Capital Bluecross NGS MRD Coverage Update

Coverage Criteria for NGS MRD Testing

inv-01: Medically necessary indications

Covered when ALL of the following apply:

Covered indications (NGS considered medically necessary): Next-generation sequencing (e.g., clonoSEQ) to detect measurable residual disease (MRD) is considered medically necessary as an alternative test when performed at the specified thresholds for the following diagnoses: (1) Acute lymphoblastic leukemia (ALL) — threshold 10^-4; (2) Chronic lymphocytic leukemia (CLL) — threshold 10^-4; (3) Multiple myeloma (MM) — threshold 10^-5 when the individual has achieved a complete response (CR).See individual items above

Concordance with flow cytometry at these thresholds and associations with progression-free or overall survival are cited in the evidence summary.

inv-02: Investigational / Not medically necessary

Not medically necessary / investigational when ANY of the following apply:

Investigational indications: Next-generation sequencing (NGS) to detect MRD at sensitivity thresholds more sensitive than those specified above (e.g., <10^-4 for ALL and CLL; <10^-5 for MM) is considered investigational. NGS to detect MRD in diffuse large B-cell lymphoma (DLBCL) and mantle cell lymphoma (MCL) is investigational. NGS to detect MRD in all other situations not specified as medically necessary in this policy is investigational.Investigational thresholds vary by disease

Policy states insufficient evidence for general use outside specified thresholds/diseases.

inv-03: Overall coverage stance and evidence

Summary of evidence and overall policy position:

Evidence summary and policy conclusion: The literature includes retrospective analyses and clinical-trial sample analyses that demonstrate associations between MRD negativity and improved outcomes in selected settings; however, evidence is limited for many indications and more-sensitive thresholds. Specific sensitivity thresholds historically used in this policy are ALL and CLL at 10^-4 and MM at 10^-5. For some malignancies and for thresholds more sensitive than those specified, evidence is insufficient to conclude that NGS-based MRD testing improves net health outcomes.ALL & CLL 10^-4; MM 10^-5 (policy history)

Guideline support is limited for several malignancies; ongoing trials may provide additional data.

Next-generation sequencing to detect measurable residual disease (MRD) is considered investigational in all other situations not explicitly listed as medically necessary in this policy. This investigational designation means that NGS MRD testing outside the covered indications lacks sufficient evidence of improved net health outcomes and may be denied.

Policy history documents prior determinations that NGS for MRD in certain lymphoma subtypes is investigational. Specifically, prior updates added investigational language for MRD testing with NGS in diffuse large B‑cell lymphoma (DLBCL) and mantle cell lymphoma (MCL), and subsequent edits clarified that these indications are investigational at any sensitivity threshold.

Use of NGS MRD testing at thresholds more sensitive than the policy-specified values is considered investigational. For example, NGS at thresholds 10^-4 for ALL and CLL or 10^-5 for multiple myeloma is investigational. The policy notes that greater analytic sensitivity may increase detection but the clinical significance of lower-level MRD and the potential for false positives or overtreatment remain uncertain.

Overall, the available evidence is limited and insufficient to conclude that NGS-based MRD assessment improves net health outcomes for many settings. Retrospective analyses and small prospective studies report associations between MRD status and outcomes, but guideline consensus and randomized trial evidence are lacking for several malignancies and sensitivity thresholds.

Indications Considered Medically Necessary

inv-28: MRD testing in MM, ALL, and CLL with listed diagnosis codes

Covered indications and example diagnosis codes:

Disease-specific monitoring (examples): NGS MRD testing performed at the medically necessary thresholds is intended for monitoring residual disease in: (a) Acute lymphoblastic leukemia (ALL) — threshold 10^-4; (b) Chronic lymphocytic leukemia (CLL) — threshold 10^-4; (c) Multiple myeloma (MM) in complete response (CR) — threshold 10^-5.See per-disease thresholds above

Example ICD-10-CM diagnosis codes associated with covered indications include: C90.00, C90.01, C90.02 (multiple myeloma variants); C91.00, C91.01, C91.02 (acute lymphoblastic leukemia variants); C91.11, C91.12 (chronic lymphocytic leukemia).

Not Covered / Investigational Uses

Not covered: NGS MRD testing is not covered (investigational) for diffuse large B‑cell lymphoma (DLBCL), mantle cell lymphoma (MCL), and for other clinical situations not specified as medically necessary in this policy. The policy history and prior reviews explicitly identify DLBCL and MCL as investigational indications.

Not covered: Next-generation sequencing for MRD in DLBCL and MCL is considered investigational per prior policy statements and remains investigational in this review. Consistent with the policy’s investigational exclusions, NGS for MRD in these lymphoma subtypes is not supported as medically necessary.

Procedure and Diagnosis Codes

Procedure CodesHCPCS

0306U
0307U
0340U

Covered when medically necessary: Procedure CodesmixedCovered

0171U
0364U
0560U
0561U
81479
81599

ICD-10-CM Diagnosis Codes (examples listed)ICD-10

C90.00	Multiple myeloma not having achieved remission
C90.01	Multiple myeloma in remission
C90.02	Multiple myeloma in relapse
C91.00	Acute lymphoblastic leukemia not having achieved remission
C91.01	Acute lymphoblastic leukemia, in remission
C91.02	Acute lymphoblastic leukemia, in relapse
C91.11	Chronic lymphocytic leukemia of B-cell type in remission
C91.12	Chronic lymphocytic leukemia of B-cell type in relapse

inv-11: NGS analytic sensitivity

Analytic sensitivity (detection limit)Next-generation sequencing: 10^-6 (detection limit ~0.1 blasts per 100,000 nucleated cells)

Quantitative NGSSensitivity listed as 10^-5 in Table 1 (detection limit ~1.0 per 100,000)

Context noteNGS sensitivity depends on input DNA amount; reported range up to 10^-6

inv-12: Flow cytometry sensitivity

Multi-parameter flow cytometry sensitivity~10^-4 (detection limit ~10 blasts per 100,000 nucleated cells)

Next-generation flow cytometryListed as 10^-5 (detection limit ~1.0 per 100,000)

Provider Responsibilities and Billing Notes

Prior Authorization

Coverage conditional on benefit and medical necessity

Coverage is conditional on member benefits and a medical necessity determination. Verify the member's specific product benefits and prior authorization requirements before ordering. Presence of a CPT/HCPCS code in the coding section does not guarantee payment — coverage is subject to the member's contract, eligibility on the date of service, and medical necessity review.

Coverage and payment are determined by the member's benefit plan and medical necessity.
Prior authorization rules vary by product; check product-specific prior authorization policies and the member's benefit booklet prior to testing.

Documentation Required

Baseline sample required for tumor-specific sequence identification

A baseline tumor-containing sample collected at time of high disease burden (typically at diagnosis or prior to treatment) is required to identify patient-specific clonal sequences for NGS-based MRD assays. If a baseline sample is not available, many NGS MRD assays cannot reliably track residual disease.

Eligibility Requirements

Eligibility requirements: There are no additional top‑level eligibility nodes beyond the disease‑specific coverage criteria in this policy. A diagnostic baseline sample obtained at high disease burden is required to identify patient‑specific tumor sequences before NGS MRD monitoring, and coverage determinations remain subject to member benefits and medical necessity review.

Background

Background: Measurable residual disease (MRD) refers to residual clonal cells in blood or bone marrow after treatment that are below routine morphologic detection. MRD is detected using flow cytometry, PCR, or NGS; conventional methods detect down to approximately 10^-4–10^-5, while NGS can detect lower levels (up to about 10^-6 depending on DNA input). A baseline (high disease‑load) specimen is required to identify tumor‑specific sequences for PCR or NGS‑based longitudinal monitoring.

Definitions and Sensitivity Thresholds

inv-24: Measurable residual disease (MRD) definition

DefinitionMeasurable residual disease (MRD) — residual clonal cells in blood or bone marrow following treatment for hematologic malignancies, detectable by flow cytometry, PCR, or NGS.

Clinical significanceMRD is used as a surrogate measure of treatment efficacy and relapse risk; residual cells below morphologic detection can be clinically relevant.

Baseline sample requirementA baseline sample at time of high disease load is required to identify patient-specific tumor sequences for PCR or NGS-based MRD monitoring.

inv-25: Sensitivity thresholds summary

Highest sensitivity (NGS)10^-6 (next-generation sequencing)

Intermediate sensitivity (NGS/PCR/next-gen flow)

OpenPayer

Next-generation sequencing for the assessment of measurable residual disease