UnitedHealthcare White Blood Cell CSF Coverage Update

Coverage and Medical Necessity Criteria

Long-Acting Pegfilgrastim Preferred Product Criteria

Long‑acting pegfilgrastim biosimilars are preferred subject to state lists; coverage for non-preferred long‑acting products is medically necessary when ONE of the following grouped conditions is met:

Preferred pegfilgrastim criteria: Either (A) both: history of a trial of adequate dose and duration of Neulasta or Udenyca resulting in minimal clinical response; and physician attests the clinical response would be expected to be superior with the alternative pegfilgrastim biosimilar; OR (B) both: history of intolerance, contraindication, or adverse event to Neulasta or Udenyca; and physician attests the same intolerance/contraindication/adverse event would not be expected to occur with the alternative pegfilgrastim biosimilar.

Applies to states without separate state policy when Diagnosis‑Specific Criteria are met.

Short-Acting Filgrastim Preferred Product Criteria

Short‑acting filgrastim biosimilars are preferred subject to state lists; coverage for non-preferred filgrastim products is medically necessary when ONE of the following grouped conditions is met:

Preferred filgrastim criteria: Either (A) both: history of a trial of adequate dose and duration of Zarxio resulting in minimal clinical response; and physician attests the clinical response would be expected to be superior with the alternative filgrastim biosimilar; OR (B) both: history of intolerance, contraindication, or adverse event to Zarxio; and physician attests the same intolerance/contraindication/adverse event would not be expected to occur with the alternative filgrastim biosimilar.

Applies to states without separate state policy when Diagnosis‑Specific Criteria are met.

Diagnosis-Specific Criteria (multiple indications)

CSFs are proven and medically necessary for specific diagnoses when the following grouped criteria are met per indication.

Bone marrow/stem cell transplant: One of: non‑myeloid malignancy undergoing myeloablative chemotherapy followed by autologous or allogeneic bone marrow transplant; OR use for mobilization of hematopoietic progenitor cells for leukapheresis; OR patient has had a peripheral stem cell transplant and received myeloablative chemotherapy.

Leukine, Neupogen, Nivestym, Nypozi, Releuko, and Zarxio referenced.

AML induction/consolidation: Both: diagnosis of acute myeloid leukemia; AND one of: achieved complete remission after induction; OR receiving consolidation chemotherapy; OR receiving specified regimens for relapsed/refractory disease (eg, fludarabine + cytarabine ± idarubicin; cladribine + cytarabine ± mitoxantrone or idarubicin).

Leukine and filgrastim products referenced.

Primary prophylaxis of FN: One of: patient receiving dose‑dense MVAC for bladder cancer; OR dose‑dense AC followed by dose‑dense paclitaxel for breast cancer; OR patient receiving chemotherapy regimens associated with >20% incidence of febrile neutropenia.

Primary and Secondary Prophylaxis; Supportive Care

Covered when criteria from ASCO/NCCN guideline-based risk assessment and indications are met

Primary prophylaxis: Administer CSF starting with the first chemotherapy cycle when the patient has approximately >=20% risk for febrile neutropenia based on patient-, disease-, and treatment-related factors or when receiving dose‑dense chemotherapy.>=20% FN risk

NCCN risk assessment includes disease type, regimen intensity, patient risk factors, and treatment intent.

Secondary prophylaxis: Administer CSF for patients who experienced a neutropenic complication from a prior cycle when dose reduction or delay would compromise outcomes.prior neutropenic complication

Document prior event and rationale.

Use in transplant and mobilization: CSFs (filgrastim and biosimilars, pegfilgrastim) may be used for autologous/allogeneic hematopoietic cell mobilization and post‑transplant supportive care to reduce duration of severe neutropenia, per transplant protocol.

Primary prophylaxis

Covered when ALL of the following are met

Primary prophylaxis: Patient is receiving myelosuppressive chemotherapy with an overall risk of febrile neutropenia >=20% OR is receiving dose‑dense chemotherapy where CSF is considered appropriate.>=20%

Consider patient-, disease-, and treatment‑related factors per guidelines

Secondary prophylaxis

Covered when ANY of the following are met

Secondary prophylaxis: Patient experienced a neutropenic complication from a prior chemotherapy cycle (without prior primary prophylaxis) AND dose reduction or delay would compromise disease‑free or overall survival or treatment outcome.

In many situations dose reduction/delay may be reasonable alternative

Therapeutic use in febrile neutropenia

Therapeutic use covered only in specified high-risk situations

Therapeutic G-CSF for FN: CSFs should not be routinely used as adjunctive treatment with antibiotics for fever and neutropenia; consider CSF in patients with fever and neutropenia who are at high risk for infection‑associated complications or have prognostic factors predictive of poor outcomes (eg, sepsis syndrome, age >65, ANC <100/mcL, neutropenia expected >10 days, pneumonia, invasive fungal infection, hospitalization at time of fever, prior FN).

EORTC/ASCO recommend limited therapeutic use in nonresponding or life‑threatening infectious complications

Transplant & mobilization

Covered when ANY of the following are met

Stem cell mobilization: CSFs may be used alone or with plerixafor to mobilize peripheral‑blood progenitor cells for leukapheresis; choice of strategy depends on cancer and transplant type.

Per ASCO guidance

Post‑autologous stem‑cell transplant: CSFs should be administered after autologous stem‑cell transplantation to reduce duration of severe neutropenia.

Per ASCO guidance

Post‑allogeneic transplant: CSFs may be administered after allogeneic stem‑cell transplantation to reduce duration of severe neutropenia (evidence low; recommendation weak).

Per ASCO guidance

Ryzneuta coverage criteria

Ryzneuta is medically necessary for specified indications when ONE of the following alternative pathways is met:

Ryzneuta coverage pathways: Pathway A: Both: (1) history of a trial of adequate dose and duration of Neulasta or Udenyca resulting in minimal clinical response; AND (2) physician attests clinical response would be expected to be superior with Ryzneuta than experienced with Neulasta or Udenyca.

Ryzneuta coverage pathways: Pathway B: Both: (1) history of intolerance, contraindication, or adverse event to Neulasta or Udenyca; AND (2) physician attests the same intolerance/contraindication/adverse event would not be expected to occur with Ryzneuta.

Any FDA‑approved white blood cell colony stimulating factor (CSF) product that is not listed by proprietary name in this policy will be treated as non‑preferred until UnitedHealthcare has reviewed the product. Coverage for non‑listed products requires meeting the policy’s Diagnosis‑Specific Criteria and any Preferred Product rules; absence from the named product list does not itself preclude review but does indicate a product‑preference pathway applies.

Per ASCO guidance cited in this policy, CSFs should not be routinely used for patients with neutropenia who are afebrile. Routine administration of colony‑stimulating factors for isolated, afebrile neutropenia is not recommended and such requests are subject to denial if they do not meet diagnosis‑specific medical necessity criteria.

The policy follows guideline recommendations that CSFs are not recommended routinely as adjunctive treatment with antibiotics for fever and neutropenia. CSFs may be considered only for patients with fever and neutropenia who are at high risk for infection‑associated complications or who have prognostic factors predictive of poor outcomes; routine adjunctive use with antibiotics is not supported by guideline evidence.

(No additional items specified in this excerpt.)

The inclusion of procedure or diagnosis codes in this policy is for reference only. Listing a code here does not imply that the service described by the code is covered or guarantee payment; benefit coverage is determined by federal, state, or contractual requirements and applicable laws, and other policies may apply.

Requests for CSF solely to treat afebrile neutropenia are inconsistent with guideline recommendations; therefore routine CSF use for afebrile neutropenia is not recommended and may be considered not medically necessary unless specific diagnosis‑level criteria supporting medical necessity are met.

Guidelines summarized in this policy explicitly note that CSFs should not be routinely used as adjunctive therapy with antibiotics in patients with febrile neutropenia. Use as an adjunct to antibiotic therapy is reserved for high‑risk patients or those with prognostic factors for poor outcomes and is not routine practice.

Coverage for colony‑stimulating factor products is contingent on meeting both the Preferred Product rules (trial of or intolerance to designated preferred biosimilars where applicable) and the policy’s Diagnosis‑Specific Criteria. In other words, product preference and the indication‑specific medical necessity criteria must both be satisfied for coverage to be approved.

Applicable Billing and Product Codes

Applicable HCPCS/J codes (part 1)HCPCS

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.
J9361	Injection, efbemalenograstim alfa-vuxw, 0.5 mg.
Q5101	Injection, filgrastim-sndz, biosimilar, (Zarxio), 1 microgram.
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.

Applicable HCPCS/Q codes (part 2)HCPCS

Q5120	Injection, pegfilgrastim-bmez (ZIEXTENZO), biosimilar, 0.5 mg.
Q5122	Injection, pegfilgrastim-apgf (Nyvepria), biosimilar, 0.5 mg.
Q5125	Injection, filgrastim-ayow, biosimilar, (Releuko), 1 mcg.
Q5127	Injection, pegfilgrastim-fpgk (stimufend), biosimilar, 0.5 mg.
Q5130	Injection, pegfilgrastim-pbbk (fylnetra), biosimilar, 0.5 mg.
Q5148	Injection, filgrastim-txid (Nypozi), biosimilar, 1 mcg.

Applicable HCPCS Q-codesHCPCS

Q5120	Injection, pegfilgrastim-bmez (ZIEXTENZO), biosimilar, 0.5 mg.
Q5122	Injection, pegfilgrastim-apgf (Nyvepria), biosimilar, 0.5 mg.
Q5125	Injection, filgrastim-ayow, biosimilar, (Releuko), 1 mcg.
Q5127	Injection, pegfilgrastim-fpgk (stimufend), biosimilar, 0.5 mg.
Q5130	Injection, pegfilgrastim-pbbk (fylnetra), biosimilar, 0.5 mg.
Q5148	Injection, filgrastim-txid (Nypozi), biosimilar, 1 mcg

FDA-labeled biologic products and biosimilars (listed by proprietary name)mixed

Neulasta	pegfilgrastim (reference product) — FDA indication: decrease incidence of infection manifested by febrile neutropenia
Fulphila, Fylnetra, Nyvepria, Stimufend, Udenyca, Ziextenzo	pegfilgrastim biosimilar products
Neupogen	filgrastim (reference product) — FDA indications include decreased incidence of infection manifested by febrile neutropenia and other recovery/mobilization uses
Nivestym, Nypozi, Releuko, Zarxio	filgrastim biosimilar products
Granix	tbo-filgrastim — indicated for reduction in duration of severe neutropenia
Leukine	sargramostim (GM-CSF) — multiple post-induction, mobilization, transplant, and radiation-exposure indications
Rolvedon, Ryzneuta, Rolvedon (listed), others	additional pegfilgrastim products with FDA FN indications listed in document

Applicable HCPCS Codes AddedHCPCS

J9361

Added HCPCS code (associated with Ryzneuta)

inv-23: Febrile Neutropenia risk — incidence thresholds used to determine prophylaxis

Incidence thresholds used>20% or 10-20% incidence of febrile neutropenia used to determine primary versus conditional prophylaxis; regimens with >20% support primary prophylaxis, 10-20% may require additional patient risk factors

Use in AML induction/consolidationChemotherapy regimens associated with 10-20% FN incidence may warrant CSF when patient has one or more risk factors (e.g., persistent neutropenia, liver or renal dysfunction, age >65)

Secondary prophylaxis triggerHistory of a neutropenic complication from a prior cycle supports secondary prophylaxis to prevent recurrence when dose reduction/delay would compromise outcomes

inv-24: FN risk categories — High/Intermediate/Low thresholds

Prior Authorization, Documentation, and Step Therapy Requirements

Prior Authorization

Prior Authorization Required

Prior authorization is required for colony-stimulating factor (CSF) products listed in this policy. Coverage is contingent on meeting diagnosis‑specific criteria in the policy and any product‑preference (preferred product / step therapy) requirements. Requests that do not document the required clinical criteria, trial history, or physician attestation may be denied.

Prior authorization required for listed HCPCS/Q‑codes (see Applicable Codes).
Coverage contingent on meeting Diagnosis‑Specific Criteria and Preferred Product Criteria.

Prior Authorization

Prior Authorization for Prophylactic and Therapeutic G‑CSF

Prior authorization is required for requests for prophylactic or therapeutic G‑CSF (pegfilgrastim and filgrastim products). For prophylactic use, document the overall febrile neutropenia (FN) risk assessment and rationale for primary prophylaxis. For therapeutic use, document the neutropenic complication and justification for G‑CSF therapy (e.g., infection‑related complication, life‑threatening situation, or failure of appropriate antibiotic management where indicated).

PA applies to both primary prophylaxis and therapeutic/secondary use.

Initial Therapy and Primary Prophylaxis Criteria

Initial Therapy / Primary Prophylaxis

Primary prophylaxis coverage conditions

Primary prophylaxis: Patient receiving dose‑dense MVAC for bladder cancer OR dose‑dense AC followed by dose‑dense paclitaxel for breast cancer OR chemotherapy regimen(s) associated with >20% incidence of febrile neutropenia.>20%

Listed products applicable.

Initiation timing

Typical initiation timing and dosing contexts from guidelines and trials

Post-chemotherapy initiation: Filgrastim and similar agents are recommended to start the day after completion of chemotherapy for prophylaxis or mobilization scenarios per NCCN guidance.start day after chemo

Continuation and Ongoing Therapy Criteria

Continuation of prophylactic G-CSF

Continuation recommendations per NCCN/ASCO

Continue same G-CSF after FN: Patients with febrile neutropenia who received prophylactic G-CSF should continue with the same G‑CSF.received prophylactic G-CSF

NCCN recommendation.

Continuation therapy

Continuation/ongoing prophylaxis

Continue CSF across cycles: Primary prophylaxis should be continued through subsequent cycles once initiated for patients with approximately 20% or higher FN risk or those receiving appropriate dose‑dense regimens.

Per ASCO guidance

Step-Therapy / Product Preference Rules

Step requirement	Details
Trial of preferred pegfilgrastim biosimilar required
Provider must document a history of a trial of adequate dose and duration of Neulasta or Udenyca resulting in minimal clinical response, OR documented intolerance/contraindication/adverse event to Neulasta or Udenyca with required physician attestation that the alternative pegfilgrastim biosimilar would be expected to be superior or better tolerated.

Step consideration	Guideline / timing notes
Agent selection per guideline preference
When multiple CSF options exist, follow guideline-preferred agents; filgrastim products are recommended to start the day after completion of chemotherapy. Selection depends on convenience, cost, and clinical situation and may require documentation of FN risk or prior complication for coverage.

Step consideration	Policy guidance
Consider alternative chemotherapy regimens
Consideration should be given to alternative, equally effective, and safe chemotherapy regimens that do not require CSF support when available prior to initiating prophylactic CSF.

Requirement	Attestation detail
Physician attestation of expected superiority for Ryzneuta
Physician must attest that, in their clinical opinion, clinical response would be expected to be superior with Ryzneuta than experienced with prior adequate trial of Neulasta or Udenyca (history of trial with minimal clinical response).

Requirement	Attestation detail
Physician attestation regarding intolerance/adverse event
Physician must attest that a documented intolerance, contraindication, or adverse event to Neulasta or Udenyca would not be expected to occur with Ryzneuta based on clinical judgment.

Administration Settings

Note

Administration settings: infusion center, hospital outpatient, office

Administration of CSFs may occur in outpatient infusion centers, hospital outpatient departments, or physician offices, including per transplant‑center protocols for mobilization and post‑transplant support.

Site‑of‑care follows transplant protocols for mobilization and post‑transplant administration.

Note

No explicit site‑of‑care restrictions — follow labeling

No explicit site‑of‑care restrictions are stated; follow product labeling and clinical protocols for administration in infusion settings.

Biosimilar Options and Preference Guidance

Billing Rule

Neulasta/Udenyca coverage contingent on documented trial/intolerance

Coverage for Neulasta or Udenyca is contingent on documentation of inadequate clinical response to or intolerance/contraindication to the preferred pegfilgrastim biosimilars when the preferred‑product rules apply to pegfilgrastim products.

Preferred long‑acting pegfilgrastim criteria specify either prior trial with minimal response plus attestation, or documented intolerance plus attestation.

Billing Rule

Zarxio coverage contingent on trial/intolerance documentation

Coverage for Zarxio is contingent on documentation of inadequate response to or intolerance/contraindication to Zarxio with physician attestation that the alternative filgrastim would be expected to be superior or better tolerated.

Definitions and Key Clinical Terms

inv-45: Febrile Neutropenia — temperature and neutropenia definition

Febrile neutropenia definition - temperature criteriaSingle oral temperature ≥ 38.3°C or ≥ 38.0°C sustained for >1 hour

Neutropenia component for FNANC < 500 neutrophils/mcL OR ANC < 1,000 neutrophils/mcL with predicted decline to ≤ 500 within 48 hours

Timing notePatient must not have received long-acting prophylactic pegfilgrastim in the prior 14 days for therapeutic FN use to apply

inv-46: Neutropenia / Severe Neutropenia — ANC thresholds

Neutropenia (ANC) thresholdANC < 1,500 neutrophils/mcL defines neutropenia

Severe neutropenia (ANC) thresholdANC < 500 neutrophils/mcL defines severe neutropenia

Background and Rationale

Neutropenia is an abnormally low neutrophil count that increases risk of infection and is a common toxicity of myelosuppressive chemotherapy. Colony‑stimulating factors (G‑CSFs and GM‑CSFs) shorten the duration and severity of neutropenia and reduce the risk of febrile neutropenia, enabling delivery of dose‑dense or curative‑intent chemotherapy when clinically appropriate. Guideline‑based use (primary prophylaxis when overall febrile neutropenia risk is ≈20% or higher, secondary prophylaxis after a prior neutropenic complication, selected transplant/mobilization indications, and limited therapeutic use in high‑risk FN) is reflected throughout this policy.

OpenPayer

White Blood Cell Colony Stimulating Factors

Coverage and Medical Necessity Criteria

Applicable Billing and Product Codes

Prior Authorization, Documentation, and Step Therapy Requirements

Initial Therapy and Primary Prophylaxis Criteria

Continuation and Ongoing Therapy Criteria

Step-Therapy / Product Preference Rules

Administration Settings

Biosimilar Options and Preference Guidance

Definitions and Key Clinical Terms

Background and Rationale