Page 177 - Haematologica May 2022

Letters to the Editor
A report from the Leukemia Electronic Abstraction of Records Network on risk of hepatotoxicity dur- ing pediatric acute lymphoblastic leukemia treat- ment
The objective of this work was to identify determi- nants of treatment-associated hepatotoxicity (TAH) in a diverse population of 782 children with acute lym- phoblastic leukemia (ALL). Based on extracted electronic medical record data, nearly all subjects experienced mild- ly elevated hepatic laboratory values (HL), particularly those given high-intensity treatment. Furthermore, 15.9% of subjects experienced TAH in at least one post- induction treatment phase, which was associated with increased body mass index, but did not affect relapse-free survival.
While modern treatment for childhood ALL confers excellent survival,1 30-50% of children experience at least one serious adverse event during upfront ALL treatment.2 TAH may be related to a number of ALL therapeutics, e.g., asparaginase, antimetabolites, and anthracyclines. The reported incidence of TAH in pediatric ALL is highly variable, likely due to inconsistent defining criteria and data-capturing methods.3-10
To comprehensively characterize the impact of ALL therapy on HL and the treatment phase-specific inci- dence of TAH, we leveraged data from the Leukemia Electronic Abstraction of Records Network (LEARN). LEARN is a multi-institutional collaboration and child- hood leukemia data repository that includes comprehen- sive demographic, anthropometric, diagnostic, treatment, laboratory, and outcome data. Given evidence for racial and ethnic disparities in childhood ALL outcomes and survival11 and the historic under-representation of chil- dren from minority groups in pediatric cancer trials,12 LEARN was constituted by institutions with highly diverse patient populations. LEARN relies on automated extraction of electronic medical record data after manual input of basic data, an ascertainment method which sig- nificantly improves reporting accuracy of laboratory adverse events.13 Here, we utilized LEARN data to assess HL changes by treatment phase and intensity, determin- ing the incidence of TAH, its risk determinants, and its impact on patients’ outcomes.
Our study utilized LEARN data from children (ages 1- 21 years) diagnosed with ALL and treated at Texas Children’s Cancer and Hematology Centers (TXCH) or the Children’s Hospital of Philadelphia (CHOP) between 2006 and 2014. Children with infant ALL and Down syn- drome were excluded, as were those who received part of their induction at another institution, did not complete induction, received non-standard agents or sequence of chemotherapy and/or a tyrosine kinase inhibitor, or underwent stem cell transplantation. Trained personnel manually populated a REDCapTM database with select data from the TXCH and CHOP electronic medical records, including date on diagnosis, dates of starting and ending chemotherapy courses, and risk stratification. Using the REDCapTM Application Programming Interface, we then auto-extracted demographic and laboratory data from each electronic medical record data warehouse. Manually-entered dates guided extraction by providing boundaries over which the data were extracted, enabling linkage of extracted data with a specific chemotherapy phase. Demographic data, disease characteristics, and HL were collected using a combination of targeted manual abstraction and extensive automated extraction from each institution’s electronic medical records.
HL included alanine aminotransaminase, aspartate aminotransferase, and total and conjugated bilirubin, normed to the age-based upper limit of normal (ULN). TAH was determined by the following criteria: (i) grade 4 transaminitis by the Common Toxicity Criteria of Adverse Events (CTCAE) v5.0, defined as alanine amino- transaminase or aspartate aminotransferase >20xULN; (ii) grade 3 hyperbilirubinemia by the CTCAE, defined as total bilirubin >3xULN, or (iii) conjugated bilirubin ≥1.2 mg/dL. TAH was defined based on established Children’s Oncology Group thresholds for dose modification con- siderations during ALL therapy. Each subject was catego- rized as having received high or standard-intensity treat- ment by phase, with high-intensity defined by inclusion of anthracycline (induction), cyclophosphamide (consoli- dation), and mercaptopurine (interim maintenance 1). Subjects were assigned final treatment intensity based on National Cancer Institute’s diagnostic criteria and interim maintenance 1 treatment assignment.
Distributions of categorical characteristics and median age were compared by treatment intensity using c2 analy- ses and the Wilcoxon rank sum test, respectively. Median normed HL values were compared by treatment intensity for each treatment phase using the Wilcoxon rank sum test. Multivariable logistic regression models of factors influencing post-induction TAH and recurrent/persistent TAH (defined as TAH in 2 or more treatment phases) were performed. Cox regression models were used to cal- culate hazard ratios (HR) and 95% confidence intervals (95% CI) to compare overall and relapse-free survival in subjects with no TAH relative to those with any TAH, considered as a time-varying exposure introduced on the day of first documentation. All multivariable analyses were adjusted for treatment intensity, age at diagnosis, race/ethnicity, gender, body mass index, ALL immunophenotype, and end-induction minimal residual disease. Covariates were selected a priori, based on our hypotheses and clinical experience, and were included in all analyses. P-values <0.05 were considered statistically significant. Statistical analyses were performed using Stata 15.0 (StataCorp LP, College Station, TX, USA).
Of 921 eligible patients, 782 met the inclusion criteria. Demographic, diagnostic, and disease characteristics of included subjects are shown in Table 1 by induction treatment intensity. Approximately one-third were Latino, 9% Black, 5% Asian, and the remainder were White. Subjects assigned to high-intensity induction were more likely to be overweight or obese (P<0.001), possibly reflecting older mean age (10.6 years vs. 4.6 years). Data on end-induction minimal residual disease were available for 681 of 782 subjects, of whom 22% (n=149) were positive for minimal residual disease, repre- senting 17% (n=60) of subjects given standard-intensity treatment and 29% (n=89) of those given high-intensity treatment.
A mean of 139.5 HL were obtained per subject. There were a greater number of HL for patients given high- intensity treatment than for those given standard-inten- sity treatment (148.9 vs. 129.3, P<0.001). The number of subjects analyzed per phase varied over time and by treatment intensity: induction, n=782; consolidation, n=691; interim maintenance 1, n=643; delayed intensifi- cation, n=625; interim maintenance 2, n=235; and main- tenance, n=571. Over 80% of subjects had a HL >ULN during at least one treatment phase, with the values being mostly 1-3xULN (Figure 1A-D). Alanine amino- transaminase was the most consistently and markedly elevated HL throughout all phases (Figure 1A). Total and conjugated bilirubin remained within normal limits for
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