Long‐term effect of NUDT15 R139C on hematologic indices in inflammatory bowel disease patients treated with thiopurine

Abstract

Background and Aim A missense variant of the nucleoside diphosphate‐linked moiety X‐type motif 15 (NUDT15) gene (R139C) predisposes Asian patients with inflammatory bowel disease (IBD) to thiopurine‐induced leukopenia. This study evaluates the long‐term effect of NUDT15 R139C heterozygosity on hematological parameters during thiopurine administration. Methods We enrolled 83 Japanese IBD patients who were on anti‐tumor necrosis factor‐α agents and had used thiopurine. NUDT15 R139C was genotyped by polymerase chain reaction. We retrospectively reviewed patient clinical charts to collect data on white blood cell (WBC) count, mean corpuscular volume (MCV), hemoglobin, and platelet count during the 24 months following thiopurine initiation. Results The included patients had either Crohn's disease (54; 65.1%) or ulcerative colitis (29; 34.9%). Genotyping of NUDT15 R139C identified 62 patients (74.7%) of genotype C/C and 21 (25.3%) of genotype C/T. The median dose of thiopurine was lower in the C/T group than in the C/C group after starting thiopurine. At 6 months, the mean WBC count of the C/T group became significantly lower than that of the C/C group (P = 0.008) and remained lower through the 24 months. The C/T group developed grade 2–4 leukopenia by 6 months, which persisted through 12–24 months. The mean MCV in the C/T group became higher than that of the C/C group after 3 months. Conclusions NUDT15 R139C heterozygosity affected the WBC count and MCV for 24 months after thiopurine administration. Our results indicate that careful monitoring of leukopenia and dose adjustment are necessary throughout treatment in IBD patients heterozygous for the NUDT15 R139C.

Long-term efficacy and tolerability of dose-adjusted thiopurine treatment in maintaining remission in inflammatory bowel disease patients with NUDT15 heterozygosity

“…Careful monitoring of WBC count is needed to avoid severe AEs as well as dose adjustment. 17 In the present study, the decrease rate in WBC count from baseline did not shown significant differences between the C/T and C/ C genotype in the early phase. However, the decrease rate of WBC count in the C/T genotype was significantly higher than that in the C/C genotype in the late phase.…”

NUDT15 gene variants and thiopurine-induced leukopenia in patients with inflammatory bowel disease

“…40 Another study demonstrated that the decrease in leukocyte and platelet count persisted longer (up to 6 months) in patients heterozygous for this variant than those without this variant. 41 Careful monitoring of leukocyte counts over time is required in such patients.…”

“…A large Japanese multicenter retrospective study showed that the time to leukopenia was shorter and tolerated doses of thiopurine were lower in patients with C/T or T/T than those with C/C [ 40 ]. Another study demonstrated that the decrease in leukocyte and platelet count persisted longer (up to 6 months) in patients heterozygous for this variant than those without this variant [ 41 ]. Careful monitoring of leukocyte counts over time is required in such patients.…”

Determination of NUDT15 variants by targeted sequencing can identify compound heterozygosity in pediatric acute lymphoblastic leukemia patients

“…From our experience with these two patients, any combination of two mutant alleles with known functional roles might be classified as compound heterozygous, and the mercaptopurine dose should be the same as that administered to homozygous patients. Because mercaptopurine is widely administered for other diseases, such as inflammatory bowel disease 33 , 34 , its clinical significance has also been validated in this subgroup of patients. The identification of these two compound heterozygous patients suggests that testing laboratories should be cautious while interpreting the c.36_37insGGAGTC and c.415C > T variants of NUDT15 in genetic testing of pediatric patients with ALL taking mercaptopurine or other related drugs, rather than only considering these genotypes.…”