ModifiedUnitedHealthcarePolicy CS372ID.D

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

Policy governing medical necessity and coverage of molecular and genomic testing (including multigene panels, comprehensive genomic profiling, and MRD testing) for diagnosis, prognosis, and treatment decisions in hematologic cancers for Idaho (including Idaho Medicaid Plus).

Policy Summary

PayerUnitedHealthcare

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

Policy CodePolicy CS372ID.D

Change TypeMaterial revisions — coverage clarifications and code additions

Effective DateMay 1, 2026

Next Review DateN/A

Key ActionOrder multigene panels (≤50 genes), CGP, or clonoSEQ only when ordered by a hematologist or oncologist and document indication and sample adequacy to support medical necessity.

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 any of the listed conditions.

Replaced criterion requiring 'the individual has myelodysplastic syndrome or myeloproliferative neoplasm is strongly suspected (as evidenced by order from hematologist/oncologist)' with 'the individual has myelodysplastic syndrome or myeloproliferative neoplasm is suspected (as evidenced by order from hematologist/oncologist)'.

Added/clarified coverage language regarding clonality assessment and MRD assessment with clonoSEQ.

Replaced criterion requiring 'strongly suspected' myelodysplastic syndrome or myeloproliferative neoplasm with 'suspected' as evidenced by order from a hematologist/oncologist.

Added criterion requiring the individual has chronic lymphocytic leukemia.

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 and added NEO AML Express as an example.

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

Added CPT codes 0560U and 0561U to Applicable Codes.

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50upper size limit for covered multigene panels

clonoSEQsingle MRD/clonality assay specified

Idahopolicy geographic scope

2new CPT codes added

13dmedian CGP turnaround

98%proportion helpful in myeloid panel study

Coverage Criteria and Medical Necessity

Multigene panels (<=50 genes)

Covered when ordered by a hematologist or oncologist for individuals with the following hematologic malignancies:

Covered indications for multigene panels (<=50 genes): Acute lymphoblastic leukemia; OR Acute myeloid leukemia; OR Multiple myeloma; OR Myelodysplastic syndrome or myeloproliferative neoplasm is suspected (as evidenced by order from hematologist/oncologist)

Panels of 50 genes or fewer at initial diagnosis and/or recurrence/relapse are proven and medically necessary when ordered by a hematologist or oncologist.

Comprehensive Genomic Profiling (CGP)

Comprehensive Genomic Profiling (CGP) is proven and medically necessary when ordered by a hematologist or oncologist for individuals with any of:

Covered indications for CGP: Acute lymphoblastic leukemia; OR Acute myeloid leukemia; OR Myelodysplastic syndrome; OR Myeloproliferative neoplasm

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

Clonality and MRD using clonoSEQ

Clonality assessment and MRD assessment using clonoSEQ are proven and medically necessary when ordered by a hematologist or oncologist for individuals with any of:

clonoSEQ covered indications: Acute lymphoblastic leukemia; OR Multiple myeloma; OR Chronic lymphocytic leukemia

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

MRD prognostic and clinical-evidence criteria

MRD testing is supported as a prognostic tool in multiple hematologic malignancies when performed with validated assays and appropriate sample types, but routine treatment changes based solely on MRD are not universally recommended outside clinical trials.

General evidence: Multiple randomized trials, cohort studies, and meta-analyses show MRD negativity is associated with improved progression-free survival and overall survival across CLL, ALL, MM, and AML when measured with sensitive assays (NGS or flow cytometry).

See trials such as FLAIR, CLL14, MASTER and systematic reviews/meta-analyses.

Assay sensitivity matters: Higher-sensitivity assays (e.g., NGS with sensitivity down to 10^-6) detect residual disease missed by lower-sensitivity methods (e.g., flow cytometry at ~10^-4) and provide additional prognostic information.sensitivity 10^-4 to 10^-6

Examples: clonoSEQ and trial assay sensitivities reported in CLL14, MASTER, Short et al., and others.

Use in treatment adaptation: Some trials used MRD-guided treatment strategies (e.g., FLAIR, MASTER MRD‑SURE, MRD‑guided ibrutinib‑venetoclax) showing benefit in selected contexts, but guideline groups caution against routine MRD‑driven therapy changes outside of clinical trials.

Use of Multigene Panels (50 Genes or Fewer) at Initial Diagnosis and/or Recurrence or Relapse

Covered when ALL of the following are met

Multigene panel (<=50 genes) coverage: Panel is 50 genes or fewer AND ordered by a hematologist or oncologist AND indication is initial diagnosis or recurrence/relapse for a listed hematologic condition (e.g., AML, ALL, CLL, MDS, myeloproliferative neoplasm, MM).panel size <=50 genes

Policy revision (05/01/2026) softened wording to 'suspected' for MDS/MPN and clarifies ordering clinician requirement.

Clonality Assessment and MRD Assessment With clonoSEQ

Covered when ALL of the following are met

Clonality/MRD with clonoSEQ: clonoSEQ is used for clonality assessment at initial diagnosis or for MRD assessment consistent with disease‑specific guidance AND ordered by a hematologist or oncologist AND appropriate baseline diagnostic testing/sampling has been performed to permit MRD interpretation.assay-specific sensitivity per CLIA/FDA labeling; recommended sensitivity often 10^-4 or better

Policy specifies clonoSEQ as the validated assay for these indications; other molecular MRD tests are considered unproven.

Medically Necessary Criteria

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

Requires hematologist/oncologist order; policy revised 05/01/2026 to clarify 'suspected' language for MDS/MPN.

Comprehensive Genomic Profiling (CGP): 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.N/A

Examples of CGP provided in policy.

Clonality and MRD testing: clonoSEQ is specified as medically necessary for initial clonality assessment and for MRD assessment; molecular tests other than clonoSEQ are unproven and not medically necessary for these indications.

Molecular tests other than clonoSEQ for clonality determination or measurable residual disease (MRD) assessment are considered unproven and not medically necessary. The policy specifically identifies clonoSEQ as the validated assay for clonality assessment at initial diagnosis and for MRD assessment when ordered by a hematologist or oncologist; use of other molecular MRD/clonality assays for these purposes is not supported by sufficient evidence and therefore is not covered.

Separately, the policy states that, because evidence of clinical benefit is limited for many broad molecular approaches in hematologic cancers, all other molecular test panels not specifically designated as proven (for example, CGP and multigene panels when not meeting stated criteria) are considered unproven and not medically necessary.

Major guideline groups caution that MRD results alone should not routinely be used to change maintenance therapy or to alter the type or duration of therapy outside of a clinical trial. For example, ASCO/CCO guidance notes there is insufficient evidence to make modifications to maintenance therapy based solely on MRD status and recommends using MRD-guided treatment decisions primarily within clinical-trial contexts.

Although some clinical trials have used MRD to adapt or stop therapy, these trial contexts do not translate into broad practice recommendations; clinicians should not change therapy exclusively on the basis of MRD without supporting trial-based protocols or guideline endorsement.

Regulatory status is provided for information only: FDA approval or clearance alone is not a basis for coverage. Laboratory operation under CLIA is a regulatory requirement for clinical testing, but CLIA status or other laboratory regulatory listings do not by themselves determine medical necessity or coverage decisions.

The policy explicitly states that molecular tests other than clonoSEQ for initial clonality assessment or for assessment of MRD are unproven and not medically necessary. This explicit exclusion applies to use of alternative molecular MRD assays in place of clonoSEQ for clonality or MRD indications described in the policy.

All other molecular test panels for hematologic cancers that are not specifically listed as proven are considered unproven and not medically necessary. Examples called out in the policy include optical genome mapping and whole transcriptome sequencing, among other unspecified molecular panels that lack sufficient evidence for clinical utility in the covered indications.

Standard diagnostic NGS assays are generally not designed for MRD assessment because their analytical sensitivity is inferior to methods intended for MRD detection. The NCCN notes that standard NGS lacks the sensitivity required for reliable MRD measurement in many contexts, and therefore use of routine diagnostic NGS assays for MRD purposes may be inappropriate for MRD-driven clinical decision-making.

In AML and other diseases, targeted NGS panels developed for diagnostic profiling do not consistently reach the sensitivity thresholds recommended for MRD (commonly 10^-4 or better), limiting their suitability for MRD monitoring.

Reiterating the policy stance, molecular tests other than clonoSEQ are described as unproven and not medically necessary for initial clonality assessment and for MRD assessment. While clonoSEQ is identified as an accepted assay for clonality and MRD in specified diagnoses, other molecular MRD assays lack sufficient peer-reviewed evidence of clinical benefit to support coverage.

Covered Indications and Clinical Contexts

Specific hematologic malignancies (ALL, AML, MM, MDS, MPN)

Covered indications for specified hematologic malignancies (grouping for multigene panels, CGP, and clonoSEQ):

Listed hematologic malignancies: Acute lymphoblastic leukemia; OR Acute myeloid leukemia; OR Multiple myeloma; OR Myelodysplastic syndrome; OR Myeloproliferative neoplasm; OR Chronic lymphocytic leukemia

Multigene panels (<=50 genes) and CGP covered when ordered by a hematologist/oncologist for these conditions; clonoSEQ specified for clonality and MRD in select diagnoses.

MRD testing for prognosis and monitoring in B-ALL, multiple myeloma, CLL, and AML

MRD testing use cases supported by evidence include:

Prognosis and monitoring: MRD testing for prognosis and monitoring in B‑ALL, multiple myeloma, chronic lymphocytic leukemia, and acute myeloid leukemia to stratify relapse risk, inform clinical trial enrollment or decisions, and in some trials to guide therapy adaptation.

Trials include FLAIR, MASTER, pooled MM analyses, and AML meta‑analyses showing prognostic value linked to assay sensitivity.

Provider Actions, Documentation, and Ordering Requirements

Documentation Required

Medical records documentation requirement

Provide comprehensive diagnostic and sampling documentation when requesting coverage for molecular/genomic testing, multigene panels, or MRD assessment. Medical records must contain relevant medical history, physical examination, and results of pertinent diagnostic tests or procedures to support medical necessity. Documentation should be legible, maintained in the patient's medical record, and made available upon request.

Include medical history, physical exam, and pertinent diagnostic test results in submitted records.
Make records available upon request to support medical necessity determinations.
Insufficient documentation may result in denial or request for records.

Prior Authorization

Multigene panel ordering requirement

Orders for multigene panels (50 genes or fewer) and tests intended to support diagnosis of myelodysplastic syndrome (MDS) or myeloproliferative neoplasm (MPN) must be placed by a hematologist or oncologist. Coverage is contingent on the ordering clinician and the order must reflect an applicable hematologic indication.

Applicable Codes and Coding Notes

Applicable Codes (group 1)CPT

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

Applicable Codes (group 2)mixed

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	Oncology (hematolymphoid neoplasm), genomic sequence analysis using multiplex (PCR) and next-generation sequencing with algorithm, quantification of dominant clonal sequence(s), reported as presence or absence of minimal residual disease (MRD) with quantitation of disease burden, when appropriate.
0413U	Oncology (hematolymphoid neoplasm), optical genome mapping for copy number alterations, aneuploidy, and balanced/complex structural rearrangements, DNA from blood or bone marrow, report of clinically significant alterations.
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 insertions/deletions, copy number alterations, fusions, microsatellite instability, and tumor mutational burden.

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Applicable CPT Codes AddedCPT

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.

Panel gene count — definition/key values

Typical panel size rangeMultigene panels generally refer to panels containing five or more genes (typical operational range cited as 5–50 genes).

Policy upper limit for covered panelsPanels of 50 genes or fewer are specified in the policy as proven and medically necessary when ordered by a hematologist or oncologist for listed indications.

Context of useCovered at initial diagnosis and/or recurrence or relapse for specified hematologic malignancies when ordered by a hematologist or oncologist.

MRD assay sensitivity thresholds — reported ranges and cutoffs

Reported sensitivity rangeMRD assay sensitivities reported across studies and reviews range approximately from 10^-4 to 10^-6.

Services Not Covered or Considered Unproven

Not covered: molecular panels and technologies that are not designated as proven for the listed hematologic indications are considered not medically necessary. The policy specifically lists optical genome mapping and whole transcriptome sequencing as examples of technologies not covered for routine clinical use in hematologic cancers.

The policy also notes limited high-quality evidence that use of an MRD assay (including clonoSEQ in some contexts) to drive management improves clinical outcomes, reinforcing that many molecular panel uses remain investigational when intended to alter therapy outside of trial protocols.

Consistent with other sections, the policy disallows using standard diagnostic NGS assays for MRD assessment because of inadequate sensitivity; and reiterates that FDA approval or clearance alone is insufficient to establish coverage.

The policy recognizes that while MRD assays such as clonoSEQ provide prognostic information, there is limited high-quality evidence that use of MRD testing to direct management decisions improves clinical outcomes in all settings. This limitation underlies the recommendation that MRD-guided treatment changes be considered mainly in the context of clinical trials.

Use of standard diagnostic NGS assays for MRD assessment is discouraged because their sensitivity is typically inadequate for MRD purposes. The policy emphasizes that FDA approval alone is not a basis for coverage, and that laboratory regulatory status (for example, CLIA) is informational and does not equate to medical necessity.

The policy confirms that molecular tests other than clonoSEQ for initial clonality assessment or for MRD assessment are considered unproven and not medically necessary and therefore not covered for those indications.

Definitions and Key Terms

Definition of Comprehensive Genomic Profiling (CGP)

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

Examples referenced in policyPolicy examples include FoundationOne Heme, Neo Comprehensive - Heme Cancers, and NEO AML Express as CGP assays used in specified hematologic malignancies.

Intended useCGP is described as useful for broad genomic characterization to inform diagnosis, prognosis, and targeted therapy selection in hematologic cancers.

Definition of Measurable Residual Disease (MRD)

DefinitionMeasurable Residual Disease (MRD) refers to a very small number of cancer cells or cancer-derived genetic material detectable during or after treatment using sensitive methods (eg, PCR, multiparametric flow cytometry, or NGS).

Eligibility Requirements

Eligibility requirements: the policy text indicates there are no additional top-level eligibility nodes specified beyond the covered-indication, ordering-clinician, and test-specific criteria (for example, multigene panels ≤50 genes, CGP for specified diagnoses, and clonoSEQ for clonality/MRD). Clinical documentation supporting the indication and specialist ordering remains necessary.

Eligibility requirements: no separate prior-testing or step-therapy prerequisites are listed as top-level eligibility conditions in the policy. Coverage is determined by meeting the specified indication and ordering clinician requirements (eg, hematologist/oncologist order where required).

Eligibility requirements: while the policy does not add top-level prior-test nodes, it emphasizes that baseline diagnostic testing and adequate specimen collection (morphology, cytogenetics, molecular-genetic/FISH, and flow cytometry as appropriate) are expected to ensure MRD or molecular results are interpretable and actionable when indicated.

Background and Clinical Context

Background: Hematologic cancers arise from blood-forming tissues and include leukemias, lymphomas, myelodysplastic syndromes, myeloproliferative neoplasms, and multiple myeloma. Molecular profiling ranges from single-gene tests to broad next-generation sequencing (NGS)–based approaches such as multigene panels and comprehensive genomic profiling (CGP), which can inform diagnosis, prognosis, and targeted therapy selection.

MRD refers to the presence of very low levels of residual malignant cells detectable by sensitive methods (eg, PCR, flow cytometry, or specialized NGS assays). MRD assessment can provide important prognostic information across multiple hematologic malignancies but requires validated assays, appropriate sampling, and careful interpretation in the clinical context.

Revision History and Policy Changes

2026-05-01policy_revisionLatest

Added and clarified coverage language: multigene panels (50 genes or fewer) are proven and medically necessary at initial diagnosis and/or recurrence/relapse when ordered by a hematologist or oncologist; revised the MDS/MPN criterion wording from 'strongly suspected' to 'suspected'; and clarified clonality and MRD assessment with clonoSEQ.

policy_revision

Replaced wording to indicate clonoSEQ references consistently and removed specific examples of unproven MRD tests; updated supporting sections and archived prior version CS372ID.C.

Policy Summary

PayerUnitedHealthcare

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

Policy CodePolicy CS372ID.D

Change TypeMaterial revisions — coverage clarifications and code additions

Effective DateMay 1, 2026

Next Review DateN/A

Key ActionOrder multigene panels (≤50 genes), CGP, or clonoSEQ only when ordered by a hematologist or oncologist and document indication and sample adequacy to support medical necessity.

SourceLink

On This Page

FLAIR and MASTER trial data demonstrate potential benefit; ASCO/CCO and other guideline cautions noted.

AML specifics: In AML, combining NGS and flow cytometry for MRD assessment provided additive prognostic value; persistent non‑DTA mutations detected by NGS during remission are associated with higher relapse risk, whereas persistent DTA mutations often reflect clonal hematopoiesis and lack prognostic value.

Data from Jongen‑Lavrencic and related analyses support these points.

Non‑clonoSEQ MRD tests considered unproven and not medically necessary per policy.

Diagnosis, prognostication, treatment decision-making, clonality assessment at diagnosis, and MRD assessment for hematologic malignancies

Disease‑specific testing roles and timing:

Diagnosis and prognostication: Diagnosis, prognostication, treatment decision‑making, clonality assessment at diagnosis, and MRD assessment for hematologic malignancies (ALL, AML, CLL, MDS, MPN, MM) per disease guidelines.

Guidelines (NCCN, CAP/ASH) describe recommended timing and assay sensitivity requirements (eg, MRD sensitivity often 10^-4 or better).

Initial diagnosis, recurrence, or relapse when ordered by hematologist/oncologist; CGP for ALL/AML/MDS/MPN; clonoSEQ for clonality and MRD

Operational summary of covered situations when ordered by a hematologist or oncologist:

Ordering contexts: Initial diagnosis, recurrence, or relapse of specified hematologic malignancies when ordered by a hematologist or oncologist; CGP for ALL, AML, MDS, or MPN; clonoSEQ for clonality and MRD.

Multigene panels (<=50 genes) covered at initial diagnosis/recurrence/relapse; clonoSEQ specified for clonality and MRD; CGP examples provided.

Multigene panels (≤50 genes) are proven and medically necessary when ordered by a hematologist/oncologist for: acute lymphoblastic leukemia, acute myeloid leukemia, multiple myeloma, or suspected MDS/MPN.
Orders that do not come from a hematologist or oncologist may be ineligible for coverage.

Documentation Required

Documentation of diagnostic and sampling adequacy

Provide required diagnostic documentation and ensure sample adequacy before submitting claims. For initial diagnosis and for tests that will inform MRD assessment or clonality, documentation should include morphologic assessment, conventional cytogenetics (karyotype), appropriate molecular-genetic testing and/or FISH, and flow cytometry as indicated by guidelines.

Obtain sufficient samples (blood, bone marrow, or tissue biopsy) and perform morphologic, immunophenotypic, cytogenetic, and molecular genetic studies when indicated.
For extramedullary presentations, process tissue biopsy for morphologic, immunophenotypic, cytogenetic, and molecular genetic studies.
Ensure flow cytometry panels are sufficient to allow subsequent MRD detection when applicable.

Documentation Required

Order and indication documentation

Orders and submitted indications must match the policy-covered hematologic indications. The ordering clinician must document the clinical indication on the order (e.g., initial diagnosis, recurrence/relapse, suspected MDS/MPN) and demonstrate that testing is medically necessary for that indication.

Orders should state the specific indication (initial diagnosis, recurrence/relapse, suspected MDS/MPN) and be consistent with the member's medical record.
Mismatch between order indication and clinical documentation may result in denial or request for additional records.

Denial Risk

Denial risk for non-clonoSEQ MRD assays

The use of molecular tests other than clonoSEQ for initial clonality assessment or MRD assessment is considered unproven and not medically necessary. Submitting claims for non-clonoSEQ molecular MRD assays carries a denial risk unless there is clear, supported evidence that meets medical necessity criteria in this policy.

clonoSEQ is the accepted molecular assay for clonality and MRD per this policy; other molecular MRD assays are unproven and not medically necessary.
Claims for non-clonoSEQ MRD assays may be denied.

Note

Therapy changes based on MRD

Therapy changes based solely on MRD status are not supported outside of clinical trials. Clinicians should exercise caution when altering maintenance or other therapies based on MRD results alone and follow guideline recommendations that do not endorse MRD-guided therapy changes outside research settings.

ASCO/CCO guidance: insufficient evidence to modify maintenance therapy based on MRD status outside clinical trials.
Clinical trial protocols (e.g., MASTER) may use MRD to guide therapy within the study context, but this does not establish routine clinical practice standards.

Step Therapy

Step therapy note

Step therapy: No specific step therapy requirements are specified in this section of the policy. Providers should verify any plan-specific utilization management rules (prior authorization, step edits) that may apply separately from this policy.

Check payer prior authorization portals or plan documents for any applicable step therapy or prior authorization requirements.
Absence of step therapy language in this policy section does not preclude plan-level edits.

Note

Provider action summary

Provider action summary: Tests intended to inform diagnosis, prognosis, clonality, or MRD must be ordered by a hematologist or oncologist for the covered indications described, supported by comprehensive documentation and appropriate diagnostic testing per guidelines.

Orders for multigene panels (≤50 genes) and clonoSEQ must come from a hematologist or oncologist.
Ensure complete supporting documentation (history, exam, test results) accompanies requests to avoid denials.
Follow guideline-recommended diagnostic testing (morphology, cytogenetics, molecular assays, flow cytometry) and ensure sample adequacy.

Billing Rule

Added CPT codes notification

Added CPT codes 0560U and 0561U were included in the policy history; verify billing and prior authorization applicability with payer billing guidance when submitting claims for new or revised codes.

Confirm correct CPT/HCPCS coding and coverage status for newly added codes prior to claim submission.
Prior authorization processes may apply to tests associated with new codes.

Common numeric cutoffs citedSpecific cutoffs referenced in the evidence include 10^-4, 10^-5, 10^-6, and a percentage cutoff of 0.1% (0.001).

Assay comparison examplesFlow cytometry sensitivity commonly ~1 x 10^-4; NGS MRD assays have been reported with sensitivities down to 1 x 10^-6 in some studies.

MRD assay sensitivity — recommended thresholds

Recommended minimum sensitivityGuideline-recommended MRD assay sensitivity is 10^-4 or better for validated MRD assessment.

Higher-sensitivity capabilitySome NGS-based MRD assays (including FDA-cleared commercial assays) have demonstrated detection limits down to 10^-6.

Clinical implicationHigher sensitivity (eg, 10^-6) can detect residual disease missed by methods with ~10^-4 sensitivity and may provide additional prognostic information.

MRD measurement is most often used in blood cancers to inform prognosis and to help assess treatment effectiveness and disease monitoring.

Common methodsCommon MRD assessment methods include real-time quantitative PCR, multicolor flow cytometry, and NGS-based assays.

Definition of Next Generation Sequencing (NGS)

DefinitionNext Generation Sequencing (NGS) describes newer sequencing techniques that can rapidly analyze multiple regions of DNA simultaneously, enabling multiplexed assessment of genomic alterations.

ApplicationsNGS is used across a range of molecular profiling tests from targeted panels to comprehensive genomic profiling and MRD assays.

Contrast with older methodsOlder sequencing methods analyzed one DNA region at a time; NGS allows high-throughput, multi-region analysis supporting panel- and genome-scale testing.

MRD negativity thresholds — definition examples

Example deep-negativity thresholdUndetectable MRD defined in some studies as < 10^-6 (example: CLL14 defined MRD negativity as <10^-6 in peripheral blood).

Example positivity thresholdsOther studies and meta-analyses used thresholds such as ≥10^-4 or 0.1% (10^-3) to define MRD positivity tied to prognostic outcomes.

Context-dependent definitionsTrials and disease contexts report differing numeric cutoffs (eg, 10^-4, 10^-5, 10^-6) that are associated with varying prognostic implications across diseases like ALL, AML, MM, and CLL.

DTA mutations (DNMT3A, TET2, ASXL1) — definition and relevance

DTA genes definedDTA mutations refer to somatic variants in DNMT3A, TET2, and ASXL1.

Clinical relevanceDTA mutations often persist after therapy and commonly represent age-related clonal hematopoiesis rather than leukemic clones.

Prognostic implicationPersistence of DTA mutations during remission generally lacks prognostic value for relapse and may confound MRD interpretation unless excluded from MRD assessments.

MRD — term reference (general)

Term definition'MRD' (Measurable Residual Disease) denotes residual cancer cells detectable below morphologic detection limits using sensitive assays; it is used as a prognostic and monitoring biomarker in hematologic malignancies.

SynonymsAlso referred to as 'minimal residual disease' in some literature; methods include PCR, flow cytometry, and NGS-based approaches.

LimitationClinical guidelines caution against routine therapy changes based solely on MRD outside clinical trials, reflecting evolving evidence for management decisions.

Molecular genetic testing — definition

DefinitionMolecular genetic testing encompasses laboratory techniques such as chromosome microarray, FISH, RT-PCR, DNA methylation studies, and NGS-based assays used for diagnosis and prognostication of hematologic malignancies.

Role in initial workupGuidelines recommend molecular-genetic testing alongside morphologic assessment, cytogenetics, and flow cytometry to provide comprehensive diagnostic information.

Documentation importanceAppropriate sample collection and documented baseline molecular/cytogenetic testing are expected to allow interpretable MRD testing over time.

CGP examples

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

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

Policy revision noteNEO AML Express was added to CGP examples in the policy revision history.

clonoSEQ — definition and policy specification

clonoSEQ definedclonoSEQ is specified in the policy as an assay used for clonality assessment at initial diagnosis and for measurable residual disease (MRD) assessment.

Assay role and limitationPolicy states molecular tests other than clonoSEQ for initial clonality assessment or MRD assessment are considered unproven and not medically necessary.

Evidence contextStudies using clonoSEQ (NGS-based) demonstrated greater sensitivity (eg, detection to 10^-6) and prognostic association compared with less sensitive methods in certain disease contexts.

Added criterion explicitly including chronic lymphocytic leukemia and expanded CGP coverage examples to include NEO AML Express; added CPT codes 0560U and 0561U.