Molecular Oncology Testing for Hematologic Cancer Diagnosis, Prognosis, and Treatment Decisions
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Defines medical necessity and coverage rationale for multigene panels, comprehensive genomic profiling, clonality and MRD testing in hematologic malignancies for UnitedHealthcare Commercial and Individual Exchange members; applies when ordered by hematologist/oncologist.
Updated list of applicable CPT codes to reflect quarterly edits; added 0644U and 0645U.
Supporting Information archived previous policy version 2026T0652G.
Coverage Criteria and Evidence Contexts
Multigene panel and CGP coverage for specific hematologic cancers
Covered when ALL of the following are met
source: chunks 4, 6
source: chunk 6
source: chunk 6
Unproven / Not medically necessary
source: chunk 9
source: chunk 9
Evidence contexts supporting testing
Clinical trial and evidence contexts where MRD or multi-gene testing informed management or prognosis
See CLL meta-analysis, AML systematic review, and individual trials cited.
Evidence supports MRD as a trial surrogate endpoint though routine clinical adoption varies.
See HM-SCREENJapan 01 and related evidence summaries.
Guideline-supported indications
Coverage aligned with guideline-recommended use in the following contexts
source: chunk 54 (NCCN v2.2025)
source: chunk 55 (NCCN v2.2025)
source: chunk 56 (NCCN Multiple Myeloma guidance)
Optical genome mapping, whole transcriptome sequencing, and other broad molecular panels are listed in this policy as unproven and not medically necessary for clonality assessment or MRD evaluation in hematologic cancers. The policy text explicitly states that the use of molecular tests other than clonoSEQ for initial clonality assessment or MRD assessment is unproven and not medically necessary, and cites optical genome mapping and whole transcriptome sequencing as examples of tests considered not medically necessary.
The policy notes that evidence supporting routine use of broad multi-gene panels (for example, FoundationOne Heme and similar comprehensive panels) is limited in quality with respect to demonstrating improved clinical outcomes. Hayes and other evidence summaries reviewed in the policy identified that large panels detect potentially actionable alterations in a substantial proportion of patients, but peer-reviewed data showing that use of these panels improves patient outcomes are sparse or low quality; turnaround time and study design limitations are additional concerns.
The document warns that somatic mutation testing is typically not designed to detect germline mutations and therefore may be inadequate to identify heritable hematologic malignancy predisposition syndromes. When a hereditary predisposition is suspected, clinical correlation and consideration of germline-focused evaluation and counseling are recommended because somatic panels may miss germline variants.
Beyond clonoSEQ and the specific covered multigene and CGP uses described elsewhere in this policy, all other molecular test panels for hematologic cancer are considered unproven and not medically necessary. The policy explicitly lists optical genome mapping and whole transcriptome sequencing among examples of technologies for which evidence of clinical benefit is insufficient to support coverage.
Consensus and guideline authors note that while MRD status has prognostic significance in CLL and other hematologic malignancies, current recommendations do not support routine MRD testing in CLL outside of clinical trials. Expert consensus emphasizes need for standardized nomenclature, assay requirements, timing/frequency of assessment, and outcome reporting before MRD testing is adopted for routine clinical practice.
Covered Indications and Use Cases
Covered hematologic disease list
source: chunks 4 and 6
source: chunk 6
Use of multi-gene genomic profiling and MRD testing in trials to inform targeted therapy selection, prognosis, and guide therapy duration
source: chunks 24, 25, 28
source: chunks 25, 28
Diagnostic evaluation and prognostication per NCCN guidance for MDS, MPN, myelofibrosis, and multiple myeloma
source: chunks 54, 55, 56 (NCCN guidelines v2.2025/v2.2026)
Applicable Codes and Coding Guidance
| 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 | 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 |
| 0560U | Oncology (minimal residual disease [MRD]), genomic sequence analysis, cell-free DNA, whole blood and tumor tissue, baseline assessment for design and construction of a personalized variant panel to evaluate current MRD and for comparison to subsequent MRD assessments. |
| 0561U | Oncology (minimal residual disease [MRD]), genomic sequence analysis, cell-free DNA, whole blood, subsequent assessment with comparison to initial assessment to evaluate for MRD. |
| 0644U | Oncology (leukemia), minimal residual disease (MRD) detection for rearrangements, blood or bone marrow, personalized assay design and baseline quantification. |
| 0645U | Oncology (leukemia), minimal residual disease (MRD) detection for rearrangements, based on digital PCR, blood or bone marrow, reported as not detected or detected with estimated abundance. |
| 81195 | Cytogenomic (genome-wide) analysis, hematologic malignancy, structural variants and copy number variants, optical genome mapping (OGM). |
| 81450 | Hematolymphoid neoplasm or disorder, genomic sequence analysis panel, 5-50 genes, interrogation for sequence variants, and copy number variants or rearrangements, or isoform expression or mRNA expression levels, if performed; DNA analysis or combined DNA and RNA analysis. |
| 81451 | Hematolymphoid neoplasm or disorder, genomic sequence analysis panel, 5-50 genes, interrogation for sequence variants, and copy number variants or rearrangements, or isoform expression or mRNA expression levels, if performed; RNA analysis. |
| 81455 | Solid organ or hematolymphoid neoplasm or disorder, 51 or greater genes, genomic sequence analysis panel, interrogation for sequence variants and copy number variants or rearrangements, or isoform expression or mRNA expression levels, if performed; DNA analysis or combined DNA and |
| 81456 | Solid organ or hematolymphoid neoplasm or disorder, 51 or greater genes, genomic sequence analysis panel, interrogation for sequence variants and copy number variants or rearrangements, or isoform expression or mRNA expression levels, if performed; RNA analysis |
| 81479 | Unlisted molecular pathology procedure. |
| 81599 | Unlisted multianalyte assay with algorithmic analysis. |
| CPT mention | CPT is referenced generically (trademark) but no specific CPT/HCPCS codes are listed in these chunks. |
| 0644U | CPT-like code added per policy history |
| 0645U | CPT-like code added per policy history |
Provider Actions, Documentation, and Authorization Notes
Order tests only when ordered by a hematologist or oncologist
Testing covered under this policy must be ordered by a hematologist or oncologist for UnitedHealthcare Commercial and Individual Exchange members; multigene panels, CGP, and clonoSEQ claims should reflect ordering provider specialty.
- Applies to UnitedHealthcare Commercial and Individual Exchange benefit plans.
- Orders for covered indications must come from a hematologist or oncologist.
No explicit prior authorization specified in this excerpt
The extracted policy text and evidence summaries in these document chunks do not state explicit prior authorization code-level requirements or an operational prior authorization process for these tests.
- Clinical evidence and trial descriptions are presented but no explicit prior authorization instructions are included in these sections.
Verify member-plan coverage and prior auth for updated codes
CPT/CPT-like code list was updated in Policy History (adds 0644U and 0645U); providers must verify member-plan coverage and any prior authorization requirements with the member-specific benefit plan.
- Operational coding update: 0644U and 0645U added (effective 08/01/2026).
- Confirm coverage and any required prior authorization per the member-specific benefit plan before ordering.
Prefer multigene panels (≤50 genes) at diagnosis/recurrence; use CGP where indicated
Use multigene panels of 50 genes or fewer at initial diagnosis or recurrence; Comprehensive Genomic Profiling (CGP) (e.g., FoundationOne Heme, Neo Comprehensive-Heme, NEO AML Express) is specified as medically necessary for listed hematologic malignancies when ordered by a hematologist/oncologist.
- Covered indications include AML, ALL, MDS/MPN suspicion, and multiple myeloma.
- CGP named as proven and medically necessary for ALL, AML, MDS, and MPN in the policy text.
Document MRD-guided therapy duration decisions used in trials
MRD-guided, time-limited therapy strategies in trials used MRD results to determine duration of therapy (for example, discontinuation after achieving MRD-negative status in MASTER and MRD-guided ibrutinib–venetoclax in FLAIR).
- When MRD-guided strategies are used clinically, document MRD timing and the decision to stop or continue therapy per trial-derived algorithms.
- Evidence examples: MASTER used MRD <10^-5 to stop therapy; FLAIR used MRD to guide ibrutinib-venetoclax duration.
Provider action placeholder — check member-specific plan
(Reserved) — no additional provider action text available in the cited chunks; refer to member-specific plan and policy sections for applicable requirements.
- This placeholder is intentionally left for policy-specific operational instructions if defined elsewhere in the member-specific plan or policy.
Be prepared to provide medical record documentation for coverage review
Medical records may be requested to determine whether the member meets clinical criteria; benefit coverage is determined by the member-specific benefit plan and applicable laws.
- Medical records documentation may be required for review and does not guarantee coverage.
- Reference the member-specific benefit plan document when assessing coverage.
Document MRD assay, sensitivity, timing, and management decisions
For MRD-guided treatment strategies, documentation should include the MRD assay used, the assay sensitivity threshold (examples referenced: <10^-5 or 10^-6), the timing of MRD assessment, and resultant treatment decisions (e.g., discontinuation or initiation of maintenance).
- Specify the MRD assay and analytic sensitivity (e.g., <10^-5).
- Document timing of the MRD measurement and the clinical action taken based on the result.
Use bone marrow aspirate/stored aspirate for baseline clonotype ID and confirm lab regulatory context
For baseline clonotype identification and some MRD assessments, bone marrow aspirate or stored aspirate samples are recommended; laboratories performing genetic tests are regulated under CLIA and FDA informational resources are referenced.
- Baseline clonotype identification at diagnosis or storage of an aspirate is recommended to permit future NGS-based MRD testing.
- Confirm laboratory regulatory status (CLIA) and consider specimen requirements (bone marrow aspirate or stored aspirate samples).
Avoid non-clonoSEQ tests for clonality/MRD — denial risk
The policy states that molecular tests other than clonoSEQ for clonality or MRD assessment are unproven and not medically necessary; ordering such tests may result in denial of coverage.
- Use of molecular tests other than clonoSEQ for initial clonality assessment or MRD is listed as unproven and not medically necessary.
- Claims for non-clonoSEQ clonality/MRD assays may be denied per the policy.
Assess turnaround time before ordering for urgent decisions
Consider test turnaround time when ordering genomic panels for urgent decisions; FoundationOne Heme reported an approximate median turnaround time of 13 days, which may be too long for urgent treatment choices.
- If treatment decisions are time-sensitive, choose tests with appropriate turnaround times or document why a longer turnaround is clinically acceptable.
Member-specific benefit plan governs coverage determinations
Coverage decisions must reference the member-specific benefit plan document; in case of conflict, the member-specific benefit plan governs and applicable federal/state mandates should be checked.
- This Medical Policy provides guidance but the member-specific benefit plan controls coverage.
- Verify applicable federal or state mandates before use.
Consider germline evaluation and counseling when indicated
Somatic mutation testing may be inadequate to detect germline mutations; consider germline evaluation and genetic counseling when hereditary predisposition is suspected.
- Somatic testing is typically not designed to detect germline variants and may miss heritable predisposition syndromes.
- Refer for germline evaluation and counseling if clinical suspicion exists.
Ensure hematologist/oncologist orders for covered tests
Tests for covered indications must be ordered by a hematologist or oncologist; ensure orders reflect appropriate specialist involvement to meet policy criteria.
- Ordering provider specialty is part of the coverage criteria for multigene panels, CGP, and clonoSEQ.
MRD testing was clinician-ordered in trials; no formal prior-auth process stated here
In the trials cited, MRD testing was ordered and used by treating hematology/oncology teams to guide therapy; the policy text does not specify a formal operational prior authorization process for MRD testing in clinical practice.
- Trial contexts used treating teams to order MRD and make treatment decisions.
- No formal prior authorization workflow for MRD testing is described in these excerpts.
Use independent medical judgment and confirm member-specific coverage
Providers should exercise independent professional medical judgment and verify coverage against the member-specific benefit plan; the policy is intended as informational and does not replace clinical judgment.
- Use this policy alongside independent clinical judgment.
- Always confirm member-specific coverage terms before proceeding.
Not Covered / Investigational Uses
Use of molecular tests other than clonoSEQ for clonality or MRD assessment is not covered. All other molecular test panels for hematologic cancer — including but not limited to optical genome mapping and whole transcriptome sequencing — are considered unproven and not medically necessary and therefore are not covered under this policy.
Routine use of broad, off-the-shelf multi-gene panels to improve clinical outcomes is not established in the available literature. The policy highlights limited or low-quality evidence that large-panel testing (for example, FoundationOne Heme) leads to improved patient outcomes, and therefore routine coverage for that purpose is not supported.
Somatic mutation panels alone do not definitively establish a diagnosis of myelodysplastic syndrome in the absence of clinical diagnostic criteria. The NCCN guidance cited in the policy endorses gene panels to detect clonal hematopoiesis and aid evaluation, but emphasizes that genetic testing by itself is inadequate to diagnose MDS without correlating clinical and morphologic criteria.
Key Definitions
Background and Rationale
Hematologic cancers originate in blood-forming tissues and include entities such as leukemia, lymphoma, and multiple myeloma. Molecular profiling—from targeted single-gene assays to larger NGS panels and CGP—can assist with diagnosis, prognostication, and selection of targeted therapies in specific contexts. For myeloid neoplasms, multigene NGS panels have been shown to improve diagnostic and prognostic yield compared with limited single-gene testing, but the clinical utility for some broad-panel and novel technologies remains under evaluation.
Eligibility Requirements
No discrete top-level eligibility requirements are specified in the extracted portions of this policy. Refer to the member-specific benefit plan document and the policy sections describing covered indications (which require that tests be ordered by a hematologist or oncologist) for applicability and plan eligibility determinations.
This policy extract does not provide additional explicit eligibility criteria at the top level. Coverage decisions should be coordinated with the member-specific benefit plan and the clinical indications listed elsewhere in the policy (for example, multigene panels ≤50 genes at initial diagnosis/recurrence for specified hematologic malignancies).
No standalone prior-testing or family-history eligibility nodes are present in the provided extract. Clinicians should follow the policy’s covered indications and ordering requirements (tests ordered by hematologist/oncologist) and consult the full policy and member benefit documents for any additional plan-specific eligibility requirements.
Where eligibility questions remain, providers should verify coverage against the member’s benefit plan. The extract contains no additional top-level eligibility definitions; the full policy and plan documents govern final determinations.
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