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ITPA Polymorphisms and the Incidence of Toxicities in Children with Acute Lymphoblastic Leukemia
Patpetra Svasdisant1, Waraporn Glomglao1, Preeyanun Siraprapapat1
1Division of Hematology and Oncology, Department of Pediatrics, Faculty of Medicine, Siriraj Hospital, Mahidol University, Bangkok, Thailand.
Insights
Inosine triphosphate pyrophosphatase (ITPA) genetic variations influenced 6-mercaptopurine (6-MP) dosing in pediatric acute lymphoblastic leukemia (ALL) patients. Homozygous ITPA variants required lower 6-MP doses, suggesting a role in managing treatment toxicity.
Area of Science:
- Pharmacogenomics
- Pediatric Oncology
- Drug Metabolism
Background:
- 6-Mercaptopurine (6-MP) is crucial for pediatric acute lymphoblastic leukemia (ALL) treatment.
- Neutropenia and hepatotoxicity are common 6-MP side effects that can impede therapy.
- Inosine triphosphate pyrophosphatase (ITPA) may mitigate toxic thiopurine metabolite accumulation, but its role in ALL is understudied.
Purpose of the Study:
- To investigate the association between ITPA genetic variations and 6-MP toxicity in children with ALL.
- To analyze the impact of ITPA polymorphisms on neutropenia, hepatotoxicity (transaminitis), and 6-MP dosage during maintenance therapy.
Main Methods:
- Retrospective analysis of 209 pediatric ALL patients (ages 1-15) treated with 6-MP maintenance therapy (2000-2020).
- Categorization of patients based on ITPA genotype: wild-type, heterozygous ITPA 94C>A (hetITPA), and homozygous ITPA 94C>A (homITPA).
- Evaluation of toxicity incidence (neutropenia, transaminitis) and mean 6-MP dose in the first year of maintenance.
Main Results:
- No significant difference in neutropenia incidence across ITPA genotypes (P=0.813).
- Transaminitis was more frequent in homITPA patients, though not statistically significant (P=0.063).
- Mean 6-MP dose was significantly lower in homITPA patients compared to hetITPA or wild-type (P=0.016).
Conclusions:
- Homozygous ITPA 94C>A variants are associated with higher transaminitis incidence and necessitate significantly lower 6-MP doses.
- ITPA polymorphisms may influence 6-MP dose requirements and toxicity profiles in pediatric ALL.
- Further research is needed to fully understand ITPA's impact on thiopurine therapy outcomes in ALL.
Background:
6-Mercaptopurine (6-MP), a thiopurine agent, is a essential medication for treating pediatric acute lymphoblastic leukemia (ALL). However, its side effects of neutropenia and hepatotoxicity might interrupt treatment, resulting in poor outcomes. Inosine triphosphate pyrophosphatase (ITPA), an enzyme in the thiopurine pathway, may prevent the accumulation of toxic thiopurine metabolites. Studies on ITPA and thiopurine-associated toxicities are scarce.
Methods:
This study retrospectively investigated 1- to 15-year-old children with ALL who received 6-MP during the maintenance phase of treatment between 2000 and 2020. Toxicity during the first year of maintenance therapy and the mean dose of 6-MP were analyzed.
Results:
The 209 patients had a median age of 4.8 (0.3-14.8) years. Of these, 124 patients (59.3%) had wild-type ITPA, 73 patients (34.9%) had heterozygous ITPA 94C>A (hetITPA), and 12 patients (5.7%) had homozygous ITPA 94C>A (homITPA), with an allele frequency of 0.23. The incidence of neutropenia among ITPA polymorphisms did not significantly differ (P = 0.813). In patients harboring homITPA, transaminitis was more frequent than other polymorphisms but without a significant difference (P = 0.063). The mean dose of 6-MP for patients with homITPA was significantly lower than that for patients with hetITPA or wild-type ITPA (P = 0.016).
Conclusions:
HomITPA had a higher incidence of transaminitis and required a significantly larger dose reduction of 6-MP than wild-type ITPA. Further study is warranted to elucidate the effects of ITPA polymorphisms on toxicity in patients with ALL treated with 6-MP.
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