Predictive Role of
            <i>NUDT15</i>
            Variants on Thiopurine-Induced Myelotoxicity in Asian Inflammatory Bowel Disease Patients

Sutiman, Natalia; Chen, Sylvia; Ling, Khoon Lin; Chuah, Sai Wei; Leong, Wai Fook; Nadiger, Vinayak; Tjai, Madeline; Kong, Chris San Choon; Schwender, Brian; Chan, Webber; Shim, Hang Hock; Lim, Wee Chian; Khor, Chiea Chuen; Cheung, Yin Bun; Chowbay, Balram

doi:10.2217/pgs-2017-0147

Cited by 37 publications

(45 citation statements)

References 27 publications

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“…We revealed that platelet count was affected by the NUDT15 variant in the long‐term use of thiopurine. Consistent with our data, a previous study showed a significant decline in platelet count with increasing copy numbers of the risk T allele of NUDT15 within 4, 8, and 12 weeks and 6 months after initiating thiopurine . Conversely, Kojima et al .…”

Section: Discussionsupporting

confidence: 92%

“…Consistent with our data, a previous study showed a significant decline in platelet count with increasing copy numbers of the risk T allele of NUDT15 within 4, 8, and 12 weeks and 6 months after initiating thiopurine. 24 Conversely, Kojima et al addressed that platelet count did not differ significantly between wild type and mutated type of NUDT15 during 16 weeks of thiopurine administration. 23 Further studies are necessary to figure out this point.…”

Section: Discussionmentioning

confidence: 98%

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

Akiyama

Matsuoka

Fukuda

et al. 2019

J of Gastro and Hepatol

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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.

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Section: Discussionsupporting

confidence: 92%

Section: Discussionmentioning

confidence: 98%

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

Akiyama

Matsuoka

Fukuda

et al. 2019

J of Gastro and Hepatol

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“…Thirteen studies were identified that evaluated NUDT15 variants as risk factors for TIL in IBD patients, one also described the association of NUDT15 activity and TIL (Table S3). The majority of studies were performed in East‐Asian cohorts, one study included only patients of European ancestry . Studied NUDT15 variants were NUDT15 R139C (rs116855232) in 13 studies, NUDT15 c.36_37ins/delGGAGTC (rs746071566) in six studies and c.52G > A (rs186364861) in four studies.…”

Section: Resultssupporting

confidence: 62%

“…The association of TPMT genotype polymorphisms and TIL was assessed in 31 studies, the association of TPMT enzymatic activity and TIL in 12 (Table S1). …”

Section: Resultsmentioning

confidence: 99%

“…Another study that evaluated the association between NUDT15 polymorphisms and WBC count showed significant more reduction in WBC count in NUDT15 variant carriers compared to nonvariant carriers after 4, 6, 8, 10, 12, 14 and 16 weeks of thiopurine use ( P < 0.001, 0.001, 0.002, <0.001, 0.026 and 0.003 respectively) . In accordance, trends of faster onset of leukopenia or neutropenia were found with increasing copy numbers of the NUDT15 rs116855232 variant, and lower WBC counts were observed in patients with low or intermediate NUDT15 activity (defined as patients with homozygous or heterozygous diplotypes) compared to normal NUDT15 activity at 4, 8, 12 and 24 weeks respectively …”

Section: Resultsmentioning

confidence: 99%

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Systematic review with meta‐analysis: risk factors for thiopurine‐induced leukopenia in IBD

Gennep

Konté

Meijer

et al. 2019

Aliment Pharmacol Ther

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Background: Thiopurine-induced leukopenia, a frequently observed and potentially life-threatening adverse event, complicates the clinical management of IBD patients. Aim:To assess risk factors for thiopurine-induced leukopenia in IBD.Methods: MEDLINE, EMBASE, BIOSIS and Cochrane library were searched for studies reporting at least one risk factor for thiopurine-induced leukopenia.Pooled odds ratio (OR) was calculated for each potential risk factor using a random effects model. Studies that were not eligible for meta-analysis were described qualitatively.Results: Seventy articles were included, 34 (11 229 patients) were included in meta-analyses. A significantly higher thiopurine-induced leukopenia risk was found for TPMT (OR 3.9, 95% [CI] 2.5-6.1) and for NUDT15 R139C (OR 6.9, 95% CI 5.2-9.1), G52A (OR 3.2, 95% CI 1.3-7.9) and 36_37ins/delGGAGTC variant carriers (OR 5.6, 95% CI 2.8-11.4). A potential association between high 6-thioguanine nucleotides (6-TGN) or 6-methylmercaptopurine (6-MMP) levels and leukopenia was observed, since most studies reported higher metabolite levels in leukopenic patients (6-TGN: 204-308 (Lennard method) and 397 (Dervieux method), 6-MMP: 4020-10 450 pmol/8 x 10 8 RBC) compared to controls (6-TGN: 170-212 (Lennard method) and 269 (Dervieux method), 6-MMP: 1025-4550 pmol/8 x 10 8 RBC). Conclusions:TPMT and NUDT15 variants predict thiopurine-induced leukopenia.High 6-TGN and 6-MMP levels might induce leukopenia, although exact cut-off values remain unclear. Potential preventive measures to reduce the risk of thiopurineinduced leukopenia include pre-treatment TPMT and NUDT15 genotyping. Routine thiopurine metabolite measurement might be efficient, yet cut-off levels must be validated in advance. | 485VAN GENNEP Et Al.

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Clinical utility of thiopurine metabolite monitoring in inflammatory bowel disease and its impact on healthcare utilization in Singapore

Yeo¹,

Cheen

Wong

et al. 2022

JGH Open

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Background and Aim Thiopurines are recommended for maintenance of steroid‐free remission (SFR) in inflammatory bowel disease (IBD). Thiopurine metabolite monitoring (MM) is increasingly used in the West but remains novel in Singapore, with limited information on its therapeutic and economic benefits. Hence, this study aims to investigate MM's clinical utility and its impact on healthcare resource utilization in Singaporean IBD patients. Methods A retrospective observational study was conducted at Singapore General Hospital outpatient IBD Centre. Patients with IBD, baseline MM during 2014–2017, and weight‐based thiopurine doses for ≥4 weeks were followed up for 1 year. Actions were taken to optimize therapy, and metabolite levels before and after the first action were documented. Outcomes assessed included SFR, no therapy escalation or surgery, healthcare resource utilization, and direct healthcare costs. Results Ninety IBD patients (50 Crohn's disease, 40 ulcerative colitis) were included. Among them, 40% had baseline metabolite levels within therapeutic range, 31.1% sub‐therapeutic, 21.1% supra‐therapeutic, and 7.8% shunters. Repeated MM with subsequent dose optimization helped 67.2% of patients achieve therapeutic levels after 1 year. Overall, 87.8% of patients achieved SFR and 90% had no therapy escalation or surgery. Despite greater outpatient visits and laboratory investigations with MM, the median total healthcare costs at 1 year only increased marginally (S$6407.66 [shunters] vs S$5215.20 [supra‐therapeutic] vs S$4970.80 [sub‐therapeutic] vs S$4370.48 [control (within therapeutic range)], P = 0.592). Conclusion MM guided timely therapy escalation for non‐responders, identification of non‐adherence, and reversal of shunting. Therefore, it is a useful clinical tool to optimize thiopurines without significantly increasing healthcare costs.

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Predictive Role of NUDT15 Variants on Thiopurine-Induced Myelotoxicity in Asian Inflammatory Bowel Disease Patients

Abstract: These findings highlight the critical relevance of NUDT15 pharmacogenetics in predicting for thiopurine-induced myelotoxicity and confirm the lack of significance of TPMT variants in Asian inflammatory bowel disease patients.

Cited by 37 publications

References 27 publications

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

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

Systematic review with meta‐analysis: risk factors for thiopurine‐induced leukopenia in IBD

Clinical utility of thiopurine metabolite monitoring in inflammatory bowel disease and its impact on healthcare utilization in Singapore

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