ModifiedUnitedHealthcarePolicy CS372.F

Molecular Oncology Testing for Hematologic Cancer Diagnosis, Prognosis, and Treatment Decisions

Policy governing coverage of molecular and genomic testing (multigene panels, comprehensive genomic profiling, MRD/clonality testing) for diagnosis, prognosis, and treatment decisions in hematologic malignancies for UnitedHealthcare members in applicable states.

Policy Summary

PayerUnitedHealthcare

PolicyMolecular Oncology Testing for Hematologic Cancer Diagnosis, Prognosis, and Treatment Decisions

Policy CodePolicy CS372.F

Change TypeCoverage clarifications and expansions (material)

Effective DateFeb 1, 2026

Next Review Date

Key ActionOrder multigene panels, CGP, or clonoSEQ only when criteria are met and tests are requested by a hematologist or oncologist.

SourceLink

POLICY UPDATE CHANGES

Added language to clarify the use of multigene panels (50 genes or fewer) at initial diagnosis and/or recurrence or relapse is proven and medically necessary when ordered by a hematologist or oncologist for individuals with listed conditions.

Replaced criterion requiring 'strongly suspected' with 'suspected' for myelodysplastic syndrome or myeloproliferative neoplasm when ordered by a hematologist/oncologist.

Added requirement that the individual has chronic lymphocytic leukemia for clonality assessment with clonoSEQ at initial diagnosis and MRD assessment with clonoSEQ.

Expanded proven and medically necessary use of comprehensive genomic profiling (CGP) to include acute lymphoblastic leukemia, acute myeloid leukemia, myelodysplastic syndrome, or myeloproliferative neoplasm.

Clarified that molecular tests other than clonoSEQ are unproven and not medically necessary for initial clonality assessment or for assessment of MRD.

Removed content/language pertaining to the state of Louisiana

Removed content/language pertaining to the state of Louisiana as part of a template update.

Replaced references to 'clon oSEQ Clonality ID' and 'clonoSEQ MRD' with 'clonoSEQ'.

Added language that medical records documentation may be required to assess coverage but does not guarantee coverage; noted benefit coverage is determined by federal, state, or contractual requirements.

Trek Health ingests and normalizes Transparency in Coverage data and payer policy updates to give provider organizations a clear view of how commercial reimbursement behaves across markets, payers, and services. Our platform transforms raw payer disclosures into structured intelligence that supports contract evaluation, payer negotiations, and service line strategy. By combining market benchmarks with ongoing policy visibility, Trek helps teams identify variability, risk, and opportunity in commercial reimbursement. The result is faster insight, stronger negotiating positions, and more informed financial decisions.

≤50Multigene panel threshold

clonoSEQNamed MRD/clonality assay

10^-4Minimum MRD sensitivity (NCCN)

OGM, WTSUnproven examples

02/01/2026Policy effective

10^-6NGS sensitivity achievable

Coverage Criteria and Clinical Rationale

Medically necessary and not medically necessary criteria

Covered when ALL of the following are met for each listed test type and diagnosis:

Multigene panels (<=50 genes): Multigene panels (50 genes or fewer) are proven and medically necessary when ordered by a hematologist or oncologist at initial diagnosis and/or recurrence or relapse for individuals with acute lymphoblastic leukemia, acute myeloid leukemia, multiple myeloma, or suspected myelodysplastic syndrome or myeloproliferative neoplasm.

Comprehensive Genomic Profiling (CGP) (examples: FoundationOne Heme, Neo Comprehensive - Heme Cancers, NEO AML Express) is proven and medically necessary for individuals with acute lymphoblastic leukemia, acute myeloid leukemia, myelodysplastic syndrome, or myeloproliferative neoplasm when ordered by a hematologist or oncologist.

Clonality assessment and MRD with clonoSEQ: Clonality assessment with clonoSEQ at initial diagnosis and MRD assessment with clonoSEQ are proven and medically necessary when ordered by a hematologist or oncologist for individuals with acute lymphoblastic leukemia, multiple myeloma, or chronic lymphocytic leukemia.

Other molecular tests for clonality/MRD: Molecular tests other than clonoSEQ are unproven and not medically necessary for initial clonality assessment or for assessment of MRD.

Other molecular test panels: All other molecular test panels for hematologic cancer (including but not limited to optical genome mapping and whole transcriptome sequencing) are unproven and not medically necessary due to insufficient evidence of efficacy.

Contexts where MRD testing shows prognostic or trial-guiding utility

Evidence contexts where MRD testing (especially NGS-based) is supported as prognostic or used to guide therapy in trials:

Chronic lymphocytic leukemia (CLL) — trial evidence: Randomized trials (e.g., FLAIR, CLL14) used MRD-guided strategies; MRD-guided ibrutinib-venetoclax produced superior progression-free and overall survival compared with FCR, and CLL14 demonstrated better PFS and strong associations between MRD negativity and outcomes (definitions included thresholds such as <10^-6 and >=10^-4 for non-response).varies (e.g., blood or marrow thresholds reported to 10^-6)

FLAIR and CLL14 cited as examples where MRD informed therapy duration and outcomes.

Multiple myeloma (MM): NGS MRD negativity (e.g., <10^-5 or <10^-6) correlates with improved progression-free survival; MRD-adapted cessation of therapy was implemented in trials such as MASTER where achieving consecutive MRD-negative results allowed treatment discontinuation.<10^-5 to <10^-6

MASTER trial showed 81% achieved MRD <10^-5 and many entered MRD-SURE with low short-term incidence of progression in most risk groups.

Guideline-aligned indications and MRD testing

Covered when aligned with specialty guideline recommendations and appropriate clinical context

Acute leukemia initial workup: Obtain sufficient samples for morphology, conventional cytogenetics (karyotype), molecular genetic and/or FISH testing, and flow cytometry; molecular/FISH testing does not replace karyotype and panels should support subsequent MRD detection.

CAP/ASH guidance (Statements 5, 11, 12) recommends comprehensive specimen collection and testing.

MRD in ALL: Use validated MRD assessment technology with sensitivity of 10^-4 or better; consider FDA-approved NGS assays to confirm negativity by flow cytometry; timing includes post-induction and post-consolidation per regimen, with baseline MRD assessment when required.sensitivity >= 10^-4

NCCN ALL guidance recommends validated MRD methods and specific timing for assessments.

MRD in AML: Monitor MRD upon achievement of morphologic remission and at clinically indicated timepoints including around allogeneic HCT; standard NGS is often not adequate for MRD due to sensitivity limitations—use PCR or validated flow cytometry where appropriate.

Revised Coverage Positions (partial)

Summary of revised coverage positions (partial — full logic located in other sections):

Multigene panels (<=50 genes): Covered when ordered by a hematologist or oncologist at initial diagnosis and/or recurrence or relapse for individuals with specified hematologic conditions.<=50 genes

Policy revision added language clarifying proven and medically necessary use.

Clonality and MRD with clonoSEQ: Covered for initial clonality assessment and MRD assessment when clinical prerequisites are met, including a requirement that the individual has chronic lymphocytic leukemia for certain clonoSEQ indications.

Policy revisions standardized clonoSEQ references and added CLL prerequisite.

Comprehensive Genomic Profiling (CGP): Proven and medically necessary for individuals with acute lymphoblastic leukemia, acute myeloid leukemia, myelodysplastic syndrome, or myeloproliferative neoplasm (examples: FoundationOne Heme, Neo Comprehensive - Heme Cancers, NEO AML Express).

The policy lists several molecular testing approaches as unproven and not medically necessary due to insufficient evidence of clinical efficacy. Specifically, optical genome mapping and whole transcriptome sequencing are identified among other molecular test panels as not medically necessary for hematologic cancers. The policy further states that molecular tests other than clonoSEQ are unproven and not medically necessary for initial clonality assessment or for assessment of measurable residual disease (MRD).

For companion diagnostic testing, the document directs readers to the separate Medical Policy titled “FDA Cleared or Approved Companion Diagnostic Testing” for guidance on those devices and assays.

Society guideline reviews and consensus statements caution against routine use of MRD testing to modify maintenance therapy or standard treatment outside of clinical trials. The ASCO/CCR guidance on multiple myeloma indicates there is insufficient evidence to change maintenance therapy or to use MRD status as a routine treatment goal outside clinical trials, and expert panels for CLL recommend that MRD assessment remains primarily a research tool pending additional standardization and outcome data.

Guidance documents therefore support the continued use of MRD testing primarily for prognostication and within clinical trials that prospectively evaluate MRD-directed treatment changes, rather than as a routine basis for altering maintenance or other standard therapies.

Information about FDA clearances or approvals is provided for context only. The policy explicitly states that FDA approval alone is not a basis for coverage, and laboratories performing genetic tests remain regulated under CLIA; coverage determinations are made on the basis of the policy’s clinical criteria and applicable benefit rules rather than regulatory status alone.

The policy reiterates that molecular tests other than clonoSEQ are considered unproven and not medically necessary when used for initial clonality assessment or for MRD assessment across hematologic malignancies. In contrast, clonality assessment and MRD assessment using clonoSEQ are listed as proven and medically necessary when ordered by a hematologist or oncologist for the specified diagnoses and when clinical prerequisites are met.

Beyond optical genome mapping and whole transcriptome sequencing, the policy provides an expanded list and an affirmative statement that other molecular test panels not specifically identified as proven are considered unproven and not medically necessary. The document names optical genome mapping and whole transcriptome sequencing explicitly and states that "all other molecular test panels for hematologic cancer" without sufficient evidence fall into the not medically necessary category.

Procedure and proprietary codes associated with many of these technologies are listed in the coding section for reference; inclusion of a code in the policy does not imply coverage and coverage decisions follow the policy clinical criteria and applicable benefit rules.

The ASCO/CCR joint guideline and other expert reviews note that current evidence is insufficient to recommend modifying treatment based solely on MRD status in multiple myeloma or chronic lymphocytic leukemia outside of clinical trials. These sources emphasize that while MRD negativity is prognostic and associated with improved outcomes, its use to guide therapy (for example, shortening or stopping maintenance therapy) should be limited to investigational settings until randomized trials demonstrate benefit in clinical outcomes.

Expert consensus documents also highlight the need for standardized MRD terminology, assay requirements, tissue selection, and timing before MRD results are broadly used to drive routine therapeutic changes.

The policy makes clear that standard NGS testing is not designed for MRD assessment because of inferior analytical sensitivity compared with dedicated MRD methods. NCCN guidance cited in the document notes that standard NGS platforms lack the sensitivity required for reliable MRD detection in many settings and that more sensitive, validated methods (for example PCR-based assays or specialized high-sensitivity NGS MRD assays) are preferable when MRD assessment is required.

The policy restates that the use of molecular tests other than clonoSEQ for MRD assessment is considered unproven and not medically necessary. This mirrors the coverage rationale which specifically designates clonoSEQ as the referenced validated clonality/MRD assay for covered indications, while other molecular MRD assays remain not covered unless explicitly supported by the policy’s criteria.

Covered Indications by Test Type

Indications list

Covered hematologic malignancies (indications list): Acute lymphoblastic leukemia; acute myeloid leukemia; multiple myeloma; myelodysplastic syndrome; myeloproliferative neoplasm; chronic lymphocytic leukemia (for clonoSEQ MRD and clonality assessment).

MRD assessment covered to provide prognostic information and to guide MRD-adapted therapy in clinical trial settings (B-ALL, MM, CLL, AML examples)

MRD for prognosis and trial-guided therapy: MRD assessment is covered to provide prognostic information and to guide MRD-adapted therapy in clinical trial settings for conditions including B-ALL, multiple myeloma, chronic lymphocytic leukemia, and acute myeloid leukemia; evidence includes trials where MRD-guided therapy improved outcomes or informed therapy cessation (e.g., clonoSEQ in ALL, MASTER in MM, FLAIR/CLL14 in CLL).

Coverage for diagnosis, prognostication, treatment selection, and MRD assessment across hematologic malignancies per society guidelines

Procedure Codes, Panels, and Assay Sensitivity

Applicable procedure codes (examples and PLA/UC codes)mixed

0017M	Oncology [diffuse large B-cell lymphoma (DLBCL)], mRNA, gene expression profiling by fluorescent probe hybridization of 20 genes, formalin-fixed paraffin-embedded tissue, algorithm reported as cell of origin.
0050U	Targeted genomic sequence analysis panel, acute myelogenous leukemia, DNA analysis, 194 genes, interrogation for sequence variants, copy number variants or rearrangements.
0120U	Oncology (B-cell lymphoma classification), mRNA, gene expression profiling by fluorescent probe hybridization of 58 genes (45 content and 13 housekeeping genes), formalin-fixed paraffin- embedded tissue, algorithm reported as likelihood for primary mediastinal B-cell lymphoma (PMBCL) and diffuse large B-cell lymphoma (DLBCL) with cell of origin subtyping in the latter.
0171U	Targeted genomic sequence analysis panel, acute myeloid leukemia, myelodysplastic syndrome, and myeloproliferative neoplasms, DNA analysis, 23 genes, interrogation for sequence variants, rearrangements, and minimal residual disease, reported as presence/absence.
0298U	Oncology (pan tumor), whole transcriptome sequencing of paired malignant and normal RNA specimens, fresh or formalin-fixed paraffin-embedded (FFPE) tissue, blood or bone marrow, comparative sequence analyses and expression level and chimeric transcript identification.
0299U	Oncology (pan tumor), whole genome optical genome mapping of paired malignant and normal DNA specimens, fresh frozen tissue, blood, or bone marrow, comparative structural variant identification.
0300U	Oncology (pan tumor), whole genome sequencing and optical genome mapping of paired malignant and normal DNA specimens, fresh tissue, blood, or bone marrow, comparative sequence analyses
0331U	Oncology (hematolymphoid neoplasia), optical genome mapping for copy number alterations and gene rearrangements utilizing DNA from blood or bone marrow, report of clinically significant alterations.
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.
0413U	Oncology (hematolymphoid neoplasm), optical genome mapping for copy number alterations, aneuploidy, and balanced/complex structural rearrangements, DNA from blood or bone marrow, report of clinically significant alterations.

1–10 of 20

1/2

Regulatory/Informational (no CPT/HCPCS listed)mixed

No codes listed

inv-15: Multigene panel size — threshold for panels considered proven and medically necessary

ThresholdMultigene panels of 50 genes or fewer are considered proven and medically necessary when ordered by a hematologist or oncologist at initial diagnosis and/or recurrence/relapse for specified hematologic malignancies.

Applicable settingsAcute lymphoblastic leukemia, acute myeloid leukemia, multiple myeloma, suspected myelodysplastic syndrome or myeloproliferative neoplasm (order must be from a hematologist/oncologist).

Ordering clinician requirementMust be ordered by a hematologist or oncologist to meet the proven and medically necessary criteria.

inv-16: Common MRD analytic thresholds — examples of thresholds reported in studies (10^-3 to 10^-6)

Common reported thresholdsExamples of analytic MRD thresholds reported in studies include 10^-3 (0.1%), 10^-4, 10^-5, and 10^-6.

Ordering, Documentation, and Sample Handling

Prior Authorization

Prior authorization and documentation may be required for multigene/CGP/MRD testing

Documentation and applicable prior authorization may be required when ordering multigene panels, comprehensive genomic profiling (CGP), or MRD/clonality testing for hematologic cancers; procedure codes listed in the policy are provided for reference and may be used in authorization inquiries.

When ordering multigene panels, CGP, or MRD/clonality testing, documentation and applicable prior authorization may be required per benefit rules.
Refer to the policy's applicable procedure codes for reference when initiating prior authorization requests.

Prior Authorization

Prior authorization not universally specified for MRD testing — verify plan rules

The policy does not specify universal prior authorization requirements for MRD testing; MRD testing is emphasized as primarily prognostic or investigational and routine use is not universally recommended—check plan-specific prior authorization rules.

Current guidance notes lack of randomized outcome data supporting routine MRD-directed therapy outside clinical trials.

Tests and Uses Considered Not Medically Necessary

Consistent with the coverage rationale, the policy’s Not Covered section reiterates that optical genome mapping, whole transcriptome sequencing, and molecular tests other than clonoSEQ for clonality or MRD assessment are considered unproven and not medically necessary and therefore not covered.

The document further notes that no benefit coverage is implied by listing of procedure codes; coverage decisions depend on whether the test meets the policy’s clinical criteria and the member’s contractual provisions.

The policy emphasizes that, to date, there is no high-quality randomized trial evidence demonstrating that use of MRD testing to direct therapy improves clinical outcomes outside of clinical trials. As a result, routine MRD-directed treatment changes are not supported by the available evidence, and the policy encourages MRD-guided therapy modifications primarily within the context of prospective clinical studies.

This position aligns with the observations in systematic reviews and guideline statements that, while MRD status is prognostic, outcome benefit from MRD-directed interventions has not been definitively established in randomized trials.

Reiterating the coverage rationale, the policy classifies molecular tests other than clonoSEQ for initial clonality assessment or MRD assessment as unproven and not medically necessary. Only clonality and MRD testing using clonoSEQ are listed as proven and medically necessary under the specific clinical prerequisites and ordering requirements described in the policy.

Member Eligibility and Clinical Preconditions

Eligibility for covered testing is defined in the Coverage Rationale. Covered uses include multigene panels (≤ 50 genes) at initial diagnosis or recurrence/relapse and Comprehensive Genomic Profiling (CGP) for specified hematologic malignancies, when ordered by a hematologist or oncologist. Clonality assessment and MRD assessment with clonoSEQ are covered for acute lymphoblastic leukemia, multiple myeloma, and chronic lymphocytic leukemia when clinical prerequisites are met.

The policy references evidence showing high-sensitivity NGS MRD assays (for example, clonoSEQ) can detect residual disease not found by flow cytometry and that greater sensitivity (e.g., to 10^-6) can provide additional prognostic information; however, coverage remains contingent on the diagnostic categories and ordering clinician requirements listed in the policy.

Additional eligibility details align with specialty guideline recommendations. For MRD testing, timing and assay selection should follow guideline-recommended time points (for example, post-induction and post-consolidation in ALL) and use validated methods with appropriate sensitivity. The NCCN and other specialty guidance referenced in the policy recommend obtaining baseline clonotype identification at diagnosis (e.g., for multiple myeloma) or storing diagnostic aspirates to allow future NGS-based MRD testing when indicated.

Tests determined to be proven and medically necessary under this policy must be ordered by a hematologist or oncologist and performed using validated methodologies consistent with guideline expectations for sample collection and assay sensitivity.

Definitions and Assay Characteristics

inv-35: CGP definition — Comprehensive Genomic Profiling definition and scope

DefinitionComprehensive Genomic Profiling (CGP) is a type of Next-Generation Sequencing (NGS) test able to detect all classes of genomic alterations, including cancer biomarkers, with a single sample.

Scope/examplesPolicy examples of CGP include FoundationOne Heme, Neo Comprehensive - Heme Cancers, and NEO AML Express for specified hematologic malignancies.

Clinical useCGP is proven and medically necessary for individuals with acute lymphoblastic leukemia, acute myeloid leukemia, myelodysplastic syndrome, or myeloproliferative neoplasm when ordered by a hematologist/oncologist.

inv-36: MRD definition — Measurable Residual Disease definition and common assessment techniques

DefinitionMeasurable Residual Disease (MRD) denotes a very small number of cancer cells or genetic material detectable during or after treatment, often not evident by routine morphology; measurement is most often used for blood cancers.

Background and Evidence Summary

Hematologic cancers such as leukemia, lymphoma, and multiple myeloma arise from blood-forming tissues and often require integrated diagnostic assessment that includes morphology, cytogenetics, flow cytometry, and molecular profiling. Next-generation sequencing (NGS)–based tests range from targeted multigene panels to comprehensive genomic profiling and high-sensitivity NGS MRD assays.

Measurable Residual Disease (MRD) denotes a very small number of cancer cells detectable during or after treatment and is used primarily in blood cancers to provide prognostic information and, in research settings, to inform MRD-adapted treatment strategies.

Guidelines and expert consensus reiterate limitations in the evidence supporting MRD-guided treatment outside of clinical trials. ASCO/CCR and international consensus panels recommend standardized nomenclature, assay requirements, specimen type, and timing for MRD assessments, and they advise that MRD testing to guide routine clinical decisions (such as changing maintenance therapy) currently lacks sufficient evidence and should be confined to investigational contexts.

These guidance statements underpin the policy’s position that MRD testing has important prognostic utility but that routine MRD-directed changes in standard care are not yet supported by high-quality randomized outcome data.

Policy Summary

PayerUnitedHealthcare

PolicyMolecular Oncology Testing for Hematologic Cancer Diagnosis, Prognosis, and Treatment Decisions

Policy CodePolicy CS372.F

Change TypeCoverage clarifications and expansions (material)

Effective DateFeb 1, 2026

Next Review Date

Key ActionOrder multigene panels, CGP, or clonoSEQ only when criteria are met and tests are requested by a hematologist or oncologist.

SourceLink

On This Page

Acute lymphoblastic leukemia (ALL): Very sensitive NGS MRD assays detect residual disease missed by multicolor flow cytometry; retrospective data (clonoSEQ use) showed NGS MRD negativity associated with lower relapse and higher long-term survival compared with MFC-negative but NGS-positive cases.~10^-6

Timing of bone marrow MRD assessment after induction and during consolidation is recommended in expert guidance.

Acute myeloid leukemia (AML): Targeted NGS can detect persistent mutations during remission; when clonal hematopoiesis-associated (DTA) mutations are excluded, NGS MRD detection is associated with higher relapse and lower survival; combining NGS and flow cytometry adds prognostic value.sensitivities reported ~10^-4 to 10^-5 (NGS) and up to 10^-6 in some assays)

Systematic reviews/meta-analyses show MRD-negativity correlates with improved DFS and OS, though sensitivity and standardization vary.

NCCN AML guidance highlights evolving role of MRD and encourages clinical trial participation.

CLL testing and MRD: Perform FISH for common cytogenetic abnormalities, TP53 sequencing, karyotyping for complex karyotype, and IGHV mutation analysis for prognostication; MRD assessment should use assays with sensitivity of 10^-4 (ERIC) or validated NGS methods and can be performed on blood or bone marrow.sensitivity >= 10^-4 (ERIC) or better; NGS may reach 10^-6

NCCN CLL guidance references FDA-cleared clonoSEQ and ERIC standards.

MDS and myeloid neoplasms: Use gene panels that include commonly mutated genes in MDS or myeloproliferative neoplasms for diagnosis and prognostication; select panels and laboratories based on indication and lab expertise.

NCCN MDS and myeloproliferative neoplasm guidance recommend targeted panels and careful test selection.

Multiple myeloma: Perform baseline clonotype identification or store aspirate sample at diagnosis for future NGS MRD assessment; NGS or SNP arrays on bone marrow may provide additional prognostic information.

NCCN Multiple Myeloma guidance recommends baseline clonotype identification to enable future MRD testing.

Revised to expand covered hematologic malignancies for CGP.

Other molecular tests for MRD: Not covered — molecular tests other than clonoSEQ are considered unproven and not medically necessary for initial clonality assessment or for assessment of MRD.

Clarified non-clonoSEQ molecular MRD assays are unproven and not medically necessary.

Guideline-consistent uses: Coverage supports diagnosis, prognostication, treatment selection, and MRD assessment across hematologic malignancies per society guidelines (CAP/ASH, NCCN): obtain comprehensive diagnostic testing, use validated MRD assays at recommended sensitivities and timings, and apply disease-specific panel testing per guideline recommendations.

Use of multigene panels (50 genes or fewer) at initial diagnosis and/or recurrence or relapse when ordered by a hematologist or oncologist

Ordering clinician requirement for multigene panels: Use of multigene panels (50 genes or fewer) at initial diagnosis and/or recurrence or relapse is proven and medically necessary when ordered by a hematologist or oncologist.

Comprehensive Genomic Profiling (CGP) coverage for AL, AML, MDS, MPN (examples listed)

CGP coverage for listed hematologic malignancies: Comprehensive Genomic Profiling (CGP) is proven and medically necessary for acute lymphoblastic leukemia, acute myeloid leukemia, myelodysplastic syndrome, or myeloproliferative neoplasm (examples: FoundationOne Heme, Neo Comprehensive - Heme Cancers, NEO AML Express).

Clonality assessment and MRD assessment using clonoSEQ when clinical prerequisites are met (e.g., CLL for certain clonoSEQ uses)

Clonality and MRD with clonoSEQ prerequisites: Clonality assessment and MRD assessment using clonoSEQ are covered when clinical prerequisites are met; for certain clonoSEQ indications the individual must have chronic lymphocytic leukemia for clonality assessment at diagnosis and for MRD assessment.

Threshold associated with greatest benefit in AML reviewStudies using an MRD cutoff of less than 0.1% (10^-3) showed the greatest benefit related to MRD negativity in AML systematic review.

Clinical study examplesNDMM and RRMM studies report improved PFS with MRD negativity at 10^-5 versus lesser thresholds; ALL and CLL studies reference 10^-6 sensitivity for prognostic discrimination.

inv-17: MRD assay sensitivity — minimum recommended sensitivity and capabilities of NGS assays

Minimum recommended sensitivityNCCN and other guideline statements recommend MRD assessment technologies with sensitivity of 10^-4 (0.01%) or better for evaluation in ALL, CLL, and other settings.

NGS capabilitySome validated NGS MRD assays (e.g., clonoSEQ) can detect MRD to the level of 10^-6, providing greater sensitivity than flow cytometry or ASO-PCR.

Limitations notedStandard (diagnostic) NGS panels may lack sufficient sensitivity for MRD in many instances; use PCR, validated flow cytometry, or validated high-sensitivity NGS for MRD assessment.

Confirm plan-specific prior authorization and coverage rules before ordering MRD-based management.

Note

Regulatory note: FDA approval is informational; labs are CLIA-regulated

FDA clearance or approval is informational only and is not by itself a basis for coverage; laboratories performing genetic tests are regulated under CLIA.

Do not rely on FDA clearance alone when determining coverage eligibility.
Ensure tests are performed in CLIA-regulated laboratories as applicable.

Prior Authorization

Ordering expectation: Hematologist/oncologist must order multigene panels (≤50 genes)

Multigene panels of 50 genes or fewer are considered proven and medically necessary when ordered by a hematologist or oncologist for specified hematologic malignancies at initial diagnosis and/or recurrence/relapse.

Order multigene panels (≤50 genes) only when requested by a hematologist or oncologist for listed indications (e.g., ALL, AML, MM, suspected MDS/MPN).
Coverage criteria were revised to clarify this ordering requirement.

Step Therapy

MRD-guided therapy adaptation observed in MASTER trial (therapy cessation after consecutive MRD-negative results)

In the MASTER trial, treatment duration and cessation were adapted based on achieving consecutive MRD-negative results; participants who achieved MRD-SURE discontinued therapy and were observed.

Therapy (Dara-KRd) was discontinued upon attainment of consecutive MRD-negative findings (MRD-SURE) with ongoing MRD monitoring.
MRD-guided treatment cessation occurred in a substantial proportion of participants (71% reached MRD-SURE in the trial).

Step Therapy

Encourage clinical trial participation when MRD testing guides treatment

Because evidence and standards for MRD-guided treatment decisions are evolving and randomized outcome data are limited, participation in clinical trials is encouraged when MRD testing will guide therapy.

NCCN and other guidance note lack of standardization and recommend clinical trial participation.
Expert reviews and guidance recognize MRD's prognostic value but advise studying MRD-guided strategies within trials.

Documentation Required

Provide medical records when requested to support coverage determination

Medical records documentation may be required to determine whether the member meets the clinical criteria for coverage; such documentation does not guarantee coverage.

Provide clinical records demonstrating indication and ordering clinician specialty as requested during reviews.
Benefit coverage is determined by federal, state, or contractual requirements in addition to clinical criteria.

Documentation Required

Obtain and process sufficient diagnostic specimens for cytogenetic and molecular analyses

Obtain sufficient diagnostic specimens and perform conventional cytogenetic (karyotype) and appropriate molecular-genetic and/or FISH testing, and flow cytometry as recommended to allow proper characterization and future MRD assessment.

Pathologist or treating clinician should ensure samples are adequate for morphology, karyotype, molecular/FISH, and flow cytometry.
Molecular/FISH testing does not replace conventional cytogenetic analysis; process specimens to permit subsequent MRD detection.

Documentation Required

Ensure sample handling and storage support morphology, karyotype, molecular/FISH, and flow cytometry

Ensure baseline specimens and handling are adequate for morphology, karyotype, molecular/FISH, and flow cytometry so that future MRD detection (including baseline clonotype identification) is possible.

Baseline clonotype identification or storage of aspirate at diagnosis is recommended for future NGS MRD assessment.
Process tissue or marrow samples per CAP/ASH recommendations to preserve material for all recommended studies.

Documentation Required

Medical records may be requested to verify clinical criteria

Medical records documentation may be requested to verify that diagnostic and clinical criteria are met for coverage determinations.

Records should document diagnosis, ordering clinician specialty, and relevant prior testing/results.
Submission of requested documentation supports review but does not ensure approval.

Denial Risk

Risk of denial if documentation does not demonstrate clinical criteria

Failure to provide medical records demonstrating that the member meets the policy's clinical criteria may result in claim denial.

Lack of supporting documentation used in reviews can lead to denial decisions.
Follow the Medical Records Documentation Used for Reviews guideline when submitting records.

Denial Risk

Denial risk if samples are inadequate for required cytogenetic/molecular testing

Insufficient or inappropriate specimen collection or processing that prevents required cytogenetic or molecular testing (including adequate material for MRD assays) may affect coverage determinations.

Ensure flow cytometry panels and molecular processing are comprehensive enough to allow subsequent MRD detection.
Inadequate samples (e.g., insufficient unique clonogenic sequences) may preclude MRD tracking and affect eligibility for covered MRD assessment.

Note

Coverage decisions informationally linked to FDA/CLIA status — FDA approval not sole basis

Coverage decisions reference FDA and CLIA status for informational purposes; FDA approval alone does not establish coverage entitlement.

Do not assume coverage based solely on FDA clearance/approval.
Confirm testing laboratory CLIA status as appropriate.

Documentation Required

Documentation may be required for review but does not guarantee coverage

Providing requested medical records may be necessary to assess whether the member meets clinical criteria, but supplying records does not guarantee that the service will be covered; benefit coverage is determined by federal/state/contractual rules.

Submit complete clinical documentation when requested during review.
Coverage determination remains subject to plan terms and applicable laws.

Prior Authorization

Ordering clinician requirement: Hematologist or oncologist must order covered tests

Tests that meet the policy's proven and medically necessary criteria must be ordered by a hematologist or oncologist; ordering clinician specialty should be documented.

Multigene panels, CGP, and clonoSEQ coverage criteria specify orders must come from a hematologist or oncologist.
Document the ordering clinician's specialty in the medical record and authorization requests.

Prior Authorization

Ordering expectation: Multigene panels (≤50 genes) must be ordered by hematologist/oncologist

To meet the policy's proven and medically necessary criteria, multigene panels (50 genes or fewer) must be ordered by a hematologist or oncologist for the specified indications.

Ensure orders for multigene panels (≤50 genes) are placed by a hematologist or oncologist and that indication matches covered conditions.
Updated policy language clarifies this ordering expectation.

Common assessment techniquesCurrent MRD assessments use real-time quantitative PCR, multiparametric flow cytometry (MFC), and/or NGS-based assays (including high-throughput sequencing/clonoSEQ).

Clinical significanceMRD detection is prognostic—MRD-negative status is associated with lower relapse risk and improved survival across multiple hematologic malignancies in numerous studies.

inv-37: NGS definition — Next Generation Sequencing explanation

DefinitionNext Generation Sequencing (NGS) refers to sequencing techniques that can rapidly analyze multiple sections of DNA simultaneously, enabling detection of diverse genomic alterations.

Role in MRD and CGPNGS underpins comprehensive genomic profiling and high-sensitivity MRD assays capable of detecting low-level variants and clonotypes not seen with older methods.

Clinical guidanceGuidelines reference validated NGS-based tests for gene fusion/mutation detection in ALL and endorse MRD assays with sensitivity >=10^-4, with some NGS assays reaching 10^-6.

inv-38: MRD negativity thresholds — Examples of thresholds (<10^-4, <10^-5, <10^-6) used in studies

Examples of MRD negativity thresholdsStudies and consensus documents report MRD negativity defined variably as <10^-4, <10^-5, or <10^-6 depending on assay and disease context.

Disease-specific notesIn multiple myeloma, MRD negativity at 10^-5 or 10^-6 is associated with improved PFS; in ALL and CLL, thresholds around 10^-6 are discussed for NGS assays.

ImplicationThreshold selected affects prognostic discrimination—higher sensitivity thresholds (e.g., 10^-6) detect additional residual disease not found at 10^-4 and correlate with outcome differences.

inv-39: Analytical sensitivity examples — Flow cytometry, ASO-PCR, high-throughput sequencing sensitivity ranges

Flow cytometry sensitivityMulticolor flow cytometry (MFC) has analytical sensitivity around 0.01% (10^-4).

ASO-PCR sensitivityAllele-specific oligonucleotide PCR (ASO-PCR) can reach approximately 0.001% (10^-5) but requires patient-specific probes.

High-throughput sequencing/NGS sensitivityHigh-throughput sequencing and validated NGS MRD assays (e.g., clonoSEQ) can achieve sensitivities approaching 10^-6.

inv-40: MRD (duplicate reference) — MRD definition reference

Definition (duplicate reference)Measurable Residual Disease (MRD): Very small number of cancer cells detectable during and after treatment; assessed by PCR, flow cytometry, or NGS and associated with relapse risk.

Assessment methods (duplicate note)Common MRD assessment methods include real-time quantitative PCR, multiparametric flow cytometry, and NGS-based assays.

Clinical use (duplicate note)MRD measurement is primarily applied in hematologic malignancies to inform prognosis and, in trials, to guide therapy adaptations.

inv-41: clonoSEQ definition — Proprietary clonality and MRD assay standardized in policy language

DefinitionclonoSEQ is the policy-standardized proprietary clonality and MRD assay referenced throughout the policy (noting previous references to multiple clonoSEQ variants were consolidated to 'clonoSEQ').

Approved uses in policyClonality assessment with clonoSEQ at initial diagnosis and MRD assessment with clonoSEQ are proven and medically necessary for ALL, multiple myeloma, and CLL when ordered by a hematologist/oncologist and clinical prerequisites are met.

Regulatory/context noteNICE and guideline documents reference clonoSEQ as an FDA-cleared commercial NGS MRD assay capable of high sensitivity (example: detection to 10^-6).

inv-42: CGP (duplicate) — CGP examples (FoundationOne Heme, Neo Comprehensive, NEO AML Express)

Examples of CGP testsPolicy-listed examples of Comprehensive Genomic Profiling include FoundationOne Heme, Neo Comprehensive - Heme Cancers, and NEO AML Express.

ScopeThese CGP examples are cited as proven and medically necessary for acute lymphoblastic leukemia, acute myeloid leukemia, myelodysplastic syndrome, or myeloproliferative neoplasm when ordered by a hematologist/oncologist.

Relation to multigene panelsCGP differs from smaller multigene panels (<=50 genes) and is specifically named for expanded genomic profiling in selected hematologic malignancies.