6-Mercaptopurine and TPMT

Mercaptopurine (Purinethol® and generic products) is often used for maintenance therapy in patients with a type of cancer called acute lymphocytic leukemia. Leukemia is a cancer of the white blood cells produced in the bone marrow that is usually treated with chemotherapy. If chemotherapy is successful, 6-mercaptopurine is still required to help the patient fully recover and prevent a relapse.

Mercaptopurine is a drug that needs to be taken up by cells so that it can be transformed into its active form. When the active form, TdGTP, is incorporated into deoxyribonucleic acid (DNA), DNA can no longer form and cannot be repaired. This results in cell death. This is helpful for the treatment of leukemia because it will prevent harmful cells from growing.

The gene of interest is thiopurine-S-methyltransferase. This gene creates a substance known as an enzyme (called TPMT) that is responsible for inactivating mercaptopurine in order to prevent too much of the active drug from collecting in the body. Without functional TPMT, the body has a hard time getting rid of the drug.

Some people have slightly different thiopurine-S- methyltransferase genes that can change how well the TPMT enzyme works. Most people (about 90%) have normal TPMT and do not have any trouble metabolizing a normal dose of mercaptopurine. It is the remaining 10% of the population whose TPMT enzymes do not work, or only partially work, that may experience dangerous side effects if given the normal dose.

As stated previously, in patients with an irregular thiopurine-S- methyltransferase gene, it is more difficult to get rid of the active form of the drug than in patients with normal TPMT. If the patient cannot get rid of the drug, a large amount of the drug will remain in the body and build up over time to a potentially harmful level. Life-threatening bone marrow suppression is one side effect that can occur from high levels of mercaptopurine. Bone marrow suppression causes a decrease in the oxygen carrying capacity of the blood, in the body’s ability to form blood clots, and in immune function. This makes a usually minor infection or virus, such as the common cold, more difficult to fight. In order to avoid this, patients with defective TPMT need to be given a reduced dose of mercaptopurine during their course of therapy.

There is a recommended genetic test that can be used to identify patients that have decreased TPMT activity.

In 2008, an eight-year old Malaysian male, Chris, had acute lymphoblastic leukemia and had been undergoing chemotherapy. His doctor prescribed him mercaptopurine to in addition to other treatments. At this time, it was not yet a standard recommendation to undergo genetic testing before administering mercaptopurine. That winter, it was difficult for Chris to fight a cold that went around his hometown and his parents were worried about his immune system. Chris’ doctor gave him a genetic test that reveals Chris has a nonfunctional TPMT allele. This means that his body is unable to get rid of the medication properly. Because of his lowered immune function, Chris needs to be hospitalized for his cold. To prevent further serious colds, Chris’ doctor lowers his dose of mercaptopurine.

In 2012, a seven-year old Malaysian female, Sally, has acute lymphoblastic leukemia and has been undergoing chemotherapy. It is now highly recommended that all patients undergo genetic testing for their TPMT genotype before administering mercaptopurine. After the test, it is revealed that Sally has the nonfunctional TPMT allele, meaning that she could experience life-threatening infections due to the buildup of mercaptopurine in her body. Her doctor was able to prescribe a reduced dose of mercaptopurine for Sally, allowing her body to better fight off infections.

TPMT genetic testing does not completely rule out the risks of taking mercaptopurine, nor does it guarantee the medication will work for you. Genetic testing is a guide to personalize the treatment of patients, maximizing benefit and minimizing harm.

The links below provide access to important articles and information relative to warfarin. The links are to external websites and will be checked regularly for consistency.

• 6-Mercaptopurine Prescribing Information
• 6-Mercaptopurine Pharmacogenomic Dosing Guidelines
• Pharmacogenomics Knowledge Base: 6-Mercaptopurine

DailyMed [Internet]. Bethesda (MD): U.S. National Library of Medicine; c1993-2012. Mercaptopurine; [cited 2012 Oct 9]; [about 4 screens]. Available from: http://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=15904472-4c32- 4224-95d3- eb131a7ff9c8/.

Dean L. Mercaptopurine Therapy and TPMT Genotype. Medical Genetics Summaries [Internet]. 2012 Sep 20 [cited 2012 Dec 3]; [about 3 screens]. Available from: https://www.ncbi.nlm.nih.gov/pubmed/?term=Dean+L.+Mercaptopurine+Therapy+and+TPMT+Genotyp e.+Medical+Genetics+Summaries.

National Center for Biotechnology Information [Internet]. Bethesda (MD): National Center for Biotechnology Information; 2012. TPMT thiopurine S-methyltransferase [ Homo sapiens (humans) ]; [cited 2012 Oct 9]; [about 15 screens]. Available from: http://www.ncbi.nlm.nih.gov/gene/7172/.

PharmGKB [Internet]. Stanford (CA): U.S. Department of Health and Human Services; c2001-2017. Mercaptopurine; [cited 2012 Oct 19]; [about 5 screens]. Available from: https://www.pharmgkb.org/chemical/PA450379/.

Relling MV, Gardner EE, Sandborn WJ, Schmiegelow K, Pui CH, Yee SW, Stein CM, Carrillo M, Evans WE, Klein TE. Clinical Pharmacogenetics Implementation Consortium guidelines for thiopurine methyltransferase genotype and thiopurine dosing. Clinical Pharmacology and Therpeutics. 2011 Mar;89(3):387-91.

Wan Rosalina WR, The LK, Mohamad N, Nasir AN. Polymorphism of ITPA 94CA and risk of adverse effects among patients with acute lymphoblastic leukaemia treated with 6-mercaptopurine. Journal of Clinical Pharmacy and Therapeutics. 2012 Apr;37(2):237-41.