Pharmacogenomic and Metabolite Markers for Patients Treated with Thiopurines

POLICY NUMBER

A.2.04.19

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 that 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 thiopurine S-methyltransferase (TPMT) enzyme. Susceptibility to drug toxicity is linked to the level of TPMT activity. The variation in TPMT activity has been related to three 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

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, 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 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. 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. 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. 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.

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 thiopurine methyltransferase. 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:

• 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:

• 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 the table below.

Identified Genetic Variants for TPMT/NUDT15 Testing

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.

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 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® 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).

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.

Mercaptopurine

• 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

• 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

• 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.

POLICY

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 EXCEPTIONS

None

POLICY GUIDELINES

The coverage guidelines outlined in the Medical Policy Manual should not be used in lieu of the Member's specific benefit plan language.

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 non-functional 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.

Medically Necessary is defined as those services, treatments, procedures, equipment, drugs, devices, items or supplies furnished by a covered Provider that are required to identify or treat a Member's illness, injury or Mental Health Disorders, and which Company determines are covered under this Benefit Plan based on the criteria as follows in A through D:

A.  consistent with the symptoms or diagnosis and treatment of the Member's condition, illness, or injury; and

B.  appropriate with regard to standards of good medical practice; and

C.  not solely for the convenience of the Member, his or her Provider; and

D.  the most appropriate supply or level of care which can safely be provided to Member. When applied to the care of an Inpatient, it further means that services for the Member's medical symptoms or conditions require that the services cannot be safely provided to the Member as an Outpatient.

For the definition of medical necessity, “standards of good medical practice” means standards that are based on credible scientific evidence published in peer-reviewed medical literature generally recognized by the relevant medical community, and physician specialty society recommendations, and the views of medical practitioners practicing in relevant clinical areas and any other relevant factors. BCBSMS makes no payment for services, treatments, procedures, equipment, drugs, devices, items or supplies which are not documented to be Medically Necessary. The fact that a Physician or other Provider has prescribed, ordered, recommended, or approved a service or supply does not in itself, make it Medically Necessary.

Investigative is defined as the use of any treatment procedure, facility, equipment, drug, device, or supply not yet recognized as a generally accepted standard of good medical practice for the treatment of the condition being treated and; therefore, is not considered medically necessary. For the definition of Investigative, “generally accepted standards of medical practice” means standards that are based on credible scientific evidence published in peer-reviewed medical literature generally recognized by the relevant medical community, and physician specialty society recommendations, and the views of medical practitioners practicing in relevant clinical areas and any other relevant factors. In order for equipment, devices, drugs or supplies [i.e, technologies], to be considered not investigative, the technology must have final approval from the appropriate governmental bodies, and scientific evidence must permit conclusions concerning the effect of the technology on health outcomes, and the technology must improve the net health outcome, and the technology must be as beneficial as any established alternative and the improvement must be attainable outside the testing/investigational setting.

POLICY HISTORY

5/2001: Approved Medical Policy Advisory Committee (MPAC).

2/12/2002: Investigational definition added.

5/2/2002: Type of Service and Place of Service deleted.

10/26/2004: Added non-covered code.

8/21/2008: Genotypic analysis policy statement changed to medically necessary. CPT 87799 moved to covered.

04/12/2010: Policy title changed to replace “Azathioprine (6-MP)” with “Thiopurines.” Policy description updated regarding immunomodulators. Policy statement regarding TPMT testing changed to indicate the following are medically necessary: “One-time genotypic OR phenotypic testing”; “or in patients on thiopurine therapy with abnormal complete blood count (CBC) results that do not respond to dose reduction.” Abbreviations in the investigational policy statement were spelled out.

08/02/2011: Policy reviewed. Added "enzyme" to the first policy statement.

07/17/2012: Policy reviewed; no changes.

10/15/2013: Policy reviewed; no changes.

09/15/2014: Policy reviewed; description updated. Added the following investigational statement: Genotypic and/or phenotypic analysis of the enzyme TPMT is considered investigational in all other situations.

08/04/2015: Code Reference section updated for ICD-10.

09/18/2015: Policy description updated. Policy statements unchanged. Policy Guidelines section updated to add medically necessary and investigative definitions.

06/06/2016: Policy number A.2.04.19 added.

12/02/2016: Policy description updated regarding laboratory-developed tests. Policy statements unchanged. Policy guidelines updated to add genetic counseling information.

12/22/2017: Code Reference section updated to add new 2018 CPT code 81335.

01/05/2018: Policy description updated regarding thiopurines and laboratory testing. Policy statements unchanged.

02/16/2018: Code Reference section updated to add CPT code 0034U.

01/07/2019: Policy description updated regarding data from a study on TPMT genotyping and phenotyping. Added information regarding metabolite markers. Policy statements unchanged.

12/10/2019: Policy reviewed; no changes.

03/17/2020: Code Reference section updated to add new CPT code 0169U, effective 04/01/2020.

03/25/2021: Policy description updated to add information regarding nudix hydrolase (NUDT15), thiopurines, phenotype testing for thiopurine methyltransferase activity, genotype testing for thiopurine methyltransferase activity/NUDT15 gene polymorphism, metabolite markers, and FDA labeling on pharmacogenomic test for thiopurines. Medically necessary policy statement updated to include NUDT15. Policy Guidelines updated to include NUDT15 testing.

12/16/2021: Code Reference section updated to add new CPT code 0286U, effective 01/01/2022.

01/27/2022: Policy description updated. Policy statements unchanged. Policy Guidelines updated to remove genetic counseling information.

12/19/2022: Code Reference section updated to add new CPT code 84433, effective 01/01/2023.

01/19/2023: Policy description updated. Policy statements updated with minor wording changes. Policy intent unchanged. Policy Guidelines updated.

12/18/2023: Policy reviewed; no changes.

01/29/2025: Policy reviewed; no changes.

SOURCE(S)

Blue Cross Blue Shield Association policy # 2.04.19

CODE REFERENCE

This may not be a comprehensive list of procedure codes applicable to this policy.

The code(s) listed below are ONLY medically necessary if the procedure is performed according to the "Policy" section of this document.

Covered Codes

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