Blue Cross Blue Shield RI MRD Testing Coverage Update

Coverage Criteria for MRD Testing

Medically Necessary Indications

Covered when supported by clinical utility and guideline recommendations for specific hematologic malignancies and lymphoma.

Indications supported by evidence/guidelines

Acute Lymphoblastic Leukemia (ALL): MRD testing is recommended to monitor complete response duration, assess quality of response after induction, and predict impending relapse; commonly used methods include flow cytometry, RT-qPCR for fusion genes (e.g., BCR-ABL1), and NGS-based assays for IgH/TCR clonal rearrangements.
NCCN guidelines; systematic review supports predictive value
Chronic Myeloid Leukemia (CML): For patients who do not achieve response milestones or who have no identifiable BCR-ABL1 mutations, NGS myeloid mutation panels are recommended to detect resistance-associated mutations (NGS detects mutations and complex/compound mutants missed by Sanger sequencing).
ELN and NCCN guidance; NEXT-in-CML study supports higher detection with NGS
Chronic Lymphocytic Leukemia (CLL): NGS-based MRD is more sensitive than flow cytometry or PCR and is an important predictor of treatment efficacy and outcomes; primary molecular targets include IgH rearrangements.
2021 NCCN guidance supports NGS MRD
Multiple Myeloma (MM): MRD testing (commonly targeting IgH) is clinically valid to predict survival outcomes, useful in assessment of relapse and monitoring maintenance therapy; MRD assessment is required for relapse assessment in NCCN MM guidelines.
Meta-analysis and 2021 NCCN guidance
Acute Myeloid Leukemia (AML): NGS-based methods and myeloid mutation panels are used for MRD assessment and to detect mutations associated with relapse risk and therapy resistance; MRD informs post-remission management decisions.
Guideline-supported utility for surveillance and treatment decisions
B-cell and other lymphomas: ctDNA/ cfDNA-based MRD testing can detect residual disease earlier than imaging (lead time ~3–6 months), characterize risk, enable serial monitoring, and support risk-adapted or pre-emptive therapy strategies; serial testing is often required due to intermittent ctDNA detectability.
NCCN supports molecular analysis for IgH/TCR rearrangements; evidence for lead time and risk adaptation

General test expectations: MRD testing should be performed using validated NGS-based assays or ctDNA methodologies with demonstrated analytical sensitivity and clinical validity for the intended hematologic malignancy or lymphoma application.

See coding/lab requirements for billing codes and test selection

MRD testing to detect residual disease, predict relapse, and guide treatment monitoring

MRD testing using NGS-based assays or circulating tumor DNA (ctDNA) is covered to detect residual disease, predict relapse, and guide treatment monitoring in hematologic malignancies and lymphoma when criteria below are met.

Covered clinical contexts

Post-induction / response assessment: Assessment of MRD after induction or definitive therapy to determine depth of response and need for additional or intensified therapy.
Useful across ALL, MM, CLL, lymphoma
Surveillance / serial monitoring: Serial MRD monitoring to detect molecular recurrence earlier than clinical or radiographic relapse and to guide surveillance intervals or initiate pre-emptive therapy.
ctDNA MRD can provide ~3–6 months lead time over imaging in lymphoma
Guidance for therapeutic decision-making: Use of MRD results to inform changes in therapy such as escalation for molecular relapse, de-escalation when durable MRD negativity is achieved, or directing targeted therapies based on detected mutations (e.g., non-BCR-ABL1 resistance mutations in CML).

MRD assessment using circulating tumor DNA (ctDNA) and NGS-based assays has recognized technical and biological limitations that affect interpretation and clinical utility. ctDNA assays may show discordance with tissue sequencing because of tumor heterogeneity, clonal evolution, or differences in timing of sampling. A key limitation is the potential for variants arising from clonal hematopoiesis of indeterminate potential (CHIP) to be present in cell-free DNA; CHIP prevalence increases with age (reported as 10->30% in adults >70) and can generate variants that mimic tumor-derived mutations unless mitigated by paired controls or analytic filters. Misclassification of CHIP as tumor-derived mutations can lead to incorrect MRD assessment and inappropriate treatment decisions.

ctDNA-based MRD testing is tumor-specific and therefore cannot be used to screen for or detect unrelated second primary tumors, even if they are in the same organ. Additionally, these assays require a sufficient quantity of ctDNA in the plasma (or other compartment) to provide reliable results; tests performed in settings with very low tumor burden (for example, small or indolent tumors) may yield insufficient ctDNA and produce invalid or unreliable MRD calls. Finally, MRD assays must achieve high sensitivity with limits of detection significantly lower than those of typical diagnostic NGS assays to be appropriate for residual disease detection.

Reliability of ctDNA/NGS MRD results is reduced when appropriate controls or mitigation strategies for CHIP are not used. Studies have shown that without paired whole-blood (white cell) controls or validated filtering algorithms, CHIP-derived variants can be misclassified as tumor mutations, potentially affecting eligibility for targeted therapies and MRD interpretation. For this reason, some investigators recommend paired peripheral blood cell or tumor tissue testing or other analytic approaches to distinguish CHIP from tumor-derived signals.

Low ctDNA abundance is another source of unreliable results. In patients with low tumor burden or indolent disease, insufficient ctDNA molecules in plasma can prevent MRD detection even when disease is present; tests not validated for ultra-sensitive limits of detection are therefore less reliable in these contexts.

The policy does not cover use of ctDNA-based MRD testing for purposes it was not designed to address. Specifically, ctDNA MRD testing is not appropriate for screening or detection of a second primary tumor, and is not reliable when there is insufficient ctDNA in the sample. Tests that do not account for CHIP (for example, lacking paired blood controls or validated CHIP-mitigation methods) may produce misleading results and are considered not appropriate for determining residual disease.

Services determined to be not medically necessary or identified as non-covered benefits under this policy are excluded from coverage. Coverage and payment decisions are subject to the member's subscriber agreement, member certificate, or employer agreement, which govern specific benefit determinations.

Non-medically necessary services and non-covered benefits may not be eligible for payment under the member's plan. Whether such services are covered depends on the member's contract terms; providers should verify member-specific benefits prior to ordering services and obtain prior authorization when required.

Coding and Test Identification

Covered CPT CodesCPTCovered

0364U

Oncology (hematolymphoid neoplasm), genomic sequence analysis using multiplex (PCR) and nextgeneration sequencing with algorithm, quantification of dominant clonal sequence(s), reported as presence or absence of minimal residual disease (MRD) with quantitation of disease burden, when appropriate (New Code Effective 4/1/2023)

Unlisted / Prior Authorization RequiredCPT

81479

Unlisted molecular pathology procedure (requires prior authorization for Medicare Advantage Plans and Commercial Products)

Limit of detection / sensitivity - MRD tests

RequirementMRD assays must achieve high analytical sensitivity with limits of detection substantially lower than those of typical diagnostic NGS assays.

RationaleHigh sensitivity is necessary because MRD aims to detect molecular recurrence or residual disease prior to clinical or radiographic evidence, enabling earlier intervention.

Implication for test selectionUse validated MRD-specific assays (eg, immune receptor sequencing, highly sensitive targeted NGS or assay-specific proprietary platforms) rather than standard diagnostic NGS panels.

Clinical consequence of insufficient sensitivityInsufficient limit of detection can produce false-negative MRD results, delaying recognition of molecular recurrence and appropriate treatment changes.

Provider Actions, Prior Authorization, and Documentation

Prior Authorization

Prior Authorization Required

Prior authorization is required for the Unlisted molecular pathology code 81479 for Medicare Advantage and Commercial Products when used for tests in this policy that lack a specific CPT code. Submit a prior authorization request with documentation of medical necessity and test details to the Blue Cross Blue Shield - Rhode Island provider services/prior authorization department before performing testing.

Affected code: 81479 (Unlisted molecular pathology procedure)
Applicable plans: Medicare Advantage Plans and Commercial Products
Action: Obtain prior authorization prior to performing testing

Billing Rule

Code Selection Guidance

Use CPT 0364U when appropriate (e.g., clonoSEQ MRD testing per code description). If no specific CPT code applies, use 81479 only after obtaining prior authorization. When submitting claims, select CPT 0364U for tests matching its definition and reserve 81479 for truly unlisted molecular pathology procedures.

Eligibility Requirements

This policy section contains no top-level eligibility requirements beyond the disease-specific criteria described elsewhere in the document. Providers should refer to the covered indications and clinical criteria for disease-specific testing guidance.

Definitions and Key Terms

MRD — Minimal/Measurable Residual Disease

TermMinimal/Measurable Residual Disease (MRD)

DefinitionMolecular or cellular-level evidence of residual malignancy detected after treatment using methods such as immunoglobulin/T‑cell receptor sequencing, flow cytometry, PCR, or next-generation sequencing.

Clinical useUsed to monitor response, predict relapse, and guide treatment decisions in hematologic malignancies including ALL, CLL, AML, MM, and some lymphomas.

MRD — alternative definition and context

Alternative phrasingMeasurable/minimal residual disease (MRD): detection of persistent malignancy at the molecular or cellular level using techniques such as immunoglobulin sequencing, flow cytometry, PCR, or next‑generation sequencing.

Methods included

Background and Scope

Next-generation sequencing (NGS)-based MRD assays and ctDNA testing are used across hematologic malignancies and B-cell lymphomas to detect residual disease, predict relapse, and guide treatment and surveillance decisions. Guideline bodies (for example, NCCN and ELN) support the use of NGS MRD in many settings. NGS approaches (including immune receptor sequencing and targeted myeloid panels) can offer greater sensitivity than conventional methods and are applied in diseases such as ALL, CML, CLL, multiple myeloma, AML, and various lymphomas to inform management after induction therapy, during surveillance, and when considering pre-emptive interventions.

When applied appropriately and with validated sensitivity, NGS MRD and ctDNA assays can detect recurrence earlier than imaging in some lymphomas and provide clinically actionable information; however, test performance depends on assay sensitivity, the presence of sufficient ctDNA, and appropriate control strategies to avoid confounding signals such as CHIP.

References and Disclaimer

This policy is provided for informational purposes and does not guarantee payment. Benefit and eligibility determinations are made according to the member's subscriber agreement, member certificate, or employer agreement, which take precedence over this policy. For member-specific benefit information, contact the provider call center. This policy is related to and should be read with the Blue Cross Blue Shield - Rhode Island policy on Proprietary Laboratory Analyses (PLA) where applicable.

47%NGS detection rate in NEXT-in-CML study

3-6 monthsctDNA lead time vs imaging in lymphoma

10-30%CHIP prevalence in adults >70 yrs

54Referenced studies cited (refs 40-89)

Revision History

disclaimer_updateLatest

Policy made available for informational purposes; benefits and eligibility determined by member agreements; BCBSRI may revise policy at any time.

OpenPayer

Minimal Residual Disease Testing for Cancer — MRD (NGS and ctDNA)