ModifiedUnitedHealthcarePolicy CS372NM.F

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

Policy governing coverage of molecular and genomic testing (including multigene panels, comprehensive genomic profiling, and MRD/clonality assays) for diagnosis, prognosis, and treatment decision-making in hematologic cancers for members in New Mexico when ordered by appropriate clinicians.

Policy Summary

PayerUnitedHealthcare

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

Policy CodePolicy CS372NM.F

Change TypeMaterial content revisions and additions

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 with documentation supporting 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 to require suspicion (rather than strong suspicion) of myelodysplastic syndrome or myeloproliferative neoplasm as evidenced by order from a hematologist/oncologist.

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

Expanded proven and medically necessary use of Comprehensive Genomic Profiling (CGP) to include individuals with acute lymphoblastic leukemia, acute myeloid leukemia, myelodysplastic syndrome, or myeloproliferative neoplasm.

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

Added detailed language about medical records documentation that may be required to assess medical necessity and that documentation must fully support the medical necessity for requested services.

50panel gene limit

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CGP (examples)named CGP examples

clonoSEQspecified MRD assay

OGM, WTSunproven tests

81%MASTER trial MRD <10^-5

Coverage Criteria

Medically Necessary Coverage

Covered when ordered by a hematologist or oncologist as specified:

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 acute lymphoblastic leukemia; acute myeloid leukemia; multiple myeloma; or when myelodysplastic syndrome or myeloproliferative neoplasm is suspected (as evidenced by order from a hematologist/oncologist).panel size <= 50 genes

Order must be from a hematologist or oncologist

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

Order must be from a hematologist or oncologist

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

Other molecular tests for clonality or MRD are unproven and not medically necessary

Unproven / Not Medically Necessary

Not medically necessary / unproven tests:

Other molecular test panels: All other molecular test panels for hematologic cancer are considered unproven and not medically necessary due to insufficient evidence of efficacy.

Includes, but is not limited to, optical genome mapping and whole transcriptome sequencing

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

Ordering such tests for these purposes may be denied

Prognostic associations where MRD negativity correlates with better outcomes

Evidence‑based prognostic use cases where MRD negativity correlates with improved outcomes:

Multiple myeloma (NDMM and RRMM): Complete response or better with MRD negativity (NGS MRD sensitivity reported ~10^-5 in pooled analyses) is associated with improved progression‑free survival across pooled studies (e.g., POLLUX, CASTOR, ALCYONE, MAIA).NGS ~10^-5

Supports prognostication; guideline groups advise caution in using MRD to change maintenance therapy outside trials

Acute myeloid leukemia (AML): MRD negativity during remission is associated with higher disease‑free and overall survival across systematic reviews and meta-analyses; typical MRD assay sensitivity reported in AML studies is approximately 10^-4 to 10^-5, and absence of detectable MRD does not rule out residual disease due to sensitivity limits.typical assay sensitivity 10^-4 to 10^-5

Combining NGS and flow cytometry can add prognostic value

Acute lymphoblastic leukemia (ALL):

Guideline recommendations limiting MRD‑guided therapy changes

Guideline cautions and limitations:

ASCO/CCR guidance on multiple myeloma: There is currently insufficient evidence to modify maintenance therapy based on depth of response, including MRD status; MRD should not be used to guide changes in type or length of therapy outside the context of a clinical trial.

Depth of response assessment frequency: at minimum every 3 months while on maintenance/after best response per ASCO/CCR guidance

Covered indications and performance requirements

Covered when testing meets disease-specific guideline criteria and assay performance requirements

NCCN-guided diagnostic and molecular testing: Use multiplex gene panels, targeted NGS, cytogenetics (karyotype), FISH, and RT‑PCR for fusion transcripts as recommended by disease‑specific NCCN guidelines (AML, ALL, CLL, MDS, myeloproliferative neoplasms, MM) for diagnosis, prognostication, and treatment planning.follow disease‑specific guideline tests and timepoints

Includes baseline clonotype identification to enable later MRD assessment in MM

MRD testing sensitivity requirement: MRD assessment should be performed using validated assays with sensitivity of 10^-4 or better; for certain indications (e.g., CLL) NGS assays capable of 10^-6 sensitivity are referenced and an FDA‑approved NGS assay can be considered to confirm flow cytometry negativity.>=10^-4 sensitivity generally; 10^-6 referenced for high‑sensitivity NGS in CLL

If MRD is negative by a lower‑sensitivity method, confirmatory testing by an FDA‑cleared NGS assay (e.g., clonoSEQ) is recommended

Covered with criteria

Selected coverage positions and criteria as summarized in policy history

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

Clarified and added in the 02/01/2026 policy revision

Clonality and MRD assessment with clonoSEQ: clonoSEQ is the specified assay for clonality assessment at initial diagnosis and for MRD assessment; coverage was expanded to explicitly include individuals with chronic lymphocytic leukemia.clonoSEQ assay

Molecular tests other than clonoSEQ are unproven and not medically necessary for these purposes

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; wording replaced prior narrower language for relapsed/recurrent AML.

The policy lists certain advanced molecular tests as unproven and not medically necessary for hematologic cancer molecular testing. Specifically, optical genome mapping and whole transcriptome sequencing are identified as examples of molecular test panels for which evidence of clinical utility is insufficient; use of these modalities for diagnostic, clonality, or MRD purposes may therefore be denied. Providers should order validated, covered assays (for example, multigene panels ≤50 genes, CGP where indicated, or clonoSEQ for clonality/MRD) when seeking coverage for molecular testing in hematologic malignancies.

Measurable residual disease (MRD) testing has important prognostic value and is actively used in clinical trials, but routine MRD testing to drive standard-of-care changes in maintenance or other treatment outside of a clinical trial is not generally recommended. Guideline and consensus documents note that MRD assessments are being studied to inform treatment‑adaptation strategies, yet routine MRD‑guided changes to standard therapy (for example, stopping or shortening maintenance regimens) remain investigational and should be limited to clinical trials or clearly defined evidence‑based protocols.

For multiple myeloma, guideline panels have concluded there is insufficient evidence to modify maintenance therapy solely on the basis of MRD status. Although MRD negativity is prognostic and MRD‑adapted discontinuation strategies have been tested in trials (e.g., MASTER), changes in the type or duration of maintenance outside clinical trials are not supported by current evidence and are therefore not recommended for routine practice.

The policy specifies that molecular tests other than clonoSEQ are considered unproven and not medically necessary when used for initial clonality assessment or for MRD assessment. Coverage for clonality identification or MRD measurement should rely on validated assays such as clonoSEQ as described in the covered indications.

Reiterating policy position: molecular tests other than clonoSEQ are unproven and not medically necessary for initial clonality testing or for assessing MRD. Requests for alternative molecular MRD or clonality assays should include evidence of validated MRD performance consistent with guideline expectations to be considered for coverage.

The policy clarifies that using MRD status alone to alter maintenance therapy or to make routine treatment‑duration decisions is not supported. Guideline statements for multiple myeloma and consensus reviews for other diseases emphasize that MRD should not be the sole determinant for changing maintenance regimens outside of a clinical trial setting.

Routine MRD monitoring after completion of therapy is generally not recommended outside of clinical studies in some disease contexts. For example, ESMO guidance for chronic lymphocytic leukemia advises that MRD assessment and bone marrow evaluation to determine complete remission and MRD status should occur within clinical trials, and routine post‑therapy MRD surveillance in clinical practice is not currently recommended.

The policy emphasizes that molecular assays other than clonoSEQ remain unproven and not medically necessary for initial clonality identification or MRD assessment. Coverage determinations favor assays with demonstrated clinical validity and performance characteristics aligned with guideline expectations.

Covered Indications

Acute lymphoblastic leukemia (ALL) — Multigene panels (<=50 genes), CGP, and clonoSEQ when indicated are proven/medically necessary

ALL: Multigene panels, CGP, and clonoSEQ: For individuals with acute lymphoblastic leukemia (ALL), multigene NGS panels (50 genes or fewer), comprehensive genomic profiling (CGP), and clonality/MRD assessment with clonoSEQ are considered proven and medically necessary when ordered by a hematologist or oncologist.panel size <=50 genes; clonoSEQ assay for clonality/MRD

Order must be from a hematologist or oncologist

Acute myeloid leukemia (AML) — Multigene panels (<=50 genes) and CGP are proven/medically necessary

AML: Multigene panels and CGP: For individuals with acute myeloid leukemia (AML), multigene NGS panels (50 genes or fewer) at initial diagnosis and/or recurrence/relapse and comprehensive genomic profiling (CGP) are proven and medically necessary when ordered by a hematologist or oncologist.panel size <=50 genes

Not Covered / Not Medically Necessary

All other molecular test panels for hematologic cancers, including platforms such as optical genome mapping and whole transcriptome sequencing, are considered unproven and are not covered. Providers should use the covered test types and specific assays listed in the policy when seeking reimbursement for molecular testing in hematologic malignancies.

MRD testing performed solely to guide routine changes in maintenance therapy or overall treatment duration outside of a clinical trial context is not covered. While trials explore MRD‑directed stopping or modification strategies, these approaches remain investigational until supported by guideline‑level evidence.

Modification of maintenance therapy in multiple myeloma based only on MRD status is not supported by current evidence and therefore is not covered. Although studies such as MASTER used MRD thresholds (e.g., <10^-5) to guide therapy discontinuation within a trial protocol, guideline recommendations advise against routine MRD‑based alterations in maintenance outside of research settings.

Molecular tests other than clonoSEQ for initial clonality assessment or for MRD assessment are not covered because they are considered unproven and not medically necessary. Coverage is limited to validated assays referenced in the policy and indicated disease contexts.

Coding

Applicable Codes (selected)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.
0050U	Targeted genomic sequence analysis panel, acute myelogenous leukemia, DNA analysis, 194 genes, interrogation for sequence variants, copy number variants or rearrangements

Applicable Codes (expanded)CPT

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,.
0413U
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.
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.

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Panel gene count threshold

Panel gene count thresholdMultigene NGS panels limited to 50 genes or fewer are considered proven and medically necessary when ordered by a hematologist or oncologist for specified hematologic malignancies.

ApplicabilityApplies at initial diagnosis and/or recurrence or relapse for ALL, AML, MM, and when MDS/MPN is suspected (order from hematologist/oncologist).

Related codingSee CPT/HCPCS panel codes for 5-50 gene panels (e.g., 81450/81451) referenced in policy coding section.

MRD sensitivity thresholds referenced

Referenced MRD sensitivity rangePolicy references MRD sensitivity thresholds ranging from ≤10^-4 to as deep as 10^-6 depending on assay and disease context.

Disease examples

Provider Actions and Requirements

Prior Authorization

Order by hematologist/oncologist required

Orders for multigene panels (50 genes or fewer), clonoSEQ®, or Comprehensive Genomic Profiling (CGP) in the covered indications must be placed by a hematologist or oncologist. Requests from non-hematology/oncology providers may not meet the policy's proven criteria and can be denied.

Multigene panels ≤50 genes: order must be from a hematologist/oncologist to meet coverage criteria.
clonoSEQ® (clonality or MRD) and CGP: order must be from a hematologist/oncologist for covered uses.

Documentation Required

Medical record documentation and availability

Patient medical records must contain documentation that fully supports the medical necessity for the requested services. Documentation may be requested during review and lack of adequate documentation may lead to denial. Documentation should include relevant history, physical exam, and results of pertinent diagnostic tests or procedures, be legible, and be made available upon request.

Eligibility Requirements

Eligibility for covered molecular testing requires that the test be ordered by a hematologist or oncologist and that the indication aligns with the listed covered conditions (for example, ALL, AML, MM, MDS/MPN, or CLL where specified). Documentation in the medical record should support the clinical indication, timing relative to therapy, and how the results will inform management when required for review.

Disease‑specific eligibility notes: covered uses include multigene panels (≤50 genes) and CGP for the indicated diagnoses, and clonality/MRD assessment with clonoSEQ for specified diseases. Orders for these covered tests must come from a hematologist or oncologist to meet the policy's eligibility requirements.

Background

Background: Hematologic cancers arise from blood and bone marrow lineages and often require molecular profiling for diagnosis, prognosis, and treatment selection. Molecular testing ranges from single‑gene assays to multigene panels and comprehensive genomic profiling; MRD assessment using sensitive assays (flow cytometry, ASO‑PCR, or NGS) provides prognostic information and is used in trials to inform treatment duration or discontinuation strategies.

Definitions

Comprehensive Genomic Profiling (CGP) definition

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

ExamplesPolicy examples include FoundationOne Heme, Neo Comprehensive - Heme Cancers, and NEO AML Express as CGP tests referenced for hematologic malignancies.

IndicationsCGP is proven and medically necessary for ALL, AML, MDS, and myeloproliferative neoplasms per policy when ordered by a hematologist/oncologist.

Measurable Residual Disease (MRD) definition

DefinitionMeasurable Residual Disease (MRD): a very small number of cancer cells or cell material detectable in the body during or after treatment using sensitive techniques (PCR, flow cytometry, NGS); presence may be associated with earlier relapse or recurrence.

Common assay types

Clinical Evidence and Metrics

50gene limit for proven multigene panels

clonoSEQnamed assay specified for clonality & MRD

10^-4minimum MRD assay sensitivity expected by guidelines

81%MASTER trial MRD <10^-5 rate (MRD-evaluable)

Clinical trials and concordance studies provide context for MRD performance and investigational MRD‑guided strategies. For example, the MASTER trial used an NGS MRD threshold of <10^-5 to stop therapy in responders and reported that 81% of MRD‑evaluable participants achieved MRD <10^-5. Other studies and meta‑analyses have compared NGS and flow cytometry, showing variable concordance and that NGS can detect MRD in samples deemed negative by flow cytometry; these results support prognostic use but not yet routine MRD‑guided standard‑of‑care changes outside trials.

Revision History

2026-02-01material_revisionLatest

Added language clarifying multigene panels (50 genes or fewer) at initial diagnosis and/or recurrence/relapse are proven and medically necessary when ordered by a hematologist or oncologist; revised coverage criteria for multigene panels.

2026-02-01material_revision

Replaced criterion wording to require suspicion (rather than strong suspicion) of myelodysplastic syndrome or myeloproliferative neoplasm as evidenced by order from a hematologist/oncologist.

2026-02-01

Policy Summary

PayerUnitedHealthcare

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

Policy CodePolicy CS372NM.F

Change TypeMaterial content revisions and additions

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 with documentation supporting medical necessity.

SourceLink

On This Page

Highly sensitive NGS MRD testing identifies patients at very low relapse risk; studies report very high sensitivity (approaching 10^-6 for some NGS assays) and NGS can detect MRD not found by multicolor flow cytometry, with NGS‑negative patients demonstrating lower relapse rates and improved survival in retrospective analyses.

Recommended MRD timing per expert consensus: end of induction, end of consolidation, and additional regimen‑specific time points

Chronic lymphocytic leukemia (CLL): Undetectable MRD is prognostic in CLL and associated with improved progression‑free survival; clinical trials have used MRD to guide therapy decisions, but routine MRD testing in clinical practice is generally not recommended outside of trials per consensus statements.varies by specimen and assay (blood or marrow); clonoSEQ referenced for 10^-6 sensitivity

clonoSEQ has FDA clearance for MRD detection in CLL; use in practice should follow guideline recommendations

Timing and indication for MRD testing: Perform MRD assessment at disease‑specific time points (examples: end of induction and end of consolidation for ALL; upon achievement of morphologic remission and post‑transplant for AML; end of fixed‑duration therapy for CLL).per disease specific guideline timing

Frequency and monitoring depend on disease and treatment regimen

Assay selection and confirmation: Select assays validated for MRD use; standard diagnostic NGS without MRD validation is generally insufficient for MRD purposes and participation in clinical trials is encouraged when MRD is used to guide therapy changes.use validated MRD assays

Consider FDA‑approved assays to confirm negative results from lower‑sensitivity methods

Policy history updated 02/01/2026

Diagnostic molecular profiling and targeted NGS per NCCN guidance; order must be from a hematologist or oncologist

Multiple myeloma (MM) — Multigene panels (<=50 genes) and clonoSEQ clonality/MRD are proven/medically necessary

MM: Multigene panels and clonoSEQ: For individuals with multiple myeloma (MM), multigene NGS panels (50 genes or fewer) and clonality/MRD assessment with clonoSEQ (including baseline clonotype identification at diagnosis) are proven and medically necessary when ordered by a hematologist or oncologist.panel size <=50 genes; clonoSEQ assay

Baseline clonotype or stored aspirate recommended to permit later MRD by NGS

Myelodysplastic syndrome or myeloproliferative neoplasm (MDS/MPN) — Multigene panels (<=50 genes) at initial diagnosis/recurrence and CGP are proven/medically necessary; suspected MDS/MPN requires order from a hematologist/oncologist

MDS/MPN: Multigene panels and CGP: For individuals with myelodysplastic syndrome or suspected myeloproliferative neoplasm (MDS/MPN), multigene NGS panels (50 genes or fewer) at initial diagnosis and/or recurrence/relapse and comprehensive genomic profiling (CGP) are proven and medically necessary when ordered by a hematologist or oncologist.panel size <=50 genes

When MDS/MPN is suspected, order must be from a hematologist or oncologist (evidencing suspicion)

Chronic lymphocytic leukemia (CLL) — clonoSEQ MRD assessment is proven/medically necessary for CLL

CLL: clonoSEQ MRD assessment: For individuals with chronic lymphocytic leukemia (CLL), MRD assessment with clonoSEQ is proven and medically necessary when ordered by a hematologist or oncologist; clonoSEQ is referenced as an FDA‑approved NGS assay with high analytical sensitivity for CLL MRD detection.clonoSEQ assay; assay sensitivity referenced to 10^-6 for high‑sensitivity NGS

Routine MRD testing in CLL outside clinical trials is not routinely recommended per some guideline bodies; testing should align with guideline‑recommended indications

Use of high‑sensitivity NGS MRD assays to provide prognostic information in AML, ALL, MM, RRMM, and CLL — prognostic and trial‑based use

Prognostic use of high‑sensitivity NGS MRD assays: High‑sensitivity NGS MRD assays can provide prognostic information in AML, ALL, MM (including RRMM), and CLL; MRD negativity measured by sensitive methods correlates with improved progression‑free and overall survival in multiple studies and meta-analyses.sensitivity referenced <=10^-4 to 10^-6 depending on disease and assay

Use for prognostication and within clinical trials; use to guide routine therapy changes outside trials is limited by guideline cautions

Diagnostic molecular profiling and MRD assessment per disease-specific guideline recommendations — includes multigene NGS panels, targeted mutation testing, FISH, RT‑PCR, and validated assays

Diagnostic molecular profiling and MRD per guidelines: Diagnostic molecular profiling and MRD assessment for hematologic malignancies (ALL, AML, CLL, MDS, myeloproliferative neoplasms, MM) should follow disease‑specific guideline recommendations and may include multigene NGS panels, targeted mutation testing (e.g., TP53, JAK2, CALR, MPL), FISH, RT‑PCR for fusion transcripts, and validated MRD assays.use guideline‑recommended tests and timepoints

Select panels appropriate to indication and lab expertise; baseline testing recommended where required for MRD tracking

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

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

Added clarification in policy revision requiring hematologist/oncologist order

Clonality assessment and MRD assessment with clonoSEQ for hematologic malignancies, explicitly including chronic lymphocytic leukemia

Clonality and MRD with clonoSEQ: Clonality assessment and MRD assessment with clonoSEQ are covered for hematologic malignancies, explicitly including chronic lymphocytic leukemia; molecular tests other than clonoSEQ for these purposes are considered unproven and not medically necessary.clonoSEQ assay

Coverage expanded to explicitly include CLL in policy revision

Comprehensive Genomic Profiling for individuals with ALL, AML, MDS, or MPN

Comprehensive Genomic Profiling (CGP) for specified diagnoses: Comprehensive Genomic Profiling (CGP) is proven and medically necessary for individuals with acute lymphoblastic leukemia, acute myeloid leukemia, myelodysplastic syndrome, or myeloproliferative neoplasm when ordered by a hematologist or oncologist.

Policy language expanded from prior narrower scope for relapsed/recurrent AML

Examples include CLL and trials where MRD <10^-6 or <10^-5 were used as prognostic or trial decision points.

Clinical implicationAssay selection should meet disease‑specific sensitivity expectations (e.g., NCCN often requires ≥10^-4; some scenarios reference 10^-6).

MRD assay sensitivity

ASO‑PCR sensitivityASO‑PCR analytical sensitivity cited in policy: approximately 0.001% (1 x 10^-5).

Flow cytometry sensitivityMulticolor flow cytometry (MFC/NGF) analytical sensitivity approximately 0.01% (1 x 10^-4).

NGS/HTS sensitivity rangeNGS/HTS methods (including FDA‑cleared assays like clonoSEQ) reported to reach sensitivities in the 10^-5 to 10^-6 range; NCCN references NGS detection to 10^-6 for CLL.

Medical records documentation may be required to assess whether the member meets clinical criteria for coverage but does not guarantee coverage.
Documentation should be maintained in the patient's medical record and provided upon request.

Denial Risk

Unproven tests — denial risk

The use of molecular tests other than clonoSEQ® for initial clonality assessment or MRD assessment is considered unproven and not medically necessary. Requests for molecular MRD or clonality assays beyond clonoSEQ® (including optical genome mapping, whole transcriptome sequencing, and other non‑clonoSEQ molecular panels) may be denied.

Molecular tests other than clonoSEQ® for clonality or MRD assessment: unproven and not medically necessary.
Examples of other molecular tests that may be unproven include optical genome mapping and whole transcriptome sequencing.

Documentation Required

Assay sensitivity expectations

MRD testing must meet assay sensitivity expectations described in guidelines. For ALL, NCCN recommends validated MRD technology with sensitivity of 10^-4 or better and, when flow cytometry is negative, confirmation with an FDA‑approved NGS assay is recommended for consideration. Use of assays with sensitivity below guideline thresholds may not meet policy expectations.

NCCN: MRD assays for ALL should have sensitivity ≥10^-4 (10-4) or better.
If MRD negative by flow cytometry, consider confirmation with FDA‑approved NGS assay.

Note

MRD timing and MRD‑guided therapy (informational)

Recommended timing for MRD assessment in ALL and examples of MRD‑guided therapy decisions are included to inform ordering and interpretation. For adults undergoing frontline treatment, bone marrow MRD assessment is recommended after end of induction, in early consolidation (~3 months after start of therapy), and approximately every 3 months for at least 3 years. MRD has been used in clinical trials to guide treatment duration and cessation (e.g., MASTER, FLAIR, CLL2‑BZAG), including stopping therapy when sustained MRD negativity is achieved (MASTER used MRD <10^-5 to stop therapy).

ALL MRD timing: end of induction; early consolidation (~3 months); then ~every 3 months for ≥3 years.
MRD‑guided therapy examples: MASTER trial stopped therapy for participants achieving MRD <10^-5; FLAIR and CLL2‑BZAG used MRD to tailor duration of therapy.

Step Therapy

Operational notes and step therapy

Operational/administrative notes: no explicit step therapy processes are specified in this policy. Providers should follow applicable federal, state, and contractual coverage rules and may be required to supply documentation supporting medical necessity. Baseline clonotype identification or storage of diagnostic aspirate is recommended (e.g., for multiple myeloma) to allow later NGS MRD assessment.

No step therapy requirements specified in this policy section.
Baseline clonotype identification or storage of aspirate at diagnosis is recommended to permit future MRD assessment by NGS.
Coverage determinations are subject to federal/state/contractual requirements.

Current MRD assessments use real‑time quantitative PCR, multiparametric flow cytometry, and/or NGS methods as noted by NCI and policy references.

Clinical roleMRD measurement is most often used for blood cancers to inform prognosis and treatment planning; policy emphasizes disease‑specific use and assay validation requirements.

Next Generation Sequencing (NGS) definition

DefinitionNext Generation Sequencing (NGS): high‑throughput sequencing techniques that can quickly analyze multiple sections of DNA simultaneously, enabling detection of mutations, fusions, and clonal rearrangements relevant to diagnosis and MRD detection.

Use in MRDNGS/HTS approaches can offer higher analytical sensitivity compared with conventional methods and are referenced for MRD detection (e.g., clonoSEQ).

Relation to CGPNGS is the underlying technology for Comprehensive Genomic Profiling (CGP) tests described in the policy definitions.

MRD negative thresholds

Variable MRD‑negative thresholdsMRD negativity is defined variably across studies and diseases; examples cited include thresholds of <10^-4, <10^-5, and <10^-6 depending on assay and clinical context.

Study examplesALL study: flow cytometry MRD negative vs NGS showed discrepancies (MFC ~1x10^-4; NGS ~1x10^-6). Multiple myeloma data reported improved PFS at 10^-5 vs lower thresholds.

Policy implicationInterpretation of 'MRD negative' must reference the assay sensitivity used and disease‑specific guideline expectations.

Analytical sensitivities for common MRD methods

Flow cytometry (MFC/NGF)Analytical sensitivity approximately 0.01% (1 x 10^-4); commonly used for end‑of‑induction MRD assessment.

ASO‑PCRReported analytical sensitivity around 0.001% (1 x 10^-5) but requires patient‑specific probe development.

NGS / HTSHigh‑throughput sequencing and FDA‑cleared NGS MRD assays (e.g., clonoSEQ) are reported to reach sensitivities of 10^-5 to 10^-6 and have lower false‑negative rates compared with flow cytometry in several studies.

MRD definition reference — presence of residual cancer cells detected by sensitive methods

Policy statementMRD is defined as the presence of residual cancer cells after treatment detected by sensitive laboratory methods (flow cytometry, PCR, NGS); such residual disease can be associated with increased relapse risk and poorer prognosis.

Evidence linkagePolicy references studies and NCI definition linking MRD detection to prognostic outcomes and use in treatment planning and trials.

Primary methodsExamples of detection methods include flow cytometry, PCR (including ASO‑PCR), and NGS‑based assays per policy references and NCI definitions.

MRD definition reference — NCI resource

NCI referencePolicy cites the National Cancer Institute (NCI) Dictionary of Cancer Terms definition for Measurable Residual Disease (MRD) as a referenced resource.

UtilityNCI MRD definition underscores MRD as a concept used primarily in hematologic cancers and aligns with policy descriptions of detection methods.

Hematologic Cancer definition — NCI resource

NCI definitionHematologic Cancer: term referenced via the National Cancer Institute describing cancers that begin in blood‑forming tissue or immune system cells (e.g., leukemia, lymphoma, myeloma).

ScopePolicy addresses molecular and genomic testing for hematologic cancers per disease‑specific guideline recommendations.

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

2026-02-01material_revision

Expanded Comprehensive Genomic Profiling (CGP) coverage to include individuals with acute lymphoblastic leukemia, acute myeloid leukemia, myelodysplastic syndrome, or myeloproliferative neoplasm (added NEO AML Express to examples).

2026-02-01material_revision

Clarified that molecular tests other than clonoSEQ are unproven and not medically necessary for initial clonality assessment or for assessment of MRD; replaced prior, narrower wording.

2026-02-01operational_update

Added detailed medical records documentation language indicating records may be requested and must fully support medical necessity, be legible, and be made available upon request.

2026-02-01editorial_change

Replaced references to clonoSEQ Clonality ID and clonoSEQ MRD with the single term clonoSEQ; updated Supporting Information (Clinical Evidence, FDA, References) sections.