ModifiedColorado Rocky Mountain Health PlansPolicy 2026T0652H

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

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Defines medical necessity and coverage rationale for multigene panels, comprehensive genomic profiling, clonality and MRD testing in hematologic malignancies for UnitedHealthcare Commercial and Individual Exchange members; applies when ordered by hematologist/oncologist.

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ModifiedColorado Rocky Mountain Health PlansPolicy 2026T0652H

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

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Policy Summary

PayerColorado Rocky Mountain Health Plans

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

Policy CodePolicy 2026T0652H

Change TypeCoding updateadded CPT-like U-codes

Effective DateAug 1, 2026

Last ReviewAug 1, 2026

Next Review Date

Key ActionOrder multigene panels and CGP only when requested by a hematologist or oncologist and verify member-plan prior authorization and coverage for newly added codes.

SourceLink

POLICY UPDATE CHANGES

Updated list of applicable CPT codes to reflect quarterly edits; added 0644U and 0645U.

Supporting Information archived previous policy version 2026T0652G.

≤50Covered panels ≤

5-50 genesPanel definition

3 examplesNamed CGP examples

2New U-codes added

13 daysMedian TAT example

Coverage Criteria and Evidence Contexts

Multigene panel and CGP coverage for specific hematologic cancers

Covered when ALL of the following are met

Initial/recurrence 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 for individuals with any of the following: Acute myeloid leukemia; Myelodysplastic syndrome or myeloproliferative neoplasm is suspected; Acute lymphoblastic leukemia; Multiple myeloma.panels ≤50 genes

source: chunks 4, 6

Comprehensive Genomic Profiling (CGP): Use of Comprehensive Genomic Profiling (CGP) (for example, FoundationOne Heme, Neo Comprehensive-Heme, NEO AML Express) is proven and medically necessary when ordered by a hematologist or oncologist for individuals with any of the following: Acute lymphoblastic leukemia; Acute myeloid leukemia; Myelodysplastic syndrome; Myeloproliferative neoplasm.per test design

source: chunk 6

Clonality 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 listed hematologic malignancies.assay-specific (clonoSEQ)

source: chunk 6

Unproven / Not medically necessary

Other molecular tests for clonality/MRD: The use of molecular tests other than clonoSEQ is unproven and not medically necessary for initial clonality assessment or for assessment of MRD.n/a

source: chunk 9

All other molecular test panels: Due to insufficient evidence of efficacy, all other molecular test panels for hematologic cancer are unproven and not medically necessary (examples include optical genome mapping and whole transcriptome sequencing).n/a

source: chunk 9

Evidence contexts supporting testing

Clinical trial and evidence contexts where MRD or multi-gene testing informed management or prognosis

MRD prognostic association: MRD negativity measured by sensitive assays is associated with improved progression-free survival and overall survival across CLL, ALL, AML, and multiple myeloma in multiple trials and meta-analyses; referenced analytic sensitivities vary (eg, 10^-4 to 10^-6).varies (10^-4 to 10^-6)

See CLL meta-analysis, AML systematic review, and individual trials cited.

MRD-guided therapy decisions in trials: Randomized and nonrandomized trials used MRD results to guide therapy duration or cessation (examples include FLAIR, trials of zanubrutinib/venetoclax/obinutuzumab, and the MASTER trial); MRD-guided strategies produced improved PFS or permitted time-limited therapy in these study contexts.MRD thresholds as defined per trial (example: <10^-5 in MASTER)

Evidence supports MRD as a trial surrogate endpoint though routine clinical adoption varies.

Multi-gene panel actionable findings:

Guideline-supported indications

Coverage aligned with guideline-recommended use in the following contexts

Myelodysplastic Syndromes (MDS): Use of gene panels including the genes most frequently somatically mutated in MDS (bone marrow or peripheral blood) is endorsed to detect clonal hematopoiesis and aid in excluding benign causes of cytopenia; testing alone does not definitively diagnose MDS without clinical diagnostic criteria.

source: chunk 54 (NCCN v2.2025)

Myeloproliferative Neoplasms (MPN): Molecular testing for JAK2 V617F, CALR, MPL, JAK2 exon 12 or a multigene NGS panel including these genes is recommended during initial workup; NGS and karyotyping are recommended at diagnosis and as clinically indicated for prognostication (eg, myelofibrosis).

source: chunk 55 (NCCN v2.2025)

Multiple Myeloma: SNP arrays or NGS panels on bone marrow can provide additional risk categorization; baseline clonotype identification or storage of aspirate at diagnosis is recommended to permit future NGS-based MRD assessment.

source: chunk 56 (NCCN Multiple Myeloma guidance)

Optical genome mapping, whole transcriptome sequencing, and other broad molecular panels are listed in this policy as unproven and not medically necessary for clonality assessment or MRD evaluation in hematologic cancers. The policy text explicitly states that the use of molecular tests other than clonoSEQ for initial clonality assessment or MRD assessment is unproven and not medically necessary, and cites optical genome mapping and whole transcriptome sequencing as examples of tests considered not medically necessary.

The policy notes that evidence supporting routine use of broad multi-gene panels (for example, FoundationOne Heme and similar comprehensive panels) is limited in quality with respect to demonstrating improved clinical outcomes. Hayes and other evidence summaries reviewed in the policy identified that large panels detect potentially actionable alterations in a substantial proportion of patients, but peer-reviewed data showing that use of these panels improves patient outcomes are sparse or low quality; turnaround time and study design limitations are additional concerns.

The document warns that somatic mutation testing is typically not designed to detect germline mutations and therefore may be inadequate to identify heritable hematologic malignancy predisposition syndromes. When a hereditary predisposition is suspected, clinical correlation and consideration of germline-focused evaluation and counseling are recommended because somatic panels may miss germline variants.

Beyond clonoSEQ and the specific covered multigene and CGP uses described elsewhere in this policy, all other molecular test panels for hematologic cancer are considered unproven and not medically necessary. The policy explicitly lists optical genome mapping and whole transcriptome sequencing among examples of technologies for which evidence of clinical benefit is insufficient to support coverage.

Consensus and guideline authors note that while MRD status has prognostic significance in CLL and other hematologic malignancies, current recommendations do not support routine MRD testing in CLL outside of clinical trials. Expert consensus emphasizes need for standardized nomenclature, assay requirements, timing/frequency of assessment, and outcome reporting before MRD testing is adopted for routine clinical practice.

Covered Indications and Use Cases

Covered hematologic disease list

Covered hematologic disease list: Multigene panels (50 genes or fewer) are covered at initial diagnosis and/or recurrence for: Acute myeloid leukemia; Myelodysplastic syndrome or myeloproliferative neoplasm when suspected; Acute lymphoblastic leukemia; Multiple myeloma. Comprehensive Genomic Profiling (CGP) is covered for ALL, AML, MDS, and MPN when ordered by a hematologist or oncologist.panels ≤50 genes; CGP per test design

source: chunks 4 and 6

CGP examples and clonality: Named CGP examples include FoundationOne Heme, Neo Comprehensive-Heme, and NEO AML Express; clonality and MRD assessment with clonoSEQ are specified as medically necessary for indicated conditions.assay-specific

source: chunk 6

Use of multi-gene genomic profiling and MRD testing in trials to inform targeted therapy selection, prognosis, and guide therapy duration

Applicable Codes and Coding Guidance

Applicable Proprietary/Panel CPT Category III / U-codes (part 1)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

Applicable Proprietary/Panel CPT Category III / U-codes (part 2)mixed

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	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.
0485U	Oncology (solid tumor), cell-free DNA and RNA by next-generation sequencing, interpretative report for germline mutations, clonal hematopoiesis of indeterminate potential, and tumor-derived single- nucleotide variants, small

Applicable MRD and genomic panel CPT/HCPCS codesmixed

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.
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.
0644U	Oncology (leukemia), minimal residual disease (MRD) detection for rearrangements, blood or bone marrow, personalized assay design and baseline quantification.
0645U	Oncology (leukemia), minimal residual disease (MRD) detection for rearrangements, based on digital PCR, blood or bone marrow, reported as not detected or detected with estimated abundance.
81195	Cytogenomic (genome-wide) analysis, hematologic malignancy, structural variants and copy number variants, optical genome mapping (OGM).
81450	Hematolymphoid neoplasm or disorder, genomic sequence analysis panel, 5-50 genes, interrogation for sequence variants, and copy number variants or rearrangements, or isoform expression or mRNA expression levels, if performed; DNA analysis or combined DNA and RNA analysis.
81451	Hematolymphoid neoplasm or disorder, genomic sequence analysis panel, 5-50 genes, interrogation for sequence variants, and copy number variants or rearrangements, or isoform expression or mRNA expression levels, if performed; RNA analysis.
81455	Solid organ or hematolymphoid neoplasm or disorder, 51 or greater genes, genomic sequence analysis panel, interrogation for sequence variants and copy number variants or rearrangements, or isoform expression or mRNA expression levels, if performed; DNA analysis or combined DNA and

Additional applicable codesmixed

81456	Solid organ or hematolymphoid neoplasm or disorder, 51 or greater genes, genomic sequence analysis panel, interrogation for sequence variants and copy number variants or rearrangements, or isoform expression or mRNA expression levels, if performed; RNA analysis
81479	Unlisted molecular pathology procedure.
81599	Unlisted multianalyte assay with algorithmic analysis.

Procedural code referencesmixed

CPT mention

CPT is referenced generically (trademark) but no specific CPT/HCPCS codes are listed in these chunks.

Applicable CPT/CPT-like codes updatedCPT

0644U	CPT-like code added per policy history
0645U	CPT-like code added per policy history

Panel gene count threshold — inv-16: Covered multigene panels and coding guidance

Covered panel sizeMultigene panels of 5–50 genes are considered covered (panels ≤50 genes)

Panels >50 genes codingPanels with 51 or more genes should be reported/coded using 81455 (DNA or combined DNA/RNA) or 81456 (RNA) as applicable

Typical coding examplesUse 81450/81451 for hematolymphoid 5–50 gene panels; use 81455/81456 for 51+ gene panels

MRD sensitivity thresholds referenced — inv-17

Referenced sensitivitiesMRD sensitivity thresholds referenced in policy: 10^-4, 10^-5, and 10^-6

Provider Actions, Documentation, and Authorization Notes

Prior Authorization

Order tests only when ordered by a hematologist or oncologist

Testing covered under this policy must be ordered by a hematologist or oncologist for UnitedHealthcare Commercial and Individual Exchange members; multigene panels, CGP, and clonoSEQ claims should reflect ordering provider specialty.

Applies to UnitedHealthcare Commercial and Individual Exchange benefit plans.
Orders for covered indications must come from a hematologist or oncologist.

Note

No explicit prior authorization specified in this excerpt

The extracted policy text and evidence summaries in these document chunks do not state explicit prior authorization code-level requirements or an operational prior authorization process for these tests.

Clinical evidence and trial descriptions are presented but no explicit prior authorization instructions are included in these sections.

Not Covered / Investigational Uses

Use of molecular tests other than clonoSEQ for clonality or MRD assessment is not covered. All other molecular test panels for hematologic cancer — including but not limited to optical genome mapping and whole transcriptome sequencing — are considered unproven and not medically necessary and therefore are not covered under this policy.

Routine use of broad, off-the-shelf multi-gene panels to improve clinical outcomes is not established in the available literature. The policy highlights limited or low-quality evidence that large-panel testing (for example, FoundationOne Heme) leads to improved patient outcomes, and therefore routine coverage for that purpose is not supported.

Somatic mutation panels alone do not definitively establish a diagnosis of myelodysplastic syndrome in the absence of clinical diagnostic criteria. The NCCN guidance cited in the policy endorses gene panels to detect clonal hematopoiesis and aid evaluation, but emphasizes that genetic testing by itself is inadequate to diagnose MDS without correlating clinical and morphologic criteria.

Key Definitions

Comprehensive Genomic Profiling (CGP) definition — inv-31

DefinitionComprehensive Genomic Profiling (CGP) is an NGS test able to detect all classes of genomic alterations, including cancer biomarkers, with a single sample

ExamplesPolicy names CGP examples such as FoundationOne Heme, Neo Comprehensive‑Heme, and NEO AML Express

Use casesCGP is described as medically necessary for specified hematologic malignancies when ordered by a hematologist/oncologist

Measurable Residual Disease (MRD) definition — inv-32

DefinitionMeasurable Residual Disease (MRD) describes a very small number of cancer cells or cell contents detectable during or after treatment, measurable by PCR, multiparameter flow cytometry, and/or NGS

Clinical relevance

Background and Rationale

Hematologic cancers originate in blood-forming tissues and include entities such as leukemia, lymphoma, and multiple myeloma. Molecular profiling—from targeted single-gene assays to larger NGS panels and CGP—can assist with diagnosis, prognostication, and selection of targeted therapies in specific contexts. For myeloid neoplasms, multigene NGS panels have been shown to improve diagnostic and prognostic yield compared with limited single-gene testing, but the clinical utility for some broad-panel and novel technologies remains under evaluation.

Eligibility Requirements

No discrete top-level eligibility requirements are specified in the extracted portions of this policy. Refer to the member-specific benefit plan document and the policy sections describing covered indications (which require that tests be ordered by a hematologist or oncologist) for applicability and plan eligibility determinations.

This policy extract does not provide additional explicit eligibility criteria at the top level. Coverage decisions should be coordinated with the member-specific benefit plan and the clinical indications listed elsewhere in the policy (for example, multigene panels ≤50 genes at initial diagnosis/recurrence for specified hematologic malignancies).

No standalone prior-testing or family-history eligibility nodes are present in the provided extract. Clinicians should follow the policy’s covered indications and ordering requirements (tests ordered by hematologist/oncologist) and consult the full policy and member benefit documents for any additional plan-specific eligibility requirements.

Where eligibility questions remain, providers should verify coverage against the member’s benefit plan. The extract contains no additional top-level eligibility definitions; the full policy and plan documents govern final determinations.

Policy Summary

PayerColorado Rocky Mountain Health Plans

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

Policy CodePolicy 2026T0652H

Change TypeCoding updateadded CPT-like U-codes

Effective DateAug 1, 2026

Last ReviewAug 1, 2026

Next Review Date

Key ActionOrder multigene panels and CGP only when requested by a hematologist or oncologist and verify member-plan prior authorization and coverage for newly added codes.

SourceLink

On This Page

Large-panel genomic profiling (eg, FoundationOne Heme in HM-SCREENJapan 01) detects somatic mutations and fusions in a high proportion of participants and identifies potentially actionable alterations in a subset, informing targeted therapy selection or trial enrollment; however, evidence of improved clinical outcomes from broad panel use remains limited.

See HM-SCREENJapan 01 and related evidence summaries.

Use in trials to guide therapy selection and duration: Multi-gene genomic profiling and MRD testing were used in clinical trials to inform targeted therapy selection, prognostication, and to guide therapy duration or cessation (for example, FLAIR used MRD-guided ibrutinib-venetoclax; MASTER used NGS MRD to permit therapy discontinuation in multiple myeloma).trial-defined MRD thresholds

source: chunks 24, 25, 28

MRD-guided outcomes: Trials employing MRD-guided strategies reported improved progression-free survival or allowed time-limited therapy in selected populations, supporting the role of MRD in research and select clinical contexts.varies by trial

source: chunks 25, 28

Diagnostic evaluation and prognostication per NCCN guidance for MDS, MPN, myelofibrosis, and multiple myeloma

Diagnostic evaluation and prognostication per NCCN: Per NCCN guidance, diagnostic evaluation and prognostication for MDS, MPN (including myelofibrosis), and multiple myeloma may include targeted gene tests (eg, JAK2, CALR, MPL), NGS panels, karyotyping, and SNP arrays; NGS MRD assessment is recommended where indicated and baseline clonotype identification/storage is advised for future MRD testing in multiple myeloma.

source: chunks 54, 55, 56 (NCCN guidelines v2.2025/v2.2026)

0.1% threshold equivalenceA threshold of 0.1% corresponds to 10^-3 and is discussed in AML MRD analyses

Assay variability notePolicy notes that assays differ in detection limits and timing, affecting comparability of MRD results

Billing Rule

Verify member-plan coverage and prior auth for updated codes

CPT/CPT-like code list was updated in Policy History (adds 0644U and 0645U); providers must verify member-plan coverage and any prior authorization requirements with the member-specific benefit plan.

Operational coding update: 0644U and 0645U added (effective 08/01/2026).
Confirm coverage and any required prior authorization per the member-specific benefit plan before ordering.

Step Therapy

Prefer multigene panels (≤50 genes) at diagnosis/recurrence; use CGP where indicated

Use multigene panels of 50 genes or fewer at initial diagnosis or recurrence; Comprehensive Genomic Profiling (CGP) (e.g., FoundationOne Heme, Neo Comprehensive-Heme, NEO AML Express) is specified as medically necessary for listed hematologic malignancies when ordered by a hematologist/oncologist.

Covered indications include AML, ALL, MDS/MPN suspicion, and multiple myeloma.
CGP named as proven and medically necessary for ALL, AML, MDS, and MPN in the policy text.

Note

Document MRD-guided therapy duration decisions used in trials

MRD-guided, time-limited therapy strategies in trials used MRD results to determine duration of therapy (for example, discontinuation after achieving MRD-negative status in MASTER and MRD-guided ibrutinib–venetoclax in FLAIR).

When MRD-guided strategies are used clinically, document MRD timing and the decision to stop or continue therapy per trial-derived algorithms.
Evidence examples: MASTER used MRD <10^-5 to stop therapy; FLAIR used MRD to guide ibrutinib-venetoclax duration.

Note

Provider action placeholder — check member-specific plan

(Reserved) — no additional provider action text available in the cited chunks; refer to member-specific plan and policy sections for applicable requirements.

This placeholder is intentionally left for policy-specific operational instructions if defined elsewhere in the member-specific plan or policy.

Documentation Required

Be prepared to provide medical record documentation for coverage review

Medical records may be requested to determine whether the member meets clinical criteria; benefit coverage is determined by the member-specific benefit plan and applicable laws.

Medical records documentation may be required for review and does not guarantee coverage.
Reference the member-specific benefit plan document when assessing coverage.

Documentation Required

Document MRD assay, sensitivity, timing, and management decisions

For MRD-guided treatment strategies, documentation should include the MRD assay used, the assay sensitivity threshold (examples referenced: <10^-5 or 10^-6), the timing of MRD assessment, and resultant treatment decisions (e.g., discontinuation or initiation of maintenance).

Specify the MRD assay and analytic sensitivity (e.g., <10^-5).
Document timing of the MRD measurement and the clinical action taken based on the result.

Documentation Required

Use bone marrow aspirate/stored aspirate for baseline clonotype ID and confirm lab regulatory context

For baseline clonotype identification and some MRD assessments, bone marrow aspirate or stored aspirate samples are recommended; laboratories performing genetic tests are regulated under CLIA and FDA informational resources are referenced.

Baseline clonotype identification at diagnosis or storage of an aspirate is recommended to permit future NGS-based MRD testing.
Confirm laboratory regulatory status (CLIA) and consider specimen requirements (bone marrow aspirate or stored aspirate samples).

Denial Risk

Avoid non-clonoSEQ tests for clonality/MRD — denial risk

The policy states that molecular tests other than clonoSEQ for clonality or MRD assessment are unproven and not medically necessary; ordering such tests may result in denial of coverage.

Use of molecular tests other than clonoSEQ for initial clonality assessment or MRD is listed as unproven and not medically necessary.
Claims for non-clonoSEQ clonality/MRD assays may be denied per the policy.

Note

Assess turnaround time before ordering for urgent decisions

Consider test turnaround time when ordering genomic panels for urgent decisions; FoundationOne Heme reported an approximate median turnaround time of 13 days, which may be too long for urgent treatment choices.

If treatment decisions are time-sensitive, choose tests with appropriate turnaround times or document why a longer turnaround is clinically acceptable.

Note

Member-specific benefit plan governs coverage determinations

Coverage decisions must reference the member-specific benefit plan document; in case of conflict, the member-specific benefit plan governs and applicable federal/state mandates should be checked.

This Medical Policy provides guidance but the member-specific benefit plan controls coverage.
Verify applicable federal or state mandates before use.

Documentation Required

Consider germline evaluation and counseling when indicated

Somatic mutation testing may be inadequate to detect germline mutations; consider germline evaluation and genetic counseling when hereditary predisposition is suspected.

Somatic testing is typically not designed to detect germline variants and may miss heritable predisposition syndromes.
Refer for germline evaluation and counseling if clinical suspicion exists.

Prior Authorization

Ensure hematologist/oncologist orders for covered tests

Tests for covered indications must be ordered by a hematologist or oncologist; ensure orders reflect appropriate specialist involvement to meet policy criteria.

Ordering provider specialty is part of the coverage criteria for multigene panels, CGP, and clonoSEQ.

Note

MRD testing was clinician-ordered in trials; no formal prior-auth process stated here

In the trials cited, MRD testing was ordered and used by treating hematology/oncology teams to guide therapy; the policy text does not specify a formal operational prior authorization process for MRD testing in clinical practice.

Trial contexts used treating teams to order MRD and make treatment decisions.
No formal prior authorization workflow for MRD testing is described in these excerpts.

Note

Use independent medical judgment and confirm member-specific coverage

Providers should exercise independent professional medical judgment and verify coverage against the member-specific benefit plan; the policy is intended as informational and does not replace clinical judgment.

Use this policy alongside independent clinical judgment.
Always confirm member-specific coverage terms before proceeding.

Residual cancer detected by MRD assessment can be associated with earlier relapse and is used to inform treatment plans

Detection methodsCommon MRD assays include real‑time quantitative PCR, ASO‑PCR, multiparameter flow cytometry (MFC), and NGS

Next Generation Sequencing (NGS) definition — inv-33

DefinitionNext‑Generation Sequencing (NGS) refers to sequencing techniques that can quickly analyze multiple sections of DNA simultaneously

Role in policyNGS is the platform for CGP, many multigene panels, and high‑sensitivity MRD assays described in the policy

Comparative sensitivityNGS MRD assays can detect MRD at lower levels than standard flow cytometry or ASO‑PCR in some settings

clonoSEQ definition — inv-34

Definition and regulatory statusclonoSEQ is an FDA‑approved NGS assay for MRD detection in B‑ALL, multiple myeloma, and CLL

Analytic sensitivityHayes assessment cited that clonoSEQ demonstrates higher analytical sensitivity than flow cytometry or ASO‑PCR in CLL and MM

Intended usePolicy designates clonoSEQ as the proven and medically necessary assay for clonality assessment and MRD when ordered by a hematologist/oncologist

FoundationOne Heme definition — inv-35

DefinitionFoundationOne Heme is a comprehensive genomic profiling test that sequences DNA (hundreds of genes) and RNA fusions from hematologic malignancy specimens to identify potentially actionable alterations

Study usePolicy cites HM‑SCREENJapan 01 using FoundationOne Heme (DNA 437 genes, RNA 265 genes) demonstrating high feasibility and actionable findings

Turnaround time noteReported median turnaround time in cited studies was approximately 13 days, which may be too long for urgent decisions

MRD negativity thresholds — inv-36

MRD negativity levels referencedPolicy references MRD negativity thresholds of 10^-4, 10^-5, and 10^-6

Prognostic correlationDegree of MRD negativity is reported to correlate with improved progression‑free and overall survival across hematologic malignancies

Assay limitationsPolicy notes assays differ in detection limits and that absence of detectable MRD does not rule out residual disease

Clonal hematopoiesis — inv-37

DefinitionClonal hematopoiesis is the presence of somatic mutations detectable by gene panels that may help exclude benign causes of cytopenia but do not by themselves establish a diagnosis of malignancy such as MDS

Testing implicationSomatic testing may not detect germline mutations and therefore may be inadequate to identify hereditary predisposition syndromes

Guideline contextNCCN endorses use of gene panels to detect clonal hematopoiesis in MDS workup but cautions panels vary by composition

Baseline clonotype identification — inv-38

DefinitionBaseline clonotype identification refers to identifying or storing a bone marrow aspirate sample at diagnosis to permit future MRD assessment via NGS

NCCN recommendationNCCN Multiple Myeloma panel recommends baseline clonotype identification or storage of aspirate at diagnosis for later NGS MRD testing

Specimen useStored diagnostic material enables construction of personalized MRD assays and comparison to subsequent assessments