Frequency of ITPA gene polymorphisms in Iranian patients with acute lymphoblastic leukemia and prediction of its myelosuppressive effects

Azimi, Fatemeh; Mortazavi, Yousef; Alavi, Samin; Khalili, Mitra; Ramazani, Ali

doi:10.1016/j.leukres.2015.06.016

Cited by 17 publications

(12 citation statements)

References 37 publications

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“…More data on the relationship between ITPA genotype and ADRs of thiopurine drugs have been reported in the literature . Some studies concerning the paediatric population are available with only two studies on paediatric patients with immune disease (IBD) . In paediatric populations, a relation between ITPA genotype with hepatotoxicity was reported in some studies but not all .…”

Section: Discussionmentioning

confidence: 99%

“…Some studies concerning the paediatric population are available with only two studies on paediatric patients with immune disease (IBD) . In paediatric populations, a relation between ITPA genotype with hepatotoxicity was reported in some studies but not all . In a paediatric population with acute lymphoblastic leukaemia, Stocco et al .…”

Section: Discussionmentioning

confidence: 99%

“… reported that TPMT and ITPA genotypes together can explain 27% of the variability in haematological toxicity, and Azimi et al . showed that patients with aberrant ITPA genotype are more likely to be myelosuppressed after treatment with 6‐MP. Concerning children with IBD, de Ridder et al .…”

Section: Discussionmentioning

confidence: 99%

“…The potential implication of ITPA in the occurrence of ADRs of AZA has been investigated. However, a number of contradictory results have been reported, from an impact of ITPA polymorphism on toxicity to no significant association . This issue remains unresolved, and no obvious statement about the benefit of introducing ITPA assay into clinical practice is currently available .…”

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confidence: 99%

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ITPA Activity in Children Treated by Azathioprine: Relationship to the Occurrence of Adverse Drug Reactions and Inflammatory Response

Citterio-Quentin

Moulsma

Gustin

et al. 2018

Basic Clin Pharma Tox

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Azathioprine (AZA), a thiopurine drug, is widely used in the treatment of children with immunological diseases such as inflammatory bowel disease (IBD) and autoimmune hepatitis (AIH); however, interindividual variability in the occurrence of adverse drug reactions (ADRs) and drug response is observed. This study investigated (i) the relationships between inosine triphosphate pyrophosphatase (ITPA) activity, an enzyme involved in thiopurine metabolism, and the occurrence of ADRs in children with immunological disease on AZA therapy, and (ii) the relationship between ITPA activity and the inflammatory activity observed in children with IBD. ITPA and TPMT activities were determined in 106 children with immunological disease on AZA therapy. Markers of hepatotoxicity, myelotoxicity, pancreatitis and inflammation as well as clinical information were retrospectively collected during regular medical visits. No significant association was found between ITPA activity and hepatotoxicity or clinical ADRs such as cutaneous reactions, arthralgia, flulike symptoms and gastrointestinal disorders. Concerning myelotoxicity, a significant relation was observed between ITPA activity and RBC mean corpuscular volume (MCV; p=0.003). This observation may be related to the significant relationship found between high ITPA activity and the increase in γ-globulin level reflecting inflammation (p=0.005). In our study, ITPA activity was not associated with occurrence of ADRs, but a relationship between high ITPA activity and γ-globulin, a marker of inflammation, was found in children with IBD. Therefore, measurement of ITPA activity may help to identify children with IBD predisposed to residual inflammation on AZA therapy. Further prospective studies are needed to confirm this result.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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ITPA Activity in Children Treated by Azathioprine: Relationship to the Occurrence of Adverse Drug Reactions and Inflammatory Response

Citterio-Quentin

Moulsma

Gustin

et al. 2018

Basic Clin Pharma Tox

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“…Because these side effects can be quite devastating to the patient, dosage alteration or discontinuation of treatment is common for individuals with ITPA polymorphism [ 53 , 59 ] (see references [ 36 , 56 , 57 ] for review). As a result, researchers have suggested including pre-therapeutic screening of patients for ITPA polymorphism to minimize the occurrence of drug toxicity [ 69 – 71 ]. Importantly, not all ITPA polymorphism is associated with thiopurine toxicity.…”

Section: Introductionmentioning

confidence: 99%

A disease spectrum for ITPA variation: advances in biochemical and clinical research

Burgis

2016

J Biomed Sci

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Human ITPase (encoded by the ITPA gene) is a protective enzyme which acts to exclude noncanonical (deoxy)nucleoside triphosphates ((d)NTPs) such as (deoxy)inosine 5′-triphosphate ((d)ITP), from (d)NTP pools. Until the last few years, the importance of ITPase in human health and disease has been enigmatic. In 2009, an article was published demonstrating that ITPase deficiency in mice is lethal. All homozygous null offspring died before weaning as a result of cardiomyopathy due to a defect in the maintenance of quality ATP pools. More recently, a whole exome sequencing project revealed that very rare, severe human ITPA mutation results in early infantile encephalopathy and death. It has been estimated that nearly one third of the human population has an ITPA status which is associated with decreased ITPase activity. ITPA status has been linked to altered outcomes for patients undergoing thiopurine or ribavirin therapy. Thiopurine therapy can be toxic for patients with ITPA polymorphism, however, ITPA polymorphism is associated with improved outcomes for patients undergoing ribavirin treatment. ITPA polymorphism has also been linked to early-onset tuberculosis susceptibility. These data suggest a spectrum of ITPA-related disease exists in human populations. Potentially, ITPA status may affect a large number of patient outcomes, suggesting that modulation of ITPase activity is an important emerging avenue for reducing the number of negative outcomes for ITPA-related disease. Recent biochemical studies have aimed to provide rationale for clinical observations, better understand substrate selectivity and provide a platform for modulation of ITPase activity.

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Role of TPMT and ITPA variants in mercaptopurine disposition

Gerbek

Ebbesen

Nersting

et al. 2018

Cancer Chemother Pharmacol

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Frequency of ITPA gene polymorphisms in Iranian patients with acute lymphoblastic leukemia and prediction of its myelosuppressive effects

Cited by 17 publications

References 37 publications

ITPA Activity in Children Treated by Azathioprine: Relationship to the Occurrence of Adverse Drug Reactions and Inflammatory Response

ITPA Activity in Children Treated by Azathioprine: Relationship to the Occurrence of Adverse Drug Reactions and Inflammatory Response

A disease spectrum for ITPA variation: advances in biochemical and clinical research

Role of TPMT and ITPA variants in mercaptopurine disposition

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