Levocarnitine for pegaspargase‐induced hepatotoxicity in older children and young adults with acute lymphoblastic leukemia

Schulte, Rachael; Hinson, Ashley R.; Huynh, Van; Breese, Erin H.; Pierro, Joanna; Rotz, Seth J.; Mixon, Benjamin A.; McNeer, Jennifer L.; Burke, Michael J.; Orgel, Etan

doi:10.1002/cam4.4281

Cited by 16 publications

(9 citation statements)

References 39 publications

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“…Asparaginase related hepatic dysfunction, including abnormalities in liver function and elevations in hepatic transaminases, bilirubin and alkaline phosphatase, often result in significant delays in treatment, and that may have a negative impact on the overall clinical outcome of patients [ 12 ]. On the other hand, inability to deliver optimal asparaginase therapy may negatively impact survival,[ 13 ] therefore it would be beneficial to predict which patients are at higher risk of toxicity to enable enhanced monitoring and hepatoprotective measures [ 14 ].…”

Section: Introductionmentioning

confidence: 99%

Hispanic ethnicity and the rs4880 variant in SOD2 are associated with elevated liver enzymes and bilirubin levels in children receiving asparaginase-containing chemotherapy for acute lymphoblastic leukemia

Wang

Alqahtani

et al. 2022

Biomedicine & Pharmacotherapy

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Section: Introductionmentioning

confidence: 99%

Hispanic ethnicity and the rs4880 variant in SOD2 are associated with elevated liver enzymes and bilirubin levels in children receiving asparaginase-containing chemotherapy for acute lymphoblastic leukemia

Wang

Alqahtani

et al. 2022

Biomedicine & Pharmacotherapy

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“…It has been proposed that l -carnitine be incorporated into ALL treatment to reduce hepatotoxic effects in adult ALL. 18 , 19 , 20 However, in a mouse model, it did not reduce asparaginase-associated hepatotoxic effects. 21 IGHMBP2 was initially discovered to bind to the immunoglobulin mu chain switch (S mu) region, 22 but its function related to IgM has not been well established.…”

Section: Discussionmentioning

confidence: 90%

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

et al. 2022

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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.

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“…Unexpectedly, the median BMI for patients who continued or discontinued PEG-asparaginase was comparable, despite the fact that a high BMI is a well-recognized risk factor for asparaginase-induced hepatotoxicity and thrombosis. 15 , 16 , 17 , 18 , 19 This may be related to the fact that asparaginase-induced hepatotoxicity and thrombosis are manageable and do not necessarily mandate permanent drug discontinuation; 1 thereby, asparaginase can be safely resumed with adequate precautions. 15 , 17 , 20 Alternately, certain toxicities (pancreatitis and hypersensitivity) that require permanent asparaginase discontinuation do not correlate with the patient’s weight.…”

Section: Discussionmentioning

confidence: 99%

The impact of early PEG-asparaginase discontinuation in young adults with ALL: a post hoc analysis of the CALGB 10403 study

et al. 2023

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Asparaginase is a key component of pediatric-inspired regimens in young adults with acute lymphoblastic leukemia (ALL). Truncation of asparaginase therapy is linked to inferior outcomes in children with ALL. However, similar correlation in adults is lacking. Here, we studied the prevalence and risk factors associated with pegylated (PEG)-asparaginase discontinuation in young adults with ALL treated on the US intergroup CALGB 10403 study and examined the prognostic impact of early discontinuation (ED) (defined as <4 of 5 or 6 planned doses) on survival outcomes. The analysis included 176 patients who achieved complete remission and initiated the delayed intensification (DI) cycle. The median number of PEG-asparaginase doses administered before DI was 5 (range: 1-6), with 57 (32%) patients with early discontinuation. The ED patients were older (median=26 vs. 23 years; P=0.023). Survival was apparently lower for ED patients compared with those receiving =/> 4 doses, but this finding was not statistically significant (HR=1.82; 95%CI: 0.97-3.43, P=0.06), with corresponding 5-year OS rates of 66% and 80%, respectively. In patients with standard-risk ALL, the early discontinuation of PEG-asparaginase adversely influenced OS (HR=2.3; 95%CI: 1.02-5.22, P=0.04) with a trend toward inferior EFS (HR=1.84; 95%CI: 0.92-3.67, P=0.08). In contrast, there was no impact of early PEG-asparaginase discontinuation on OS (P=0.64) or EFS (P=0.32) in patients with high-risk disease based on the presence of high-risk cytogenetics, Ph-like genotype, and/or high WBC at presentation. In conclusion, early PEG-asparaginase discontinuation is common in young adults with ALL and may adversely impact survival of patients with standard-risk ALL.

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Levocarnitine for pegaspargase‐induced hepatotoxicity in older children and young adults with acute lymphoblastic leukemia

Abstract: This is an open access article under the terms of the Creat ive Commo ns Attri bution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

Cited by 16 publications

References 39 publications

Hispanic ethnicity and the rs4880 variant in SOD2 are associated with elevated liver enzymes and bilirubin levels in children receiving asparaginase-containing chemotherapy for acute lymphoblastic leukemia

Hispanic ethnicity and the rs4880 variant in SOD2 are associated with elevated liver enzymes and bilirubin levels in children receiving asparaginase-containing chemotherapy for acute lymphoblastic leukemia

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

The impact of early PEG-asparaginase discontinuation in young adults with ALL: a post hoc analysis of the CALGB 10403 study

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