Pharmacogenomic and Metabolite Markers for Patients Treated with Thiopurines
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Policy governing coverage of one-time TPMT and NUDT15 genotypic or phenotypic testing and the stance on thiopurine metabolite (6-TGN, 6-MMP) monitoring for patients starting or receiving thiopurine therapy.
Added nudix hydrolase (NUDT15) to Items A and B such that TPMT and NUDT15 testing may be considered medically necessary and that genotypic/phenotypic analysis of TPMT and NUDT15 is experimental/investigational in other situations.
Added CPT/PLA and other procedure codes including 0034U, 0169U, 81335 and later 84433 to the coding section.
Removed genetic counseling requirement from Policy Guidelines.
Coverage Criteria
Medically necessary indications for TPMT/NUDT15 testing
Covered when ANY of the following are met:
One-time genotypic or phenotypic analysis of TPMT and NUDT15 may be considered medically necessary
One-time genotypic or phenotypic analysis of TPMT and NUDT15 may be considered medically necessary
Medically necessary testing
Covered when ALL of the following are met:
Reflects policy language adding NUDT15 to TPMT testing criteria and guideline support (e.g., NCCN, NASPGHAN).
Experimental / investigational
Not covered (considered experimental / investigational):
Considered experimental / investigational
Therapeutic drug/metabolite monitoring
Use of metabolite testing or therapeutic drug monitoring:
AGA: evidence low to very low; may offer benefit in reactive situations.
From NASPGHAN and AGA summaries; routine therapeutic drug monitoring for stable patients not generally indicated.
Accurate TPMT phenotyping is unreliable after recent blood transfusion. Phenotypic assays measure erythrocyte enzyme activity and transfused donor red blood cells can distort results; therefore phenotyping should not be used to guide management in individuals who have received a recent transfusion.
Except for the specific clinical scenarios defined in the Policy (one-time genotypic or phenotypic TPMT and NUDT15 testing for patients starting azathioprine/6‑MP/6‑TG or for patients on thiopurines with abnormal CBC not responsive to dose reduction), genotypic and/or phenotypic analysis of TPMT and NUDT15 is considered experimental/investigational and is not covered.
The available evidence does not establish that routine or repeat measurement of thiopurine metabolites (e.g., 6‑TGN, 6‑MMP) reliably improves clinical outcomes. Systematic review and randomized trials are limited, at high risk of bias, and do not demonstrate a clear benefit; therefore routine or reactive thiopurine metabolite monitoring to guide treatment changes is considered experimental/investigational due to insufficient evidence.
Guideline and evidence summaries find that the benefit of routine TPMT measurement for all patients starting thiopurines is uncertain. The American Gastroenterological Association concluded the overall quality of evidence is low to very low and routine therapeutic drug monitoring for stable patients is not generally indicated; TPMT testing may avoid serious harm in a small fraction of patients but is not proven superior to empiric dosing for all.
Covered Indications
One-time TPMT and/or NUDT15 testing prior to or during thiopurine therapy
One-time testing may be considered medically necessary when the following clinical scenario is present:
Phenotyping accuracy is affected by recent blood transfusion; testing need only be performed once.
When to consider TPMT/NUDT15 testing
Consider testing in the following clinical contexts:
NCCN and NASPGHAN recommend TPMT and NUDT15 testing in these contexts; dosing recommendations for TPMT phenotypes are provided by guidelines.
Guidelines suggest testing both TPMT and NUDT15, particularly for patients at higher genetic risk.
Coding
| 81335 | TPMT (thiopurine S-methyltransferase) (e.g., drug metabolism), gene analysis, common variants (e.g., *2, *3). |
| 84433 | Thiopurine S-methyltransferase. |
| 0034U | TPMT (thiopurine S-methyltransferase), NUDT15 (nudix hydroxylase 15) gene analysis, common variants (Mayo Clinic). |
| 0169U | NUDT15 (nudix hydrolase 15) and TPMT (thiopurine S-methyltransferase) gene analysis, common variants. |
| 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 |
| K50.018 | Crohn's disease of small intestine with other complication |
| 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 |
Provider Actions & Billing
Use Specified Procedure Codes
Use the listed procedure codes when billing for TPMT and NUDT15 testing; these codes are informational and coverage applies only when services are performed according to the Policy section.
Coverage-Triggering Clinical Scenarios
Testing is considered medically necessary ONLY in the covered clinical scenarios: (1) one-time genotypic or phenotypic TPMT and/or NUDT15 analysis for patients beginning therapy with azathioprine, mercaptopurine, or thioguanine, OR (2) one-time testing for individuals on thiopurine therapy who have abnormal complete blood count (CBC) results that do not respond to dose reduction. All other indications are considered experimental/investigational and are not covered.
Required Clinical Documentation
Document the clinical indication in the medical record: either (a) patient is being started on azathioprine, mercaptopurine, or thioguanine, OR (b) patient is on ongoing thiopurine therapy with abnormal CBC unresponsive to dose reduction. Include relevant clinical notes, recent CBC results, prior dose adjustments and rationale for testing. Verify member contract benefits at time of service.
Clinical Management Expectations
Dosage reduction is recommended for patients with reduced TPMT or NUDT15 activity. Individuals who are homozygous for nonfunctional alleles (low/absent activity) should generally avoid thiopurines and alternative therapies should be considered. TPMT/NUDT15 genotyping or phenotyping need only be performed once. Phenotyping may be unreliable after recent blood transfusion.
Therapeutic Monitoring Expectations
Therapeutic drug monitoring or metabolite testing (e.g., 6-TGN, 6-MMP) may be used reactively to guide dosing adjustments or assess adherence in patients with active disease or suspected nonadherence. Routine or repeat metabolite testing is of limited value in patients who are clinically stable on an acceptable thiopurine dose. TPMT/NUDT15 testing does not replace routine CBC/WBC monitoring.
Eligibility Requirements
No eligibility criteria are specified in this section.
No eligibility criteria are specified in this section.
Not Covered
Measurement of thiopurine metabolite markers (erythrocyte 6‑TGN and 6‑MMP) is considered experimental/investigational and not covered. Metabolite testing has limited high-quality evidence to support routine use to improve net health outcomes.
Outside the defined covered indications (one-time testing for individuals initiating azathioprine, mercaptopurine, or thioguanine, or for individuals on thiopurines with abnormal CBC not responsive to dose reduction), genotypic and/or phenotypic analysis of TPMT and NUDT15 is considered experimental/investigational and not covered.
Background
Thiopurines (azathioprine, mercaptopurine, thioguanine) are metabolized variably between individuals. TPMT and NUDT15 enzyme activity influence thiopurine metabolism and toxicity; reduced activity is associated with higher risk of severe myelosuppression. Genotypic testing detects common variant alleles, and phenotypic assays measure erythrocyte TPMT activity. Phenotyping is affected by recent transfusion, and genotyping may miss rare or novel no-function alleles. Clinical guidelines (e.g., NCCN, NASPGHAN) recommend testing TPMT and NUDT15 prior to thiopurine initiation or when excessive toxicity occurs, and dosing recommendations are provided based on TPMT phenotype.
Definitions
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