Abstract
Introduction: Hepatotoxicity is a challenging adverse event associated with acute lymphoblastic leukemia (ALL) therapy. Due to a lack of large, diverse, and well-characterized cohorts in pediatric ALL, factors predictive of therapy-related adverse events such as hepatotoxicity are not well understood. Here, we leveraged a data repository jointly developed between two large pediatric oncology treatment centers to assess the impact of host and disease-related factors on risk for liver dysfunction. Our aim was to better understand risk determinants of hepatotoxicity in patients risk-stratified to receive one of two potentially hepatotoxic regimens during their first interim maintenance (IM1) therapy phase.
Methods: All patients were treated for ALL between 2006-2014 at either Children's Hospital of Philadelphia (CHOP) or Texas Children's Hospital (TCH). We collected patient data by combining targeted manual abstraction and extensive semi-automated extraction of patient electronic medical record (EMR) data. Demographic information, disease-related data, and all laboratory values collected during treatment (along with age-related normal values) were obtained and stored in REDCap™ databases. To reduce cohort heterogeneity and better address our objective of understanding hepatotoxicity risk with standard ALL regimens, we removed patients who received non-standard ALL therapies. We separated the remaining patients into those who received more intensive IM1 therapy with high dose methotrexate ('HDMTX': 5grams/m2 intravenously over 24hrs q2 weeks x 4) vs. those who received less intensive therapy with Capizzi methotrexate ('Capizzi': dose escalation by 50 mg/m2 every 10 days x 5, starting at 100mg/m2). We restricted our analysis to liver-relevant labs obtained during this phase: AST (SGOT), ALT (SGPT), total bilirubin, conjugated bilirubin, and creatinine. Each was normalized as a ratio of the age-related upper limit of normal (ULN), and then each lab obtained throughout the phase was averaged across all patients within the two treatment groups. Multivariate mixed-effects linear regression with random effects was used to identify differences in each averaged lab value during IM1 related to the following covariates: race/ethnicity, sex, age, treating center, and overweight/obesity (yes/no). Significance cutoff: p <0.05
Results: Out of 923 ALL patients, 658 received IM1 as their third block of ALL therapy and were included for analysis. Mean age was 7.1 years, with those receiving HDMTX older than those receiving Capizzi, as expected (4.91 years vs. 10.03 years, p <0.0001). Non-Hispanic white patients comprised nearly 50% of patients, followed by Hispanic patients (35%), and the remaining Non-Hispanic black, Asian, and other each <10%. There was no difference between sex, treating center, or being overweight/obese between the Capizzi and HDMTX groups (Table 1). Both treatment intensity groups had mildly elevated mean transaminases (ALT, AST) during IM1 (Table 2), however the HDMTX group slightly higher transaminase averages than the Capizzi group (ALT: 2.72 vs. 2.42; AST: 1.70 vs. 1.22). For all patients, both mean bilirubin (total and conjugated) and mean creatinine were below the ULN. Analysis of all potential covariates identified that both race and age were significantly associated with higher ALT and AST, but only in the Capizzi group (Tables 3 and 4). Markedly, Hispanic patients treated with Capizzi were 2.5x more likely than non-Hispanic white patients to have higher ALT. There was no effect on bilirubin by any of the covariates.
Conclusions: This is the first comprehensive study of factors related to hepatotoxicity in a large and uniformly-treated cohort of pediatric patients of ALL. A wide distribution of liver function laboratory values was seen in IM1 for both Capizzi and HDMTX groups, with modest ALT and AST elevations noted but not bilirubin. Not surprisingly, HDMTX patients (who received both high-dose methotrexate and 6-mercaptopurine in IM1) did have slightly higher ALT/AST on average than those who received Capizzi. Race and/or age influence ALT and AST during IM1 for the Capizzi group only. Further studies are needed to delineate the temporal correlation of liver function changes in IM1 and, more broadly, all phases of therapy to predict toxicities, guide dose modifications, and help guide the incorporation of investigational agents into existing ALL regimens.
No relevant conflicts of interest to declare.
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