Association of Inherited Genetic Factors With Drug-Induced Hepatic Damage Among Children With Acute Lymphoblastic Leukemia

Abstract

ImportanceAcute lymphoblastic leukemia (ALL) is the most common childhood cancer. Hepatotoxic effects, including hyperbilirubinemia and elevated alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels, are common during all phases of therapy and are linked to several chemotherapeutic agents, including asparaginase, mercaptopurine, and methotrexate.ObjectiveTo determine which genetic variants were associated with hyperbilirubinemia and elevated ALT and AST levels in children, adolescents, and young adults treated for ALL.Design, Setting, and ParticipantsThis retrospective analysis of a multiethnic genome-wide association study was conducted between January 1, 2019, and April 15, 2022, including patients treated as part of Children’s Oncology Group (COG) trials with centers in the United States, Canada, and Australia, which accrued data from December 29, 2003, to January 21, 2011 (AALL0232), and from January 22, 2007, to July 24, 2014 (AALL0434). Germline genotypes were interrogated using genome-wide arrays and imputed using a National Institutes of Health TOPMed Imputation server. Mixed-effects logistic regressions were used to account for multiple episodes for an individual patient. Genotype × treatment phase interaction was tested to uncover phase-specific genetic risk factors.ExposuresTotal duration of multiagent protocol chemotherapy ranging from 2.5 to 3.5 years.Main Outcomes and MeasuresThe primary outcomes were National Cancer Institute Common Terminology Criteria for Adverse Events (version 4) hyperbilirubinemia of grade 3 or higher and elevated liver ALT and AST levels.ResultsA total of 3557 participants were included in the analysis (2179 [61.3%] male; median age, 11.1 [range, 1-30] years). Among 576 known variants associated with these liver function test results in the general population, UGT1A1 variant rs887829 and PNPLA3 variant rs738409 were associated with increased risk of hyperbilirubinemia (odds ratio [OR], 2.18 [95% CI, 1.89-2.53]; P = 6.7 × 10−27) and ALT and AST levels (OR, 1.27 [95% CI, 1.15-1.40]; P = 3.7 × 10−7), respectively, during treatment for ALL. Corresponding polygenic risk scores were associated with hepatotoxic effects across all therapy phases and were largely driven by UGT1A1 and PNPLA3 variants. Genome-wide association analysis revealed an age-specific variant near the CPT1A gene that was only associated with elevated ALT and AST levels among patients younger than 10 years (OR, 1.28 [95% CI, 1.18-1.39]; P = 8.7 × 10−10).Conclusions and RelevanceThese results suggest a strong genetic basis for interpatient variability in hyperbilirubinemia and aminotransferase level elevations during leukemia chemotherapy.

Assessment of longitudinal changes in body composition of children with lymphoma and rhabdomyosarcoma

“…Finally, we also observed a higher risk of grade ≥3 nonhematologic toxicity in patients with race/ethnicity other than non‐Hispanic White or Black. The existing literature shows a higher risk of treatment‐related toxicities among patients of certain racial or ethnic groups due to pharmacogenomic variations 36–39 . It is possible that these unmeasured differences, in addition to body composition, mediate the risk of treatment‐related toxicities and thus deserve further investigation in future studies.…”

“…The existing literature shows a higher risk of treatment-related toxicities among patients of certain racial or ethnic groups due to pharmacogenomic variations. [36][37][38][39] It is possible that these unmeasured differences, in addition to body composition, mediate the risk of treatment-related toxicities and thus deserve further investigation in future studies. Small numbers of patients with race/ethnicity other than non-Hispanic White or Black preclude a detailed investigation in this study.…”

Hepatic Dysfunction during Induction Chemotherapy in Children with Acute Lymphoblastic Leukemia and Lymphoblastic Lymphoma and Its Effects on Subsequent Therapy and Outcome

“…5 Hepatic dysfunction could be due to leukemic infiltrates in the liver, nonalcoholic steatohepatitis, sepsis, hepatotropic viral infections, therapy-related toxicity seen due to asparaginase, rarely hyperinflammatory syndromes like hemophagocytic lymphohistiocytosis (HLH), and indirect hyperbilirubinemia due to underlying genetic syndromes like Gilbert's syndrome. 6 Hepatic dysfunction can contribute to morbidity by adding on to the underlying disease, delaying chemotherapy, dose modifications of chemotherapeutic agents, and rarely can cause mortality due to fulminant hepatic failure. This study was intended to find out the prevalence of hepatic dysfunction during induction therapy and its risk factors and effects on therapy and outcome.…”

Quantitative analysis of the UDP‐glucuronosyltransferase transcriptome in human tissues

“…Many factors regulate the expression of UGTs, including cis‐acting genetic polymorphisms, 5,9 alternative splicing, 17 transcription factors (TFs), 18–20 miRNAs, 21 inducers, 22,23 and diseases 24–26 . Variation in the expression and activity of the UGTs contributes to differences in drug responses, toxicity, hormone homeostasis, and disease/cancer risks 3,8,27–29 . Moreover, the expression levels of several UGTs are changed in cancer and have been associated with cancer prognosis and treatment outcomes 8,30 .…”

“…[24][25][26] Variation in the expression and activity of the UGTs contributes to differences in drug responses, toxicity, hormone homeostasis, and disease/cancer risks. 3,8,[27][28][29] Moreover, the expression levels of several UGTs are changed in cancer and have been associated with cancer prognosis and treatment outcomes. 8,30 Yet, the tissue-specific expression profiles of the UGTs and their transcriptional regulation in normal tissues are still not fully understood.…”