CurrentUnitedHealthcarePolicy CS372.F

Molecular Oncology Hematologic Cancer Diagnosis Cs

Defines UnitedHealthcare medical policy CS372.F regarding when multigene NGS panels, comprehensive genomic profiling (CGP), and clonality/MRD testing (clonoSEQ) are considered medically necessary or not, applicable to hematologic malignancies; includes applicable CPT/HCPCS proprietary codes and evidence background. Excludes specific states per application section.

Policy Summary

PayerUnitedHealthcare

PolicyMolecular Oncology Hematologic Cancer Diagnosis Cs

Policy CodePolicy CS372.F

Change TypeRevisions (02/01/2026) + template update

Effective DateFeb 1, 2026

Next Review Date

Key ActionOrder multigene panels, CGP, or clonoSEQ only when criteria are met and the test is ordered by a hematologist or oncologist; documentation may be requested.

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 listed conditions.

Clonality assessment with clonoSEQ® at initial diagnosis and MRD assessment with clonoSEQ®: added criterion requiring the individual has chronic lymphocytic leukemia for some uses.

Replaced prior coverage language to state Comprehensive Genomic Profiling (CGP) is proven and medically necessary for individuals with ALL, AML, MDS, or myeloproliferative neoplasm.

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

Removed content/language pertaining to the state of Louisiana.

Updated Clinical Evidence, FDA, and References sections to reflect current information.

Coverage Summary

This policy (Policy Number CS372.F, Effective Date February 1, 2026) defines UnitedHealthcare medical policy for molecular oncology testing in hematologic malignancies. It addresses coverage for multigene NGS panels (≤50 genes), Comprehensive Genomic Profiling (CGP) (examples: FoundationOne® Heme, Neo Comprehensive™ - Heme Cancers, NEO AML Express™), and clonoSEQ® for clonality assessment and measurable residual disease (MRD). Coverage stance: mixed — certain uses of multigene NGS panels, CGP, and clonoSEQ are proven and medically necessary under specified clinical criteria; other molecular technologies are considered unproven/not medically necessary. The policy application excludes specific states per the Application section (see state-specific notes).

Key thresholds and facts

Gene panel size (coverage criterion)50 genes or fewer

MRD sensitivity examples referenced10^-4, 10^-5, 10^-6 (study-specific thresholds)

Assay sensitivity range notedNGS/clonoSEQ achievable sensitivity 10^-6; guideline-recommended minimum 10^-4

TP53 VAF example linked to prognosisTP53 variant allele frequency ≥ 40% associated with markedly poor prognosis (HM-SCREENJapan01)

MRD impact examplesUndetectable MRD associated with improved PFS/OS across CLL, ALL, MM, AML studies (meta-analyses and trials)

Covered indications counts (high-level stats)Covered indications: multigene panels (≤50 genes) = 4; CGP = 4; clonoSEQ (clonality/MRD) = 3; unproven tech examples listed = 2; guideline-supported categories ≥4

Medical-Necessity Criteria

Coverage Rationale - Multigene panels (<=50 genes)

Covered when ALL of the following are met:

ALL of the following

Indication ANY
- Acute lymphoblastic leukemia
- Acute myeloid leukemia
- Multiple myeloma
- Myelodysplastic syndrome or myeloproliferative neoplasm (as evidenced by order from a hematologist or oncologist)

Not Medically Necessary / Unproven Technologies

Not Medically Necessary / Unproven

Molecular tests other than clonoSEQ for initial clonality assessment or for MRD assessment

These uses are considered unproven and not medically necessary

All other molecular test panels for hematologic cancer due to insufficient evidence of efficacy (includes but not limited to optical genome mapping and whole transcriptome sequencing)

Unproven and not medically necessary

The policy states that molecular tests other than clonoSEQ are considered unproven and not medically necessary for initial clonality assessment or for assessment of MRD. Examples specifically noted as unproven include optical genome mapping and whole transcriptome sequencing (policy indicates the list is not exhaustive).

Coding

Referenced Proprietary and CPT/PLA (CMS) Codes in policy textmixed

0017M	Oncology [diffuse large B-cell lymphoma (DLBCL)], mRNA, gene expression profiling by fluorescent probe hybridization of 20 genes, FFPE tissue, algorithm reported as cell of origin.
0050U	Targeted genomic sequence analysis panel, acute myelogenous leukemia, DNA analysis, 194 genes.
0120U	Oncology (B-cell lymphoma classification), mRNA, gene expression profiling by fluorescent probe hybridization of 58 genes, FFPE tissue, algorithm reported as likelihood for PMBCL and DLBCL with cell of origin subtyping.
0171U	Targeted genomic sequence analysis panel, AML, MDS, and MPN, DNA analysis, 23 genes, including MRD, reported presence/absence.
0298U	Oncology (pan tumor), whole transcriptome sequencing of paired malignant and normal RNA specimens.
0299U	Oncology (pan tumor), whole genome optical genome mapping of paired malignant and normal DNA specimens.
0300U	Oncology (pan tumor), whole genome sequencing and optical genome mapping, paired malignant and normal DNA specimens.
0331U	Oncology (hematolymphoid neoplasia), optical genome mapping for copy number alterations and gene rearrangements using blood or bone marrow DNA.
0364U	Oncology (hematolymphoid neoplasm), genomic sequence analysis using multiplex (PCR) and NGS with algorithm, quantification of dominant clonal sequence(s), reported presence/absence of MRD with quantitation.
0413U	Oncology (hematolymphoid neoplasm), optical genome mapping for copy number alterations, aneuploidy, and balanced/complex structural rearrangements.

1–10 of 20

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Example CGP tests named in policymixedCovered

FoundationOne® Heme	Example of Comprehensive Genomic Profiling (CGP) that is proven and medically necessary for specified hematologic malignancies
Neo Comprehensive™ - Heme Cancers	Example of CGP that is proven and medically necessary for specified hematologic malignancies
NEO AML Express™	Example of CGP that is proven and medically necessary for specified hematologic malignancies

ClonoSEQ testmixedCovered

clonoSEQ®

FDA-cleared NGS-based assay for MRD detection and clonality assessment (used for ALL, MM, CLL per evidence/clearances)

Code listings and procedure codes in this policy are provided for reference only; inclusion does not imply coverage or guarantee reimbursement. Documentation and plan/contract, federal, or state requirements determine benefit coverage.

Provider Actions / Billing

Prior Authorization

Ordering provider specialty requirement

Orders for molecular oncology testing described in this policy must be placed by a hematologist or oncologist. The payer may request medical records to verify the ordering provider's specialty and the clinical indication; submission of records does not guarantee coverage.

Documentation Required

Medical records documentation may be required

Medical records documentation may be required to assess whether the member meets the policy clinical criteria. Documentation submitted for review does not guarantee coverage of the requested service.

Background & Evidence

This policy covers molecular profiling technologies used for diagnosis, prognosis, and MRD assessment in hematologic cancers, including Next Generation Sequencing (NGS) panels, Comprehensive Genomic Profiling (CGP), and MRD assays such as clonoSEQ. The background summarizes evidence from systematic reviews, trials, and assessments (e.g., Hayes, NICE, multiple clinical trials) supporting associations between MRD negativity and improved progression-free and overall survival, and demonstrating diagnostic and prognostic utility of NGS/CGP in myeloid and lymphoid malignancies.

Study/Source	Key findings
Soderquist et al. (2024)
98% of NGS panel outcomes provided helpful clinical data; 89% led to or clarified diagnosis; 94% provided prognostic information; 19% detected potential therapeutic targets.
HM-SCREENJapan01 (Hosono et al., 2023)
Genomic alterations identified in 97.3% of participants; actionable mutations in 38%; TP53 VAF ≥40% associated with poor prognosis; feasible using paraffin-embedded BM clot specimens.
CLL MRD meta-analysis (Rios-Olais et al., 2024)
Undetectable MRD associated with higher 24-month PFS (91.9% vs 75.3%); supports MRD as prognostic and surrogate endpoint in trials.
MASTER trial (Costa et al., 2023)
81% achieved MRD <10^-5; 71% reached MRD-SURE and discontinued therapy; outcomes poorer for individuals with two or more high-risk chromosome abnormalities.
CLL MRD meta-analysis (Molica et al., 2019)
Undetectable MRD associated with superior PFS and OS in CLL across analyzed studies.
NGS vs flow cytometry in AML (Jongen-Lavrencic 2018)
NGS detection of MRD after induction associated with higher relapse and lower RFS/OS; combining NGS with flow cytometry adds prognostic value.
clonoSEQ FDA clearance / Hayes assessment
clonoSEQ cleared for MRD detection and monitoring in ALL, MM, and CLL; Hayes assessment notes lower sensitivity threshold versus other methods and predictive validity in studies.

Comprehensive Genomic Profiling (CGP): A type of NGS test that detects all classes of genomic alterations, including cancer biomarkers, with a single sample.

Measurable Residual Disease (MRD): Very small number of cancer cells detectable during/after treatment not seen on routine techniques; used to guide prognosis and treatment decisions.

Next Generation Sequencing (NGS): Sequencing techniques that analyze multiple DNA sections simultaneously.

MRD (alternate term): Measurable (minimal) residual disease — small number of cancer cells that remain during or after treatment and can be detected using sensitive molecular or flow cytometry methods.

CGP (alternate term): Comprehensive Genomic Profiling — broad genomic testing to identify genomic alterations for diagnosis, prognosis, or targeted treatment planning.

Revision History

02/01/2026revisedLatest

Replaced stronger 'strongly suspected' language with 'suspected' for MDS/myeloproliferative neoplasm; clarified multigene panels (50 genes or fewer) at initial diagnosis and/or recurrence or relapse are proven and medically necessary when ordered by a hematologist or oncologist for listed conditions.

02/01/2026revisedLatest

Broadened clonoSEQ indications and clarified MRD testing language: added criterion requiring the individual has chronic lymphocytic leukemia for some clonoSEQ uses; specified 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 ALL, MM, and CLL.

Policy Summary

PayerUnitedHealthcare

PolicyMolecular Oncology Hematologic Cancer Diagnosis Cs

Policy CodePolicy CS372.F

Change TypeRevisions (02/01/2026) + template update

Effective DateFeb 1, 2026

Next Review Date

Key ActionOrder multigene panels, CGP, or clonoSEQ only when criteria are met and the test is ordered by a hematologist or oncologist; documentation may be requested.

SourceLink

On This Page

Use of Multigene Panels (50 genes or fewer) at Initial Diagnosis and/or Recurrence or Relapse

Use when ALL of the following are met:

ALL of the following

Multigene panel of 50 genes or fewer (panel size threshold: <= 50 genes)
Order should be placed by a hematologist or oncologist; panel size threshold is 50 genes or fewer
Indication ANY: Acute lymphoblastic leukemia; Acute myeloid leukemia; Multiple myeloma; Myelodysplastic syndrome or myeloproliferative neoplasm (as evidenced by order from hematologist/oncologist)
Use at initial diagnosis and/or recurrence or relapse
Operational node: ensure documentation in order that a hematologist/oncologist suspected the listed hematologic cancer

Coverage Rationale - Comprehensive Genomic Profiling (CGP)

Covered when ALL of the following are met:

ALL of the following

Indication ANY
- Acute lymphoblastic leukemia
- Acute myeloid leukemia
- Myelodysplastic syndrome
- Myeloproliferative neoplasm
Comprehensive Genomic Profiling (CGP) test (able to detect multiple classes of genomic alterations in a single sample)

Comprehensive Genomic Profiling (CGP)

Use when ALL of the following are met:

ALL of the following

Comprehensive Genomic Profiling (CGP) test ordered by a hematologist or oncologist
Indication ANY: Acute lymphoblastic leukemia; Acute myeloid leukemia; Myelodysplastic syndrome; Myeloproliferative neoplasm

Coverage Rationale - Clonality assessment and MRD using clonoSEQ

Covered when ALL of the following are met:

ALL of the following

Test is clonoSEQ®
Ordered by a hematologist or oncologist to document clonality and/or assess measurable residual disease (MRD)
Indication ANY
- Acute lymphoblastic leukemia
- Multiple myeloma
- Chronic lymphocytic leukemia

Molecular tests other than clonoSEQ for clonality or MRD

Not covered when ANY of the following apply:

ANY of the following

Molecular tests other than clonoSEQ® for clonality assessment or MRD assessment
All other molecular test panels for hematologic cancer not specifically listed as covered (e.g., optical genome mapping, whole transcriptome sequencing, whole genome sequencing)

Billing Rule

Use of named tests

When ordering named tests such as Comprehensive Genomic Profiling (e.g., FoundationOne® Heme, Neo Comprehensive™ - Heme Cancers) or clonoSEQ®, use the appropriate test identifier and include supporting clinical documentation (order indication and relevant medical records) to facilitate prior authorization and claims review.