Coverage Policy Manual - Arkansas Blue Cross and Blue Shield

Genetic Test: Genetic (TPMT, NUDT15, CEP72) and Metabolite (6-MMP, 6-TGN) Testing for Thiopurine Treatment

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.

Thiopurines or purine analogues are immunomodulators. They include azathioprine (Imuran), mercaptopurine (6-MP; Purinethol), and thioguanine (6-TG; Tabloid). Thiopurines are used to treat malignancies, rheumatic diseases, dermatologic conditions, and inflammatory bowel disease, and are used in solid organ transplantation. These agents are also considered an effective immunosuppressive treatment of inflammatory bowel disease, particularly in patients with the corticosteroid-resistant disease. However, the use of thiopurines is limited by both 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 one 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 (Vande Casteele, 2017). 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 (Yang, 2014). 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 percent of the standard dose. Several variant alleles have been identified with varying prevalence among different populations and varying degrees of functional effects (Moriyama, 2017). 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 (Mayo Clinic Laboratories, 2020).

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 (ARUP Laboratories, 2023):

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 (LabCorp, 2023):

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: less than 6.3 to units/ml RBC

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

TPMT Allele*1

cDNA Nucleotide Change: None (wild type)

Amino Acid Change: None (wild type)

Effect on Enzyme Metabolism: Normal function

TPMT Allele*2

cDNA Nucleotide Change: c.238G>C

Amino Acid Change: p.Ala80Pro (p.A80P)

Effect on Enzyme Metabolism: No activity

TPMT Allele*3A

cDNA Nucleotide Change: c.460G>A and c.719A>G

Amino Acid Change: p.Ala154Thr (p.A154T) and p.Tyr240Cys (p.Y240C)

Effect on Enzyme Metabolism: No activity

TPMT Allele*3B

cDNA Nucleotide Change: c.460G>A

Amino Acid Change: p.Ala154Thr (p.A154T)

Effect on Enzyme Metabolism: No activity

TPMT Allele*3C

cDNA Nucleotide Change: c.719A>G

Amino Acid Change: p.Tyr240Cys (p.Y240C)

Effect on Enzyme Metabolism: No activity

TPMT Allele*4

cDNA Nucleotide Change: c.626-1G>A

Amino Acid Change: Not applicable, splice site

Effect on Enzyme Metabolism: No activity

TPMT Allele*5

cDNA Nucleotide Change: c.146T>C

Amino Acid Change: p.Leu49Ser (p.L49S)

Effect on Enzyme Metabolism: No activity

TPMT Allele*8

cDNA Nucleotide Change: c.644G>A

Amino Acid Change: p.Arg215His (p.R215H)

Effect on Enzyme Metabolism: Reduced activity

TPMT Allele*12

cDNA Nucleotide Change: c.374C>T

Amino Acid Change: p.Ser125Leu (p.S125L)

Effect on Enzyme Metabolism: Reduced activity

NUDT15 Allele*1

cDNA Nucleotide Change: None (wild type)

Amino Acid Change: None (wild type)

Effect on Enzyme Metabolism: Normal activity

NUDT15 Allele*2 or 3

cDNA Nucleotide Change: c.415C>T

Amino Acid Change: p.Arg139Cys (p.R139C)

Effect on Enzyme Metabolism: No activity

NUDT15 Allele*4

cDNA Nucleotide Change: c.416G>A

Amino Acid Change: p.Arg139His (p.R139H)

Effect on Enzyme Metabolism: No activity

NUDT15 Allele*5

cDNA Nucleotide Change: c.52G>A

Amino Acid Change: p.Val18Ile (p.V18I)

Effect on Enzyme Metabolism: No activity

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 genotypes, 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 has chosen not to require any regulatory review of this test.

Prometheus is a commercial laboratory that offers thiopurine genotype, phenotype, and metabolite testing for those undergoing thiopurine therapy. The tests are referred to as Prometheus TPMT Genetics, Prometheus TMPT 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).

The FDA has included pharmacogenomics information in the physician prescribing information (drug labels) 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.

Mercaptopurine (Purixan, 2020)

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 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 (Imuran, 2020)

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 (Tabloid, 2020)

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 (red blood cell 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.

Coding

Effective January 2018, there is a specific Proprietary Laboratory Analysis (PLA) code for gene analysis of TPMT and NUDT15. CPT 0034U is specifically for use with the Thiopurine Methyltransferase (TPMT) and Nudix Hydrolase (NUDT15) Genotyping test performed by Mayo Clinic laboratory.

0034U TPMT (thiopurine S-methyltransferase), NUDT15 (nudix hydroxylase 15) (e.g., thiopurine metabolism), gene analysis, common variants (i.e., TPMT*2, *3A, *3B, *3C, *4, *5, *6, *8, *12; NUDT15*3, *4, *5)

Effective in 2012, the analysis of common variants of the TPMT gene would be reported with CPT code 81401

81401 Molecular pathology procedure, Level 2 (e.g., 2-10 single nucleotide polymorphisms [SNPs], 1 methylated variant, or 1 somatic variant [typically using nonsequencing target variant analysis], or detection of a dynamic mutation disorder/triplet repeat).

Effective January 2022, there is a specific Proprietary Laboratory Analysis (PLA) code for gene analysis, common variants of CEP72, NUDT15 and TPMT (CNT genotyping panel). CPT 0286U is specifically for use with the genotyping panel performed by RPRD Diagnostics.

0286U CEP72 (centrosomal protein, 72-KDa), NUDT15 (nudix hydrolase 15) and TPMT (thiopurine S-methyltransferase) (e.g., drug metabolism) gene analysis, common variants

There are no specific CPT codes for metabolite markers of azathioprine, mercaptopurine (6-MP) or thioguanine.

Policy/
Coverage:

Effective October 2024, coverage policies 2002002 [Genetic Test: Azathioprine, 6MP Sensitivity, Genotyping & Phenotyping (TPMT) (NUDT15)] and 2009022 (Metabolite Testing, Monitor Antimetabolite Therapy for Inflammatory Bowel and Collagen Vascular Disease, Acute Lymphoblastic Leukemia) were combined into one policy. Policy 2009022 is archived effective October 2024.

Effective October 2024

Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria

for individuals beginning therapy with azathioprine (AZA), mercaptopurine (6-MP) or thioguanine (6-TG) OR
for individuals on thiopurine therapy with abnormal complete blood count (CBC) results that do not respond to dose reduction OR
for pediatric individuals with acute lymphoblastic leukemia who are to be treated with thiopurine chemotherapy.

Analysis of the metabolite markers of azathioprine and mercaptopurine, including 6-methyl-mercaptopurine (6-MMP) ribonucleotides and 6-thioguanin nucleotides (6-TGN), meets member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness when it is performed four weeks or longer after initiation of antimetabolite therapy for patients with:

Inflammatory bowel disease
Collagen vascular disease
Acute lymphoblastic leukemia

Repeat testing is covered only when there is a change in the patient's status that necessitates an alteration in dosage.

Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria

Genotypic or phenotypic analysis of TPMT or NUDT15 for any indication not listed above does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes.

For members with contracts without primary coverage criteria, genotypic or phenotypic analysis of TPMT or NUDT15 for any indication other than listed is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.

Gene analysis of CEP72 does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes.

For members with contracts without primary coverage criteria, gene analysis of CEP72 is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.

Analysis of the metabolite markers of azathioprine and mercaptopurine, including 6-methyl-mercaptopurine ribonucleotides and 6-thioguanine nucleotides, for any indication not listed above does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes.

For members with contracts without primary coverage criteria, analysis of the metabolite markers of azathioprine and mercaptopurine, including 6-methyl-mercaptopurine ribonucleotides and 6-thioguanine nucleotides, for any indication not listed above is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.

Effective March 2024 – September 2024

Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria

One-time genotypic or phenotypic analysis of the thiopurine methyltransferase (TPMT) or nudix hydolase (NUDT 15) meets member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes for patients beginning therapy with azathioprine (AZA), mercaptopurine (6-MP) or thioguanine (6-TG) OR for patients on thiopurine therapy with abnormal complete blood count (CBC) results that do not respond to dose reduction and in pediatric patients with acute lymphoblastic leukemia who are to be treated with thiopurine chemotherapy.

Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria

For members with contracts without primary coverage criteria, genotypic or phenotypic analysis of TPMT or NUDT15 for any indication other than listed is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.

Gene analysis of CEP72, NUDT15 and TPMT (common variants) does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes.

For members with contracts without primary coverage criteria, gene analysis of CEP72, NUDT15 and TPMT (common variants) is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.

Analysis of the metabolite markers of azathioprine and mercaptopurine, including 6-methyl-mercaptopurine ribonucleotides and 6-thioguanine nucleotides, does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes.

For members with contracts without primary coverage criteria, analysis of the metabolite markers of azathioprine and mercaptopurine, including 6-methyl-mercaptopurine ribonucleotides and 6-thioguanine nucleotides, is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.

Effective January 2022 through February 2024

Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria

Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria

Effective April 2018 to December 2021

One-time genotypic or phenotypic analysis of the TPMT or NUDT 15 meets primary coverage criteria for patients beginning therapy with azathioprine (AZA), mercaptopurine (6-MP) or thioguanine (6-TG) OR for patients on thiopurine therapy with abnormal complete blood count (CBC) results that do not respond to dose reduction and in pediatric patients with acute lymphoblastic leukemia who are to be treated with thiopurine chemotherapy.

Genotypic or phenotypic analysis of TPMT or NUDT15 for any indication not listed above does not meet primary coverage criteria for effectiveness.

For contracts without primary coverage criteria genotypic or phenotypic analysis of TPMT or NUDT15 for any indication other than listed above is considered investigational. Investigational services are an exclusion in the member benefit certificate.

Effective August 2009 – March 2018

One-time genotypic or phenotypic analysis of the TPMT meets primary coverage criteria for patients beginning therapy with azathioprine (AZA), mercaptopurine (6-MP) or thioguanine (6-TG) OR for patients on thiopurine therapy with abnormal complete blood count (CBC) results that do not respond to dose reduction and in pediatric patients with acute lymphoblastic leukemia who are to be treated with thiopurine chemotherapy.

Genotypic or phenotypic analysis of TPMT for any indication not listed above does not meet primary coverage criteria for effectiveness.

For contracts without primary coverage criteria genotypic or phenotypic analysis of TPMT for any indication other than listed above is considered investigational. Investigational services are an exclusion in the member benefit certificate.

Effective 2006

Analysis of the metabolite markers of azathioprine and 6-mercaptopurine, including 6-MMP and 6-TG is covered for members with inflammatory bowel disease who are unresponsive to azathioprine after six months of continuous therapy.

Analysis of the metabolite markers of azathioprine and 6-mercaptopurine, including 6-MMP and 6-TG, is covered for members with collagen vascular disease who are unresponsive to azathioprine after six months of continuous therapy.

Measurement of TPMT genotype to identify homozygous TPMT deficient patients is covered for pediatric patients with acute lymphoblastic leukemia who are to be treated with thiopurine chemotherapy.

For group contracts furnished or renewed on or after July 1, 2004 or individual contracts furnished on or after July 1, 2004, genotypic analysis of the TPMT gene and the analysis of the metabolite markers in other circumstances do not meet Primary Coverage Criteria for effectiveness.

For those individual contracts in force prior to July 1, 2004, genotypic analysis of the TPMT gene and the analysis of the metabolite markers in other circumstances are considered investigational. Investigational services are an exclusion in the member certificate of coverage.

Effective 2003

Genotypic analysis of the TPMT gene is considered investigational and is not covered.

The analysis of the metabolite markers in other circumstances would be considered investigational and not covered. Investigational services are a benefit contract exclusion.

Effective 2002

Genotypic analysis of the TPMT gene is considered investigational and is not covered.

be considered investigational and not covered. Investigational services are a benefit contract exclusion.

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 21, 2023.

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)

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 (Vande Casteele, 2017). 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 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 (Dassopoulos, 2014).,Reinshagen et al 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) (Reinshagen, 2007). 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 (Vande Casteele, 2017).

National Comprehensive Cancer Network

National Comprehensive Cancer Network (v. 2.2023) guidelines on adult and adolescent/young adult acute lymphoblastic leukemia state (NCCN, 2023):

"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.1.202 4) guidelines for pediatric acute lymphoblastic leukemia state (NCCN, 2023):

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 below.
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.

Dosing Guidelines for Thiopurines on TPMT Phenotype:

Homozygous for normal function alleles (e.g., *1/*1); normal metabolizer

Dosing Recommendations for 6-MP Starting dose should be based on treatment protocol (typically 75 mg/m2/day). Allow 2 weeks to achieve steady state prior to making dosing adjustments
Dosing Recommendations for 6-TG Starting dose should be based on treatment protocol (typically 60 mg/m2/day). Allow 2 weeks to achieve steady state prior to making dosing adjustments

Heterozygous for no function alleles (e.g., *1/*2, 3A, 3B, 3C, or 4); intermediate metabolizer

Dosing Recommendations for 6-MP Starting dose at 30 to 80% of full dose. Adjust dose based on degree of myelosuppression as dictated by protocol. Allow 2 to 4 weeks to achieve steady state prior to making dosing adjustments.
Dosing Recommendations for 6-TG Reduce starting dose by 30 to 80%. Adjust dose based on degree of myelosuppression as dictated by protocol. Allow 2 to 4 weeks to achieve steady state prior to making dosing adjustments.

Homozygous for no function alleles (e.g., *2/*3A, *3/*4); poor metabolizer

Dosing Recommendations for 6-MP Starting dose at approx 10% of full dose. Adjust dose based on degree of myelosuppression as dictated by protocol. Allow 4 to 6 weeks to achieve steady state prior to making dosing adjustments.
Dosing Recommendations for 6-TG Starting dose at approx 10% of full dose as dictated by protocol. Allow 4 to 6 weeks to achieve steady state prior to making dosing adjustments.

American Gastroenterological Association Institute

Recommendations from the American Gastroenterological Association Institute guidelines on therapeutic drug monitoring in IBD are summarized below (Feuerstein, 2017; Vande Casteele, 2017).

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

In patients with IBD being started on thiopurines, is routine TPMT measurement (to guide dosing) superior to no TPMT measurement (with empiric weight-based dosing of thiopurines)? Conclusion: Benefit is uncertain but may avoid serious harm in a small fraction of patients Quality of Evidence: Low
In patients with active IBD treated with thiopurines or with side effects thought to be due to thiopurine toxicity, is reactive therapeutic drug monitoring to guide treatment changes superior to no therapeutic drug monitoring with empiric treatment changes? Conclusion: May be a benefit Quality of Evidence: Very low
In patients with IBD treated with thiopurines, is routine therapeutic drug monitoring to guide thiopurine dosing superior to empiric weight-based dosing? Conclusion: Benefit is uncertain Quality of Evidence: Very low

Ongoing and Unpublished Clinical Trials

Some currently ongoing and unpublished trials that might influence this review are listed below.

Summary of Key Trials:

NCT02929706 Effectiveness of Thiopurine Dose Optimization by NUDT15 R139C on Reducing Thiopurine-Induced Leucopenia in Inflammatory Bowel Disease has a planned enrollment of 400 and a planned completion date of August 2018. Of note, last update was May 2018.
NCT03093818 PREemptive Pharmacogenomic Testing for Preventing Adverse Drug REactions (PREPARE) has a planned enrollment of 6950 and a completion date of April 2021.

2024 Update

Annual policy review completed with a literature search using the MEDLINE database through November 2024. No new literature was identified that would prompt a change in the coverage statement.

CPT/HCPCS:

0034U	TPMT (thiopurine S methyltransferase), NUDT15 (nudix hydroxylase 15) (eg, thiopurine metabolism) gene analysis, common variants (ie, TPMT 2, 3A, 3B, 3C, 4, 5, 6, 8, 12; NUDT15 3, 4, 5)
0169U	NUDT15 (nudix hydrolase 15) and TPMT (thiopurine S methyltransferase) (eg, drug metabolism) gene analysis, common variants
0286U	CEP72 (centrosomal protein, 72 KDa), NUDT15 (nudix hydrolase 15) and TPMT (thiopurine S methyltransferase) (eg, drug metabolism) gene analysis, common variants
81335	TPMT (thiopurine S methyltransferase) (eg, drug metabolism), gene analysis, common variants (eg, 2, 3)
81401	Molecular pathology procedure, Level 2 (eg, 2-10 SNPs, 1 methylated variant, or 1 somatic variant [typically using nonsequencing target variant analysis], or detection of a dynamic mutation disorder/triplet repeat) ABCC8 (ATP-binding cassette, sub-family C [CFTR/MRP], member 8) (eg, familial hyperinsulinism), common variants (eg, c.3898-9G>A [c.3992-9G>A], F1388del) ABL1 (ABL proto-oncogene 1, non-receptor tyrosine kinase) (eg, acquired imatinib resistance), T315I variant ACADM (acyl-CoA dehydrogenase, C-4 to C-12 straight chain, MCAD) (eg, medium chain acyl dehydrogenase deficiency), commons variants (eg, K304E, Y42H) ADRB2 (adrenergic beta-2 receptor surface) (eg, drug metabolism), common variants (eg, G16R, Q27E) APOB (apolipoprotein B) (eg, familial hypercholesterolemia type B), common variants (eg, R3500Q, R3500W) APOE (apolipoprotein E) (eg, hyperlipoproteinemia type III, cardiovascular disease, Alzheimer disease), common variants (eg, 2, 3, *4) CBFB/MYH11 (inv(16)) (eg, acute myeloid leukemia), qualitative, and quantitative, if performed CBS (cystathionine-beta-synthase) (eg, homocystinuria, cystathionine beta-synthase deficiency), common variants (eg, I278T, G307S) CFH/ARMS2 (complement factor H/age-related maculopathy susceptibility 2) (eg, macular degeneration), common variants (eg, Y402H [CFH], A69S [ARMS2]) DEK/NUP214 (t(6;9)) (eg, acute myeloid leukemia), translocation analysis, qualitative, and quantitative, if performed E2A/PBX1 (t(1;19)) (eg, acute lymphocytic leukemia), translocation analysis, qualitative, and quantitative, if performed EML4/ALK (inv(2)) (eg, non-small cell lung cancer), translocation or inversion analysis ETV6/RUNX1 (t(12;21)) (eg, acute lymphocytic leukemia), translocation analysis, qualitative, and quantitative, if performed EWSR1/ATF1 (t(12;22)) (eg, clear cell sarcoma), translocation analysis, qualitative, and quantitative, if performed EWSR1/ERG (t(21;22)) (eg, Ewing sarcoma/peripheral neuroectodermal tumor), translocation analysis, qualitative, and quantitative, if performed EWSR1/FLI1 (t(11;22)) (eg, Ewing sarcoma/peripheral neuroectodermal tumor), translocation analysis, qualitative, and quantitative, if performed EWSR1/WT1 (t(11;22)) (eg, desmoplastic small round cell tumor), translocation analysis, qualitative, and quantitative, if performed F11 (coagulation factor XI) (eg, coagulation disorder), common variants (eg, E117X [Type II], F283L [Type III], IVS14del14, and IVS14+1G>A [Type I]) FGFR3 (fibroblast growth factor receptor 3) (eg, achondroplasia, hypochondroplasia), common variants (eg, 1138G>A, 1138G>C, 1620C>A, 1620C>G) FIP1L1/PDGFRA (del[4q12]) (eg, imatinib-sensitive chronic eosinophilic leukemia), qualitative, and quantitative, if performed FLG (filaggrin) (eg, ichthyosis vulgaris), common variants (eg, R501X, 2282del4, R2447X, S3247X, 3702delG) FOXO1/PAX3 (t(2;13)) (eg, alveolar rhabdomyosarcoma), translocation analysis, qualitative, and quantitative, if performed FOXO1/PAX7 (t(1;13)) (eg, alveolar rhabdomyosarcoma), translocation analysis, qualitative, and quantitative, if performed FUS/DDIT3 (t(12;16)) (eg, myxoid liposarcoma), translocation analysis, qualitative, and quantitative, if performed GALC (galactosylceramidase) (eg, Krabbe disease), common variants (eg, c.857G>A, 30-kb deletion) GALT (galactose-1-phosphate uridylyltransferase) (eg, galactosemia), common variants (eg, Q188R, S135L, K285N, T138M, L195P, Y209C, IVS2-2A>G, P171S, del5kb, N314D, L218L/N314D) H19 (imprinted maternally expressed transcript [non-protein coding]) (eg, Beckwith-Wiedemann syndrome), methylation analysis IGH@/BCL2 (t(14;18)) (eg, follicular lymphoma), translocation analysis; single breakpoint (eg, major breakpoint region [MBR] or minor cluster region [mcr]), qualitative or quantitative (When both MBR and mcr breakpoints are performed, use 81278) KCNQ1OT1 (KCNQ1 overlapping transcript 1 [non-protein coding]) (eg, Beckwith-Wiedemann syndrome), methylation analysis LINC00518 (long intergenic non-protein coding RNA 518) (eg, melanoma), expression analysis LRRK2 (leucine-rich repeat kinase 2) (eg, Parkinson disease), common variants (eg, R1441G, G2019S, I2020T) MED12 (mediator complex subunit 12) (eg, FG syndrome type 1, Lujan syndrome), common variants (eg, R961W, N1007S) MEG3/DLK1 (maternally expressed 3 [non-protein coding]/delta-like 1 homolog [Drosophila]) (eg, intrauterine growth retardation), methylation analysis MLL/AFF1 (t(4;11)) (eg, acute lymphoblastic leukemia), translocation analysis, qualitative, and quantitative, if performed MLL/MLLT3 (t(9;11)) (eg, acute myeloid leukemia), translocation analysis, qualitative, and quantitative, if performed MT-ATP6 (mitochondrially encoded ATP synthase 6) (eg, neuropathy with ataxia and retinitis pigmentosa [NARP], Leigh syndrome), common variants (eg, m.8993T>G, m.8993T>C) MT-ND4, MT-ND6 (mitochondrially encoded NADH dehydrogenase 4, mitochondrially encoded NADH dehydrogenase 6) (eg, Leber hereditary optic neuropathy [LHON]), common variants (eg, m.11778G>A, m.3460G>A, m.14484T>C) MT-ND5 (mitochondrially encoded tRNA leucine 1 [UUA/G], mitochondrially encoded NADH dehydrogenase 5) (eg, mitochondrial encephalopathy with lactic acidosis and stroke-like episodes [MELAS]), common variants (eg, m.3243A>G, m.3271T>C, m.3252A>G, m.13513G>A) MT-RNR1 (mitochondrially encoded 12S RNA) (eg, nonsyndromic hearing loss), common variants (eg, m.1555A>G, m.1494C>T) MT-TK (mitochondrially encoded tRNA lysine) (eg, myoclonic epilepsy with ragged-red fibers [MERRF]), common variants (eg, m.8344A>G, m.8356T>C) MT-TL1 (mitochondrially encoded tRNA leucine 1 [UUA/G]) (eg, diabetes and hearing loss), common variants (eg, m.3243A>G, m.14709 T>C) MT-TL1 MT-TS1, MT-RNR1 (mitochondrially encoded tRNA serine 1 [UCN], mitochondrially encoded 12S RNA) (eg, nonsyndromic sensorineural deafness [including aminoglycoside-induced nonsyndromic deafness]), common variants (eg, m.7445A>G, m.1555A>G) MUTYH (mutY homolog [E. coli]) (eg, MYH-associated polyposis), common variants (eg, Y165C, G382D) NOD2 (nucleotide-binding oligomerization domain containing 2) (eg, Crohn's disease, Blau syndrome), common variants (eg, SNP 8, SNP 12, SNP 13) NPM1/ALK (t(2;5)) (eg, anaplastic large cell lymphoma), translocation analysis PAX8/PPARG (t(2;3) (q13;p25)) (eg, follicular thyroid carcinoma), translocation analysis PRAME (preferentially expressed antigen in melanoma) (eg, melanoma), expression analysis PRSS1 (protease, serine, 1 [trypsin 1]) (eg, hereditary pancreatitis), common variants (eg, N29I, A16V, R122H) PYGM (phosphorylase, glycogen, muscle) (eg, glycogen storage disease type V, McArdle disease), common variants (eg, R50X, G205S) RUNX1/RUNX1T1 (t(8;21)) (eg, acute myeloid leukemia) translocation analysis, qualitative, and quantitative, if performed SS18/SSX1 (t(X;18)) (eg, synovial sarcoma), translocation analysis, qualitative, and quantitative, if performed SS18/SSX2 (t(X;18)) (eg, synovial sarcoma), translocation analysis, qualitative, and quantitative, if performed VWF (von Willebrand factor) (eg, von Willebrand disease type 2N), common variants (eg, T791M, R816W, R854Q)
82657	Enzyme activity in blood cells, cultured cells, or tissue, not elsewhere specified; nonradioactive substrate, each specimen
83520	Immunoassay for analyte other than infectious agent antibody or infectious agent antigen; quantitative, not otherwise specified
84433	Thiopurine S-methyltransferase
88350	Immunofluorescence, per specimen; each additional single antibody stain procedure (List separately in addition to code for primary procedure)

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