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

Gennep, Sara van; Konté, Kadère; Meijer, Berrie; Heymans, Martijn W.; D’Haens, Geert R.; Löwenberg, Mark; Boer, Nanne K. H. de

doi:10.1111/apt.15403

Cited by 34 publications

(25 citation statements)

References 103 publications

(318 reference statements)

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“…31 A recent systematic review and meta-analysis on predictive factors of thiopurine induced leucopenia in more than 11 000 IBD patients showed that patients with NUDT15 R139C variant have 6.9-fold higher odds of developing leucopenia (3.9-fold for TPMT variants). 32 Our study further reiterates this strong association. was identified in two third of patients (12.3% homozygous and 54.3% heterozygous mutation variant).…”

Section: Discussionsupporting

confidence: 78%

NUDT15 C415T variant compared with TPMT genotyping in predicting azathioprine‐induced leucopenia: prospective analysis of 1014 inflammatory bowel disease patients in India

Banerjee

Vishnubhotla

Pal

et al. 2020

Aliment Pharmacol Ther

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SummaryBackgroundRecent studies reported that Nudix Hydrolase 15(NUDT 15) gene variant (C415T) can better predict thiopurine induced leucopenia in Asian patients with inflammatory bowel disease (IBD) than thiopurine S‐methyl transferase (TPMT).AimTo evaluate the role of the NUDT variant compared with TPMT in predicting azathioprine induced leucopenia in Indian IBD patients.MethodsProspectively collected data of consecutive patients treated with azathioprine from a large IBD registry were analysed for side effects, discontinuation time, and initial and maximum dose tolerated. Genotyping of NUDT15 C415T (rs116855232; p.R139C) was carried out retrieving blood samples from bio‐repository employing real time polymerase chain reaction with age and sex‐matched healthy volunteers. The association of NUDT15 C415T with leucopenia (<3 × 109/L) and neutropenia (<1.5 × 109/L) was evaluated. TPMT genotyping was done in patients who developed leucopenia.ResultsAmong 1014 patients (mean age 35.84 ± 12.74 years; 61% males; 54% ulcerative colitis, 44% Crohn's disease and 2% IBD‐unclassified), 79 were excluded due to inadequate blood samples. Of the remaining 935, 81 (9%) developed leucopenia and 70 (7.5%) developed neutropenia. The variant “T” allele [heterozygous (CT) and homozygous (TT) versus wild type (CC)] was associated with a 19‐fold higher odds (OR19.35, 95% CI11.55‐32.42; P < 0.0001) of leucopenia and 21‐fold higher odds of neutropenia (OR21.41, 95% CI12.25‐37.41). There was significant difference in median dose tolerated between CC, CT and TT (1.35, 1.38 and 0.92 mg/kg body weight, respectively) (P = 0.037) and median duration of therapy (18, 15 and 10 months for CC/CT/TT) (P = 0.003). NUDT15 genotype was an independent risk factor for leucopenia (hazard ratio (HR): CT 11.31, 95% CI6.85‐18.03, P < 0.0001 and TT 31.283, 95% CI14.76‐66.30 compared to CC) and neutropenia (HR: CT 13.04, 95% CI7.65‐22.22, P < 0.0001 and TT 43.39, 95% CI20.21‐92.68 compared to CC). The sensitivities for predicting leucopenia and neutropenia by number of mutant NUDT 15 alleles based on additive predictive model were 66.67% and 70% with a receptor operator characteristic curve area under curve value of 0.791 and 0.807, respectively. Among patients with leucopenia, only 6.2% were heterozygous and none were homozygous for TPMT variants.ConclusionNUDT15 variant genotyping appears to be a better predictor for azathioprine‐induced leucopenia in an Indian population than TPMT with high accuracy and can be useful in optimizing azathioprine dosage.

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Section: Discussionsupporting

confidence: 78%

NUDT15 C415T variant compared with TPMT genotyping in predicting azathioprine‐induced leucopenia: prospective analysis of 1014 inflammatory bowel disease patients in India

Banerjee

Vishnubhotla

Pal

et al. 2020

Aliment Pharmacol Ther

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“…The potential use of a steady-state 6TGN level above 450 pmol/8 × 10 8 red blood cells (RBC) to predict toxicity is still controversial[9-14]. Several studies have reported that 6TGN levels are not significantly correlated with TIL, and no applicable therapeutic range for 6TGN has been determined[15-18]. For example, a prospective study found that only three out of ten Japanese patients with TIL exhibited high 6TGN levels (> 450 pmol/8 × 10 8 RBC)[17].…”

Section: Introductionmentioning

confidence: 99%

Nucleoside diphosphate-linked moiety X-type motif 15 R139C genotypes impact 6-thioguanine nucleotide cut-off levels to predict thiopurine-induced leukopenia in Crohn’s disease patients

Zhu¹,

Chao²,

Li³

et al. 2019

WJG

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BACKGROUNDThiopurine-induced leukopenia (TIL) is a life-threatening toxicity and occurs with a high frequency in the Asian population. Although nucleoside diphosphate-linked moiety X-type motif 15 (NUDT15) variants significantly improve the predictive sensitivity of TIL, more than 50% of cases of this toxicity cannot be predicted by this mutation. The potential use of the 6-thioguanine nucleotide (6TGN) level to predict TIL has been explored, but no decisive conclusion has been reached. Can we increase the predictive sensitivity based on 6TGN by subgrouping patients according to their NUDT15 R139C genotypes?AIMTo determine the 6TGN cut-off levels after dividing patients into subgroups according to their NUDT15 R139C genotypes.METHODSPatients’ clinical and epidemiological characteristics were collected from medical records from July 2014 to February 2017. NUDT15 R139C, thiopurine S-methyltransferase, and 6TGN concentrations were measured.RESULTSA total of 411 Crohn’s disease patients were included. TIL was observed in 72 individuals with a median 6TGN level of 323.4 pmol/8 × 108 red blood cells (RBC), which was not different from that of patients without TIL (P = 0.071). Then, we compared the 6TGN levels based on NUDT15 R139C. For CC (n = 342) and CT (n = 65) genotypes, the median 6TGN level in patients with TIL was significantly higher than that in patients without (474.8 vs 306.0 pmol/8 × 108 RBC, P = 9.4 × 10-5; 291.7 vs 217.6 pmol/8 × 108 RBC, P = 0.039, respectively). The four TT carriers developed TIL, with a median 6TGN concentration of 135.8 pmol/8 × 108 RBC. The 6TGN cut-off levels were 411.5 and 319.2 pmol/8 × 108 RBC for the CC and CT groups, respectively.CONCLUSIONThe predictive sensitivity of TIL based on 6TGN is dramatically increased after subgrouping according to NUDT15 R139C genotypes. Applying 6TGN cut-off levels to adjust thiopurine therapies based on NUDT15 is strongly recommended.

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“…These findings highlight the importance of NUDT15 genotyping, alongside TPMT phenotype, or genotype testing. This is supported by a recent systematic review and meta-analysis (23), and recently published guidelines provide suggested dosing regimens in patients with TPMT or NUDT15 variants (24).…”

Section: Predictors Of Toxicitymentioning

confidence: 81%

“…A recent multicenter, international retrospective study showed that 6-TGN levels were associated with mucosal healing, and that a level of 397 pmol/10 8 RBC was 86.7% specific but only 35.3% sensitive for mucosal healing (75). However, higher 6-TGN levels are also associated with increased rates of early or late myelotoxicity (23), particularly above 450 pmol/8 × 10 8 RBC (76), and so a fine balance exists between response and toxicity. Interestingly, while a lower thiopurine dose may be sufficient for Asian patients, as discussed above, it is the 6-TGN and not the dose that was associated with mucosal healing in a cohort including a large proportion of Chinese patients (75).…”

Section: Predictors Of Response To Thiopurinesmentioning

confidence: 99%

Can We Predict the Toxicity and Response to Thiopurines in Inflammatory Bowel Diseases?

et al. 2019

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Thiopurines are a cheap, effective treatment option in the management of inflammatory bowel disease (IBD). However, with the growing choice of targeted therapies available, as well as the well-documented toxicities of thiopurines, the role of thiopurines has been questioned. Nevertheless, given their inexpense in an era of spiraling healthcare costs, thiopurines remain an attractive option in the right patients. In the age of personalized medicine, being able to predict patients who will respond as well as those that will develop toxicity to a treatment is vital to tailoring therapy. This review will summarize the available literature with respect to predictors of response and toxicity to thiopurines in order to guide management in IBD. Specifically, toxicities addressed will include myelotoxicity, hepatotoxicity, pancreatitis, alopecia, gastrointestinal and flu-like symptoms, and complications associated with Epstein-Barr virus. While more work needs to be done to further our ability to predict both response to and side effects from therapies, pharmacogenomic research shows significant promise in its ability to personalize our use of thiopurines.

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

Cited by 34 publications

References 103 publications

NUDT15 C415T variant compared with TPMT genotyping in predicting azathioprine‐induced leucopenia: prospective analysis of 1014 inflammatory bowel disease patients in India

NUDT15 C415T variant compared with TPMT genotyping in predicting azathioprine‐induced leucopenia: prospective analysis of 1014 inflammatory bowel disease patients in India

Nucleoside diphosphate-linked moiety X-type motif 15 R139C genotypes impact 6-thioguanine nucleotide cut-off levels to predict thiopurine-induced leukopenia in Crohn’s disease patients

Can We Predict the Toxicity and Response to Thiopurines in Inflammatory Bowel Diseases?

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