Colorado Rocky Mountain Health Plans MRD Coverage Update

Coverage Criteria and Clinical Rationale

Medically necessary molecular testing

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

Multigene panels (≤50 genes): Multigene panels (50 genes or fewer) are proven and medically necessary at initial diagnosis and/or recurrence or relapse when ordered by a hematologist or oncologist for acute lymphoblastic leukemia, acute myeloid leukemia, multiple myeloma, or when myelodysplastic syndrome or myeloproliferative neoplasm is suspected.panel size ≤ 50 genes

Order must be from a hematologist or oncologist

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

Examples provided in policy

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 acute lymphoblastic leukemia, multiple myeloma, and chronic lymphocytic leukemia.clonoSEQ assay

Other molecular tests for clonality/MRD are considered unproven for these uses

Unproven / not medically necessary

Not covered / not medically necessary:

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

All other molecular test panels: Due to insufficient evidence, all other molecular test panels for hematologic cancer are unproven and not medically necessary; examples include optical genome mapping and whole transcriptome sequencing.

Examples listed in policy are not exhaustive.

Clinical use and trial-based MRD-guided therapy

Evidence supports MRD as a prognostic marker and as a guide in trial settings; use outside trials remains limited and sometimes not recommended.

Prognostic association: Multiple studies and meta-analyses report that MRD-negativity is associated with improved progression-free survival and overall survival across AML, CLL, ALL, and multiple myeloma.various (see guidelines and studies)

See cited trials and guideline summaries for disease-specific evidence

MRD-guided therapy in clinical trials

Trials have used MRD results to determine therapy duration or treatment changes.

Examples of MRD-guided decisions: Trials have applied MRD to adapt therapy: e.g., FLAIR used MRD to determine duration of ibrutinib-venetoclax with improved PFS vs comparator; MASTER used sustained MRD-negativity to discontinue Dara-KRd (MRD-SURE) and observe participants.trial-specific MRD thresholds (see trial reports)

Outcomes and applicability vary by trial and patient risk features

Analytic method and sensitivity implications

Different assay methods have differing sensitivity and may yield discordant results affecting prognostication.

Method comparison: NGS/HTS assays detect MRD at higher sensitivity (reports to 10^-6) and identify additional MRD-positive individuals compared with flow cytometry (≈10^-4); combining assays can add independent prognostic value, but higher sensitivity does not by itself establish standardized clinical actions outside trials.flow cytometry ≈10^-4; NGS up to 10^-6

Assay selection and interpretation should consider sensitivity and clinical context

Guideline-aligned MRD testing

Covered when aligned with guideline-based indications and assay performance:

General MRD coverage conditions: MRD testing is supported when used for prognostic assessment or as specified by disease-specific guidelines (e.g., NCCN, ESMO, CAP/ASH) using validated assays with recommended sensitivity (≥10^-4) and performed at appropriate time points such as end of induction, end of consolidation, post-transplant monitoring, or for baseline clonotype identification for future monitoring.assay sensitivity ≥ 10^-4 recommended; NGS may reach 10^-6

Timing and specific indications vary by disease and guideline

Accepted MRD assay types

Specific test modality considerations:

Test modality: Acceptable technologies include validated multicolor flow cytometry, allele-specific PCR (ASO-PCR), RT-qPCR for fusion transcripts, and FDA-cleared or validated NGS/HTS assays (e.g., clonotype or fusion detection) for clonality and MRD assessment.sensitivity varies by method (FC ~10^-4, ASO-PCR ~10^-3 to 10^-5, NGS reported to 10^-6)

If MRD is negative by flow cytometry, consider FDA-approved NGS assay to confirm negativity per NCCN guidance

Therapy guidance limitations

Limits on clinical actionability:

Therapy modification: Routine modification of maintenance or other therapy based solely on MRD status is not supported outside clinical trials in some diseases (e.g., multiple myeloma and CLL); guideline authors recommend caution and encourage use of MRD primarily within clinical trial contexts for therapy decisions.

Refer to ASCO/CCO and disease-specific guidelines for detailed recommendations

Revised coverage criteria highlights

Coverage stance updates and clarified criteria (summary):

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

Policy language updated to clarify application to Oxford membership

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.

CGP examples cited in policy history

clonoSEQ for clonality and MRD: Use of clonoSEQ is specified for initial clonality assessment and MRD assessment; molecular tests other than clonoSEQ are unproven and not medically necessary for these uses.clonoSEQ assay

The policy lists specific molecular technologies as examples of tests considered unproven and not medically necessary for routine hematologic cancer panels. Optical genome mapping and whole transcriptome sequencing are explicitly cited as examples of molecular tests that are not covered as part of general hematologic cancer molecular panel testing.["8","4"]

Clinical guideline authors note that although MRD is a strong prognostic marker, current evidence is insufficient to support using MRD status alone to modify maintenance therapy or to change the type or duration of therapy outside of a clinical trial. Providers should therefore not routinely alter ongoing maintenance regimens solely on the basis of MRD results unless done in a trial context.["37","23"]

For multiple myeloma, guideline panels conclude there is insufficient evidence to change the type or length of therapy based on depth of response or MRD status outside clinical trials. Achieving MRD-negativity is prognostically favorable, but MRD-directed changes to standard treatment are recommended only within research protocols at this time.["37","23"]

Policy revision history documents that the prior enumerated list of example assays considered unproven for MRD assessment was removed from the policy. The current policy no longer presents a separate enumerated list of unproven MRD molecular tests in the MRD section.["58","57"]

The policy states that any molecular test panels for hematologic cancer that are not specifically listed as proven and medically necessary should be considered unproven and not medically necessary. Examples given in the policy text include optical genome mapping and whole transcriptome sequencing, and the policy clarifies that the examples are not exhaustive; tests not named as proven are therefore treated as not medically necessary.["4","56"]

Clinical practice guidelines indicate that routine MRD assessment for post-therapy monitoring is not recommended in some diseases outside of clinical studies. For example, ESMO guidance for chronic lymphocytic leukemia states that MRD assessment is generally not recommended for monitoring after therapy outside clinical trials at this time.["41","37"]

The policy specifies that molecular tests other than clonoSEQ are considered unproven and not medically necessary for initial clonality assessment and for MRD assessment. clonoSEQ is identified as the validated clonotype/NGS MRD assay with proven indications in this policy; alternative molecular MRD assays are treated as unproven for these uses.["4","33"]

Indications and Approved Uses

Covered diagnoses for CGP and multigene panels (≤50 genes)

Covered diagnoses for CGP and multigene panels (≤50 genes): Acute lymphoblastic leukemia, acute myeloid leukemia, multiple myeloma, myelodysplastic syndrome, and myeloproliferative neoplasm are covered indications for CGP and multigene panels (≤50 genes) when ordered by a hematologist or oncologist.panel size ≤ 50 genes or CGP

Order must be from a hematologist or oncologist

clonoSEQ NGS MRD testing

clonoSEQ NGS MRD testing is indicated for monitoring/detection of MRD in B-ALL, multiple myeloma, and CLL per FDA clearance and supporting assessments.clonoSEQ assay specifications

Clinical validity data cited; use for prognostication supported, therapy-guidance primarily in trials

Procedure Codes and Assay Sensitivity

Applicable procedure codes referencedmixed

0017M	Oncology (diffuse large B-cell lymphoma [DLBCL]), mRNA, gene expression profiling by fluorescent probe hybridization of 20 genes, formalin-fixed paraffin-embedded tissue, algorithm reported as cell of origin.
0050U	Targeted genomic sequence analysis panel, acute myelogenous leukemia, DNA analysis, 194 genes, interrogation for sequence variants, copy number variants or rearrangements.
0120U	Oncology (B-cell lymphoma classification), mRNA, gene expression profiling by fluorescent probe hybridization of 58 genes (45 content and 13 housekeeping genes), formalin-fixed paraffin-embedded tissue, algorithm reported as likelihood for primary mediastinal B-cell lymphoma (PMBCL) and diffuse large B-cell lymphoma (DLBCL) with cell of origin subtyping in the latter.
0171U	Targeted genomic sequence analysis panel, acute myeloid leukemia, myelodysplastic syndrome, and myeloproliferative neoplasms, DNA analysis, 23 genes, interrogation for sequence variants, rearrangements and minimal residual disease, reported as presence/absence.
0298U	Oncology (pan tumor), whole transcriptome sequencing of paired malignant and normal RNA specimens, fresh or formalin-fixed paraffin-embedded (FFPE) tissue, blood or bone marrow, comparative sequence analyses and expression level and chimeric transcript identification.
0299U	Oncology (pan tumor), whole genome optical genome mapping of paired malignant and normal DNA specimens, fresh frozen tissue, blood, or bone marrow, comparative structural variant identification.
0300U	Oncology (pan tumor), whole genome sequencing and optical genome mapping of paired malignant and normal DNA specimens, fresh tissue, blood, or bone marrow, comparative sequence analyses and variant identification.
0331U	Oncology (hematolymphoid neoplasia), optical genome mapping for copy number alterations and gene rearrangements utilizing DNA from blood or bone marrow, report of clinically significant alterations.
0364U	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.

1–10 of 20

1/2

Regulatory/Coding referencesmixed

No codes listed

inv-19: MRD assay sensitivity thresholds

0.1% (10^-3)Reported as an MRD cutoff associated with prognostic differences in AML systematic reviews; studies using a threshold of <0.1% showed greatest benefit for MRD-negativity.

10^-4Commonly cited analytic sensitivity for validated MRD methods (multicolor flow cytometry and recommended minimum sensitivity per guidelines); systematic reviews note assays achieving 1x10^-4 to 1x10^-5 for AML.

10^-5Described as within the achievable sensitivity range for some MRD assays (NGS/HTS and ASO-PCR in select contexts) and reported in AML literature as an attainable threshold.

10^-6Shown in studies using high-sensitivity NGS (eg, clonoSEQ) to detect MRD at levels down to 1 x 10^-6, identifying additional MRD-positive individuals not detected by flow cytometry and providing added prognostic information.

inv-20: Assay sensitivity

Ordering, Documentation, and Prior Authorization Notes

Documentation Required

Ordering, Documentation, and Prior Authorization Notes

Prior authorization may apply for listed molecular tests — multigene panels (≤50 genes), CGP, and clonoSEQ — when these tests are described as medically necessary in the Coverage Rationale. No explicit payer authorization or denial triggers are specified in this policy; authorization requirements (if any) depend on the member-specific benefit plan and any plan-administered prior authorization program.

Medical records documentation may be required to assess whether the member meets clinical criteria for coverage; submission of relevant records does not guarantee coverage.
Tests ordered outside the named proven indications (for example, multigene panels >50 genes, molecular tests other than clonoSEQ for initial clonality or MRD assessment, optical genome mapping, whole transcriptome sequencing, and other unproven assays) are considered unproven and may be not covered.
When MRD or clonotype testing is indicated, ordering should be done by a hematologist or oncologist.
Ordering for suspected myelodysplastic syndrome (MDS) or myeloproliferative neoplasm (MPN) should be evidenced by an order from a hematologist/oncologist.
Providers should follow CAP/ASH and NCCN guidance on obtaining adequate specimens; obtain and store baseline clonotype identification or diagnostic aspirate at diagnosis to enable future NGS-based MRD assessment.
Guideline-recommended timing for MRD assessment: for ALL—bone marrow after end of induction, in early consolidation (≈3 months after start of therapy), and approximately every 3 months for at least 3 years (or per clinical scenario); for MM—assess depth of response with each cycle and at minimum every 3 months while on maintenance (frequency may be decreased once best response is attained).

Excluded and Not Medically Necessary Services

Optical genome mapping, whole transcriptome sequencing, and similar molecular tests named in the policy as examples of unproven assays are listed under not covered services. These tests are not covered when ordered for general hematologic cancer molecular panel purposes unless specifically identified as a proven and medically necessary indication elsewhere in the policy.["4","56"]

Guideline authorities and consensus statements advise that using MRD results to alter maintenance therapy or as a routine clinical decision point outside of clinical trials is not supported by current evidence. Therefore, routine clinical decisions to change maintenance or other ongoing therapy based solely on MRD are not covered by the policy outside trial contexts.["37","23"]

The policy reminds readers that FDA clearance or approval is provided for informational purposes and that FDA approval alone is not a basis for coverage. Laboratories performing molecular testing must operate under CLIA, and regulatory status is not in itself dispositive of medical necessity.["49"]

The policy states that molecular tests other than clonoSEQ for initial clonality assessment or for MRD assessment are considered unproven and not medically necessary. As such, requests for alternative molecular MRD assays for these indications are described as outside the proven coverage criteria.["4","33"]

Key Definitions

inv-38: Definition — Comprehensive Genomic Profiling (CGP)

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

ExamplesPolicy cites CGP examples such as FoundationOne Heme, Neo Comprehensive - Heme Cancers, and NEO AML Express as representative CGP platforms.

Use casesCGP is described as proven and medically necessary for specified hematologic malignancies (eg, ALL, AML, MDS, MPN) to identify actionable genomic alterations.

inv-39: Definition — Measurable Residual Disease (MRD)

DefinitionMeasurable Residual Disease (MRD) refers to a very small number of cancer cells or cancer-derived material detectable in the body during or after treatment using sensitive methods, even when no clinical signs or morphologic evidence of disease are present.

Member and Test Eligibility

There are no top‑level eligibility requirement nodes in the inventory. The policy history documents revisions to coverage language and criteria but does not add separate, standalone eligibility requirement items in the policy inventory.["57","58"]

No discrete eligibility requirement nodes were added in the revision history; eligibility for covered tests continues to be determined by the clinical criteria and ordering provider requirements specified elsewhere in the policy (for example, tests must be ordered by a hematologist or oncologist for listed indications).["57","58"]

The policy content and revision notes do not create new top‑level eligibility requirements in the inventory. Coverage remains contingent on the clinical conditions and ordering provider roles described in the coverage rationale sections.["57","58"]

Clinical Background and Evidence Summary

Hematologic cancers arise from blood‑forming tissues and include diseases such as leukemia, lymphoma, and multiple myeloma. Molecular profiling using NGS and related technologies—ranging from targeted multigene panels and Comprehensive Genomic Profiling (CGP) to clonotype NGS assays—can inform diagnosis, prognostication, baseline clonotype identification, and identification of actionable mutations at relapse. MRD testing detects low levels of residual disease and is prognostically informative, but clinical use and timing should follow disease‑specific guideline recommendations and validated assay performance characteristics.["37","6","4"]

OpenPayer

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

Coverage Criteria and Clinical Rationale

Indications and Approved Uses

Procedure Codes and Assay Sensitivity

Ordering, Documentation, and Prior Authorization Notes

Excluded and Not Medically Necessary Services

Key Definitions

Member and Test Eligibility

Clinical Background and Evidence Summary