This Article Full Text Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Save to my personal folders Download to citation manager Rights & Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Evans, W. E. Articles by Relling, M. V. Search for Related Content PubMed PubMed Citation Articles by Evans, W. E. Articles by Relling, M. V. Social Bookmarking                            What's this?

Preponderance of Thiopurine S-Methyltransferase Deficiency and Heterozygosity Among Patients Intolerant to Mercaptopurine or Azathioprine

From the St Jude Children’s Research Hospital and University of Tennessee, Memphis; Vanderbilt University Medical Center, Nashville; East Tennessee State University, Johnson City, TN; Baylor College of Medicine, Houston; Cook Children’s Medical Center, Fort Worth; University of Texas Southwestern Medical Center at Dallas, Dallas, TX; Stanford University, Stanford; Children’s Hospital of Los Angeles, Los Angeles; Children’s Hospital of San Diego, San Diego, CA; University of New Mexico, Albuquerque, NM; West Virginia University, Morgantown, WV; Miami Children’s Hospital, Miami, FL; Children’s Hospital of Michigan, Detroit, MI; and Ospedale Pediatrics Meyer, Florence, Italy.

Address reprint requests to William E. Evans, PharmD, St Jude Children’s Research Hospital, 332 N Lauderdale, PO Box 318, Memphis, TN 38101-0318; email: william.evans{at}stjude.org

PURPOSE: To assess thiopurine S-methyltransferase (TPMT) phenotype and genotype in patients who were intolerant to treatment with mercaptopurine (MP) or azathioprine (AZA), and to evaluate their clinical management.

PATIENTS AND METHODS: TPMT phenotype and thiopurine metabolism were assessed in all patients referred between 1994 and 1999 for evaluation of excessive toxicity while receiving MP or AZA. TPMT activity was measured by radiochemical analysis, TPMT genotype was determined by mutation-specific polymerase chain reaction restriction fragment length polymorphism analyses for the TPMT*2, *3A, *3B, and *3C alleles, and thiopurine metabolites were measured by high-performance liquid chromatography.

RESULTS: Of 23 patients evaluated, six had TPMT deficiency (activity < 5 U/mL of packed RBCs [pRBCs]; homozygous mutant), nine had intermediate TPMT activity (5 to 13 U/mL of pRBCs; heterozygotes), and eight had high TPMT activity (> 13.5 U/mL of pRBCs; homozygous wildtype). The 65.2% frequency of TPMT-deficient and heterozygous individuals among these toxic patients is significantly greater than the expected 10% frequency in the general population (P < .001, ²). TPMT phenotype and genotype were concordant in all TPMT-deficient and all homozygous-wildtype patients, whereas five patients with heterozygous phenotypes did not have a TPMT mutation detected. Before thiopurine dosage adjustments, TPMT-deficient patients experienced more frequent hospitalization, more platelet transfusions, and more missed doses of chemotherapy. Hematologic toxicity occurred in more than 90% of patients, whereas hepatotoxicity occurred in six patients (26%). Both patients who presented with only hepatic toxicity had a homozygous-wildtype TPMT phenotype. After adjustment of thiopurine dosages, the TPMT-deficient and heterozygous patients tolerated therapy without acute toxicity.

CONCLUSION: There is a significant (> six-fold) overrepresentation of TPMT deficiency or heterozygosity among patients developing dose-limiting hematopoietic toxicity from therapy containing thiopurines. However, with appropriate dosage adjustments, TPMT-deficient and heterozygous patients can be treated with thiopurines, without acute dose-limiting toxicity.

CiteULike    Complore    Connotea    Del.icio.us    Digg    Facebook    Reddit    Technorati    Twitter    What's this?

This article has been cited by other articles:

				J. J. Yang, C. Cheng, W. Yang, D. Pei, X. Cao, Y. Fan, S. B. Pounds, G. Neale, L. R. Trevino, D. French, et al. Genome-wide Interrogation of Germline Genetic Variation Associated With Treatment Response in Childhood Acute Lymphoblastic Leukemia JAMA, January 28, 2009; 301(4): 393 - 403. [Abstract] [Full Text] [PDF]

				TPMT testing before azathioprine therapy? DTB, January 1, 2009; 47(1): 9 - 12. [Abstract] [Full Text] [PDF]

				J. A. Williams, T. Andersson, T. B. Andersson, R. Blanchard, M. O. Behm, N. Cohen, T. Edeki, M. Franc, K. M. Hillgren, K. J. Johnson, et al. PhRMA White Paper on ADME Pharmacogenomics J. Clin. Pharmacol., July 1, 2008; 48(7): 849 - 889. [Abstract] [Full Text] [PDF]

				S. M. Davies, M. J. Borowitz, G. L. Rosner, K. Ritz, M. Devidas, N. Winick, P. L. Martin, P. Bowman, J. Elliott, C. Willman, et al. Pharmacogenetics of minimal residual disease response in children with B-precursor acute lymphoblastic leukemia: a report from the Children's Oncology Group Blood, March 15, 2008; 111(6): 2984 - 2990. [Abstract] [Full Text] [PDF]

				D. Perri, D. E. C. Cole, O. Friedman, E. Piliotis, S. Mintz, and N. K. J. Adhikari Azathioprine and diffuse alveolar haemorrhage: the pharmacogenetics of thiopurine methyltransferase Eur. Respir. J., November 1, 2007; 30(5): 1014 - 1017. [Abstract] [Full Text] [PDF]

				R. H.J. Mathijssen, F. A. de Jong, W. J. Loos, J. M. van der Bol, J. Verweij, and A. Sparreboom Flat-Fixed Dosing Versus Body Surface Area Based Dosing of Anticancer Drugs in Adults: Does It Make a Difference? Oncologist, August 1, 2007; 12(8): 913 - 923. [Abstract] [Full Text] [PDF]

				C. Hartford, E. Vasquez, M. Schwab, M. J. Edick, J. E. Rehg, G. Grosveld, C.-H. Pui, W. E. Evans, and M. V. Relling Differential Effects of Targeted Disruption of Thiopurine Methyltransferase on Mercaptopurine and Thioguanine Pharmacodynamics Cancer Res., May 15, 2007; 67(10): 4965 - 4972. [Abstract] [Full Text] [PDF]

				C. J. Zheng, L. Y. Han, B. Xie, C. Y. Liew, S. Ong, J. Cui, H. L. Zhang, Z. Q. Tang, S. H. Gan, L. Jiang, et al. PharmGED: Pharmacogenetic Effect Database Nucleic Acids Res., January 12, 2007; 35(suppl_1): D794 - D799. [Abstract] [Full Text] [PDF]

				D. M. Roden, R. B. Altman, N. L. Benowitz, D. A. Flockhart, K. M. Giacomini, J. A. Johnson, R. M. Krauss, H. L. McLeod, M. J. Ratain, M. V. Relling, et al. Pharmacogenomics: Challenges and Opportunities. Ann Intern Med, November 21, 2006; 145(10): 749 - 757. [Abstract] [Full Text] [PDF]

				H. H. Ezzeldin and R. B. Diasio Genetic testing in cancer therapeutics. Clin. Cancer Res., July 15, 2006; 12(14): 4137 - 4141. [Full Text] [PDF]

				V Gauba, M Saldanha, C Vize, and G M Saleh Thiopurine methyltransferase screening before azathioprine therapy Br J Ophthalmol, July 1, 2006; 90(7): 923 - 924. [Full Text] [PDF]

				M. Monzo, S. Brunet, A. Urbano-Ispizua, A. Navarro, G. Perea, J. Esteve, R. Artells, M. Granell, J. Berlanga, J. M. Ribera, et al. Genomic polymorphisms provide prognostic information in intermediate-risk acute myeloblastic leukemia Blood, June 15, 2006; 107(12): 4871 - 4879. [Abstract] [Full Text] [PDF]

				D. N. Juurlink, M. M. Mamdani, A. Kopp, and D. A. Redelmeier The Risk of Suicide With Selective Serotonin Reuptake Inhibitors in the Elderly Am J Psychiatry, May 1, 2006; 163(5): 813 - 821. [Abstract] [Full Text] [PDF]

				S. Brown and N. J Reynolds Atopic and non-atopic eczema BMJ, March 11, 2006; 332(7541): 584 - 588. [Full Text] [PDF]

				M. V. Relling, C.-H. Pui, C. Cheng, and W. E. Evans Thiopurine methyltransferase in acute lymphoblastic leukemia Blood, January 15, 2006; 107(2): 843 - 844. [Full Text] [PDF]

				S. M. Davies Pharmacogenetics, Pharmacogenomics and Personalized Medicine: Are We There Yet? Hematology, January 1, 2006; 2006(1): 111 - 117. [Abstract] [Full Text] [PDF]

				M. Arenas, G. Simpson, C. M. Lewis, E.-M. Shobowale-Bakre, E. Escuredo, L. D. Fairbanks, J. A. Duley, A. Ansari, J. D. Sanderson, and A. M. Marinaki Genetic Variation in the MTHFR Gene Influences Thiopurine Methyltransferase Activity Clin. Chem., December 1, 2005; 51(12): 2371 - 2374. [Full Text] [PDF]

				W. P. Petros, P. J. Hopkins, S. Spruill, G. Broadwater, J. J. Vredenburgh, O. M. Colvin, W. P. Peters, R. B. Jones, J. Hall, and J. R. Marks Associations Between Drug Metabolism Genotype, Chemotherapy Pharmacokinetics, and Overall Survival in Patients With Breast Cancer J. Clin. Oncol., September 1, 2005; 23(25): 6117 - 6125. [Abstract] [Full Text] [PDF]

				G. Zaza, M. Cheok, W. Yang, J. C. Panetta, C.-H. Pui, M. V. Relling, and W. E. Evans Gene expression and thioguanine nucleotide disposition in acute lymphoblastic leukemia after in vivo mercaptopurine treatment Blood, September 1, 2005; 106(5): 1778 - 1785. [Abstract] [Full Text] [PDF]

				W. Lee, A. C. Lockhart, R. B. Kim, and M. L. Rothenberg Cancer Pharmacogenomics: Powerful Tools in Cancer Chemotherapy and Drug Development Oncologist, February 1, 2005; 10(2): 104 - 111. [Abstract] [Full Text] [PDF]

				D. P. Richman and M. A. Agius Treatment of autoimmune myasthenia gravis Neurology, December 23, 2003; 61(12): 1652 - 1661. [Abstract] [Full Text] [PDF]

				T. D. Bjornsson, J. A. Wagner, S. R. Donahue, D. Harper, A. Karim, M. S. Khouri, W. R. Murphy, K. Roman, D. Schneck, D. S. Sonnichsen, et al. A Review and Assessment of Potential Sources of Ethnic Differences in Drug Responsiveness J. Clin. Pharmacol., September 1, 2003; 43(9): 943 - 967. [Abstract] [Full Text] [PDF]

				W E Evans Pharmacogenomics: marshalling the human genome to individualise drug therapy Gut, May 1, 2003; 52(90002): ii10 - 18. [Abstract] [Full Text]

				W. E. Evans and H. L. McLeod Pharmacogenomics -- Drug Disposition, Drug Targets, and Side Effects N. Engl. J. Med., February 6, 2003; 348(6): 538 - 549. [Full Text] [PDF]

				P. Chiusolo, G. Reddiconto, I. Casorelli, L. Laurenti, F. Sora, L. Mele, L. Annino, G. Leone, and S. Sica Preponderance of methylenetetrahydrofolate reductase C677T homozygosity among leukemia patients intolerant to methotrexate Ann. Onc., December 1, 2002; 13(12): 1915 - 1918. [Abstract] [Full Text] [PDF]

				C. Siva, W. M. Yokoyama, and H. L. McLeod Pharmacogenetics in rheumatology: the prospects and limitations of an emerging field Rheumatology, November 1, 2002; 41(11): 1273 - 1279. [Abstract] [Full Text] [PDF]

				B. A. Chabner Cytotoxic Agents in the Era of Molecular Targets and Genomics Oncologist, August 1, 2002; 7(90003): 34 - 41. [Abstract] [Full Text] [PDF]

				H. L. McLeod Genetic Strategies to Individualize Supportive Care J. Clin. Oncol., June 15, 2002; 20(12): 2765 - 2767. [Full Text] [PDF]

				S. Schaub, M. Dickenmann, E. Cynke, A. Bircher, and J. Steiger Prednisone-induced neutropenia after cadaveric kidney transplantation Nephrol. Dial. Transplant., June 1, 2002; 17(6): 1119 - 1121. [Full Text] [PDF]