Anti-TPMT monoclonal antibody, clone BU3F8

The Clinical Pharmacogenetics Implementation Consortium (CPIC) Guideline for Thiopurine Methyltransferase Genotype and Thiopurine Dosing was originally published in March 2011. We reviewed recent literature and concluded that although relevant new evidence has been generated, none of the evidence would change the primary dosing recommendations in the original guideline; therefore, the original publication remains clinically current. Up-to-date information on thiopurine methyltransferase (TPMT) gene alleles and nomenclature can be found at PharmGKB (http://www.pharmgkb.org).

A small proportion of patients with acute lymphoblastic leukemia (ALL) may experience severe leukopenia after treating with 6-mercaptopurine (6MP), which can be largely explained by germline variants in TPMT and NUDT15. However, a minority of patients who suffered such adverse drug reaction have NUDT15(wt/wt)TPMT(wt/wt) genotype, indicating that other genetic factors may take part in. In this study, we genotyped 539 exon-located nonsilent pharmacogenetic variants in genes involved in phase I/II of drug metabolism in 173 pediatric patients with ALL and conducted association screening for 6MP-induced leukopenia. Besides NUDT15 (rs116855232, P = 6.4 x 10(-11)) and TPMT (rs1142345, P = 0.003), a novel variant was identified in CYP2A7 gene (i.e., rs73032311, P = 0.0007), which is independent of NUDT15/TPMT variant. In addition, a variant (i.e., rs4680) in COMT is significantly associated with 6MP-induced hepatotoxicity (P = 0.007). In conclusion, variants in CYP2A7 and COMT may be considered as novel potential pharmacogenetic markers for 6MP-induced toxicities, but additional independent validations with large sample size and investigations on related mechanisms are further needed.