White Blood Cell Colony Stimulating Factors In Cs

Coverage Summary & Scope

Policy scope: This is an Indiana-only UnitedHealthcare medical benefit drug policy (Policy CSIND0061.14) for White Blood Cell Colony Stimulating Factors (CSFs) that defines medically necessary indications, diagnosis-specific criteria, and applicable HCPCS/J-codes for covered products. The policy lists long-acting pegfilgrastim agents, short-acting filgrastim agents, sargramostim (GM-CSF), and newer agents (e.g., Rolvedon, Ryzneuta) and specifies billing codes including J9361.

Coverage stance: CSF products are covered with criteria (proven and medically necessary) for specific diagnosis groups when the policy’s diagnosis-specific criteria are met. Covered indications include: primary and secondary prophylaxis of chemotherapy-induced febrile neutropenia (FN) (including dose-dense or high-risk regimens and intermediate-risk regimens with patient risk factors), treatment of febrile neutropenia when infection-complication risk factors are present, severe chronic neutropenia (SCN), use in bone marrow/stem cell transplant settings and mobilization of hematopoietic progenitor cells, and hematopoietic syndrome of acute radiation syndrome. Coverage for specific products (e.g., Nypozi, Rolvedon, Ryzneuta) is contingent on meeting the Diagnosis-Specific Criteria (InterQual) in the policy.

Key thresholds and scope highlights

Overall risk threshold for prophylactic G-CSF>= 20% risk of febrile neutropenia (FN)

Intermediate regimen FN risk10-20% — consider patient factors (age >65, liver/renal dysfunction, prior neutropenia) to determine overall risk

Geographic ScopeIndiana-only UnitedHealthcare medical benefit drug policy

New CSF addedRyzneuta (efbemalenograstim alfa-vuxw) added and designated medically necessary for specified indications

HCPCS codes addedJ9361 (efbemalenograstim alfa-vuxw) added to Applicable Codes

Diagnosis-Specific Medical Necessity Criteria

Diagnosis-Specific Criteria

CSF products are proven and medically necessary when the following diagnosis-specific criteria are met as detailed below:

Indication groups

Bone Marrow/Stem Cell Transplant (Nypozi)
- Bone Marrow/Stem Cell Transplant (Nypozi)
  - Bone Marrow/Stem Cell Transplant (Nypozi) - criterion 1: Patient has nonmyeloid malignancies and is undergoing myeloablative chemotherapy followed by autologous or allogeneic bone marrow transplant (BMT)
  - Bone Marrow/Stem Cell Transplant (Nypozi) - criterion 2: Used for mobilization of hematopoietic progenitor cells into the peripheral blood for collection by leukapheresis

Provider Actions / Prior Authorization & Billing

Prior Authorization

Prior authorization requirement (inferred)

Coverage for specific CSF products is contingent on meeting the policy's diagnosis-specific clinical criteria and InterQual criteria; submit clinical information to demonstrate that the applicable criteria are met when requesting coverage.

Refer to the InterQual guideline referenced in the policy for diagnosis-specific medical necessity criteria.

Documentation Required

Support diagnosis and prior neutropenic events

Document the diagnosis, the chemotherapy regimen and its estimated febrile neutropenia (FN) risk (percent), any history of prior neutropenic events or chemotherapy dose delays, and relevant patient risk factors when requesting coverage for primary or secondary prophylaxis.

Applicable HCPCS / J-Codes

Applicable HCPCS/J-codes for CSFsmixed

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, excludes biosimilar, 0.5 mg
J2820	Injection, sargramostim (GM-CSF), 50 mcg
J9361	Injection, efbemalenograstim alfa-vuxw, 0.5 mg
Q5101	Injection, filgrastim-sndz, biosimilar, (Zarxio), 1 mcg
Q5108	Injection, pegfilgrastim-jmdb (Fulphila), biosimilar, 0.5 mg
Q5110	Injection, filgrastim-aafi, biosimilar, (Nivestym), 1 microgram
Q5111	Injection, pegfilgrastim-cbqv (Udenyca), biosimilar, 0.5 mg

1–10 of 16

1/2

Added/Applicable HCPCSHCPCSCovered

J9361

Added HCPCS code (document indicates code was added to Applicable Codes)

Reference and Biosimilar mapping (informational)mixed

Neulasta	Reference product; biosimilars: Fulphila, Fylnetra, Nyvepria, Stimufend, Udenyca, Ziextenzo
Neupogen	Reference product; biosimilars: Nivestym, Nypozi, Releuko, Zarxio

Clinical Evidence & Guideline Summary

Reduced median days severe neutropenia 19 → 14 (p=0.0001)AML filgrastim RCT: median duration of severe neutropenia reduced from 19 to 14 days (p=0.0001)

60-day survival 91% vs 48% (p=0.0014)Non-human primate pegfilgrastim radiation model: increased 60-day survival 91% vs 48% (p=0.0014)

Guideline threshold ≥20%EORTC/NCCN/ASCO recommend primary prophylaxis when overall FN risk ≥20%

ASCO strong recASCO recommends primary and secondary prophylaxis per risk criteria (strong evidence)

Guideline recommendations: NCCN and ASCO recommend assessing FN risk prior to the first chemotherapy cycle and using primary prophylactic CSF when the overall FN risk is approximately 20% or higher (NCCN/ASCO) and using secondary prophylaxis for patients who experienced a neutropenic complication when dose reduction or delay would compromise outcome. The EORTC similarly recommends prophylactic G-CSF when the overall FN risk is >= 20% and to consider patient factors when the regimen risk is 10–20% (Recommendation grade A). ASCO also recommends CSFs to enable dose-dense chemotherapy when supported by efficacy data and consideration of patient risk factors each cycle.

FDA indications: Multiple CSF agents (examples include pegfilgrastim products such as Neulasta, Fulphila, Fylnetra, pegfilgrastim biosimilars, and filgrastim products such as Neupogen, Nivestym, Nypozi, Zarxio, and others) are indicated to decrease the incidence of infection manifested as febrile neutropenia in patients with non-myeloid malignancies receiving myelosuppressive anti-cancer drugs associated with a clinically significant incidence of FN. Specific agents also have labeled indications for shortening time to neutrophil recovery in AML, mobilization of hematopoietic progenitor cells, use after BMT, severe chronic neutropenia, and increasing survival after acute exposure to myelosuppressive radiation (hematopoietic syndrome of acute radiation syndrome).

Background & Definitions

Background: Neutropenia is an abnormally low neutrophil count and a major toxicity of myelosuppressive systemic cancer chemotherapy that increases risk of febrile neutropenia (FN) and infection. Colony-stimulating factors (CSFs) — including granulocyte colony-stimulating factors (G-CSFs) and granulocyte-macrophage CSFs (GM-CSFs) — stimulate production of infection-fighting white blood cells (neutrophils and, for GM-CSF, macrophages) and have been shown to reduce the duration and severity of neutropenia and the risk of FN.

Clinical utility: By reducing neutropenia and FN risk, CSFs enable delivery of more intensive or dose-dense chemotherapy regimens when indicated, support neutrophil recovery after induction/consolidation or bone marrow transplant, and are used for mobilization of hematopoietic progenitor cells. Animal and clinical studies support their efficacy, including reduced days of severe neutropenia in AML and improved survival in non-human primate radiation models, which underlie use for hematopoietic syndrome of acute radiation syndrome.

Term	Definition
Adverse Event
Adverse Event is any unfavorable symptom, sign, or disease temporally associated with use of a medical treatment or procedure; graded 0-5 per CTC.
Febrile Neutropenia
Temperature ≥ 38.3°C orally or ≥ 38.0°C over 1 hour and ANC < 500/mcL or < 1,000/mcL with predicted decline to ≤ 500/mcL over 48 hours.
Neutropenia
ANC < 1,500 neutrophils/mcL.
Severe Neutropenia
ANC < 500 neutrophils/mcL.
Biosimilar product
A biologic product approved based on demonstrating high similarity to an FDA-approved reference product with no clinically meaningful differences in safety or effectiveness.

Revision History

10/01/2025material_changeLatest

Ryzneuta added to the list of applicable white blood cell colony stimulating factors (efbemalenograstim alfa-vuxw) and designated proven and medically necessary for hematopoietic syndrome of acute radiation syndrome, primary prophylaxis of chemotherapy-induced febrile neutropenia, secondary prophylaxis of febrile neutropenia, and treatment of febrile neutropenia when policy criteria are met.

10/01/2025material_changeLatest

Applicable Codes section updated to add HCPCS code J9361 (Injection, efbemalenograstim alfa-vuxw, 0.5 mg).

Secondary Prophylaxis of Febrile Neutropenia (Nypozi, Rolvedon, Ryzneuta)

Eligible treatment intent
- Curative intent: Patient is receiving myelosuppressive anticancer drug(s) given with a curative intent (curative chemotherapy, chemotherapy in curative adjuvant/neoadjuvant setting)
- Definitive therapy: Patient is receiving myelosuppressive anticancer drug(s) for definitive therapy (bridge to stem cell transplant, organ transplant, definitive surgery for oligometastatic disease)
Neutropenic history or alternatives
- Documented neutropenic event criteria
  - Prior neutropenic event during same regimen: Patient 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
  - Documented history from prior course: Patient has a documented history of neutropenic event from a previous course of chemotherapy
  - Non-curative intent with additional criteria
    Non-curative intent prerequisite: Patient is receiving myelosuppressive anticancer drug(s) given with non-curative intent
    One of additional criteria
    Documented history of FN: Patient has documented history of Febrile Neutropenia
    Dose reduction trial then neutropenic event: Patient has had a trial of dose reduction, followed by a dose-limiting neutropenic event (nadir count or day of treatment count that could otherwise impact planned dose of chemotherapy) that results in delay in therapy
    Use consistent with FDA label: Patient is receiving myelosuppressive anticancer drug(s) and use of secondary prophylaxis is in accordance with the U.S. FDA approved label
Treatment of Febrile Neutropenia (Off-Label) (Nypozi, Rolvedon, Ryzneuta)
- FN diagnosis: Diagnosis of Febrile Neutropenia
- No long-acting pegfilgrastim in last 14 days: Patient has not received long-acting prophylactic pegfilgrastim in the last 14 days
- One or more infection-complication risk factors
  - Sepsis syndrome
  - Age >65: Age > 65 years
  - ANC <100: Absolute Neutrophil Count (ANC) < 100/mcL
Severe Chronic Neutropenia (SCN) (Nypozi)
- SCN diagnosis: Diagnosis of SCN (congenital, cyclic, and idiopathic Neutropenias with chronic ANC ≤ 500 neutrophils/mcL)
- Dosing per FDA label: Medication is dosed in accordance with the U.S. FDA approved labeling
- Prescribed by hematologist or oncologist: Prescribed by or in consultation with a hematologist or oncologist
Hematopoietic Syndrome of Acute Radiation Syndrome (Nypozi, Rolvedon, Ryzneuta)
- Acute radiation exposure: Patient has been acutely exposed to myelosuppressive doses of radiation
- Dosing per FDA label: Medication is dosed in accordance with the U.S. FDA approved labeling
- Prescribed by hematologist or oncologist: Prescribed by or in consultation with a hematologist or oncologist