Abstract
Background/Aim: Chemotherapy for acute leukemia includes agents known to cause hepatotoxicity. This study evaluated the role of monoammonium glycyrrhizinate for the prevention of hepatotoxicity after the first methotrexate-containing intrathecal chemotherapy (ITC) in children and adolescents with leukemia. Patients and Methods: Patients with newly diagnosed acute leukemia (age 0-18 years) who received ITC during the first week of induction therapy at our hospital between April 2016 and March 2021 were enrolled. Intravenous monoammonium glycyrrhizinate (IVMG) was defined as the intravenous administration of monoammonium glycyrrhizinate initiated on the day before or the day of the first ITC. Results: Overall, 39 of 118 patients (33%) developed grade 3-4 hepatotoxicity. The inverse probability of treatment weighting logistic regression model showed that IVMG was not associated with the development of grade 3-4 hepatotoxicity (OR=1.9, 95%CI=0.808-4.468). Conclusion: IVMG did not protect against the development of grade 3-4 hepatotoxicity after the first methotrexate-containing ITC for leukemia.
Hepatotoxicity is one of the common adverse effects of chemotherapy in patients with cancer (1-5). The clinical presentation and severity of hepatotoxicity vary widely, from asymptomatic laboratory abnormalities to liver failure. Standardized criteria developed by the National Cancer Institute (6) have been widely used to quantify the severity of treatment-related hepatotoxicity in patients receiving chemotherapy. The major mechanism of chemotherapy-related hepatotoxicity has been suggested to be the production of reactive metabolites through oxidation (7). Moreover, it has been suggested that prior liver disease, infection, supportive therapy, drugs, and radiation therapy contribute to liver injury during chemotherapy (5, 7).
Therapeutic regimens for acute leukemia usually consist of multiple agents with different mechanisms, and they include agents known to cause hepatotoxicity, such as methotrexate (MTX) and cytarabine (1-3). MTX is an antimetabolite drug, which is widely used for the treatment of various cancers. Intrathecal MTX administration is standard prophylactic therapy for central nervous system relapse in patients with acute leukemia, which induces greater systemic MTX exposure than systemic administration (8, 9). The major adverse effects of MTX include myelosuppression, mucocutaneous toxicity, and hepatotoxicity (10). High-dose or prolonged MTX therapy has been reported to be associated with liver injury (2) and can cause liver fibrosis and cirrhosis (2, 11).
Since severe hepatotoxicity can lead to dose reduction or discontinuation of chemotherapy (4), there seems to be a need to prevent chemotherapy-related hepatotoxicity. Several drugs have been investigated for the prophylaxis of chemotherapy-related hepatotoxicity (12, 13). Glycyrrhizic acid is a triterpene glycoside that is extracted from the root of the licorice plant (Glycyrrhiza glabra). A variety of pharmacological activities of glycyrrhizic acid have been reported, including anti-inflammatory, anti-viral, and anti-oxidative effects (14-17). Previous studies have also shown a protective effect of glycyrrhizic acid on drug-induced hepatotoxicity (18-20). Currently, there is little evidence regarding the prophylactic effect of glycyrrhizic acid on chemotherapy-related hepatotoxicity in patients with cancer. The aim of the study was to determine whether intravenous monoammonium glycyrrhizinate (IVMG) affects the development of hepatotoxicity after the first MTX-containing intrathecal chemotherapy (ITC) in children and adolescents with newly diagnosed acute leukemia.
Patients and Methods
Patients. A total of 122 consecutive patients aged between 0 and 18 years who received the first ITC during the initial week of induction therapy at the Kobe Children’s Hospital between April 2016 and March 2021 were enrolled in a retrospective cohort study. Patients with therapy-related myeloid neoplasms, prior treatment for leukemia before admission, grade 3-4 hepatotoxicity at diagnosis of leukemia, or early death during the first week of induction therapy were excluded. Patients who received oral or intravenous glycyrrhizinate more than two days prior to the day of the first ITC were also excluded. The baseline characteristics of the patients and information on the use of concomitant drugs during the first week of induction were obtained from the patients’ medical records.
Definitions. Body surface area (BSA) was calculated using the Mosteller formula [BSA (m2)=square root of (height (cm)×weight (kg)/3,600)]. IVMG was defined as the intravenous administration of monoammonium glycyrrhizinate (27 to 53 mg/BSA) initiated on the day before or the day of the first ITC. Hepatotoxicity was defined as an increased serum total bilirubin, aspartate aminotransferase (AST), or alanine aminotransferase (ALT) level, according to the Common Terminology Criteria for Adverse Events, Version 5.0 (6).
Chemotherapy and supportive therapy. The first ITC consisted of MTX (for age 1 year 8 mg, 2 years 10 mg, 3 years or older 12 mg) for patients with acute lymphoblastic leukemia (ALL). For patients younger than 1 year with ALL, MTX (for age 2 months or younger 3 mg, 3-11 months 6 mg), cytarabine (for age 2 months or younger 6 mg, 3-11 months 15 mg), and hydrocortisone (10 mg) were used for ITC. Similarly, the first ITC consisted of MTX (for age 2 months or younger 3 mg, 3-11 months 6 mg, 1 year 8 mg, 2 years 10 mg, 3 years or older 12 mg), cytarabine (for age 2 months or younger 6 mg, 3-11 months 15 mg, 1 year 20 mg, 2 years 25 mg, 3 years or older 30 mg), and hydrocortisone (for age 11 months or younger 10 mg, 1 year 15 mg, 2 years 20 mg, 3 years or older 25 mg) for patients with acute myeloid leukemia (AML). During the first week of induction, patients with ALL received prednisolone, and patients with AML received etoposide, cytarabine, and mitoxantrone, in addition to ITC. All patients received intravenous granisetron prophylactically twice daily on the day of chemotherapy. Trimethoprim/sulfamethoxazole was used for prophylaxis of pneumocystis pneumonia in all patients. Selection of additional supportive therapy including antibiotics, antifungal agents, prevention of tumor lysis syndrome, and IVMG was determined by the attending physicians.
Statistical analysis. The primary outcome was the development of grade 3-4 hepatotoxicity during the week after the first ITC. The characteristics of patients were compared between patients with and without the development of grade 3-4 hepatotoxicity, using the Mann-Whitney U-test for quantitative variables, and the chi-squared test and Fisher’s exact test for qualitative variables. The risk difference and risk ratio with 95% confidence intervals (CIs) between patients with and without IVMG were calculated for the development of grade 3-4 hepatotoxicity. All patients included in the analysis were used as the standard population to estimate the standardized risk difference and risk ratio. A multivariate logistic regression model was used to assess the association between IVMG and the development of grade 3-4 hepatotoxicity. The number of covariates examined in the model was determined by the number of outcome events, with 10 events required for one covariate (21). In addition, age, sex, diagnosis, initial peripheral white blood cell count, concomitant drugs, and baseline serum bilirubin, AST, and ALT levels were included in another logistic regression model to calculate the propensity score for the probability of a patient receiving IVMG (22). The inverse probability of treatment weighting (IPTW) method based on the inverse propensity score was used to adjust for potential baseline confounders (23). After IPTW adjustment, a univariate logistic regression analysis was performed to investigate the effect of IVMG on the development of grade 3-4 hepatotoxicity. A p-Value of less than 0.05 was considered significant; all tests were two-tailed. All statistical analyses were performed using Stata/SE version 16.1 (StataCorp, College Station, TX, USA).
Ethical considerations. This study was approved by the Institutional Review Board of Kobe Children’s Hospital (approval number: R3-12) and conducted in accordance with the Ethical Guidelines for Medical and Health Research Involving Human Subjects of the Ministry of Health, Labour and Welfare, Japan.
Results
The process of patient enrollment is shown in Figure 1. Overall, 4 patients were excluded from the analysis. A total of 118 patients were included in the analysis. The baseline characteristics of patients are summarized in Table I. The median age at diagnosis was 5 years [interquartile range (IQR)=3-11 years]. Patients with acute mixed lineage leukemia (n=2) received the same chemotherapy including ITC during the first week of induction as patients with ALL. Of the 118 patients, 53 (45%) received IVMG. The median age was similar between patients with IVMG (IVMG group) and those without IVMG (non-IVMG group). The proportion of females was lower in the IVMG group than in the non-IVMG group.
Patient enrollment process. ITC, Intrathecal chemotherapy.
Characteristics of patients.
Incidence and risk of grade 3-4 hepatotoxicity. During the week after the first ITC, 39 patients (33%) developed grade 3-4 hepatotoxicity. Grade 3-4 AST and ALT elevations were observed in 29 (25%) and 39 (33%) patients, respectively. No patients developed grade 3-4 hyperbilirubinemia. The median onset of grade 3-4 hepatotoxicity was 3 (IQR 2-4) days after the first ITC. In the IVMG group, 22 patients (42%) had grade 3-4 hepatotoxicity, whereas 17 patients (26%) experienced grade 3-4 hepatotoxicity in the non-IVMG group. Table II shows the comparison of the characteristics between patients with and without grade 3-4 hepatotoxicity during the week after the first ITC. A higher proportion of patients younger than 10 years developed grade 3-4 hepatotoxicity (82% vs. 58%, p=0.010). There were no significant differences in sex, diagnosis, initial peripheral white blood cell count, baseline laboratory data, drugs used in ITC, and concomitant drugs between patients with and without grade 3-4 hepatotoxicity during the week after the first ITC.
Comparison of characteristics of patients with and without grade 3-4 hepatotoxicity during the week after the first ITC.
Association between IVMG and hepatotoxicity. The crude risk difference between the IVMG group and the non-IVMG group for the development of grade 3-4 hepatotoxicity during the week after the first ITC was 0.154 (95% CI=–0.017-0.324). The crude risk ratio for the development of grade 3-4 hepatotoxicity during the week after the first ITC was 1.587 (95% CI=0.945-2.666). After age group (<10 vs. ≥10 years) standardization, the standardized risk difference was 0.172 (95% CI=0.008-0.336), and the standardized risk ratio was 1.670 (95% CI=1.011-2.760) between the 2 groups. On multivariate logistic regression analysis, IVMG was associated with the development of grade 3-4 hepatotoxicity when adjusted for age group (<10 vs. ≥10 years) and diagnosis (adjusted odds ratio (OR)=2.300, 95% CI=1.015-5.213, p=0.046) (Table III). The IPTW-adjusted model showed that IVMG was not associated with the development of grade 3-4 hepatotoxicity (OR=1.900, 95% CI=0.808-4.468, p=0.141).
Adjusted association between IVMG and the development of grade 3-4 hepatotoxicity during the week after the first ITC.
Discussion
In the present study, IVMG was not associated with prevention of grade 3-4 hepatotoxicity after the first MTX-containing ITC in children and adolescents with newly diagnosed acute leukemia. Patients with IVMG were even at higher risk of grade 3-4 hepatotoxicity. These findings were confirmed in both crude and adjusted analyses. There was also a relatively high incidence of grade 3-4 hepatotoxicity after the first MTX-containing ITC in these patients. Overall, 33% of patients developed grade 3-4 hepatotoxicity. It should be noted that there has been little information on liver injury after ITC in leukemia treatment, although ITC with MTX has played a role in the evolution of treatment for pediatric leukemia (24). In addition, younger age was a potent risk factor for the development of hepatotoxicity after the first MTX-containing ITC.
The strengths of this study are the description of chemotherapy-related hepatotoxicity during the early phase of treatment for leukemia, and the identification of a possible association between age and development of chemotherapy-related hepatotoxicity. This study is distinct from most previous studies on the prophylaxis of chemotherapy-related hepatotoxicity in patients with leukemia, in that the prevention of hepatotoxicity was examined during the early phase of induction therapy. For patients receiving maintenance therapy for ALL, several randomized, controlled studies have shown the effectiveness of drug intervention in preventing chemotherapy-related hepatotoxicity (12, 13). Previous reports have suggested that oxidative stress and elevation of proinflammatory cytokines contribute to the pathogenesis of MTX-induced liver injury (25, 26). Given that the intensity of therapy is higher in induction than in maintenance therapy and that an association between proinflammatory cytokines and acute leukemia has been suggested (27, 28), patients with leukemia may be at higher risk of hepatotoxicity at the beginning of induction therapy. Since there is limited information on the prevention of chemotherapy-related hepatotoxicity during the early treatment course in patients with leukemia (29), the clinical significance of hepatotoxicity and its prophylaxis in this period should be clarified. Additionally, reports on chemotherapy-related liver injury in patients with AML have also been scarce (30). The present results showed a similar incidence of grade 3-4 hepatotoxicity after the first MTX-containing ITC between patients with AML and those with ALL.
Younger age (<10 years) was found to be associated with the development of hepatotoxicity after the first MTX-containing ITC in this study. Combination therapy with biological agents, obesity, and hypercholesterolemia were shown to be risk factors for transaminase elevation in patients with rheumatic diseases receiving MTX (31, 32). Interestingly, a retrospective study of children and adolescents with ALL reported that older age (≥10 years) was identified as a predictor of grade 4 hepatotoxicity during the ALL treatment course (33). It is difficult to explain the difference in the effect of age between the present results and prior findings, because there are many differences between the studies, especially with regard to length of the observation period (33). Considering age-related pharmacokinetics observed in ITC with MTX and high-dose MTX therapy (34-36), the present results may also suggest the impact of age on the development of MTX-induced hepatotoxicity.
The weaknesses of this study lie in the retrospective and its observational nature. The hospital-based population is the primary major limitation, which makes it hard to predict whether the findings are common to all children and adolescents with acute leukemia. The relatively small patient number is also a major limitation of the study, which may limit the power to detect significant differences. Additionally, the small number of outcome events in our patients limited the number of covariates that could be included in the model. Another key limitation is that the observed differences in the risk of the primary outcome between the two groups could be attributed to confounding from other factors. Although the IPTW method was used to balance baseline characteristics, it does not account for unmeasured confounding factors. Despite these limitations, the present study provides useful information for the management of hepatotoxicity in patients with childhood acute leukemia.
In conclusion, IVMG did not prevent the development of grade 3-4 hepatotoxicity after the first MTX-containing ITC in children and adolescents with newly diagnosed acute leukemia. The incidence of grade 3-4 hepatotoxicity after the first MTX-containing ITC was relatively high. Further studies are needed to determine the optimal prophylaxis of chemotherapy-related hepatotoxicity in patients with leukemia.
Footnotes
Authors’ Contributions
Dr. Kishimoto conceptualized and designed the study, carried out the initial analyses, drafted the initial manuscript, and critically reviewed the manuscript for important intellectual content. Dr. Uemura, Dr. Nakamura, Dr. Kozaki, Dr. Saito, Dr. Ishida, and Dr. Mori collected data, and reviewed and revised the manuscript. Dr. Hasegawa and Dr. Kosaka conceptualized and designed the study, coordinated and supervised data collection, and reviewed and revised the manuscript. All Authors approved the final manuscript as submitted and agree to be accountable for all aspects of the work.
Conflicts of Interest
The Authors have no conflicts of interest to declare that are relevant to the content of this article.
- Received August 9, 2021.
- Revision received August 28, 2021.
- Accepted September 28, 2021.
- Copyright © 2021 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.
References
In this issue
Jump to section
Related Articles
Cited By...
- No citing articles found.