Coverage Policy Manual
Policy #: 2009022
Category: Laboratory
Initiated: January 2002
Last Review: December 2022
  Metabolite Testing, Monitor Antimetabolite Therapy for Inflammatory Bowel and Collagen Vascular Disease, Acute Lymphoblastic Leukemia

Description:
Metabolite testing for patients on antimetabolite therapy was removed from policy 2002002 which now addresses only TPMT genotyping and phenotyping.
 
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. 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 (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% 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, 2022).
 
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.
 
For coverage of TMPT genotyping and phenotyping please see policy 2002002.
  
REGULATORY STATUS
Clinical laboratories may develop and validate tests in-house and market them as a laboratory service; laboratory-developed tests (LDTs) 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 CLIA. Laboratories that offer LDTs must be licensed by 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, 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).
 
Coding
There are no specific CPT codes for metabolite markers of AZA, 6-MP or thioguanine.

Policy/
Coverage:
Effective August 2009
 
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
 
Analysis of the metabolite markers of azathioprine and 6-mercaptopurine, including 6-MMP and 6-TG, 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
Analysis of metabolite markers for any other indication does not meet member benefit certificate primary coverage criteria for effectiveness.   
 
For members with contracts without primary coverage criteria, the analysis of metabolite markers, including 6-MMP and 6-TG, in any circumstance other than those above, is considered investigational.  Investigational services are an exclusion in the member certificate of coverage.  
 
Effective May 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 January 2003:
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.
 
Effective December 2002:
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.  The analysis of the metabolite markers in other circumstances would be considered  investigational and not covered.

Rationale:
This policy was originally developed when requests for coverage received.  The information contained here was previously found in policy 2002002, genetic testing for TPMT.
 
Metabolite markers have been assessed using HPLC (i.e., high performance liquid chromatography) technology. It would be optimal to assess metabolite markers in peripheral leukocytes, since they reflect the status of bone marrow precursors. However, it is technically easier to measure metabolites in red blood cells (RBC) instead of leukocytes. Cuffari and colleagues (1996) reported that RBC and leukocyte 6-TG levels were directly correlated.
 
Several case series have explored the correlation between levels of 6-TG, toxicity of azathioprine and treatment effectiveness. Cuffari and colleagues (1996) measured the metabolites 6-TG and 6-MMP in 25 pediatric patients with Crohn’s disease.  Achievement of clinical remission was correlated with 6-TG levels, but not 6-MMP. In 1 patient, low 6-TG levels suggested noncompliance, which was subsequently confirmed on further questioning. Dubinsky and colleagues (2000) measured 6-TG and 6-MMP levels in 92 pediatric patients.  Higher median levels of 6-TG were observed at points of clinical response versus non-response. Quartile analysis on all samples revealed that the best probability of treatment occurred when 6-TG levels were greater than 235 (measured in pmol/8 x 10 to the eighth). The 6-MMP levels did not correlate with disease activity, but elevated levels did correlate with hepatotoxicity, observed in 16 patients. Elevated 6-TG levels were also associated with hematologic toxicity. In contrast, Gupta and colleagues (2001) reported discordant results in a case series of 54 patients with inflammatory bowel disease being treated with azathioprine.   A total of 36% of patients in relapse had 6-TG levels greater than 230, compared with 30% of those in remission. Conversely, 57% of patients with 6-TG levels less than 230 were in remission, versus 50% of patients with 6-TG levels greater than 230. These results question the 235 cut-off point suggested by Dubinsky. Similarly, Lowry and colleagues (2001) reported that the 6-TG concentration did not correlate with disease activity or leukopenia in a case series of 170 patients with inflammatory bowel disease.
 
The following clinical applications of metabolite testing have been proposed.
    • Based on the Dubinsky (2000) study, patients may undergo metabolite monitoring to tailor azathioprine therapy. For example, when 6-TG levels reach a target of 235, tapering of steroids may be considered. In the past, the onset of leukopenia was considered a target point for steroid tapering. The use of 235 as a cut-off is challenged by the results of Gupta et al.(2001) and Lowry et al.(2001), reviewed above.
    • Noncompliance may be suspected in patients with very low 6-TG levels.
    • 6-TG levels higher than 400 are associated with an increased risk of myelosuppression; dose reduction may be suggested.
    • Excessive TPMT activity may be suspected when 6-TG levels are low, while 6-MMP levels are elevated. This profile may provide an explanation for drug resistance.
 
2002-2005 Update
No prospective studies were identified that focused on the use of metabolite testing in the actual management of the patient. Therefore, the policy statement is unchanged. However, numerous cross sectional studies in different populations of patients continue to support the scientific basis of both tests, and to support their theoretical use in the management of the patient ( Belaiche, 2001; Bloomfeld, 2003; Goldenberg, 2004).
 
2007 Update
A literature review was conducted through July 2007.  No large, well-designed studies were identified that prospectively demonstrated the value of this testing in improving clinical outcomes.
 
There is an ongoing trial to identify an optimal weight-based dose of azathioprine for the treatment of active Crohn’s disease and for maintaining remission in those subjects.  Secondary outcome measures of this trial:
    • To characterize prospectively the predictive value of erythrocyte thioguanine nucleotide levels for response to azathioprine in those who are wild-type for the  TMPT gene
    • To explore the relationship of 6-TGN levels to TPMT enzyme activity
    • To prospectively determine the rate of adverse events associated with a range  of doses of azathioprine
    • To preliminarily identify genetic polymorphisms associated with therapeutic response of toxicity to azathioprine.
 
2009 Update
The above mentioned trial, NCT00098111, sponsored by the FDA Office of Orphan Products Development, was terminated.  A phase II trial (NCT00113503), sponsored by the National Institute of Diabetes and Digestive and Kidney Diseases, comparing azathioprine dosing based on weight or on the patient’s ability to breakdown the drug, monitored by 6-TGN levels, has also been terminated.  
 
A literature search through May 2009 did not identify reports of new trials or revised clinical guidelines.
 
2011 Update
A literature search was conducted using the MEDLINE database.  There were no randomized controlled trials identified that would prompt a change in the coverage statement.
  
2012 Update
A literature search was conducted using the MEDLINE database through June 2012.  There was no new information identified that would prompt a change in the coverage statement.
 
2013 Update
A literature search conducted did not identify any new literature that would prompt a change in the coverage statement. The following is a summary of the key identified literature.
 
In 2012, Kennedy and colleagues published a study retrospectively reviewing medical records of patients who had undergoing metabolite testing after it was introduced in South Australia (Kennedy, 2013). The analysis reported on 151 patients with IBD who had been taking a thiopurine for at least 4 weeks, underwent at least 1 metabolite test, and were managed at 1 of the study sites. The 151 patients had a total of 157 tests. Eighty of 157 tests (51%) were done because of flare or lack of medication efficacy, 18 (12%) were for adverse effects and 54 tests (34%) were routine tests. Forty-four of the 80 patients (55%) who had a metabolite test due to flare or lack of efficacy had improved outcomes after the test was performed. Outcomes were also improved after testing for 5 of 18 patients (28%) with a suspected adverse reaction to a thiopurine. For patients who had routine metabolite tests, 7 of 54 (13%) had improved outcomes following testing. The rate of benefit was significantly higher in patients tested due to flare or lack of efficacy compared to those who underwent routine metabolite testing (p<0.001). Changes in patient management included medication dose adjustments, change in medication and surgical treatment. The study lacked a control group and thus outcomes cannot be compared to patients managed without metabolite testing. It is possible that, even in the absence of metabolite testing, patients who were not experiencing efficacy or who were experiencing adverse events would have had their treatments adjusted which could lead to improved outcomes.
 
In 2013, the North American Society for Pediatric Gastroenterology, Hepatology and Nutrition (NASPGHAN) Committee on IBD published consensus recommendations on the role of TMPT and thiopurine metabolite testing in pediatric IBD (Benkov, 2013). Recommendations included:
 
    • TPMT testing is recommended before initiation of thiopurines and individuals who are homozygous recessive or have extremely low TPMT activity should avoid use of thiopurines because of risk of leucopenia.
    • Individuals on thiopurines should have routine monitoring of blood counts to evaluate for leucopenia regardless of TPMT testing results.
    • Metabolite testing can be used to determine adherence to thiopurine activity.
    • Metabolite testing can be used to guide dosing changes in patients with active disease.
    • Routine and repeat metabolite testing has little or no role in patients who are responding well to medication and taking an acceptable dose of thiopurines.
 
2014 Update
A literature search conducted through June 2014 did not reveal any new information that would prompt a change in the coverage statement. The key identified literature is summarized below.
 
One systematic review was identified and this focused on studies conducted in the pediatric population. In a literature search through January 4, 2013, Konidari and colleagues identified 15 studies including a total of 1026 children with IBD (Konidari, 2014). T here were 9 retrospective and 6 prospective case series and no RCTs. The authors did not pool study findings. Among studies that evaluated the association between metabolite markers and clinical remission, 5 found significantly higher rates of remission with higher levels of 6-thioguanine nucleotides (6-TGN) and 6 studies did not find significant differences in 6-TGN levels between responders and nonresponders. Moreover, 5 studies found significant associations between 6-methyl-mercaptopurine ribonucleotides (6-MMRP) levels and hepatotoxicity and 3 studies did not find significant associations.
 
One 2013 retrospective study found a positive correlation between levels of 6-TGN and 6-MMP and weight-based azathioprine dose in children with IBD (Nguyen, 2013).
 
2015 Update
A literature search conducted through May 2015 did not reveal any new information that would prompt a change in the coverage statement.  The key identified literature is summarized below.
 
A 2015 meta-analysis by Liu and colleagues evaluated the relationship between TPMT polymorphisms and adverse drug reactions (ADRs) in patients with IBD taking thiopurine drugs (Liu, 2015). This study was an update of a 2010 meta-analysis by Dong et al and findings of the two analyses were similar.5 The Liu review included studies that compared TPMT polymorphism frequencies in patients who did and did not experience ADRs. The investigators initially screened 353 articles and 14 studies with 2276 IBD patients were ultimately found to meet eligibility criteria. In a meta-analysis of data from 10 studies, 67 of 476 patients with an ADR (14.1%) and 57 of 1192 patients (4.8%) without an ADR were TPMT heterozygous or homozygous. The pooled odds ration (OR) was 3.36 (95% CI, 1.82 to 6.19), and the difference between groups was statistically significant. In analyses of specific adverse reactions, there were statistically significant associations between the presence of TPMT alleles and bone marrow toxicity, but not hepatotoxicity, pancreatitis or other ADRs (e.g., gastric intolerance, skin reactions). The number of events in some analyses was relatively small and these may have been underpowered to detect differences between groups. For example, 2 of 62 (3.3%) IBD patients with pancreatitis were TPMT heterozygous/homozygous compared with 116 of 1500 (7.7%) patients without pancreatitis (OR=0.97; 95% CI, 0.38 to 2.48).
 
A 2014 study by Kopylov and colleagues found that 6-MMP/6-TGN ratios performed better than 6-TGN levels for predicting relapse in pediatric patients with Crohn disease (Kopylov, 2014). The study included 237 patients who had been treated with a thiopurine for at least 3 months. A total of 7.7% were TPMT heterozygous, and none were TPMT homozygous. Patients were followed for 18 months; 6-MP metabolite concentration levels were measured every 3 to 4 months, or at the time of a clinical relapse or adverse event. The investigators found that 6-MMP/6-TGN ratios between 4 and 24 were significantly protective against relapse. 6-TGN levels alone were not significantly associated with relapse rates.
 
There is insufficient evidence from prospective studies on whether metabolite markers will lead to improved outcomes (primarily improved disease control and/or less adverse drug effects). Findings of studies evaluating the association between metabolite markers and clinical remission are mixed, and no prospective comparative trials have compared health outcomes in patients managed with metabolite markers compared with current approaches to care. Thus, analysis of metabolite markers is considered investigational.
 
The 2014 (version 2) acute lymphoblastic leukemia guideline from the National Comprehensive Cancer Network (NCCN) states that testing for TPMT gene polymorphisms should be considered for patients receiving 6-MP, particular in patients who develop severe neutropenia on 6-MP (NCCN, 2014)
 
2016 Update
A literature search conducted through November 2016 did not reveal any new information that would prompt a change in the coverage statement. The key identified literature is summarized below.
 
In 2016, Roy and colleagues reported on the association between TPMT genotype or phenotype tests and a reference standard, such that it was possible to determine sensitivity, specificity, positive predictive value, negative predictive value, or concordance, in patients receiving thiopurines (Roy, 2016). A total of 66 studies were included and appraised for quality. Based on data from 25 studies reporting on test performance on genotyping, the calculated sensitivity for TPMT genotyping to detect a heterozygous or homozygous TPMT mutation ranged from 13.4-100.0%, while the specificity ranged from 90.9-100.0%. A smaller 2016 systematic review by Zur and colleagues reported higher sensitivities and specificities for TPMT genotyping (Zur, 2016).
 
In 2015, Coenen and colleagues published results of the TOPIC trial, which randomized 761 patients with IBD across 30 centers to receive standard treatment or pretreatment screening for 1 of 3 common TPMT genotype variants, followed by reduced thiopurine (azathioprine or 6-mercaptopurine) treatment doses if patients were found to be heterozygous or homozygous carriers (Coenen, 2015). For the study’s primary outcome  hematology adverse drug events (ADRs), there were no significant differences in rates over the 20-week study period between the intervention group (n=405) and control group (n=378) (7.4% vs 7.9%; relative risk [RR] 0.93, 95% confidence interval [CI] 0.57 to 1.52). However, a significantly smaller proportion of TPMT carriers in the intervention (testing) group developed hematologic ADRs than those in the control group (2.6% vs 22.9%; RR 0.11, 95% CI 0.01 to 0.85).
 
2017 Update
A literature search was conducted using the MEDLINE database through November 2017. There was no information identified that would prompt a change in the coverage statement.
     
2018 Update
A literature search was conducted through November 2018.  There was no new information identified that would prompt a change in the coverage statement.  The key identified literature is summarized below.
 
METABOLITE MARKER TESTING
 
Randomized Controlled Trials
Friedman et al conducted a multicenter RCT in which 73 patients with clinically active or steroid dependent IBD were randomized to 2 different doses of adjunctive allopurinol with thiopurine (azathioprine or mercaptopurine) therapy (Friedman, 2018). The purpose of the trial was to compare the efficacy of the 2 different doses of allopurinol (50 mg or 100 mg), as the thiopurine dose was modified based on metabolite testing at 4, 12, and 18 weeks. The modifications in dosing were aimed at achieving a therapeutic level of more than 260 pmol/8´108 red blood cells. The primary outcome was the proportion of patients in steroid-free clinical remission at 24 weeks.
 
Observational Studies
Garritsen et al measured thiopurine metabolite levels in patients with atopic dermatitis and/or chronic dermatitis during maintenance (n=32) and dose escalation (n=8) (Garritsen, 2018). The patient population included both high and intermediate activity genotypes and 6-TGN metabolite levels varied widely, from 42 to 696 pmol/8´108 red blood cells. Interpretation of results is limited due to the small sample size and the heterogeneity in patient genotypes and drug doses.
 
Meijer et al retrospectively reviewed the charts of 24 patients with 6-MMP-induced leukocytopenia (Meijer, 2017). The authors reported that patients’ symptoms resolved on altering the treatment regimens. However, due to the retrospective nature of the study, the altering of treatment regimens cannot be attributed directly to metabolite testing.
 
Goldberg et al retrospectively reviewed medical records of patients (N=169) with IBD who were treated with thiopurines for at least 4 weeks (Goldberg, 2016). Metabolite levels of 6-TGN showed 52% were subtherapeutic, 34% were therapeutic, and 14% were supratherapeutic. Among patients who experienced active disease despite therapy, 86% were managed differently following metabolite testing. Clinical outcomes following the management changes were not reported.
 
Smith et al retrospectively reviewed medical records of 189 patients with IBD who had 6-TGN metabolite monitoring during thiopurine treatment (Smith, 2013). When 6-TGN concentrations were below the therapeutic range (n=47), 18 of the patients were given dose increases and 2 patients were given a combination of allopurinol with azathioprine. When 6-TGN concentrations were above the upper limit of the therapeutic range (n=55), 14 of the patients were given dose reductions. When nonresponders (n=53) were identified, 74% underwent treatment changes including dose increases, switching to a treatment combination of allopurinol and azathioprine or methotrexate, or surgery. Clinical outcomes related to the management changes were not reported.
 
2019 Update
Annual policy review completed with a literature search using the MEDLINE database through November 2019. No new literature was identified that would prompt a change in the coverage statement.
 
2020 Update
Annual policy review completed with a literature search using the MEDLINE database through November 2020. No new literature was identified that would prompt a change in the coverage statement. The key identified literature is summarized below.
 
The American Gastroenterological Association published a systematic review on the role of therapeutic drug monitoring in the management of inflammatory bowel diseases 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 vs empiric treatment changes. Two small, randomized studies that evaluated routine therapeutic drug monitoring to guide thiopurine dosing compared to empiric weight-based dosing were identified.
 
The first was a double-blind RCT conducted in the United States using 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 control arm (Dassopoulos, 2014). The second RCT was 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 vs standard AZA 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 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 TDM-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 (RR, 1.44; 95% CI, 0.59 to 3.52). The rate of serious adverse events (requiring discontinuation of therapy) was comparable between the 2 arms (TDM-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 overall quality of evidence as very low quality (Vande Casteele, 2017).
 
2021 Update
Annual policy review completed with a literature search using the MEDLINE database through November 2021. No new literature was identified that would prompt a change in the coverage statement.
 
2022 Update
Annual policy review completed with a literature search using the MEDLINE database through November 2022. No new literature was identified that would prompt a change in the coverage statement.

CPT/HCPCS:
82657Enzyme activity in blood cells, cultured cells, or tissue, not elsewhere specified; nonradioactive substrate, each specimen
83520Immunoassay for analyte other than infectious agent antibody or infectious agent antigen; quantitative, not otherwise specified
88350Immunofluorescence, per specimen; each additional single antibody stain procedure (List separately in addition to code for primary procedure)

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Benkov K, Lu Y, Patel A et al.(2013) Role of thiopurine metabolite testing and thiopurine methyltransferase determination in pediatric IBD. J Pediatr Gastroenterol Nutr 2013; 56(3):333-40.

Bloomfeld RS, Onken JE.(2003) Mercaptopurine metabolite results in clinical gastroenterology practice. Aliment Pharmacol Ther, 2003; 17(1):69-73.

Coenen MJ, de Jong DJ, van Marrewijk CJ, et al.(2015) Identification of Patients With Variants in TPMT and Dose Reduction Reduces Hematologic Events During Thiopurine Treatment of Inflammatory Bowel Disease. Gastroenterology. Oct 2015;149(4):907-917 e907. PMID 26072396

Cuffari C, Hunt S, Bayless T.(2001) Utilisation of erythrocyte 6-thioguanine metabolite levels to optimise azathioprine therapy in patients with inflammatory bowel disease. Gut, 2001; 48(5):642-6.

Cuffari C, Seidman EG, et al.(1996) Quantitation of 6-thioguanine in peripheral blood leukocyte DNA in Crohn's disease patients on maintenance 6-mercaptopurine therapy. Can J Physiol Pharmacol, 1996; 74(5):580-5.

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Cuffari C.(2008) How useful is thiopurine metabolite monitoring in pediatric inflammatory bowel disease? Nature Clin Prac-Gastroenterol Hepatol, 2008; 5(1):12-3.

Dassopoulos T, Dubinsky MC, Bentsen JL, et al.(2014) 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

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Dubinsky MC, Reyes E, et al.(2005) A cost-effectiveness analysis of alternative disease management strategies in patients with Crohn's disease treated with azathioprine or 6-mercaptopurine. Am J Gastroenterol, 2005; 100(10):2239-47.

Dubinsky MC, Yang H, et al.(2002) 6-MP metabolite provides a biochemical explanation for 6-MP resistance in patients with inflammatory bowel disease. Gastroenterol, 2002; 122(4):904-15.

Friedman AB, Brown SJ, Bampton P, et al.(2018) Randomised clinical trial: efficacy, safety and dosage of adjunctive allopurinol in azathioprine/mercaptopurine nonresponders (AAA Study). Aliment Pharmacol Ther. Apr 2018;47(8):1092-1102. PMID 29468701

Garritsen FM, van der Schaft J, Bruijnzeel-Koomen CAF, et al.(2018) Thiopurine metabolite levels in patients with atopic dermatitis and/or chronic hand/foot eczema treated with azathioprine. J Dermatolog Treat. Jun 2018;29(4):375-382. PMID 28914560

Glas J, Torok HP, et al.(2005) The leukocyte count predicts the efficacy of treatment with azathioprine in inflammatory bowel disease. Eur J Med Res, 2005; 10(12):535-8.

Goldberg R, Moore G, Cunningham G, et al.(2016) Thiopurine metabolite testing in inflammatory bowel disease. J Gastroenterol Hepatol. Mar 2016;31(3):553-560. PMID 26510636

Goldenberg BA, Rawsthorne P, Bernstein CN.(2004) The utility of 6-thioguanine metabolite levels in managing patients with inflammatory bowel disease. Am J Gastroenterol, 2004; 99(9):1744-8.

Gupta P, Gokhale R, Kirschner BS.(2001) 6-mercaptopurine metabolite levels in children with inflammatory bowel disease. J Pediatr Gastroenterol Nutr, 2001; 33(4):450-4.

Hindorf U, Lyrenas E, et al.(2004) Monitoring of long-term thiopurine therapy among adults with inflammatory bowel disease. Scand J Gastroenterol, 2004; 39(11):1105-12.

Kennedy NA, Asser TL, Mountifield RE et al.(2013) Thiopurine metabolite measurement leads to changes in management of inflammatory bowel disease. Intern Med J 2013; 43(3):278-86.

Konidari A, Anagnostopoulos A, Bonnett LJ et al.(2014) Thiopurine monitoring in children with inflammatory bowel disease: a systematic review. Br J Clin Pharmacol 2014.

Kopylov U, Amre D, Theoret Y, et al.(2014) Thiopurine metabolite ratios for monitoring therapy in pediatric Crohn disease. J Pediatr Gastroenterol Nutr. Oct 2014;59(4):511-515. PMID 24918978

Liu YP, Wu HY, Yang X, et al.(2015) Association between thiopurine S-methyltransferase polymorphisms and thiopurine-induced adverse drug reactions in patients with inflammatory bowel disease: a meta-analysis. PLoS One. 2015;10(3):e0121745. PMID 25799415

Lowry PW, Franklin CL, et al.(2001) Measurement of thiopurine methyltransferase activity and azathioprine metabolites in patients with inflammatory bowel disease. Gut, 2001; 49(5):665-70.

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