CurrentProvidence Health PlanPolicy 110

Next Generation Sequencing for Minimal Residual Disease Detection

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Coverage of next-generation sequencing for minimal residual disease detection in selected hematologic malignancies; other MRD methods and solid-tumor testing are outside coverage.

Policy Summary

PayerProvidence Health Plan

PolicyNext Generation Sequencing for Minimal Residual Disease Detection

Policy CodePolicy 110

Change TypeQuarterly code set update

Effective DateOct 1, 2026

Last ReviewAug 1, 2026

Next Review DateJun 1, 2027

Key ActionObtain prior authorization when submitting an unlisted molecular pathology code for a potentially covered service.

SourceLink

POLICY UPDATE CHANGES

A quarterly code set update was made without a stated change to coverage criteria.

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CurrentProvidence Health PlanPolicy 110

Next Generation Sequencing for Minimal Residual Disease Detection

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Get alerted when Policy 110 changes without checking for updates manually.

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Coverage of next-generation sequencing for minimal residual disease detection in selected hematologic malignancies; other MRD methods and solid-tumor testing are outside coverage.

Policy Summary

PayerProvidence Health Plan

PolicyNext Generation Sequencing for Minimal Residual Disease Detection

Policy CodePolicy 110

Change TypeQuarterly code set update

Effective DateOct 1, 2026

Last ReviewAug 1, 2026

Next Review DateJun 1, 2027

Key ActionObtain prior authorization when submitting an unlisted molecular pathology code for a potentially covered service.

SourceLink

POLICY UPDATE CHANGES

A quarterly code set update was made without a stated change to coverage criteria.

4Hematologic malignancy indications

Not coveredSolid-tumor MRD testing

10^-4CLL MRD assay sensitivity

19Molecular and unlisted procedure codes

Coverage Criteria

Covered indications

NGS-based minimal residual disease detection may be considered medically necessary when ANY of the following covered indications is present:

Covered hematologic malignancy indications

Acute lymphocytic leukemia: The patient has acute lymphocytic leukemia.
Acute myeloid leukemia: The patient has acute myeloid leukemia.
Chronic lymphocytic leukemia or small lymphocytic lymphoma: The patient has chronic lymphocytic leukemia or small lymphocytic lymphoma.
Multiple myeloma: The patient has multiple myeloma.

Not medically necessary

NGS-based minimal residual disease detection is considered not medically necessary when ALL of the following apply:

Indication not met: The patient does not have any of the hematologic malignancies listed under the covered indications, including acute lymphocytic leukemia, acute myeloid leukemia, chronic lymphocytic leukemia or small lymphocytic lymphoma, or multiple myeloma.

This includes, but is not limited to, use in solid tumors.

Lymphoid malignancy MRD testing

NGS-based MRD detection may be considered medically necessary when ALL of the following apply:

Qualifying lymphoid malignancy and billing requirements

Qualifying diagnosis
- The patient has acute lymphoblastic leukemia.
- The patient has acute myeloid leukemia.
- The patient has chronic lymphocytic leukemia.
- The patient has multiple myeloma.
Applicable billing diagnosis

Solid tumors

NGS-based MRD detection is considered not medically necessary when ALL of the following apply:

Solid tumor exclusion: The patient has a solid tumor indication for minimal residual disease detection using next-generation sequencing.

The policy cites insufficient large, well-designed studies evaluating clinical utility in solid tumors and states that no MRD tests for solid tumors have received FDA approval.

Other minimal residual disease techniques, including flow cytometry and polymerase chain reaction, are outside the scope of this policy.

NGS-based MRD detection is not medically necessary for solid tumors when the covered hematologic malignancy criteria are not met. Examples include the Signatera and Guardant Reveal assays.

The policy considers NGS-based MRD detection for patients with solid tumors not medically necessary. The evidence is insufficient, and no MRD tests for solid tumors have received FDA approval.

An unlisted code submitted for a non-covered service addressed by this policy is denied as not covered.

NGS-based MRD detection is considered not medically necessary when criterion I is not met, including use in solid tumors.

NGS-based MRD detection may be considered medically necessary for patients with qualifying lymphoid malignancies, including acute lymphoblastic leukemia, acute myeloid leukemia, chronic lymphocytic leukemia, and multiple myeloma, when supported by the applicable clinical criteria and billing diagnosis codes. This consideration does not extend to solid tumors.

Covered Hematologic Malignancy Indications

Acute lymphocytic leukemia

NGS-based MRD detection may be considered medically necessary when ALL of the following apply:

Acute lymphocytic leukemia: The patient has acute lymphocytic leukemia.

The covered service is MRD detection using next-generation sequencing.

Acute myeloid leukemia

NGS-based MRD detection may be considered medically necessary when ALL of the following apply:

Acute myeloid leukemia: The patient has acute myeloid leukemia.

The covered service is MRD detection using next-generation sequencing.

Chronic lymphocytic leukemia or small lymphocytic lymphoma

NGS-based MRD detection may be considered medically necessary when ALL of the following apply:

Eligibility Requirements

Monitoring assays that use a patient-specific panel require comparison with a previously analyzed patient-specific panel or an initial baseline assessment, as specified by the applicable procedure description.

Not Covered Services

NGS-based MRD detection for solid tumors is not covered when the policy’s covered hematologic malignancy criteria are not met. This includes assays such as Signatera and Guardant Reveal; the policy cites insufficient evidence and no FDA-approved MRD tests for solid tumors.

Coding and Applicable Codes

Multiple MyelomaICD-10Covered

C90.00	Multiple myeloma not having achieved remission
C90.01	Multiple myeloma in remission
C90.02	Multiple myeloma in relapse

Acute Lymphoblastic LeukemiaICD-10Covered

C91.00	Acute lymphoblastic leukemia not having achieved remission
C91.01	Acute lymphoblastic leukemia, in remission
C91.02	Acute lymphoblastic leukemia, in relapse

Chronic Lymphocytic LeukemiaICD-10Covered

C91.1	Chronic lymphocytic leukemia of B-Cell type
C91.10	Chronic lymphocytic leukemia of B-Cell type not having achieved remission
C91.11	Chronic lymphocytic leukemia of B-Cell type in remission
C91.12	Chronic lymphocytic leukemia of B-Cell type in relapse

Listed MRD and NGS Procedure CodesCPT

0171U	Targeted genomic sequence analysis panel, acute myeloid leukemia, myelodysplastic syndrome, and myeloproliferative neoplasms, DNA analysis, 23 genes, interrogation for sequence variants, rearrangements
0306U	Oncology (minimal residual disease [MRD]), next-generation targeted sequencing analysis, cell-free DNA, initial (baseline) assessment to determine a patient-specific panel for future comparisons
0307U	MRD Oncology (minimal residual disease [MRD]), next-generation targeted sequencing analysis of a patient-specific panel, cell-free DNA, subsequent assessment with comparison to previously analyzed patient
0340U	Oncology (pan-cancer), analysis of minimal residual disease (MRD) from plasma, with assays personalized to each patient based on prior next-generation sequencing
0364U	Oncology (hematolymphoid neoplasm), genomic sequence analysis using multiplex (PCR) and next-generation sequencing with algorithm, quantification of dominant clonal sequence(s), reported as presence or absence of minimal residual disease (MRD)
0467U	Oncology (bladder), DNA, next-generation sequencing (NGS) of 60 genes and whole genome aneuploidy, urine, algorithms reported as minimal residual disease (MRD) status positive or negative and quantitative

Chronic Lymphocytic Leukemia Diagnosis CodesICD-10

C91.1	Chronic lymphocytic leukemia of B-Cell type
C91.10	Chronic lymphocytic leukemia of B-Cell type not having achieved remission
C91.11	Chronic lymphocytic leukemia of B-Cell type in remission
C91.12	Chronic lymphocytic leukemia of B-Cell type in relapse

Molecular and MRD Procedure CodesCPT

0171U	Targeted genomic sequence analysis panel, acute myeloid leukemia, myelodysplastic syndrome, and myeloproliferative neoplasms, DNA analysis, 23 genes, interrogation for sequence variants, rearrangements; MyMRD NGS Panel
0306U	Oncology (minimal residual disease [MRD]), next-generation targeted sequencing analysis, cell-free DNA, initial (baseline) assessment to determine a patient-specific panel for future comparisons; Invitae PCM Tissue Profiling and MRD Baseline Assay, Invitae
0307U	MRD Oncology (minimal residual disease [MRD]), next-generation targeted sequencing analysis of a patient-specific panel, cell-free DNA, subsequent assessment with comparison to previously analyzed patient; Invitae PCM MRD Monitoring, Invitae Corporation
0340U	Oncology (pan-cancer), analysis of minimal residual disease (MRD) from plasma, with assays personalized to each patient based on prior next-generation sequencing; Signatera, Natera, Inc.
0364U	Oncology (hematolymphoid neoplasm), genomic sequence analysis using multiplex PCR and next-generation 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; clonoSEQ Assay, Adaptive
0467U	Oncology (bladder), DNA, next-generation sequencing (NGS) of 60 genes and whole genome aneuploidy, urine, algorithms reported as minimal residual disease (MRD) status positive or negative and quantitative disease burden; UroAmp MRD, Convergent Genomics
0470U	Oncology (oropharyngeal), detection of minimal residual disease by next-generation sequencing (NGS) based quantitative evaluation of 8 DNA targets, cell-free HPV; HPV-SEQ Test, Sysmex Inostics
0560U	Oncology (minimal residual disease [MRD]), genomic sequence analysis, cell-free DNA, whole blood and tumor tissue, baseline assessment for design and construction of a personalized variant panel to evaluate current MRD and for comparison to subsequent MRD assessments; Haystack MRD Baseline, Quest Diagnostics
0561U	Oncology (minimal residual disease [MRD]), genomic sequence analysis, cell-free DNA, whole blood, subsequent assessment with comparison to initial assessment to evaluate for MRD; Haystack MRD Monitoring, Quest Diagnostics
0569U	Oncology (solid tumor), next-generation sequencing analysis of tumor methylation markers (>20000 differentially methylated regions) present in cell-free circulating tumor DNA (ctDNA), whole blood, algorithm reported as presence or absence of ctDNA with tumor burden; Guardant Reveal, Guardant Health, Inc.

1–10 of 19

1/2

HCPCSHCPCS

81479

Unlisted molecular pathology procedure

MRD Assay Sensitivity for CLL

Assay sensitivity10^-4

Clinical contextMRD evaluation in chronic lymphocytic leukemia (CLL)

Referenced methodsStandardized ERIC method or standardized NGS method

Provider and Billing Actions

Prior Authorization

Obtain prior authorization for potentially covered unlisted services

For potentially covered services addressed in this policy, prior authorization is recommended when submitting an unlisted molecular pathology code, including 81479, to help avoid post-service denial.

Documentation Required

Document and report a qualifying diagnosis for ClonoSEQ

For ClonoSEQ Assay billing, document the applicable hematologic malignancy diagnosis and bill with one of the listed ICD-10 codes.

Multiple myeloma: C90.00, C90.01, or C90.02
Acute lymphoblastic leukemia: C91.00, C91.01, or C91.02
Chronic lymphocytic leukemia: C91.1, C91.10, C91.11, or C91.12

Background

Minimal residual disease (MRD) refers to the small number of cancer cells remaining after treatment. MRD may be assessed using blood or bone marrow aspiration samples. NGS is one testing method that examines DNA or RNA to detect very small amounts of malignant cells; this policy addresses NGS-based MRD detection.

Definitions

Minimal Residual Disease (MRD)

DefinitionThe small number of cancer cells that remain in the body following treatment

Blood specimenMRD testing may use samples drawn from the patient's blood

Bone marrow specimenMRD testing may use bone marrow aspiration samples

Next-Generation Sequencing (NGS)

DefinitionA form of MRD testing

Genetic material examinedStretches of DNA or RNA

Detection purposeTo detect very small amounts of malignant cells and other genetic abnormalities

Policy Summary

PayerProvidence Health Plan

PolicyNext Generation Sequencing for Minimal Residual Disease Detection

Policy CodePolicy 110

Change TypeQuarterly code set update

Effective DateOct 1, 2026

Last ReviewAug 1, 2026

Next Review DateJun 1, 2027

Key ActionObtain prior authorization when submitting an unlisted molecular pathology code for a potentially covered service.

SourceLink

On This Page

For ClonoSEQ Assay billing, the claim uses an applicable ICD-10 diagnosis code for multiple myeloma: C90.00, C90.01, or C90.02.

For ClonoSEQ Assay billing, the claim uses an applicable ICD-10 diagnosis code for acute lymphoblastic leukemia: C91.00, C91.01, or C91.02.

For ClonoSEQ Assay billing, the claim uses an applicable ICD-10 diagnosis code for chronic lymphocytic leukemia: C91.1, C91.10, C91.11, or C91.12.

Chronic lymphocytic leukemia or small lymphocytic lymphoma: The patient has chronic lymphocytic leukemia or small lymphocytic lymphoma.

The covered service is MRD detection using next-generation sequencing.

Multiple myeloma

NGS-based MRD detection may be considered medically necessary when ALL of the following apply:

Multiple myeloma: The patient has multiple myeloma.

The covered service is MRD detection using next-generation sequencing.

Minimal residual disease detection by NGS in selected lymphoid malignancies

NGS-based MRD detection may be considered medically necessary within the following evidence-supported scope:

Selected lymphoid malignancy management context

NCCN-supported indication
- The patient has acute lymphoblastic leukemia; NCCN identifies NGS-based MRD testing, including quantification of immunoreceptor genes, as a suitable method for MRD quantification.
- The patient has acute myeloid leukemia; NCCN describes MRD as part of disease evaluation during sequential therapy and recommends assessment after initial induction, before allogeneic hematopoietic cell transplantation, and at additional regimen-guided time points.
- The patient has chronic lymphocytic leukemia or small lymphocytic lymphoma; NCCN identifies MRD evaluation as an important predictor of treatment efficacy and recommends an assay sensitivity of 10^-4 using the standardized ERIC or NGS method.
- The patient has multiple myeloma; NCCN recognizes NGS as an MRD detection technique and recommends bone marrow NGS panels as a useful adjunct for further risk categorization.
Indication scope: The service is NGS-based minimal residual disease detection for one of the listed hematologic malignancies.
The evidence supports MRD testing as an essential component of management for acute lymphoblastic leukemia, acute myeloid leukemia, chronic lymphocytic leukemia, and multiple myeloma; solid-tumor MRD testing is not medically necessary under this policy.

Billing Rule

Support unlisted molecular pathology claims

All unlisted molecular pathology claims are reviewed at the claim level for medical necessity, correct coding, and pricing. Submit documentation and coding that support the service and its medical necessity.

Denial Risk

Confirm the policy indication before testing

NGS-based MRD detection is considered not medically necessary when the patient does not have one of the policy’s listed indications. This includes, but is not limited to, use in solid tumors such as Signatera or Guardant Reveal.

Denial Risk

Avoid non-covered solid tumor MRD testing

Next-generation sequencing for MRD detection in patients with solid tumors is not medically necessary. The policy cites insufficient large, well-designed studies assessing clinical utility and notes that no MRD tests for solid tumors have received FDA approval.

Denial Risk

Do not use an unlisted code for a non-covered service

An unlisted code submitted for a non-covered service addressed in this policy will be denied as not covered. Unlisted codes are also reviewed for medical necessity, correct coding, and pricing at the claim level.

Unlisted molecular pathology code 81479 is subject to this review.

Billing Rule

Review contract, benefit, eligibility, and coding-edit requirements

Claims remain subject to provider contracts, member benefits, eligibility, and potential utilization audit, even when a code appears on the policy’s list. HCPCS/CPT codes may also be subject to NCCI procedure-to-procedure bundling edits and CMS medically unlikely edits; this policy does not take precedence over those edits.

Lymphoid Malignancies

DefinitionCancers that originate from lymphocytes

Representative exampleMultiple myeloma

Other examplesNon-Hodgkin lymphoma, Hodgkin lymphoma, and lymphocytic leukemias

Laboratory-Developed Test (LDT)

DefinitionA test developed by a laboratory, validated, and performed in-house

Regulatory bodyRegulated by the Centers for Medicare and Medicaid (CMS)

Regulatory classificationHigh-complexity tests under the Clinical Laboratory Improvement Amendments of 1988 (CLIA '88)