ModifiedCapital BluecrossPolicy MP 2.357

Genetic testing for FLT3, NPM1, and CEBPA variants in cytogenetically normal acute myeloid leukemia

Defines medical necessity and investigational uses of genetic testing for FLT3-ITD, NPM1, CEBPA (and FLT3-TKD) variants in patients with cytogenetically normal AML and related contexts; applies to Capital Blue Cross products with noted product variations.

Policy Summary

PayerCapital Bluecross

PolicyGenetic testing for FLT3, NPM1, and CEBPA variants in cytogenetically normal acute myeloid leukemia

Policy CodePolicy MP 2.357

Change TypeCriteria revisedcoding table updates

Effective DateSep 1, 2025

Next Review DateN/A

Key ActionVerify member benefit and U-code coverage before ordering; FLT3-TKD testing is no longer covered as of 02/20/2025.

SourceLink

POLICY UPDATE CHANGES

Updated criteria; no longer cover FLT3-TKD.

0046U and 0049U moved to non-covered coding table as these tests are for MRD per the manufacturer.

FLT3-TKD testing was previously considered medically necessary but later changed to not covered as of 02/20/2025 update.

Removed code 0056U as of 10/01/2022.

MP 2.357Policy identifier

Not coveredFLT3-TKD status

0046U,0049UMRD tests moved

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7 listedCovered procedure codes

6 listedInvestigational codes

Coverage Criteria

Medically Necessary Indication — Covered when ALL of the following are met

Covered when ALL of the following are met:

ALL of the following

Patient has a diagnosis of cytogenetically normal acute myeloid leukemia (AML).
Genetic testing is requested for variants in FLT3-ITD, NPM1, and/or CEBPA to inform prognostic risk stratification and subsequent treatment decisions (e.g., consideration of hematopoietic stem cell transplantation) rather than for patients receiving only low‑dose chemotherapy or best supportive care).
Policy Guidelines: testing intended to guide management decisions in individuals who would receive active therapy beyond low‑dose chemotherapy or supportive care.
Test results will be used to guide clinical management (risk stratification) in accordance with published evidence and clinical guidelines.

Initial diagnostic risk stratification — Covered when used for prognostic risk stratification in cytogenetically normal AML

Covered when used for initial diagnostic prognostic risk stratification in cytogenetically normal AML:

ALL of the following

Testing is performed to determine risk stratification at initial diagnosis for individuals with cytogenetically normal AML.
Clinically actionable variants include FLT3-ITD, NPM1 (without FLT3-ITD), and biallelic CEBPA; FLT3-ITD confers poorer prognosis, while NPM1 (without FLT3-ITD) and biallelic CEBPA confer more favorable prognosis.
Results are intended to influence treatment decisions (for example, recommendations regarding allogeneic hematopoietic stem cell transplantation).

Measurable residual disease (MRD) monitoring — MRD monitoring using these variants

Measurable residual disease (MRD) monitoring — Coverage and evidence statements:

ANY of the following

Use of these variants (FLT3, NPM1, CEBPA) for MRD monitoring is considered investigational — evidence is insufficient to demonstrate that MRD testing using these genetic variants improves health outcomes; prospective studies using MRD results to direct treatment decisions are needed.
Detection of MRD based on NPM1 variant presence has been associated with higher relapse risk and lower overall survival, but evidence is limited and does not establish improved outcomes when used to guide therapy.
Manufacturer-marketed MRD tests (including codes previously mapped to 0046U and 0049U) have been moved to non-covered coding as of prior administrative updates when intended solely for MRD per manufacturer.

General coverage statement — Policy scope and notable coverage changes

General coverage statement and notable coverage changes:

ALL of the following

Genetic testing for FLT3-ITD, NPM1, and CEBPA variants is covered for prognostic risk stratification in cytogenetically normal AML as described above.
Genetic testing for FLT3-TKD (FLT3 tyrosine kinase domain) variants is no longer covered as of 02/20/2025; FLT3-TKD testing is considered investigational due to uncertain prognostic effect and insufficient evidence of benefit.
0046U and 0049U (manufacturer MRD tests) have been moved to the non-covered coding table as they are intended for MRD per the manufacturer (administrative update).

Covered Indications

Cytogenetically normal AML to guide management decisions when more-than-supportive therapy is being considered

Covered when ALL of the following are met:

Use in cytogenetically normal AML to guide management: Genetic testing for FLT3-ITD, NPM1, and CEBPA variants is indicated to guide management decisions (for example, consolidation therapy or transplant planning) when more-than-supportive therapy is being considered.

Testing is intended to influence decisions for patients who would receive treatment beyond low-dose chemotherapy or best supportive care.

Risk stratification of patients with cytogenetically normal AML using FLT3, NPM1, and CEBPA variant testing

Risk stratification criteria: Testing for FLT3-ITD, NPM1, and CEBPA variants is supported by evidence demonstrating prognostic significance: FLT3-ITD associated with poorer prognosis; NPM1 (in absence of FLT3-ITD) and biallelic CEBPA associated with favorable prognosis. Treatment decisions (including consideration of transplantation) may be influenced by these results.

Not Covered / Investigational Uses

Use of genetic testing for indications other than cytogenetically normal AML, testing of FLT3-TKD, and use of FLT3/NPM1/CEBPA testing for MRD are considered not covered / investigational. The policy lists specific procedure codes identified as investigational (for example, 0046U, 0049U, 0050U, 0171U, and 81246) and documents administrative updates that moved MRD-designated U-codes to the non-covered table and removed other U-codes per the policy history.

The policy identifies specific procedure codes as investigational and not covered. Codes listed under investigational/not covered include 0046U, 0049U, 0050U, 0171U, and 81246.

FLT3-TKD testing was changed to non-covered status in the 02/20/2025 policy update. The policy history documents this administrative change and indicates FLT3-TKD is no longer covered as of that date.

Tests corresponding to manufacturer-designated MRD U-codes 0046U and 0049U have been moved to the non-covered coding table. These codes are also listed among investigational procedure codes in the coding section and may be denied if billed as covered services.

Coding and Procedure Codes

Investigational; therefore, not coveredCPTNot Covered

0046U
0049U
0050U
0171U
81246

Covered when medically necessary: Procedure CodesCPTCovered

81218
81245
81310
0023U

Relevant ICD-10 Diagnosis CodesICD-10

C92.00	Acute myeloblastic leukemia, not having achieved remission
C92.01	Acute myeloblastic leukemia, in remission
C92.02	Acute myeloblastic leukemia, in relapse
C92.60	Acute myeloid leukemia with 11q23-abnormality not having achieved remission
C92.61	Acute myeloid leukemia with 11q23-abnormality in remission
C92.62	Acute myeloid leukemia with 11q23-abnormality in relapse
C92.A0	Acute myeloid leukemia with multilineage dysplasia, not having achieved remission
C92.A1	Acute myeloid leukemia with multilineage dysplasia, in remission
C92.A2	Acute myeloid leukemia with multilineage dysplasia, in relapse

Policy-specific U-codes (added/removed/moved)HCPCS

0171U	New code added as investigational (per 04/01/2020 update)
0056U	Removed effective 10/01/2022
0046U	Moved to non-covered coding table (tests for MRD per manufacturer)
0049U	Moved to non-covered coding table (tests for MRD per manufacturer)

Policy change dates — removed/updated codes and coverage status

Removed U-code0056U removed effective 2022-10-01.

MRD test coding movedCodes 0046U and 0049U moved to non-covered coding table (manufacturer-designated MRD tests) in 04/21/2023 update.

FLT3-TKD coverage changeFLT3-TKD testing is no longer covered as of criteria update dated 2025-02-20.

Provider Actions and Billing Guidance

Prior Authorization

Product/Program Prior Authorization Note

This policy applies only to specific Capital BlueCross programs and products; prior authorization requirements may vary by product/program. Confirm any applicable prior authorization or utilization management program before ordering tests.

See member’s benefit plan for program-specific requirements.
FEP PPO: refer to FEP Medical Policy Manual for FEP plan rules.

Documentation Required

Medical Necessity Required for Covered Codes

Procedure codes listed in the coding section are covered only when the test is medically necessary for the indicated clinical situations. Coverage is determined by member benefits and clinical medical necessity.

Covered procedure codes apply only when documentation meets the policy’s medical necessity criteria.
Identification of a code here does not guarantee payment; final determination depends on member eligibility and benefit limits.

Background

Acute myeloid leukemia (AML) is a heterogeneous hematologic malignancy in which cytogenetic and molecular abnormalities guide prognosis and treatment. In cytogenetically normal AML, molecular testing for genes such as FLT3 (including FLT3-ITD), NPM1, and CEBPA provides prognostic information: FLT3-ITD is associated with poorer prognosis, NPM1 (in the absence of FLT3-ITD) and biallelic CEBPA variants are associated with favorable prognosis. These prognostic distinctions are the rationale for genetic testing to inform decisions about consolidation and transplant planning in patients who will receive more-than-supportive therapy.

Definitions

FLT3-ITD (internal tandem duplication)

DefinitionInternal tandem duplication (ITD) variants in FLT3 occur in or near the juxtamembrane domain of the receptor.

Prognostic significanceFLT3-ITD variants are a well-documented adverse prognostic marker associated with increased relapse risk and inferior overall survival.

PrevalenceOccurs in approximately 30% of newly diagnosed adult AML cases.

FLT3-TKD (tyrosine kinase domain point mutations)

DefinitionFLT3-TKD are point mutations (single amino-acid substitutions) within the activation loop of the tyrosine kinase domain.

Prognostic impactThe prognostic effect of FLT3-TKD variants is uncertain/less certain compared with FLT3-ITD.

Policy Summary

PayerCapital Bluecross

PolicyGenetic testing for FLT3, NPM1, and CEBPA variants in cytogenetically normal acute myeloid leukemia

Policy CodePolicy MP 2.357

Change TypeCriteria revisedcoding table updates

Effective DateSep 1, 2025

Next Review DateN/A

Key ActionVerify member benefit and U-code coverage before ordering; FLT3-TKD testing is no longer covered as of 02/20/2025.

SourceLink

On This Page

Evidence includes randomized trials, observational studies, and systematic reviews showing impact on prognostic classification.

Genetic testing for FLT3, NPM1, and CEBPA variants in patients with cytogenetically normal AML (policy governed indications and subtest specifics)

Policy governance and subtest specifics: Genetic testing for FLT3, NPM1, and CEBPA variants in patients with cytogenetically normal AML is governed by policy MP 2.357. The policy specifies covered versus investigational subtests (for example, FLT3-ITD testing covered; FLT3-TKD testing investigational/not covered) and documents coding updates and administrative changes.

Review policy MP 2.357 and policy history for coding lists, U-code movements, and effective dates of changes (e.g., removal of 0056U, movement of 0046U/0049U to non-covered, and 02/20/2025 FLT3-TKD exclusion).

Billing Rule

Verify U-code Coverage Before Ordering

Administrative updates have changed the coverage status of certain U-codes. Verify current coverage and member benefit for specific U-codes before ordering testing to avoid unexpected denials.

Confirm payor-specific coverage for U-codes (e.g., 0171U, 0023U, 0046U/0049U) prior to testing.
Ensure billing and documentation use the most current code designations.

Denial Risk

Non-covered MRD Test Codes

Codes specific to minimal residual disease (MRD) testing have been moved to the non-covered coding table and may be denied if billed for MRD detection. Do not bill these codes for MRD indications.

0046U and 0049U are designated non-covered for MRD per administrative update.
Testing for MRD with FLT3/NPM1/CEBPA assays is considered investigational and may be denied.

Documentation Required

Clinical Intent and Documentation

Document the clinical intent for testing: testing should be ordered to guide management decisions for individuals with cytogenetically normal AML who will receive therapy beyond low-intensity or supportive care. Include how results will influence treatment.

Include in the record that test results will inform selection of targeted therapy, enrollment in trials, or other changes in active treatment.
For patients planned for low-intensity therapy or supportive care only, testing intent should be clearly justified or may be considered not medically necessary.

Note

Member Eligibility and Medical Necessity

Payment is subject to the member’s benefit plan, eligibility on the date of service, and medical necessity determinations. Codes listed in this policy do not themselves guarantee coverage or payment.

Verify member eligibility and benefit limitations prior to service.
Final claim adjudication is based on the terms of the member’s contract and documented medical necessity.

Billing Rule

Coding Alignment and Updates

Ensure coding on claims matches the latest administrative updates and the identifiers used in ordering and reporting systems. Remove or map retired codes appropriately to avoid claim processing errors.

Update internal code lists when codes are removed or reclassified (e.g., 0056U removed; 0046U/0049U reclassified).
Use the current CPT/HCPCS/U-code set in the ordering system and on claims to ensure alignment with policy status.

Note

Therapy Selection and Test Impact

FLT3 mutation status may influence targeted therapy decisions (for example, eligibility for FLT3 inhibitor therapy). When ordering tests, indicate how results will affect therapy selection and subsequent management.

Document intended use of results to select targeted agents or direct other treatment changes.
Consider companion diagnostic requirements when linking test results to FDA-approved therapies.

PrevalenceOccurs in about 10% of AML patients.

NPM1 mutation

Gene/variantNPM1 variant (nucleophosmin gene mutation) frequently observed in AML.

Prognostic significanceMutated NPM1 confers an independent favorable prognosis in cytogenetically normal AML.

PrevalenceFound in approximately 28% to 35% of AML cases; more common in cytogenetically normal AML.

CEBPA variants

Variant typesCEBPA variants may be monoallelic or biallelic (double variants).

Prognostic distinctionBiallelic CEBPA variants are associated with a favorable prognosis; monoallelic variants do not confer this favorable prognosis.

PrevalenceCEBPA variants occur in approximately 7% to 11% of AML patients.

FLT3-ITD (re-iterated)

Variant descriptionInternal tandem duplication (ITD) in FLT3 — duplication of sequence in/near the juxtamembrane domain.

Clinical impactFLT3-ITD is associated with poor prognosis, increased relapse risk, and inferior overall survival compared with FLT3 wild-type.

Therapeutic relevanceFLT3-ITD status can influence consideration of transplant and use of FLT3-targeted therapies.

Biallelic CEBPA

DefinitionBiallelic CEBPA refers to variants occurring on both alleles of the CEBPA gene.

Prognostic implicationCEBPA variants on both alleles (biallelic) are associated with a favorable prognosis in cytogenetically normal AML.

Clinical consequenceBiallelic status may inform risk stratification and treatment planning (e.g., consolidation decisions).

Minimal/Measurable Residual Disease (MRD)

DefinitionMinimal/measurable residual disease (MRD) is the presence of residual leukemic cells after treatment detectable by molecular methods.

Detection methodsMolecular detection methods include PCR and next-generation sequencing (NGS) assays referenced in consensus documents (ELN MRD working party).

Evidence statusEvidence for MRD monitoring using FLT3, NPM1, and CEBPA is limited; NPM1 MRD detection is associated with higher relapse risk but prospective treatment-directed data are lacking.

Cytogenetically normal acute myeloid leukemia

DefinitionCytogenetically normal AML refers to acute myeloid leukemia cases without cytogenetic abnormalities.

Testing relevanceFLT3, NPM1, and CEBPA variant testing is specifically applicable and covered for prognostic risk stratification in cytogenetically normal AML.

Clinical useTesting is intended to guide management when more-than-supportive therapy is being considered (e.g., consolidation, transplant planning).