Continuing Education Activity

Mercaptopurine is a medication used in the management and treatment of acute lymphoblastic leukemia. It is in the class of medications known as purine antagonists. This activity reviews the indications, action, and contraindications for mercaptopurine as a valuable agent in treating and managing leukemias and inflammatory autoimmune disorders. This activity will highlight the mechanism of action, adverse event profile, and other key factors (e.g., off-label uses, dosing, pharmacodynamics, pharmacokinetics, monitoring, relevant interactions) pertinent for members of the healthcare team in the treatment of patients with acute lymphoblastic leukemia and some inflammatory autoimmune-related conditions.

Objectives:

• Identify the mechanism of action and administration of mercaptopurine.
• Describe the potential adverse effects of mercaptopurine.
• Review the appropriate monitoring for patients on mercaptopurine.
• Summarize the interprofessional team strategies for improving care coordination and communication to advance mercaptopurine and improve outcomes.

Indications

Mercaptopurine (6MP) was approved by the Food and Drug Administration (FDA) for use in acute lymphoblastic leukemia in children and adults as part of combination therapy. However, there are several off-label uses for 6MP[1][2][3][4][5]: 

• Maintenance treatment in childhood acute promyelocytic leukemia
• Non-Hodgkin lymphoma
• Lymphoblastic lymphoma
• Crohn disease management after surgical resection or as a steroid-sparing therapy
• Induction and remission maintenance in ulcerative colitis
• Rheumatoid arthritis
• Systemic lupus erythematosus (SLE)
• Psoriasis
• Childhood severe atopic eczema
• Treating autoimmune hepatitis in children
• Preventing tissue rejection after organ transplantation
• Other dermatological conditions

Mechanism of Action

Mercaptopurine and azathioprine are prodrugs of a purine analog hypoxanthine that works as an antagonist to endogenous purines required for DNA replication during the S-phase of the cell cycle and inhibition of RNA and protein synthesis. Azathioprine breaks down into 88% mercaptopurine and 12% other thiopurine metabolites. 6MP requires conversion into 6-thioguanine nucleotides (6TGN) to become active and exert antileukemic effects.[6]

The prodrug is metabolized in the liver, GI tract and taken up by lymphocytes, where mercaptopurine is metabolized via the purine salvage enzyme via hypoxanthine-guanine phosphoribosyltransferase (HGPRT) to thioguanine nucleotides 6TGN and thioinosine monophosphate (TIMP). Inosine triphosphate (ITPA) catalyzes the hydrolysis of thioinosine triphosphate (TITP) to thioinosine monophosphate (TIMP), which increases 6TGN levels.[7]

There is also a secondary pathway via thiopurine methyltransferase (TPMT), which produces inactive methylated bases, 6-methylmercaptopurine. The methylated metabolite, methyl-thioinosine monophosphate (Me-TIMP), is a potent inhibitor of the purine de novo synthesis. Me-TIMP further reduces purines available for incorporation in DNA synthesis.[7]

Deoxy-6-thioguanine triphosphate (6-dTGTP) incorporates into DNA, and 6-thioguanine triphosphate (6-TGTP) inserts into RNA. 6-TGTP also binds to Rac1, resulting in the inactivation of the Vav-Rac1 signaling pathway in T-lymphocytes. This process further prevents the activation of Rac1 target genes such as nuclear factor kappa beta (NF-kB), which induces apoptosis of activated T-lymphocytes.[6]

The replacement of the endogenous purines with these synthetic thiopurine nucleotides results in purine deprivation within the cells, which halts DNA, RNA, and protein synthesis leading to decreased cell proliferation and cytotoxicity.[8][9][10]

Administration

Mercaptopurine comes as a 50 mg tablet that may be administered orally as either a tablet or suspension, preferably on an empty stomach at the same time each day.[11] The dosage varies from 1 to 3 mg/kg or 50 to 150 mg/day for long-term therapy.[12] The therapeutic response is generally observable after three months of therapy, but it may take longer to observe results. Dosages may need to be adjusted based on the patient's renal or hepatic impairments. 

Adverse Effects

Patients may exhibit non-dose dependent or dose-dependent side effects while undergoing treatment with mercaptopurine. Allergic reactions such as nausea, fever, rash, flu-like symptoms, and arthralgias are considered non-dose-dependent symptoms that may require changing the timing of dosing to night-time administration or discontinuation of therapy.[13]

These symptoms may also reoccur in patients reintroduced to azathioprine or mercaptopurine after an initial adverse reaction. [14] To reduce these symptoms, administering 6MP at night may be required.[13]

Dose-dependent adverse reactions that are potentially observable with 6MP are[13]:

• Jaundice 
• Pancreatitis (3.3%)
• Myelosuppression (2 to 15%)
• Elevation of transaminases (30%) 
• Drug hepatitis (0.3%) 
• Hepatotoxicity
• Nodular regenerative hyperplasia and veno-occlusive disease
• Leukopenia
• Myelosuppression with high levels of 6TGN (2 to 15%)
• EB virus-positive lymphoma 
• Hepatosplenic T-cell lymphoma (HSTCL)

There are various forms of hepatotoxicity resulting from both acute and chronic mercaptopurine intake. Acute liver injury is usually observed as elevated liver enzymes with fatigue and jaundice within one to six months after starting therapy. The liver biopsy depicts mixed hepatocellular-cholestatic injury with cholestasis, focal hepatocellular necrosis, bile duct injury, and variable inflammation.[12]

In chronic therapy, nodular regenerative hyperplasia (NRH) and symptomatic portal hypertension with ascites and varices were observed from six months to several years after starting therapy. This condition physically presented itself in patients as ascites, varices, mild liver enzyme abnormalities, and jaundice. It is a cause of concern because it can progress to hepatic failure if 6MP therapy is not discontinued.[15][12]

Hepatosplenic T-cell lymphoma (HSTCL) is a rare complication with a high mortality rate reported in men with inflammatory bowel disease who have been immunosuppressed long term with thiopurines such as mercaptopurine with or without anti-tumor necrosis factor therapy. They present with fatigue, fever, hepatosplenomegaly, and pancytopenia. Diagnosis is from either bone marrow or liver biopsy showing marked infiltration with malignant T cells.[12]

Also, NUDT15 correlates with thiopurine-induced myelosuppression.[16] 

It is important to note that switching from 6MP to AZA does not reduce the risk of side effects.[17] 

Contraindications

If patients are previously known to have severe allergic or hypersensitivity reactions, they are required to discontinue the use of the medication immediately. Mercaptopurine is also contraindicated for use in patients who have previously shown resistance to the drug.

There should be at least a two-month window between the cessation of mercaptopurine treatment and vaccination with live viral or bacterial vaccines to prevent severe and fatal infections.[18] Approximately 2 to 4% of patients receiving treatment with thiopurines develop thiopurine-induced pancreatitis. This condition is an absolute contraindication to the reintroduction of thiopurines.[19]

Monitoring

• All patients require complete blood count and liver enzymes every two weeks for six to eight weeks since starting azathioprine or mercaptopurine treatment. The testing should be followed by changes or adjustments in treatment as well.[20]
• Monitoring 6TG level concentrations to be maintained between 230 and 400 proves to be related to sufficient bone marrow suppression and reduces the chances of liver toxicity.[21]
• Research has found some medications to increase mercaptopurine levels in the plasma. Allopurinol and febuxostat inhibit the first-pass metabolism of 6MP via enzyme xanthine oxidase (XO), which resulted in a fivefold increase in plasma 6MP concentrations and a threefold increase in steady-state erythrocyte 6-TGN concentrations.[22] This effect may be useful in inducing shunting of 6MMP metabolites towards 6TG in patients with 6MP resistance.[23][24][25]
• Methotrexate can also increase 6MP plasma levels by forming active metabolites via XO inhibition and other mechanisms.[22] 
• In patients with IBD, vigilant monitoring of CBC counts is necessary when receiving combined therapy that includes mercaptopurine. 5-aminosalicylates cause in vitro inhibition of TPMT. Combining 6MP with mesalazine or sulfasalazine induced mild to moderate leukopenia.[26]
• Concurrent treatment of warfarin while being treated with 6MP is known to diminish the anticoagulant effects. Also, discontinuing 6MP with an adjusted warfarin dose can lead to bleeding in a previously stable patient.[27]
• NSAIDs such as naproxen, mefenamic acid, tolfenamic acid exhibit noncompetitive inhibition of TPMT activity in vitro and thus require monitoring while the patient receives treatment with mercaptopurine.[13]
• Mercaptopurine therapy should be reduced by 50% of the current dose or discontinued if the patient exhibits leukopenia (WBC =< 4000 cells/mm^3) or thrombocytopenia (platelet count < 150,000/microL). If the patient continues to show persistent cytopenia with the dosage reduction, the medication should be permanently discontinued.[28]
• If mild hepatitis (transaminitis) is present, it is reversible by lowering the dose of 6MP. If ALT and AST levels continue to remain elevated, a further dose reduction by 33 to 50% will be necessary. Liver function tests require monitoring and evaluation every two weeks. ALT and AST levels should not exceed two times the upper limit of normal. If such an event occurs, the medication should be discontinued until the liver enzyme levels normalize, at which point 6MP may be reintroduced cautiously at a lower dose.[12]
• Macrocytosis should have close monitoring, with CBC every two weeks for one month to exclude other causes such as vitamin B12 or folate deficiencies.  
• Mercaptopurine may be used during pregnancy with close monitoring. There is no known risk of teratogenicity or higher rates of pregnancy complications with the use of this medication. Concentrations of 6MP have not been detected in breast milk.[13]

Toxicity

It is important to maintain a constant dose titration to maintain steady thiopurine exposure while minimizing toxicity. There have been observations that in patients with nonfunctional variant alleles of TPMT or with reduced TPMT enzyme activity, there is a resulting accumulation of 6TGN in hematopoietic tissues causing toxicity.[16]

Enhancing Healthcare Team Outcomes

Due to its narrow therapeutic index, mercaptopurine requires continuous monitoring for toxicity in patients due to enzyme activity levels and interactions with other medications. This medication is listed in the Institute for Safe Medication Practices (ISMP), where it is among a list of drugs classified as having a heightened risk of causing significant patient harm when used in error. Because 6MP is a maintenance treatment for inflammatory disorders and leukemia with other disease-modifying agents or chemotherapy, adjustments may be needed frequently or intermittently throughout the time of administration. 

Most, if. not all, of the diseases that require mercaptopurine therapy are chronic conditions requiring long-term treatment. Pharmacists need to ensure that dosage levels are appropriately administered based on side effects and contraindications. The patients will require both inpatient and at-home care throughout the course of their treatment. Also, to ensure the efficacy of the treatment, patient compliance will need to be taken into account because this is a slow-acting medication. This level of monitoring requires the actions of an interprofessional team, with coordinated activity and communication between specialists, general practitioners, mid-level practitioners, nurses, pharmacists, and care staff involved in the patient's care. There is also a long-term risk of secondary leukemia or malignancies occurring with mercaptopurine therapy, which will require follow-up and screening among patients undergoing such treatment.[29] [Level 3]

Review Questions

• Access free multiple choice questions on this topic.
• Comment on this article.

References

1.

Shah ED, Coburn ES, Nayyar A, Lee KJ, Koliani-Pace JL, Siegel CA. Systematic review: hepatosplenic T-cell lymphoma on biologic therapy for inflammatory bowel disease, including data from the Food and Drug Administration Adverse Event Reporting System. Aliment Pharmacol Ther. 2020 Mar;51(5):527-533. [PMC free article: PMC7018581] [PubMed: 31990422]

2.

Veerman AJ, Hählen K, Kamps WA, Van Leeuwen EF, De Vaan GA, Solbu G, Suciu S, Van Wering ER, Van der Does-Van der Berg A. High cure rate with a moderately intensive treatment regimen in non-high-risk childhood acute lymphoblastic leukemia. Results of protocol ALL VI from the Dutch Childhood Leukemia Study Group. J Clin Oncol. 1996 Mar;14(3):911-8. [PubMed: 8622039]

3.

Martins R, Carmona C, George B, Epstein J., Guideline Committee. Management of Crohn's disease: summary of updated NICE guidance. BMJ. 2019 Nov 01;367:l5940. [PubMed: 31676715]

4.

Pratt DS, Flavin DP, Kaplan MM. The successful treatment of autoimmune hepatitis with 6-mercaptopurine after failure with azathioprine. Gastroenterology. 1996 Jan;110(1):271-4. [PubMed: 8536867]

5.

Mason C, Krueger GG. Thioguanine for refractory psoriasis: a 4-year experience. J Am Acad Dermatol. 2001 Jan;44(1):67-72. [PubMed: 11148479]

6.

Moon W, Loftus EV. Review article: recent advances in pharmacogenetics and pharmacokinetics for safe and effective thiopurine therapy in inflammatory bowel disease. Aliment Pharmacol Ther. 2016 Apr;43(8):863-883. [PubMed: 26876431]

7.

Gerbek T, Ebbesen M, Nersting J, Frandsen TL, Appell ML, Schmiegelow K. Role of TPMT and ITPA variants in mercaptopurine disposition. Cancer Chemother Pharmacol. 2018 Mar;81(3):579-586. [PubMed: 29387964]

8.

Dervieux T, Brenner TL, Hon YY, Zhou Y, Hancock ML, Sandlund JT, Rivera GK, Ribeiro RC, Boyett JM, Pui CH, Relling MV, Evans WE. De novo purine synthesis inhibition and antileukemic effects of mercaptopurine alone or in combination with methotrexate in vivo. Blood. 2002 Aug 15;100(4):1240-7. [PubMed: 12149204]

9.

Dervieux T, Blanco JG, Krynetski EY, Vanin EF, Roussel MF, Relling MV. Differing contribution of thiopurine methyltransferase to mercaptopurine versus thioguanine effects in human leukemic cells. Cancer Res. 2001 Aug 01;61(15):5810-6. [PubMed: 11479220]

10.

Wojtuszkiewicz A, Barcelos A, Dubbelman B, De Abreu R, Brouwer C, Bökkerink JP, de Haas V, de Groot-Kruseman H, Jansen G, Kaspers GL, Cloos J, Peters GJ. Assessment of mercaptopurine (6MP) metabolites and 6MP metabolic key-enzymes in childhood acute lymphoblastic leukemia. Nucleosides Nucleotides Nucleic Acids. 2014;33(4-6):422-33. [PubMed: 24940700]

11.

Bostrom BC, Sensel MR, Sather HN, Gaynon PS, La MK, Johnston K, Erdmann GR, Gold S, Heerema NA, Hutchinson RJ, Provisor AJ, Trigg ME., Children's Cancer Group. Dexamethasone versus prednisone and daily oral versus weekly intravenous mercaptopurine for patients with standard-risk acute lymphoblastic leukemia: a report from the Children's Cancer Group. Blood. 2003 May 15;101(10):3809-17. [PubMed: 12531809]

12.

LiverTox: Clinical and Research Information on Drug-Induced Liver Injury [Internet]. National Institute of Diabetes and Digestive and Kidney Diseases; Bethesda (MD): Aug 17, 2017. Mercaptopurine. [PMC free article: PMC547852] [PubMed: 31643863]

13.

Sahasranaman S, Howard D, Roy S. Clinical pharmacology and pharmacogenetics of thiopurines. Eur J Clin Pharmacol. 2008 Aug;64(8):753-67. [PubMed: 18506437]

14.

Marinaki AM, Ansari A, Duley JA, Arenas M, Sumi S, Lewis CM, Shobowale-Bakre el-M, Escuredo E, Fairbanks LD, Sanderson JD. Adverse drug reactions to azathioprine therapy are associated with polymorphism in the gene encoding inosine triphosphate pyrophosphatase (ITPase). Pharmacogenetics. 2004 Mar;14(3):181-7. [PubMed: 15167706]

15.

Bayoumy AB, Simsek M, Seinen ML, Mulder CJJ, Ansari A, Peters GJ, De Boer NK. The continuous rediscovery and the benefit-risk ratio of thioguanine, a comprehensive review. Expert Opin Drug Metab Toxicol. 2020 Feb;16(2):111-123. [PubMed: 32090622]

16.

Kim H, Seo H, Park Y, Min BJ, Seo ME, Park KD, Shin HY, Kim JH, Kang HJ. APEX1 Polymorphism and Mercaptopurine-Related Early Onset Neutropenia in Pediatric Acute Lymphoblastic Leukemia. Cancer Res Treat. 2018 Jul;50(3):823-834. [PMC free article: PMC6056975] [PubMed: 28882023]

17.

Korelitz BI, Zlatanic J, Goel F, Fuller S. Allergic reactions to 6-mercaptopurine during treatment of inflammatory bowel disease. J Clin Gastroenterol. 1999 Jun;28(4):341-4. [PubMed: 10372932]

18.

Rosenbaum EH, Cohen RA, Glatstein HR. Vaccination of a patient receiving immunosuppressive therapy for lymphosarcoma. JAMA. 1966 Nov 14;198(7):737-40. [PubMed: 5953328]

19.

Kennedy NA, Rhatigan E, Arnott ID, Noble CL, Shand AG, Satsangi J, Lees CW. A trial of mercaptopurine is a safe strategy in patients with inflammatory bowel disease intolerant to azathioprine: an observational study, systematic review and meta-analysis. Aliment Pharmacol Ther. 2013 Nov;38(10):1255-66. [PubMed: 24117596]

20.

Lichtenstein GR, Abreu MT, Cohen R, Tremaine W., American Gastroenterological Association. American Gastroenterological Association Institute medical position statement on corticosteroids, immunomodulators, and infliximab in inflammatory bowel disease. Gastroenterology. 2006 Mar;130(3):935-9. [PubMed: 16530531]

21.

Dubinsky MC, Lamothe S, Yang HY, Targan SR, Sinnett D, Théorêt Y, Seidman EG. Pharmacogenomics and metabolite measurement for 6-mercaptopurine therapy in inflammatory bowel disease. Gastroenterology. 2000 Apr;118(4):705-13. [PubMed: 10734022]

22.

Zimm S, Grygiel JJ, Strong JM, Monks TJ, Poplack DG. Identification of 6-mercaptopurine riboside in patients receiving 6-mercaptopurine as a prolonged intravenous infusion. Biochem Pharmacol. 1984 Dec 15;33(24):4089-92. [PubMed: 6594999]

23.

Sparrow MP, Hande SA, Friedman S, Lim WC, Reddy SI, Cao D, Hanauer SB. Allopurinol safely and effectively optimizes tioguanine metabolites in inflammatory bowel disease patients not responding to azathioprine and mercaptopurine. Aliment Pharmacol Ther. 2005 Sep 01;22(5):441-6. [PubMed: 16128682]

24.

Sparrow MP, Hande SA, Friedman S, Cao D, Hanauer SB. Effect of allopurinol on clinical outcomes in inflammatory bowel disease nonresponders to azathioprine or 6-mercaptopurine. Clin Gastroenterol Hepatol. 2007 Feb;5(2):209-14. [PubMed: 17296529]

25.

Rahhal RM, Bishop WP. Initial clinical experience with allopurinol-thiopurine combination therapy in pediatric inflammatory bowel disease. Inflamm Bowel Dis. 2008 Dec;14(12):1678-82. [PubMed: 18521913]

26.

Gilissen LP, Bierau J, Derijks LJ, Bos LP, Hooymans PM, van Gennip A, Stockbrügger RW, Engels LG. The pharmacokinetic effect of discontinuation of mesalazine on mercaptopurine metabolite levels in inflammatory bowel disease patients. Aliment Pharmacol Ther. 2005 Oct 01;22(7):605-11. [PubMed: 16181300]

27.

Ng HJ, Crowther MA. Azathioprine and inhibition of the anticoagulant effect of warfarin: evidence from a case report and a literature review. Am J Geriatr Pharmacother. 2006 Mar;4(1):75-7. [PubMed: 16730624]

28.

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 May;48(5):642-6. [PMC free article: PMC1728278] [PubMed: 11302961]

29.

Korelitz BI. Expert opinion: experience with 6-mercaptopurine in the treatment of inflammatory bowel disease. World J Gastroenterol. 2013 May 28;19(20):2979-84. [PMC free article: PMC3662937] [PubMed: 23716977]

Disclosure: Hala Sharma declares no relevant financial relationships with ineligible companies.

Disclosure: Roopma Wadhwa declares no relevant financial relationships with ineligible companies.