Clinical Pharmacogenetics Implementation Consortium Guideline for Thiopurine Dosing Based on TPMT and NUDT15 Genotypes: 2018 Update

Thiopurine methyltransferase (TPMT) activity exhibits a monogenic codominant inheritance and catabolizes thiopurines. TPMT variant alleles are associated with low enzyme activity and pronounced pharmacologic effects of thiopurines. Loss‐of‐function alleles in the NUDT15 gene are common in Asians and Hispanics and reduce the degradation of active thiopurine nucleotide metabolites, also predisposing to myelosuppression. We provide recommendations for adjusting starting doses of azathioprine, mercaptopurine, and thioguanine based on TPMT and NUDT15 genotypes (updates on www.cpicpgx.org).

[1]  Wei Zhang,et al.  Combination of common and novel rare NUDT15 variants improves predictive sensitivity of thiopurine-induced leukopenia in children with acute lymphoblastic leukemia , 2018, Haematologica.

[2]  D. Chang,et al.  Measurements of 6-thioguanine nucleotide levels with TPMT and NUDT15 genotyping in patients with Crohn’s disease , 2017, PloS one.

[3]  Motohiro Kato,et al.  The effects of inherited NUDT15 polymorphisms on thiopurine active metabolites in Japanese children with acute lymphoblastic leukemia , 2017, Pharmacogenetics and genomics.

[4]  R. Mägi,et al.  Polymorphic Variation in TPMT Is the Principal Determinant of TPMT Phenotype: A Meta‐Analysis of Three Genome‐Wide Association Studies , 2017, Clinical pharmacology and therapeutics.

[5]  K. Schmiegelow,et al.  DNA-thioguanine nucleotide concentration and relapse-free survival during maintenance therapy of childhood acute lymphoblastic leukaemia (NOPHO ALL2008): a prospective substudy of a phase 3 trial. , 2017, The Lancet. Oncology.

[6]  M. Relling,et al.  Genomewide Approach Validates Thiopurine Methyltransferase Activity Is a Monogenic Pharmacogenomic Trait , 2017, Clinical pharmacology and therapeutics.

[7]  L. Jingli,et al.  Further evidence that a variant of the gene NUDT15 may be an important predictor of azathioprine‐induced toxicity in Chinese subjects: a case report , 2016, Journal of clinical pharmacy and therapeutics.

[8]  U. Hofmann,et al.  NUDT15 polymorphisms alter thiopurine metabolism and hematopoietic toxicity , 2016, Nature Genetics.

[9]  O. Inatomi,et al.  NUDT15 R139C-related thiopurine leukocytopenia is mediated by 6-thioguanine nucleotide-independent mechanism in Japanese patients with inflammatory bowel disease , 2017, Journal of Gastroenterology.

[10]  Henk-Jan Guchelaar,et al.  Identification of Patients With Variants in TPMT and Dose Reduction Reduces Hematologic Events During Thiopurine Treatment of Inflammatory Bowel Disease. , 2015, Gastroenterology.

[11]  M. Relling,et al.  Inherited NUDT15 variant is a genetic determinant of mercaptopurine intolerance in children with acute lymphoblastic leukemia. , 2015, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[12]  Jianjun Liu,et al.  A common missense variant in NUDT15 confers susceptibility to thiopurine-induced leukopenia , 2014, Nature Genetics.

[13]  S. Gillen.  Getting personal. , 2012, Mental health today.

[14]  Amira Hosni-Ahmed,et al.  Thiopurine Methyltransferase Predicts the Extent of Cytotoxicty and DNA Damage in Astroglial Cells after Thioguanine Exposure , 2011, PloS one.

[15]  J. Berg,et al.  Thiopurine S-methyltransferase (TPMT) assessment prior to starting thiopurine drug treatment; a pharmacogenomic test whose time has come , 2010, Journal of Clinical Pathology.

[16]  W. Newman,et al.  Are patients with intermediate TPMT activity at increased risk of myelosuppression when taking thiopurine medications? , 2010, Pharmacogenomics.

[17]  K. Schmiegelow,et al.  Long-term results of NOPHO ALL-92 and ALL-2000 studies of childhood acute lymphoblastic leukemia , 2010, Leukemia.

[18]  R. Altman,et al.  Thiopurine pathway. , 2010, Pharmacogenetics and genomics.

[19]  R. Weinshilboum,et al.  Thiopurine methyltransferase activity is related to the risk of relapse of childhood acute lymphoblastic leukemia: results from the NOPHO ALL-92 study , 2009, Leukemia.

[20]  M. Relling,et al.  Genetic Polymorphism of Inosine Triphosphate Pyrophosphatase Is a Determinant of Mercaptopurine Metabolism and Toxicity During Treatment for Acute Lymphoblastic Leukemia , 2009, Clinical pharmacology and therapeutics.

[21]  M. Relling,et al.  Differential effects of targeted disruption of thiopurine methyltransferase on mercaptopurine and thioguanine pharmacodynamics. , 2007, Cancer research.

[22]  N. Reynolds,et al.  Azathioprine dosed by thiopurine methyltransferase activity for moderate-to-severe atopic eczema: a double-blind, randomised controlled trial , 2006, The Lancet.

[23]  W. Tremaine,et al.  American Gastroenterological Association Institute technical review on corticosteroids, immunomodulators, and infliximab in inflammatory bowel disease. , 2006, Gastroenterology.

[24]  M. Relling,et al.  Thiopurine methyltransferase in acute lymphoblastic leukemia. , 2006, Blood.

[25]  N. Reynolds,et al.  Guidelines for prescribing azathioprine in dermatology , 2004, The British journal of dermatology.

[26]  Michel Eichelbaum,et al.  Comprehensive analysis of thiopurine S-methyltransferase phenotype-genotype correlation in a large population of German-Caucasians and identification of novel TPMT variants. , 2004, Pharmacogenetics.

[27]  K. Schmiegelow,et al.  Methylated Metabolites of 6‐mercaptopurine are Associated with Hepatotoxicity , 2004, Clinical pharmacology and therapeutics.

[28]  W. Evans.  Pharmacogenetics of Thiopurine S-Methyltransferase and Thiopurine Therapy , 2004, Therapeutic drug monitoring.

[29]  W. Sandborn.  Pharmacogenomics and IBD: TPMT and Thiopurines , 2004, Inflammatory bowel diseases.

[30]  R. Weinshilboum.  Inheritance and drug response. , 2003, The New England journal of medicine.

[31]  E. Louis,et al.  Safe treatment of thiopurine S-methyltransferase deficient Crohn’s disease patients with azathioprine , 2003, Gut.

[32]  W. Sandborn,et al.  Helicobacter pylori, harmful to the brain? , 2001, Gut.

[33]  M. Relling,et al.  Preponderance of thiopurine S-methyltransferase deficiency and heterozygosity among patients intolerant to mercaptopurine or azathioprine. , 2001, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[34]  R. Weinshilboum,et al.  Severe 6-thioguanine-induced marrow aplasia in a child with acute lymphoblastic leukemia and inherited thiopurine methyltransferase deficiency. , 2000, Journal of pediatric hematology/oncology.

[35]  M. Relling,et al.  Mercaptopurine therapy intolerance and heterozygosity at the thiopurine S-methyltransferase gene locus. , 1999, Journal of the National Cancer Institute.

[36]  W. Evans,et al.  Pharmacogenetics of cancer therapy: getting personal. , 1998, American journal of human genetics.

[37]  Ching-Hon Pui,et al.  Molecular Diagnosis of Thiopurine S-Methyltransferase Deficiency: Genetic Basis for Azathioprine and Mercaptopurine Intolerance , 1997, Annals of Internal Medicine.

[38]  J. Lilleyman,et al.  Individualizing therapy with 6-mercaptopurine and 6-thioguanine related to the thiopurine methyltransferase genetic polymorphism. , 1996, Therapeutic drug monitoring.

[39]  D. C. Henckel,et al.  Case report. , 1995, Journal.

[40]  W. Evans,et al.  Altered mercaptopurine metabolism, toxic effects, and dosage requirement in a thiopurine methyltransferase-deficient child with acute lymphocytic leukemia. , 1991, The Journal of pediatrics.