ModifiedEmblemHealthPolicy AHS-G2115

Reimbursement Policy: Metabolite Markers of Thiopurines Testing

This document governs reimbursement for thiopurine metabolite and pharmacogenetic testing (TPMT, NUDT15), describes coverage-linked clinical scenarios, and details Lab Benefit Program (LBM) applicability and coding updates.

Policy Summary

PayerEmblemHealth

PolicyMetabolite Markers of Thiopurines Testing

Policy CodePolicy AHS-G2115

Change TypeCPT addition and plan expansion

Effective DateMar 1, 2023

Next Review DateN/A

Key ActionOrder TPMT or NUDT15 testing prior to initiating thiopurine therapy or monitor thiopurine metabolites for suspected toxicity or nonresponse as indicated by coverage criteria.

SourceLink

POLICY UPDATE CHANGES

CPT code 84433 was added to Applicable CPT/HCPCS Procedure Codes with an effective date of 3/15/2025.

Lab Benefit Program (LBM) was expanded to include EmblemHealth HMO/PPO (Non-City) Commercial, Medicare and Medicaid plans effective 10/1/2024.

Policy was updated for clarity in 11/2023 with no changes in coding or coverage criteria.

3procedure codes referenced

≥4clinical scenarios listed

1CPT code added

10/1/2024

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Coverage-linked Clinical Criteria

Coverage-linked clinical criteria

Clinical guideline-based scenarios where testing is recommended or considered:

ALL of the following

Pre-treatment TPMT/NUDT15 assessment
- TPMT testing is performed before initiating azathioprine or 6-mercaptopurine to identify individuals with low or absent TPMT activity who are at high risk for severe leukopenia (recommendation from NASPGHAN and BSG).
- When available, NUDT15 genotyping is tested or considered prior to thiopurine use; if NUDT15 status is unknown and thiopurines are required, monitor closely for toxicity. (CPIC, BSG).
Indications for metabolite monitoring
- Reactive thiopurine metabolite monitoring is used for adult or pediatric patients with active IBD or adverse effects suggestive of thiopurine toxicity to guide treatment changes (AGA, NASPGHAN).
- Measure 6-TG and 6-MMP levels to optimize dosing in patients with incomplete response on a stable thiopurine dose, suspected nonadherence, new leucopenia, or elevated transaminases (ECCO/ESPGHAN, BSG, NASPGHAN).
- Check metabolites in patients with myelotoxicity or newly abnormal liver function tests to inform management and potential use of adjunctive therapies (e.g., allopurinol) or therapy change. (BSG, NASPGHAN).
Routine monitoring stance: Guidelines generally advise against routine, proactive metabolite monitoring in unselected patients in remission; routine and repetitive metabolite testing has little or no role in patients who are clinically well on an acceptable thiopurine dose. (AGA, NASPGHAN).

ALL of the following

If TPMT genotype is indeterminate, consider measuring TPMT erythrocyte activity to assess phenotype. (CPIC).

ALL of the following

Use measured 6-TG and 6-MMP concentrations to optimize dosing, consider adjunctive allopurinol to shift metabolites when appropriate, or change therapy based on inadequate response or toxicity. (NASPGHAN, ECCO/ESPGHAN, BSG).

Coverage and applicability notes

Reimbursement stance and applicability as stated in the policy and revision history.

ALL of the following

This policy covers reimbursement for metabolite markers of thiopurines testing under the Lab Benefit Program (LBM).

ALL of the following

Lab Benefit Program (LBM) was expanded to include EmblemHealth HMO/PPO (Non-City) Commercial, Medicare and Medicaid plans effective 10/1/2024. (Revision History).

ALL of the following

CPT code 84433 was added to the list of applicable CPT/HCPCS procedure codes effective 3/15/2025. (Revision History).

ALL of the following

Procedure Codes and Effective Dates

Referenced procedure codesCPT

80299	Quantitation of therapeutic drug, not elsewhere specified.
82657	Enzyme activity in blood cells, cultured cells, or tissue, not elsewhere specified; nonradioactive substrate, each specimen.
84433	Thiopurine S-methyltransferase (TPMT)

Applicable CPT/HCPCS Procedure Codes (addition noted)CPTCovered

84433

Enzyme activity assay (example code added per revision history)

CPT addition effective date

Effective date3/15/2025

Provider-Facing Reimbursement and Billing Notes

Note

LBM reimbursement policy reference

Policy references the Lab Benefit Program (LBM) as the reimbursement program governing metabolite markers of thiopurines testing; providers should follow LBM billing and reimbursement processes when ordering these tests.

Billing Rule

Reimbursement Policy — Metabolite Markers of Thiopurines Testing (LBM)

Reimbursement for metabolite markers of thiopurines testing is governed by the Lab Benefit Program (LBM); providers must bill under LBM rules and note that the policy explicitly covers these tests.

Test Definitions and References

TPMT/NUDT15 testing and LDTs

Definition of assaysTPMT and NUDT15 testing include genotyping for sequence variants and phenotyping by TPMT erythrocyte enzyme activity to guide thiopurine dosing

Regulatory status of LDTsMany TPMT/NUDT15 and metabolite assays are laboratory-developed tests (LDTs) validated and performed in-house and are regulated by CMS under CLIA; they are not FDA-approved or cleared

When to use phenotyping vs genotypingCPIC notes consideration of TPMT erythrocyte activity evaluation for indeterminate TPMT genotypes or when genotype/phenotype discordance is suspected

Cited clinical references

ACG Clinical Guideline (Ulcerative Colitis)Rubin DT et al., ACG Clinical Guideline: Ulcerative Colitis in Adults (2019)

AGA Technical Review