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Azathioprine, which is a pro-drug 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 one 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 be 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 two active metabolites; either 6-thioguanine nucleotides (6-TG) by the enzyme IMPDH, or to 6-methyl-mecaptopurine 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 three distinct TMPT 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 two normal (wild-type) alleles for TPMT, those with intermediate activity are heterozygous (i.e., have a mutation on one 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 proactively identifying 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.

TPMT activity can also be measured by phenotypic testing. Phenotypic testing determines the level of thiopurine nucleotides or TPMT activity in erythrocytes and can also be informative. Caution must be taken with Phenotyping, since some coadministered drugs can influence measurement of TPMT activity in blood and recent blood transfusions will misrepresent a patient’s actual TPMT activity.

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 counts, liver function, and pancreatic function tests. However, recently there has been interest 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 and phenotyping of TPMT would only be performed once, metabolite markers might be tested at multiple times during the course of the disease.

Prometheus is the only commercial laboratory that offers pharmacogenomic and metabolite testing for those undergoing azathioprine therapy. The tests are referred to as Pro-Predict Rx TPMT and Pro-Predict Rx 6MP, respectively.  Other laboratories that offer TPMT genotyping include Quest (TPMT Genotype) and Specialty Laboratories (TPMT GenoTypR^TM ).

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

Investigative service is defined as the use of any treatment procedure, facility, equipment, drug, device, or supply not yet recognized by certifying boards and/or approving or licensing agencies or published peer review criteria as standard, effective medical practice for the treatment of the condition being treated and as such therefore is not considered medically necessary.

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

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.

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

Covered Codes

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