ModifiedUnitedHealthcarePolicy CS372TN.F

Molecular Oncology Testing for Hematologic Cancer Diagnosis, Prognosis, and Treatment Decisions (for Tennessee Only)

Defines medical necessity and coverage for molecular and genomic testing (multigene panels, comprehensive genomic profiling, MRD/clonality testing) for diagnosis, prognosis, and treatment decisions in hematologic cancers for Tennessee Medicaid and CoverKids.

Policy Summary

PayerUnitedHealthcare

PolicyMolecular Oncology Testing for Hematologic Cancer Diagnosis, Prognosis, and Treatment Decisions (for Tennessee Only)

Policy CodePolicy CS372TN.F

Change TypeCoverage criteria clarified and expanded

Effective DateFeb 1, 2026

Next Review DateN/A

Key ActionOrder multigene panels (≤50 genes), CGP, or clonoSEQ only when requested by a hematologist or oncologist and document clinical indication in the medical record.

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.

Revised medically necessary coverage criteria for use of multigene panels (50 genes or fewer) at initial diagnosis and/or recurrence or relapse, replacing requirement language about strong suspicion with suspected (as evidenced by order from hematologist/oncologist).

Added criterion requiring the individual has chronic lymphocytic leukemia for clonality assessment and MRD assessment with clonoSEQ.

Expanded proven and medically necessary use of Comprehensive Genomic Profiling (CGP) to include individuals with 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.

Added medical records documentation language clarifying that documentation may be required to assess whether the member meets clinical criteria for coverage and that documentation must support medical necessity.

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multigene panel gene limit

clonoSEQnamed MRD assay covered

CGP expandedCGP indication change

Unprovenunproven tests listed

Coverage Criteria for Molecular and Genomic Testing

Multigene panels (<=50 genes)

Covered when ALL of the following are met:

Multigene panels (<=50 genes): Ordered by a hematologist or oncologistpanel size <= 50 genes

Indications include acute lymphoblastic leukemia, acute myeloid leukemia, multiple myeloma, and myelodysplastic syndrome or myeloproliferative neoplasm when suspected as evidenced by the order; applies at initial diagnosis and/or recurrence or relapse.

Comprehensive Genomic Profiling (CGP)

Covered when ordered by a hematologist or oncologist for the following diagnoses:

CGP covered indications: Comprehensive Genomic Profiling (CGP) is medically necessary for individuals with acute lymphoblastic leukemia, acute myeloid leukemia, myelodysplastic syndrome, or myeloproliferative neoplasm.

Examples of CGP cited in the policy include FoundationOne Heme, Neo Comprehensive - Heme Cancers, and NEO AML Express.

Clonality and MRD testing (clonoSEQ)

Covered when ordered by a hematologist or oncologist for the following diagnoses:

clonoSEQ for clonality and MRD: Clonality assessment at initial diagnosis and MRD assessment with clonoSEQ are medically necessary for individuals with acute lymphoblastic leukemia, multiple myeloma, or chronic lymphocytic leukemia.

Must be ordered by a hematologist or oncologist; molecular tests other than clonoSEQ are considered unproven and not medically necessary for initial clonality assessment or MRD assessment.

Contexts where MRD testing has demonstrated prognostic/decision impact

Evidence summary and contexts where MRD testing has prognostic or decision-making implications in studies:

CLL MRD-guided therapy evidence: Randomized trial evidence (FLAIR) shows MRD-guided ibrutinib-venetoclax produced superior progression-free and overall survival versus FCR; MRD-guided strategies were used to determine therapy duration.various (10^-4 to 10^-6)

FLAIR reported 3-year PFS 97.2% vs 76.8% favoring MRD-guided ibrutinib-venetoclax (chunk 18).

MM MRD response-adapted therapy: The MASTER trial used NGS MRD (<10^-5) to direct discontinuation of therapy (MRD-SURE) with high MRD-negativity rates and therapy-free intervals; outcomes varied by high-risk cytogenetic status.<10^-5

MASTER found 81% achieved MRD <10^-5 and MRD-SURE led to therapy discontinuation in many participants, but those with >=2 HRCAs had higher progression (chunks 21-22).

ALL MRD prognostic value:

Covered Testing Criteria

Covered when criteria below are met based on disease-specific recommendations and ordering clinician:

Multigene panels (<=50 genes): Multigene panels (50 genes or fewer) are proven and medically necessary when ordered by a hematologist or oncologist for individuals at initial diagnosis and/or recurrence or relapse of listed hematologic malignancies.panel size <= 50 genes

Ordering clinician evidence required (hematologist/oncologist).

Comprehensive Genomic Profiling (CGP) (e.g., 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.

Expanded CGP indications per policy revision.

clonoSEQ clonality and MRD: clonoSEQ testing is covered for clonality assessment at diagnosis and for MRD assessment; coverage explicitly includes individuals with chronic lymphocytic leukemia.

Other molecular MRD/clonality tests are considered unproven and not medically necessary.

Revised medical necessity positions

Selected revised and added coverage positions from policy history:

Multigene panels (<=50 genes) at initial diagnosis/recurrence/relapse: Multigene panels (50 genes or fewer) are proven and medically necessary when ordered by a hematologist or oncologist for individuals with the listed hematologic conditions.50 genes

Revision clarifies ordering specialist requirement and panel size limit (02/01/2026).

Clonality and MRD assessment with clonoSEQ: clonoSEQ is recognized for clonality assessment at initial diagnosis and for MRD assessment; policy added that coverage includes individuals with chronic lymphocytic leukemia.

Policy states molecular tests other than clonoSEQ are unproven and not medically necessary for initial clonality assessment or MRD assessment.

Comprehensive Genomic Profiling (CGP) expansion: CGP (e.g., FoundationOne Heme, Neo Comprehensive - Heme Cancers, NEO AML Express) is proven and medically necessary for individuals with ALL, AML, MDS, or MPN.

The policy states that molecular tests other than clonoSEQ are considered unproven and not medically necessary for both initial clonality assessment and for measurable residual disease (MRD) assessment. clonoSEQ is the named assay recognized for clonality and MRD evaluation when ordered by a hematologist or oncologist for specified hematologic malignancies (e.g., ALL, MM, CLL).

Professional guidance cited in the policy cautions that there is insufficient evidence to change the type or duration of therapy solely on the basis of MRD status outside of clinical trials. ASCO/CCR and related guideline statements recommend MRD be used for prognostication and within trial contexts for therapy adaptation, but they do not endorse routine therapy modification based only on MRD results.

Explicitly, the policy declares that the use of molecular tests other than clonoSEQ is unproven and not medically necessary for initial clonality assessment or for assessment of MRD. This NMN determination applies to unspecified alternative molecular MRD or clonality assays.

The policy reiterates that molecular tests other than clonoSEQ are not medically necessary for initial clonality or MRD evaluation and adds that medical-record documentation may be required to determine whether the member meets clinical criteria for coverage; documentation alone does not guarantee coverage.

As examples of technologies considered unproven, the policy lists optical genome mapping and whole transcriptome sequencing among other molecular test panels for hematologic cancer that are considered not medically necessary due to insufficient evidence.

ASCO/CCR guidance summarized in the policy states there is insufficient evidence to modify maintenance therapy based on MRD status and that MRD should not be used to guide treatment goals outside of clinical trials; MRD negativity is prognostically favorable but not, by itself, a recommended trigger for routine therapy changes.

The policy again affirms that the use of molecular tests other than clonoSEQ is unproven and not medically necessary for both initial clonality assessment and MRD assessment; clonoSEQ remains the named assay supported for these uses when criteria are met.

Restating the policy position: molecular assays other than clonoSEQ for clonality or MRD evaluation are considered unproven and not medically necessary. Coverage for clonality and MRD is limited to clonoSEQ when ordered under the policy’s specified indications.

Covered Indications by Disease

Acute lymphoblastic leukemia (ALL)

Coverage applicability for the listed hematologic conditions when the specified test type and ordering requirements are met:

Acute lymphoblastic leukemia (ALL): Multigene panels (<=50 genes), Comprehensive Genomic Profiling (CGP), and clonoSEQ (where specified) are medically necessary when ordered by a hematologist or oncologist per guideline-directed indications and timing.

NCCN recommends validated MRD assessment technology with sensitivity >=10^-4 and consideration of FDA-approved NGS assays to confirm negativity when flow cytometry is negative (chunk 40).

Acute myeloid leukemia (AML)

Coverage applicability when the specified test type and ordering requirements are met:

Acute myeloid leukemia (AML): Multigene panels (<=50 genes) and Comprehensive Genomic Profiling (CGP) are medically necessary when ordered by a hematologist or oncologist for AML, including for relapse evaluation and actionable mutation determination.

NCCN indicates multiplex gene panels and targeted NGS are indicated for ongoing management and relapse profiling (chunk 41).

Coding and Test Definitions

Applicable CPT/HCPCS Codesmixed

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 and variant identification.
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	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.
0413U	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 19

1/2

Coding referenced (none specified)mixed

not listed

No explicit CPT/HCPCS/ICD codes are listed in these chunks.

Referenced test groupsmixed

affected codes

Policy references tests and panels (multigene panels, Comprehensive Genomic Profiling [CGP], clonoSEQ) but specific CPT/HCPCS codes are listed in the Applicable Codes section of the policy.

Panel gene count threshold

Panel definitionMultigene panels of 5–50 genes (50 genes or fewer) are defined as covered in specified contexts (CPT codes 81450/81451 correspond to 5–50 gene panels).

Covered contextsCovered when ordered by a hematologist or oncologist at initial diagnosis and/or recurrence or relapse for listed hematologic malignancies (ALL, AML, multiple myeloma, suspected MDS/MPN).

BoundaryPanels of 51 or greater genes are categorized separately (CPT codes 81455/81456 for 51+ genes) and not included in the ≤50 gene panel coverage statement.

Ordering requirementOrder must be from a hematologist or oncologist as evidenced in the medical record.

Policy citationSee Coverage Rationale: 'The use of multigene panels (50 genes or fewer) at initial diagnosis and/or recurrence or relapse is proven and medically necessary...' (Policy History 02/01/2026).

Provider Actions, Ordering, and Documentation

Prior Authorization

Code Reference and Prior Authorization Note

The following code lists are provided for reference and do not guarantee coverage or reimbursement; prior authorization rules may apply per contract or state requirements. Inclusion of a code here is informational only and may require documentation to support medical necessity.

0017M, 0050U, 0120U, 0171U, 0298U, 0299U, 0300U, 0331U, 0364U, 0413U, 0485U, 0560U, 0561U, 81195, 81450, 81451, 81455, 81456, 81479

Note

No Specific Provider Authorization in Policy Text

There are no explicit provider authorization rules contained in this policy beyond specialty ordering and standard medical necessity review; providers should follow applicable federal, state, and contractual requirements and any plan-specific authorization processes.

Not Covered / Not Medically Necessary

The policy’s NOT COVERED list specifically includes optical genome mapping, whole transcriptome sequencing, and other unspecified molecular test panels for hematologic cancers as unproven and not medically necessary for diagnosis or MRD assessment.

The policy notes that altering maintenance therapy or making routine treatment changes solely on the basis of MRD status is not supported by ASCO/CCR guidance and therefore is not an accepted basis for coverage outside clinical trials.

Molecular tests other than clonoSEQ are listed as not covered for use in initial clonality assessment or for MRD assessment. clonoSEQ is named as the assay accepted for these uses when the policy’s clinical criteria are met.

The policy repeats that molecular assays other than clonoSEQ for clonality or MRD are considered unproven and not medically necessary and thus are not covered under the listed indications.

Definitions and Key Terms

Comprehensive Genomic Profiling (CGP) — definition and examples

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

Examples citedPolicy examples include FoundationOne Heme, Neo Comprehensive - Heme Cancers, and NEO AML Express as CGP platforms.

Covered indicationsCGP is proven and medically necessary for individuals with ALL, AML, MDS, or myeloproliferative neoplasm when ordered by a hematologist/oncologist.

Measurable Residual Disease (MRD) — definition and detection methods

DefinitionMeasurable Residual Disease (MRD) refers to a very small number of cancer cells or genetic material detectable during or after treatment using sensitive methods.

Detection methods

Eligibility Requirements

This policy applies to members of the Tennessee Medicaid and CoverKids plans; coverage determinations follow the policy effective date and any federal, state or contractual requirements that may apply. Tests governed by this policy (multigene panels, CGP, and clonoSEQ) must be ordered by a hematologist or oncologist for the specified covered indications to meet the ordering requirement.

Additional eligibility and procedural expectations described in the policy include that pathologists and treating clinicians should obtain sufficient specimens and perform guideline-recommended baseline testing (e.g., cytogenetics, molecular/genetic and flow cytometry). The policy also emphasizes that medical record documentation must fully support medical necessity and may be requested to assess whether coverage criteria are met.

Clinical Background and Rationale

Hematologic cancers (leukemias, lymphomas, and multiple myeloma) arise from blood-forming tissues and frequently rely on molecular profiling for diagnosis, prognosis, and targeted treatment selection. The policy recognizes MRD assessment as an important prognostic tool across these diseases but limits coverage of clonality and MRD testing to specified assays and clinical contexts (e.g., clonoSEQ for clonality and MRD in indicated diagnoses).

Policy Summary

PayerUnitedHealthcare

PolicyMolecular Oncology Testing for Hematologic Cancer Diagnosis, Prognosis, and Treatment Decisions (for Tennessee Only)

Policy CodePolicy CS372TN.F

Change TypeCoverage criteria clarified and expanded

Effective DateFeb 1, 2026

Next Review DateN/A

Key ActionOrder multigene panels (≤50 genes), CGP, or clonoSEQ only when requested by a hematologist or oncologist and document clinical indication in the medical record.

SourceLink

On This Page

High-sensitivity NGS MRD detects residual disease missed by multicolor flow cytometry and NGS MRD negativity is associated with lower relapse and improved survival in ALL cohorts.

Retrospective cohort showed NGS (10^-6) detected MRD when MFC (10^-4) was negative and NGS negativity predicted lower relapse (chunk 23).

AML MRD and combined assay value: Targeted NGS and flow cytometry provide complementary prognostic information in AML; excluding DTA mutations increases MRD specificity for relapse prediction.~10^-4 to 10^-5

Systematic reviews and pooled analyses show MRD negativity correlates with improved DFS/OS across AML studies though standardization and cutoffs vary (chunks 26-27, 31).

Guideline context: Professional guidelines recognize MRD's prognostic value but generally advise against changing standard maintenance or therapy solely on MRD outside clinical trials; they emphasize standardized methods, timing, and adequate sampling.n/a

ASCO/CCR and CAP/ASH guidance cite insufficient evidence to alter maintenance therapy based only on MRD and recommend standardized assessment (chunk 35, 36).

MRD assay selection and sensitivity: Guidelines recommend MRD assays with sensitivity of 10^-4 or better for many hematologic malignancies; selection and timing should follow disease-specific guidance (e.g., NCCN recommendations for ALL, AML, CLL, MM).sensitivity >= 10^-4 where specified

Policy references guideline-recommended assay sensitivity and timing for MRD assessments.

Replaced prior narrower language that limited CGP to relapsed/recurrent AML.

Multiple myeloma

Coverage applicability when the specified test type and ordering requirements are met:

Multiple myeloma: Multigene panels (<=50 genes) and clonoSEQ for clonality assessment and MRD monitoring are medically necessary when ordered by a hematologist or oncologist.

MASTER trial evidence supports MRD-guided therapy discontinuation strategies using NGS MRD (<10^-5) though outcomes vary by HRCA status (chunks 21-22).

Myelodysplastic syndrome (MDS) and Myeloproliferative neoplasm (MPN)

Coverage applicability when the specified test type and ordering requirements are met:

Myelodysplastic syndrome (MDS) and Myeloproliferative neoplasm (MPN): Multigene panels (<=50 genes) and Comprehensive Genomic Profiling (CGP) are medically necessary when the diagnosis is suspected and the order is placed by a hematologist or oncologist.panel size <= 50 genes

Policy revision clarified 'suspected' as evidenced by order from a hematologist/oncologist (chunk 54-55).

Chronic lymphocytic leukemia (CLL)

Coverage applicability when the specified test type and ordering requirements are met:

Chronic lymphocytic leukemia (CLL): clonoSEQ for MRD assessment and clonality evaluation is considered medically necessary when ordered by a hematologist or oncologist; MRD assessments should use guideline-recommended assay sensitivity and specimen types.sensitivity >= 10^-4 (guideline-recommended); NGS assays up to 10^-6 available

NCCN references clonoSEQ and recommends MRD assessment with sensitivity of 10^-4 per ERIC or standardized NGS; NGS provides additional prognostic information at higher sensitivity (chunks 31, 42).

MRD assessment for prognostication and disease monitoring across diseases

Study-based contexts and assay sensitivity notes where MRD assessment has demonstrated prognostic or decision impact:

MRD for prognostication across diseases: Multiple studies and meta-analyses demonstrate MRD negativity is associated with improved PFS/DFS and OS across B-ALL, CLL, MM, and AML; sensitivity thresholds in studies range from ~10^-4 to 10^-6 with higher sensitivity assays detecting residual disease missed by lower-sensitivity methods.various (10^-4 to 10^-6)

Meta-analyses and trials (FLAIR, MASTER, Short et al., Thompson et al.) support prognostic value though guideline recommendations caution against routine therapy changes based solely on MRD outside trials (chunks 18,21-23,26-27,31,35).

Use of multigene panels (50 genes or fewer) at initial diagnosis and/or recurrence/relapse

Covered when ALL of the following are met:

Use of multigene panels (<=50 genes) at initial diagnosis and/or recurrence/relapse: Order placed by a hematologist or oncologist and diagnosis or suspected diagnosis documented in the medical record (e.g., ALL, AML, MM, MDS/MPN).panel size <= 50 genes

Policy specifies 50-gene limit for covered multigene panels and requires specialist ordering evidence (chunks 2, 54).

CGP for individuals with ALL, AML, MDS, or MPN

Covered when ordered by a hematologist or oncologist for the specified diagnoses:

CGP for hematologic malignancies: Comprehensive Genomic Profiling (CGP) is medically necessary for individuals with ALL, AML, MDS, or MPN; examples of CGP platforms cited include FoundationOne Heme, Neo Comprehensive - Heme Cancers, and NEO AML Express.

Policy revision expanded CGP indications to include these diagnoses (chunk 55).

clonoSEQ for clonality assessment and MRD assessment, including for chronic lymphocytic leukemia

Covered when ordered by a hematologist or oncologist for the specified indications:

clonoSEQ for clonality and MRD in multiple myeloma and other diseases: clonoSEQ is covered for clonality assessment at diagnosis and for MRD assessment in multiple myeloma, and is named as an accepted MRD assay in the policy across multiple diagnoses.

MASTER trial demonstrates use of NGS MRD (<10^-5) to guide therapy duration in MM; policy names clonoSEQ specifically (chunks 21-22, 55).

Clonality assessment and MRD monitoring using clonoSEQ

Covered when ordered by a hematologist or oncologist for indicated diagnoses:

Clonality assessment and MRD monitoring using clonoSEQ: clonoSEQ is covered for initial clonality assessment and for MRD monitoring when ordered by a hematologist or oncologist; for clonality/MRD coverage the individual may have chronic lymphocytic leukemia as specified.

Policy emphasizes clonoSEQ as the named FDA-cleared commercial assay and clarifies other molecular MRD/clonality tests are unproven (chunks 2,31,55).

CGP for ALL, AML, MDS, or MPN

Covered when ordered by a hematologist or oncologist for the listed diagnoses:

CGP for ALL/AML/MDS/MPN (platform examples): Comprehensive Genomic Profiling is appropriate for acute lymphoblastic leukemia, acute myeloid leukemia, myelodysplastic syndrome, or myeloproliferative neoplasm; policy lists example platforms such as FoundationOne Heme and Neo Comprehensive - Heme Cancers.

NCCN guidance supports comprehensive molecular characterization in ALL and AML (chunk 40-41).

Multigene panels (50 genes or fewer) at initial diagnosis and/or recurrence/relapse for listed hematologic conditions

Covered when ALL of the following are met:

Multigene panels (<=50 genes) at initial diagnosis/recurrence/relapse for listed hematologic conditions: Order placed by a hematologist or oncologist with documentation of diagnosis or suspected diagnosis in the medical record.panel size <= 50 genes

Policy enforces the 50-gene limit and specialist ordering requirement for covered panels (chunks 2,54).

MRD analytic sensitivity thresholds

Analytic sensitivity tiersSensitivity levels discussed include approximately 10^-4, 10^-5, and 10^-6 depending on assay and disease context.

10^-4Flow cytometry and some guideline-recommended MRD methods typically have sensitivity around 10^-4; NCCN recommends MRD assays with sensitivity ≥10^-4 for many diseases.

10^-5High-sensitivity NGS MRD assays used in trials and pooled analyses commonly report thresholds near 10^-5 and were used to define MRD negativity in multiple myeloma pooled analyses.

10^-6Very high-sensitivity NGS assays (including FDA‑approved clonoSEQ) can detect MRD to ~10^-6; studies (e.g., Thompson et al., Short et al.) report prognostic differences when using 10^-6 versus 10^-4.

Clinical implicationHigher analytic sensitivity may detect residual disease missed by less sensitive methods and can provide additional prognostic information, but guideline interpretation and treatment decisions may vary by disease.

Multigene panel size limit

Multigene panel size limit50 genes or fewer (panels of 5–50 genes) is the policy-specified size limit for covered multigene panels.

Coverage applicationThis 50‑gene threshold applies to panels ordered at initial diagnosis and/or recurrence/relapse for listed hematologic malignancies when ordered by a hematologist/oncologist.

Distinct coding for larger panelsPanels >50 genes are coded separately (CPT 81455/81456 for 51+ genes) and are not covered under the 5–50 gene panel criterion.

Denial Risk

Documentation-Related Denial Risk

Benefit coverage is determined by contractual, federal, or state requirements and documentation that does not guarantee coverage. Lack of sufficient documentation may result in denial of services.

Medical records must be legible and made available upon request
Inadequate documentation may lead to claim denial

Documentation Required

Medical Record Documentation Requirements

The patient's medical record must contain documentation that fully supports medical necessity for requested tests, including relevant medical history, physical examination findings, and results of pertinent diagnostic tests or procedures. Documentation may be requested during review.

Include history, exam findings, and pertinent diagnostic test results
Maintain legible records and make available upon request

Documentation Required

Specimen and Testing Documentation

Pathologists and treating clinicians are responsible for obtaining adequate specimens and performing conventional cytogenetic, molecular-genetic and/or FISH testing and flow cytometric immunophenotyping per CAP/ASH guidance. Ensure specimen adequacy and proper collection to support testing and interpretation.

Obtain sufficient blood and bone marrow samples for morphology, karyotype, molecular testing, FISH, and flow cytometry as indicated
Follow CAP/ASH recommendations for laboratory testing and specimen handling

Note

MRD-Guided Treatment Decision Documentation (Study Contexts)

MRD testing with FDA-cleared clonoSEQ has been used in clinical trials to guide treatment decisions (for example, treatment discontinuation in the MASTER trial for multiple myeloma). When MRD-guided decisions are made, document the clinical context, assay used, sample source, timing of testing relative to therapy, and how results informed management.

Document assay name (e.g., clonoSEQ), specimen type (bone marrow or peripheral blood), and sensitivity threshold
Record timing of MRD assessments and any treatment changes based on consecutive MRD results

Step Therapy

Step Therapy / Timing (Informational)

No formal step therapy requirements are specified in this policy. Follow guideline-recommended timing for MRD assessment and participation in clinical trials when applicable. Operational timing recommendations (e.g., monitoring upon achievement of morphologic remission or at specified intervals) should be followed per disease-specific guidelines.

Follow NCCN-recommended timing for MRD assessment (disease-specific)
Participation in clinical trials is encouraged when appropriate

Common MRD detection methods include real‑time quantitative PCR, multiparametric flow cytometry (MFC), and NGS-based assays.

Clinical roleMRD measurement is most often used for blood cancers to inform prognosis and assess treatment effectiveness; specific timing and use follow disease‑specific guidelines.

Next Generation Sequencing (NGS)

DefinitionNext‑Generation Sequencing (NGS) comprises sequencing techniques that can rapidly analyze multiple DNA regions simultaneously, enabling multi‑gene panels and CGP.

Role in policyNGS is the platform for multigene panels (5–50 genes), CGP, and high‑sensitivity MRD assays (e.g., clonoSEQ) referenced in the policy.

Comparative sensitivityNGS‑based MRD assays can reach sensitivities (~10^-5 to 10^-6) greater than standard flow cytometry (~10^-4), providing additional prognostic information in some studies.

MRD negativity thresholds

DefinitionMRD negativity denotes that no residual disease is detected at a specified assay sensitivity threshold. Examples reported include MRD <10^-4, <10^-5, and <10^-6 depending on assay and study.

Example — 10^-4Multicolor flow cytometry (MFC) commonly has sensitivity around 10^-4 and is used in guideline‑recommended MRD assessment for several diseases.

Example — 10^-5Pooled analyses and trials in multiple myeloma and other settings use a 10^-5 sensitivity threshold for defining MRD negativity in some study protocols.

Example — 10^-6NGS assays (including clonoSEQ) have been used to define MRD negativity at ~10^-6 in CLL and ALL studies, with prognostic differences observed compared with 10^-4 assessments.

DTA mutations — clonal hematopoiesis note

DTA gene setDNMT3A, TET2, ASXL1 (collectively 'DTA' mutations) are noted as commonly persisting after therapy and frequently represent age‑related clonal hematopoiesis rather than leukemic MRD.

ImplicationExcluding DTA mutations from MRD interpretation improves specificity for detecting leukemic residual disease and predicting relapse.

Study supportJongen‑Lavrencic et al. reported high persistence of DTA mutations (78.9%) compared with lower persistence for RAS pathway mutations.

MRD — quick reference

TermMeasurable Residual Disease (MRD): very small numbers of cancer cells detectable during or after treatment using sensitive laboratory methods.

Common usesUsed for prognosis, monitoring treatment response, and guiding clinical decision‑making within disease‑specific guidance and trial contexts.

Detection methodsDetected by PCR, flow cytometry, or NGS-based assays.

IGHV mutation status — definition and prognostic role

DefinitionIGHV mutation status refers to the mutation status of the immunoglobulin heavy chain variable region gene, used for prognostication in CLL.

Prognostic roleMutated IGHV is associated with higher likelihood of achieving undetectable MRD by sensitive NGS assays post‑treatment compared with unmutated IGHV (Thompson et al.).

Guideline contextNCCN recommends IGHV and other molecular tests for prognostication and treatment planning in CLL.

clonoSEQ — named assay reference

Assay nameclonoSEQ® (Adaptive Biotechnologies) is the named FDA‑cleared commercial NGS assay referenced for clonality assessment and MRD evaluation in the policy.

Policy roleclonoSEQ is specified for clonality assessment at diagnosis and MRD assessment in B‑ALL, MM, and CLL; molecular tests other than clonoSEQ are considered unproven for these uses.

Evidence summaryHayes and multiple clinical studies cited in the policy evaluate clonoSEQ's higher sensitivity versus PCR/flow cytometry, though direct evidence of improved outcomes from testing is limited.

CGP — example platforms

ExamplesPolicy‑cited examples of Comprehensive Genomic Profiling platforms include FoundationOne Heme, Neo Comprehensive - Heme Cancers, and NEO AML Express.

Use casesThese CGP platforms are referenced as proven and medically necessary for individuals with ALL, AML, MDS, or myeloproliferative neoplasm when ordered by a hematologist/oncologist.

Relation to CGP definitionThese examples illustrate CGP's role as broad NGS assays that detect multiple classes of genomic alterations from a single sample.