From Medscape Genomic Medicine > Practical Pharmacogenomics

Pharmacogenomics of 6-Mercaptopurine: Clinical Implications

Maurie Markman, MD

Posted: 11/01/2011

Background

Advances in the outcome of treatment for childhood acute lymphoblastic leukemia (ALL) are among the major success stories in the oncology arena over the past 50 years. Although ALL was once a universally fatal illness, currently, the majority of children with this malignancy can be anticipated to experience long-term disease-free survival.^[1]
6-Mercaptopurine (6-MP) is one of the foundational antineoplastic cytotoxic agents in the curative regimens for ALL.^[1] [Note: While this discussion focuses on the use of 6-MP in cancer, 6-MP and its prodrug azathioprine are also used in a range of autoimmune disorders, including inflammatory bowel disease.]
6-MP is metabolized to the inactive methyl-6-MP by the enzyme thiopurine S-methyltransferase (TPMT), while other enzymes convert 6-MP to cytotoxic thioguanine nucleotides. It has been known for more than 30 years that activity of TPMT varies within the population. Genetic studies have identified a number of polymorphisms that affect TPMT activity in different ethnic groups, but only a few seem to have clinical relevance.^[2-4] In general, individuals can be grouped into 3 major TPMT-activity phenotype subgroups based on homozygosity or heterozygosity of functional or nonfunctional alleles. Approximately 90% of individuals in the general population have 2 functional alleles and normal level of enzyme activity. Approximately 10% are heterozygous and possess an intermediate level of enzyme activity, which is typically manifested by an accumulation of thioguanine nucleotides and a higher risk for toxicity. The 0.3%-0.5% of the population that is homozygous for the nonfunctional allele show little to no TPMT activity and are considered TPMT deficient. These individuals accumulate excessive thioguanine nucleotides and are predisposed to severe toxicity reactions, particularly rapid and potentially life-threatening myelosuppression.^[4]

Is There a Role for Genetic Testing?

Despite the clear link between TPMT deficiency and excess 6-MP toxicity, there remains insufficient data to provide a definitive recommendation for routine screening for the presence of nonfunctional TPMT alleles prior to the administration of 6-MP in patients with ALL. However, if an initial course of therapy with this agent produces unexpectedly severe toxicity, genetic testing for a nonfunctional TPMT allele is clearly indicated.^[5]

Unfortunately, there are also no guidelines on how to proceed with treatment if an individual shows reduced TPMT activity. Dose reductions are recommended to avoid excess toxicity, and it is thought that patients with TPMT deficiency can be successfully treated with a 10- to 15-fold lower dosage.^[4,5] However, there are as yet no established guidelines or models that can be used to determine optimal dosing strategies,^[5,6] and polymorphisms in other genes have also been implicated in 6-MP toxicity,^[7] indicating that additional research into the development of drug toxicity is warranted.

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Pharmacogenomics of 6-Mercaptopurine: Clinical Implications