Thiopurine-induced Myelosuppression Research Articles

A systematic review of aspects of NUDT15 pharmacogenomic variants and thiopurine-induced myelosuppression

Abstract Objectives Evidence for NUDT15 pharmacogenomic variants and thiopurine-induced myelosuppression (TIM), consists predominantly of association data in Asian, mixed variant homozygote/heterozygote populations. We therefore sought evidence on; (i) NUDT15 genotype-guided thiopurine dosing. (ii) Association data for TIM in NUDT15 variant heterozygotes with inflammatory bowel disease. (iii) Association data for NUDT15 variants with TIM in Europeans. (iv) Health economic data for NUDT15 genotyping in inflammatory bowel disease. Methods A systematic review was conducted, consisting of database searches, screening against pre-defined inclusion/exclusion criteria, and assessment of risk of bias using study-specific appraisal tools. Key findings Titles/abstracts of 493 articles were screened, with 29 studies included. (i) Significant reductions in TIM with genotype-guided thiopurine dosing were reported by both trials and a cohort study. (ii) TIM rates were significantly higher in NUDT15*3 heterozygotes vs. wild type. Data were conflicting for rarer variants. (iii) Four of five studies reported an association with TIM for at least one or a combination of NUDT15 variants in Europeans (OR 9.5–38.2), but data were conflicting. (iv) Both health economic analyses found TPMT/NUDT15 genotyping cost-effective in Asian populations, but not when a European population was considered. Conclusion Limited data showed an association with TIM in NUDT15 variant heterozygotes and Europeans and the potential for genotype-guided dosing to reduce TIM. Studies were generally small, heterogenous, and of variable quality. The low prevalence of rarer NUDT15 variants/variants in Europeans likely contributed to contradictory findings. Further research on the clinical utility of genotyping in diverse populations will help inform future economic analyses.

OP11 Exploring the potential clinical utility of NUDT15 pharmacogenetic testing in clinical practice: a ‘focused reverse phenotyping’ study in the UK IBD Bioresource

Abstract Background In a previous study we recruited patients with inflammatory bowel disease (IBD) and a history of thiopurine induced myelosuppression (TIM) and identified associated variants in NUDT15. This widely used phenotype-first approach, is limited by ascertainment and recall bias, which impacts understanding of penetrance, expressivity, and variant pathogenicity that are key to clinical implementation. The United Kingdom (UK) National Institute for Health Research (NIHR) IBD Bioresource allows investigators to select large numbers of subjects based on genomic variants of interest, rather than phenotypes, to overcome these biases. Using this ‘focused reverse phenotyping’ approach we sought to investigate the cumulative 6-month risk of myelosuppression in patients with NUDT15 variants. Methods Cases and controls were identified from whole exome sequencing data. Cases included all participants with a loss of function NUDT15 variant (*2, *3, *4, *5, *6 and *9). Control subjects were selected based on wild-type carriage of NUDT15 and TPMT, matched for ethnicity. Our primary outcome measure was time to TIM. Myelosuppression was defined as a white cell count (WCC) <3.5x109/L or a neutrophil count <2.0x109/L that occurred within six months of achieving the maximum thiopurine dose, or in the absence of blood test results, a decision to reduce the dose of or withdraw the thiopurine due to myelosuppression. Severe myelosuppression was defined as a WCC <2.5x109/L or neutrophil count <1.0x109/L and a decision to either reduce the dose of or stop the thiopurine. Results We screened 23,082 patients recruited to the UK NIHR IBD bioresource with whole exome sequence data and identified 451 patients with a loss of function NUDT15 variant. We matched, based on ethnicity, these patients to 916 controls. Overall, 271/21,136 (1.3%) Caucasians and 127/1,089 (11.7%) South Asian carried an NUDT15 variant allele. 239/451 (60%) cases had a history of thiopurine exposure. The median weight-adjusted maximum thiopurine dose amongst cases and controls was 1.78 and 1.79 mg/kg/day, respectively. The time to myelosuppression was shorter in patients with NUDT15 variants as shown in Figure 1. The risk of myelosuppression, severe myelosuppression, and hospitalisation was also higher in patients with NUDT15 variants as shown in table 1. Conclusion In this reverse phenotyping study, the time to myelosuppression was significantly shorter in patients who carried a loss of function NUDT15 variant. The overall risk of myelosuppression was lower than previously observed in phenotype-first studies. Prior to implementation further analysis of the cost-effectiveness of NUDT15 testing is required.

P440 Prevalence of NUDT15 polymorphisms and incidence of thiopurine-induced leukopenia in Inflammatory Bowel Disease patients: A systematic review and meta-analysis

Abstract Background Nudix hydrolase 15 (NUDT15) genetic polymorphisms confer an increased risk of thiopurine-induced myelosuppression (TIM). Thiopurines continue to be widely used as maintenance therapy for inflammatory bowel disease (IBD) in patients worldwide. However, the global prevalence of NUDT15 variants and incidence of TIM in IBD remains unclear. We aimed to evaluate the global prevalence of NUDT15 polymorphisms in IBD patients and incidence of thiopurine-induced leukopenia in patients with these polymorphisms. Methods We searched Medline, Embase, Emcare, CINAHL, APA PsycInfo and the Cochrane Library databases from inception until 7 July 2022. Full-text articles and conference abstracts reporting the frequency of any NUDT15 polymorphism and/or frequency of leukopenia in adult IBD patients with these variants, were included. Studies that examined paediatric populations or mixed disease populations, or reported duplicate data, were excluded. A random effects model was performed to estimate the pooled prevalence of NUDT15 variants, pooled prevalence of early (≤8 weeks) and late (>8 weeks) leukopenia and relative risk (RR) of developing leukopenia. Results 20 studies comprising 5232 IBD patients were included. The pooled prevalence of the *1/*1 wild type genotype was 83% (95% CI: 0.78-0.88). The pooled prevalence of the *1/*3 c.415C>T C/T variant was 13% (95% CI: 0.10-0.18), *3/*3 c.415C>T T/T variant was 2% (95% CI: 0.01-0.02), *1/*5 c.52G>A G/A variant was 2% (95% CI: 0.01-0.03) and *1/*6 c.36_37insGGAGTC ins/- variant was 7% (95% CI: 0.04-0.12). Subgroup analyses showed a higher pooled prevalence of the *1/*3 c.415C>T C/T variant in Japanese (20%, 95% CI: 0.16-0.24) and Chinese patients (18%, 95% CI: 0.12-0.27). Patients with the *1/*3 c.415C>T C/T variant had a RR of 4.12 (95% CI: 2.87-5.91) of developing leukopenia relative to the *1/*1 genotype, and the pooled prevalence of early leukopenia was 20% (95% CI: 0.16-0.26) and late leukopenia was 36% (95% CI: 0.26-0.49). Patients with the *3/*3 c.415C>T T/T variant had a RR of 9.38 (95% CI: 5.17-17.01) of developing leukopenia relative to the *1/*1 genotype, and the pooled prevalence of early leukopenia was 99% (95% CI: 0.07-1.00). The pooled prevalence of early leukopenia was 49% (95% CI: 0.29-0.69) in patients with the *1/*6 c.36_37insGGAGTC ins/- variant. Conclusion NUDT15 polymorphisms are common in IBD patients and strongly predict thiopurine-induced leukopenia. The most common variant was the *1/*3 c.415C>T C/T variant and the *3/*3 c.415C>T T/T variant was associated with the highest risk of leukopenia. Pre-treatment genotyping for NUDT15 variants should be considered particularly in Asian populations, to guide individualised thiopurine dosing and avoid myelotoxicity.

Nudix hydrolase 15 (NUDT15) loss-of-function variants in an Australian inflammatory bowel disease population.

Thiopurine-related adverse events such as leukopenia, liver dysfunction and pancreatitis are associated with variants in the NUDT15 gene. Loss-of-function (low or no enzyme activity) alleles are more common in Asian and Hispanic populations. The prevalence of these variants in the Australian inflammatory bowel disease (IBD) population has not yet been reported. To evaluate the presence of NUDT15 loss-of-function alleles *2,*3,*9 in the Australian IBD population. The NUDT15 screening cohort included 423 IBD patients from Brisbane, Australia. Study patients were recruited by: (i) retrospective review of clinical charts for thiopurine-related severe adverse events; (ii) pathology data (white blood cell (WBC) and neutrophil counts). NUDT15 genotyping was performed using polymerase chain reaction (PCR)-high-resolution melt (HRM), TaqMan genotyping and Sanger sequencing. NUDT15 mutation R139C (allele *3) was identified in 8 of 423 (1.9%) IBD patients. Seven of eight patients were R139C heterozygous (C/T) and one patient was R139C homozygous (T/T). One of the C/T group and the T/T patient developed thiopurine-induced myelosuppression (TIM) within 60 days of dosing. One patient in the C/T group developed TIM after 60 days of thiopurine dosing. The remaining five patients in the C/T group did not show TIM; however, other thiopurine-related events could not be ruled out and therefore careful monitoring over a long period is recommended. This is the first study to report the frequency of NUDT15 haplotypes *2,*3,*9 in an Australian IBD population. The most common variant detected was the R139C mutation. PCR and Sanger sequencing are efficient and cost-effective approaches for NUDT15 genotyping.

Precision Medicine in Inflammatory Bowel Diseases: Challenges and Considerations for the Path Forward

Precision Medicine in Inflammatory Bowel Diseases: Challenges and Considerations for the Path Forward

Pharmacogenetics-based personalized treatment in patients with inflammatory bowel disease: A review

The development of treatment options has revolutionized the prognosis of inflammatory bowel disease (IBD). However, a particular group of patients still experience therapeutic failure or drug side effects. Although the high inter-patient variability in therapy is associated with clinical factors, including age, disease behavior, and disease duration, they attribute only a small proportion of inter-individual variability. Thus, pharmacogenetics evaluating associations between specific genetic variations and drug responses or side effects have focused on optimizing therapeutic efficacy and minimizing toxicity in IBD treatment. Thiopurine S-methyltransferase (TPMT) and nudix hydrolase 15 (NUDT15) are well-established predictive markers of thiopurine-induced myelosuppression. Low TPMT activity is related to increased 6-thioguanine nucleotide levels, subsequently leading to myelotoxicity. NUDT15 variants are strongly associated with thiopurine-induced early leukopenia in Asians, with a lower incidence of TPMT-deficient allele. The Korean Association for the Study of Intestinal Diseases guidelines recommend pretreatment determination of NUDT15 genotypes, especially in East Asians, and NUDT15 R139C measurement has been approved for clinical use since 2019. Several studies have attempted to identify powerful genetic markers for personalized medicine. In this article, we review the identified pharmacogenetics of currently available drugs, focusing on 5-aminosalicylic acid, glucocorticosteroids, thiopurines, and anti-tumor necrosis factor-alpha agents.

Meta-Analysis of NUDT15 Genetic Polymorphism on Thiopurine-Induced Myelosuppression in Asian Populations.

Backgound: The high incidence of thiopurine-induced myelosuppression in Asians is known to be attributable to genetic variation in thiopurine metabolism. A quantitative synthesis to summarize the genetic association with thiopurine-induced myelosuppression in Asians was therefore conducted. Methods: A Literature search was performed from January 2016 to May 2021 in the following databases: PubMed, Web of Science, and Embase and addition search included the studies from Zhang et al. Two reviewers independently extracted the following data: the author’s name, year of publication, ethnicity, drugs, diseases, genetic polymorphisms, onset, type of myelosuppression and results of Hardy-Weinberg equilibrium. The Newcastle-Ottawa Scale was used to assess the quality of the studies. The pooled odds ratios (OR) and 95% confidence intervals (CI) were calculated to evaluate the associations of NUDT15 and the risk of thiopurine-induced myelosuppression stratified by onset and type of myelosuppressive. Subgroup analysis by NUDT15 genetic polymorphisms was performed. Results: A total of 30 studies was included in this meta-analysis. The overall OR for the relationship between NUDT15 genetic polymorphisms and thiopurine-induced early onset of leukopenia and neutropenia in Asian populations were 11.43 (95% CI 7.11–18.35) and 16.35 (95% CI 10.20–26.22). Among NUDT15 polymorphisms, NUDT15*3 showed a significantly increased risk of early leukopenia (OR 15.31; 95% CI 9.65–24.27) and early neutropenia (OR 15.85; 95% CI 8.80–28.53). A significantly higher thiopurine-induced early neutropenic risk was also found for NUDT15*2 (OR 37.51; 95% CI 1.99–708.69). Whereas, NUDT15*5 and NUDT15*6 variants showed a lower risk of leukopenia. Conclusion: This study suggests that NUDT15*3 and NUDT15*2 are important genetic markers of thiopurine-induced early onset of myelotoxicity in Asians, therefore, early detection of these variants before initiating thiopurine therapy is necessary.

A novel single-tube multiplex real-time PCR assay for genotyping of thiopurine intolerance-causing variant NUDT15 c.415C>T.

Thiopurines are commonly used in the treatment of acute lymphoblastic leukaemia and autoimmune conditions, can be limited by myelosuppression. The NUDT15 c.415C>T variant is strongly associated with thiopurine-induced myelosuppression, especially in Asians. The purpose of this study was to develop a fast and reliable genotyping method for NUDT15 c.415C>T and investigate the polymorphic distribution among different races in China. A single-tube multiplex real-time PCR assay for NUDT15 c.415C>T genotyping was established using allele-specific TaqMan probes. In 229 samples, the genotyping results obtained through the established method were completely concordant with those obtained by Sanger sequencing. The distributions of NUDT15 c.415C>T among 173 Han Chinese, 48 Miaos, 40 Kazakhs, and 40 Kirghiz were different, with allelic frequencies of 0.06, 0.02, 0.07, and 0, respectively. This method will provide a powerful tool for the implementation of the genotyping-based personalized prescription of thiopurines in clinical settings.

Thiopurine-induced Myelosuppression with Severe Sepsis in a Patient with Crohn's Disease: A Case Report

Thiopurines by their glucocorticoid-sparing property help in maintaining remission for patients with inflammatory bowel disease (IBD), when glucocorticoids are reduced and withdrawn. However, due to bone marrow suppression, it cannot be used in various conditions where it is indicated.A 17-year-old patient presented with pancytopenia with neutropenic sepsis and alopecia after 3 weeks of starting azathioprine for her underlying Crohn's disease. Thiopurine S-methyltransferase (TPMT;*2, *3A, *3C) analysis resulted in a wild-type genotype, whereas homozygous Nudix hydrolase 15 (NUDT 15 C415T) variant was positive. Azathioprine was stopped immediately, and she was started on broad-spectrum antibiotics that led to some clinical improvements initially, but later on, the patient developed intestinal obstruction along with postoperative complications leading to death.In this report, we highlight a case of serious hematological toxicity associated with azathioprine use in a patient with Crohn's disease with homozygous NUDT 15 variant, thus favoring the implementation of a pharmacogenomic approach before starting azathioprine, particularly in the Asian population.How to cite this articleDebnath P, Nair S, Jain S, Udgirkar S, Contractor Q, Rathi P. Thiopurine-induced Myelosuppression with Severe Sepsis in a Patient with Crohn's Disease: A Case Report. Indian J Crit Care Med 2021;25(2):228–230.Prior presentation of case report at professional meetingThe case was presented in abstract form at the American College of Gastroenterology Annual Scientific Meeting, held at San Antonio, TX, USA 2019.Informed consent for publication of case detailsObtained from patient's relatives.

Genetic Polymorphisms of Drug-Metabolizing Enzymes Involved in 6-Mercaptopurine-Induced Myelosuppression in Thai Pediatric Acute Lymphoblastic Leukemia Patients.

Genetic polymorphisms of thiopurine S-methyltransferase (TPMT) and nucleoside diphosphate-linked moiety X-type motif 15 ( NUDT15 ) genes have been proposed as key determinants of 6-mercaptopurine (6-MP)-induced myelosuppression in pediatric acute lymphoblastic leukemia (ALL). In the present study, genotypes of TPMT and NUDT15 were investigated in 178 Thai pediatric patients with ALL by the TaqMan SNP genotyping assay and DNA sequencing. The frequency of TPMT*3C was 0.034. Among NUDT15 variants, NUDT15*3 is the most common variant with the allele frequency of 0.073, whereas those of NUDT15*2 , NUDT15*5 , and NUDT15*6 variants were 0.022, 0.011, and 0.039. These data suggest that a high proportion of Thai pediatric ALL patients may be at risk of thiopurine-induced myelosuppression.

Predicting (side) effects for patients with inflammatory bowel disease: The promise of pharmacogenetics.

Inflammatory bowel disease (IBD) is a chronic and heterogeneous intestinal inflammatory disorder. The medical management of IBD aims for long-lasting disease remission to prevent complications and disease progression. Early introduction of immunosuppression forms the mainstay of medical IBD management. Large inter-individual variability in drug responses, in terms of both efficacy and toxicity, leads to high rates of therapeutic failure in the management of IBD. Better patient stratification is needed to maximize patient benefit and minimize the harm caused by adverse events. Pre-treatment pharmacogenetic testing has the potential to optimize drug selection and dose, and to minimize harm caused by adverse drug reactions. In addition, optimizing the use of cheap conventional drugs, and avoiding expensive ineffective drugs, will lead to a significant reduction in costs. Genetic variation in both TPMT and NUDT15, genes involved in thiopurine metabolism, is associated to an increased risk of thiopurine-induced myelosuppression. Moreover, specific HLA haplotypes confer risk to thiopurine-induced pancreatitis and to immunogenicity to tumor necrosis factor-antagonists, respectively. Falling costs and increased availability of genetic tests allow for the incorporation of pre-treatment genetic tests into clinical IBD management guidelines. In this paper, we review clinically useful pharmacogenetic associations for individualized treatment of patients with IBD and discuss the path from identification of a predictive pharmacogenetic marker to implementation into IBD clinical care.

Association of Genetic Variants in NUDT15 With Thiopurine-Induced Myelosuppression in Patients With Inflammatory Bowel Disease

Use of thiopurines may be limited by myelosuppression. TPMT pharmacogenetic testing identifies only 25% of at-risk patients of European ancestry. Among patients of East Asian ancestry, NUDT15 variants are associated with thiopurine-induced myelosuppression (TIM). To identify genetic variants associated with TIM among patients of European ancestry with inflammatory bowel disease (IBD). Case-control study of 491 patients affected by TIM and 679 thiopurine-tolerant unaffected patients who were recruited from 89 international sites between March 2012 and November 2015. Genome-wide association studies (GWAS) and exome-wide association studies (EWAS) were conducted in patients of European ancestry. The replication cohort comprised 73 patients affected by TIM and 840 thiopurine-tolerant unaffected patients. Genetic variants associated with TIM. Thiopurine-induced myelosuppression, defined as a decline in absolute white blood cell count to 2.5 × 109/L or less or a decline in absolute neutrophil cell count to 1.0 × 109/L or less leading to a dose reduction or drug withdrawal. Among 1077 patients (398 affected and 679 unaffected; median age at IBD diagnosis, 31.0 years [interquartile range, 21.2 to 44.1 years]; 540 [50%] women; 602 [56%] diagnosed as having Crohn disease), 919 (311 affected and 608 unaffected) were included in the GWAS analysis and 961 (328 affected and 633 unaffected) in the EWAS analysis. The GWAS analysis confirmed association of TPMT (chromosome 6, rs11969064) with TIM (30.5% [95/311] affected vs 16.4% [100/608] unaffected patients; odds ratio [OR], 2.3 [95% CI, 1.7 to 3.1], P = 5.2 × 10-9). The EWAS analysis demonstrated an association with an in-frame deletion in NUDT15 (chromosome 13, rs746071566) and TIM (5.8% [19/328] affected vs 0.2% [1/633] unaffected patients; OR, 38.2 [95% CI, 5.1 to 286.1], P = 1.3 × 10-8), which was replicated in a different cohort (2.7% [2/73] affected vs 0.2% [2/840] unaffected patients; OR, 11.8 [95% CI, 1.6 to 85.0], P = .03). Carriage of any of 3 coding NUDT15 variants was associated with an increased risk (OR, 27.3 [95% CI, 9.3 to 116.7], P = 1.1 × 10-7) of TIM, independent of TPMT genotype and thiopurine dose. Among patients of European ancestry with IBD, variants in NUDT15 were associated with increased risk of TIM. These findings suggest that NUDT15 genotyping may be considered prior to initiation of thiopurine therapy; however, further study including additional validation in independent cohorts is required.

472 - NUDT15 Variants Contribute to Thiopurine-Induced Myelosuppression in European Populations

Introduction Thiopurines are commonly used in the maintenance treatment of inflammatory bowel disease (IBD) but this is limited by myelosuppression in 7% of patients.1 Thiopurine S-methyltransferase (TPMT) variants only explain 20% of thiopurine-induced myelosuppression (TIM) in Europeans suggesting the presence of other genetic determinants.2 We aimed to identify the clinical features of TIM and to identify novel variants associated with TIM through a genome wide association study and whole exome sequencing. Method We recruited 491 IBD patients with TIM from 82 hospitals. Inclusion criteria included drug exposure in the 7 days prior to TIM, white blood cell count ≤2.5 ×109/L, or neutrophil count ≤1.0 ×109/L and that TIM necessitated dose reduction/drug withdrawal. After expert adjudication, 329 cases assigned a high likelihood of causality were genotyped and exome sequenced with 635 thiopurine-tolerant IBD controls for use in the final analyses. Results We first confirmed an association of TIM with TPMT in an initial GWAS. We then, using exome sequencing, discovered a novel 6 bp in-frame deletion (rs746071566; AGGAGTC/A,p.Gly17_Val18del) at position 48611918 of chromosome 13 in exon 1 of NUDT15 (5.8% cases, 0.2% controls, OR=38.2,p=1.33×10-8). This deletion was replicated in an independent cohort (3/75 [4%] cases vs. 2/785 [0.3%] thiopurine-tolerant IBD controls; OR=16.2, p=0.006). All NUDT15 coding variants were confirmed with complete concordance by Sanger sequencing. Multivariable logistic regression demonstrated that adjusted dose (OR 2.2,p=9.4×10-11), NUDT15 genotype (OR 21.7,p=2.0×10-8) and TPMT genotype (OR 2.2,p=2.6×10-4 for MUT/WT and OR 51.2,p=1.8×10-4 for MUT/MUT) were independently associated with TIM. Conclusion These are the largest ever clinical and genetic analyses of thiopurine-induced myelosuppression. We identified NUDT15 coding variants, including a novel 6 bp deletion; carriage of any coding variant confers a 22-fold increase in the odds of TIM, independent of TMPT genotype and thiopurine dose. Although NUDT15 variants are less common than TPMT variants, their effect size for heterozygotes is greater. The number of patients needed to genotype to prevent TIM due to NUDT15 coding variant heterozygosity is 100. The estimated absolute risk of TIM in NUDT15 heterozygotes is 59%. A future clinical decision tool incorporating NUDT15 and TPMT genotypes will offer personalised thiopurine therapy and prevent the considerable morbidity and costs associated with severe bone marrow toxicity. Reference . Gisbert JP & Gomollon F.doi10.1111/j.1572-0241.2008.01848.x (2008) . Yang SK et al. doi10.1038/ng.3060 (2014) Disclosure of Interest None Declared

OP035 NUDT15 variants contribute to thiopurine-induced myelosuppression in European populations

OP035 NUDT15 variants contribute to thiopurine-induced myelosuppression in European populations

A coding variant in FTO confers susceptibility to thiopurine-induced leukopenia in East Asian patients with IBD

ObjectiveMyelosuppression is a life-threatening complication of thiopurine therapy, and the incidence of thiopurine-induced myelosuppression is higher in East Asians than in Europeans. We investigated genetic factors associated with thiopurine-induced leukopenia...

Are Patients with Intermediate TPMT Activity at Increased Risk of Myelosuppression When Taking Thiopurine Medications?

Thiopurine S-methyltransferase (TPMT) metabolizes thiopurine medications, including azathioprine and 6-mercaptopurine. Absent TPMT activity (i.e., in individuals homozygous for a variant TPMT allele) is associated with an increased risk of myelosuppression in patients taking thiopurine drugs. However, it is not clear if there is also an increased risk for patients with intermediate TPMT activity (i.e., in individuals heterozygous for a variant TPMT allele). To quantify the increased risk of myelosuppression for patients with intermediate TPMT activity. A systematic review identified published studies, up to 29 September 2008, that explored the relationship between TMPT and hematological adverse drug reactions to thiopurines. Following a critical appraisal of the quality of published studies, a meta-analysis calculated the odds ratio of myelosuppression for patients with intermediate TPMT activity compared with wild-type. A total of 67 studies were identified, the majority retrospective cohort in design. Patients with two TPMT variant alleles who are TPMT deficient have a substantial increase in their risk of myelotoxicity (86% of deficient patients developed myelosuppression). The increase in odds ratio of developing leukopenia for patients with intermediate TPMT activity or one TPMT variant allele compared with wild-type was 4.19 (95% CI: 3.20-5.48). This meta-analysis suggests that individuals with both intermediate and absent TPMT activity have an increased risk of developing thiopurine-induced myelosuppression, compared with individuals with normal activity. However, there is significant variability in the quality of the reported studies and large prospective studies to clarify the size of the effect of TPMT variant alleles on the risk of myelosuppression should be conducted. Accurate risk assessments will provide important data to inform clinical guidelines.