RXMP-06 White Blood Cell Growth Factors Form

White Blood Cell Growth Factors

Updated on: 12/5/2025

Page 1 of 17 Criteria Short Cuts | Top of Criteria Acute Myeloid Leukemia (AML) Induction or Consolidation Therapy Bone Marrow/Stem Cell Transplant
Hematopoietic Syndrome of Acute Radiation Syndrome
Primary Prophylaxis of Chemotherapy-Induced Febrile Neutropenia (FN) Secondary Prophylaxis of Febrile Neutropenia (FN)
Severe Chronic Neutropenia (SCN)
Treatment of Febrile Neutropenia (FN)

Policy Number RXMP-06 Line of Business Medicaid & Medicare Effective Date 2/13/2019 Revision Date 12/5/2025

Products Long-acting pegfilgrastim agents: Fulphila (pegfilgrastim-jmdb), Fylnetra (pegfilgrastim-pbbk), Neulasta (pegfilgrastim), Nyvepria (pegfilgrastim-apgf), Udenyca (pegfilgrastim-cbqv), Stimufend (pegfilgrastim- fpgk), Ziextenzo (pegfilgrastim-bmez) Short-acting filgrastim agents: Granix (tbo-filgrastim), Neupogen (filgrastim), Nivestym (filgrastim-aafi), Nypozi (filgrastim-txid), Releuko (filgrastim-ayow), Zarxio (filgrastim-sndz)
Leukine (sargramostim) (refer to the Diagnosis-Specific Criteria)
Rolvedon (eflapegrastim-xnst)
Ryzneuta (efbemalenograstim alfa-vuxw) Any FDA-approved white blood cell colony stimulating factor product not listed here

Override(s)
Approval Duration
Prior Authorization, QL Up to 1 year

HCPCS Code Description Medical Benefit: Authorization Required; Pharmacy Benefit: PA Required 96377 Application of on-body injector (includes cannula insertion) for timed subcutaneous injection [Neulasta OnPro injector] Long-Acting CSF Agents J2506 Injection, pegfilgrastim, excludes biosimilar, 0.5 mg (Neulasta) (preferred) Q5111 Injection, pegfilgrastim-cbqv, biosimilar, (Udenyca), 0.5 mg (preferred) Q5120 Injection, pegfilgrastim-bmez, biosimilar, (Ziextenzo), 0.5 mg Q5122 Injection, pegfilgrastim-apgf, biosimilar, (Nyvepria), 0.5 mg
Q5108 Injection, pegfilgrastim-jmdb, biosimilar, (Fulphila), 0.5 mg
Q5127 Injection, pegfilgrastim-fpgk (Stimufend), biosimilar, 0.5 mg Q5130 Injection, pegfilgrastim-pbbk (Fylnetra), biosimilar, 0.5 mg Short-Acting CSF Agents J1442 Injection, filgrastim (g-csf), excludes biosimilars, 1 microgram (Neupogen) J1447 Injection, tbo-filgrastim, 1 microgram (Granix) Q5101 Injection, filgrastim-sndz, biosimilar, (Zarxio), 1 microgram (preferred) Q5110 Injection, filgrastim-aafi, biosimilar, (Nivestym), 1 microgram (preferred) Q5125 Injection, filgrastim-ayow, biosimilar, (Releuko), 1 microgram C9173 & Q5148 Injection, filgrastim-txid (Nypozi), biosimilar, 1 microgram Miscellaneous CSF Agents J1449 Injection, eflapegrastim-xnst, 0.1 mg [Rolvedon] J2820 Injection, sargramostim (GM-CSF), 50 mcg [Leukine, Prokine] J9361 Injection, efbemalenograstim alfa-vuxw, 0.5mg (Ryzneuta) Medicare (new starts) /Medicaid preferred agents: Neulasta/Udenyca; Zarxio/Nivestym

White Blood Cell Growth Factors

Updated on: 12/5/2025

Page 2 of 17 Criteria Short Cuts | Top of Criteria Acute Myeloid Leukemia (AML) Induction or Consolidation Therapy Bone Marrow/Stem Cell Transplant
Hematopoietic Syndrome of Acute Radiation Syndrome
Primary Prophylaxis of Chemotherapy-Induced Febrile Neutropenia (FN) Secondary Prophylaxis of Febrile Neutropenia (FN)
Severe Chronic Neutropenia (SCN)
Treatment of Febrile Neutropenia (FN)

Medicare CMS Criteria: Medicare Part B Coverage Criteria
• Review using the most current Local Coverage Determination (LCD), National Coverage Determination (NCD), or Local Coverage Article (LCA) that applies to the Hawaii region. The LCD, NCD, or LCA can be found at: https://www.cms.gov/medicare-coverage-database/search.aspx. • No LCD or NCD available as of 10/19/2025. • For new starts, step therapy criteria must be met in addition to clinical criteria before a request may be approved. Medicare Part B 90-Day Transition Period For new Medicare members, a 90-day transition period applies. During this time, if a member is currently on an active course of the requested treatment, including when furnished by an out-of-network provider, Coverage and Step Therapy do not apply. After the first 90 days of enrollment, Coverage and Step Therapy Criteria must be met for continued coverage. Medicare Part B Step Therapy Criteria Long-acting granulocyte colony stimulating factors (G-CSFs):

1. For Fulphila, Fylnetra, Leukine, Neulasta, Prokine, Rolvedon, Ryzneuta, Stimufend, and Ziexenzo for the following indication: Acute Myeloid Leukemia (AML) Induction or Consolidation Therapy, Bone Marrow/Stem Cell Transplant, Hematopoietic Syndrome of Acute Radiation Syndrome, Primary Prophylaxis of Chemotherapy- Induced Febrile Neutropenia (FN), Secondary Prophylaxis of Febrile Neutropenia (FN), Severe Chronic Neutropenia (SCN), and Treatment of Febrile Neutropenia (FN); AND

2. For Fulphila, Fylnetra, Leukine, Neulasta, Prokine, Rolvedon, Ryzneuta, Stimufend, and Ziexenzo for new start: The member has an inadequate response to, intolerable adverse event to, or has a contraindication to Neulasta or Udenyca.

   Short-acting granulocyte colony stimulating factors (G-CSFs)

3. Granix, Neupogen, Nivestym, and Zarxio, Releuko for the following indication: Acute Myeloid Leukemia (AML) Induction or Consolidation Therapy, Bone Marrow/Stem Cell Transplant, Hematopoietic Syndrome of Acute Radiation Syndrome, Primary Prophylaxis of Chemotherapy-Induced Febrile Neutropenia (FN), Secondary Prophylaxis of Febrile Neutropenia (FN), Severe Chronic Neutropenia (SCN), and Treatment of Febrile Neutropenia (FN); AND

4. Granix, Neupogen, and Releuko (new start): The member has an inadequate response to, intolerable adverse event to, or has a contraindication to Zarxio or Nivestym.

   CLINICAL CRITERIA FOR APPROVAL FOR MEDICARE/MEDICAID: NOTE: Pharmacy staff: For QUEST & non-ABD members with cancer, send ADRC referral with chart notes.

   Criteria Short Cuts | Top of Criteria Acute Myeloid Leukemia (AML) Induction or Consolidation Therapy Bone Marrow/Stem Cell Transplant
   Hematopoietic Syndrome of Acute Radiation Syndrome
   Primary Prophylaxis of Chemotherapy-Induced Febrile Neutropenia (FN) Secondary Prophylaxis of Febrile Neutropenia (FN)
   Severe Chronic Neutropenia (SCN)
   Treatment of Febrile Neutropenia (FN)

   Bone Marrow/Stem Cell Transplant
   Leukine, Neupogen, Nivestym (preferred), Releuko, and Zarxio (preferred)

White Blood Cell Growth Factors

Updated on: 12/5/2025

Page 3 of 17 Criteria Short Cuts | Top of Criteria Acute Myeloid Leukemia (AML) Induction or Consolidation Therapy Bone Marrow/Stem Cell Transplant
Hematopoietic Syndrome of Acute Radiation Syndrome
Primary Prophylaxis of Chemotherapy-Induced Febrile Neutropenia (FN) Secondary Prophylaxis of Febrile Neutropenia (FN)
Severe Chronic Neutropenia (SCN)
Treatment of Febrile Neutropenia (FN)

1. Preferred agent may be approved if criteria is met. Non-preferred agent, the member must have tried and failed 2 preferred agents from each drug class. However, if there is only one preferred, then only one preferred agent is required; AND
2. Member has nonmyeloid malignancies and is undergoing myeloablative chemotherapy followed by autologous or allogeneic bone marrow transplant (BMT); OR

3. Used for mobilization of hematopoietic progenitor cells into the peripheral blood for collection by leukapheresis; or Patient has had a peripheral stem cell transplant (PSCT) and has received myeloablative chemotherapy.

   Acute Myeloid Leukemia (AML) Induction or Consolidation Therapy Leukine, Neupogen, Nivestym (preferred), Releuko, and Zarxio (preferred)

4. Preferred agent may be approved if criteria is met. Non-preferred agent, the member must have tried and failed 2 preferred agents from each drug class. However, if there is only one preferred, then only one preferred agent is required; AND
5. Diagnosis of AML; AND

6. One of the following: a. Member achieved complete remission after induction therapy; OR b. Member is receiving consolidation chemotherapy; OR c. Member is receiving fludarabine, cytarabine with or without idarubicin for relapsed or refractory disease; OR d. Member is receiving cladribine, cytarabine with or without mitoxantrone or idarubicin for relapsed or refractory disease.

   Primary Prophylaxis of Chemotherapy-Induced Febrile Neutropenia (FN) Fulphila, Fylnetra, Granix, Leukine, Neulasta (preferred), Neupogen, Nivestym (preferred), Nyvepria, Releuko, Rolvedon, Ryzneuta, Stimufend, Udenyca (preferred), Zarxio (preferred), and Ziextenzo

7. Preferred agent may be approved if criteria is met. Non-preferred agent, the member must have tried and failed 2 preferred agents from each drug class. However, if there is only one preferred, then only one preferred agent is required; AND
8. One of the following: ▪ Member is receiving dose dense MVAC (methotrexate, vinblastine, doxorubicin, cisplatin) for bladder cancer; OR ▪ Member is receiving dose dense AC (doxorubicin, cyclophosphamide) followed by dose-dense paclitaxel for breast cancer; OR ▪ Member is receiving chemotherapy regimen(s) associated with > 20% incidence of FN; OR

9. Both of the following: ▪ Member is receiving chemotherapy regimen(s) associated with 10-20% incidence of FN; AND ▪ Member has one or more risk factors for chemotherapy-induced febrile neutropenia such as: a. Persistent neutropenia due to prior chemotherapy, radiation therapy or bone marrow involvement by tumor (< 500 neutrophils/mcL or < 1,000 neutrophils/mcL and a predicted decline to ≤ 500 neutrophils/mcL over the next 48 hours); b. Liver dysfunction (bilirubin > 2.0); c. Renal dysfunction (creatinine clearance < 50); d. Age > 65 years receiving full chemotherapy dose intensity.

   *Note: Chemotherapy regimen associated incidence of FN will be based on the clinical trial(s) with the highest level of evidence. Chemotherapy regimens and associated incidence of FN based on the clinical trial(s) according to the grade based on Common Terminology Criteria for Adverse Events (CTCAE) by the National Cancer Institute (NCI). The

White Blood Cell Growth Factors

Updated on: 12/5/2025

Page 4 of 17 Criteria Short Cuts | Top of Criteria Acute Myeloid Leukemia (AML) Induction or Consolidation Therapy Bone Marrow/Stem Cell Transplant
Hematopoietic Syndrome of Acute Radiation Syndrome
Primary Prophylaxis of Chemotherapy-Induced Febrile Neutropenia (FN) Secondary Prophylaxis of Febrile Neutropenia (FN)
Severe Chronic Neutropenia (SCN)
Treatment of Febrile Neutropenia (FN)

reference document is not a substitute for the experience and judgment of a physician or other health care professional. Any clinician must use independent medical judgment in the context of individual clinical circumstances to determine any patient’s care or treatment.

Secondary Prophylaxis of Febrile Neutropenia (FN)
Fulphila, Fylnetra, Granix, Leukine, Neulasta (preferred), Neupogen, Nivestym (preferred), Nyvepria, Releuko, Rolvedon, Ryzneuta, Stimufend, Udenyca (preferred), Zarxio (preferred), and Ziextenzo

1. Preferred agent may be approved if criteria is met. Non-preferred agent, the member must have tried and failed 2 preferred agents from each drug class. However, if there is only one preferred, then only one preferred agent is required; AND
2. Both of the following: a. One of the following: 1) Member is receiving myelosuppressive anticancer drug(s) given with a curative intent (curative chemotherapy, chemotherapy in curative adjuvant/neoadjuvant setting); OR 2) Member is receiving myelosuppressive anticancer drug(s) given with a non-curative intent and use of secondary prophylaxis is in accordance with the United States Food and Drug Administration approved labeling; OR 3) Member is receiving myelosuppressive anticancer drug(s) for definitive therapy (bridge to stem cell transplant, organ transplant, definitive surgery for oligometastatic disease); AND b. One of the following: 1) Member has a documented history of a neutropenic event (febrile neutropenia or low neutrophil count leading to delay of subsequent cycle) during a previous cycle of the same chemotherapy regimen at full dose for which primary prophylaxis was not received; OR 2) Member has a documented history of neutropenic event from a previous course of chemotherapy. OR

3. One of the following: a. Both of the following: 1) Member is receiving myelosuppressive anticancer drug(s) given with non-curative intent; AND 2) Member has a documented history of neutropenic event (febrile neutropenia or low neutrophil count leading to delay of subsequent cycle) during a previous cycle of the same chemotherapy regimen after a trial of dose reduction. OR b. Member is receiving myelosuppressive anticancer drug(s) where primary prophylaxis is indicated.

   Treatment of Febrile Neutropenia (FN)
   Fulphila, Fylnetra, Leukine, Neulasta (preferred), Neupogen, Nivestym (preferred), Nyvepria, Releuko, Rolvedon, Ryzneuta, Stimufend, Udenyca (preferred), Zarxio (preferred), and Ziextenzo (Off-Label)

4. Preferred agent may be approved if criteria is met. Non-preferred agent, the member must have tried and failed 2 preferred agents from each drug class. However, if there is only one preferred, then only one preferred agent is required; AND
5. Diagnosis of febrile neutropenia; AND
6. Member has not received long-acting prophylactic pegfilgrastim in the last 14 days; AND
7. Member has one or more risk factors for an infection-associated complication such as:16 a. Sepsis syndrome; b. Age > 65 years;

White Blood Cell Growth Factors

Updated on: 12/5/2025

Page 5 of 17 Criteria Short Cuts | Top of Criteria Acute Myeloid Leukemia (AML) Induction or Consolidation Therapy Bone Marrow/Stem Cell Transplant
Hematopoietic Syndrome of Acute Radiation Syndrome
Primary Prophylaxis of Chemotherapy-Induced Febrile Neutropenia (FN) Secondary Prophylaxis of Febrile Neutropenia (FN)
Severe Chronic Neutropenia (SCN)
Treatment of Febrile Neutropenia (FN)

c. Absolute Neutrophil Count (ANC) < 100/mcL; d. Neutropenia expected to be > 10 days in duration; e. Pneumonia; f. Clinically documented infections including invasive fungal infection; g. Hospitalization at the time of fever; h. Prior episode(s) of FN;

Severe Chronic Neutropenia (SCN)
Neupogen, Nivestym (preferred), Releuko, Zarxio (preferred)

1. Diagnosis of SCN (i.e., congenital, cyclic, and idiopathic neutropenia with chronic ANC ≤ 500 neutrophils/mcL50); AND
2. Medication is dosed in accordance with the U.S. Food and Drug Administration (FDA) approved labeling; AND

3. Prescribed by or in consultation with a Hematologist or Oncologist.

   Hematopoietic Syndrome of Acute Radiation Syndrome
   Fulphila, Fylnetra, Leukine, Neulasta, Neupogen, Nivestym (preferred), Nyvepria, Releuko, Rolvedon, Ryzneutra, Stimufend, Udenyca (preferred), Zarxio (preferred), and Ziextenzo

4. Member has been acutely exposed to myelosuppressive doses of radiation; AND
5. Medication is dosed in accordance with the U.S. Food and Drug Administration (FDA) approved labeling; AND

6. Prescribed by or in consultation with a hematologist or oncologist.

   Clinical Evidence The National Comprehensive Cancer Network (NCCN) publishes clinical practice guidelines for Oncology (NCCN Guidelines®) specific to myeloid growth factors.16 The “NCCN Guidelines for Myeloid Growth Factors” are focused on the use of myeloid growth factors (MGFs) in the cancer setting. The guidelines begin with an evaluation of risk for chemotherapy-induced FN prior to the first cycle of chemotherapy. The risk assessment includes disease type, chemotherapy regimen (high-dose, dose-dense, or standard-dose therapy), patient risk factors, and treatment intent (curative/adjuvant vs. palliative). Based on the chemotherapy regimen and patient-related risk factors, the patient is assigned to either an overall high-risk group (> 20% risk of FN), intermediate-risk group (10%-20% risk), or low-risk group (< 10% risk). Of note, there is currently no consensus nomogram for risk assessment. While the NCCN Panel outlines criteria to aid in the assessment of FN risk, independent clinical judgment should be exercised based on the patient’s situation.

   The NCCN Panel identifies possible patient risk factors for febrile neutropenia. According to the NCCN panel, risk factors may include: • Prior chemotherapy or radiation therapy • Persistent neutropenia • Bone marrow involvement by tumor • Recent surgery and/or open wounds • Liver dysfunction (bilirubin > 2.0) • Renal dysfunction (creatinine clearance < 50) • Age > 65 years receiving full chemotherapy dose intensity

   Other recommendations include: • The NCCN Panel recommends that patients with FN who received prophylactic G-CSF should continue with the same G-CSF.

White Blood Cell Growth Factors

Updated on: 12/5/2025

Page 6 of 17 Criteria Short Cuts | Top of Criteria Acute Myeloid Leukemia (AML) Induction or Consolidation Therapy Bone Marrow/Stem Cell Transplant
Hematopoietic Syndrome of Acute Radiation Syndrome
Primary Prophylaxis of Chemotherapy-Induced Febrile Neutropenia (FN) Secondary Prophylaxis of Febrile Neutropenia (FN)
Severe Chronic Neutropenia (SCN)
Treatment of Febrile Neutropenia (FN)

• For patients who have not received prophylactic MGFs, the NCCN Panel recommends an evaluation for risk factors for infection-related complications or poor clinical outcome. • The NCCN Panel recommends administration of filgrastim, filgrastim-sndz, tbo-filgrastim, or filgrastim-aafi as a single agent or as part of a chemo-mobilization regimen, starting on the day after completion of chemotherapy. • The NCCN Panel recommends single-agent filgrastim, filgrastim-sndz, or tbo-filgrastim for allogeneic hematopoietic cell mobilization and for granulocyte transfusion. • The NCCN Panel recommends consideration of MGFs in the supportive care setting post-autologous hematopoietic cell transplant. Filgrastim, filgrastim-sndz, tbo-filgrastim, filgrastim-aafi, and pegfilgrastim can be considered in the supportive care setting.

Patients with Acute Myeloid Leukemia Receiving Induction or Consolidation Chemotherapy The safety and efficacy of filgrastim to reduce the time to neutrophil recovery and the duration of fever, following induction or consolidation chemotherapy treatment of patients with acute myeloid leukemia (AML) was established in a randomized, doubleblind‚ placebo-controlled‚ multi-center trial in patients with newly diagnosed, de novo AML. The initial induction therapy consisted of intravenous daunorubicin days 1, 2, and 3; cytosine arabinoside days 1 to 7; and etoposide days 1 to 5. Patients were randomized to receive subcutaneous filgrastim (n = 259) at a dose of 5 mcg/kg/day or placebo (n = 262) from 24 hours after the last dose of chemotherapy until neutrophil recovery (ANC ≥ 1,000/mm3 for 3 consecutive days or ≥ 10,000/mm3 for 1 day) or for a maximum of 35 days. The demographic and disease characteristics were balanced between arms with a median age of 54 (range 16 to 89) years; 54% males; initial white blood cell count (65% < 25,000/mm3 and 27% > 100,000/mm3 ); 29% unfavorable cytogenetics. The main efficacy endpoint was median duration of severe neutropenia defined as neutrophil count < 500/mm3 . Treatment with filgrastim resulted in a clinically and statistically significant reduction in median number of days of severe neutropenia, filgrastim-treated patients 14 days, placebo-treated patients 19 days [p = 0.0001: difference of 5 days (95% CI: -6.0, -4.0)]. There was a reduction in the median duration of intravenous antibiotic use, filgrastim-treated patients: 15 days versus placebo-treated patients: 18.5 days; a reduction in the median duration of hospitalization, filgrastim-treated patients: 20 days versus placebo-treated patients: 25 days. There were no statistically significant differences between the filgrastim and the placebo groups in complete remission rate (69% - filgrastim, 68% - placebo), median time to progression of all randomized patients (165 days - filgrastim, 186 days - placebo), or median overall survival (380 days - filgrastim, 425 days - placebo).

The efficacy of sargramostim in the treatment of AML was evaluated in a multicenter, randomized, double-blind placebocontrolled trial of 99 newly diagnosed adult patients, 55-70 years of age, receiving induction with or without consolidation. A combination of standard doses of daunorubicin (days 1-3) and ara-C (days 1-7) was administered during induction and high dose ara-C was administered days 1-6 as a single course of consolidation, if given. Bone marrow evaluation was performed on day 10 following induction chemotherapy. If hypoplasia with < 5% blasts was not achieved, patients immediately received a second cycle of induction chemotherapy. If the bone marrow was hypoplastic with < 5% blasts on day 10 or four days following the second cycle of induction chemotherapy, sargramostim (250 mcg/m2/day) or placebo was given intravenously over four hours each day, starting four days after the completion of chemotherapy. Study drug was continued until an ANC ≥ 1,500 cells/mm3 for three consecutive days was attained or a maximum of 42 days. Sargramostim or placebo was also administered after the single course of consolidation chemotherapy if delivered. Study drug was discontinued immediately if leukemic regrowth occurred.

Sargramostim significantly shortened the median duration of ANC < 500 cells/mm3 by 4 days and < 1,000 cells/mm3 by 7 days following induction. Of patients receiving sargramostim, 75% achieved ANC > 500 cells/mm3 by day 16, compared to day 25 for patients receiving placebo. Sargramostim significantly shortened the median times to neutrophil recovery whether one cycle (12 vs. 15 days) or two cycles (14 vs. 23 days) of induction chemotherapy was administered. Median

White Blood Cell Growth Factors

Updated on: 12/5/2025

Page 7 of 17 Criteria Short Cuts | Top of Criteria Acute Myeloid Leukemia (AML) Induction or Consolidation Therapy Bone Marrow/Stem Cell Transplant
Hematopoietic Syndrome of Acute Radiation Syndrome
Primary Prophylaxis of Chemotherapy-Induced Febrile Neutropenia (FN) Secondary Prophylaxis of Febrile Neutropenia (FN)
Severe Chronic Neutropenia (SCN)
Treatment of Febrile Neutropenia (FN)

times to platelet (> 20,000 cells/mm3 ) and RBC transfusion independence were not significantly different between treatment groups.

During the consolidation phase of treatment, sargramostim did not shorten the median time to recovery of ANC to 500 cells/mm3 (13 days) or 1,000 cells/mm3 (14.5 days) compared to placebo. There were no significant differences in time to platelet and RBC transfusion independence. The incidence of severe infections and deaths associated with infections was significantly reduced in patients who received sargramostim. During induction or consolidation, 27 of 52 patients receiving sargramostim and 35 of 47 patients receiving placebo had at least one grade 3, 4, or 5 infection (p = 0.02). Twenty-five patients receiving sargramostim and 30 patients receiving placebo experienced severe and fatal infections during induction only. There were significantly fewer deaths from infectious causes in the sargramostim arm (3 vs. 11, p = 0.02). The majority of deaths in the placebo group were associated with fungal infections with pneumonia as the primary infection.

Patients with Cancer Undergoing Bone Marrow Transplantation The safety and efficacy of filgrastim to reduce the duration of neutropenia in patients with nonmyeloid malignancies undergoing myeloablative chemotherapy followed by autologous bone marrow transplantation was evaluated in two randomized controlled trials of patients with lymphoma (Study 1 and Study 2). The safety and efficacy of filgrastim to reduce the duration of neutropenia in patients undergoing myeloablative chemotherapy followed by allogeneic bone marrow transplantation was evaluated in a randomized placebo-controlled trial (Study 3). In Study 1, patients with Hodgkin’s disease received a preparative regimen of intravenous cyclophosphamide, etoposide, and BCNU (“CVP”), and patients with non-Hodgkin’s lymphoma received intravenous BCNU, etoposide, cytosine arabinoside and melphalan (“BEAM”). There were 54 patients randomized 1:1:1 to control, filgrastim 10 mcg/kg/day, and Neupogen 30 mcg/kg/day as a 24-hour continuous infusion starting 24 hours after bone marrow infusion for a maximum of 28 days. The median age was 33 (range 17 to 57) years; 56% males; 69% Hodgkin’s disease and 31% non-Hodgkin’s lymphoma. The main efficacy endpoint was duration of severe neutropenia ANC < 500/mm3 . A statistically significant reduction in the median number of days of severe neutropenia (ANC < 500/mm3 ) occurred in the filgrastim-treated groups versus the control group [23 days in the control group‚ 11 days in the 10 mcg/kg/day group, and 14 days in the 30 mcg/kg/day group (11 days in the combined treatment groups‚ p = 0.004)]. In Study 2, patients with Hodgkin’s disease and non- Hodgkin’s lymphoma received a preparative regimen of intravenous cyclophosphamide, etoposide, and BCNU (“CVP”). There were 43 evaluable patients randomized to continuous subcutaneous infusion filgrastim 10 mcg/kg/day (n = 19), filgrastim 30 mcg/kg/day (n = 10) and no treatment (n = 14) starting the day after marrow infusion for a maximum of 28 days. The median age was 33 (range 17 to 56) years; 67% males; 28% Hodgkin’s disease and 72% nonHodgkin’s lymphoma. The main efficacy endpoint was duration of severe neutropenia. There was statistically significant reduction in the median number of days of severe neutropenia (ANC < 500/mm3) in the filgrastim-treated groups versus the control group (21.5 days in the control group versus 10 days in the filgrastim-treated groups, p < 0.001). The number of days of febrile neutropenia was also reduced significantly in this study (13.5 days in the control group versus 5 days in the filgrastimtreated groups‚ p < 0.0001). In Study 3, 70 patients scheduled to undergo bone marrow transplantation for multiple underlying conditions using multiple preparative regimens were randomized to receive filgrastim 300 mcg/m2/day (n = 33) or placebo (n = 37) days 5 through 28 after marrow infusion. The median age was 18 (range 1 to 45) years, 56% males. The underlying disease was: 67% hematologic malignancy, 24% aplastic anemia, 9% other. A statistically significant reduction in the median number of days of severe neutropenia occurred in the treated group versus the control group (19 days in the control group and 15 days in the treatment group‚ p < 0.001) and time to recovery of ANC to ≥ 500/mm3 (21 days in the control group and 16 days in the treatment group‚ p < 0.001).

The efficacy of sargramostim on time to myeloid reconstitution following autologous BMT was established by three single center, randomized, placebo-controlled and double-blinded studies (studies 301, 302, and 303) in adult and pediatric patients undergoing autologous BMT for lymphoid malignancies. A total of 128 patients (65 sargramostim, 63

White Blood Cell Growth Factors

Updated on: 12/5/2025

Page 8 of 17 Criteria Short Cuts | Top of Criteria Acute Myeloid Leukemia (AML) Induction or Consolidation Therapy Bone Marrow/Stem Cell Transplant
Hematopoietic Syndrome of Acute Radiation Syndrome
Primary Prophylaxis of Chemotherapy-Induced Febrile Neutropenia (FN) Secondary Prophylaxis of Febrile Neutropenia (FN)
Severe Chronic Neutropenia (SCN)
Treatment of Febrile Neutropenia (FN)

placebo) were enrolled in these three studies. The median age was 38 years (range 3-62 years), and 12 patients were younger than 18 years of age. The majority of the patients had lymphoid malignancy (87 NHL, 17 all), 23 patients had Hodgkin’s lymphoma, and one patient had AML. In 72 patients with NHL or all, the bone marrow harvest was purged with one of several monoclonal antibodies prior to storage. Compared to placebo, administration of sargramostim in two studies (study 301: 44 patients, 23 patients treated with sargramostim, and study 303: 47 patients, 24 treated with sargramostim) significantly improved the following hematologic and clinical endpoints: time to neutrophil recovery, duration of hospitalization and infection experience or antibacterial usage. In the third study (study 302: 37 patients who underwent autologous BMT, 18 treated with sargramostim) there was a positive trend toward earlier myeloid engraftment in favor of sargramostim.

Patients Undergoing Autologous Peripheral Blood Progenitor Cell Collection and Therapy The safety and efficacy of filgrastim to mobilize autologous peripheral blood progenitor cells for collection by leukapheresis was supported by the experience in uncontrolled trials, and a randomized trial comparing hematopoietic stem cell rescue using filgrastim mobilized autologous peripheral blood progenitor cells to autologous bone marrow. Patients in all these trials underwent a similar mobilization/collection regimen: filgrastim was administered for 6 to 7 days‚ in most cases the apheresis procedure occurred on days 5‚ 6, and 7. The dose of filgrastim ranged between 10 to 24 mcg/kg/day and was administered subcutaneously by injection or continuous intravenous infusion.

Engraftment was evaluated in 64 patients who underwent transplantation using filgrastim mobilized autologous hematopoietic progenitor cells in uncontrolled trials. Two of the 64 patients (3%) did not achieve the criteria for engraftment as defined by a platelet count ≥ 20‚000/mm3 by day 28. In clinical trials of filgrastim for the mobilization of hematopoietic progenitor cells‚ filgrastim was administered to patients at doses between 5 to 24 mcg/kg/day after reinfusion of the collected cells until a sustainable ANC (≥ 500/mm3 ) was reached. The rate of engraftment of these cells in the absence of filgrastim post transplantation has not been studied. A randomized, unblinded study of patients with Hodgkin’s disease or non-Hodgkin’s lymphoma undergoing myeloablative chemotherapy‚ 27 patients received filgrastim-mobilized autologous hematopoietic progenitor cells and 31 patients received autologous bone marrow. The preparative regimen was intravenous BCNU, etoposide, cytosine arabinoside and melphalan (“BEAM”). Patients received daily filgrastim 24 hours after stem cell infusion at a dose of 5 mcg/kg/day. The median age was 33 (range 1 to 59) years; 64% males; 57% Hodgkin’s disease and 43% non-Hodgkin’s lymphoma. The main efficacy endpoint was number of days of platelet transfusions. Patients randomized to filgrastim-mobilized autologous peripheral blood progenitor cells compared to autologous bone marrow had significantly fewer days of platelet transfusions (median 6 vs. 10 days).

A retrospective review was conducted of data from adult patients with cancer undergoing collection of peripheral blood progenitor cells (PBPC) at a single transplant center. Mobilization of PBPC and myeloid reconstitution post-transplant were compared between four groups of patients (n = 196) receiving sargramostim for mobilization and a historical control group who did not receive any mobilization treatment [progenitor cells collected by leukapheresis without mobilization (n = 100)]. Sequential cohorts received sargramostim. Leukaphereses were initiated for all mobilization groups after the WBC reached 10,000 cells/mm3. Leukaphereses continued until both a minimum number of mononucleated cells (MNC) were collected (6.5 or 8.0 × 108 /kg body weight) and a minimum number of aphereses (5-8) were performed. Both minimum requirements varied by treatment cohort and planned conditioning regimen. Marked mobilization effects were seen in patients administered the higher dose of sargramostim (250 mcg/m2) either IV (n = 63) or SC (n = 41). PBPCs from patients treated at the 250 mcg/m2/day dose had a significantly higher number of granulocyte-macrophage colony-forming units (CFU-GM) than those collected without mobilization. A second retrospective review of data from patients undergoing PBPC at another single transplant center was also conducted. Sargramostim was given SC at 250 mcg/m2/day once a day (n = 10) or twice a day (n = 21) until completion of apheresis. Apheresis was begun on day 5 of sargramostim administration and continued until the targeted MNC count of 9 ×

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Primary Prophylaxis of Chemotherapy-Induced Febrile Neutropenia (FN) Secondary Prophylaxis of Febrile Neutropenia (FN)
Severe Chronic Neutropenia (SCN)
Treatment of Febrile Neutropenia (FN)

108/kg or CD34 + cell count of 1 × 106/kg was reached. There was no difference in CD34 + cell count in patients receiving sargramostim once or twice a day.

Hematopoietic Syndrome of Acute Radiation Syndrome Efficacy studies of filgrastim, pegfilgrastim, or sargramostim 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 filgrastim and pegfilgrastim’s effect on severe neutropenia in patients with cancer receiving myelosuppressive chemotherapy.

The efficacy of pegfilgrastim for the acute radiation syndrome setting was studied in a randomized, placebo-controlled nonhuman primate model of radiation injury. Rhesus macaques were randomized to either a control (n = 23) or treated (n = 23) cohort. On study day 0, animals (n = 6 to 8 per irradiation day) were exposed to total body irradiation (TBI) of 7.50 ± 0.15 Gy delivered at 0.8 ± 0.03 Gy/min, representing a dose that would be lethal in 50% of animals by 60 days of follow-up (LD50/60). Animals were administered subcutaneous injections of a blinded treatment [control article (5% dextrose in water) or pegfilgrastim (300-319 mcg/kg/day)] on study day 1 and on study day 8. The primary endpoint was survival. Animals received medical management consisting of intravenous fluids, antibiotics, blood transfusions, and other support as required. Pegfilgrastim significantly (at 0.0014 level of significance) increased 60-day survival in irradiated non-human primates: 91% survival (21/23) in the pegfilgrastim group compared to 48% survival (11/23) in the control group.

The efficacy of filgrastim was studied in a randomized, blinded, placebo-controlled study in a non-human primate model of radiation injury. The planned sample size was 62 animals, but the study was stopped at the interim analysis with 46 animals because efficacy was established. Rhesus macaques were randomized to a control (n = 22) or treated (n = 24) group. Animals were exposed to total body irradiation of 7.4 ± 0.15 Gy delivered at 0.8 ± 0.03 Gy/min, representing a dose that would be lethal in 50% of animals by 60 days of follow-up (LD50/60). Starting on day 1 after irradiation, animals received daily subcutaneous injections of placebo (5% dextrose in water) or filgrastim (10 mcg/kg/day). Blinded treatment was stopped when one of the following criteria was met: ANC ≥ 1,000/mm3 for 3 consecutive days, or ANC ≥ 10,000/mm3 for more than 2 consecutive days within study day 1 to 5, or ANC ≥ 10,000/mm3 any time after study day 5. Animals received medical management consisting of intravenous fluids, antibiotics, blood transfusions, and other support as required. Filgrastim significantly (at 0.023 level of significance) reduced 60-day mortality in the irradiated non-human primates: 21% mortality (5/24) in the filgrastim group compared to 59% mortality (13/22) in the control group.

The efficacy of sargramostim was studied in a randomized, blinded, placebo-controlled study in a nonhuman primate model of radiation injury. Rhesus macaques (50% male) were randomized to a control (n = 36) or treated (n = 36) group. Animals were exposed to total body irradiation at a dose that would be lethal in 50% to 60% of animals (655 cGy) by day 60 post irradiation [lethal dose (LD) 50-60/60]. Starting 48 ± 1 hour after irradiation, animals received daily SC injections of placebo (sterile water for injection, USP) or sargramostim (7 mcg/kg/day). Blinded treatment was stopped when one of the following criteria was met: ANC ≥ 1,000 cells/mm3 for three consecutive days or if the ANC ≥ 10,000 cells/mm3 . Animals received minimal supportive care that included a prophylactic antibiotic, antiemetic, analgesics, and parenteral fluids. No whole blood, blood products or individualized antibiotics were provided. sargramostim significantly (p = 0.0018) increased survival at day 60 in irradiated nonhuman primates: 78% survival (28/36) in the sargramostim group compared to 42% survival (15/36) in the control group. In the same study, an exploratory cohort of 36 rhesus macaques randomized to control (n = 18) or treated (n = 18) was exposed to total body irradiation at a dose that would be lethal in 70-80% of animals (713 cGY) by day 60 post irradiation. Sargramostim increased survival at day 60 in irradiated nonhuman primates: 61% survival (11/18) in the sargramostim group compared to 17% survival (3/18) in the control group.

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Primary Prophylaxis of Chemotherapy-Induced Febrile Neutropenia (FN) Secondary Prophylaxis of Febrile Neutropenia (FN)
Severe Chronic Neutropenia (SCN)
Treatment of Febrile Neutropenia (FN)

FDA INDICATIONS, DOSING & ADMINISTRATION: This section is to be used for informational purposes only. FDA approval alone is not a basis for coverage.
Drug Name/Indications Fulphila® (pegfilgrastim-jmdb) is a leukocyte growth factor indicated to decrease the incidence of infection, as manifested by febrile neutropenia, in patients with nonmyeloid malignancies receiving myelosuppressive anti-cancer drugs associated with a clinically significant incidence of febrile neutropenia.42
Fylnetra® (pegfilgrastim-pbbk) 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.52 Granix® (tbo-filgrastim) is a leukocyte growth factor indicated for reduction in the duration of severe neutropenia in patients with nonmyeloid malignancies receiving myelosuppressive anti-cancer drugs associated with a clinically significant incidence of febrile neutropenia.37 Leukine® (sargramostim) is a recombinant human granulocyte-macrophage colony stimulating factor indicated for use following induction chemotherapy in older adult patients with acute myelogenous leukemia (AML) to shorten time to neutrophil recovery and to reduce the incidence of severe and life-threatening infection and infections resulting in death; the mobilization of hematopoietic progenitor cells into peripheral blood for collection by leukapheresis; the acceleration of myeloid recovery in patients with non-Hodgkin’s lymphoma (NHL), acute lymphoblastic leukemia (all) and Hodgkin’s disease undergoing autologous bone marrow transplantation (BMT); the acceleration of myeloid recovery in patients undergoing allogenic BMT from HLA-matched related donors; for patients who have undergone allogeneic or autologous BMT in whom engraftment is delayed or has failed; and 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).3 Neulasta® (pegfilgrastim) is a leukocyte growth factor indicated to decrease the incidence of infection, as manifested by febrile neutropenia, in patients with nonmyeloid malignancies receiving myelosuppressive anti-cancer drugs associated with a clinically significant incidence of febrile neutropenia; and to increase survival in patients acutely exposed to myelosuppressive doses of radiation (Hematopoietic Subsyndrome of Acute Radiation Syndrome). Neulasta is not indicated for the mobilization of peripheral blood progenitor cells for hematopoietic stem cell transplantation.1 Neupogen® (filgrastim) is a leukocyte growth factor indicated to decrease the incidence of infection, as manifested by febrile neutropenia, in patients with nonmyeloid malignancies receiving myelosuppressive anti-cancer drugs associated with a significant incidence of severe neutropenia with fever; reduce the time to neutrophil recovery and the duration of fever, following induction or consolidation chemotherapy treatment of patients with AML; reduce the duration of neutropenia and neutropenia-related clinical sequelae, e.g., febrile neutropenia, in patients with nonmyeloid malignancies undergoing myeloablative chemotherapy followed by BMT; mobilize autologous hematopoietic progenitor cells into the peripheral blood for collection by leukapheresis; 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; and to increase survival in patients acutely exposed to myelosuppressive doses of radiation (Hematopoietic Syndrome of Acute Radiation Syndrome).2 Nivestym® (filgrastim-aafi) is a leukocyte growth factor indicated to decrease the incidence of infection, as manifested by febrile neutropenia, in patients with nonmyeloid malignancies receiving myelosuppressive anti-cancer drugs associated with a significant incidence of severe neutropenia with fever; reduce the time to neutrophil recovery and the duration of fever, following induction or consolidation chemotherapy treatment of patients with AML; reduce the duration of neutropenia and neutropenia-related clinical sequelae, e.g., febrile neutropenia, in patients with nonmyeloid malignancies undergoing myeloablative chemotherapy followed by BMT; mobilize autologous

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Primary Prophylaxis of Chemotherapy-Induced Febrile Neutropenia (FN) Secondary Prophylaxis of Febrile Neutropenia (FN)
Severe Chronic Neutropenia (SCN)
Treatment of Febrile Neutropenia (FN)

hematopoietic progenitor cells into the peripheral blood for collection by leukapheresis; and 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.43 Nyvepria™ (pegfilgrastim-apgf) is a leukocyte growth factor indicated to decrease the incidence of infection, as manifested by febrile neutropenia, in patients with nonmyeloid malignancies receiving myelosuppressive anti-cancer drugs associated with a clinically significant incidence of febrile neutropenia.50 Releuko® (filgrastim-ayow) is a leukocyte growth factor indicated to decrease the incidence of infection‚ as manifested by febrile neutropenia‚ in patients with nonmyeloid malignancies receiving myelosuppressive anti-cancer drugs associated with a significant incidence of severe neutropenia with fever; reduce the time to neutrophil recovery and the duration of fever, following induction or consolidation chemotherapy treatment of patients with acute myeloid leukemia (AML); reduce the duration of neutropenia and neutropenia-related clinical sequelae‚ e.g.‚ febrile neutropenia, in patients with nonmyeloid malignancies undergoing myeloablative chemotherapy followed by bone marrow transplantation (BMT); 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.51 Rolvedon® is a leukocyte growth factor 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.54 Ryzneuta is a leukocyte growth factor 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 a clinically significant incidence of febrile neutropenia. Stimufend® (pegfilgrastim-fpgk) 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.53 Udenyca® (pegfilgrastim-cbqv) is a leukocyte growth factor indicated to decrease the incidence of infection, as manifested by febrile neutropenia, in patients with nonmyeloid malignancies receiving myelosuppressive anti-cancer drugs associated with a clinically significant incidence of febrile neutropenia.44 Zarxio® (filgrastim-sndz) is a leukocyte growth factor indicated to decrease the incidence of infection, as manifested by febrile neutropenia, in patients with nonmyeloid malignancies receiving myelosuppressive anti-cancer drugs associated with a significant incidence of severe neutropenia with fever; reduce the time to neutrophil recovery and the duration of fever, following induction or consolidation chemotherapy treatment of patients with AML; reduce the duration of neutropenia and neutropenia-related clinical sequelae, e.g., febrile neutropenia, in patients with nonmyeloid malignancies undergoing myeloablative chemotherapy followed by BMT; mobilize autologous hematopoietic progenitor cells into the peripheral blood for collection by leukapheresis; and 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.38, 40 Ziextenzo® (pegfilgrastim-bmez) is a leukocyte growth factor indicated to decrease the incidence of infection, as manifested by febrile neutropenia, in patients with nonmyeloid malignancies receiving myelosuppressive anti-cancer drugs associated with a clinically significant incidence of febrile neutropenia.47

Professional Societies
American Society of Clinical Oncology (ASCO) The ASCO published guidelines in 2015 entitled, “Recommendations for the Use of WBC Growth Factors: American Society of Clinical Oncology Clinical Practice Guideline Update.”41 The ASCO guidelines provide direction as to how colony-stimulating factors (CSFs) should be used in people with cancer. Recommendations include:

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Primary Prophylaxis of Chemotherapy-Induced Febrile Neutropenia (FN) Secondary Prophylaxis of Febrile Neutropenia (FN)
Severe Chronic Neutropenia (SCN)
Treatment of Febrile Neutropenia (FN)

1. Primary prophylaxis with a CSF starting with the first cycle and continuing through subsequent cycles of chemotherapy is recommended in patients who have an approximately 20% or higher risk for febrile neutropenia based on patient-, disease- and treatment-related factors. Primary CSF prophylaxis should also be administered in patients receiving dose dense chemotherapy when considered appropriate. Consideration should be given to alternative, equally effective, and safe chemotherapy regimens not requiring CSF support when available. (Type: evidence based, benefits outweigh harms. Evidence quality: high. Strength of recommendation: strong.)
2. Secondary prophylaxis with a CSF is recommended for patients who experienced a neutropenic complication from a prior cycle of chemotherapy (for which primary prophylaxis was not received), in which a reduced dose or treatment delay may compromise disease-free or overall survival or treatment outcome. In many clinical situations, dose reduction or delay may be a reasonable alternative. (Type: evidence based, benefits outweigh harms. Evidence quality: high. Strength of recommendation: strong.)
3. CSFs should not be routinely used for patients with neutropenia who are afebrile. (Type: evidence based, benefits outweigh harms. Evidence quality: high. Strength of recommendation: strong.)
4. CSFs should not be routinely used as adjunctive treatment with antibiotic therapy for patients with fever and neutropenia. However, CSFs should be considered in patients with fever and neutropenia who are at high risk for infection-associated complications or who have prognostic factors predictive of poor clinical outcomes. (Type: evidence based, benefits outweigh harms. Evidence quality: high. Strength of recommendation: strong.)
5. Dose-dense regimens with CSF support should only be used if supported by convincing efficacy data or within an appropriately designed clinical trial. Efficacy data support the use of dose-dense chemotherapy in the adjuvant treatment of high-risk breast cancer and the use of high-dose intensity methotrexate, vinblastine, doxorubicin, and cisplatin in urothelial cancer. There are limited and conflicting data on the value of dose-dense regimens with CSF support in non-Hodgkin’s lymphoma, and it cannot routinely be recommended at this time. (Type: evidence based, benefits outweigh harms. Evidence quality: high for breast cancer and lymphoma; intermediate for urothelial cancer. Strength of recommendation: strong for breast cancer and lymphoma; moderate for urothelial cancer.)
6. CSFs may be used alone, after chemotherapy, or in combination with plerixafor to mobilize peripheral-blood progenitor cells. Choice of mobilization strategy depends in part on type of cancer and type of transplantation. (Type: evidence based, benefits outweigh harms. Evidence quality: strong. Strength of recommendation: high.)
7. CSFs should be administered after autologous stem-cell transplantation to reduce the duration of severe neutropenia. (Type: evidence based, benefits outweigh harms. Evidence quality: high. Strength of recommendation: strong.)
8. CSFs may be administered after allogeneic stem-cell transplantation to reduce the duration of severe neutropenia. (Type: evidence based. Evidence quality: low. Strength of recommendation: weak).
9. Prophylactic CSFs for patients with diffuse aggressive lymphoma age ≥ 65 years treated with curative chemotherapy (cyclophosphamide, doxorubicin, vincristine, prednisone, and rituximab) should be considered, particularly in the presence of comorbidities. (Type: evidence based, benefits outweigh harms. Evidence quality: intermediate. Strength of recommendation: moderate.)
10. The use of CSFs in pediatric patients will almost always be guided by clinical protocols. As in adults, the use of CSFs is reasonable as primary prophylaxis for pediatric patients with a high likelihood of febrile neutropenia. Similarly, the use of CSFs for secondary prophylaxis or for therapy should be limited to high-risk patients. (Type: evidence based, benefits outweigh harms. Evidence quality: high. Strength of recommendation: strong.)
11. For pediatric indications in which dose-intense chemotherapy is known to have a survival benefit, such as Ewing sarcoma, CSFs should be used to enable the administration of these regimens. (Type: evidence based, benefits outweigh harms. Evidence quality: high. Strength of recommendation: strong.)
12. CSFs should not be used in pediatric patients with non-relapsed acute lymphoblastic leukemia or non-relapsed acute myeloid leukemia who do not have an infection. (Type: informal consensus. Evidence quality: intermediate. Strength of recommendation: moderate.)

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Primary Prophylaxis of Chemotherapy-Induced Febrile Neutropenia (FN) Secondary Prophylaxis of Febrile Neutropenia (FN)
Severe Chronic Neutropenia (SCN)
Treatment of Febrile Neutropenia (FN)

13. Pegfilgrastim, filgrastim, tbo-filgrastim, and filgrastim-sndz (and other biosimilars, as they become available) can be used for the prevention of treatment-related febrile neutropenia. The choice of agent depends on convenience, cost, and clinical situation. There have been no additional data comparing granulocyte CSFs and granulocyte- macrophage CSFs since the 2006 update; therefore, there is no change in the recommendation regarding their therapeutic equivalency. (Type: evidence based, benefits outweigh harms. Evidence quality: high. Strength of recommendation: strong.)

14. Current recommendations for the management of patients exposed to lethal doses of total-body radiotherapy, but not doses high enough to lead to certain death resulting from injury to other organs, include the prompt administration of CSFs or pegylated granulocyte CSFs. [Type: formal consensus (by others), benefits outweigh harms. Evidence quality: intermediate. Strength of recommendation: moderate.]

    European Organisation for Research and Treatment of Cancer (EORTC) The EORTC published clinical practice guidelines in 2011 entitled, “2010 update of EORTC guidelines for the use of granulocyte-colony stimulating factor to reduce the incidence of chemotherapy-induced febrile neutropenia in adult patients with lymphoproliferative disorders and solid tumors.”43 The EORTC guidelines provide direction on the use of colony stimulating factors for prevention of chemotherapy-induced febrile neutropenia (FN) in patients with cancer. Recommendations are graded on a scale of A-D, based on levels of evidence applied by the EORTC Guidelines Working Party. Levels of evidence are as follows: I = evidence obtained from meta-analysis of multiple, well-designed, controlled studies or from high-power randomized, controlled clinical trials; II = Evidence obtained from at least one well-designed experimental study or low-power randomized, controlled clinical trial; III = Evidence obtained from well-designed, quasi-experimental studies such as nonrandomized, controlled single-group, pre-post, cohort, time or matched case- control series; IV = studies such as comparative and correlational descriptive and case studies; and V= evidence obtained from case reports and clinical examples. Grading recommendations are as follows: A = evidence of type I or consistent findings from multiple studies of types II, III or IV; B = evidence of types II, III or IV and findings are generally consistent; C = evidence of types II, III or IV but findings are inconsistent; and D = little or no systematic empirical evidence. Recommendations include: Recommendation Number Recommendations Recommendation 1: Patient- related risk factors for increased incidence of FN Patient-related risk factors should be evaluated in the overall assessment of FN risk before administering each cycle of chemotherapy. Particular consideration should be given to the elevated risk of FN for elderly patients (aged 65 and over). Other adverse risk factors that may influence FN risk include: advanced stage of disease; experience of previous episode(s) of FN; lack of G-CSF use and absence of antibiotic prophylaxis. However, please note that the indiscriminate use of antibiotic prophylaxis for patients undergoing treatment for solid tumors or lymphoma is not recommended either by this working party or the EORTC Infectious Disease Group. Recommendation grade: B. Recommendation 2:
    Chemotherapy regimens associated with increased risk of FN

    Consideration should be given to the elevated risk of FN when using certain chemotherapy regimens. Recommendation grade: A/B (depending on the evidence for each chemotherapy regimen). For the list of identified chemotherapy regimens, reference Table 5. It should be noted that this list is not comprehensive and there may be other drugs or regimens associated with an increased risk of FN. Recommendation 3: G-CSF to support chemotherapy • In situations where dose-dense or dose-intense chemotherapy strategies have survival benefits, prophylactic G-CSF should be used as a supportive treatment. Recommendation grade: A. • If reductions in chemotherapy dose intensity or density are known to be associated with a poor prognosis, primary GCSF prophylaxis should be used to

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Primary Prophylaxis of Chemotherapy-Induced Febrile Neutropenia (FN) Secondary Prophylaxis of Febrile Neutropenia (FN)
Severe Chronic Neutropenia (SCN)
Treatment of Febrile Neutropenia (FN)

Recommendation Number Recommendations maintain chemotherapy. Examples of this could be when the patient is receiving adjuvant or potentially curative treatment or when the treatment intent is to prolong survival. Recommendation grade A. Where treatment intent is palliative, use of less myelosuppressive chemotherapy or dose/schedule modification should be considered. Recommendation grade: B. Recommendation 4: Impact of the overall FN risk on G-CSF use The risk of complications related to FN should be assessed individually for each patient at the beginning of each cycle. When assessing FN risk, the clinician should take into account patient-related risk factors (recommendation 1), the chemotherapy regimen and associated complications (recommendations 2 and 3) and treatment intent (recommendation 3). Prophylactic G-CSF is recommended when there is a P20% overall risk of FN. When chemotherapy regimens associated with an FN risk of 10–20%, particular attention should be given to the assessment of patient characteristics that may increase the overall risk of FN. Recommendation grade: A. Recommendation 5: G-CSF in patients with existing FN Treatment with G-CSF for patients with solid tumors and malignant lymphoma and ongoing FN is indicated only in special situations. These are limited to those patients who are not responding to appropriate antibiotic management and who are developing life-threatening infectious complications (such as severe sepsis or septic shock). Recommendation grade: B. Recommendation 6: Choice of formulation Filgrastim, lenograstim and pegfilgrastim have clinical efficacy and we recommend the use of any of these agents, according to current administration guidelines, to prevent FN and FN-related complications, where indicated. Filgrastim biosimilars are now also a treatment option in Europe. Recommendation grade: A.

Miscellaneous Information: ECOG or Eastern Cooperative Oncology Group Performance Status: A scale and criteria used by doctors and researchers to assess how an individual’s disease is progressing, assess how the disease affects the daily living abilities of the individual, and determine appropriate treatment and prognosis. This scale may also be referred to as the WHO (World Health Organization) or Zubrod score which is based on the following scale: • 0 = Fully active, able to carry on all pre-disease performance without restriction • 1 = Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature, for example, light house work, office work • 2 = Ambulatory and capable of all self-care but unable to carry out any work activities. Up and about more than 50% of waking hours • 3 = Capable of only limited self-care, confined to bed or chair more than 50% of waking hours • 4 = Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair • 5 = Dead

Definitions Key Term Definition Adverse Event An adverse event is any unfavorable symptom, sign, or disease (including an abnormal laboratory finding) temporally associated with the use of a medical treatment or procedure that may or may NOT be considered related to the medical treatment or procedure. The

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Primary Prophylaxis of Chemotherapy-Induced Febrile Neutropenia (FN) Secondary Prophylaxis of Febrile Neutropenia (FN)
Severe Chronic Neutropenia (SCN)
Treatment of Febrile Neutropenia (FN)

Key Term Definition common terminology criteria (CTC) provides descriptive terminology for adverse event reporting. A grading (severity) scale is provided for each adverse event term.51 Biosimilar Product A biologic product that is approved based on demonstrating that it is highly similar to an FDA‐ approved biologic product, known as a reference product, and has no clinically meaningful differences in terms of safety and effectiveness from the reference product. Only minor differences in clinically inactive components are allowable in biosimilar products. The chart below highlights the white blood cell colony stimulating factor reference products and respective biosimilar product.55 Reference Product Biosimilar Product Neulasta Fulphilia, Fylnetra, Nyvepria, Stimufend, Udenyca, Ziextenzo Neupogen Nivestym, Releuko, Zarxio Grades (general definition) 0 = No adverse event or within normal limits 1 = Mild adverse event 2 = Moderate adverse event 3 = Severe and undesirable adverse event 4 = Life-threatening or disabling adverse event 5 = Death related to adverse event Febrile Neutropenia Febrile neutropenia is defined as single temperature: ≥ 38.3 °C orally or 38.0 °C for a duration of over 1 hour; and neutropenia: < 500 neutrophils/mcL or < 1,000 neutrophils/mcL and a predicted decline to ≤ 500 neutrophils/mcL over the next 48 hours.16 Neutropenia Neutropenia is defined as an absolute neutrophil count (ANC) of less than 1,500 per microliter (< 1,500 neutrophils/mcL).50 Severe Neutropenia Severe neutropenia is defined as an ANC of less than 500 neutrophils/mcL (< 500 neutrophils/mcL).50

Applicable Codes The following list(s) of procedure and/or diagnosis codes is provided for reference purposes only and may not be all inclusive. Listing of a code in this policy does not imply that the service described by the code is a covered or non- covered health service. Benefit coverage for health services is determined by federal, state, or contractual requirements and applicable laws that may require coverage for a specific service. The inclusion of a code does not imply any right to reimbursement or guarantee claim payment. Other Policies and Guidelines may apply. HCPCS Code Description C9399 Unclassified drugs or biologics J1442 Injection, filgrastim, (G-CSF), excludes biosimilars, 1 microgram J1447 Injection, tbo-filgrastim, 1 microgram J1449 Injection, eflapegrastim-xnst, 0.1 mg J2506 Injection, pegfilgrastim, 0.5 mg J2820 Injection, sargramostim (GM-CSF), 50 mcg J3490 Unclassified drugs J3590 Unclassified biologics J9361 Injection, efbemalenograstim alfa-vuxw, 0.5 mg Q5101 Injection, filgrastim-sndz, biosimilar (Zarxio), 1 microgram Q5108 Injection, pegfilgrastim-jmdb, biosimilar, (Fulphilia), 0.5 mg Q5110 Injection, filgrastim-aafi, biosimilar, (Nivestym), 1 microgram

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Primary Prophylaxis of Chemotherapy-Induced Febrile Neutropenia (FN) Secondary Prophylaxis of Febrile Neutropenia (FN)
Severe Chronic Neutropenia (SCN)
Treatment of Febrile Neutropenia (FN)

Q5111 Injection, pegfilgrastim-cbqv, biosimilar, (Udenyca), 0.5 mg Q5120 Injection, pegfilgrastim-bmez, biosimilar, (Ziextenzo), 0.5 mg Q5122 Injection, pegfilgrastim-apgf, biosimilar, (Nyvepria), 0.5 mg Q5125 Injection, filgrastim-ayow, biosimilar, (Releuko), 1 microgram Q5127 Injection, pegfilgrastim-fpgk, biosimilar, (Stimufend), 0.5 mg Q5130 Injection, pegfilgrastim-pbbk, biosimilar, (Fylnetra), 0.5 mg

REFERENCES:

1. National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines in Oncology. Hematopoietic Growth Factors. V1.2025. Accessed September 1, 2025.
2. Smith TJ, Bohlke K, Lyman GH, et al. Recommendations for the Use of WBC Growth Factors: American Society of Clinical Oncology Clinical Practice Guideline Update. J Clin Oncol. 2015;33:3199-3212.
3. National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines in Oncology. Breast Cancer. v.4.2025. Accessed September 12, 2025..
4. Citron ML, Berry DA, Cirrincione C, et al. Randomized trial of dose-dense versus conventionally scheduled and sequential versus concurrent combination chemotherapy as postoperative adjuvant treatment of node-positive primary breast cancer: first report of Intergroup Trial C9741/Cancer and Leukemia Group B trial. J Clin Oncol. 2003;21(8):1431-9.
5. National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines in Oncology. Prevention and Treatment of Cancer-Related Infections. v.1.2025. Accessed September 11, 2025.
6. Hudis CA, Schmitz. Dose-dense chemotherapy in breast cancer and lymphoma. Seminar in Oncol. 2004;31(Suppl 8):19-23.
7. Nemunaitis J, Rosenfeld CS, Ash R, et al. Phase III Randomized, double-blind placebo-controlled trial of rhGM-CSF following allogenic bone marrow transplantation. Bone Marrow Transplant. 1995;72:949-54.
8. Nemunaitis J, Buckner CD, Appelbaum FR et al. Phase I/II trial of recombinant human granulocyte-macrophage colony stimulating factor following allogeneic bone marrow transplantation. Blood. 1991;77:2065-71.
9. Nemunaitis J, Rabinowe SN, Singer JW et al. Recombinant granulocyte-macrophage colony-stimulating factor after autologous bone marrow transplantation for lymphoid cancer. N Engl J Med. 1991;324:1773-8.
10. Rabinowe SN, Neuberg D, Bierman PJ et al. Long-term follow-up of a phase III study of recombinant human granulocytemacrophage colony-stimulating factor after autologous bone marrow transplantation for lymphoid malignancies. Blood. 1993;81:1903-8.
11. Grant SM, Heel RC. Recombinant granulocyte-macrophage colony-stimulating factor (rGM-CSF): a review of its pharmacological properties and prospective role in the management of myelosuppression. Drugs 1992;43:516-60.
12. McEvoy GK, ed. AHFS Drug Information 2006. Bethesda, MD: American Society of Health-System Pharmacists;
14. Nemunaitis J, Singer JW, Buckner CD et al. Use of recombinant human granulocyte-macrophage colony-stimulating factor in graft failure after bone marrow transplantation. Blood. 1990;76:245-53.
15. Rowe JN, Andersen JW, Mazza JJ et al. A randomized placebo-controlled phase III study of granulocyte-macrophage colony-stimulating factor in adult patients (> 55 to 70 years of age) with acute myelogenous leukemia: a study of the Eastern Cooperative Oncology Group (E1490). Blood. 1995;86:457-62.
16. Vogel CL, Wojtukiewicz MZ, Carroll RR, et al. First and subsequent cycle use of pegfilgrastim prevents febrile neutropenia in patients with breast cancer: a multicenter, double-blind, placebo-controlled phase III study. J Clin Oncol. 2005;23(6):1178-84.
17. Kuderer NM, Dale DC, Crawford J, Lyman GH. Impact of primary prophylaxis with granulocyte colony-stimulating factor on febrile neutropenia and mortality in adult cancer patients receiving chemotherapy: a systematic review. J Clin Oncol. 2007;25(21):3158-67.

White Blood Cell Growth Factors

Updated on: 12/5/2025

Page 17 of 17 Criteria Short Cuts | Top of Criteria Acute Myeloid Leukemia (AML) Induction or Consolidation Therapy Bone Marrow/Stem Cell Transplant
Hematopoietic Syndrome of Acute Radiation Syndrome
Primary Prophylaxis of Chemotherapy-Induced Febrile Neutropenia (FN) Secondary Prophylaxis of Febrile Neutropenia (FN)
Severe Chronic Neutropenia (SCN)
Treatment of Febrile Neutropenia (FN)

17. National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines in Oncology. Acute Myeloid Leukemia. v.2.2023. Accessed March 30, 2023.
18. Centers for Disease Control and Prevention. Guidelines for Prevention and Treatment of Opportunistic Infections in HIVInfected Adults and Adolescents: recommendations from CDC, the National Institutes of Health, and the Infectious Diseases Society of America. MMWR 2009;58(No. RR-4):1-216.
19. Granix® [package insert]. North Wales, PA: Teva Pharmaceutical Industries Ltd.; March 2023.
20. Zarxio® [package insert]. Princeton, NJ: Sandoz Inc.; March 2023.
21. Smith TJ, et al. Recommendations for the Use of WBC Growth Factors: American Society of Clinical Oncology Clinical Practice Guideline Update. Journal of Clin Oncol. 2015;33(28):3199-3212.
22. Neutropenia (low neutrophil count). Mayo Clinic. Available at: http://www.mayoclinic.org/symptoms/neutropenia/basics/definition/sym-20050854. Accessed March 30, 2023.
23. Aapro MS, Bohlius J, Cameron DA, et al. 2010 update of EORTC guidelines for the use of granulocyte-colony stimulating factor to reduce the incidence of chemotherapy-induced febrile neutropenia in adult patients with lymphoproliferative disorders and solid tumors. Eur Journal of Cancer. 2011;47:8-32.
24. Fulphila® [package insert]. Zurich, Switzerland: Mylan GmbH; March 2023.
25. Nivestym® [package insert]. Lake Forest, IL; Hospira, Inc.; March 2023.
26. Udenyca® [package insert]. Redwood City, CA; Coherus BioSciences, Inc.; March 2023.
27. Ziextenzo® [package insert]. Princeton, NJ; Sandoz, Inc.; March 2023.
28. Taplitz RA, Kennedy EB, Bow EJ, et al. Outpatient Management of Fever and Neutropenia in Adults Treated for Malignancy: American Society of Clinical Oncology and Infectious Diseases Society of America Clinical Practice Guideline Update. J Clin Oncol. 2018;36(14):1443–1453. doi:10.1200/JCO.2017.77.6211.
29. Freifeld AG, Bow EJ, Sepkowitz KA, et al. Clinical practice guideline for the use of antimicrobial agents in neutropenic patients with cancer: 2010 Update by the Infectious Diseases Society of America. Clin Infect Dis. 2011;52(4):427–431. doi:10.1093/cid/ciq147.
30. American Academy of Allergy, Asthma, and Immunology. Neutropenia Definition. Accessed March 30, 2023.
31. National Cancer Institute. Cancer Therapy Evaluation Program: Common Toxicity Criteria Manual (Version 6.0). Accessed March 30, 2023.
32. Nyvepria™ [package inset]. New York, NY: Pfizer Inc.; March 2023.
33. Releuko® [package insert]. Piscataway, NJ: Kashiv BioSciences LLC.; March 2023.
34. Fylnetra® [package insert]. Piscataway, NJ: Kashiv BioSciences LLC.; March 2023.
35. Stimufend® [package insert]. Lake Zurich, IL: Fresenius Kabi USA LLC; March 2023.
36. Rolvedon® [package insert]. Irvine, CA: Spectrum Pharmaceuticals, Inc.; March 2023.
37. National Cancer Institute. Biosimilar Drug. Available at: https://www.cancer.gov/publications/dictionaries/cancer- terms/def/biosimilar-drug. Accessed March 30, 2023.

38. Ryzneutra® [package insert]. Singabore: Evive Biotechnolog Singapore PTE. LTD. August 2025.

    Change History

39. Colony-Stimulating Factors, supersedes prior version, 5/26/23 HB.
40. Added Continuity of Care requirement, 4/2/25 AP.
41. Adopt Optum Health’s White Blood Cell Guidelines and changed criteria name, 10/19/2025.
42. Updated preferred status, 12/5/2025 AP.