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ModifiedAnthemPolicy CC-0002

Colony Stimulating Factor Agents

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Clinical coverage and medical necessity criteria for granulocyte and granulocyte-macrophage colony stimulating factor (CSF) agents used primarily to prevent or treat chemotherapy-induced febrile neutropenia and for certain mobilization/adjunctive indications; applies to Anthem medical benefit determinations.

Policy Summary

PayerAnthem

PolicyColony Stimulating Factor Agents

Policy CodePolicy CC-0002

Change TypeCoding and step therapy clarifications

Effective DateMar 26, 2026

Last ReviewDec 8, 2025

Next Review DateDec 8, 2025

Key ActionSubmit prior authorization with documentation of chemotherapy regimen FN risk and patient-specific risk factors to support CSF coverage.

SourceLink

POLICY UPDATE CHANGES

Added new biosimilar Armlupeg to Neulasta criteria and coding (HCPCS NOC C9399 and J3590) for Armlupeg.

Added override criteria allowing use of a non-preferred vial agent when the preferred product is only available as a prefilled pen and cannot provide required accurate dosing.

Step therapy tables updated multiple times (March 2026, March 2026, and other recent dates).

20%+FN risk threshold for automatic primary prophylaxis coverage

10-19%Intermediate FN risk range requiring ≥1 patient risk factor for prophylaxis

~6Distinct drug product sections covered

<=500 / <1500ANC thresholds referenced for severe or persistent neutropenia

Neulasta / UdenycaCommercial preferred long-acting agents (examples)

Clinical Coverage Criteria

Rolvedon Clinical Criteria

Requests for Rolvedon (eflapegrastim-xnst) may be approved if:

Rolvedon primary prophylaxis - high regimen risk: Individual with nonmyeloid malignancy is using for primary prophylaxis of Febrile Neutropenia (FN)regimen FN risk >= 20%

NCCN 2A

Rolvedon primary prophylaxis - intermediate regimen risk with patient factor: Individual with nonmyeloid malignancy is using for primary prophylaxis of FN and regimen FN risk 10-19% and has at least one listed patient risk factorregimen FN risk 10-19%

See patient risk factor node

Patient risk factors for FN

Policy Summary

PayerAnthem

PolicyColony Stimulating Factor Agents

Policy CodePolicy CC-0002

Change TypeCoding and step therapy clarifications

Effective DateMar 26, 2026

Last ReviewDec 8, 2025

Next Review DateDec 8, 2025

Key ActionSubmit prior authorization with documentation of chemotherapy regimen FN risk and patient-specific risk factors to support CSF coverage.

SourceLink

On This Page

Ryzneuta Clinical Criteria

Requests for Ryzneuta (efbemalenograstim alfa-vuxw) may be approved if:

Ryzneuta primary prophylaxis - high regimen risk: Individual with nonmyeloid malignancy is using for primary prophylaxis of Febrile Neutropenia (FN)regimen FN risk >= 20%

NCCN 2A

Ryzneuta primary prophylaxis - intermediate regimen risk with patient factor: Individual with nonmyeloid malignancy is using for primary prophylaxis of FN and regimen FN risk 10-19% and has at least one listed patient risk factorregimen FN risk 10-19%

Patient risk factors enumerated in child node

Patient risk factors for FN (Ryzneuta)

age: Age greater than 65 years
performance_status: Poor performance status (ECOG 3 or 4) or HIV with low CD4 (<=450/µL)
prior_radiation: Prior radiation therapy within previous 1 year
bone_marrow_involvement: Bone marrow involvement producing cytopenias
persistent_neutropenia: Persistent neutropenia (ANC < 1500/mm3)
renal_dysfunction: GFR < 60 mL/min
liver_dysfunction: AST or ALT >=2x ULN or bilirubin >2.0 mg/dL
recent_surgery: Recent surgery performed as part of cancer management within previous 30 days
recent_infection: History of active infection within previous 60 days
open_wound: Current open wound and chemotherapy cannot be delayed

Ryzneuta secondary prophylaxis: Individual is using for secondary prophylaxis of FNprior neutropenic complication from prior cycle and dose reduction would compromise outcomes

NCCN 2A

Ryzneuta adjunctive/treatment and radiation exposure

Adjunctive treatment for FN: Using as adjunctive treatment for FN AND has not received prophylactic pegfilgrastim AND has high risk for infection-associated complications
Radiation exposure: Using after accidental or intentional total body radiation >2 Gy (H-ARS)
NCCN 2A

Ryzneuta (efbemalenograstim) — Initial and other indications

Ryzneuta (efbemalenograstim alfa-vuxw) — covered when criteria below are met

Ryzneuta indications summary

Primary prophylaxis >=20%: Individual with nonmyeloid malignancy using for primary prophylaxis and regimen FN risk >=20%
Primary prophylaxis 10-19% + risk factors: Individual with nonmyeloid malignancy using for primary prophylaxis and regimen FN risk 10-19% AND any of: age>65, ECOG 3-4 or HIV with low CD4, prior radiation within 1 year, bone marrow involvement, ANC<1500/mm3, GFR<60 mL/min, AST/ALT >=2x ULN or bilirubin>2.0 mg/dL, recent cancer surgery within 30 days, active infection within 60 days, current open wound and chemotherapy cannot be delayed
Secondary prophylaxis: Experienced neutropenic complication from prior cycle and dose reduction would compromise disease-free or overall survival
Adjunctive FN use: Using as adjunctive treatment for FN AND not received prophylactic pegfilgrastim AND high risk for infection-associated complications (prolonged profound neutropenia, age>65, pneumonia/clinically documented infections, hypotension/multiorgan dysfunction, invasive fungal infection, prior FN, hospitalized with fever)
Radiation exposure: Using after accidental/intentional total body radiation >2 Gy (H-ARS)

Primary prophylaxis - high regimen risk (detail): Nonmyeloid malignancy using for primary prophylaxis and regimen FN risk >=20%

Primary prophylaxis - intermediate regimen risk (detail): Nonmyeloid malignancy using for primary prophylaxis and regimen FN risk 10-19% AND any listed risk factors

Secondary prophylaxis (detail): Experienced neutropenic complication from prior cycle and dose reduction would compromise outcomes

Adjunctive FN use (detail): Using as adjunctive treatment for FN AND not received prophylactic pegfilgrastim AND high risk for infection-associated complications

Radiation exposure (detail): Using after accidental/intentional total body radiation >2 Gy (H-ARS)

Pegfilgrastim products — Initial and other indications

Pegfilgrastim biologics/biosimilars (Neulasta and biosimilars, Onpro, Udenyca, etc.) — covered when criteria below are met

Pegfilgrastim indications summary

Primary prophylaxis >=20%: Nonmyeloid malignancy using for primary prophylaxis and regimen FN risk >=20%
Primary prophylaxis 10-19% + risk factors: Nonmyeloid malignancy using for primary prophylaxis and regimen FN risk 10-19% AND any listed risk factors (age>65, ECOG 3-4/HIV, prior radiation, bone marrow involvement, ANC<1500, GFR<60, LFTs >=2x ULN or bilirubin>2, recent surgery, recent infection, open wound)
Secondary prophylaxis: Prior neutropenic complication and dose reduction would compromise outcomes
Other labeled/compendium indications: Includes: Classic Hodgkin lymphoma (18-60) with brentuximab vedotin regimens; Pediatric aggressive mature B-cell lymphomas; dose-dense adjuvant breast cancer; total body radiation >2 Gy; HSCT engraftment support; hematopoietic cell mobilization; Wilms Tumor; autologous HSC mobilization for FDA-approved ex vivo gene therapy

Primary prophylaxis - high regimen risk: Nonmyeloid malignancy using for primary prophylaxis and regimen FN risk >=20%

Primary prophylaxis - intermediate regimen risk: Nonmyeloid malignancy using for primary prophylaxis and regimen FN risk 10-19% AND any listed risk factors

Secondary prophylaxis: Prior neutropenic complication and dose reduction would compromise outcomes

Other labeled/compendium indications: Classic Hodgkin lymphoma (age 18-60) with brentuximab vedotin regimens; Pediatric aggressive mature B-cell lymphomas; dose-dense adjuvant breast cancer; H-ARS; HSCT engraftment support; hematopoietic cell mobilization; Wilms Tumor; autologous HSC mobilization for ex vivo gene therapy

Filgrastim (Neupogen and biosimilars) — Initial and multiple indications

Filgrastim products (Neupogen and biosimilars) — covered when criteria below are met

Filgrastim indications summary: Covered for: primary prophylaxis when regimen FN risk >=20%; OR primary prophylaxis when regimen FN risk 10-19% with >=1 qualifying risk factor; OR secondary prophylaxis after prior neutropenic complication affecting dosing; OR adjunctive FN treatment; OR multiple labeled/compendium uses including AML post-induction, pediatric B-cell lymphomas, hairy cell leukemia with severe neutropenia, Classic Hodgkin lymphoma with brentuximab regimens, MDS severe neutropenia or recurrent infections, MDS-RS in combination with Reblozyl, dose-dense breast cancer, chronic congenital neutropenia, drug-induced neutropenia, glycogen storage disease type 1b, HIV-associated neutropenia, post-radiation H-ARS, HSCT engraftment support, mobilization, donor mobilization, CAR T-cell related neutropenia support, autologous HSC mobilization for ex vivo gene therapy, and others as specified.

Primary prophylaxis - high regimen risk: Individual with nonmyeloid malignancy using for primary prophylaxis and regimen FN risk >=20%

Primary prophylaxis - intermediate regimen risk with risk factors: Individual with nonmyeloid malignancy using for primary prophylaxis and regimen FN risk 10-19% AND any listed risk factors

Secondary prophylaxis: Experienced neutropenic complication from prior cycle and dose reduction would compromise outcomes

Labeled/compendium indications (selected): AML post-induction/consolidation, Pediatric Aggressive Mature B-Cell Lymphomas, Hairy Cell Leukemia with severe neutropenia, Classic Hodgkin lymphoma with brentuximab regimens, MDS severe neutropenia or recurrent infections, MDS-RS with Reblozyl, dose-dense adjuvant breast cancer, chronic congenital neutropenia, drug-induced neutropenia, glycogen storage disease type 1b, HIV-associated neutropenia, H-ARS, HSCT engraftment support, PBSC mobilization, donor mobilization, CAR T-cell support, autologous HSC mobilization for ex vivo gene therapy

Granix (tbo-filgrastim) — Indications

Granix (tbo-filgrastim) — covered when criteria below are met

Granix indications summary: Primary prophylaxis when regimen FN risk >=20%; OR primary prophylaxis when regimen FN risk 10-19% with >=1 qualifying risk factor; OR secondary prophylaxis after prior neutropenic complication where dose reduction would compromise outcomes; OR adjunctive treatment for FN; OR prior prophylactic Granix use; OR multiple labeled/compendium indications including post-HSCT engraftment support, MDS severe neutropenia, combination with Reblozyl for MDS-RS, Classic Hodgkin lymphoma with brentuximab regimens; mobilization for PBSC collection; autologous donor mobilization; and other specified indications.

Primary prophylaxis - high regimen risk: Individual with nonmyeloid malignancy using Granix for primary prophylaxis and regimen FN risk >=20%

Primary prophylaxis - intermediate regimen risk with risk factors: Individual with nonmyeloid malignancy using Granix for primary prophylaxis and regimen FN risk 10-19% AND any listed risk factors

Secondary prophylaxis: Experienced neutropenic complication from prior cycle and dose reduction would compromise outcomes

Adjunctive FN use: Using Granix as adjunctive treatment for FN

Medically Necessary Indications

Covered when ALL of the following indication-specific criteria are met as applicable:

General indication logic

High infection-associated complication risk: Any of: expected prolonged >10 days and profound ANC <0.1 x10^9/L; age >65; pneumonia or other documented infection; hypotension/multi-organ dysfunction (sepsis); invasive fungal infection; prior febrile neutropenia; hospitalized at time of fever onset.
NCCN 2A
Hematologic thresholds: Severe neutropenia ANC <=500/mm3 OR recurrent/resistant infections.ANC <=500/mm3
NCCN 2A
Additional risk factors: Persistent neutropenia ANC <1500/mm3; GFR <60 mL/min; liver dysfunction (AST/ALT >=2x ULN or bilirubin >2.0 mg/dL); recent surgery within prior 30 days; history of active infection within 60 days; current open wound and chemotherapy cannot be delayed.
References: Lyman/Aagaard
Specific diagnostic indications: Post HPCT/HSCT for myeloid reconstitution; MDS including MDS-RS or MDS/MPN-RS-T with criteria (IPSS-R Very Low/Low/Intermediate symptomatic anemia, no del(5q), serum EPO <=500 mU/mL, used with ESA after no response to ESA or luspatercept); mobilization for autologous donors and for gene therapy collections; Classic Hodgkin lymphoma age 18-60 in combination with brentuximab vedotin-containing regimens.serum EPO <=500 mU/mL
NCCN 2A and AHFS

Measurable thresholds referenced: See child nodes for ANC, duration, GFR and liver function thresholds used to establish high risk or qualify specific diagnostic indications.

Regimens and FN Risk Tables

Regimen / Context	FN Risk Category	Coverage implication
Chemotherapy regimens associated with regimen-specific febrile neutropenia (FN) risk ≥20% (see Appendix, Table 1 for selected regimens)	High (≥20%)	Supports primary prophylactic CSF use when regimen FN risk ≥20% (prior authorization required; document regimen and indication)
Chemotherapy regimens with FN risk 10–19%	Intermediate (10–19%)	May qualify for primary prophylaxis when the patient has ≥1 listed risk factor (age >65, poor performance status, persistent neutropenia ANC <1500/mm3, renal/liver dysfunction, recent surgery or infection, bone marrow involvement, etc.); document risk factors per Table 1/criteria
Chemotherapy regimens with FN risk <10%	Low (<10%)	Generally do not support primary prophylactic CSF use absent other labeled/compendium indications or specific high-risk features

Regimen / Context	Example setting	Coverage implication
Dose-dense (every 2 weeks) adjuvant chemotherapy for breast cancer	Adjuvant breast cancer (dose-dense scheduling)	Supported indication for CSF prophylaxis (primary prophylaxis) to maintain dose intensity (ASCO Smith 2015 cited); prior authorization and documentation of dose-dense regimen required
Dose-dense regimens in other contexts (when used to maintain dose intensity)	Variable (regimen-dependent)	May be considered for prophylactic CSF use when regimen FN risk and patient factors align with policy criteria; document regimen and rationale

Regimen / Combination	Disease setting / Age limits	Coverage implication
Brentuximab vedotin combined with AVD (adriamycin/doxorubicin, vinblastine, dacarbazine)	Classic Hodgkin lymphoma	Supported — CSF coverage for prophylaxis/support as indicated (policy lists Classic Hodgkin lymphoma among labeled/compendium indications); document combination regimen
Brentuximab vedotin combined with multi-agent regimens (eg, brentuximab vedotin + etoposide, cyclophosphamide, doxorubicin, dacarbazine, dexamethasone)	Classic Hodgkin lymphoma	Supported — CSF coverage for prophylaxis/support when used in these combinations; document regimen and indication

Regimen / Combination	Age or population	Coverage implication
Brentuximab vedotin with AVD or brentuximab vedotin-containing combined regimens	Classic Hodgkin lymphoma, age 18–60 years	Supported as a labeled/compendium indication for CSF use to prevent/treat neutropenia in this population; document age and regimen per criteria

Selected regimen (example)	FN risk category (per Table 1)	Coverage note
Adjuvant TC (docetaxel + cyclophosphamide) in patients ≥65 years	Intermediate	May qualify for primary prophylaxis if patient has additional risk factors; document age and regimen per Table 1
Neoadjuvant TCHP (docetaxel, carboplatin, trastuzumab, pertuzumab)	High	Supports primary prophylactic CSF use for high-risk regimens; document regimen in prior authorization submission
FOLFIRINOX for pancreatic cancer	Intermediate	Intermediate-risk regimen — consider patient-specific risk factors to determine need for prophylactic CSF
Docetaxel (advanced breast cancer) — dosing dependent	Low to Intermediate (dose dependent)	Support for CSF prophylaxis depends on docetaxel dose (≥75 mg/m2 more likely intermediate); document dosing and risk per Table 1

Prior Authorization, Documentation, and Step Therapy

Prior Authorization

Prior Authorization Required for CSF Agents

Prior authorization is required for colony-stimulating factor (CSF) agents. Providers must submit PA requests for CSF products (short- and long-acting agents, biosimilars, and related growth factors) and confirm the request matches an approvable indication per clinical criteria (primary prophylaxis, secondary prophylaxis, adjunctive treatment for FN, or other approved uses).

Applies to long-acting (pegfilgrastim and biosimilars) and short-acting (filgrastim and biosimilars) agents, sargramostim, tbo-filgrastim, eflapegrastim, efbemalenograstim and others.

Denial Risk

PA Contingent on Regimen FN Risk and Patient Risk Factors

PA approvals are contingent on documentation that the chemotherapy regimen and patient meet FN-risk thresholds (≥20% risk, or 10–19% with specified patient risk factors), or meet secondary/adjunctive treatment criteria. Requests lacking documentation of regimen FN risk or patient-specific risk factors (as required below) may be denied.

Regimen FN risk must reference Appendix Table 1 or NCCN guidance.
If regimen FN risk is 10–19%, document ≥1 listed risk factor (e.g., age >65, poor performance status, prior radiation, bone marrow involvement, persistent neutropenia, renal/liver dysfunction, recent major surgery, recent infection, open wound).

Documentation Required

Required Clinical Documentation

Medical records must document the cancer type, the specific chemotherapy regimen, the estimated FN risk of that regimen, and any patient-specific FN risk factors. Clinical documentation should also include intent of use (primary prophylaxis, secondary prophylaxis, adjunctive treatment), prior CSF prophylactic therapy status, and treatment setting (age, disease-specific context).

Document the exact chemotherapy regimen and relevant Appendix Table 1 entry or literature reference.
Document patient age, performance status, ANC values, renal and liver function, recent surgeries, infection history, and prior use of filgrastim or other CSFs where applicable.

Denial Risk

May Not Be Approved — Denial Triggers

Requests may be denied when the use does not meet the policy criteria. Common denial triggers include use as routine prophylaxis or treatment when criteria are not satisfied, use for uncomplicated FN as adjunctive therapy, chemosensitization of myeloid leukemias, continuation despite no response within 28–42 days, or investigational/off-label uses not supported by cited compendia.

May not be approved uses include: prophylaxis/treatment when criteria unmet; adjunctive therapy for uncomplicated FN; chemosensitization of myeloid leukemias; therapy to treat damaged myocardium; continuation after inadequate response in specified timeframe.

Step Therapy

Step Therapy and Preferred Agent Trial Requirements

Step therapy requirements may apply per the member's benefit: non-preferred long-acting pegfilgrastim agents generally require trial and inadequate response or intolerance to one preferred long-acting agent; similarly, non-preferred short-acting filgrastim agents generally require trial and inadequate response or intolerance to one preferred short-acting agent. Exceptions exist when the preferred agent is not FDA-approved for the indication or when dosage form limits dosing precision.

Non-preferred long-acting approval requires trial and inadequate response or intolerance to a preferred long-acting agent.
Non-preferred short-acting approval requires trial and inadequate response or intolerance to a preferred short-acting agent, OR preferred product not FDA-approved for the indication, OR preferred formulation cannot achieve required dose precision (e.g., volumes <0.3 mL).
Policy does not specify an explicit sequence beyond preferred→non-preferred trial (agent-specific indications presented separately).

Billing Rule

PA and Coding Updates — Check Revision History

PA, coding, and formulary statuses have been updated periodically; providers should use current coding and HCPCS guidance when submitting requests and claims. Historical updates include additions/removals of HCPCS codes, quantity limits, and inclusion of biosimilars and new agents. Check the latest policy revision notes and coding table when preparing requests.

Recent revision history includes coding and step-therapy updates (see revision log: 12/08/2025 and prior entries).
Providers should reference current HCPCS/NDC coding when submitting PAs and claims.

Note

Prior Authorization Subject to Applicable Laws and Contract Terms

Coverage, PA and step therapy requirements are subject to federal/state laws, contract language, and plan-specific utilization management programs. These legal or contractual requirements may take precedence over the clinical criteria in this policy.

Verify whether state Medicaid, Medicare, or commercial contract terms alter PA, step therapy, or preferred/non-preferred designations.

Note

Verify Member-Specific Formulary and UM Requirements

Verify member-specific formulary and utilization management requirements and the effective dates for preferred and non-preferred agent listings; preferred status can vary by benefit type and date (Commercial, Medicare, Medicaid). Prescribing a non-preferred short- or long-acting agent may result in non-preferred coverage and require documentation of trial or exception.

Commercial, Medicare, and Medicaid benefit lists specify preferred vs non-preferred agents with effective dates — confirm member benefit and date of service.
Examples: Commercial preferred/non-preferred lists and Medicare/Medicaid lists change over time; confirm whether requested agent is preferred for that member on the relevant date.

Codes and Billing References

Listed CSF agents (product names)NDC

NDC(s) not listed

Product list includes pegfilgrastim and filgrastim products and biosimilars, tbo-filgrastim, eflapegrastim, efbemalenograstim, and sargramostim.

CPT CodesCPT

96377

Application of on-body injector (includes cannula insertion) for timed subcutaneous injection [Neulasta OnPro, Udenyca Onbody]

HCPCS/J/Q CodesHCPCS

C9399	Unclassified drugs or biologicals [when specified as Armlupeg (pegfilgrastim-unne)]
J1442	Injection, filgrastim (G-CSF), excludes biosimilars, 1 mcg [Neupogen]
J1447	Injection, tbo-filgrastim, 1 mcg [Granix]
J1449	Injection, eflapegrastim-xnst, 0.1 mg [Rolvedon]
J2506	Injection, pegfilgrastim, excludes biosimilar, 0.5 mg [Neulasta, Neulasta Onpro]
J2820	Injection, sargramostim (GM-CSF), 50 mcg [Leukine]
J3590	Unclassified biologics [when specified as Armlupeg (pegfilgrastim-unne)]
J9361	Injection, efbemalenograstim alfa-vuxw, 0.5 mg [Ryzneuta]
Q5101	Injection, filgrastim-sndz, biosimilar, (Zarxio), 1 mcg
Q5108	Injection, pegfilgrastim-jmdb (Fulphila), biosimilar, 0.5 mg

1–10 of 18

1/2

Historically modified HCPCS/Q/J codes for CSF productsHCPCS

Q5122	HCPCS code added for a CSF product (documented addition)
Q5120	HCPCS code added (effective 7/1/2020)
Q5111	HCPCS code added (12/20/2018)
Q5108	HCPCS code for Fulphila added/removed in coding reviews
Q5110	HCPCS code for Nivestym added
C9399	HCPCS code added for Armlupeg/Ziextenzo in historical revisions
C9058	HCPCS code removed 6/30/2020
J3590	J-code added/removed historically for biosimilars
J2505	Neulasta Onpro added to J2505 (historical entry)
S9537	HCPCS S9537 removed

American Medical Association CPT copyright notice

Referenced coding authorityCPT

CPT Only - American Medical Association

Chemotherapy regimen FN risk — thresholds for primary prophylaxis

Automatic primary prophylaxis thresholdChemotherapy regimen FN risk ≥20% (supports routine primary prophylaxis)

Intermediate-risk conditionRegimen FN risk 10–19%: primary prophylaxis may be covered only if the patient has ≥1 qualifying risk factor

Low-risk guidanceRegimen FN risk <10%: primary prophylaxis generally not supported absent other approved indications or compendium/labeled uses

Prolonged / profound neutropenia definitions

Prolonged neutropeniaExpected duration greater than 10 days

Profound neutropeniaANC less than 0.1 x 10^9/L (profound)

Combined criterion used for high infection riskExpected prolonged (>10 days) AND profound (<0.1 x 10^9/L) neutropenia constitutes high risk for infection-associated complications

FN risk by chemotherapy regimen — primary prophylaxis criteria

Primary prophylaxis (regimen-based) — high-riskChemotherapy regimens with FN risk ≥20% support primary prophylaxis

Primary prophylaxis — intermediate-risk with factorsRegimens with FN risk 10–19% may qualify if the patient has ≥1 listed risk factor (age >65, poor performance status, ANC <1500/mm3, GFR <60 mL/min, LFTs ≥2x ULN or bilirubin >2.0 mg/dL, prior radiation within 1 year, bone marrow involvement, recent surgery, recent infection, open wound)

Regimen documentationChemotherapy regimen FN risk should be documented per Appendix Table 1 to support primary prophylaxis decisions

ANC thresholds — persistent, severe, and profound

Persistent neutropeniaANC <1500/mm3 cited as persistent neutropenia (qualifying risk factor)

Severe neutropeniaANC ≤500/mm3 defined as severe neutropenia

Profound neutropeniaANC <0.1 x10^9/L used in combination with expected duration >10 days to define prolonged profound neutropenia

ANC (absolute neutrophil count) — numeric thresholds

Neutropenia thresholdNeutrophils <1,500/mm3 considered neutropenic (ANC <1500/mm3)

High-risk infection thresholdANC <500 cells/mm3 (≤500/mm3) considered high risk for infection

Profound neutropenia numericANC <0.1 x10^9/L used to denote profound neutropenia

GFR threshold reference

GFR thresholdGlomerular filtration rate (GFR) less than 60 mL/min is listed as a qualifying risk factor for FN and influences CSF decisions

Context of useGFR <60 mL/min cited alongside other patient risk factors when regimen FN risk is 10–19%

ReferencesGFR threshold supported by Lyman 2014; Aagaard 2018 as cited in policy

Liver function thresholds

AST/ALT thresholdAST or ALT at least 2x upper limit of normal (≥2x ULN) is a qualifying liver dysfunction threshold

Bilirubin thresholdTotal bilirubin >2.0 mg/dL is cited as a qualifying liver dysfunction criterion

Use as risk factorLiver dysfunction (AST/ALT ≥2x ULN or bilirubin >2.0 mg/dL) qualifies a patient on intermediate-risk regimens (10–19%) for primary prophylaxis

Radiation dose threshold for H-ARS

H-ARS radiation thresholdTotal body radiation of myelosuppressive doses greater than 2 Gray (Gy) (H-ARS) is an indication for CSF use

ContextUse after accidental or intentional total body radiation >2 Gy referenced under adjunctive/radiation-induced myelosuppression criteria

Guideline citationListed as NCCN 2A–supported indication in the policy

Febrile Neutropenia Risk Thresholds (High/Intermediate/Low)

High-risk definitionHigh-risk chemotherapy regimen: ≥20% probability of developing febrile neutropenia

Intermediate-risk definitionIntermediate-risk: ≥10% to ≤20% incidence of FN — consider patient-specific risk factors for prophylaxis decisions

Low-risk definitionLow-risk: <10% incidence of FN — primary prophylaxis generally not supported absent other indications

Definitions and Clinical Terms

Febrile neutropenia definition

Fever criterion for FNFever ≥38.3°C for >1 hour in association with ANC <0.5 x10^9/L qualifies as febrile neutropenia

Alternate ANC fever criterionFever with ANC <1.0 x10^9/L and predicted decline to ≤0.5 x10^9/L within 48 hours also meets FN definition

Clinical implicationFN definition used to determine need for adjunctive CSF treatment and documentation requirements

ANC / Neutropenia definitions and numeric thresholds

Neutropenia thresholdANC <1,500/mm3 considered neutropenic (persistent neutropenia referenced as ANC <1500/mm3)

Severe neutropeniaANC ≤500/mm3 defined as severe neutropenia/high infection risk

Profound neutropeniaANC <0.1 x10^9/L used to define profound neutropenia (often paired with duration >10 days)

Primary prophylaxis — definition

Primary prophylaxis — definitionPrevention of febrile neutropenia with the first cycle of a specified chemotherapy regimen

Indication basisInitiated based on regimen FN risk (≥20% automatically; 10–19% when patient has ≥1 risk factor)

DocumentationChemotherapy regimen and FN risk per Appendix Table 1 should be documented to support primary prophylaxis requests

Secondary prophylaxis — definition

Secondary prophylaxis — definitionPrevention of FN given with the second and/or subsequent cycle after a neutropenic complication from a prior cycle when dose reduction would compromise outcomes

QualificationRequires documentation of prior neutropenic complication from a prior cycle for which prophylaxis was not used

Clinical goalUsed to preserve dose intensity when dose reduction would compromise disease-free or overall survival

Primary prophylaxis (regimen-based) — definition and qualifying factors

Regimen-based primary prophylaxis (>=20%)Primary prophylaxis indicated when chemotherapy regimen FN risk ≥20%

Intermediate-risk with patient factors (10–19%)Regimen FN risk 10–19% requires ≥1 listed patient risk factor to justify primary prophylaxis

Patient risk factors listAge >65, ECOG 3–4, prior radiation within 1 year, bone marrow involvement, ANC <1500/mm3, GFR <60 mL/min, AST/ALT ≥2x ULN or bilirubin >2.0 mg/dL, recent surgery, recent infection, current open wound

Secondary prophylaxis — after neutropenic complication

Secondary prophylaxis after neutropenic complicationUse in second/subsequent cycles after a neutropenic complication when dose reduction would compromise outcomes (document prior event)

Documentation requirementMedical record must document prior neutropenic complication and rationale that dose reduction would compromise outcomes

Relation to adjunctive useSecondary prophylaxis distinct from adjunctive treatment of active FN; both have specific documentation needs

ANC ≤ 500/mm3 — severe neutropenia

Severe neutropenia numeric thresholdANC ≤500/mm3 (≤500 cells/mm3) — defined as severe neutropenia and high infection risk

Clinical useSevere neutropenia used as a criterion for treatment or supportive CSF use in the policy

Related definitionsSevere neutropenia distinguished from persistent neutropenia (ANC <1500/mm3) and profound neutropenia (<0.1 x10^9/L)

Expected >10 days and ANC <0.1 x 10^9/L — prolonged profound neutropenia

Prolonged profound neutropenia criteriaExpected duration >10 days AND ANC <0.1 x10^9/L (profound) — qualifies as prolonged profound neutropenia

Use-caseListed as a high infection-associated complication risk that supports adjunctive CSF therapy

Policy referencesCited in multiple agent sections (Rolvedon, filgrastim, Granix) as qualifying high-risk feature

High / Intermediate / Low-risk chemotherapy regimen definitions

High-risk regimenRegimen FN risk ≥20% = High risk (supports primary prophylaxis)

Intermediate-risk regimenRegimen FN risk 10–20% = Intermediate risk (consider patient-specific risk factors)

Low-risk regimenRegimen FN risk <10% = Low risk (primary prophylaxis generally not indicated)

NCCN guideline citation

NCCN guideline referenceNCCN Clinical Practice Guidelines in Oncology (multiple 2023–2024 versions referenced; e.g., Hematopoietic Growth Factors V2.2024)

Use in policyPolicy cites NCCN as evidence/consensus source for regimen- and patient-specific FN risk guidance (NCCN 2A referenced)

Access noteNCCN guidelines updated periodically; specific versions cited in References section

Lexi-Comp reference

Lexi-Comp citationLexi-Comp ONLINE with AHFS referenced as a pharmacology/drug reference supporting drug information

ContextListed among references used to inform product/compendia information in the policy

VersioningLexi-Comp is updated periodically and cited in References (2020 entry shown)

Short-acting CSF — term and context

Short-acting CSF termShort-acting colony stimulating factor agents (filgrastim and biosimilars) — used for multiple labeled and supportive indications

ExamplesNeupogen, filgrastim biosimilars (Zarxio, Nivestym, Releuko, Nypozi) cited in policy code and criteria sections

Role in step therapyShort-acting agents are distinguished for step therapy requirements relative to preferred agents

Long-acting CSF — term and context

Long-acting CSF termLong-acting colony stimulating factor agents (pegfilgrastim and long-acting analogs such as eflapegrastim, efbemalenograstim) — used for primary prophylaxis and other indications

ExamplesNeulasta, Neulasta OnPro, Udenyca, Rolvedon, Ryzneuta referenced in product-specific sections and coding lists

Step therapy relevanceLong-acting agents have preferred vs non-preferred designations and step therapy criteria in the policy

Line of Therapy Guidance

first-line | second-line

First-line: Primary prophylaxis: First cycle of specified chemotherapy regimen when regimen FN risk >=20% OR regimen risk 10-19% with ≥1 patient risk factor

Second-line: Secondary prophylaxis: Use in second or subsequent cycles when prior neutropenic complication occurred and dose reduction would compromise outcomes

first-line

First-line use contexts: Indicated across lines: primary prophylaxis for myelosuppressive chemotherapy, secondary prophylaxis after prior neutropenic event, adjunctive treatment of FN, post-induction/consolidation in AML, post-HSCT engraftment support, mobilization for transplantation, and supportive care for CAR T-cell therapy-related neutropenia.

supportive

Supportive use in Hodgkin lymphoma: Supportive use in Classic Hodgkin lymphoma (age 18-60) when used in combination with brentuximab vedotin + AVD or specified combination regimens.

first-line

Regimen entries (Table 1 guidance): Table 1 lists regimens across disease settings (adjuvant, neoadjuvant, metastatic/advanced) with assigned FN risk categories to inform CSF prophylaxis decisions.

Document History and Updates

2025-12-08revisionLatest

Comprehensive revision recorded (document marked Revised: 12/08/2025) consolidating prior updates including step therapy and coding changes.

2021-02-26coding_update

Step therapy table updates; added HCPCS Q5122, removed HCPCS J3590 for Nyvepria; Neulasta Onpro added to J2505.

2020-12-14coding_and_criteria_update

Select review added Leukine+Danyelza criteria for neuroblastoma and included coding changes (added HCPCS Q5122; removed J3590 for Nyvepria; Neulasta Onpro added to J2505 effective 2/23/21).

2020-11-20criteria_update

Clarified pegfilgrastim product quantity limits and removed HCPCS S9537 from coding; Appendix expanded with additional FN chemotherapy regimens.

2020-08-21product_and_coding_update

Updated Neulasta criteria to add biosimilar Nyvepria (pegfilgrastim-apgf), updated NP long-acting step therapy to include Nyvepria, and added HCPCS J3590 for Nyvepria.

2020-05-15annual_review_and_coding

Annual review updated Neupogen and Neulasta criteria (removed ALL leukemia criteria), added Appendix for FN regimen risk, and coding reviewed with addition of HCPCS Q5120 (effective 7/1/2020) and deletion of C9058 and J3590 (6/30/2020).

2020-03-16select_review

Updated criteria for patient-specific risk factors for prophylaxis of febrile neutropenia; administrative consistency updates applied.

2020-02-21select_review_and_coding

Updated Leukine criteria to include FDA combination use for pediatric high-risk neuroblastoma and added Ziextenzo (pegfilgrastim-apgf) to Neupogen criteria; coding additions included HCPCS C9399, C9058, and J3590 for Ziextenzo.

2019-11-15select_review

Added 'may not be approved' criterion for CSF use in damaged myocardium; coding unchanged.

2019-08-16annual_review

Maintained FN risk categorizations and removed Leukine prophylaxis criteria for primary prophylaxis of FN.

2019-03-18product_and_step_therapy_update

Updated Neulasta and Fulphila criteria to include Udenyca and included Udenyca in NP long-acting CSF step therapy; removed off-label Clinical Pharmacology indications.

2018-12-20coding_update

HCPCS changes recorded with addition of Q5111.

2018-11-09coding_review

Removed J3590 for Fulphila and added Q5108 for Fulphila and Q5110 for Nivestym during coding review.

2018-08-17annual_review_and_biosimilars_inclusion

Annual review updated PAs per FDA and compendia; included biosimilars Nivestym and Fulphila in product tables and NP CSF step therapy.

2025-12-08operational_revisionLatest

Document revision dated 12/08/2025 notes multiple prior PA and step therapy table updates and coding changes across earlier years.

2021-02-26step_therapy_update

Step therapy table updates applied (02/26/2021) reflecting operational changes to preferred/non-preferred listings.

2020-08-21step_therapy_and_product_update

Updated long-acting NP step therapy to include new biosimilar Nyvepria and adjusted quantity limits (08/21/2020).

Requests that do not demonstrate the chemotherapy regimen confers an FN risk ≥20% (or 10–19% with qualifying patient risk factors), or that seek CSF use for excluded indications (for example, afebrile neutropenia without supporting criteria, uncomplicated FN, chemosensitization of myeloid leukemias, continued use with no response, or myocardial repair), may be denied under the policy.

Colony Stimulating Factor Agents

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Clinical Coverage Criteria

Regimens and FN Risk Tables

Prior Authorization, Documentation, and Step Therapy

Codes and Billing References

Definitions and Clinical Terms

Line of Therapy Guidance

Background and Rationale

Document History and Updates