Pharmacogenetic Risk Factors for Thiopurine-Induced Leukopenia in Patients with Inflammatory Bowel Disease.

NUDT15 intermediate and poor metabolisers: impaired thioguanine nucleotide dephosphorylation and myelotoxicity; an independent contribution of IL6 is proposed.

Retrospective analysis of 218 thiopurine-treated patients with inflammatory bowel disease from two independent cohorts with whole-exome sequencing. Pharmacogenetic subgroups were defined using CPIC star allele-based molecular phenotypes or genotype-based classifications, and leukopenia (white blood cell count ≤ 3,000/µL) was analysed with Andersen-Gill models adjusted for clinical covariates. NUDT15 intermediate metabolisers (HR 5.21; p < 0.001), poor metabolisers (HR 6.42; p < 0.001) and IL6 heterozygotes (HR 4.35; p < 0.001) showed reproducible, independent associations with leukopenia risk. Adding IL6 to the conventional TPMT/NUDT15 model significantly improved sensitivity (p = 0.0156) and negative predictive value (p = 0.046).

Synthesis written by Geno'X. For the full original abstract, please refer to the source publication.

Confirming the weight of NUDT15 in Korean patients is no surprise and supports pre-treatment genotyping already recommended in East Asia. The novel element is IL6, whose effect looks strong on paper but must be replicated outside Korea before clinical use: 218 patients, two cohorts from the same country, no functional evidence and no dosing rule proposed. The gain in negative predictive value nonetheless deserves attention, since that is exactly what the TPMT/NUDT15 model lacks to provide reassurance before starting a thiopurine.

Analysis by Dr Thibaut Benquey