ModifiedUnitedHealthcarePolicy CS372NJ.E

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

This New Jersey–only UnitedHealthcare medical policy governs coverage of molecular and genomic testing (including multi-gene panels, comprehensive genomic profiling, and MRD/clonality assays) for diagnosis, prognosis, and treatment decisions in hematologic malignancies when ordered by hematologists/oncologists.

Policy Summary

PayerUnitedHealthcare

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

Policy CodePolicy CS372NJ.E

Change TypeCoverage criteria revised and additions (multigene panel clarification, clonoSEQ criterion added)

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 to meet coverage criteria.

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 the listed hematologic conditions.

Revised coverage criteria for use of multigene panels (50 genes or fewer) at initial diagnosis and/or recurrence or relapse, replacing prior wording about suspected MDS/MPN order origin with a clarified diagnostic criterion tied to hematologist/oncologist orders.

Added criterion requiring the individual has chronic lymphocytic leukemia for clonoSEQ at initial diagnosis and MRD assessment.

Expanded statement that Comprehensive Genomic Profiling (CGP) is proven and medically necessary for individuals with ALL, AML, MDS, or myeloproliferative neoplasm (examples: FoundationOne Heme, Neo Comprehensive - Heme Cancers, NEO AML Express).

Replaced prior, narrower wording to state that molecular tests other than clonoSEQ are unproven and not medically necessary for initial clonality assessment or MRD assessment.

Added notation that CPT codes 0485U, 0560U, 0561U, and 81195 are not on the State of New Jersey Medicaid Fee Schedule and may not be covered by the New Jersey Medicaid Program.

Added medical records documentation language indicating benefit coverage is determined by federal/state/contractual requirements and that medical records may be required to assess clinical criteria for coverage.

Removed list examples of unproven and not medically necessary molecular tests for assessment of MRD (editorial cleanup).

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≤50panel gene threshold

97.3%alterations identified (HM‑SCREENJapan)

13 daysmedian TAT (FoundationOne Heme)

81%MASTER trial MRD <10^-5

4NJ Medicaid-excluded CPT codes

Coverage Criteria and Clinical Context

Multigene panels (<=50 genes)

Covered when ALL of the following are met

Multigene panels at initial diagnosis/recurrence: Use of a multigene NGS panel (50 genes or fewer) 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; multiple myeloma; or when myelodysplastic syndrome or myeloproliferative neoplasm is suspected (as evidenced by an order from a hematologist or oncologist).panel size <= 50 genes

Order must come from a hematologist or oncologist

Comprehensive Genomic Profiling (CGP)

Covered when ALL of the following are met

Comprehensive Genomic Profiling (CGP) (examples: FoundationOne Heme, Neo Comprehensive - Heme Cancers, 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; or myeloproliferative neoplasm.CGP test

Examples provided in policy; order must come from a hematologist or oncologist

clonoSEQ clonality and MRD testing

Covered when ALL of the following are met

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 individuals with any of the following: acute lymphoblastic leukemia; multiple myeloma; chronic lymphocytic leukemia (criterion added).clonoSEQ assay

Molecular tests other than clonoSEQ are considered unproven and not medically necessary for initial clonality assessment or MRD assessment; order must come from a hematologist or oncologist

Guideline and trial contexts where MRD is used

Clinical guideline and trial-derived contexts where MRD assessment is recommended or studied

ASCO/CCR guidance for multiple myeloma: ASCO/CCR guidance states there is insufficient evidence to modify maintenance therapy based on MRD status; MRD-negative status is prognostic but should not be used to guide treatment outside clinical trials; depth of response should be assessed regularly (minimum every 3 months once best response attained).

Emphasizes prognostic value but advises against routine MRD-directed therapy changes outside trials.

Wierda et al. CLL consensus: Consensus recommendations note undetectable MRD at end of treatment is prognostic in CLL and call for standardized nomenclature, methodology, sampling, and timing (at least 2 months after completion of treatment and aligned with response assessment); routine MRD testing in clinical practice is not currently recommended outside trials.

Consensus from expert panel; MRD mainly used in trials.

ALL timing and recommendations: For adults with ALL, guideline authors recommend bone marrow MRD assessment after completion of induction, in early consolidation (~3 months after start), and approximately every 3 months for at least 3 years; NGS is promising but requires larger prospective study before routine adoption.

Trial MRD decision algorithms

Examples of MRD-guided therapy decision rules used in clinical trials

FLAIR trial MRD-guided therapy: In the FLAIR trial, the ibrutinib-venetoclax arm used MRD testing to determine treatment duration (MRD-guided therapy); MRD-guided ibrutinib-venetoclax demonstrated superior progression-free survival and overall survival compared with FCR (e.g., 3-year PFS 97.2% vs. 76.8%).

Length of therapy adapted according to MRD results in trial setting.

MASTER trial MRD-adapted stopping rule: In the MASTER trial, participants attaining MRD-negativity (<10^-5) during or after consolidation who achieved MRD-SURE discontinued Dara-KRd and entered observation; participants without two consecutive MRD-negative findings started lenalidomide maintenance.MRD < 1e-5

Used to stop or continue therapy in trial setting.

Covered testing and conditions

Covered when ALL of the following are met for specified hematologic malignancy contexts (per guideline-aligned policy language):

Required diagnostic laboratory evaluation for acute leukemias: Pathologists or treating clinicians should obtain sufficient samples and perform conventional cytogenetic analysis (karyotype), appropriate molecular-genetic and/or FISH testing, and flow cytometric immunophenotyping for initial diagnosis; molecular/FISH testing does not replace conventional cytogenetics.

CAP/ASH Statement 5 (strong recommendation).

Extramedullary disease specimen processing: For extramedullary presentations without bone marrow or blood involvement, tissue biopsy should be processed for morphologic, immunophenotypic, cytogenetic, and molecular genetic studies as would be performed for bone marrow specimens.

CAP/ASH Statement 11 (strong recommendation).

MRD assay sensitivity requirement by disease: Use validated MRD assessment technology with sensitivity of 10^-4 or better for ALL; for CLL use assays with sensitivity of 10^-4 per ERIC or standardized NGS methods; NGS assays may achieve sensitivity to 10^-6.

Covered Tests and Uses

Covered when ordered by a hematologist or oncologist for specified hematologic malignancies

Multigene panels (≤50 genes): 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 hematologic conditions.panel size ≤50 genes

Applies at initial diagnosis and/or recurrence/relapse; order must come from a hematologist or oncologist

Comprehensive Genomic Profiling (CGP): Comprehensive Genomic Profiling (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.

Examples are illustrative; order must come from a hematologist or oncologist

clonoSEQ is proven and medically necessary for clonality assessment at initial diagnosis and for MRD assessment when the individual has chronic lymphocytic leukemia, acute lymphoblastic leukemia, or multiple myeloma.

Due to insufficient evidence of clinical benefit, all other molecular test panels for hematologic cancer that are not specified as proven in this policy are considered unproven and not medically necessary. Examples explicitly noted in the policy include optical genome mapping and whole transcriptome sequencing, but the exclusion applies to other molecular panels not designated as covered.

The joint ASCO/CCR guideline concludes there is insufficient evidence to change maintenance therapy or length of therapy based on depth of response or MRD status outside of a clinical trial setting. MRD has prognostic value, but the guideline advises that MRD should not be used to guide therapy decisions in routine practice outside of trials.

FDA clearance or approval is provided for informational purposes only; FDA approval alone is not a basis for coverage. Laboratory regulation under CLIA is noted as informational and does not, by itself, determine coverage eligibility.

The policy specifies that molecular tests other than clonoSEQ are considered unproven and not medically necessary for either initial clonality assessment or for measurement of MRD. clonoSEQ is the named assay identified as proven when criteria are met.

Reiterating the coverage rationale, the use of molecular tests other than clonoSEQ for initial clonality testing or MRD assessment is unproven and not medically necessary and therefore not supported for coverage under this policy.

Guideline authors note that while undetectable MRD is prognostic in certain diseases, current guidance does not support routine MRD-guided treatment changes in clinical practice. Specifically, ASCO/CCR state there is insufficient evidence to modify maintenance therapy based on MRD in multiple myeloma, and consensus guidance in CLL recommends standardized methods and acknowledges that routine MRD testing in practice is not currently recommended outside of trials.

The NCCN and other guideline panels note that standard NGS testing is not designed for MRD assessment due to inferior sensitivity. Established MRD methods—such as targeted PCR and multicolor flow cytometry—are commonly used, and MRD assays intended for monitoring should meet validated sensitivity requirements (often cited in the range of 10^-4 to 10^-6).

To clarify policy stance: except for the named and specified assay clonoSEQ, the policy considers other molecular assays for clonality or MRD assessment to be unproven and not medically necessary and therefore not covered for those indications.

Covered Indications and Clinical Scenarios

Acute lymphoblastic leukemia, acute myeloid leukemia, multiple myeloma, myelodysplastic syndrome, and myeloproliferative neoplasm

Covered when ALL of the following are met

Acute lymphoblastic leukemia (ALL): Permitted tests: multigene panels (≤50 genes) for diagnostic/prognostic characterization; CGP when indicated; MRD and clonality testing with clonoSEQ for diagnosis and monitoring as specified by disease guidelines and policy criteria.panel size ≤50 genes; validated MRD sensitivity (eg >=1e-4)

Ordering must be by a hematologist or oncologist; follow disease-specific MRD timing per guidelines.

Acute myeloid leukemia (AML): Permitted tests: multigene panels (≤50 genes) for diagnostic and relapse profiling; CGP for AML management; MRD assessment per NCCN guidance (use validated methods; standard NGS not adequate unless validated for MRD).panel size ≤50 genes; validated MRD sensitivity

Ordering must be by a hematologist or oncologist; consider participation in clinical trials for MRD-directed decisions.

Coding, Panel Size, and Assay Sensitivity

Applicable molecular oncology codesmixed

0017M	Oncology (diffuse large B-cell lymphoma [DLBCL]), mRNA, gene expression profiling by fluorescent probe hybridization of 20 genes, algorithm reported as cell of origin
0050U	Targeted genomic sequence analysis panel, acute myelogenous leukemia, DNA analysis, 194 genes
0120U	Oncology (B-cell lymphoma classification), mRNA, gene expression profiling by fluorescent probe hybridization of 58 genes
0171U	Targeted genomic sequence analysis panel, acute myeloid leukemia, myelodysplastic syndrome, and myeloproliferative neoplasms, DNA analysis, 23 genes
0298U	Oncology (pan tumor), whole transcriptome sequencing of paired malignant and normal RNA specimens
0299U	Oncology (pan tumor), whole genome optical genome mapping of paired malignant and normal DNA specimens
0300U	Oncology (pan tumor), whole genome sequencing and optical genome mapping of paired malignant and normal DNA specimens
0331U	Oncology (hematolymphoid neoplasia), optical genome mapping for copy number alterations and gene rearrangements
0364U	Oncology (hematolymphoid neoplasm), genomic sequence analysis with algorithm, quantification of dominant clonal sequence(s) for MRD
0413U	Oncology (hematolymphoid neoplasm), optical genome mapping for copy number alterations, aneuploidy, and balanced/complex structural rearrangements

1–10 of 20

1/2

Applicable Codes with NJ Medicaid fee schedule noteCPT

0485U	CPT code noted as not on NJ Medicaid Fee Schedule
0560U	CPT code noted as not on NJ Medicaid Fee Schedule
0561U	CPT code noted as not on NJ Medicaid Fee Schedule
81195	CPT code noted as not on NJ Medicaid Fee Schedule

Panel gene count threshold

Policy thresholdMultigene panels of 50 genes or fewer are specified as proven and medically necessary at initial diagnosis and/or recurrence or relapse when ordered by a hematologist or oncologist.

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

Ordering requirementOrder must be placed by a hematologist or oncologist to meet coverage criteria for ≤50-gene panels.

Policy change noteClarified and added 02/01/2026: explicit statement that multigene panels (50 genes or fewer) are proven and medically necessary in listed indications.

MRD analytic sensitivity / thresholds referenced

Provider Ordering, Documentation, and Denial Risk

Note

Prior Authorization

No prior authorization requirement is specified in this policy for the tests and indications described. Regulatory clearances (for example, FDA clearance of clonoSEQ) are discussed in the clinical rationale, but there is no explicit payer prior authorization rule documented here—providers should follow normal plan authorization workflows if required by the member's benefit plan.

Documentation Required

Ordering by Hematologist or Oncologist Required

Coverage for multigene panels (50 genes or fewer) and for clonoSEQ (clonality and MRD) is limited to orders placed by a hematologist or oncologist. Orders originating from other specialties may not meet the coverage criteria.

Applies to multigene panels (50 genes or fewer) at initial diagnosis and/or recurrence/relapse.
Applies to clonoSEQ for clonality assessment and MRD assessment.

Tests and Uses Considered Not Medically Necessary

The following technologies are explicitly listed as not covered because they are unproven for the intended hematologic oncology uses: optical genome mapping, whole transcriptome sequencing, and other molecular panels not specified as covered in this policy.

Changes to maintenance therapy or duration of therapy in multiple myeloma based solely on MRD status are not supported by the available evidence; therefore, using MRD results to alter maintenance treatment or its length is not supported and not covered by this policy outside of a clinical trial.

Because standard NGS methods often lack validated analytic sensitivity for MRD purposes, such methods are considered inadequate for MRD assessment unless specifically validated to the required sensitivity. Use of unvalidated NGS approaches for MRD may be considered not covered for MRD testing.

Molecular tests other than clonoSEQ for initial clonality assessment or for MRD monitoring are considered unproven and not medically necessary and are therefore not covered in these contexts.

Definitions and Assay Names

Comprehensive Genomic Profiling (CGP)

DefinitionComprehensive Genomic Profiling (CGP): a type of Next-Generation Sequencing (NGS) test that detects all classes of genomic alterations, including cancer biomarkers, from a single sample.

Policy examplesPolicy cites CGP examples such as FoundationOne Heme, Neo Comprehensive - Heme Cancers, and NEO AML Express as illustrative CGP tests.

Intended useCGP is described in policy as proven and medically necessary for individuals with ALL, AML, MDS, or myeloproliferative neoplasm.

Measurable Residual Disease (MRD)

DefinitionMeasurable Residual Disease (MRD): very small number of cancer cells or cell contents detectable during or after treatment, not evident by routine morphology; used primarily in blood cancers to assess depth of response and relapse risk.

Assessment methods

Background and Evidence Context

Hematologic cancers arise from blood-forming tissues such as bone marrow and immune system cells. Molecular profiling using NGS and related technologies can range from small targeted panels to comprehensive genomic profiling and may inform prognosis and targeted therapy selection. Measurable Residual Disease (MRD) refers to very small numbers of residual cancer cells detectable after treatment and is used as a prognostic marker and for monitoring, but its role in guiding routine therapy is evolving.

Policy Summary

PayerUnitedHealthcare

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

Policy CodePolicy CS372NJ.E

Change TypeCoverage criteria revised and additions (multigene panel clarification, clonoSEQ criterion added)

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 to meet coverage criteria.

SourceLink

On This Page

Timing and specimen guidance specified.

sensitivity >= 1e-4 (preferred up to 1e-6)

NCCN recommendations.

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

Policy revision effective 02/01/2026.

Disease-specific recommended testing examples: Guidelines recommend disease-specific molecular testing: comprehensive NGS and FISH/RT-PCR for ALL; multiplex/targeted NGS panels for AML and relapse profiling; FISH, TP53 sequencing and IGHV for CLL; gene panels including JAK2/CALR/MPL for MPN and appropriate panels for MDS and MM.

Multiple NCCN guideline citations.

Molecular tests other than clonoSEQ are considered unproven and not medically necessary for initial clonality assessment or MRD assessment; order must come from a hematologist or oncologist

Multiple myeloma (MM): Permitted tests: multigene panels (≤50 genes) for diagnostic/prognostic purposes; baseline clonotype identification and sample storage for future clonoSEQ MRD testing; clonoSEQ MRD assessment when ordered by hematologist/oncologist.panel size ≤50 genes

ASCO/CCR advises against changing maintenance therapy based on MRD outside trials; follow guideline timing for MRD assessment.

Myelodysplastic syndrome (MDS) and myeloproliferative neoplasm (MPN): Permitted tests: multigene panels (≤50 genes) for diagnostic evaluation when MDS/MPN suspected; CGP indicated for MDS/MPN per policy examples; targeted testing for JAK2/CALR/MPL and other guideline-recommended genes.panel size ≤50 genes

Order must come from a hematologist or oncologist; molecular testing complements but does not replace cytogenetics.

MRD assessment for prognostication and monitoring in B-ALL, MM, CLL, and AML

Covered when ALL of the following are met

MRD for prognostication and monitoring: NGS MRD assays (for example, clonoSEQ) have demonstrated prognostic associations in B-ALL, MM, CLL, and AML; clonoSEQ has FDA clearance for MRD detection/monitoring in relevant indications, and MRD negativity is associated with improved outcomes in multiple studies.use validated assay sensitivity (eg >=1e-4; NGS may reach 1e-6)

Use of MRD to direct therapy is primarily in clinical trials; routine MRD-guided therapy changes are not generally recommended outside trials.

Limitations and assay selection: Standard (non-validated) NGS methods without demonstrated MRD-level sensitivity are not appropriate for MRD purposes; choose assays with established analytic and clinical validity for MRD detection.validated MRD sensitivity required

MFC, ASO-PCR, and standardized NGS/ERIC methods are noted; NGS assays may provide higher sensitivity.

Initial diagnosis, recurrence/relapse, and ongoing management

Covered when ALL of the following are met

Multigene panels (≤50 genes) for initial diagnosis and recurrence/relapse: Multigene panels (50 genes or fewer) are proven and medically necessary at initial diagnosis and for recurrence/relapse when ordered by a hematologist or oncologist for hematologic malignancies (ALL, AML, CLL, MDS/MPN, MM).panel size ≤50 genes

Order must come from a hematologist or oncologist

CGP for specified indications: Comprehensive Genomic Profiling is proven and medically necessary for ALL, AML, MDS, and MPN when ordered by a hematologist or oncologist; named examples in policy are illustrative.CGP test

Order must come from a hematologist or oncologist

Covered indications for initial diagnosis, recurrence/relapse, or relapsed/recurrent disease

Covered when ALL of the following are met

Indications covered (summary): Multigene panels (≤50 genes), Comprehensive Genomic Profiling (CGP), and clonoSEQ for clonality/MRD are covered for initial diagnosis, recurrence/relapse, or relapsed/recurrent disease in hematologic malignancies including acute lymphoblastic leukemia, acute myeloid leukemia, myelodysplastic syndrome, myeloproliferative neoplasm, chronic lymphocytic leukemia, and multiple myeloma when ordered by a hematologist or oncologist and when testing informs prognosis or treatment.see individual test thresholds (eg panel size ≤50 genes; validated MRD sensitivity)

Ordering must be by a hematologist or oncologist; molecular tests other than clonoSEQ are unproven for initial clonality/MRD assessment.

Common analytic thresholds referenced

10^-4, 10^-5, 10^-6, and 0.1% (0.001).

CLL study exampleCLL14 defined MRD response as peripheral blood <10^-6 and MRD non-response as ≥10^-4; MRD negativity at these thresholds associated with longer PFS.

MASTER trial exampleMASTER used MRD <10^-5 as the primary MRD-negative endpoint to inform treatment discontinuation (MRD-SURE).

Multiple myeloma pooled analysisPOLLUX/CASTOR/ALCYONE/MAIA pooled analysis used NGS MRD sensitivity threshold of 10^-5 to assess association with PFS.

MRD assay sensitivity

Compact sensitivity rangeMRD assay analytical sensitivity documented as approximately 10^-4 to 10^-6.

NCCN guidance (ALL)NCCN recommends validated MRD assessment technology with sensitivity of 10^-4 or better for ALL; FDA-approved NGS assays may be used to confirm flow cytometry negativity.

NCCN guidance (CLL)NCCN notes NGS-based assays can detect to 10^-6 and recommends assays with sensitivity of at least 10^-4 (ERIC or standardized NGS methods) for CLL.

Multigene panel size

Policy threshold reiteratedMultigene panel size of 50 genes or fewer is the policy-specified threshold for proven and medically necessary coverage.

IndicationsCovered for initial diagnosis and/or recurrence/relapse in listed hematologic malignancies when ordered by a hematologist/oncologist.

Relation to codingCPT panel codes for 5-50 gene panels (e.g., 81450/81451) align with the policy's ≤50-gene coverage threshold.

Denial Risk

Potential Denial for Nonconforming Multigene Panel Orders

Multigene panel orders that do not conform to the policy limits (for example, panels larger than 50 genes or orders not placed by a hematologist/oncologist) risk denial as not meeting medical necessity criteria.

Potential denial applies when panel size exceeds 50 genes.
Potential denial applies when ordering clinician is not a hematologist/oncologist.

Documentation Required

Specimen and Medical Records Documentation Guidance

Medical records and specimen documentation must support the medical necessity of testing. Ensure adequate sample collection and that diagnostic testing performed at initial evaluation is complete and available for review.

Documentation must include relevant medical history, physical exam, and results of pertinent diagnostic tests or procedures.
Obtain sufficient samples and perform conventional cytogenetic analysis (karyotype), appropriate molecular-genetic and/or FISH testing, and flow cytometry as recommended by CAP/ASH guidance.
For extramedullary presentations, biopsy tissue should be processed for morphologic, immunophenotypic, cytogenetic, and molecular genetic studies and documentation provided.
Records must be legible, maintained in the patient's medical record, and made available upon request.

Note

Therapy Decisions Informed by MRD in Trials

MRD-guided therapy modifications have been used in clinical trials (for example, MRD-adapted discontinuation of therapy in the MASTER trial for multiple myeloma), but trial designs and populations may not generalize to routine clinical practice.

Therapy decisions in trials used serial NGS MRD testing to stop or continue treatment based on consecutive MRD results.
Evidence supporting improved clinical outcomes from routine MRD-guided therapy changes remains evolving.

Note

Clinical Trial Consideration for MRD in AML

For AML and other hematologic malignancies where the role of MRD is evolving, clinicians are encouraged to consider enrollment in clinical trials when MRD assessment is being used to guide prognosis or treatment decisions.

NCCN notes the role of MRD in AML is evolving and encourages clinical trial participation.
Standard NGS is not designed for MRD assessment due to inferior sensitivity; use validated MRD methods when available.

Current MRD assessments use real-time quantitative PCR, multiparametric flow cytometry, and/or NGS.

Clinical significanceResidual disease detected by MRD testing can be associated with earlier relapse or recurrence and informs prognosis and treatment planning in hematologic malignancies.

Next Generation Sequencing (NGS)

DefinitionNext Generation Sequencing (NGS): sequencing techniques that rapidly analyze multiple DNA regions simultaneously, enabling multi-gene and panel testing.

Role in MRD and CGPNGS underpins CGP and high-sensitivity MRD assays; FDA-cleared NGS MRD assays are referenced in NCCN guidance for confirmation of flow cytometry results.

Clinical applicationNGS-based assays can detect MRD to levels as low as 10^-6 depending on the assay and are used for genomic profiling and MRD monitoring in hematologic cancers.

Analytical sensitivity comparison

Flow cytometry (FC)Analytical sensitivity approximately 1 x 10^-4 (0.01%).

ASO-PCRAnalytical sensitivity approximately 1 x 10^-3 (0.001%) and requires patient-specific probes.

NGS-based MRD assaysNGS MRD assays can achieve greater sensitivity (documented to 10^-5 to 10^-6) and identify MRD missed by FC; highlight: NGS can detect MRD to 10^-6 in some assays.

MRD-SURE (MASTER trial concept)

MRD-SURE definitionMRD-SURE (as used in the MASTER trial): a protocol-defined observation state entered after attaining consecutive MRD-negative results (MRD <10^-5) during/after consolidation, at which Dara-KRd therapy was discontinued and observation with MRD monitoring continued.

Trial-specific actionIn MASTER, participants without two consecutive MRD-negative findings began lenalidomide maintenance; MRD-SURE defined a pathway for therapy termination in many participants.

Outcome contextAmong MRD-evaluable participants in MASTER, 81% achieved MRD <10^-5 and 71% reached MRD-SURE, with most remaining therapy-free and MRD-negative at follow-up.

MRD — brief definition

Short labelMRD = Measurable Residual Disease (small numbers of cancer cells detectable after treatment).

SynonymAlso referred to as minimal residual disease.

Clinical useUsed for prognosis and monitoring in hematologic malignancies; assessed via PCR, flow cytometry, or NGS.

clonoSEQ (named assay)

clonoSEQ — assay identityclonoSEQ (Adaptive Biotechnologies): a named, FDA-referenced NGS assay specified for clonality assessment at diagnosis and for MRD monitoring in hematologic malignancies.

Policy rolePolicy specifies clonoSEQ as proven and medically necessary for clonality assessment at initial diagnosis and for MRD assessment when ordered by a hematologist/oncologist for ALL, MM, or CLL (CLL criterion added).

Comparative performanceclonoSEQ is cited as a very sensitive NGS MRD assay used in studies demonstrating prognostic associations and greater sensitivity compared with flow cytometry in some settings.

CGP — named examples

CGP examples cited in policyExamples of Comprehensive Genomic Profiling (CGP) named in the policy include FoundationOne Heme, Neo Comprehensive - Heme Cancers, and NEO AML Express.

Intended useThese CGP examples are presented as proven and medically necessary for individuals with ALL, AML, MDS, or myeloproliferative neoplasm.

Policy noteExamples are illustrative and used in policy rationale to clarify CGP coverage scope.