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Medical Policy: 02.01.28
Original Effective Date: November 2007
Reviewed: November 2011
Revised:
Benefit Application
Benefit determinations are based on the applicable contract language in effect at the time the
services were rendered. Exclusions, limitations or exceptions may apply. Benefits may vary
based on contract, and individual member benefits must be verified. Wellmark determines medical
necessity only if the benefit exists and no contract exclusions are applicable. This medical
policy may not apply to FEP. Benefits are determined by the Federal Employee Program.
This Medical Policy document describes the status of medical technology at the time the document
was developed. Since that time, new technology may have emerged or new medical literature may
have been published. This Medical Policy will be reviewed regularly and be updated as scientific
and medical literature becomes available.
Description:
Azathioprine, which is a prodrug of 6-mercaptopurine (6-MP), is considered an effective immunosuppressive treatment of inflammatory bowel disease, particularly in patients with steroid-resistant disease. For example, in the course of 1 year, 50% of patients with Crohn’s disease will require steroids for its treatment; of these, 50% will either be steroid resistant or steroid dependent, and thus candidates for immunosuppressive therapy. Azathioprine therapy eliminates the need for corticosteroids in about 75% of patients; azathioprine is also considered an effective therapy for fistulizing disease. Results of a recent randomized clinical trial of children with Crohn’s disease suggest that compared to prednisone alone, inclusion of azathioprine with prednisone at the time of initial diagnosis is associated with improved maintenance of remission while simultaneously decreasing the dose of prednisone.
However, the use of azathioprine is limited by both its long onset of action (3–4 months) and drug toxicities, which include hepatotoxicity, bone marrow suppression, pancreatitis, and allergic reactions. Long-term drug use has been associated with neoplasia. Due to these side effects it is estimated that less than 5% of patients with Crohn’s disease ever receive azathioprine.
Pharmacogenomics
Azathioprine is converted to 6-mercaptopurine in vivo, where it is subsequently metabolized to 2 active metabolites; either 6-thioguanine nucleotides (6-TG) by the enzyme IMPDH, or to 6-methyl-mercaptopurine ribonucleotides (6-MMRP) by the enzyme TPMT. TPMT also converts 6-MP to an inactive metabolite 6-methyl-mercaptopurine (6-MMP). 6-TG is considered cytotoxic and thus is associated with bone marrow suppression, while 6-MMRP is associated with hepatotoxicity. In population studies, the activity of the enzyme TPMT has been shown to be trimodal, with 90% of subjects having high activity, 10% intermediate activity, and 0.3% with low or no activity. In patients with intermediate to low activity, the metabolism of 6-MP is shunted toward the IMPDH pathway with greater accumulation of 6-TG nucleotides; these patients are considered to be at risk for bone marrow suppression.
This variation in TPMT activity has been related to 3 distinct TPMT mutations and has permitted the development of TPMT genotyping based on a polymerase chain reaction (PCR). For example, patients with high TPMT activity are found to have 2 normal (wild-type) alleles for TPMT; those with intermediate activity are heterozygous (i.e., have a mutation on 1 chromosome), while those with low TPMT activity are homozygous for TPMT mutations (i.e., a mutation is found on both chromosomes.) Genetic analysis has been explored as a technique to identify patients at risk for bone marrow suppression; those with intermediate TPMT activity may be initially treated with lower doses of azathioprine, while those with low TPMT activity may not be good candidates for azathioprine therapy.
Prescribing information for azathioprine states that prospective TPMT genotyping or phenotyping may help identify patients who may be at increased risk of developing severe, life-threatening myelotoxicity.
Metabolite Markers
Monitoring of azathioprine therapy has been based on clinical assessment of response in addition to monitoring blood cell counts, liver function, and pancreatic function tests. However, there has been interest recently in monitoring intracellular levels of azathioprine metabolites to predict response and complications, with the ultimate aim of tailoring drug therapy to each individual patient. While genotyping of TPMT would only be performed once, metabolite markers might be tested at multiple times during the course of the disease.
Prometheus™ is a commercial laboratory that offers pharmacogenomics and metabolite testing for those undergoing azathioprine therapy. The tests are referred to as Pro-Predict Rx TPMT and Pro-Predict Rx 6MP, respectively. The following clinical applications of pharmacogenomics testing have been proposed:
- TPMT genotyping before the initiation of therapy may identify those patients who are at higher risk for hematologic toxicity and who may benefit from more intense surveillance.
- Patients with 2 TPMT mutations are at highest risk for bone marrow toxicity and therefore alternative therapy may be considered.
- In patients with 1 TPMT mutation, azathioprine therapy may be safely initiated, but a lower (50%) dose may be considered.
- In patients with no TPMT mutations, azathioprine may be initiated at a higher dose.
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Azathioprine is typically given orally, but in some cases, it may be initially given intravenously to accelerate its onset of action. IV dosing may be considered contraindicated in patients with 2 TPMT mutations.
Monitoring of azathioprine therapy has been based on clinical assessment of response in addition to monitoring blood cell counts, liver function, and pancreatic function tests. However, there has been interest recently in monitoring intracellular levels of azathioprine metabolites to predict response and complications, with the ultimate aim of tailoring drug therapy to each individual patient. While genotyping of TPMT would only be performed once, metabolite markers might be tested at multiple times during the course of the disease.
The following clinical applications of metabolite testing have been proposed.
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Prior Approval:
Not applicable
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Policy:
Determination of thiopurine S-methyltransferase (TPMT) enzyme status by genotyping or phenotyping may be considered medically necessary as a one-time assay for individuals being considered for azathioprine or mercaptopurine therapy.
Analysis of the metabolite markers of azathioprine and 6-mercaptopurine, including 6-MMP and 6-TG may be considered medically necessary to assess response during the course of treatment.
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Procedure Codes and Billing Guidelines:
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To report provider services, use appropriate CPT* codes, Modifiers, Alpha Numeric (HCPCS level 2) codes, Revenue codes, and/or ICD-9-CM diagnostic codes.
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There are not specific CPT codes for genotypic analysis of the TPMT gene or metabolite markers of azathioprine and 6-mercaptopurine.
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There is a CPT genetic testing modifier that is specific to TPMT; 9A
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83890 Molecular diagnostics; molecular isolation or extraction, each nucleic acid type (ie, DNA or RNA)
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83891 Molecular diagnostics; isolation or extraction of highly purified nucleic acid, each nucleic acid type (ie, DNA or RNA)
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83892 Molecular diagnostics; enzymatic digestion, each enzyme treatment
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83896 Molecular diagnostics; nucleic acid probe, each
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83898 Molecular diagnostics; amplification, target, each nucleic acid sequence
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83900 Molecular diagnostics; amplification, target, multiplex, first 2 nucleic acid sequences
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83909 Molecular diagnostics; separation and identification by high resolution technique (eg, capillary electrophoresis), each nucleic acid preparation
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83912 Molecular diagnostics; interpretation and report
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83914 Mutation identification by enzymatic ligation or primer extension, single segment, each segment (eg, oligonucleotide ligation assay [OLA], single base chain extension [SBCE], or allele-specific primer extension [ASPE])
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Selected References:
- Colombel JF, Ferrari N, Debuysere H et al. Genotypic Analysis of Thiopurine S-Methyltransferase in Patients with Crohn’s Disease and Severe Myelosuppression During azathioprine Therapy. Gastroenterology. 2000 Jun; 118(6):1025-30.
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Lennard L. TPMT in the Treatment of Crohn’s Disease with azathioprine. Gut. 2002; 51:143-46.
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Campbell S, Kingston K, Ghosh S. Relevance of Thiopurine Methyltransferase Activity in Inflammatory Bowel Disease Patients Maintained in Low-dose azathioprine. Aliment Pharmacol Ther. 2002 Mar; 16(3):389-98.
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Gearry RB, Barclay ML, Roberts RL et al. Thiopurine Methyltransferase and 6-thioguanine Nucleotide Measurement: Early Experience of Use in Clinical Practice. Intern Med J. 2005 Oct; 35(10):580-5.
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Dubinsky MC, Reyes E, Ofman J et al. 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 Oct; 100(10):2239-47.
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Sies C, Florkowski C, George P et al. Measurement of Thiopurine Methyltransferase Activity Guides Dose-initiation and Prevents Toxicity from azathioprine. N Z med J. 2005 Feb 25; 118(1210):U1324.
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Clunie GP, Lennard L. Relevance of thiopurine methyltransferase status in rheumatology patients receiving azathioprine. Rheumatology (Oxford). 2004 Jan; 43(1):13-8. Epub 2003 Oct. 17.
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Corominas H, Domenech M, Laiz A et al. Is thiopurine methyltransferase genetic polymorphism a major factor for withdrawal of azathioprine in rheumatoid arthritis patients? Rheumatology (Oxford). 2003 Jan; 42(1):40-5.
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Marra CA, Esdaile JM, Anis AH. Practical pharmacogenetics: the cost effectiveness of screening for thiopurine s-methyltransferase polymorphisms in patients with rheumatological conditions treated with azathioprine. J Rheumatol. 2002 Dec; 29(12):2507-12.
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Kurzawski M, Dziewanowski K, Gawronska-Szlarz B et al. The impact of thiopurine s-methyltransferase polymorphism in azathioprine-induced myelotoxicity in renal transplant recipients. Ther Drug Monit. 2005 Aug; 27(4):435-41.
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Formea CM, Myers-Huentelman H, Wu R et al. Thiopurine S-methyltransferase genotype predicts azathioprine-induced myelotoxicity in kidney transplant recipients. Am J Transplant. 2004 Nov; 4(11):1810-7.
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Thervet E, Anglicheau D, Toledano N et al. Long-term results of TPMT activity monitoring in azathioprine-treated renal allograft recipients. J Am Soc Nephrol. 2001 Jan; 12(1):170-6.
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Hindorf U, Lindqvist M, Peterson C et al. Pharmacogenetics during standardized initiation of thiopurine treatment in inflammatory bowel disease. Gut. 2006 Oct; 55(10):1423-31.
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Teml A, Schaeffeler E, Herrlinger KR et al. Thiopurine treatment in inflammatory bowel disease: clinical pharmacology and implication of pharmacogenetically guided dosing. Clin Pharmacokinet. 2007;46(3):187-208.
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Derijks LJ, Gilissen LP, Engels LG et al. Pharmacokinetics of 6-thioguanine in patients with inflammatory bowel disease. Ther Drug Monit. 2006 Feb;28(1):45-50.
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Banerjee S, Bishop WP. Evolution of thiopurine use in pediatric inflammatory bowel disease in an academic center. J Pediatr Gastroenterol Nutr. 2006 Sep;43(3):324-30.
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Derijks LJ, Gilissen LP, Hooymans PM et al. Thiopurines in Inflammatory Bowel Disease. Aliment Pharmacol Ther. 2006;24(5):715-29.
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Haines ML, Ajlouni Y, Irving PM et al. Clinical usefulness of therapeutic drug monitoring of thiopurines in patients with inadequately controlled inflammatory bowel disease. Inflamm Bowel Dis. 2010 Sep 1 [Epub ahead of print].
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Van Asseldonk DP, de Boer NK, Peters GJ et al. On therapeutic drug monitoring of thiopurines in inflammatory bowel disease; pharmacology, pharmacogenomics, drug intolerance and clinical relevance. Curr Drug Metab. 2009 Nov;10(9):981-97.
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Donnan JR, Ungar WJ, Mathews M et al. Systematic review of thiopurine methyltransferase genotype and enzymatic testing strategies. Ther Drug Monit. 2011 Apr; 33(2):192-9.
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Waljee AK, Joyce JC, Wang S et al. Algorithms outperform metabolite tests in predicting response of patients with inflammatory bowel disease to thiopurines. Clin Gastroenterol Hepatol. 2010 Feb; 8(2):143-50. Epub 2009 Oct 14.
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Chouchana L, Narjoz C, Beaune P et al. Review article: benefits of pharmacogenetics for improving thiopurine therapy in inflammatory bowel disease. Aliment Pharmacol Ther. 2011 Nov 2. doi: 10.1111/j.1365-2036.2011.04905.x. [Epub ahead of print].
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Policy History:
Date Reason Action
November 2010 Annual review Policy renewed
November 2011 Annual review Policy renewed
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*Current Procedural Terminology © 2010 American Medical Association. All Rights Reserved.
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