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

Abstract

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 http://www.cpicpgx.org).

Identification of NUDT15 gene variants in Amazonian Amerindians and admixed individuals from northern Brazil

“…The international population databases show that the frequency of the mutations that reduce the functional activity of the enzyme, such as those described by the PharmVar Consortium, exceeds 1% only in Asians, Latin American and Amerindian populations [14,15,25]. The most frequent mutations of these groups include the rs116855232 variant, either in isolation or combined with rs1272632214.…”

“…A C>T transition in the rs116855232 (p.Arg139Cys) variant is assigned to two haplotypes (NUDT15 � 2 and NUDT15 � 3), which present an extreme loss of gene function, associated with the presence of the T allele of this polymorphism. The T allele of rs116855232 is found more commonly in East Asian [13], Latin [14] and Native American [15] populations, but is rare in populations from Europe, Africa, and South Asia.…”

Pharmacogenetic studies of thiopurine methyltransferase genotype-phenotype concordance and effect of methotrexate on thiopurine metabolism

“…The population in our study was not randomly selected since all were subjects for thiopurine treatment. However, since the natural function of TPMT, strangely enough, is still unknown, only individuals on thiopurine treatment are suffering from defective TPMT enzyme [19,47] and consequently this group is the most relevant to study. Although, disease or treatment could influence the results of TPMT enzyme activity measurement (chapter 5.3) and these are, together with high labor intensity and costs, the largest disadvantages of phenotyping.…”

“…Implementation into clinical pharmacogenetic routine testing is not very expanded. Most used and recommended today is testing of TPMT, NUDT15 [19] (both used in thiopurine treatment, described in chapter 1.3) and UGT1A1 (treatment with irinotecan, used against, e.g., metastatic colon cancer). Other drugs where pharmacogenetic testing have been proposed or recommended are warfarin (up to 40% of the variation in drug response between individuals are reported to come from the VKORC1 and CYP2C9 genotypes) and tamoxifen [6] (the proportion of CYP2D6 poor metabolizers is up to 12% in some populations whereas ultra-rapid phenotype frequencies are up to 29% of other populations) [13].…”

“…In 1992, NOPHO established their first common ALL treatment protocol and this was updated in 2000 and 2008. In the 2000 update, TPMT determination and dose reduction were included (wildtype: 75 mg/m 2 /day, heterozygous: 50 mg/m 2 /day, defective: 5 mg/m 2 /day [19]) and from 2008 all treatment with irradiation was omitted and replaced by intrathecal chemotherapy (CNS ALL). In the 2008 protocol, the target WBC was decreased from 3.5 to 3.0 x 10 9 /L.…”