CurrentCapital BluecrossPolicy MP 2.357

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

Policy defines when genetic testing for FLT3-ITD, NPM1, and CEBPA variants is considered medically necessary for patients with cytogenetically normal acute myeloid leukemia (AML), and states investigational uses in other contexts.

Policy Summary

PayerCapital Bluecross

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

Policy CodePolicy MP 2.357

Change TypeNo material change

Effective DateSep 1, 2025

Next Review DateN/A

Key ActionDocument cytogenetically normal AML and order testing to guide chemotherapy, transplant consideration, or best supportive care when clinically indicated.

SourceLink

POLICY UPDATE CHANGES

No material clinical or coverage changes in this revision.

3Genes addressed

~30%FLT3‑ITD prevalence

28–35%NPM1 prevalence

7–11%CEBPA prevalence

2025-09-01

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Coverage Criteria — When Testing Is Medically Necessary

Genetic testing in cytogenetically normal AML

Covered when ALL of the following are met

Primary coverage criteria: Patient has cytogenetically normal acute myeloid leukemia; genetic testing for FLT3-ITD, NPM1, and CEBPA is ordered to guide chemotherapy, transplantation decisions, or best supportive care; testing is performed at initial diagnosis for diagnostic and prognostic stratification (not for MRD monitoring)

Policy states testing in this specific population is medically necessary.

Risk stratification and MRD monitoring

Covered when testing is performed to risk-stratify cytogenetically normal AML:

Primary coverage criteria: Testing for FLT3, NPM1, and CEBPA variants is supported by evidence (randomized trials, observational studies, and systematic reviews) showing prognostic value for risk stratification in cytogenetically normal AML.

FLT3-ITD = poor prognosis; NPM1 (without FLT3-ITD) and biallelic CEBPA = favorable prognosis; evidence sufficient for clinical utility for initial risk stratification.

MRD monitoring: Use of these genetic variants for measurable residual disease (MRD) monitoring has limited evidence (retrospective observational studies) and is considered insufficient to demonstrate net health outcome improvement when used to direct treatment decisions.

Detection of NPM1 MRD is associated with higher relapse risk and lower overall survival; prospective evaluations are needed.

Genetic testing for FLT3-ITD, NPM1, and CEBPA variants is considered investigational and not covered except when performed in patients with cytogenetically normal acute myeloid leukemia to inform initial diagnostic risk stratification and treatment planning. The policy states that testing outside this specific population lacks sufficient evidence to demonstrate net health benefit. FLT3-TKD testing is also considered investigational. (See policy summary and evidence review.)

The following procedure codes are listed as investigational and not covered: 0046U, 0049U, 0171U, and 81246.

Policy history and administrative notes indicate coding updates and status changes that affect coverage. For example, on 04/01/2020 code 0171U was added as investigational per an administrative coding update. Providers should be aware that historical and ongoing coding adjustments may affect claim adjudication and that listed investigational codes are excluded from coverage.

Use of genetic testing for FLT3, NPM1, or CEBPA variants solely for measurable/minimal residual disease (MRD) monitoring is considered investigational and not medically necessary. While retrospective studies show that detection of certain variants (for example, NPM1) as MRD is associated with higher relapse risk and lower overall survival, the evidence is limited and does not establish that MRD-directed changes in management improve net health outcomes.

The policy concludes that using genetic variants to detect MRD is currently insufficient to demonstrate an improvement in net health outcome. Detection of variant-based MRD (notably NPM1) correlates with relapse risk in retrospective data, but prospective evaluations demonstrating that MRD-guided interventions change clinical outcomes are lacking; consequently MRD-directed use of these tests is not supported as medically necessary.

The document does not include additional explicit 'not medically necessary' statements beyond the investigational determinations already specified for non–cytogenetically normal use and for MRD monitoring. Policy history entries primarily document coding and administrative updates rather than new clinical exclusions.

Billing Codes and Coverage Status

Investigational; therefore not coveredCPTNot Covered

0046U	Investigational procedure code (listed as investigational; not covered)
0049U	Investigational procedure code (listed as investigational; not covered)
0171U	Investigational procedure code (listed as investigational; not covered)
81246	Investigational procedure code (listed as investigational; not covered)

Covered when medically necessarymixedCovered

81245	Procedure code listed as covered when medically necessary
81310	Procedure code listed as covered when medically necessary
0023U	Procedure code listed as covered when medically necessary
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 11923-abnormality not having achieved remission (as listed)
C92.61	Acute myeloid leukemia with 11923-abnormality in remission (as listed)

Policy history / referenced codesCPT

0171U

Code added as investigational (per policy history)

Provider Actions, Documentation, and Billing Guidance

Prior Authorization

Product-specific prior authorization

Product-specific prior authorization — This policy applies only to certain Capital Blue Cross products and programs. Verify member-specific benefit design and prior authorization requirements before ordering testing.

Applicable products and programs may have additional prior authorization requirements. See member benefit information and program-specific guidance.

Documentation Required

Medical necessity required for covered molecular test codes

Medical necessity required for covered molecular test codes — Genetic testing for FLT3-ITD, NPM1, and CEBPA variants is considered medically necessary only for cytogenetically normal acute myeloid leukemia when testing is intended to guide chemotherapy or supportive care. Coverage is determined by member benefit and documentation of medical necessity.

Testing intended to guide chemotherapy or best supportive care (cytogenetically normal AML).

Background — Disease and Testing Context

Background: Acute myeloid leukemia (AML) is a heterogeneous hematologic malignancy in which cytogenetic and molecular abnormalities are key to diagnosis, prognosis, and treatment selection. Molecular variants such as FLT3-ITD (associated with poorer prognosis), NPM1 (favorable prognosis when present without FLT3-ITD), and biallelic CEBPA (favorable prognosis) inform risk stratification at diagnosis. Measurable residual disease (MRD) refers to residual clonal cells detectable after therapy by sensitive methods (flow cytometry or PCR); although MRD detection—including variant-based MRD—correlates with relapse risk, the evidence is currently limited for using these genetic assays to guide therapy changes that improve outcomes.

Definitions and Biomarker Descriptions

inv-25: FLT3-ITD — definition and prognostic relevance

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

Prognostic relevanceFLT3-ITD variants are a well-documented adverse prognostic marker in AML and are associated with higher relapse rates and worse prognosis compared with wild-type FLT3, particularly in adults with normal- or intermediate-risk cytogenetics.

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

inv-26: FLT3-TKD — definition; testing investigational

DefinitionPoint mutations in the tyrosine kinase domain (TKD) of FLT3 resulting in single amino acid substitutions.

Policy statusPrognostic impact is uncertain and conflicting; FLT3‑TKD testing is considered investigational by this policy.

Line of Therapy — Applicable Use

first-line

Intended use: Testing performed at diagnosis for risk stratification to inform initial induction and post-remission therapy decisions (for example, consideration of hematopoietic cell transplantation and use of targeted agents for FLT3-mutated disease)

Policy links testing to guiding chemotherapy, transplant considerations, and selection of FLT3-targeted therapies when applicable.

first-line

Initial risk stratification: Genetic testing for FLT3, NPM1, and CEBPA is used at diagnosis to stratify prognosis and inform treatment decisions (including consideration of transplantation and targeted agents).

Evidence supports prognostic utility at initial diagnosis; guideline and trial references cited (NCCN, ELN, and key literature).

Biomarker Requirements and Reporting

inv-36: FLT3-ITD — allelic ratio prognostically relevant (higher worse)

Allelic ratio relevanceThe FLT3‑ITD allelic ratio is prognostically relevant: higher FLT3‑ITD‑to‑wild‑type allelic ratios are associated with worse outcomes.

Clinical implicationAllelic ratio may influence the degree to which an NPM1 mutation mitigates FLT3‑ITD adverse impact (benefit possibly only when allelic ratio is low).

Testing noteFLT3‑ITD presence alone confers poor prognosis and is used for risk stratification at diagnosis in cytogenetically normal AML.

inv-37: NPM1 — biomarker requirement/notes

RequirementNPM1 mutation status is used for risk stratification in cytogenetically normal AML and is a required biomarker for determining favorable prognosis when present without FLT3‑ITD.

Interaction with FLT3‑ITD

Revision History and References

2022-03-23minor_reviewLatest

FLT3-TKD testing status updated to medically necessary and cross-references, background, coding, and references were updated.

2021-03-16consensus_review

Updated product variations, description/background, policy guidelines, summary of evidence, and references.

2020-04-01administrative_update

Policy Summary

PayerCapital Bluecross

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

Policy CodePolicy MP 2.357

Change TypeNo material change

Effective DateSep 1, 2025

Next Review DateN/A

Key ActionDocument cytogenetically normal AML and order testing to guide chemotherapy, transplant consideration, or best supportive care when clinically indicated.

SourceLink

On This Page

Not medically necessary / investigational for other indications (see investigational callout).

Denial Risk

Investigational codes — denial risk

Investigational codes — Denial risk for listed procedure codes considered investigational and therefore not covered.

Procedure codes: 0046U, 0049U, 0171U, 81246 — investigational; therefore not covered.

Documentation Required

Documentation to support medical necessity

Documentation to support medical necessity — Include documentation of cytogenetic results showing normal karyotype and clinical rationale that testing will guide chemotherapy choice or supportive care. Record relevant clinical details in the medical record: diagnosis, disease status, treatment intent, and how results will affect management.

Document cytogenetically normal AML and purpose of testing (to guide chemotherapy or best supportive care).
Include clinical history, prior cytogenetic and molecular results, and planned management changes based on test results.

Billing Rule

Claim and benefit documentation

Claim and benefit documentation — The presence of a code in the coding section does not guarantee coverage. Submit claims consistent with member benefits and include required documentation to support medical necessity. Not all covered services are eligible for separate reimbursement.

Identification of a code in the policy’s coding section does not denote coverage; coverage is subject to member benefits.
Provide supporting documentation with claims to substantiate medical necessity.

Note

Supporting references

Supporting references — When applicable, include guideline citations or relevant references in the medical record or supporting documentation. Key references supporting policy determinations include ELN recommendations and Blue Cross Blue Shield Association policy guidance.

Dohner H, et al. Diagnosis and management of AML in adults: ELN recommendations (2017, 2022).
Blue Cross Blue Shield Association Medical Policy Reference Manual 2.04.124 (Feb 2025).

Step Therapy

Step therapy

No step therapy specified / not applicable — There is no step therapy requirement described in this policy.

Step therapy: Not applicable.

Relative frequencyFLT3‑TKD variants occur in about 10% of patients (less common than FLT3‑ITD).

inv-27: NPM1 mutation — definition and prognostic role

DefinitionVariants in the NPM1 (nucleophosmin 1) gene commonly seen in AML.

Prognostic roleMutated NPM1 confers an independent favorable prognosis in cytogenetically normal AML and may mitigate the adverse impact of FLT3‑ITD when the FLT3‑ITD allelic ratio is low.

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

inv-28: CEBPA variants — biallelic vs monoallelic prognostic implications

DefinitionVariants in CEBPA (CCAAT/enhancer-binding protein alpha), which may be monoallelic or biallelic (double) variants.

Prognostic implicationBiallelic (double) CEBPA variants are associated with a favorable prognosis (higher complete remission rates and overall survival); monoallelic variants do not confer a favorable prognosis and are similar to wild-type CEBPA.

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

inv-29: FLT3-ITD short label (definition)

Short definitionFLT3‑ITD = internal tandem duplication variants in FLT3 occurring near the juxtamembrane domain; adverse prognostic marker.

Clinical noteAssociated with worse prognosis and higher relapse risk compared with FLT3 wild-type.

FrequencyApproximately 30% prevalence in newly diagnosed adult AML.

inv-30: NPM1 short label (definition)

Short definitionNPM1 = nucleophosmin 1 gene mutation commonly seen in AML that conveys a favorable prognosis in cytogenetically normal AML.

Interaction noteMay mitigate adverse impact of FLT3‑ITD when the FLT3‑ITD allelic ratio is low.

PrevalenceFound in ~28%–35% of AML cases.

inv-31: CEBPA mutations on both alleles (short label)

Short definitionBiallelic CEBPA = CEBPA mutations on both alleles (double variants) that are associated with favorable prognosis in cytogenetically normal AML.

ContrastMonoallelic CEBPA variants do not confer favorable prognosis and resemble wild-type CEBPA.

PrevalenceCEBPA variants occur in ~7%–11% of AML patients.

inv-32: MRD — definition

DefinitionMeasurable residual disease (MRD) refers to the detection of persistent clonal leukemic cells after therapy using sensitive molecular or other assays.

Policy noteUse of FLT3, NPM1, and CEBPA variant testing for MRD monitoring is considered investigational and not medically necessary due to limited evidence that MRD-directed decisions improve net health outcomes.

EvidenceRetrospective observational studies associate NPM1 MRD detection with higher relapse risk and lower overall survival; prospective evaluations are needed.

inv-33: FLT3 variants — general note including ITD and TKD relevance

ScopeFLT3 variants include FLT3‑ITD (internal tandem duplications) and FLT3‑TKD (tyrosine kinase domain point mutations).

Prognostic summaryFLT3‑ITD confers a poor prognosis; the prognostic significance of FLT3‑TKD is uncertain and findings are conflicting.

Clinical relevanceFLT3 variants are among the most frequently encountered mutations in AML and inform risk stratification and consideration of FLT3‑targeted therapies.

An NPM1 mutation may mitigate the adverse prognostic effect of FLT3‑ITD when the FLT3‑ITD allelic ratio is low.

PrevalenceOccurs in ~28%–35% of AML cases and is more common in cytogenetically normal AML.

inv-38: CEBPA (biallelic) — biallelic/double variants required to confer favorable prognosis

RequirementBiallelic (double) CEBPA variants are required to confer a favorable prognosis in cytogenetically normal AML.

Monoallelic noteMonoallelic CEBPA variants do not confer favorable prognosis and are prognostically similar to wild‑type CEBPA.

Clinical useCEBPA biallelic status is used for initial risk stratification to identify a favorable‑risk subset.

inv-39: FLT3 (including FLT3-ITD and TKD) — prognostic notes; ITD poor prognosis, TKD uncertain

FLT3‑ITD prognostic noteFLT3‑ITD presence confers poor prognosis and is associated with worse outcomes when treated with conventional chemotherapy.

FLT3‑TKD uncertaintyPrognostic significance of FLT3‑TKD variants is uncertain and conflicting across studies.

Clinical roleFLT3 variants inform risk stratification and identification of candidates for FLT3‑targeted therapies (FDA‑approved agents exist for FLT3‑mutated AML).

inv-40: NPM1 — biomarker requirement (short form)

Short requirementNPM1 mutation status is a required biomarker for risk stratification in cytogenetically normal AML (favorable when present without FLT3‑ITD).

Mitigating effectMay mitigate adverse effect of FLT3‑ITD at low FLT3‑ITD allelic ratios.

Prevalence notePresent in ~28%–35% of AML cases.

inv-41: CEBPA (biallelic) — biallelic association with favorable prognosis (short form)

Short statementBiallelic CEBPA mutations are associated with favorable prognosis in cytogenetically normal AML.

Monoallelic contrastMonoallelic CEBPA does not confer favorable prognosis.

UsageBiallelic CEBPA status is used to identify a favorable‑risk subgroup at diagnosis.

inv-42: FLT3 (ITD and TKD) — additional biomarker entry

EntryFLT3 variants include ITD and TKD types; FLT3‑ITD confers worse prognosis while FLT3‑TKD prognostic impact is uncertain.

Clinical implicationFLT3 testing informs consideration of FLT3‑targeted therapies and risk stratification in cytogenetically normal AML.

FrequencyFLT3‑ITD ~30% prevalence; FLT3‑TKD ~10% prevalence in newly diagnosed adult AML.

inv-43: NPM1 — additional biomarker entry

EntryNPM1 mutation is used for risk stratification in cytogenetically normal AML and indicates favorable prognosis when present without FLT3‑ITD.

InteractionMay reduce the adverse effect of FLT3‑ITD when FLT3‑ITD allelic ratio is low.

PrevalenceFound in ~28%–35% of AML cases; more common in cytogenetically normal AML.

inv-44: CEBPA — additional biomarker entry

EntryCEBPA biallelic mutations identify a favorable prognosis subgroup and are required to classify CEBPA‑mutated cases as favorable risk.

Monoallelic noteSingle‑allele CEBPA variants do not confer favorable prognosis and are similar to wild‑type.

PrevalenceCEBPA variants occur in ~7%–11% of AML patients.

Coding update: new code 0171U added as investigational; coding and references reviewed during consensus review the same day.

2019-03-25consensus_review

Consensus review performed; background, summary of evidence, and references reviewed with no change to policy statements.