BCBSRI MRD Testing Coverage & Prior Auth

Coverage Criteria for MRD Testing

MRD testing medical necessity (liquid-based proprietary tests)

Covered when ALL of the following are met

Medicare Advantage / Commercial medical necessity criteria: 1. The patient has advanced cancer, plans to be treated for the cancer, and has not previously been tested with the same test for the same genetic content; OR 2. The patient has a personal history of cancer within the test's intended use population; AND 3. Identification of recurrence or progression within the intended use population is recognized in NCCN or other established guidelines as requiring a definitive change in patient management; AND 4. The test has demonstrated it can identify molecular recurrence or progression before clinical, biological, or radiographical evidence and demonstrates sensitivity and specificity of subsequent recurrence or progression comparable with or superior to radiographical or other standard-of-care evidence; AND 5. Use of the test precludes other surveillance/monitoring tests intended to provide the same or similar information, unless those tests are required to confirm findings or are medically required for further assessment and management.

Applies to Guardant Response and Guardant Reveal as listed; prior authorization is required for Medicare Advantage Plans and recommended for Commercial Products; unlisted CPT codes require prior authorization.

clonoSEQ hematologic malignancy coverage

Covered when ALL of the following are met

clonoSEQ indications: clonoSEQ may be considered medically necessary for Acute lymphoblastic leukemia (ALL), Multiple myeloma (MM), Chronic lymphocytic leukemia (CLL), and Diffuse Large B-Cell Lymphoma (DLBCL).

See Coding section for CPT 0364U and related coding details; prior authorization requirements apply as stated in policy.

Disease-specific supportive coverage contexts

Clinical contexts where MRD testing is supported by evidence/guidelines

Established hematologic uses: MRD testing is established and supported by guidelines for CML (BCR-ABL1 qPCR), AML/APL (molecular targets such as NPM1, PML-RARA, CBF fusions), ALL, MM, CLL and certain lymphomas for risk stratification and treatment decisions.

Methodologies (PCR, flow, NGS) and targets vary by disease; follow disease-specific guideline schedules.

AML/MDS specifics: In AML and MDS, molecular MRD (e.g., NPM1, PML-RARA, core‑binding factor fusions) predicts relapse and can guide decisions such as referral for allogeneic HSCT or pre-emptive therapy (e.g., azacitidine in RELAZA2-like contexts).

Supported by ELN and NCCN endorsements and trial evidence.

CML specifics: BCR-ABL1 RT-qPCR is the standard MRD test in CML and guides switching TKIs, HSCT referral, or TKI discontinuation when qPCR sensitivity meets MR4.5 thresholds.

See biomarker thresholds for BCR-ABL1 sensitivity requirements.

Clinical utility and constraints

Clinical context and utility statements extracted from the document describing where MRD/ctDNA testing demonstrates utility

Hematologic malignancies (CLL, ALL, MM, lymphoma): NGS-based MRD assessment targeting IgH or other tumor-specific targets has higher sensitivity and better prediction of outcomes than flow cytometry or PCR in many contexts and is an important predictor of treatment efficacy and prognosis.

NCCN and other guidelines recognize MRD for risk stratification and management decisions.

ctDNA in lymphoma and solid tumors: ctDNA assays can detect residual disease earlier than imaging (lead times reported of approximately 3–6 months in lymphoma and measurable lead times in solid tumor studies), enabling risk-adapted strategies and potential reduction in surveillance imaging frequency.

Serial monitoring is important because patients can convert from ctDNA-negative to positive over time.

Limitations and necessary considerations: ctDNA results may be discordant with tissue due to tumor heterogeneity and clonal evolution; clonal hematopoiesis of indeterminate potential (CHIP) can confound ctDNA results and lead to misclassification unless paired controls or algorithmic filters are used; sufficient ctDNA burden is required for reliable detection.

Some genetic testing services may be contractually excluded for self-funded groups that have opted out of expanded biomarker testing under the state mandate (R.I.G.L. §27-19-81). Coverage for those groups is governed by the groupspecific Benefit Booklet or Subscriber Agreement; a list of which genetic testing services are covered with prior authorization, considered not medically necessary, or excluded by contract can be found in the Coding section of the Genetic Testing Services or Proprietary Laboratory Analyses policies. Providers should verify the member's benefit booklet to determine whether the member's plan includes expanded biomarker coverage.

ctDNA-based MRD assays are designed to detect residual disease specific to the tumor(s) targeted by the assay and therefore cannot be used to detect a separate second primary tumor, even if located in the same organ. Additionally, the assay requires a sufficient quantity of circulating tumor DNA in the tested compartment (typically plasma); insufficient ctDNA limits test applicability and may produce false-negative or indeterminate results. Interpretation is further complicated by tumor heterogeneity, clonal evolution, and potential confounding from CHIP (clonal hematopoiesis), which can produce somatic variants in cfDNA that mimic tumor-derived mutations.

This policy is provided for informational purposes only and does not guarantee payment. Coverage and payment decisions are determined by the member's subscriber agreement, member certificate, and/or employer agreement, which take precedence over this policy. Providers should not treat this document as authorization or assurance of coverage without verifying the member's specific benefits and any required preauthorization.

Benefits and covered services may vary by group and contract. Determinations of whether a service is covered or considered not medically necessary are made based on the member's Benefit Booklet, Evidence of Coverage, or Subscriber Agreement. Providers must verify member-specific benefits and consult applicable participation or employer agreements when planning testing or billing.

ctDNA MRD assays that do not use paired controls (for example, a matched whole-blood sample) or that do not account for CHIP-related variants may misclassify somatic changes detected in cfDNA as tumor-derived. Such misclassification can lead to incorrect clinical decisions (for example, inappropriate eligibility determination for targeted therapies) and misleading MRD interpretations. Where available, paired blood or tissue controls or analytic approaches that filter CHIP-associated variants are recommended to reduce this risk.

Services determined to be not medically necessary or non-covered benefits may not be paid. Providers may not bill or collect payment from a member for services that are denied as not medically necessary unless the member has been informed in advance and has provided written agreement to accept financial responsibility. For member-specific coverage or billing questions, contact the provider call center and review the member's subscriber documentation.

Coding and Diagnosis Codes

Named MRD test CPT codes and unlisted codeCPT

0364U	clonoSEQ (Adaptive Biotechnologies)
0569U	Guardant Reveal (Guardant Health) - New Code Effective 7/1/2025
0422U	Guardant Response (Guardant Health)
81479	Unlisted molecular pathology procedure (used prior to 7/1/2025 for Guardant Reveal dates of service)

Covered CPT Codes (clonoSEQ)CPTCovered

0364U

Oncology (hematolymphoid neoplasm), genomic sequence analysis using multiplex (PCR) and nextgeneration 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

Covered CPT Codes (Guardant Response)CPTCovered

0422U

Oncology (pan-solid tumor), analysis of DNA biomarker response to anti-cancer therapy using cellfree circulating DNA, biomarker comparison to a previous baseline pre-treatment cell-free circulating DNA analysis using next-generation sequencing, algorithm reported as a quantitative change from baseline, including specific alterations, if appropriate

Covered CPT Codes (Guardant Reveal)CPTCovered

0569U

Oncology (solid tumor) next-generation sequencing analysis of tumor methylation markers (>20,000 differentially methylated regions) present in cell-free circulating tumor DNA (ctDNA), whole blood, algorithm reported as presence or absence of ctDNA with tumor fraction, if appropriate

Unlisted CPT CodeCPT

81479

Unlisted molecular pathology procedure (requires prior authorization when used for tests without a specific CPT code)

Applicable ICD-10 Diagnosis CodesICD-10

C83.10 - C83.19	Follicular and related non-Hodgkin lymphoma codes as listed
C83.30 - C83.3A	Other specified lymphoma codes as listed
C90.00 - C90.02	Multiple myeloma codes as listed
C91.00 - C91.02	Lymphoid leukemia codes as listed
C91.10 - C91.12	Chronic lymphocytic leukemia / small lymphocytic lymphoma codes as listed
Z85.6	Personal history of leukemia
Z85.79	Personal history of other malignant neoplasm of lymphoid, hematopoietic and related tissue

BCR-ABL1 sensitivity requirement for TKI discontinuation — inv-17

Required analytic sensitivityqPCR sensitivity to BCR-ABL1 on the International Scale (IS) ≤0.0032% (molecular response MR4.5)

Turnaround timeTime to results < 2 weeks

Intended useRequired when discontinuing TKI therapy in CML patients per policy criteria

Prior Authorization, Billing, and Provider Obligations

Prior Authorization

Prior Authorization Required

Prior authorization is required for Medicare Advantage Plans and recommended for Commercial Products. All unlisted molecular pathology procedures (CPT 81479) require prior authorization to determine the specific service rendered and whether it is covered or medically necessary. Prior authorization for participating providers is obtained via the online tool. Laboratories are prohibited from obtaining or facilitating authorizations on behalf of ordering physicians; only the ordering physician may obtain authorization. If a laboratory provides a service that was not authorized, the service will be denied and the financial liability will be the laboratory's.

Prior authorization required for CPT 81479 (Unlisted molecular pathology procedure).
Prior authorization obtained via BCBSRI online tool for participating providers.
Laboratories are not permitted to obtain or facilitate prior authorization; ordering physician must obtain authorization.

Background on MRD Testing

Measurable residual disease (MRD) testing employs highly sensitive genomic technologies such as targeted PCR assays or next-generation sequencing (NGS) to detect tumor-derived genetic material at very low levels in blood or other minimally invasive specimens. Liquid-based MRD approaches commonly analyze circulating tumor DNA (ctDNA or cell-free DNA) and often require establishing a tumor baseline from diagnostic tissue or prior plasma samples, with subsequent serial testing to monitor for molecular recurrence, progression, or therapeutic response. Established single-gene PCR MRD tests (for example, BCR-ABL1 in CML) follow disease-specific guideline testing schedules and can guide treatment decisions when performed with appropriate sensitivity and clinical context.

Definitions and Key Terms

MRD — inv-31

DefinitionMeasurable residual disease (MRD): detection of tumor-derived genetic material (e.g., ctDNA or disease-specific molecular targets) at very low levels to identify residual tumor presence or molecular recurrence.

Specimen typesMay be assessed using liquid biopsy (plasma cfDNA/ctDNA), bone marrow aspirate, or tumor tissue baseline plus serial minimally invasive samples.

Clinical roleUsed for early detection of progression/recurrence, monitoring treatment response, risk stratification, and guiding management decisions in hematologic malignancies and select solid tumors.

ctDNA / cfDNA — inv-32

DefinitionctDNA / cfDNA: circulating tumor DNA (ctDNA) or cell-free DNA (cfDNA) present in plasma used as the analyte for liquid-biopsy MRD testing.

Limitations

Line-of-Therapy Contexts and Timing

mixed

Use contexts: MRD testing may be used to detect recurrence or progression before clinical evidence, to monitor response to therapy (including immune checkpoint inhibitors), and to guide treatment decisions such as referral for HSCT or treatment modification.

Serial assays establishing a tumor baseline and subsequent minimally invasive specimens are typical parts of MRD services; frequency follows guidelines when the patient is in surveillance without active disease.

informational

Uses: MRD/ctDNA testing may be used for prognostication, monitoring treatment response, surveillance for relapse, and guiding risk-adapted or pre-emptive therapy decisions.

Evidence supports earlier detection of recurrence and use of MRD to inform management changes per established guidelines; results are informational and should be interpreted in the clinical context.

Assay and Biomarker Requirements

Biomarker examples & sensitivity notes — inv-38

Examples of disease-specific biomarkersBCR-ABL1 (CML qPCR), NPM1 and PML-RARA (AML/APL), IgH/TCR rearrangements (ALL, CLL, MM, lymphomas)

Sensitivity notesBCR-ABL1 qPCR can detect ~1 leukemic cell per 100,000 normal cells; some NGS IgH assays detect down to low DNA inputs (e.g., 200–500 ng) with high sensitivity.

Clinical applicationThese biomarkers are used for MRD-guided decisions such as TKI discontinuation, HSCT referral, and pre-emptive therapy in hematologic malignancies.

CHIP / clonal hematopoiesis — inv-39

Confounding riskCHIP can produce somatic cfDNA variants (including in DNA repair genes) that may be mistaken for tumor-derived mutations, leading to misclassification and inappropriate therapy decisions.

Observed impact

Therapeutic Actions Guided by MRD

Clinical context	MRD-guided action / consideration
Chronic Myeloid Leukemia (CML): molecular response monitoring by BCR-ABL1 RT-qPCR
Use BCR-ABL1 RT-qPCR results to guide tyrosine kinase inhibitor (TKI) management — including switching TKIs for inadequate molecular response, referral for allogeneic HSCT when indicated, or consideration of TKI discontinuation when sustained deep molecular response is documented (requires qPCR sensitivity to BCR-ABL1 IS ≤0.0032% [MR4.5] with time to results <2 weeks).

Clinical context	MRD-guided action / study outcome
Acute Myeloid Leukemia (AML) / Myelodysplastic Syndrome (MDS): molecular MRD positivity after therapy
Persistent MRD may prompt referral for allogeneic HSCT in certain AML subtypes; pre-emptive therapy (for example, azacitidine in RELAZA2) has been shown to prevent or delay relapse in high-risk MRD-positive patients. (Informational)

OpenPayer

Minimal Residual Disease (MRD) Testing for Cancer