ModifiedColorado Rocky Mountain Health PlansPolicy 2026T0652H

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

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Defines coverage and medical necessity criteria for multigene panels, comprehensive genomic profiling (CGP), and clonality/MRD testing for hematologic malignancies under UnitedHealthcare Commercial and Individual Exchange plans.

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ModifiedColorado Rocky Mountain Health PlansPolicy 2026T0652H

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

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Sign up for Colorado Rocky Mountain Health Plans Policy 2026T0652H alerts

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Policy Summary

PayerColorado Rocky Mountain Health Plans

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

Policy CodePolicy 2026T0652H

Change TypeCode list updateadded 2 CPT codes

Effective DateAug 1, 2026

Last ReviewAug 1, 2026

Next Review DateN/A

Key ActionOrder multigene panels, CGP, or clonoSEQ only when requested by a hematologist or oncologist and include documentation of assay type and sensitivity for MRD-based decisions.

SourceLink

POLICY UPDATE CHANGES

Updated list of applicable CPT codes to reflect quarterly edits; added 0644U and 0645U.

Supporting Information: Archived previous policy version 2026T0652G.

clonoSEQClonality / MRD assay named as covered

≤50 genesMultigene panel size referenced

13 daysMedian turnaround time (approx.)

Added 2 codesNew CPT codes added

>40References cited

Coverage and Medical Necessity Criteria

Medically necessary coverage

Covered when ordered by a hematologist or oncologist and when the individual has one of the specified diagnoses

Multigene panels (≤50 genes): Multigene panels (50 genes or fewer) are proven and medically necessary when ordered by a hematologist or oncologist for individuals with any of: acute myeloid leukemia; suspected myelodysplastic syndrome or myeloproliferative neoplasm (order from a hematologist/oncologist).

From Coverage Rationale

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

From Coverage Rationale

Clonality and MRD testing (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 listed hematologic malignancies.

clonoSEQ specifically named as proven/medically necessary

Unproven or not medically necessary tests

Not medically necessary / unproven

Unproven molecular tests: Due to insufficient evidence of efficacy, all other molecular test panels for hematologic cancer are unproven and not medically necessary. Examples include, but are not limited to, optical genome mapping and whole transcriptome sequencing. The use of molecular tests other than clonoSEQ for initial clonality assessment or MRD assessment is considered unproven and not medically necessary.

From Medicare Advantage Policy excerpt

Guideline-derived coverage considerations

Coverage and use considerations drawn from major guidelines and evidence summaries:

ALL: MRD assessment: Validated MRD assessment (minimum sensitivity >= 10^-4) is an essential component of evaluation during sequential ALL treatment; timing includes end of induction, end of consolidation, and additional regimen-determined time points. Baseline MRD may be required for some techniques and increased monitoring is appropriate for molecular relapse or persistent low-level disease.sensitivity >=10^-4

NCCN: consider FDA-approved NGS to confirm flow cytometry negativity

CLL: molecular and MRD testing: Cytogenetics, TP53 sequencing, IGHV mutation status, and MRD assessment using assays with at least 10^-4 sensitivity are recommended for prognostication and treatment decisions; NGS assays (up to 10^-6 sensitivity, e.g., clonoSEQ) are referenced by NCCN and may be used to increase sensitivity.sensitivity >=10^-4; NGS up to 10^-6

NCCN CLL guidance and FDA-cleared assay referenced

AML: molecular profiling and MRD:

Guideline-informed coverage considerations

Coverage considerations informed by guideline recommendations and test purpose

NCCN: MDS gene panels: NCCN endorses use of gene panels that include the genes most frequently somatically mutated in MDS to aid detection of clonal hematopoiesis, recognizing that such findings do not alone establish an MDS diagnosis without clinical criteria; testing selection should account for laboratory expertise.

NCCN Myelodysplastic Syndromes, v2.2025

MPN initial testing: NCCN recommends molecular testing for JAK2 V617F, CALR, MPL, JAK2 exon 12 or a multigene NGS panel during initial workup for suspected myeloproliferative neoplasm; NGS and karyotype are recommended at diagnosis and as indicated for myelofibrosis.

NCCN Myeloproliferative Neoplasms, v2.2025

MM: baseline clonotype for MRD: NCCN recommends baseline clonotype identification at diagnosis or storage of aspirate for future clonotype identification to permit MRD assessment via NGS and assessment for circulating plasma cells when clinically indicated.

NCCN Multiple Myeloma, v2.2026

Use of molecular tests other than clonoSEQ for initial clonality assessment or for measurable residual disease (MRD) assessment is considered unproven and not medically necessary. The policy explicitly lists optical genome mapping and whole transcriptome sequencing as examples of molecular tests that are not medically necessary for these purposes due to insufficient evidence of efficacy.

Results from multi-gene panels may not be timely for urgent treatment decisions; the policy notes a reported median turnaround time of approximately 13 days, which can limit the utility of panel results when rapid therapeutic action is required.

Major guideline groups advise caution about using MRD to change maintenance or other therapy outside of research settings. ASCO/CCO state there is insufficient evidence to modify maintenance therapy based on depth of response, including MRD status, and recommend MRD status not be used to guide treatment goals outside clinical trials. NCCN guidance similarly emphasizes MRD as an essential prognostic tool with defined timing but does not support routine MRD-directed therapy changes outside trial contexts.

Genetic testing designed to identify somatic mutations is typically not optimized to detect germline variants. The policy warns that somatic mutation panels may be inadequate to identify underlying heritable hematologic malignancy predisposition syndromes, so germline evaluation should be pursued when indicated.

The policy considers all other molecular test panels for hematologic cancers (beyond those specified as proven) to be unproven and not medically necessary due to insufficient evidence. Examples called out include optical genome mapping and whole transcriptome sequencing, among other panels and proprietary tests listed in the applicable codes section.

Current evidence does not support changing the type or duration of therapy solely on the basis of depth of response or MRD status outside of clinical trials. ASCO/CCO guidance specifically states there is insufficient evidence to support changes in therapy based only on MRD, and such decisions should be confined to research protocols.

FDA clearance or approval of a test is informational but not, by itself, a basis for coverage. The policy requires that tests be evaluated in the context of the available clinical evidence and the member’s specific benefit plan; laboratory CLIA certification and FDA resources are referenced for informational purposes only.

Applicable Procedure and Regulatory Codes

Applicable procedure codesmixed

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	Comparative sequence analyses and variant identification (description in document truncated).
0331U	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.

1–10 of 21

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Applicable CPT codes (updated)CPT

0644U	newly added code (policy lists as added)
0645U	newly added code (policy lists as added)

Regulatory identifiersmixed

CLIA	Clinical Laboratory Improvement Amendments - laboratory certification referenced

Multi-gene panel size — inv-15: Multi-gene panel size

Definition (policy)Multi-gene analysis generally refers to a gene panel containing five or more genes; policy distinguishes panels of 5-50 genes and panels of 51 or greater genes where applicable.

Applicable CPT groupingsCPT 81451 described for genomic sequence analysis panels of 5-50 genes; CPT 81455/81456 used for panels of 51 or greater genes.

Use contextMultigene panels (≤50 genes) are covered at initial diagnosis and/or recurrence/relapse when ordered by a hematologist or oncologist for listed hematologic malignancies.

MRD sensitivity thresholds — inv-16

Reported sensitivity rangeMRD detection ranges reported in studies include 10^-4, 10^-5, and 10^-6 depending on assay and study.

Ordering, Prior Authorization, and Documentation Requirements

Prior Authorization

Plan applicability and ordering clinician

This policy applies to UnitedHealthcare Commercial and Individual Exchange plans and specifies that covered clonality and MRD testing and multigene/CGP panels must be ordered by a hematologist or oncologist.

Prior Authorization

Prior authorization for molecular tests

The policy describes use of multi-gene panels (e.g., FoundationOne Heme) and MRD assays (e.g., clonoSEQ) for hematologic cancers; any prior authorization requirements or coverage determinations must follow payer rules and the member-specific benefit plan.

FoundationOne Heme is discussed as an example of a multi-gene/CGP test.
clonoSEQ is named as an MRD/clonality assay addressed in the policy.

Clinical Background and Rationale

Hematologic cancers arise in blood-forming tissues (for example, bone marrow) and include leukemia, lymphoma, and multiple myeloma. Molecular profiling approaches range from single-gene assays to multi-gene panels and comprehensive genomic profiling (CGP); these tests can inform prognosis and targeted therapy selection, but test choice and interpretation should align with clinical indication, assay design, and guideline recommendations.

Key Terms and Definitions

Comprehensive Genomic Profiling (CGP) — inv-35

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

PurposeDetects sequence variants, copy number variants, rearrangements and other alteration classes to inform prognosis and targeted therapy selection.

ExamplesPolicy lists examples such as FoundationOne Heme, Neo Comprehensive-Heme, and NEO AML Express in coverage rationale contexts.

Measurable Residual Disease (MRD) — inv-16

DefinitionMeasurable Residual Disease (MRD) refers to a very small number of cancer cells or genetic material detectable during or after cancer treatment; assessment methods include PCR, multiparameter flow cytometry, and/or NGS.

Clinical significance

Intended Line of Therapy and Test Use Cases

informational

Informational: Multigene panels, CGP, and validated MRD/clonality assays are described with indications across hematologic malignancies; refer to coverage rationale and guideline sections for disease-specific details.

Informational summary

first-line | relapsed/refractory

First-line and relapsed/refractory uses: MRD assessment is utilized in both first-line and relapsed/refractory settings to guide therapy duration and prognostication in CLL, MM, ALL, and AML; some randomized trials used MRD-guided strategies to determine therapy length or discontinuation (e.g., FLAIR, MASTER).

Clinical evidence summaries

multiple

Key Biomarkers and Thresholds

FLT3, IDH1/2, TP53, KIT, WT1, DNMT3A — inv-49

Listed biomarkersFLT3, IDH1/2, TP53, KIT, WT1, DNMT3A are listed as biomarkers identified by CGP that may be actionable or prognostic in AML and other hematologic malignancies.

Clinical useThese biomarkers are used for prognostication and to identify potential targeted therapy options where applicable.

Evidence exampleHM-SCREENJapan01 identified actionable mutations including FLT3 and IDH1/2 supporting targeted therapy selection in a subset of participants.

TP53 — inv-50

Prognostic thresholdTP53 variant allele frequency ≥ 40% was associated with markedly poor prognosis in the HM-SCREENJapan01 study.

Clinical implicationHigh TP53 VAF may inform prognostication and treatment determination in AML and other hematologic malignancies.

Regimens and MRD-Adapted Trial Examples

Regimen	Indication / Setting	MRD-guided action	Coverage label
Zanubrutinib + venetoclax + obinutuzumab
Relapsed or refractory chronic lymphocytic leukemia (CLL)
Time-limited treatment with MRD-guided discontinuation after achievement of deep MRD remissions based primarily on peripheral blood MRD measurements
Informational

Regimen	Indication / Setting	MRD-guided action / Key trial outcome	Coverage label
Ibrutinib + venetoclax
Frontline (previously untreated) chronic lymphocytic leukemia (CLL)
MRD-guided duration of therapy (as used in the FLAIR trial); compared to FCR, MRD-guided ibrutinib‑venetoclax showed superior progression‑free and overall survival at ~3 years
Informational

Regimen	Indication / Setting	MRD-guided action / Key trial outcome	Coverage label
Daratumumab + carfilzomib + lenalidomide + dexamethasone (Dara-KRd)
Newly diagnosed multiple myeloma (enrolled in MASTER trial; induction followed by ASCT and consolidation)
MRD-SURE protocol: NGS MRD assessment during/after consolidation; if two consecutive MRD‑negative results (<10^-5), therapy discontinued and observation commenced; otherwise start lenalidomide maintenance
Informational

Policy Summary

PayerColorado Rocky Mountain Health Plans

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

Policy CodePolicy 2026T0652H

Change TypeCode list updateadded 2 CPT codes

Effective DateAug 1, 2026

Last ReviewAug 1, 2026

Next Review DateN/A

Key ActionOrder multigene panels, CGP, or clonoSEQ only when requested by a hematologist or oncologist and include documentation of assay type and sensitivity for MRD-based decisions.

SourceLink

On This Page

Multiplex gene panels and targeted NGS are indicated for management and relapse evaluation in AML. MRD assessment is prognostically important but routine adoption is limited by lack of standardization; commonly used MRD methods include RT-qPCR and multicolor flow cytometry, as standard NGS is generally not designed for MRD due to lower sensitivity.

NCCN AML guidance; participation in clinical trials encouraged

MM: MRD and response assessment: Depth of response including MRD has prognostic significance in multiple myeloma, but current evidence is insufficient to support changing maintenance therapy or altering treatment solely on MRD status outside of clinical trials; IMWG criteria should be used for response assessment with routine frequency recommendations while on maintenance (at minimum every 3 months).clinical trial context for MRD-guided therapy changes

ASCO/CCO and IMWG recommendations

MDS/MPN: molecular testing at diagnosis: Gene panels including commonly mutated genes in MDS and targeted testing for JAK2, CALR, MPL (or a multigene NGS panel including these) are endorsed by NCCN for initial workup to aid diagnosis and prognostication; selection of test panel should consider indication and laboratory expertise. In myelofibrosis, NGS and karyotyping at diagnosis and as clinically indicated are recommended.test selection based on indication

NCCN MDS and MPN guidance

Assay variabilityDifferent MRD detection methods (MFC, ASO-PCR, NGS) have varied sensitivity and specificity, which can affect comparability across studies.

Clinical relevanceUndetectable MRD is associated with improved progression-free survival in CLL and better median PFS in MM at higher sensitivity thresholds (e.g., 10^-5 to 10^-6).

MRD assay sensitivity thresholds — inv-17

Guideline minimum sensitivityGuidelines recommend MRD assays with a minimum sensitivity of 10^-4 for MRD assessment.

NGS assay capabilityNGS-based assays (including FDA-authorized tests) can achieve higher sensitivity, with some assays detecting MRD to the level of 10^-6.

Confirmation recommendationIf MRD is negative by flow cytometry, consideration of an FDA-approved NGS assay to confirm negativity is recommended by guidelines.

Documentation Required

Use validated MRD assays and report sensitivity

When MRD-based decisions are used, requests should document use of validated MRD assays and state the assay sensitivity; guidelines cite a minimum recommended sensitivity of 10^-4 and recommend considering FDA-authorized NGS assays (e.g., clonoSEQ) to confirm negativity when flow cytometry is negative.

NCCN and guideline text cite MRD assay sensitivity thresholds (minimum 10^-4; NGS assays may detect to 10^-6).
Document the assay type and sensitivity with prior authorization or clinical review.

Billing Rule

Confirm prior auth and billing for updated CPT codes

The policy coding list was updated to reflect quarterly edits and two new CPT-level codes (0644U and 0645U) were added; providers should verify whether these updated codes affect prior authorization or billing requirements for the member's plan.

New codes added to policy: 0644U and 0645U (see applicable codes list).
Check member-specific plan for any changes to prior authorization tied to new codes.

Step Therapy

Step therapy not specified

No step therapy requirements are specified in this policy excerpt.

Note

Follow MRD-guided trial protocols where applicable

Clinical trials cited in the policy used MRD-guided therapy duration to stop or limit therapy (examples include zanubrutinib + venetoclax + obinutuzumab and ibrutinib + venetoclax); follow documented MRD-guided protocols when applied in those trial contexts.

MASTER trial (Dara-KRd with MRD-SURE) used MRD to discontinue therapy in multiple myeloma.
FLAIR trial adapted to use MRD to determine duration of ibrutinib-venetoclax in CLL.

Denial Risk

Do not alter maintenance therapy based on MRD outside trials

Per ASCO/CCO and other guideline statements cited in the policy, depth of response including MRD should not be used outside clinical trials to modify maintenance therapy or to change the type or length of therapy.

ASCO/CCO: insufficient evidence to modify maintenance therapy based on MRD outside clinical trials.

Documentation Required

Medical records may be required for coverage review

Medical records and documentation may be requested to determine whether the member meets the clinical criteria for coverage; benefit coverage is determined by the member-specific benefit plan and applicable laws.

Medical records may be required to support that clinical criteria are met.
Refer to member-specific benefit plan for coverage determination.

Documentation Required

Document MRD results, assay sensitivity, and treatment actions

Document MRD testing results clearly, including the assay used, stated sensitivity threshold (e.g., 10^-4, 10^-5, 10^-6), timing of assessment, and any treatment decisions made (for example, therapy discontinuation per MRD-SURE).

Record assay type and sensitivity and the time point of MRD assessment.
Document consequent treatment decisions such as discontinuation or maintenance initiation.

Documentation Required

Obtain and document sufficient diagnostic samples and testing performed

Ensure and document that sufficient samples were obtained for morphologic assessment, karyotype, molecular genetic and/or FISH testing, and flow cytometry as appropriate; for extramedullary disease, document processing of tissue biopsy for morphologic, immunophenotypic, cytogenetic, and molecular genetic studies.

Document sample type(s) collected (bone marrow, peripheral blood, tissue) and tests performed.
Document that flow cytometry panels and cytogenetic testing were adequate per CAP/ASH guidance.

Prior Authorization

Verify member plan benefits and governing documents

When making coverage decisions, reference the member-specific benefit plan document; in the event of conflict, the member plan governs. Check the member's plan and applicable federal/state mandates before ordering or billing tests.

Member-specific benefit plan terms supersede this policy if there is a conflict.
Verify plan coverage for specific variants or tests before ordering.

Denial Risk

Avoid unsupported MRD/clonality tests other than clonoSEQ

The policy states that use of molecular tests other than clonoSEQ for clonality assessment or MRD assessment is unproven and not medically necessary; ordering such tests risks denial.

clonoSEQ is specifically named as proven/medically necessary; other molecular MRD/clonality assays are considered unproven.

Denial Risk

Timeliness risk for multi-gene panel results

Be aware that multi-gene panel turnaround time may be lengthy (median ~13 days reported for FoundationOne Heme) and that delays may render results unusable for urgent treatment decisions.

Consider the reported median turnaround time (~13 days) when ordering tests for urgent clinical decisions.

Documentation Required

Do not omit conventional cytogenetics; document required diagnostic testing

Molecular genetic and/or FISH testing does not replace conventional cytogenetic analysis; failure to obtain sufficient samples and perform recommended testing may limit diagnostic accuracy and risk inadequate evaluation.

CAP/ASH: obtain sufficient samples and perform karyotype, molecular-genetic and/or FISH testing, and flow cytometry at diagnosis.
Document that conventional cytogenetic analysis was performed as indicated.

Denial Risk

FDA clearance alone does not guarantee coverage

Coverage decisions should not be based solely on FDA clearance; tests must be interpreted in the context of clinical evidence, CLIA certification, and the member-specific benefit plan—reliance on FDA approval alone may not prevent denial.

FDA approval alone is not a basis for coverage per the policy.
Laboratories must be CLIA-certified; coverage still depends on medical necessity and member plan.

Residual evidence of cancer after treatment can be associated with earlier relapse and can inform treatment planning and monitoring.

Typical useMRD measurement is most often used for blood cancers (e.g., ALL, CLL, MM) and is used for prognostic assessment and clinical trial endpoints.

Next Generation Sequencing (NGS) — inv-37

DefinitionNext Generation Sequencing (NGS) comprises sequencing techniques that can quickly analyze multiple sections of DNA simultaneously, enabling multi-gene panels and CGP.

Role in MRD and CGPNGS is used for both comprehensive genomic profiling and high-sensitivity MRD assays; some NGS assays detect MRD down to 10^-6.

ImplicationNGS-based results can identify actionable alterations but may have longer turnaround times relevant to urgent treatment decisions.

MRD (measurable residual disease) — inv-38

Definition (policy)MRD refers to detection of residual cancer cells after treatment using sensitive molecular or flow cytometry techniques; reported detection thresholds in studies vary (e.g., 10^-4 to 10^-6).

Clinical findingsNGS assays can detect MRD when flow cytometry is negative and provide additional prognostic information, though standardization across methods is lacking.

GuidanceGuidelines and consensus publications note MRD is prognostically significant but routine clinical use to alter maintenance therapy outside trials is not yet recommended.

Multi-gene panel (e.g., FoundationOne Heme) — inv-39

Definition / assay typeMulti-gene panels (e.g., FoundationOne Heme) are next-generation sequencing assays that profile genes (DNA and RNA) to identify somatic mutations, fusions, and potentially actionable alterations.

Study findingsFoundationOne Heme studies reported detection of potentially actionable alterations in 32% to 90% of individuals in evaluated studies and identified targetable mutations in HM-SCREENJapan01 (38% of participants).

Coverage contextPolicy references FoundationOne Heme as an example of CGP used to inform therapeutic options in hematologic cancers.

clonoSEQ — inv-40

Test identityclonoSEQ is an FDA-authorized NGS assay for MRD detection in B-ALL, multiple myeloma, and CLL.

PerformanceHayes and NICE reviews report clonoSEQ has greater sensitivity and standardization compared with some other MRD techniques, though randomized outcome data are limited.

Use in policyPolicy names clonoSEQ specifically as a proven and medically necessary option for clonality and MRD testing when ordered by a hematologist or oncologist for listed indications.

MRD sensitivity threshold — inv-41

DefinitionMRD sensitivity threshold is the lowest fraction of residual malignant cells an assay can reliably detect; guidelines cite a minimum sensitivity of 10^-4 for MRD assays.

Higher sensitivity optionsSome FDA-approved NGS assays (e.g., clonoSEQ) are capable of detecting MRD to levels of 10^-6, which may identify cases missed by flow cytometry.

Guideline recommendationNCCN and expert consensus recommend use of validated assays with at least 10^-4 sensitivity and consideration of NGS confirmation when flow cytometry is negative.

DTA mutations — inv-42

Definition and examplesDTA mutations refer to mutations in DNMT3A, TET2, and ASXL1 often associated with age-related clonal hematopoiesis that may persist after therapy and frequently do not indicate active malignant disease.

Implication for MRDDTA mutations commonly persist and may represent non-leukemic clones, requiring exclusion when interpreting MRD for relapse risk assessment.

Study evidenceIn AML NGS MRD studies, DTA mutations persisted at high rates (e.g., 78.9%) and were excluded to improve MRD-based prognostic associations.

Clonal hematopoiesis — inv-43

DefinitionClonal hematopoiesis is the presence of somatic mutations frequently seen in MDS that indicate clonal cell populations and can help exclude benign causes of cytopenia but do not alone establish an MDS diagnosis.

Testing considerationsGene panels including frequently mutated MDS genes are endorsed by guidelines to detect clonal hematopoiesis; however, somatic testing is not sufficient to diagnose MDS without clinical criteria.

Germline limitationSomatic mutation testing is typically not designed to detect germline mutations and may be inadequate to identify heritable predisposition syndromes.

Minimal/Measurable residual disease (MRD) — inv-44

DefinitionMinimal/Measurable residual disease (MRD) denotes low-level disease persistence detectable by high-sensitivity assays (e.g., NGS) used for prognostic assessment and treatment guidance in multiple myeloma, ALL, and CLL.

Clinical roleMRD status is prognostically significant across several hematologic malignancies, but routine use to alter maintenance therapy outside clinical trials is not currently recommended.

Assay examplesCommon MRD assay methods include multiparameter flow cytometry, ASO-PCR, and NGS (including FDA-authorized assays like clonoSEQ).

Multiple timing examples:

Examples of MRD timing: CLL — at least 2 months after completion of treatment and aligned with response assessment; ALL — after end of induction, early consolidation (~3 months), and approximately every 3 months for at least 3 years; MM — assessed during response evaluation and in trials; AML — at diagnosis for marker establishment, after two cycles and at end of treatment, with additional timing guided by regimen. These examples reflect guideline and consensus recommendations.

From expert consensus and trials

diagnostic/initial

Diagnostic/initial testing: During initial workup for suspected myeloproliferative neoplasms, NCCN recommends testing for JAK2 V617F, CALR, MPL, and JAK2 exon 12 or a multigene NGS panel including these genes; baseline clonotype identification or sample storage is recommended in multiple myeloma to permit later MRD assessment via NGS.

NCCN recommendations for initial evaluation

Study contextFinding derived from prospective genomic profiling using FoundationOne Heme in HM-SCREENJapan01 (n=188).

FLT3, IDH1/2, DNMT3A — inv-51

Biomarkers listedFLT3, IDH1/2, DNMT3A are included among biomarkers identified by CGP for potential targeted alteration identification.

Use caseDetection of these alterations can support consideration of targeted therapies or clinical trial options.

Evidence sourceReported in HM-SCREENJapan01 and Hayes Molecular Test Assessment summaries.

TP53, del(17p) — inv-52

BiomarkersTP53 and del(17p) are listed as important biomarkers for prognostication and treatment determination in CLL.

Clinical recommendationNCCN recommends TP53 sequencing and assessment of del(17p) by FISH as part of CLL workup for prognostication and therapy selection.

ContextUsed in conjunction with IGHV status and MRD assessment for comprehensive CLL evaluation.

JAK2 V617F, CALR, MPL, JAK2 exon 12 — inv-53

Biomarkers for MPN workupJAK2 V617F, CALR, MPL, and JAK2 exon 12 mutations are recommended for initial molecular testing in suspected myeloproliferative neoplasms.

Testing settingTesting can be performed on blood or bone marrow and NGS panels including these genes are acceptable during initial workup.

Guideline sourceRecommendation per NCCN Myeloproliferative Neoplasms v2.2025.

Common somatic mutations in MDS panels — inv-54

Common MDS panel targetsPolicy references gene panels including the genes most frequently somatically mutated in MDS to aid diagnosis when MDS is uncertain.

Interpretation cautionDetection of these somatic mutations indicates clonal hematopoiesis but does not by itself establish an MDS diagnosis without clinical criteria.

Laboratory selectionBecause commercially available tests differ in genes analyzed, consider the clinical indication and laboratory expertise when selecting a panel.

JAK2 V617F — inv-55

BiomarkerJAK2 V617F is listed as a recommended molecular test for initial workup of suspected myeloproliferative neoplasm.

SpecimenCan be detected in blood or bone marrow; included in targeted mutation panels and multigene NGS panels.

GuidelineNCCN MPN guideline recommends testing for JAK2 V617F during initial evaluation.

CALR — inv-56

BiomarkerCALR mutations are recommended targets for molecular testing in suspected myeloproliferative neoplasms.

Clinical roleDetection assists diagnosis and prognostication, and can be included in NGS panels at initial workup.

Guideline sourceRecommended by NCCN Myeloproliferative Neoplasms v2.2025.

MPL — inv-57

BiomarkerMPL mutations are recommended for testing during initial evaluation for suspected myeloproliferative neoplasms.

UseIncluded in targeted assays or multigene NGS panels to support diagnosis and risk assessment.

GuidancePart of NCCN-recommended initial molecular testing for MPNs.

JAK2 exon 12 — inv-58

BiomarkerJAK2 exon 12 mutations are listed for evaluation during initial workup of suspected myeloproliferative neoplasms.

Testing contextConsidered when JAK2 V617F is negative and clinical suspicion for MPN remains; can be included on targeted or NGS panels.

GuidelineRecommended by NCCN as part of initial molecular evaluation for MPNs.