ModifiedCapital BluecrossPolicy MP 2.218

Pharmacogenomic and Metabolite Markers for Patients Treated with Thiopurines

Criteria for TPMT and NUDT15 genotypic/phenotypic testing and metabolite testing in patients being started on or receiving thiopurine drugs (azathioprine, mercaptopurine, thioguanine); who is eligible and which tests are considered investigational.

Policy Summary

PayerCapital Bluecross

PolicyPharmacogenomic and Metabolite Markers for Patients Treated with Thiopurines

Policy CodePolicy MP 2.218

Change TypeMaterial revisions and coding updates (investigational designation for metabolite testinggene added)

Effective DateJan 1, 2026

Next Review Date

Key ActionObtain one-time TPMT and/or NUDT15 genotypic or phenotypic testing for patients starting azathioprine, mercaptopurine, or thioguanine, or for those on therapy with abnormal CBC not responsive to dose reduction.

SourceLink

POLICY UPDATE CHANGES

Addition of NUDT15 as medically necessary.

Analysis and monitoring of metabolites is investigational.

CPT 80299 and 82542 moved to investigational.

Added CPT code 0286U.

Added CPT code 84433.

Benefit Variations Section removed.

Updated disclaimer and editorial updates with no change to intent.

NUDT15 addedGene added as medically necessary

80299, 82542Codes moved to investigational

Trek Health ingests and normalizes Transparency in Coverage data and payer policy updates to give provider organizations a clear view of how commercial reimbursement behaves across markets, payers, and services. Our platform transforms raw payer disclosures into structured intelligence that supports contract evaluation, payer negotiations, and service line strategy. By combining market benchmarks with ongoing policy visibility, Trek helps teams identify variability, risk, and opportunity in commercial reimbursement. The result is faster insight, stronger negotiating positions, and more informed financial decisions.

0286U, 84433Codes added administratively

MP 2.218Policy identifier

2 RCTsRandomized trials

≈1 in 300Homozygous TPMT frequency

Coverage Criteria

Medically necessary TPMT/NUDT15 testing

Covered when ALL of the following are met

Initial or reactive testing: Testing is performed one time for individuals beginning azathioprine, mercaptopurine, or thioguanine therapy OR for individuals on thiopurine therapy with abnormal complete blood count (CBC) results that do not respond to dose reduction.one-time

TPMT genotype and/or phenotype and NUDT15 genotype applicable; phenotyping not accurate after recent blood transfusion.

Test types: Genotypic testing for NUDT15 and TPMT and/or phenotypic testing for TPMT (red blood cell TPMT activity) are acceptable modalities to identify reduced enzyme activity.

Clinical rationale: Testing is intended to identify patients with reduced or absent TPMT or NUDT15 activity to guide dosing decisions; patients with homozygous deficiency require substantial dosage reductions.

Metabolite marker testing (investigational)

Not covered / Investigational

Investigational metabolite testing: Analysis of thiopurine metabolite markers (6-methylmercaptopurine ribonucleotides [6-MMP] and 6-thioguanine nucleotides [6-TGN]) is considered investigational for all indications in this policy window.

Insufficient evidence that metabolite monitoring improves net health outcomes; RCTs and systematic review do not demonstrate clear benefit.

Genotype/phenotype testing for TPMT and NUDT15

Covered when used to identify enzyme deficiency or guide dosing in patients treated with thiopurines

Primary coverage logic: TPMT genotyping or phenotyping and NUDT15 genotyping can identify patients with reduced enzyme activity and are covered when used to evaluate deficiency or to guide dosing for patients treated with azathioprine, mercaptopurine, or thioguanine.

Supported by FDA labeling references and policy rationale; testing may inform dose reduction or alternative therapy for patients with low/absent activity.

Indications for testing: Consider testing for patients who experience severe bone marrow toxicities or repeated episodes of myelosuppression; perform pretreatment evaluation to guide dosage reductions.

Dose adjustment implication: Patients with homozygous TPMT or NUDT15 deficiency require substantial dosage reductions of thiopurines.

Thiopurine metabolite monitoring

Therapeutic drug/metabolite monitoring

Therapeutic monitoring evidence summary: Routine or reactive therapeutic drug monitoring of thiopurine metabolites to guide treatment has inconclusive evidence: pooled RCTs did not show statistically significant improvements in clinical remission or serious adverse events versus standard weight-based dosing; evidence is insufficient to conclude a net health benefit.

Both randomized trials had high risk of bias, early termination, and high dropout rates.

Summary determinations

Policy-level determinations and recent changes

Policy determinations: NUDT15 was added as medically necessary in 06/16/2021. Analysis and monitoring of thiopurine metabolites was designated investigational in the 01/15/2025 major review; certain CPT codes (80299, 82542) were moved to investigational.

Full procedural and coding details available in coding section and policy history.

Genotypic and/or phenotypic analysis of TPMT and NUDT15 is considered investigational when used in any situation other than the specific medically necessary indications described in this policy (one-time testing for individuals beginning azathioprine, mercaptopurine, or thioguanine therapy, or for individuals on thiopurine therapy with abnormal CBC results that do not respond to dose reduction). There is insufficient evidence to support a general conclusion regarding health outcomes or benefit for other uses.

Procedure codes 80299 and 82542 are listed in the policy as investigational and not covered. Claims submitted using these codes may be denied under this policy.

As of the policy major review on 01/15/2025, certain tests and analyses reported under specific CPT codes (for example 80299 and 82542) were moved to investigational status and are considered not covered under this policy.

Therapeutic monitoring using thiopurine metabolite markers (including 6-MMP and 6-TGN) is considered investigational in this policy. The evidence is insufficient to conclude that metabolite monitoring improves health outcomes.

Routine or reactive monitoring of thiopurine metabolites to guide treatment decisions is of uncertain benefit. Systematic review and randomized trial data did not demonstrate statistically significant improvements in clinical remission or serious adverse events versus standard dosing; the evidence is therefore insufficient to establish a net health benefit.

Analysis and monitoring of thiopurine metabolites were declared investigational in the 01/15/2025 major review and associated CPT codes were moved to investigational status. Such analyses are considered not covered under this policy.

Covered Indications

One-time TPMT and/or NUDT15 testing for patients beginning azathioprine, mercaptopurine, or thioguanine therapy; or for patients on thiopurine therapy with abnormal CBC not responsive to dose reduction.

One-time testing for therapy initiation or abnormal CBC: One-time TPMT and/or NUDT15 genotypic or phenotypic testing is covered for patients beginning azathioprine, mercaptopurine, or thioguanine therapy; or for patients on thiopurine therapy who have abnormal CBC results that do not respond to dose reduction.

Phenotype testing is not reliable after recent blood transfusion; testing need only be performed once.

Patients treated with thiopurines who experience severe bone marrow toxicities or repeated myelosuppression; pretreatment evaluation to identify TPMT or NUDT15 deficiency to guide dosing.

Severe toxicity or repeated myelosuppression: Perform TPMT and NUDT15 testing in patients treated with thiopurines who experience severe bone marrow toxicities or repeated episodes of myelosuppression to evaluate for enzyme deficiency and guide dosing decisions.

Dose reduction is recommended for patients with reduced activity; consider alternative therapy for patients with low or absent activity.

Coding

Investigational / Not Covered Procedure CodesCPTNot Covered

80299	Procedure Codes - Investigational (not covered)
82542	Procedure Codes - Investigational (not covered)

Covered Procedure Codes (when medically necessary)CPTCovered

81335	Covered procedure code listed in policy
82657	Covered procedure code listed in policy
84433	Covered procedure code listed in policy
0034U	Covered procedure code listed in policy
0169U	Covered procedure code listed in policy
0286U	Covered procedure code listed in policy
0461U	Covered procedure code listed in policy

Diagnosis Codes (selected inflammatory bowel disease codes)ICD-10

K50.00	Crohn's disease of small intestine without complications
K50.011	Crohn's disease of small intestine with rectal bleeding
K50.012	Crohn's disease of small intestine with intestinal obstruction
K50.013	Crohn's disease of small intestine with fistula
K50.014	Crohn's disease of small intestine with abscess
K50.019	Crohn's disease of small intestine with unspecified complications
K50.10	Crohn's disease of large intestine without complications
K50.111	Crohn's disease of large intestine with rectal bleeding
K50.112	Crohn's disease of large intestine with intestinal obstruction
K50.113	Crohn's disease of large intestine with fistula

1–10 of 30

1/3

Policy-associated CPT changesCPT

0286U	CPT code added (document notes addition on 12/01/2021)
84433	CPT code added (document notes addition on 12/01/2022)
80299	CPT code moved to investigational (01/15/2025)
82542	CPT code moved to investigational (01/15/2025)

Dose reduction requirement for homozygous deficiency

RequirementPatients with homozygous TPMT or NUDT15 deficiency require substantial dosage reductions of thiopurines.

ContextApplies when genotyping or phenotyping identifies reduced enzyme activity

Clinical implicationTesting can guide dosage reductions or alternative therapy to reduce risk of severe myelosuppression

Provider Actions & Billing Guidance

Prior Authorization

Code list and medical necessity requirement

Prior authorization and medical necessity determine coverage for TPMT/NUDT15 testing. Verify member benefits and obtain prior authorization when the test is being requested to initiate azathioprine, mercaptopurine, or thioguanine therapy, or for patients on thiopurine therapy with abnormal CBC results that do not respond to dose reduction.

Prior authorization requirements vary by code and benefit plan — confirm prior auth before testing.
Coverage is contingent on medical necessity and member benefits; identification of a code here does not guarantee coverage.

Billing Rule

Verify code-level authorization

Check that the specific CPT/HCPCS code being billed is listed as covered for the indication and that it has not been reclassified (covered → investigational) since the request. If a code has been moved to investigational status, prior authorization may not be available.

Not Covered / Investigational

Testing of thiopurine metabolites (for example measurement of 6-MMP and 6-TGN) is considered investigational and not covered. The available randomized trials and systematic review do not provide sufficient evidence that metabolite testing to guide treatment improves clinical outcomes.

Procedures reported under CPT codes 80299 and 82542 are classified as investigational and not covered by this policy and may be denied if billed.

Any testing or metabolite analyses billed under CPT codes that were moved to investigational status (for example 80299 and 82542) are considered investigational / not covered per the policy changes effective 01/15/2025.

Definitions

TPMT phenotype/genotype

Definition (phenotype)Measurement of TPMT enzyme activity in red blood cells via assay; results reported as quantitative activity categories (TPMT activity).

Definition (genotype)TPMT genotyping uses PCR-based methods to detect known TPMT variants listed in Table 1 (identifies normal, intermediate, or no-activity alleles).

Testing notePhenotype testing is not accurate after recent blood transfusion; genotyping is not affected by transfusion status.

NUDT15 genotype

DefinitionNUDT15 genotyping is a polymerase chain reaction–based analysis to detect NUDT15 gene variants (alleles listed in Table 1) that alter thiopurine tolerance.

Clinical relevance

Background

Thiopurines — including azathioprine (a prodrug of mercaptopurine), mercaptopurine (6-MP), and thioguanine (6-TG) — are immunomodulatory agents used to treat inflammatory bowel disease, certain malignancies, rheumatic and dermatologic conditions, and in transplantation. These drugs carry risks of significant toxicity, notably bone marrow suppression and hepatotoxicity. TPMT and NUDT15 encode enzymes involved in thiopurine metabolism; genetic variants or reduced enzyme activity increase risk of myelosuppression. TPMT activity can be assessed by genotype or by measuring red blood cell enzyme activity (phenotype), and NUDT15 is assessed by genotyping. Testing is intended to identify patients at increased risk for toxicity and to guide dose reductions or alternative therapy.

Policy Summary

PayerCapital Bluecross

PolicyPharmacogenomic and Metabolite Markers for Patients Treated with Thiopurines

Policy CodePolicy MP 2.218

Change TypeMaterial revisions and coding updates (investigational designation for metabolite testinggene added)

Effective DateJan 1, 2026

Next Review Date

SourceLink

On This Page

NUDT15 and TPMT genotyping for patients being considered for thiopurine therapy — NUDT15 explicitly added as medically necessary in 06/16/2021.

NUDT15 addition to medically necessary genes: NUDT15 and TPMT genotyping are covered for patients being considered for thiopurine therapy; NUDT15 was explicitly added as medically necessary on 06/16/2021.

Verify current coding list in the policy prior to claim submission.
Examples: CPT 80299 and 82542 were moved to investigational (not covered) and may be denied if billed as covered.

Denial Risk

Investigational code risk

Tests or procedure codes that have been designated investigational are not covered and may be denied if submitted for reimbursement. Avoid billing investigational codes for services expected to be covered; confirm an alternative covered code or clinical justification if applicable.

Investigational / not covered example codes: 80299, 82542.
Confirm code status with the payer if uncertain to reduce risk of denial.

Documentation Required

Clinical indication and CBC documentation

Document the clinical indication clearly in the medical record. Testing is considered medically necessary when performed for patients beginning azathioprine, mercaptopurine, or thioguanine therapy, or for patients on thiopurine therapy with abnormal CBC results that do not respond to dose reduction. Include recent CBC results and notes on therapeutic intent or prior dose adjustments.

Include documentation that testing is for initiation of AZA, 6‑MP, or 6‑TG OR for evaluation of abnormal CBC unresponsive to dose reduction.
Attach recent CBC values, dates, and any dose reduction attempts and responses.

Prior Authorization

Benefit & eligibility verification

Confirm member eligibility and benefit coverage on the date of service before ordering tests. Payment is subject to the member's benefit program, eligibility, and medical necessity determination. Providers should obtain any required prior authorization and retain evidence of benefit verification.

Verify eligibility and benefits for the specific test and indication.
Obtain and document prior authorization when required by the member's plan.

Documentation Required

Documentation note

Maintain contemporaneous documentation to support medical necessity and coding. Policy history and coding updates occur periodically; reference the current policy coding list and keep records of prior authorization approvals, clinical notes, lab results, and any genetic counseling provided.

Retain prior authorization approvals and clinical records that justify the test.
Reference the most recent policy coding and policy history when submitting claims.

Note

Dose reduction and monitoring expectations

Follow expected management steps when TPMT or NUDT15 abnormalities are identified: monitor CBCs, consider dose reduction, and document response. Patients with heterozygous deficiency usually require dosage reduction; homozygous deficiency often requires substantial dosage reduction or alternative therapies. Testing does not replace routine CBC monitoring and is generally performed once.

Dose reduction and repeated CBC monitoring are standard management after abnormal results.
Homozygous TPMT or NUDT15 deficiency typically necessitates substantial dose reductions or alternative therapy.
Phenotype/genotype testing is usually a one‑time test; phenotyping may be unreliable after recent blood transfusion.

NUDT15 variants affect thiopurine metabolism and are used to identify patients at increased risk of hematologic toxicity.

Policy noteNUDT15 was added as medically necessary in the policy (06/16/2021) for pretreatment and toxicity evaluation.

CROHN'S DISEASE

DefinitionCROHN'S DISEASE is a chronic inflammatory bowel disease of unknown origin, usually affecting the ileum, the colon, or another part of the gastrointestinal tract.

Clinical contextThiopurines are among immunomodulators used in Crohn's disease management but carry toxicity risks warranting TPMT/NUDT15 evaluation in some patients.

Relevance to policySelected IBD diagnosis codes (eg, Crohn's disease) are listed among covered indications where thiopurine pharmacogenomic testing may be applied.

PHARMACOGENOMIC

DefinitionPHARMACOGENOMIC refers to the study of the effects of genetic differences among people and the impact these differences have on the uptake, effectiveness, toxicity, and metabolism of drugs.

ApplicationUsed to inform drug selection and dosing (eg, TPMT and NUDT15 testing to guide thiopurine dosing).

Policy relevancePharmacogenomic testing is the basis for TPMT/NUDT15 genotyping being considered medically necessary in specified situations.

TPMT

DefinitionTHIOPURINE METHYLTRANSFERASE ENZYME (TPMT) is an enzyme active in the metabolism of azathioprine and other thiopurines.

FunctionTPMT methylates mercaptopurine and thioguanine; activity level influences susceptibility to thiopurine-induced toxicity.

Testing modalitiesTPMT status can be assessed by RBC enzyme activity (phenotype) or by genotyping for known TPMT variants.

Genetic tests that predict thiopurine metabolism and toxicity

Tests includedGenotyping of TPMT and NUDT15 to predict thiopurine metabolism and risk of hematologic toxicity.

Alternate test (investigational)Measurement of thiopurine metabolites (6-MMP, 6-TGN) is discussed but designated investigational for routine monitoring in this policy.

Clinical useGenetic tests are used for pretreatment evaluation or in patients with severe/recurrent myelosuppression to guide dosing decisions.