Variants in TPMT, ITPA, ABCC4 And ABCB1 Genes as Predictors of 6-Mercaptopurine Induced Toxicity in Children with Acute Lymphoblastic Leukemia

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Acute lymphoblastic leukemia is the most common childhood malignancy. Optimal use of anti leukemic drugs has led to less toxicity and adverse reactions, and a higher survival rate. Thiopurine drugs, including 6-mercaptopurine, are mostly used as antileukemic medications in the maintenance phase of treatment for children with acute lymphoblastic leukemia. For those patients, TPMT genotype- tailored 6-mercaptopurine therapy is already implemented in the treatment protocols. We investigated the role of TPMT, ITPA, ABCC4 and ABCB1 genetic variants as predictors of outcome and 6-mercaptopurine induced toxicity during the maintenance phase of treatment in pediatric acute lymphoblastic leukemia. Sixty-eight children with acute lymphoblastic leukemia were enrolled in this study. Patients have been treated according to ALL IC-BFM 2002 or ALL IC-BFM 2009 protocols. Toxicity and adverse events have been monitored via surrogate markers (off-therapy weeks, episodes of leu - ko penia and average 6-mercaptopurine dose) and a prob- abilistic model was employed to predict overall 6-mercaptopurine related toxicity. We confirmed that patients with acute lymphoblastic leukemia that carry inactive TPMT allele(s) require 6- mercaptopurine dose reduction. ITPA and ABCC4 genetic variants failed to show an association with 6-mercapto - purine induced toxicity during the maintenance phase. Carriers of ABCB1 variant allele experienced greater hepatotoxicity. The probabilistic model Neural net which considered all the analysed genetic variants was assessed to be the best prediction model. It was able to discriminate ALL patients with good and poor 6-mercaptopurin tolerance in 71% of cases (AUC=0.71). This study contributes to the design of a panel of pharmacogenetic markers for predicting thiopurineinduced toxicity in pediatric ALL.

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  • 1. Pui C Mullighan CG Evans WE Relling MV. Pediatric acute lymphoblastic leukemia: where are we going and how do we get there? Blood 2012; 120(6): 1-3.

  • 2. Kim H Kang HJ Kim HJ Jang MK Kim NH Oh Y et al. Pharmacogenetic Analysis of Pediatric Patients with Acute Lymphoblastic Leukemia: A Possible Association between Survival Rate and ITPA Polymorphism. PLoS One 2012; 7(9): 1-10.

  • 3. Paugh SW Stocco G Evans WE. Pharmacogenomics in pediatric leukemia. Curr Opin Pediatr 2010; 22: 703-10.

  • 4. Relling MV Gardner EE Sandborn WJ Schmiegelow K Pui C-H Yee SW et al. Clinical Pharmacogenetics Implementation Consortium guidelines for thiopurine methyltransferase genotype and thiopurine dosing. Clin Pharmacol Ther 2011; 89: 387-91.

  • 5. Stocco G Franca R Verzegnassi F Londero M Rabusin M Decorti G. Multilocus genotypes of relevance for drug metabolizing enzymes and therapy with thio - purines in patients with acute lymphoblastic leukemia. Front Genet 2013; 3: 1-9.

  • 6. Shipkova M Franz J Abe M Klett C Wieland E Andus T. Association between adverse effects under azathioprine therapy and inosine triphosphate pyrophosphatase activity in patients with chronic inflammatory bowel disease. Ther Drug Monit 2011; 33(3): 321-8.

  • 7. Abla N Chinn L Nakamura T Liu L. The human multidrug resistance protein 4 (MRP4 ABCC4): functional analysis of a highly polymorphic gene. J Pharmacol Exp Ther 2008; 325(3): 859-68.

  • 8. Azimi F Mortazavi Y Alavi S Khalili M Ramazani A. Frequency of ITPA gene polymorphisms in Iranian patients with acute lymphoblastic leukemia and prediction of its myelosuppressive effects. Leuk Res 2015; 39(10): 1048-54.

  • 9. Krishnamurthy P Schwab M Takenaka K Nachagari D Morgan J Leslie M et al. Transporter-mediated protection against thiopurine-induced hematopoietic toxicity. Cancer Res 2008; 68: 4983-9.

  • 10. Lopez-Lopez E Ballesteros J Piñan MA Sanchez de Toledo J Garcia de Andoin N Garcia-Miguel P et al. Polymorphisms in the methotrexate transport pathway: a new tool for MTX plasma level prediction in pediatric acute lymphoblastic leukemia. Pharmacogenet Geno - mics 2013; 23: 53-61.

  • 11. Balamurugan S Sugapriya D Shanthi P Thilaka V Venkatadesilalu S Pushpa V et al. Multidrug resistance 1 gene expression and AgNOR in childhood acute leukemias. Indian J Hematol Blood Transfus 2007; 23: 73-8.

  • 12. Zhai X Wang H Zhu X Miao H Qian X Li J et al. Gene polymorphisms of ABC transporters are associated with clinical outcomes in children with acute lymphoblastic leukemia. Arch Med Sci 2012; 8: 659-71.

  • 13. Plasschaert SLA De Bont ESJM Boezen M Vander Kolk DM Daenen SMJG Faber KN et al. Expression of multidrug resistance-associated proteins predicts prognosis in childhood and adult acute lymphoblastic leuke - mia. Clin Cancer Res 2005; 11(24): 8661-8.

  • 14. Stary J Zimmermann M Campbell M Castillo L Dibar E Donska S et al. Intensive chemotherapy for childhood acute lymphoblastic leukemia: results of the randomized intercontinental trial ALL IC-BFM 2002. J Clin Oncol 2014; 32(3): 174-84.

  • 15. Dokmanovic L Urosevic J Janic D Jovanovic N Petru - cev B Tosic N et al. Analysis of thiopurine S-methyltransferase polymorphism in the population of Serbia and Montenegro and mercaptopurine therapy tolerance in childhood acute lymphoblastic leukemia. Ther Drug Monit 2006 Dec; 28(6): 800-6.

  • 16. Yates CR Krynetski EY Loennechen T Fessing MY Tai HL Pui CH et al. Molecular diagnosis of thiopurine Smethyltransferase deficiency: genetic basis for azathioprine and mercaptopurine intolerance. Ann Intern Med 1997; 126(8): 608-14.

  • 17. Penna G Allegra A Alonci A Aguennouz M Garufi A Cannavò A et al. MDR-1 polymorphisms (G2677T and C3435T) in B-chronic lymphocytic leukemia: an impact on susceptibility and prognosis. Med Oncol 2010; 28(4): 1549-54.

  • 18. Vucicevic K Jakovljevic V Colovic N Tosic N Kostic T Glumac I Pavlovic S Karan-Djurasevic T Colovic M. Association of bax expression and bcl2/bax ratio with clinical and molecular prognostic markers in chronic lymphocytic leukemia. J Med Biochem 2016; 35: 150-7.

  • 19. Theodorson E. Quality assurance in clinical chemistry: a touch of statistics and a lot of common sense. J Med Biochem 2016; 35; 103-12.

  • 20. Friedman J Hastie T Tibshirani R. Regularization paths for generalized linear models via coordinate descent. J Stat Softw 2010; 33: 1-22.

  • 21. Venables WN Ripley BD. Modern Applied Statistics With S. Vol. 12 4th edn. New York: Springer 2002.

  • 22. Liaw A Wiener M. Classification and regression by random forest. R News 2002; 2: 18-22.

  • 23. Sing T Sander O Beerenwinkel N Lengauer T. ROCR: visualizing classifier performance in R. Bioinfor matics 2005; 21(20) pp. 7881.

  • 24. Freeman EA Moisen G. PresenceAbsence: An R Pack - age for Presence-Absence Model Analysis. Journal of Statistical Software 2008; 23(11): 1-31.

  • 25. Wan Rosalina WR Teh LK Mohamad N Nasir A Yusoff R Baba AA et al. Polymorphism of ITPA 94C>A and risk of adverse effects among patients with acute lymphoblastic leukaemia treated with 6-mercaptopurine. J Clin Pharm Ther 2012; 37: 237-41.

  • 26. Stocco G Cheok MH Crews KR Dervieux T French D Pei D et al. Genetic polymorphism of inosine triphosphate pyrophosphatase is a determinant of mercapto - purine metabolism and toxicity during treatment for acute lymphoblastic leukemia. Clin Pharmacol Ther 2009; 85(2): 164-72.

  • 27. Adam de Beaumais T Fakhoury M Medard Y Azo - ugagh S Zhang D Yakouben K et al. Determinants of mercaptopurine toxicity in paediatric acute lymphoblastic leukemia maintenance therapy. Br J Clin Pharmacol 2011; 71: 575-84.

  • 28. Hawwa AF Collier PS Millership JS McCarthy A Dempsey S Cairns C et al. Population pharmacokinetic and pharmacogenetic analysis of 6-mercaptopurine in paediatric patients with acute lymphoblastic leuka e - mia. Br J Clin Pharmacol 2008; 66: 826-37.

  • 29. Al Hadithy a. FY de Boer NKH Derijks LJJ Escher JC Mulder CJJ Brouwers JRBJ. Thiopurines in inflammatory bowel disease: Pharmacogenetics therapeutic drug monitoring and clinical recommendations. Dig Liver Dis 2005; 37: 282-97.

  • 30. Ansari M Sauty G Labuda M Gagné V Laverdière C Moghrabi A et al. Polymorphisms in multidrug resistance- associated protein gene 4 is associated with outcome in childhood acute lymphoblastic leukemia. Blood 2009; 114: 1383-6.

  • 31. Gregers J Gréen H Christensen IJ Dalhoff K Schroe - der H Carlsen N et al. Polymorphisms in the ABCB1 gene and effect on outcome and toxicity in childhood acute lymphoblastic leukemia. The Pharmacogenomics Journal 2015; 15: 372-9.

  • 32. Evans DM Visscher PM Wray NR. Harnessing the in - formation contained within genome-wide association studies to improve individual prediction of complex disease risk. Hum Mol Genet 2009; 18(18): 3525-31.

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