Monitoring thiopurine metabolites in inflammatory bowel disease

González-Lama, Yago; Gisbert, Javier P.

doi:10.1136/flgastro-2015-100681

Cited by 23 publications

(18 citation statements)

References 83 publications

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“…One of the strongest ways to determine initial 6-MP dose is an experimental assessment of potential for drug adverse reactions, such as severe neutropenia by monitoring 6-MP metabolite concentration or using in vitro activity profiles (Dubinsky et al, 2000; Ansari et al, 2002;; Cuffari, 2005; Bradford, 2011; Supandi et al, 2018). However, applying such methods into routine clinical practice for predicting drug-induced toxicity is still challenging because it is extremely time-consuming, expensive, and inefficient (González-Lama and Gisbert, 2016).…”

Section: Introductionmentioning

confidence: 99%

Star Allele-Based Haplotyping versus Gene-Wise Variant Burden Scoring for Predicting 6-Mercaptopurine Intolerance in Pediatric Acute Lymphoblastic Leukemia Patients

et al. 2019

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Nudix Hydrolase 15 (NUDT15) and Thiopurine S-Methyltransferase (TPMT) are strong genetic determinants of thiopurine toxicity in pediatric acute lymphoblastic leukemia (ALL) patients. Since patients with NUDT15 or TPMT deficiency suffer severe adverse drug reactions, star (*) allele-based haplotypes have been used to predict an optimal 6-mercaptopurine (6-MP) dosing. However, star allele haplotyping suffers from insufficient, inconsistent, and even conflicting designations with uncertain and/or unknown functional alleles. Gene-wise variant burden (GVB) scoring enables us to utilize next-generation sequencing (NGS) data to predict 6-MP intolerance in children with ALL. Whole exome sequencing was performed for 244 pediatric ALL patients under 6-MP treatments. We assigned star alleles with PharmGKB haplotype set translational table. GVB for NUDT15 and TPMT was computed by aggregating in silico deleteriousness scores of multiple coding variants for each gene. Poor last-cycle dose intensity percent (DIP < 25%) was considered as 6-MP intolerance, resulting therapeutic failure of ALL. DIPs showed significant differences ( p < 0.05) among NUDT15 poor (PM, n = 1), intermediate (IM, n = 48), and normal (NM, n = 195) metabolizers. TPMT exhibited no PM and only seven IMs. GVB showed significant differences among the different haplotype groups of both NUDT15 and TPMT ( p < 0.05). Kruskal–Wallis test for DIP values showed statistical significances for the seven different GVB score bins of NUDT15 . GVB NUDT15 outperformed the star allele-based haplotypes in predicting patients with reduced last-cycle DIPs at all DIP threshold levels (i.e., 5%, 10%, 15%, and 25%). In NUDT15 -and- TPMT combined interaction analyses, GVB NUDT15 , TPMT outperformed star alleles [area under the receiver operating curve (AUROC) = 0.677 vs. 0.645] in specificity (0.813 vs. 0.796), sensitivity (0.526 vs. 0.474), and positive (0.192 vs. 0.164) and negative (0.953 vs. 0.947) predictive values. Overall, GVB correctly classified five more patients (i.e., one into below and four into above 25% DIP groups) than did star allele haplotypes. GVB analysis demonstrated that 6-MP intolerance in pediatric ALL can be reliably predicted by aggregating NGS-based common, rare, and novel variants together without hampering the predictive power of the conventional haplotype analysis.

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Section: Introductionmentioning

confidence: 99%

Star Allele-Based Haplotyping versus Gene-Wise Variant Burden Scoring for Predicting 6-Mercaptopurine Intolerance in Pediatric Acute Lymphoblastic Leukemia Patients

et al. 2019

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“…Hematological toxicity in the form of myelosuppression, secondary to either thiopurine or elevated levels of its metabolite 6-thioguanine (6-TGN), is the most serious ADR. A review of 66 trials including 8302 patients reported a cumulative incidence of myelosuppression of 7%, predominantly occurring within the initial few months of treatment [10,14].…”

Section: Introductionmentioning

confidence: 99%

Azathioprine dosing and metabolite measurement in pediatric inflammatory bowel disease: does one size fit all?

Walker

Kammermeier

Vora

et al. 2019

aog

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Background Azathioprine is widely used for the maintenance of remission in children with inflammatory bowel disease (IBD). Measuring thiopurine metabolites 6-thioguanine (6-TGN) and 6-methyl-mercaptopurine (6-MMP) can aid in optimizing treatment and preventing toxicity. We report a proactive approach combining early metabolite measurements with IBD activity index to achieve optimal azathioprine dosing. Methods The reporting of azathioprine dosing, IBD activity indexes and thiopurine metabolites was evaluated retrospectively in 40 children with IBD. Additional treatments and the effect of azathioprine on blood counts were also examined. Results Forty children (40% female) with IBD (26 Crohn’s disease, 12 ulcerative colitis, and 2 unclassified IBD), mean age 12.2±3.4 years, were included in the study. The mean azathioprine dose was 1.3±0.4 mg/kg; mean 6-TGN level was 280±151 pmol/8 × 10 8 red blood cells (RBC) and mean 6-MMP level 1022±1007 pmol/8 × 10 8 RBC. Disease activity index (Crohn’s and ulcerative colitis, pediatric specific) at the time of metabolite measurement was 6.5±8. Twenty-eight children did not require azathioprine dose adjustment, while it was increased in 12. Data from children with azathioprine monotherapy were analyzed separately and the results were similar. Conclusion Timely measurement of thiopurine metabolites and clinical assessment can provide a powerful tool to optimize azathioprine dosing and reduce serious adverse effects in children with IBD.

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“…In most populations, approximately 10% of individuals are heterozygotes and a further 0.3% carry homozygous variants of the non-functional TPMT alle les. 14,20,21,24,25 In the present study, none of the participating patients were identified as being homozygous for any mutation. TPMT genotyping has been demonstrated to show high sensitivity, 19,23,26 with reported sensitivities and specificities of 88.9% (81.6-97.5%) and 99.2% (98.4-99.9%), respectively.…”

Section: Discussionmentioning

confidence: 75%

Thiopurine S-methyltransferase genetic polymorphisms in adult patients with inflammatory bowel diseases in the Latvian population

Zaļizko

Stefanovics

Sokolovska

et al. 2020

Therap Adv Gastroenterol

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Background: Thiopurine methyltransferase (TPMT) plays a significant role in the metabolism of thiopurines, and, for patients with inflammatory bowel disease (IBD), it is useful to perform TPMT genotyping prior to azathioprine (AZA) treatment. In this study, we determined TPMT gene polymorphisms in a cohort of IBD patients in Latvia. Methods: DNA samples were obtained from 244 IBD patients, and qPCR was performed for detection of rs1800462, rs1800460, and rs1142345 single-nucleotide polymorphisms (SNPs). Three common, non-functional TPMT alleles ( TPMT*2, *3B, and *3C) were identified (women, 51%; men, 49%). TPMT*2, *3A, *3B, and *3C allelic variants detected using qPCR were consistent with restriction fragment length polymorphism (RFLP) data. Results: Among patients, 78% had ulcerative colitis and 22% had Crohn’s disease, with 93.9% of the former carrying a wild-type homozygous TPMT*1/*1 genotype and 6.1% carrying heterozygous genotypes. The most frequent polymorphisms were TPMT*1/*3A (5.3%: two variants: TPMT*3B and TPMT*3C), TPMT*1/*3C (0.4%), and TPMT*1/*2 (0.4%). None of the patients carried a TPMT*3B polymorphism and no patients were homozygous for any mutation. Conclusion: This is the first study to identify TPMT gene polymorphisms in adult IBD patients in Latvia. The results indicate that the frequency of common TPMT alleles is similar to that of other European populations.

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Monitoring thiopurine metabolites in inflammatory bowel disease

Cited by 23 publications

References 83 publications

Star Allele-Based Haplotyping versus Gene-Wise Variant Burden Scoring for Predicting 6-Mercaptopurine Intolerance in Pediatric Acute Lymphoblastic Leukemia Patients

Star Allele-Based Haplotyping versus Gene-Wise Variant Burden Scoring for Predicting 6-Mercaptopurine Intolerance in Pediatric Acute Lymphoblastic Leukemia Patients

Azathioprine dosing and metabolite measurement in pediatric inflammatory bowel disease: does one size fit all?

Thiopurine S-methyltransferase genetic polymorphisms in adult patients with inflammatory bowel diseases in the Latvian population

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