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The use of thiopurines, medications for treating inflammatory bowel disease (IBD) and other conditions, is limited by a high rate of drug toxicity. Susceptibility to drug toxicity has been linked to the level of activity of the enzyme thiopurine methyltransferase (TPMT) which converts thiopurines into metabolites. This variation in TPMT activity has been related to 3 distinct TPMT mutations. Pharmacogenomic analysis of TPMT status is proposed to identify patients at risk of thiopurine drug toxicity and adjust medication doses accordingly. Measurement of metabolite markers has also been proposed.
Thiopurines or purine analogues are immunomodulators. They include azathioprine (AZA) (Imuran), mercaptopurine (6-MP) (Purinethol), and thioguanine (6-TG) (Tabloid). Thiopurines are used to treat malignancies, rheumatic diseases, dermatologic conditions, inflammatory bowel disease and are used in solid organ transplantation. In particular, they are 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 its long onset of action (3-4 months) and drug toxicities, which include hepatotoxicity, bone marrow suppression, pancreatitis, and allergic reactions.
Thiopurines are converted to 6-mercaptopurine in vivo, where it is subsequently metabolized to two active metabolites; either 6-thioguanine nucleotides (6-TGN) 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-TGNs are considered cytotoxic and thus are 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 myelotoxicity (ie, 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 identify patients at risk for myelotoxicity; those with intermediate TPMT activity may be initially treated with lower doses of thiopurines, while those with low TPMT activity may not be good candidates for thiopurine 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.
Monitoring of thiopurine therapy has been based on clinical assessment of response in addition to monitoring blood cell counts, liver function, and pancreatic function tests. However, recently there has been interest in monitoring intracellular levels of thiopurine metabolites (ie, 6-TGN and 6-MMRP) 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 ie, to aid in determining initial dose and to evaluate ongoing dosing.
Prometheus® is a commercial laboratory that offers thiopurine genotype, phenotype and metabolite testing for those undergoing 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 (TPMT Genotype) and Specialty Laboratories (TPMT GenoTypRTM).
POLICYOne-time genotypic or phenotypic analysis of the enzyme TPMT may be considered medically necessary in patients beginning therapy with azathioprine (AZA), mercaptopurine (6-MP) or thioguanine (6-TG) OR in patients on thiopurine therapy with abnormal complete blood count (CBC) results that do not respond to dose reduction.
Genotypic and/or phenotypic analysis of the enzyme TPMT is considered investigational in all other situations.
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.
POLICY GUIDELINESTPMT testing can not substitute for complete blood count (CBC) monitoring in patients receiving thiopurines. Early drug discontinuation may be considered in patients with abnormal CBC results. Dosage reduction is recommended in patients with reduced TPMT activity. Alternate therapies may need to be considered for patients who have low or absent TPMT activity (homozygous for non-functional alleles). Accurate phenotyping results are not possible in patients who received recent blood transfusions. Genotyping and phenotyping of TPMT 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 Nervous/Mental Conditions, 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 Medically Necessary, “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.
The coverage guidelines outlined in the Medical Policy Manual should not be used in lieu of the Member's specific benefit plan language.
POLICY HISTORY5/2001: 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 added.
SOURCE(S)Blue Cross Blue Shield Association policy # 2.04.19
CODE REFERENCEThis 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.