Notification Issue Date:

Medicare Advantage Policy

Title:Pharmacogenetics and Metabolite Monitoring for Using Azathioprine (AZA)/6-Mercaptopurine (6-MP) Therapy
Policy #:MA06.014d

This policy is applicable to the Company’s Medicare Advantage products only. Policies that are applicable to the Company’s commercial products are accessible via a separate commercial policy database.

The Company makes decisions on coverage based on the Centers for Medicare and Medicaid Services (CMS) regulations and guidance, benefit plan documents and contracts, and the member’s medical history and condition. If CMS does not have a position addressing a service, the Company makes decisions based on Company Policy Bulletins. Benefits may vary based on contract, and individual member benefits must be verified. The Company determines medical necessity only if the benefit exists and no contract exclusions are applicable. Although the Medicare Advantage Policy Bulletin is consistent with Medicare’s regulations and guidance, the Company’s payment methodology may differ from Medicare.

When services can be administered in various settings, the Company reserves the right to reimburse only those services that are furnished in the most appropriate and cost-effective setting that is appropriate to the member’s medical needs and condition. This decision is based on the member’s current medical condition and any required monitoring or additional services that may coincide with the delivery of this service.

This Policy Bulletin document describes the status of CMS coverage, medical terminology, and/or benefit plan documents and contracts at the time the document was developed. This Policy Bulletin will be reviewed regularly and be updated as Medicare changes their regulations and guidance, scientific and medical literature becomes available, and/or the benefit plan documents and/or contracts are changed.


Coverage is subject to the terms, conditions, and limitations of the member's Evidence of Coverage.


Determining a thiopurine methyltransferase (TPMT) enzyme status by genotyping or phenotyping is considered medically necessary and, therefore, covered as a one-time screening assay for individuals who are being considered for azathioprine (AZA)/6-mercaptopurine (6-MP) therapy.

Diagnostic TPMT testing by genotyping and phenotyping is considered medically necessary and, therefore, covered once AZA therapy has been initiated under one of the following circumstances:
  • The individual has not previously undergone diagnostic TPMT and has abnormal complete blood count (CBC) results that do not respond to dose reduction.
  • The individual has clinical or laboratory evidence of severe bone marrow toxicity, particularly myelosuppression, and has not previously undergone diagnostic TPMT.

Metabolite monitoring for AZA/6-MP therapy is considered medically necessary and, therefore, covered for individuals who are at an increased risk for toxicity following the initiation of AZA/6-MP therapy when the analysis is used to:
  • Assess therapeutic response
  • Optimize pharmacological dosing (repeat testing may be necessary)


The individual's medical record must reflect the medical necessity for the care provided. These medical records may include, but are not limited to: records from the professional provider's office, hospital, nursing home, home health agencies, therapies, and test reports.

The Company may conduct reviews and audits of services to our members, regardless of the participation status of the provider. All documentation is to be available to the Company upon request. Failure to produce the requested information may result in a denial for the service.
Policy Guidelines

There is no Medicare coverage criteria addressing this service; therefore, the Company policy is applicable.

Pharmacogenetic testing and metabolite monitoring for using azathioprine (AZA)/6-mercaptopurine (6-MP) therapy are available by national and proprietary laboratories, which are currently nonparticipating with the Company.


Subject to the terms and conditions of the applicable Evidence of Coverage, pharmacogenetics and metabolite monitoring for using azathioprine (AZA)/6-mercaptopurine (6-MP) therapy is covered under the medical benefits of the Company’s Medicare Advantage products when the medical necessity criteria listed in this medical policy are met.


The thiopurine drugs, 6-mercaptopurine (6-MP) and azathioprine (AZA), are cytotoxic and immunosuppressant agents used for the treatment of leukemia and rheumatologic and autoimmune disorders; for solid organ transplant; and for second-line therapy of steroid-dependent and steroid-refractory inflammatory bowel disease (IBD). AZA is a prodrug, or derivative, of 6-MP. Clinical use of AZA and 6-MP is limited by the long onset of action (about three months) and by the toxic side effects associated with these agents, including hepatotoxicity and myelosuppression.

AZA and 6-MP act by interfering with nucleic acid metabolism and cell proliferation. Following absorption, AZA is converted to 6-MP and then to 6-methylmercaptopurine (6-MMRP) by thiopurine methyltransferase (TPMT). A complex action of several enzymes initiates an additional intracellular pathway where 6-MP is converted to the active metabolite thioinosine monophosphate (TIMP), and then to 6-thioguanine nucleotides (6-TGNs). It is thought that the incorporation of active metabolites into the ribonucleic acid (RNA) and deoxyribonucleic acid (DNA) of cells results in both the therapeutic and immunosuppressive actions of AZA.


Thiopurine dosing was traditionally based on an individual's weight or a physician's empirical judgment. A recently discovered variation in an enzyme-producing gene has led to the understanding that inherited differences in drug metabolism may influence both the toxicity and the efficacy of the thiopurines. This variability of response and the tailoring of dosing based on genetic information is known as pharmacogenetics.

TPMT red blood cell (RBC) activity is genetically determined as a result of polymorphisms in the TPMT gene. High TPMT activity has been shown to reduce the formation of 6-TGNs. Conversely, TPMT deficiency is associated with excessively high levels of 6-TGN in hematopoietic tissues. Two alleles confer high TPMT and low TPMT activity, respectively. Homozygotes with absent or low TPMT activity (0.3 percent of the population) and heterozygotes with intermediate TPMT activity (10-15 percent of the population) generate higher 6-TGN concentrations and are more likely to experience high levels of toxicity. The remaining 85-90 percent of individuals are homozygous for a gene that results in high levels of TPMT activity. These individuals are not susceptible to toxic side effects but are more likely to be refractory to treatment.

The role of the TPMT enzyme in purine metabolism has been well documented, and polymerase chain reaction (PCR) methods reliably predict mutant alleles. TPMT genotyping, when used prior to AZA/6-MP therapy, is predictive for intermediate and low-enzyme activity in up to 95 percent of cases and may, therefore, identify individuals who are at risk for developing toxic myelosuppression with standard doses of AZA/6-MP. The measurement of TPMT activity (phenotyping) is sensitive, with a genotype correlation of 97 percent. This leads some clinicians to suggest that phenotyping provides a safer and more optimal approach to thiopurine treatment than the traditional methods of weight-based or empiric dosing.

Toxic events, some of which can be severe or even fatal, result in the discontinuation of AZA/6-MP therapy in 10-28 percent of cases. Individuals with zero TPMT activity are most likely to experience severe myelosuppression on standard AZA doses and should be considered for alternative treatment or extremely low doses of AZA. Individuals with higher-than-average TPMT activity may be refractory to the conventional dosage of AZA, and higher doses may be required, while those with intermediate TPMT activity can be safely treated with 30-50 percent of the standard dose.

Because the risk of life-threatening toxicity is high in individuals with TPMT deficiency who receive thiopurine drugs, genotyping by PCR or phenotyping by analysis of TPMT enzyme activity in erythrocytes is being advocated to identify polymorphisms in the TPMT gene. Monitoring of 6-MP metabolite level in erythrocytes has recently been investigated as a means to predict toxicity and nonresponse during treatment with AZA/6-MP.

The Mayo Clinic and St. Jude Hospital for Children genotype individuals who have acute lymphocytic leukemia (ALL) prior to administering thiopurines. Recently, a US Food and Drug Administration (FDA) Pharmacology Advisory Committee recommended that information on genetic testing be added to thiopurine labeling.


Individuals with ALL who are receiving AZA/6-MP therapy have been shown to present elevated RBC 6-TGN concentrations and leukopenia that are correlated. Therefore, routine measurement of 6-MP metabolites has been advocated as a means of assessing drug effect in the pediatric ALL population. Many recent studies concentrate on the effect of 6-MP metabolite monitoring in individuals who have IBD and autoimmune disorders. Historically, mild leukopenia has been used as the measure of appropriate therapeutic dosing for AZA/6-MP therapy, but research indicates that 6-MP metabolite levels may be a more effective guide.

Metabolite monitoring is not a universally accepted practice. For instance, the American College of Gastroenterology and the British Society of Gastroenterology advise that clinical indicators and blood tests are sufficient evidence of drug efficacy. However, they recommend that clinical implementation be delayed until the results of randomized controlled trials, which are currently in progress, are available. Others maintain that cross-sectional and retrospective studies already support the efficacy of these assays. Given the price of hospitalization and rescue therapy for individuals who experience severe effects of the therapy, as well as the costs associated with those who do not respond to therapy, metabolite monitoring may optimize treatment for certain individuals, most notably those receiving co-administration of allopurinol, nonresponders, and those in whom noncompliance is suspected.

Ansari M, Krajinovic M. Pharmacogenomics in cancer treatment defining genetic bases for inter-individual differences in responses to chemotherapy. Curr Opin Pediatr. 2007;19(1):15-22.

Baker DE. Pharmacogenomics of azathioprine and 6-mercaptopurine in gastroenterologic therapy. Rev Gastroenterol Disord. 2003;3(3):150-157.

Carter MJ, Lobo AJ, Travis SP; IBD Section, British Society of Gastroenterology. Guidelines for the management of inflammatory bowel disease in adults. Gut. 2004;53 Suppl 5:V1-V16.

Clunie GP, Lennard L. Relevance of thiopurine methyltransferase status in rheumatology patients receiving azathioprine. Rheumatology (Oxford). 2004;43(1):13-18.

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;118(6):1025-1030.

Corominas H, Domčnech M, González D, et al. Allelic variants of the thiopurine S-methyltransferase deficiency in patients with ulcerative colitis and in healthy controls. Am J Gastroenterol. 2000;95(9):2313-2317.

Cuffari C, Dassopoulos T, Turnbough L, Thompson RE, Bayless TM. Thiopurine methyltransferase activity influences clinical response to azathioprine in inflammatory bowel disease. Clin Gastroenterol Hepatol. 2004;2(5):410-417.

Cuffari C, Hunt S, Bayless T. Utilisation of erythrocyte 6-thioguanine metabolite levels to optimise azathioprine therapy in patients with inflammatory bowel disease. Gut. 2001;48(5):642-646.

David SP. Pharmacogenetics. Prim Care. 2004;31(3):543-559.

Derijks LJ, Gilissen LP, Engels LG, et al. Pharmacokinetics of 6-mercaptopurine in patients with inflammatory bowel disease: implications for therapy. Ther Drug Monit. 2004;26(3):311-318.

Dubinsky MC. Optimizing immunomodulator therapy for inflammatory bowel disease. Curr Gastroenterol Rep. 2003;5(6):506-511.

Dubinsky MC, Lamothe S, Yang HY, et al. Pharmacogenomics and metabolite measurement for 6-mercaptopurine therapy in inflammatory bowel disease. Gastroenterology. 2000;118(4):705-713.

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;100(10):2239-2247.

Gilissen LP, Derijks LJ, Bos LP, et al. Some cases demonstrating the clinical usefulness of therapeutic drug monitoring in thiopurine-treated inflammatory bowel disease patients. Eur J Gastroenterol Hepatol. 2004;16(7):705-710.

Gupta P, Gokhale R, Kirschner BS. 6-mercaptopurine metabolite levels in children with inflammatory bowel disease. J Pediatr Gastroenterol Nutr. 2001;33(4):450-454.

Ho GT, Lees C, Satsangi J. Pharmacogenetics and inflammatory bowel disease. Inflamm Bowel Dis. 2004;10(2):148-158.

Innocenti F, Danesi R, Favre C, et al. Variable correlation between 6-mercaptopurine metabolites in erythrocytes and hematologic toxicity: implications for drug monitoring in children with acute lymphoblastic leukemia [abstract]. Ther Drug Monit. 2000;22(4):375-382.

Kornbluth A, Sachar DB; Practice Parameters Committee of the American College of Gastroenterology. Ulcerative colitis practice guidelines in adults (update): American College of Gastroenterology, Practice Parameters Committee. Am J Gastroenterol. 2004;99(7):1371-1385.

Mardini HE, Arnold GL. Utility of measuring 6-methylmercaptopurine and 6-thioguanine nucleotide levels in managing inflammatory bowel disease patients treated with 6-mercaptopurine in a clinical practice setting. J Clin Gastroenterol. 2003;36(5):390-395.

Marshall E. Preventing toxicity with a gene test. Science. 2003;302:588-590.

McLeod HL, Yu J. Cancer pharmacogenomics: SNPs, chips, and the individual patient. Cancer Invest. 2003;21(4):630-640.

Mendoza JL, Urcelay E, Lana R, et al. MDRI polymorphisms and response to azathioprine therapy in patients with Crohn’s disease. Inflamm Bowel Dis. 2007;13(5):585-590.

Ooi CY, Bohane TD, Lee D, Naidoo D, Day AS. Thiopurine metabolite monitoring in paediatric inflammatory bowel disease. Ailment Pharmacol Ther. 2007;25(8):941-947.

Polifka JE, Friedman JM. Teratogen update: azathioprine and 6-mercaptopurine. Teratology. 2002;65(5):240-261.

Reuther LO, Sonne J, Larsen NE, et al. Pharmacological monitoring of azathioprine therapy. Scand J Gastroenterol. 2003;38(9):972-977.

Ross CJ, Katzov H, Carleton B, Hayden MR. Pharmacogenomics and its implications for autoimmune disease. J Autoimmun. 2007;28(2-3):122-128.

Sandborn WJ. Pharmacogenomics and IBD: TPMT and thiopurines. Inflamm Bowel Dis. 2004;10:Supp1:S35-S37.

Sanderson J, Ansari A, Marinaki T, Duley J. Thiopurine methyltransferase: should it be measured before commencing thiopurine drug therapy? Ann Clin Biochem. 2004;41(Pt 4):294-302.

Seidman EG. Clinical use and practical application of TPMT enzyme and 6-mercaptopurine metabolite monitoring in IBD. Rev Gastroenterol Disord. 2003;3 Suppl1:S30-S38.

Su C, Lichtenstein GR. Treatment of inflammatory bowel disease with azathioprine and 6-mercaptopurine. Gastroenterol Clin North Am. 2004;33(2):209-234.

Tamboli CP. Current medical therapy for chronic inflammatory bowel diseases. Surg Clin North Am. 2007;87(3):697-725.

US Food and Drug Administration (FDA). Table of valid genomic biomarkers in the context of approved drug labels. [FDA Web site]. Original: 09/15/06. (Revised: 09/10/08).Available at: . Accessed November 12, 2013.

Valdes R. Guidelines and recommendations for laboratory analysis and application of pharmacogenetics to clinical practice. 3rd Draft. [National Academy of Clinical Biochemistry (NACB) Web site]. December 2007. Available at: Accessed November 12, 2013.


Inclusion of a code in this table does not imply reimbursement. Eligibility, benefits, limitations, exclusions, precertification/referral requirements, provider contracts, and Company policies apply.

The codes listed below are updated on a regular basis, in accordance with nationally accepted coding guidelines. Therefore, this policy applies to any and all future applicable coding changes, revisions, or updates.

In order to ensure optimal reimbursement, all health care services, devices, and pharmaceuticals should be reported using the billing codes and modifiers that most accurately represent the services rendered, unless otherwise directed by the Company.

The Coding Table lists any CPT, ICD-9, ICD-10, and HCPCS billing codes related only to the specific policy in which they appear.

CPT Procedure Code Number(s)



82542, 82657




Professional and outpatient claims with a date of service on or before September 30, 2015, must be billed using ICD-9 codes. Professional and outpatient claims with a date of service on or after October 1, 2015, must be billed using ICD-10 codes.

Facility/Institutional inpatient claims with a date of discharge on or before September 30, 2015, must be billed with ICD-9 codes. Facility/Institutional inpatient claims with a date of discharge on or after October 1, 2015, must be billed with ICD-10 codes.

ICD - 10 Procedure Code Number(s)


Professional and outpatient claims with a date of service on or before September 30, 2015, must be billed using ICD-9 codes. Professional and outpatient claims with a date of service on or after October 1, 2015, must be billed using ICD-10 codes.

Facility/Institutional inpatient claims with a date of discharge on or before September 30, 2015, must be billed with ICD-9 codes. Facility/Institutional inpatient claims with a date of discharge on or after October 1, 2015, must be billed with ICD-10 codes.

ICD -10 Diagnosis Code Number(s)


HCPCS Level II Code Number(s)

G0452 Molecular pathology procedure; physician interpretation and report

Revenue Code Number(s)


Misc Code



Coding and Billing Requirements

Policy History

Revisions from MA06.014d
04/012020This version of the policy went through a code update process effective 04/01/2020, and 0169U was added to this policy on that date.

Revisions from MA06.014c
08/29/2018The policy has been reviewed and reissued to communicate the Company’s continuing position on Pharmacogenetics and Metabolite Monitoring for Using Azathioprine (AZA)/6-Mercaptopurine (6-MP) Therapy.
06/21/2017This policy has been reissued in accordance with the Company's annual review process.
07/01/2016This version of the policy will become effective on 07/01/2016.

The following updates were made to the coding table were made:
  • CPT code 82491 was removed from the policy because this code was termed effective 01/01/2016
  • CPT code 82542 was added as representative of metabolite monitoring. This code is already included in the policy as representative of phenotyping and will remain as such.

Revisions from MA06.014b
03/16/2016The policy has been reviewed and reissued to communicate the Company’s continuing position on Pharmacogenetics and Metabolite Monitoring for Using Azathioprine (AZA)/6-Mercaptopurine (6-MP) Therapy.
01/01/2016This policy has been identified for the CPT code update, effective 01/01/2016.

The list of gene tests listed for the following CPT code have been revised:


Revisions from MA06.014a
07/29/2015Revised policy number MA06.014a was issued as a result of the department's annual review process. The references were updated accordingly. The policy was updated to be consistent with current template wording and format. The policy statements and adoptable sources remain the same.

Revisions from MA06.014
01/01/2015This is a new policy.

Note: This policy has been identified for the CPT code update, effective 01/01/2015:
The following CPT narrative has been revised in this policy: 82542

Version Effective Date: 04/01/2020
Version Issued Date: 04/02/2020
Version Reissued Date: N/A