Medical Policy

Policy Num:       11.003.039
Policy Name:     Pharmacogenomic and Metabolite Markers for Patients Treated With Thiopurines
Policy ID:          [11.003.039]  [Ac / B / M+ / P+]  [2.04.19]

Last Review:       December 20, 2024
Next Review:      December 20, 2025

Related Policies: None

Pharmacogenomic and Metabolite Markers for Patients Treated With Thiopurines

Summary

Description

The thiopurine class of drugs, which include azathioprine (a pro-drug for mercaptopurine), mercaptopurine, and thioguanine, are used to treat a variety of diseases; however, it is recommended the use of thiopurines be limited due to a high rate of drug toxicity. The TPMT and NUDT15 genes encode for the enzymes thiopurine S-methyltransferase (TPMT) and Nudix Hydrolase (NUDT15), respectively. These enzymes are involved in the metabolism of thiopurines. Genetic variants in TPMT and NUDT15 genes affect drug hydrolysis and hence, increase susceptibility to drug-induced toxicity. Mercaptopurine and thioguanine are directly metabolized by the TPMT enzyme. Susceptibility to drug toxicity is linked to the level of TPMT activity. The variation in TPMT activity has been related to 3 distinct TPMT variants. TPMT can be assessed through genetic analysis for polymorphisms in leukocyte DNA (genotype) or by measurement of the enzyme activity in circulating red blood cells (RBCs; phenotype). NUDT15 is measured by genetic analysis only (genotype). Pharmacogenomic analysis of TPMT/NUDT15 status is proposed to identify patients at risk of thiopurine drug toxicity and adjustment of medication doses accordingly. Measurement of metabolite markers has also been proposed.

Summary of Evidence

For individuals who are treated with thiopurines and receive thiopurines metabolite monitoring to guide treatment , the evidence includes 2 randomized controlled trials (RCTs). Relevant outcomes are change in disease status, treatment-related mortality, and treatment-related morbidity. The evidence for the use of reactive thiopurine metabolite monitoring to guide treatment in patients being treated with thiopurines includes only retrospective studies that were not included in this review. The evidence for the use of routine thiopurine drug monitoring to guide treatment in patients being treated with thiopurines includes 2 randomized studies. Both studies were terminated early due to slow recruitment and failure to meet prespecified enrollment targets. Additionally, there was a high attrition rate in both trials (33% to 46%). The pooled analysis of both trials reported in the systematic review did not show a statistically significant difference in clinical remission in patients who underwent routine therapeutic drug monitoring-guided dose adaptation compared with standard weight-based dosing. The rate of serious adverse events (requiring discontinuation of therapy) was also comparable between the 2 arms. Based on 2 RCTs at high risk of bias, there is uncertainty whether reactive or routine thiopurine metabolite monitoring to guide treatment are superior to empirical clinical-based or standard weight-based dosing changes. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

For individuals who are treated with thiopurines and who receive thiopurine methyltransferase and nudix hydrolase phenotype or genotype analysis to guide treatment, the evidence includes FDA-approved labels for azathioprine (a prodrug for mercaptopurine), mercaptopurine, and thioguanine that include clear and specific directives on use of pharmacogenomic testing. Evidence for these indications was not evaluated.

Additional Information

Not applicable.

Objective

The objective of this evidence review is to determine whether metabolite marker analysis improves the net health outcome in patients treated with thiopurines.

Policy Statements

One time genotypic or phenotypic analysis of thiopurine methyltransferase (TPMT) and nudix hydrolase (NUDT15) may be considered medically necessary in patients beginning therapy with azathioprine, mercaptopurine, or thioguanine OR in individuals on thiopurine therapy with abnormal complete blood count results that do not respond to dose reduction.

Genotypic and/or phenotypic analysis of the TPMT and NUDT15 genes is considered investigational in all other situations.

Analysis of the metabolite markers of azathioprine and mercaptopurine, including 6-methyl-mercaptopurine ribonucleotides and 6-thioguanine nucleotides, is considered investigational.

Policy Guidelines

Thiopurine methyltransferase (TPMT) and/or nudix hydrolase (NUDT15) testing cannot substitute for complete blood count monitoring in individuals receiving thiopurines. Early drug discontinuation may be considered in individuals with abnormal complete blood count results. Dosage reduction is recommended in individuals with reduced TPMT/NUDT15 activity. Alternative therapies may need to be considered for individuals who have low or absent TPMT/NUDT15 activity (homozygous for nonfunctional alleles). Accurate phenotyping results are not possible in individuals who have received recent blood transfusions. TPMT/NUDT15 genotyping and phenotyping would only need to be performed once.

Plans may need to alter local coverage medical policy to conform to state law regarding coverage of biomarker testing.

Coding

See the Codes table for details.

Benefit Application

BlueCard/National Account Issues

Some Plans may have contract or benefit exclusions for genetic testing.

Benefits are determined by the group contract, member benefit booklet, and/or individual subscriber certificate in effect at the time services were rendered.  Benefit products or negotiated coverages may have all or some of the services discussed in this medical policy excluded from their coverage.

Background

Thiopurines

Thiopurines or purine analogues are immunomodulators. These agents include azathioprine (Imuran®), mercaptopurine (6-MP; Purinethol®), and thioguanine (6-TG; Tabloid®). Thiopurines are used to treat malignancies, rheumatic diseases, dermatologic conditions, and in solid organ transplantation. These agents are also considered an effective immunosuppressive treatment of inflammatory bowel disease (IBD), particularly in patients with corticosteroid-resistant disease. However, the use of thiopurines is limited by both a long onset of action (3 to 4 months) and drug toxicities, which include hepatotoxicity, bone marrow suppression, pancreatitis, and allergic reactions.

Thiopurines are metabolized by a complex pathway to several metabolites including 6-thioguanine (6-TGN) and 6-methylmercaptopurine (6-MMP). Thiopurine methyltransferase (TPMT) is 1 of the key enzymes in thiopurine metabolism. Patients with low or absent TPMT enzyme activity can develop bone marrow toxicity with thiopurine therapy due to excess production of 6-TGN metabolites, while elevated 6-MMP levels have been associated with hepatotoxicity.^1, In population studies, the activity of the TPMT enzyme has been shown to be trimodal, with 90% of subjects having high activity, 10% intermediate activity, and 0.3% with low or no activity. Variants in another metabolizing enzyme, NUDT15 (nudix hydrolase, NUDIX 15), have been identified that strongly influence thiopurine tolerance in patients with IBD.^2, Homozygous carriers of NUDT15 variants are intolerant of thiopurine compounds because of risk of bone marrow suppression. Individuals with this variant are sensitive to 6-MP and have tolerated only 8% of the standard dose. Several variant alleles have been identified with varying prevalence among different populations and varying degrees of functional effects.^3, NUDT deficiency is most common among East Asians (22.6%), followed by South Asians (13.6%), and Native American populations (12.5% to 21.2%). Studies in other populations are ongoing.^4,

Phenotype Testing for Thiopurine Methyltransferase Activity

Testing involves incubation of red blood cell (RBC) lysate in a multisubstrate cocktail. The enzymatically generated thiomethylated products are measured by liquid chromatography tandem mass spectrometry to produce an activity profile for TPMT. Multiple assays are available and use different reference standards. Results are based on the quantitative activity level of TPMT (in categories) along with clinical interpretation. Two commercial tests are illustrated below as examples:

ARUP Labs:^5,

• Normal TPMT activity levels: Individuals are predicted to be at low risk of bone marrow toxicity (myelosuppression) as a consequence of standard thiopurine therapy; no dose adjustment is recommended.

• Intermediate TPMT activity levels: Individuals are predicted to be at intermediate risk of bone marrow toxicity (myelosuppression), as a consequence of standard thiopurine therapy; a dose reduction and therapeutic drug management is recommended.

• Low TPMT activity: Individuals are predicted to be at high risk of bone marrow toxicity (myelosuppression) as a consequence of standard thiopurine dosing. It is recommended to avoid the use of thiopurine drugs.

• High TPMT activity: Individuals are not predicted to be at risk for bone marrow toxicity (myelosuppression) as a consequence of standard thiopurine dosing, but may be at risk for therapeutic failure due to excessive inactivation of thiopurine drugs. Individuals may require higher than the normal standard dose. Therapeutic drug management is recommended.

Lab Corp:^6,

• Normal: 15.1 to 26.4 units/ml RBC

• Heterozygous for low TPMT variant: 6.3 to 15.0 units/ml RBC

• Homozygous for low TPMT variant: <6.3 to units/ml RBC

Genotype Testing for Thiopurine Methyltransferase Activity/Nudix Hydrolase (NUDT15) Gene Polymorphism

The genotypic analysis of the TPMT/NUDT15 gene is based on polymerase chain reaction technology to detect distinct variants. These are listed in Table 1.

Table 1. Identified Genetic Variants for TPMT/NUDT15 Testing^4,

Metabolite Markers

The therapeutic effect of thiopurines has been associated with the level of active 6-TGN metabolites, and hepatotoxicity has been associated with higher levels of the inactive metabolites, 6-MMP and 6-methylmercaptopurine ribonucleotides. Therefore, it has been proposed that therapeutic monitoring of these metabolites may improve patient outcomes by identifying the reason for a non-response or sub-optimal response. Conversely by measuring 6-MMP levels, a subgroup of patients can be identified who preferentially convert 6-MP to 6-MMP (toxic metabolite) and often do not achieve sufficient 6-TGN levels. This group of patients, often described as “shunters,” may be susceptible to hepatotoxicity because thiopurine dose escalation leads to 6-MMP accumulation.

Therapeutic monitoring of thiopurine metabolite levels is typically performed in patients with IBD as 1) a reactive strategy in response to either lack of clinical improvement or observed treatment-related toxicity or 2) routine proactive clinical care in patients with quiescent disease.

Regulatory Status

Clinical laboratories may develop and validate tests in-house and market them as a laboratory service; laboratory-developed tests must meet the general regulatory standards of the Clinical Laboratory Improvement Amendments (CLIA). Several thiopurine genotype, phenotype, and metabolite tests are available under the auspices of the CLIA. Laboratories that offer laboratory-developed tests must be licensed by the CLIA for high-complexity testing. To date, the U.S. Food and Drug Administration (FDA) has chosen not to require any regulatory review of these tests.

Prometheus, a commercial laboratory, offers thiopurine genotype, phenotype, and metabolite testing for those on thiopurine therapy. The tests are referred to as Prometheus® TPMT Genetics, Prometheus® TPMT enzyme, and Prometheus® thiopurine metabolites, respectively. Other laboratories that offer TPMT genotyping include: Quest Diagnostics (TPMT Genotype); ARUP Laboratories (TPMT DNA); Specialty Laboratories (TPMT GenoTypR™); PreventionGenetics (TPMT Deficiency via the TPMT Gene); Genelex (TPMT); Fulgent Genetics (TPMT); and LabCorp (TPMT enzyme activity and genotyping).

FDA Labeling on Pharmacogenomic Test for Thiopurines

The FDA has included pharmacogenomics information in the physician prescribing information of multiple drugs. In most cases, this information is general and lacks specific directives for clinical decision making. In the following examples, the FDA has given clear and specific directives on use of pharmacogenomic testing for azathioprine (a prodrug for mercaptopurine), mercaptopurine, and thioguanine. Therefore, evidence for these indications is not reviewed in the Rationale section.

Mercaptopurine^7,

• Consider testing for TPMT and NUDT15 deficiency in patients who experience severe myelosuppression or repeated episodes of myelosuppression.

• Homozygous deficiency in either TPMT or NUDT15: Patients with homozygous deficiency of either enzyme typically require 10% or less of the recommended dosage. Reduce the recommended starting dosage in patients who are known to have homozygous TPMT or NUDT15 deficiency.

• Heterozygous deficiency in TPMT and/or NUDT15: Reduce the dosage based on tolerability. Most patients with heterozygous TPMT or NUDT15 deficiency tolerate the recommended dosage, but some require dose reduction based on adverse reactions. Patients who are heterozygous for both TPMT and NUDT15 may require more substantial dose reductions.

Azathioprine^8,

• Consider testing for TPMT and NUDT15 deficiency in patients who experience severe bone marrow toxicities. Early drug discontinuation may be considered in patients with abnormal complete blood count (CBC) results that do not respond to dose reduction.

• Homozygous deficiency in either TPMT or NUDT15: Because of the risk of increased toxicity, consider alternative therapies for patients who are known to have TPMT or NUDT15 deficiency.

• Heterozygous deficiency in TPMT and/or NUDT15: Because of the risk of increased toxicity, dosage reduction is recommended in patients known to have heterozygous deficiency of TPMT or NUDT15. Patients who are heterozygous for both TPMT and NUDT15 deficiency may require more substantial dosage reductions.

Thioguanine^9,

• Consider testing for TPMT and NUDT15 deficiency in patients who experience severe bone marrow toxicities or repeated episodes of myelosuppression.

• Evaluate patients with repeated severe myelosuppression for TPMT or NUDT15 deficiency. TPMT genotyping or phenotyping (RBC TPMT activity) and NUDT15 genotyping can identify patients who have reduced activity of these enzymes. Patients with homozygous TPMT or NUDT15 deficiency require substantial dosage reductions.

Rationale

This evidence review was created in December 2000 and has been updated regularly with searches of the PubMed database. The most recent literature update was performed through September 30 , 2024.

The primary goal of pharmacogenomics testing and personalized medicine is to achieve better clinical outcomes compared with the standard of care. Drug response varies greatly between individuals, and genetic factors are known to play a role. However, in most cases, the genetic variation only explains a modest portion of the variance in the individual response because clinical outcomes are also affected by a wide variety of factors including alternate pathways of metabolism and patient- and disease-related factors that may affect absorption, distribution, and elimination of the drug. Therefore, assessment of clinical utility cannot be made by a chain of evidence from clinical validity data alone. In such cases, evidence evaluation requires studies that directly demonstrate that the pharmacogenomic test alters clinical outcomes; it is not sufficient to demonstrate that the test predicts a disorder or a phenotype.

Evidence reviews assess the clinical evidence to determine whether the use of technology improves the net health outcome. Broadly defined, health outcomes are the length of life, quality of life, and ability to function, including benefits and harms. Every clinical condition has specific outcomes that are important to patients and managing the course of that condition. Validated outcome measures are necessary to ascertain whether a condition improves or worsens; and whether the magnitude of that change is clinically significant. The net health outcome is a balance of benefits and harms.

To assess whether the evidence is sufficient to draw conclusions about the net health outcome of technology, 2 domains are examined: the relevance, and quality and credibility. To be relevant, studies must represent 1 or more intended clinical use of the technology in the intended population and compare an effective and appropriate alternative at a comparable intensity. For some conditions, the alternative will be supportive care or surveillance. The quality and credibility of the evidence depend on study design and conduct, minimizing bias and confounding that can generate incorrect findings. The randomized controlled trial (RCT) is preferred to assess efficacy; however, in some circumstances, nonrandomized studies may be adequate. Randomized controlled trials are rarely large enough or long enough to capture less common adverse events and long-term effects. Other types of studies can be used for these purposes and to assess generalizability to broader clinical populations and settings of clinical practice.

Promotion of greater diversity and inclusion in clinical research of historically marginalized groups (e.g., People of Color [African-American, Asian, Black, Latino and Native American]; LGBTQIA (Lesbian, Gay, Bisexual, Transgender, Queer, Intersex, Asexual); Women; and People with Disabilities [Physical and Invisible]) allows policy populations to be more reflective of and findings more applicable to our diverse members. While we also strive to use inclusive language related to these groups in our policies, use of gender-specific nouns (e.g., women, men, sisters, etc.) will continue when reflective of language used in publications describing study populations.

Population Reference No. 1 

Thiopurine Metabolite Monitoring

Clinical Context and Therapy Purpose

The purpose of monitoring thiopurine metabolite (6-thioguanine [6-TGN] and 6-methylmercaptopurine [6-MMP]) levels in patients treated with thiopurines is to provide an advantage over no therapeutic drug monitoring with empiric treatment changes or standard weight-based dosing.

Potential benefits of monitoring thiopurine metabolite levels may include the following:

• to guide treatment changes in the event of observed drug toxicity or lack of efficacy (reactive strategy)

• routine use to guide thiopurine dosing (proactive strategy)

The following PICO was used to select literature to inform this review.

Populations

The relevant population of interest is patients treated with thiopurines.

Interventions

The therapy being considered is monitoring of thiopurine metabolite levels. Commercial tests are available from multiple labs and companies. Metabolite markers are measured from red blood cell (RBC) samples using high-performance liquid chromatography.

Comparators

The relevant comparator is no monitoring for thiopurine metabolite levels with empiric treatment changes or standard weight-based dosing.

Outcomes

The general outcomes of interest are change in disease status, treatment-related mortality, and treatment-related morbidity.

Potential beneficial outcomes of interest are improvement in disease status and reduction or elimination of toxicity associated with thiopurines (eg, bone marrow toxicity, hepatotoxicity, pancreatitis, gastric intolerance, skin reactions). In contrast, empiric treatment changes, such as escalation of therapy in patients with suboptimal response, may result in excessively high 6-TGN levels, which increases risk of leukopenia, or excessively high 6-MMP levels due to shunting, which increases risk of hepatotoxicity. Inappropriate treatment changes can also potentially delay use of more effective therapy.

Study Selection Criteria

Methodologically credible studies were selected using the following principles:

• To assess efficacy outcomes, comparative controlled prospective trials were sought, with a preference for RCTs;

• In the absence of such trials, comparative observational studies were sought, with a preference for prospective studies.

• To assess long-term outcomes and adverse events, single-arm studies that capture longer periods of follow-up and/or larger populations were sought.

• Studies with duplicative or overlapping populations were excluded.

Review of Evidence

Systematic Reviews

The American Gastroenterological Association published a systematic review on the role of therapeutic drug monitoring in the management of inflammatory bowel disease (IBD) in 2017.^1, The authors did not identify any randomized trials or prospective comparative studies in thiopurine-treated IBD patients comparing reactive therapeutic drug monitoring to guide treatment changes versus empiric treatment changes. Two randomized studies that evaluated routine therapeutic drug monitoring to guide thiopurine dosing compared to empiric weight-based dosing were identified.

Randomized Controlled Trials

Dassopoulos et al (2014) reported the results of a double-blind RCT conducted in the United States using thiopurine S-methyltransferase (TPMT) phenotype testing to guide initial dosing, followed by prospective 6-TGN guided dose adaptation compared with empiric weight-based dosing with gradual dose escalation if well tolerated (regardless of TPMT activity) in the control arm.^10,Reinshagen et al (2007) reported the results of an open-label randomized trial conducted in Germany, which investigated scheduled thiopurine metabolite testing with successive adaptation of azathiopurine therapy to a target 6-TGN concentration of 250 to 400 pmol/8 X 10⁸ RBCs versus standard azathioprine weight based dosing (2.5 mg/kg body weight).^11, Both studies were terminated early due to slow recruitment and failure to meet prespecified enrollment targets. Additionally, there was a high attrition rate in both trials (33% to 46%), although the analyses were conducted in an intention-to-treat manner with worst-case scenario imputation. In the pooled analysis of both trials reported in the systematic review, there was a numerically higher proportion of patients achieving clinical remission in patients who underwent routine therapeutic drug monitoring -guided dose adaptation compared with standard weight-based dosing (21 of 50 [42%] vs. 18 of 57 [31.6%]) at 16 weeks, but the difference was not statistically significant (relative risk [RR], 1.44; 95% confidence interval [CI], 0.59 to 3.52). The rate of serious adverse events (requiring discontinuation of therapy) was comparable between the 2 arms (therapeutic drug monitoring-guided dose adaptation vs. empiric dosing: 16 of 50 [32.0%] vs. 15 of 57 [26.3%]; RR, 1.20; 95% CI, 0.50 to 2.91). The systematic review concluded the overall quality of evidence was very low quality.^1,

Section Summary: Thiopurine Metabolite Monitoring

The evidence for the use of reactive thiopurine metabolite monitoring to guide treatment in patients being treated with thiopurines mostly include retrospective studies. These were not included in this review. Review of the literature yielded 2 randomized studies. Both studies were terminated early due to slow recruitment and failure to meet prespecified enrollment targets. Additionally, there was a high attrition rate in both trials (33% to 46%). The pooled analysis of both trials reported in the systematic review did not show a statistically significant difference in clinical remission in patients who underwent routine therapeutic drug monitoring-guided dose adaptation compared with standard weight-based dosing. The rate of serious adverse events (requiring discontinuation of therapy) was also comparable between the 2 arms. Based on 2 RCTs at high risk of bias, there is uncertainty whether reactive or routine thiopurine metabolite monitoring to guide treatment changes are superior to empirical clinical-based or standard weight-based dosing changes.

Summary of Evidence

For individuals who receive thiopurines metabolite monitoring to guide treatment changes, the evidence includes 2 RCTs. Relevant outcomes are change in disease status, treatment-related mortality, and treatment-related morbidity. The evidence for the use of reactive thiopurine metabolite monitoring to guide treatment changes in patients being treated with thiopurines includes only retrospective studies that were not included in this review. The evidence for the use of routine thiopurine drug monitoring to guide treatment changes in patients being treated with thiopurines includes 2 small, randomized studies. Both studies were terminated early due to slow recruitment and failure to meet prespecified enrollment targets. Additionally, there was a high attrition rate in both trials (33% to 46%). The pooled analysis of both trials reported in the systematic review did not show a statistically significant difference in clinical remission in patients who underwent routine therapeutic drug monitoring-guided dose adaptation compared with standard weight-based dosing. The rate of serious adverse events (requiring discontinuation of therapy) was also comparable between the 2 arms. Based on 2 small RCTs at high risk of bias, there is uncertainty whether reactive or routine thiopurine metabolite monitoring to guide treatment changes are superior to empirical clinical-based or standard weight-based dosing changes. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome. Nevertheless, following practice guidelines and position statements, in some cases, this technology might be considered medically necessary. 

Population Reference No. 2 

Thiopurine Methyltransferase and Nudix Hydrolase Phenotype or Genotype Analysis

For individuals who receive thiopurine methyltransferase and nudix hydrolase phenotype or genotype analysis to guide treatment, the evidence included FDA-approved labels for azathioprine (a prodrug for mercaptopurine), mercaptopurine, and thioguanine that include clear and specific directives on use of pharmacogenomic testing. Evidence for these indications was not evaluated.

Summary of Evidence

For individuals who are treated with thiopurines and who receive thiopurine methyltransferase and nudix hydrolase phenotype or genotype analysis to guide treatment, the evidence includes FDA-approved labels for azathioprine (a prodrug for mercaptopurine), mercaptopurine, and thioguanine that include clear and specific directives on use of pharmacogenomic testing. Evidence for these indications was not evaluated.

Supplemental Information

The purpose of the following information is to provide reference material. Inclusion does not imply endorsement or alignment with the evidence review conclusions.

Practice Guidelines and Position Statements

Guidelines or position statements will be considered for inclusion in ‘Supplemental Information' if they were issued by, or jointly by, a US professional society, an international society with US representation, or National Institute for Health and Care Excellence (NICE). Priority will be given to guidelines that are informed by a systematic review, include strength of evidence ratings, and include a description of management of conflict of interest.

National Comprehensive Cancer Network

National Comprehensive Cancer Network (v. 2.2024 ) guidelines on adult and adolescent/young adult acute lymphoblastic leukemia state:^12,

• "For patients receiving 6-MP, consider testing for TPMT [thiopurine methyltransferase] gene polymorphisms, particularly in patients who develop severe neutropenia after starting 6-MP. Testing for both TPMT and NUDT15 variant status should be considered, especially for patients of East Asian origin."

National Comprehensive Cancer Network ( v.1.2025 ) guidelines for pediatric acute lymphoblastic leukemia state:^13,

• Genetic testing for no function alleles of TPMT and NUDT-15 should be considered prior to the initiation of thiopurine therapy, or if excessive toxicity is encountered following treatment with thiopurines.

• Dosing recommendation for patients who are heterozygous or homozygous for TPMT no function allele are summarized in Table 2.

• For patients homozygous for normal function TPMT and NUDT15, who do not appear to tolerate thiopurines, consider measuring erythrocyte thiopurine metabolites and/or erythrocyte TPMT activity. Genetic testing may fail to identify rare or previously undiscovered no function alleles.

Table 2. Dosing Guidelines for Thiopurines on TPMT Phenotype

  a For patients already receiving a reduced starting dose of thiopurines (<75 mg/m2/day of 6-MP or <40 mg/m2/day of 6-TG), a further dose reduction may not be needed. 

American Gastroenterological Association Institute

Recommendations from the American Gastroenterological Association Institute (2017) guidelines on therapeutic drug monitoring in IBD are summarized in Table 3.^14,1,

Table 3. Summary of Findings of the American Gastroenterological Association Institute Technical Review on the Role of Therapeutic Drug Monitoring in the Management of IBD

   IBD: inflammatory bowel disease; QOE: quality of evidence; TPMT: thiopurine methyltransferase.

U.S. Preventive Services Task Force Recommendations

Not applicable.

Medicare National Coverage

There is no national coverage determination. In the absence of a national coverage determination, coverage decisions are left to the discretion of local Medicare carriers.

Ongoing and Unpublished Clinical Trials

Some currently ongoing and unpublished trials that might influence this review are listed in Table 4.

Table 4. Summary of Key Trials

  NCT: national clinical trial.

References

1. Vande Casteele N, Herfarth H, Katz J, et al. American Gastroenterological Association Institute Technical Review on the Role of Therapeutic Drug Monitoring in the Management of Inflammatory Bowel Diseases. Gastroenterology. Sep 2017; 153(3): 835-857.e6. PMID 28774547
2. Yang SK, Hong M, Baek J, et al. A common missense variant in NUDT15 confers susceptibility to thiopurine-induced leukopenia. Nat Genet. Sep 2014; 46(9): 1017-20. PMID 25108385
3. Moriyama T, Yang YL, Nishii R, et al. Novel variants in NUDT15 and thiopurine intolerance in children with acute lymphoblastic leukemia from diverse ancestry. Blood. Sep 07 2017; 130(10): 1209-1212. PMID 28659275
4. Mayo Clinic Laboratories. Thiopurine Methyltransferase (TPMT) and Nudix Hydrolase (NUDT15) Genotyping. Available at https://www.mayocliniclabs.com/test-catalog/overview/610062. Accessed September 26, 2024.
5. ARUP Laboratories. Thiopurine Methyltransferase, RBC. Available at https://ltd.aruplab.com/Tests/Pub/0092066. Accessed September 30, 2024.
6. LabCorp. Thiopurine Methyltransferase (TPMT), Enzyme Activity, Erythrocytes. Available at https://www.labcorp.com/tests/510750/thiopurine-methyltransferase-tpmt-enzyme-activity-erythrocytes. Accessed September 25, 2024.
7. PURIXAN (mercaptopurine) oral suspension: Prescribing Label. Available at https://www.accessdata.fda.gov/drugsatfda_docs/label/2024/205919s008lbl.pdf. Accessed September 27, 2024.
8. IMURAN (azathioprine) 50-mg Scored Tablets: Prescribing Label. Available at https://www.accessdata.fda.gov/drugsatfda_docs/label/2024/016324s040lbl.pdf. Accessed September 24, 2024.
9. TABLOID (Thioguanine) 40-mg Scored Tablets: Prescribing Label. Available at https://www.accessdata.fda.gov/drugsatfda_docs/label/2024/012429s029lbl.pdf. Accessed on September 23, 2024.
10. Dassopoulos T, Dubinsky MC, Bentsen JL, et al. Randomised clinical trial: individualised vs. weight-based dosing of azathioprine in Crohn's disease. Aliment Pharmacol Ther. Jan 2014; 39(2): 163-75. PMID 24237037
11. Reinshagen M, Schütz E, Armstrong VW, et al. 6-thioguanine nucleotide-adapted azathioprine therapy does not lead to higher remission rates than standard therapy in chronic active crohn disease: results from a randomized, controlled, open trial. Clin Chem. Jul 2007; 53(7): 1306-14. PMID 17495015
12. National Comprehensive Cancer Network (NCCN). NCCN Clinical practice guidelines in oncology: Acute Lymphoblastic Leukemia. Version 2.2024. https://www.nccn.org/professionals/physician_gls/pdf/all.pdf. Accessed September 29, 2024.
13. National Comprehensive Cancer Network (NCCN). NCCN Clinical practice guidelines in oncology: Pediatric Acute Lymphoblastic Leukemia. Version 1.2025. https://www.nccn.org/professionals/physician_gls/pdf/ped_all.pdf. Accessed September 28, 2024.
14. Feuerstein JD, Nguyen GC, Kupfer SS, et al. American Gastroenterological Association Institute Guideline on Therapeutic Drug Monitoring in Inflammatory Bowel Disease. Gastroenterology. Sep 2017; 153(3): 827-834. PMID 28780013

Codes

Policy History