other than English. The inclusion of a cost analysis would have made this study more comprehensive but couldn’t be carried out since most studies didn’t include it in their reporting. Based on donor type or stem cell source, subgroup analysis was not performed as outcomes reported by the studies did not allow for the same.
Neutropenia Following Lung Transplantation
An UpToDate review on "Noninfectious complications following lung transplantation" (Ahya and Kawut, 2023) does not mention G-CSF as a management tool.
Granulocyte Colony Stimulating Factor Therapy for Stroke
Huang and colleagues (2017) stated that G-CSF is a therapeutic candidate for stroke that has demonstrated anti-inflammatory and neuroprotective properties. Data from pre-clinical and clinical studies have suggested the safety and effectiveness of G-CSF in stroke; however, the exact effects and utility of this cytokine in patients remain disputed. These investigators performed a meta-analysis of RCTs of G-CSF in ischemic and hemorrhagic stroke to evaluate its safety and effectiveness. Electronic databases were searched for relevant publications in English and Chinese. A total of 14 trials met the inclusion criteria; G-CSF (cumulative dose range, 1 to 135 μg/kg/day) was tested against placebo in a total of 1,037 participants. There was no difference in the rate of mortality between groups (OR, 1.23; 95 % CI: 0.76 to 1.97, p = 0.40). Moreover, the rate of serious AEs did not differ between groups and provided evidence for the safety of G-CSF administration in stroke patients (OR, 1.11; 95 % CI: 0.77 to 1.61, p = 0.57). No significant outcome benefits were noted with respect to the National Institutes of Health Stroke Scale (NIHSS; MD, -0.16; 95 % CI: -1.02 to 0.70, p = 0.72); however, improvements were noted with respect to the Barthel Index (BI) (MD, 8.65; 95 % CI: 0.98 to 16.32; p = 0.03). The authors concluded that it appeared to be safe in administration of G-CSF, but it will increase leukocyte count; G-CSF was weakly significant benefit with improving the BI scores, while there was no improvement in the NIHSS scores. They stated that larger and more robustly designed trials of G-CSF in stroke are needed to confirm these findings.
Granulocyte Colony-Stimulating Factor in Assisted Reproductive Technology
Kunicki and colleagues (2017) evaluated the effect of G-CSF on unresponsive thin (less than 7 mm) endometrium in women undergoing frozen-thawed embryo transfer at the blastocyst stage. A total of 62 women with thin unresponsive endometrium were included in the study, of which, 29 received a G-CSF infusion and 33 who opted out of the study served as controls. Patients in both groups had similar endometrial thickness at the time of the initial evaluation: 6.50 mm (5.50 to 6.80) in the G-CSF and 6.40 mm (5.50 to 7.0) in the control group. However, after the infusion endometrial thickness increased significantly in the G-CSF group in comparison with the controls (p = 0.01), (Δ) 0.5 (0.02 to 1.2) (p = 0.005). In the G-CSF group endometrium expanded to 7.90 mm (6.58 to 8.70) while in the control group to 6.90 mm (6.0 to 7.75); 5 women in each group conceived. The clinical pregnancy rate was 5/29 (17.24 %) in the G-CSF treated group and 5/33 (15.15 %) in the control group (p > 0.05). The live-birth rate was 2/29 (6.89 %) in the G-CSF group and 2/33 (6.06 %) in the control group (p > 0.05). The authors concluded that G-CSF infusion led to an improvement in endometrium thickness but not to any improvement in the clinical pregnancy and live-birth rates. They stated that until more data are available, G-CSF treatment should be considered to be of limited value in increasing pregnancy rate.
Li and co-workers (2017) noted that evidence for the effect of G-CSF on infertile women undergoing in-vitro fertilization (IVF) remains inconsistent. These researchers evaluated the effectiveness of G-CSF on infertile women undergoing IVF. PubMed and Embase databases were searched before August 2016. Comparing the transvaginal perfusion of G-CSF and placebo or no treatment, the available studies were considered. The pooled RR with 95 % CIs was used in the analysis and 6 studies were included. Transvaginal perfusion of G-CSF was significantly associated with a higher clinical pregnancy rate versus the placebo (RR = 1.563, 95 % CI: 1.122 to 2.176), especially for the Asian population. Among patients with a thin endometrium or repeated IVF failure, the implantation and biochemical pregnancy rates were also significantly increased in patients with the use of G-CSF (implantation rate: RR = 1.887, 95 % CI: 1.256 to 2.833; biochemical pregnancy rate: RR = 2.385, 95 % CI: 1.414 to 4.023). However, no statistical significance in increasing endometrial thickness was detected. The authors concluded that transvaginal perfusion of G-CSF for infertile women may play a critical role in assisting human reproduction, especially for patients with a thin endometrium or repeated IVF failure in the Asian population.
Kamath and associates (2017) noted that G-CSF has been used in women undergoing assisted reproductive technology (ART). These researchers performed a systematic review to evaluate the effectiveness of G-CSF in women with thin endometrium and recurrent implantation failure (RIF) undergoing ART. The outcomes included an increase in endometrial thickness, live-birth, clinical pregnancy rates and adverse effects. They included 2 trials evaluating women with thin endometrium and another 2 trials evaluating women with RIF. The pooled data did not reveal statistically significant increase in endometrial thickness following G-CSF in women with thin endometrium (MD 0.47, 95 % CI: -1.36 to 2.31; I2 82 %). However significantly higher clinical pregnancy rate was noted (RR 2.43, 95 % CI: 1.09 to 5.40; I2 0 %) following G-CSF compared to no intervention and quality of evidence for both these outcomes was very low. In RIF population, the administration of G-CSF was associated with a significantly higher clinical pregnancy rate compared to no intervention with pooled RR of 2.51 (95 % CI: 1.36 to 4.63; I2 0 %) and quality of evidence being low. The authors concluded that findings of current review suggested a possible benefit of G-CSF in women with thin endometrium undergoing ART and RIF. However, they stated that these findings need to be further validated in larger trials before G-CSF can be used in routine clinical practice.
Pegfilgrastim (Neulasta) for the Treatment of Autoimmune Neutropenia
Bacrie et al (2018) noted that febrile neutropenia (FN) is one of the most common and most critical adverse effects of chemotherapy. Despite many existing guidelines based on the use of granulocyte-colony stimulating factor (G-CSF), FN continues to impair the quality of life (QOL) and interfere with the treatment of many patients. These researchers examined the incidence and management of FN associated with chemotherapy for early breast cancer in routine clinical practice. All patients with early-stage breast cancer (ESBC) treated by chemotherapy at Institut Curie, Hôpital René Huguenin, in 2014 were retrospectively included. The incidence and management of FN were reported. Risk factors associated with FN were studied by robust-error-variance Poisson regression. A total of 524 patients received either neoadjuvant (n = 130) or adjuvant chemotherapy (n = 394). Most patients (80 %) were treated with a combination of 5-fluorouracil (5FU), epirubicin, and cyclophosphamide (FEC100; 3 cycles) followed by docetaxel 100 mg/m2 (D; 3 cycles). The overall incidence of FN was 17 %; and 18 % of patients received primary prophylaxis (PP) for FN with G-CSF, using pegfilgrastim in 64 % of cases and 74 % of patients over the age of 70 received PP. Less than 5 % of patients who received PP experienced FN. Recurrent FN after secondary prophylaxis was observed in 9 % of patients; 47 % of cases of FN occurred after the 1st cycle and 30 % occurred after the 4th cycle, corresponding to D ± trastuzumab (T). The FEC100 regimen was associated with a relative risk (RR) of FN of 1.98 (p = 0.09). Autoimmune (AI) and inflammatory diseases were associated with a higher risk of FN (RR 3.08; p < 0.01). No significant difference in the incidence of FN was observed between adjuvant and neoadjuvant chemotherapy. FN was managed on an out-patient basis in 72 % of cases. Out-patients with FN were mainly treated by a combination of amoxicillin-clavulanic acid and ciprofloxacin. Dose reduction or chemotherapy regimen modification were necessary in 25 % of patients after FN; no toxic death was reported. The author concluded that the incidence of FN induced by adjuvant/neoadjuvant chemotherapy in ESBC was higher in routine clinical practice than in clinical trials. AI or inflammatory diseases were significant independent risk factors for FN. Primary prophylaxis in patients at risk (elderly, co-morbid patients), especially treated with the FEC regimen, was the keystone of management of this adverse effect. Prevention and management of FN to ensure the patient's safety and QOL are a major issue for both medical oncologists and supportive care physicians.
Furthermore, an UpToDate review on "Immune neutropenia" Coates, 2023) does not mention pegfilgrastim as a therapeutic option.
Appendix
Source: Smith et al, 2006; NCCN, 2023
*Applies to chemotherapy regimens with or without monoclonal antibodies (e.g., trastuzumab, rituximab).
This list is not comprehensive; there are other agents/regimens that have an intermediate/high risk for development of febrile neutropenia.
Source: Smith et al, 2006; NCCN, 2023
Patient Risk Factors
Footnote2 **Source: Smith et al, 2006; NCCN, 2023
Requires Precertification:
Precertification of long-acting granulocyte colony stimulating factor (G-CSF) products [Fulphila (pegfilgrastim-jmdp); Fylnetra (pegfilgrastim-pbbk); Neulasta (pegfilgrastim); Nyvepria (pegfilgrastim-apgf); Rolvedon (eflapegrastim-xnst), Stimufend (pegfilgrastim-fpgk); Udenyca (pegfilgrastim-cbqv); Ziextenzo (pegfilgrastim-bmez)], short-acting G-CSF products [Neupogen (filgrastim); Nivestym (filgrastim-aafi); Releuko, (filgrastim-ayow); Zarxio (filgrastim-sndz)], Granix (tbo-filgrastim), and Leukine (sargramostim)] is required of all Aetna participating providers and members in applicable plan designs. For precertification of these medications, call (866) 752-7021 (Commercial), or fax (888) 267-3277. For Statement of Medical Necessity (SMN) precertification forms, see
Specialty Pharmacy Precertification.
For Medicare Part B plan designs, call (866) 503-0857, or fax (844) 268-7263.
Short-acting Granulocyte Colony Stimulating Factors (G-CSFs): Granix (tbo-filgrastim), Neupogen (filgrastim), Nivestym (filgrastim-aafi), Releuko, (filgrastim-ayow), and Zarxio (filgrastim-sndz)
Criteria for Initial Approval
Neutropenia in cancer members receiving myelosuppressive chemotherapy
Aetna considers short-acting granulocyte colony stimulating factors (G-CSFs), Granix (tbo-filgrastim), Neupogen (filgrastim), Nivestym (filgrastim-aafi), Releuko, (filgrastim-ayow), and Zarxio (filgrastim-sndz), medically necessary for prevention or treatment of febrile neutropenia when
allof the following criteria are met:
The requested medication will be used for primary prophylaxis in members with solid tumors or non-myeloid malignancies who have received, are currently receiving, or will be receiving
anyof the following:
: In the absence of special circumstances, most commonly used regimens have risks of FN of less than 20 %. When available, alternative regimens offering equivalent efficacy, but not requiring CSF support, should be utilized (Smith et al, 2006).
The requested medication will be used for secondary prophylaxis in members with solid tumors or non-myeloid malignancies who experienced a febrile neutropenic complication or a dose-limiting neutropenic event (a nadir or day of treatment count impacting the planned dose of chemotherapy) from a prior cycle of similar chemotherapy, with the same dose and schedule planned for the current cycle (for which primary prophylaxis was not received);
Note: Colony-stimulating factors should not be routinely used for afebrile neutropenia (Smith et al, 2006).
The requested medication will be used for treatment of high risk febrile neutropenia (FN) in members who have any of the following prognostic factors that are predictive of clinical deterioration:
Other Indications
Aetna considers all other indications as experimental and investigational (for additional information, see Experimental and Investigational and Background sections).
Continuation of Therapy
Aetna considers continuation of short-acting G-CSF products medically necessary for all members (including new members) requesting authorization who meet all initial medical necessity criteria.
Long-acting Granulocyte Colony Stimulating Factors (G-CSFs): Neulasta (pegfilgrastim), Fulphila (pegfilgrastim-jmdb), Fylnetra (pegfilgrastim-pbbk), Nyvepria (pegfilgrastim-apgf), Stimufend (pegfilgrastim-fpgk), Udenyca (pegfilgrastim-cbqv), and Ziextenzo (pegfilgrastim-bmez)
Criteria for Initial Approval
Prevention of neutropenia in cancer members receiving myelosuppressive chemotherapy
The requested medication will be used for primary prophylaxis in members with a solid tumor or non-myeloid malignancies who have received, are currently receiving, or will be receiving
anyof the following:
: In the absence of special circumstances, most commonly used regimens have risks of FN of less than 20 %. When available, alternative regimens offering equivalent efficacy, but not requiring CSF support, should be utilized (Smith et al, 2006).
The requested medication will be used for secondary prophylaxis in members with solid tumors or non-myeloid malignancies who experienced a febrile neutropenic complication or a dose-limiting neutropenic event (a nadir or day of treatment count impacting the planned dose of chemotherapy) from a prior cycle of similar chemotherapy, with the same dose and schedule planned for the current cycle (for which primary prophylaxis was not received).
Note: Colony-stimulating factors should not be routinely used for afebrile neutropenia (Smith et al, 2006).
Other Indications
Aetna considers long-acting G-CSF products medically necessary for
anyof the following indications:
Aetna considers all other indications as experimental and investigational (for additional information, see Experimental and Investigational and Background sections).
Continuation of Therapy
Aetna considers continuation of long-acting G-CSF products medically necessary for all members (including new members) requesting authorization who meet all initial medical necessity criteria.
Granulocyte-macrophage Colony-stimulating Factor (GM-CSF): Leukine (sargramostim)
Criteria for Initial Approval
Neutropenia in cancer members receiving myelosuppressive chemotherapy
Aetna considers granulocyte-macrophage colony stimulating factor (GM-CSF), Leukine (sargramostim), medically necessary for prevention or treatment of febrile neutropenia when
allof the following criteria are met:
The requested medication will be used for primary prophylaxis in members with solid tumors or non-myeloid malignancies who have received, are currently receiving, or will be receiving
anyof the following:
In the absence of special circumstances, most commonly used regimens have risks of FN of less than 20 %. When available, alternative regimens offering equivalent efficacy, but not requiring CSF support, should be utilized (Smith et al, 2006)
The requested medication will be used for secondary prophylaxis in members with solid tumors or non-myeloid malignancies who experienced a febrile neutropenic complication or a dose-limiting neutropenic event (a nadir or day of treatment count impacting the planned dose of chemotherapy) from a prior cycle of similar chemotherapy, with the same dose and schedule planned for the current cycle (for which primary prophylaxis was not received);
Note:Colony-stimulating factors should not be routinely used for afebrile neutropenia (Smith et al, 2006)
The requested medication will be used for treatment of high risk febrile neutropenia (FN) in members who have
anyof the following prognostic factors that are predictive of clinical deterioration:
Neuroblastoma
Aetna considers granulocyte-macrophage colony stimulating factor (GM-CSF), Leukine (sargramostim), medically necessary for treatment of high-risk neuroblastoma when used with
eitherof the following:
Other Indications
Aetna considers granulocyte-macrophage colony stimulating factor (GM-CSF), Leukine (sargramostim), medically necessary for
anyof the following indications:
Aetna considers all other indications as experimental and investigational (for additional information, see Experimental and Investigational and Background sections).
Continuation of Therapy
Aetna considers continuation of granulocyte-macrophage colony stimulating factor (GM-CSF), Leukine (sargramostim) therapy medically necessary for all members (including new members) requesting authorization who meet all initial medical necessity criteria.
Rolvedon (eflapegrastim-xnst)
Criteria for Initial Approval
Prevention of neutropenia in cancer members receiving myelosuppressive chemotherapy
Aetna considers Rolvedon (eflapegrastim-xnst) medically necessary for prevention of febrile neutropenia when
allof the following criteria are met:
The requested medication will be used for primary prophylaxis in members with a solid tumor or non-myeloid malignancies who have received, are currently receiving, or will be receiving
anyof the following:
In the absence of special circumstances, most commonly used regimens have risks of FN of less than 20 %. When available, alternative regimens offering equivalent efficacy, but not requiring CSF support, should be utilized (Smith et al, 2006).
The requested medication will be used for secondary prophylaxis in members with solid tumors or non-myeloid malignancies who experienced a febrile neutropenic complication or a dose-limiting neutropenic event (a nadir or day of treatment count impacting the planned dose of chemotherapy) from a prior cycle of similar chemotherapy, with the same dose and scheduled planned for the current cycle (for which primary prophylaxis was not received).
Note:Colony-stimulating factors should not be routinely used for afebrile neutropenia (Smith et al, 2006).
Other Indications
Aetna considers Rolvedon (eflapegrastim-xnst) medically necessary for
anyof the following indications:
Aetna considers all other indications as experimental and investigational (for additional information, see Experimental and Investigational and Background sections).
Continuation of Therapy
Aetna considers continuation of Rolvedon (eflapegrastim-xnst) therapy medically necessary for all members (including new members) requesting authorization who meet all initial medical necessity criteria.