Abstract
Acute lymphocytic leukemia (ALL) is a hematologic malignancy commonly treated with pegasparaginase (PEG-ASP). Limited data exist on PEG-ASP-induced hepatotoxicity in the Saudi population; therefore, this study aimed to determine the rate and risk factors of PEG-ASP-induced hepatotoxicity in Saudi pediatric and adult ALL patients. This retrospective cohort study reviewed the records of ALL patients who had been treated with or received at least 1 dose of PEG-ASP between 2014 and 2021. Hepatotoxicity was graded using the Common Terminology Criteria for Adverse Events (CTCAE) Version 5. Bivariate and multiple logistic regression analyses were used to analyze the relationships between the variables and the risk of PEG-ASP-induced hepatotoxicity. A total of 368 patients were included in the study, with an overall hepatotoxicity rate of 38.8 (95% CI = 33.9–43.8) per 100 patients. Hepatotoxicity was observed in 35.7% (n = 117/328) of pediatric patients and 7.6% (n = 25/328) of adult patients. Risk factors of hepatotoxicity were identified: bilirubin level (odds ratio = 1.324, 95% CI = 1.089–1.610), presence of hyperdiploidy (OR = 1.456, 95% CI = 1.112–1.907), PEG-ASP dose (OR = 1.287, 95% CI = 1.021–1.623), and vincristine administration (OR = 1.398, 95% CI = 1.087–1.798). Additionally, the liver function test levels included alanine aminotransferase (OR = 1.512, 95% CI = 1.198–1.909), aspartate aminotransferase (OR = 1.445, 95% CI = 1.156–1.806), and gamma-glutamyl transferase (OR = 1.367, 95% CI = 1.089–1.716). PEG-ASP-induced hepatotoxicity poses a significant risk to Saudi patients with ALL. Further studies are needed to identify additional risk factors and improve the management of hepatotoxicity in ALL patients receiving PEG-ASP.
Keywords: acute lymphocytic leukemia, hepatotoxicity, pegasparaginase, Saudi population
1. Background
Acute lymphocytic leukemia (ALL) is a common heterogeneous hematologic malignancy characterized by a large number of differentiated lymphoid cells in the bone marrow, peripheral blood, and other organs.[1] The American Cancer Society estimated that about 6660 new cases of ALL (3740 in males and 2920 in females) and about 1560 deaths (880 in males and 680 in females) from ALL in 2022.[2] ALL cases occur mainly in children, with an incidence of 3 to 4/100,000 in children younger than 5 years of age and peak incidence at 2–5 years of age.[3] The risk of developing ALL in adults is lower and accounts for about 20% of ALL cases.[3] The main treatment for ALL in pediatric and adult patients is multiagent chemotherapy, of which pegasparaginase (PEG-ASP) is a key component.[4] Pediatric treatment regimens are increasingly being used in younger adult patients and have shown a higher cure rate in adult patients compared to the historic regimen, which used much less PEG-ASP.[5,6] PEG-ASP’s tolerability profile is well established by clinical trials and postmarketing use.[3]
PEG-ASP is associated with several adverse events, including hepatotoxicity, pancreatitis, thrombosis, and hypersensitivity. Among these, hepatotoxicity is the most frequently reported which is characterized by increased activated partial thromboplastin time, hypertriglyceridemia, hyperglycemia, and febrile neutropenia.[7,8] Hepatotoxicity is associated with more than 5% of reported adverse events, including elevated transaminases and increased bilirubin. Moreover, up to 40% of adults treated with pediatric-inspired regimens experience high-grade (grade 3 or 4) hyperbilirubinemia. This risk has been found to increase with age, high dosages, and obesity.[6,9,10] The German Multicenter Study Group for Adult ALL (GMALL) found that high dosages (above 1000 IU/m2) and patient age (>45 years) were associated with high-grade hyperbilirubinemia.[9] Another study that investigated ASP-associated hepatotoxicity identified both obesity and age (≥10 years) as risk factors for hepatotoxicity in children and adolescents.[11] In a study conducted in the United States by Cancer and Leukemia Group B, the study found that in the PEG-ASP group, toxicities occurred more frequently in the induction phase but less frequently in the post-remission therapy group.[5,6]
Compared to other hematologic malignancies, ALL poses a particular hepatotoxicity risk due to the central role of PEG-ASP in the treatment regimen. Additionally, ALL’s prolonged treatment duration and the necessary maintenance of PEG-ASP throughout multiple treatment phases contribute to cumulative hepatotoxicity. The risk of liver toxicity is magnified in adults, as hepatic metabolism and detoxification capacity decline with age, which makes elderly patients more vulnerable to severe hepatotoxicity.[5,9]
At the national level, only a few studies have explored pegasparaginase–related toxicities. Awwad et al conducted a single-center study in pediatric patients with ALL, reporting hepatotoxicity as one of the most frequent adverse events (31% of 191 patients).[7] More recently, Alrasheedi et al conducted a multicenter study focusing specifically on pegasparaginase–induced pancreatitis in pediatric patients with ALL.[12] Despite their contributions, both were limited to pediatric populations and/or restricted to specific toxicity types (i.e., pancreatitis), highlighting the need for broader, age-inclusive research focused on PEG-ASP induced hepatotoxicity. Therefore, the aim of this study is to investigate the rate and risk factors associated with PEG-ASP-induced hepatotoxicity in both adult and pediatric ALL patients in Saudi Arabia to provide valuable insights into its impact within this specific population.
2. Methods
2.1. Study design
This retrospective study involved a chart review of the electronic health records of patients diagnosed with ALL who were treated with PEG-ASP and had received at least 1 dose between 2014 and 2021. This study adheres to the STROBE (strengthening the reporting of observational studies in epidemiology) checklist, in line with the EQUATOR (enhancing the quality and transparency of health research) guidelines (Appendix 1, Supplemental Digital Content, https://links.lww.com/MD/R45).
2.2. Eligibility criteria
Patients diagnosed with ALL who were treated with PEG-ASP and had received at least 1 dose between 2014 and 2021 comprised the study population. This population included both adult (aged 18 and above) and pediatric (aged 0–17 years) patients, regardless of Philadelphia chromosome status.
2.3. Setting and subjects
The study was conducted in 2 tertiary hospitals in the Riyadh region, both of which are considered comprehensive cancer centers: the Ministry of National Guard Health Affairs (MNGHA) hospital and King Fahad Medical City. The study population included adult (aged 18 and above) and pediatric (aged 1–18 years) patients with ALL, regardless of Philadelphia chromosome status. Patients who were identified with preexisting liver problems (defined by ALT, AST, GGT, or total bilirubin ≥ 2 × upper limit of normal (ULN) before PEG-ASP administration) were not included in the analysis to avoid misclassification bias.
2.4. Main outcome measures
Hepatotoxicity was defined according to Common Terminology Criteria for Adverse Events (CTCAE) Version 5 as any of the following: alanine aminotransferase (ALT) or aspartate aminotransferase (AST) elevation ≥ 3 times the ULN, total bilirubin ≥ 1.5 times ULN, or gamma-glutamyl transferase (GGT) ≥ 2 times ULN. The primary outcome was the rate of hepatotoxicity after the first dose of PEG-ASP, defined by CTCAE V5.[13] The secondary measure was the identification of the potential risk factors associated with PEG-ASP-induced hepatotoxicity (demographic, clinical, and treatment factors).
2.5. Data collection
A local study site coordinator facilitated the recruitment and training of data collectors who used standardized data collection forms. Data collectors reviewed patient medical records to extract information on demographics (age at diagnosis, gender, height, weight), ALL diagnosis details (immunophenotype, Philadelphia chromosome status, CNS status, FISH abnormalities, MLL rearrangements, and hypo- or hyperdiploidy), and baseline LFTs (AST, ALT, total bilirubin, GGT, and neutrophil counts) were defined as those measured within 72 hours before the dose of PEG-ASP. Post-baseline LFTs were monitored within 14 days during the induction phase, after the PEG-ASP dose), which aligns with the PEG-ASP’s 5- to 7-day half-life to assess the hepatotoxicity risk. The use of concomitant hepatotoxic drugs was also reported (e.g., tyrosine kinase inhibitors and vincristine). Age was categorized into 6 groups: 1 to 11, 12 to 17, 18 to 29, 30 to 39, 40 to 60, and >60 years. These cutoffs were selected to reflect distinct clinical management phases, from young pediatric patients to elderly adults, and to allow for adequate subgroup comparisons based on the age distribution of the study population. Data verification methods included double-checking a subset of records for consistency and completeness. The data collection process was standardized through training sessions for all data collectors.
2.6. Ethical considerations
The study was approved by the institutional review boards of both centers: King Fahad Medical City (Ref. no. 22-331E) and the King Abdullah International Medical Research Center, which hosts the MNGHA institutional review board office (Ref.no. NRC22R/440/09).
2.7. Statistical analysis
The statistical analysis was performed using Python (Version 3.13). Descriptive analysis was conducted to measure the rate of hepatotoxicity per 100 patients screened, using means and standard deviations for continuous variables, and count and frequencies for categorical variables. Bivariate analysis and chi-squared (χ2) tests were used to analyze the correlations between the observed variables. Multiple logistic regression analysis was used to assess the association between 2 or more independent variables (e.g., gender) and the single dependent variable of PEG-ASP-related hepatotoxicity. Continuous laboratory parameters (bilirubin, ALT, AST, GGT) were included in the multivariable logistic regression model as continuous variables. Patients with confirmed hepatotoxicity with missing grades were categorized as “not reported” to evaluate the impact of missing values. Therefore, a sensitivity analysis was conducted assuming the worst-case scenario where all missing cases were considered as Grade 3 or higher toxicity. Odds ratios were interpreted as the change in odds of hepatotoxicity per 1-unit increase in the respective value (bilirubin (µmol/L), ALT, AST, GGT (U/L)). Variables with P-values of <0.05 at the bivariate level were included in the multivariate analysis. To maintain statistical power, T-ALL versus B-ALL, as well as Ph + and Ph− participants, were analyzed as covariates in multivariate models due to limited subgroup sizes to adjust for confounding.
3. Results
3.1. Characteristics of the study population
A total of 368 patients were included in the analysis: 58.7% (n = 216) were male, and 41.3% (n = 152) were female. All patients included were diagnosed with ALL, 15.2% (n = 56) of whom were diagnosed with T-cell ALL, and 84.7% (n = 312) with B-cell ALL. In most patients (88.3%; n = 341), the Philadelphia chromosome status was negative. After standardizing PEG-ASP doses by body surface area, patients receiving > 2000 IU/m2 showed significantly higher hepatotoxicity rates (22.5% vs 8.4% in controls; χ2=38.6, P < .001). Baseline liver function tests (LFTs) were obtained ≤ 72 hours pre-PEG-ASP administration, with all values falling within institutional normal ranges (ALT: 7–40 U/L; AST: 8–40 U/L; Bilirubin: 3–20 μmol/L; GGT: 9–48 U/L). The patients’ characteristics are summarized in Table 1. Age, dose, CNS status, the presence of hyperdiploidy, whether the patients received vincristine, and ALT, AST, GGT, and bilirubin baseline levels showed a significant association in the bivariate analysis and χ2 tests.
Table 1.
Patient characteristics.
| Variable | All patients (n = 368) | Developed hepatotoxicity (n = 142) | Did not develop hepatotoxicity (n = 226) | χ2 | P-value |
|---|---|---|---|---|---|
| Gender, n (%) | |||||
| Male | 216 (58.7) | 92 (64.7) | 124 (54.8) | 3.54 | .06 |
| Female | 152 (41.3) | 50 (3.5) | 102 (45.1) | ||
| Age (yr) at the time of diagnosis, (mean) ± SD | |||||
| <1–11 | (4.9) ± 2.94 | (4.75) ± 3.1 | (4.97) ± 2.88 | 2.11 | .83 |
| 12–17 | (14.1) ± 1.65 | (14.1) ± 1.65 | (14.3) ± 1.69 | ||
| 18–29 | (23.0) ± 3.7 | (23.8) ± 3.34 | (21) ± 4.14 | ||
| 30–39 | (32.7) ± 2.8 | (32.8) ± 3.59 | (32.8) ± 2.59 | ||
| 40–60 | (43) ± 4.2 | (40) ± 0 | (46) ± 0 | ||
| >60 | (62) ± 1.4 | (0) 0 | (62) ± 1.4 | ||
| BMI in kg/m2, (mean) ± SD | |||||
| Pediatric | (15.65) ± 3.29 | (82) ± 150 | 209 (70.9) ± 645.2 | 0.15 | .90 |
| Adults | (26.3) ± 3.7 | (13) ± 7.19 | 16 (26.4) ± 3.8 | ||
| Diagnosis, n (%) | |||||
| LBL | 16 (4.3) | 6 (4.2) | 10 (4.4) | 0.008 | .92 |
| Leukemia | 352 (95.6) | 136 (95.7) | 216 (95.5) | ||
| ALL immunophenotype, n (%) | |||||
| B-cell | 312 (84.7) | 118 (83.0) | 194 (85.8) | 0.5 | .48 |
| T-cell | 56 (15.2) | 24 (16.9) | 32 (14.1) | ||
| PEG-ASP dose (IU/m2) n (%) | |||||
| ≤1500 | 185 (50.3%) | 48 (33.8%) | 137 (60.6%) | 38.6 | .001** |
| 1501–2000 | 132 (35.9%) | 62 (43.7%) | 70 (31.0%) | ||
| >2000 | 51 (13.8%) | 32 (22.5%) | 19 (8.4%) | ||
| Ph status†, n (%) | |||||
| Positive | 27 (6.9) | 10 (7.0) | 17 (7.5) | 0.029 | .86 |
| Negative | 341 (88.3) | 132 (92.9) | 209 (92.4) | ||
| Central nervous system, n (%) | |||||
| Positive | 60 (16.3) | 16 (11.2) | 44 (19.4) | 4.29 | .03** |
| Negative | 308 (83.6) | 126 (88.7) | 182 (80.5) | ||
| Mutation, n (%) | |||||
| Positive | 267 (72.5) | 99 (69.7) | 168 (74.3) | 0.93 | .33 |
| Negative | 101 (27.4) | 43 (30.3) | 58 (25.6) | ||
| FISH abnormality, n (%) | |||||
| Positive | 267 (72.5) | 99 (69.7) | 168 (74.3) | 0.93 | .33 |
| Negative | 101 (27.4) | 42 (29.5) | 58 (25.6) | ||
| MLL rearrangement, n (%) | |||||
| Positive | 11 (2.9) | 5 (41.6) | 6 (2.6) | 0.22* | .70 |
| Negative | 357 (97.0) | 137 (96.4) | 220 (97.3) | ||
| Hypodiploidy, n (%) | |||||
| Positive | 3 (0.8) | 1 (0.7) | 2 (0.8) | 0.03* | 1.00 |
| Negative | 365 (99.1) | 141 (99.2) | 224 (99.1) | ||
| Hyperdiploidy, n (%) | |||||
| Positive | 104 (28.2) | 31 (21.8) | 73 (32.3) | 4.7 | .03** |
| Negative | 264 (71.7) | 111 (78.1) | 153 (67.6) | ||
| Prior stem cell transplant, n (%) | |||||
| Yes | 1 (0.2) | 1 (0.7) | 0 (0) | 1.59* | .38 |
| No | 367 (99.7) | 141 (99.2) | 226 (100.0) | ||
| Prior malignancy, n (%) | |||||
| Yes | 6 (1.6) | 4 (2.8) | 2 (0.8) | 2 | .21 |
| No | 362 (98.3) | 138 (97.1) | 224 (99.1) | ||
| Prior chemotherapy, n (%) | |||||
| Yes | 8 (2.1) | 4 (28.5) | 4 (1.4) | 0.45* | .49 |
| No | 360 (97.8) | 138 (97.1) | 222 (98.2) | ||
| Received vincristine, n (%) | |||||
| 5 d | 302 (82.1) | 106 (74.6) | 196 (87.7) | 7.84 | .005** |
| 6–10 d | 66 (17.9) | 36 (25.3) | 30 (13.2) | ||
| Received TKI, n (%) | |||||
| Imatinib | 11 (2.9) | 5 (3.5) | 5 (2.2) | 1.4* | .75 |
| Nilotinib | 1 (0.2) | 0 (0) | 1 (0.4) | ||
| Dasatinib | 4 (1.0) | 2 (0.8) | 2 (0.8) | ||
| None | 352 (95.6) | 135 (95.0) | 218 (96.4) | ||
| Baseline liver function test, median (IQR) | |||||
| ALT (U/L) | 28.5 (18–60) | 28.5 (18–60) | 25 (16–38.2) | W = 8555 | .001** |
| AST (U/L) | 27.5 (19–4 4) | 34 (19–54) | 24 (18–35) | W = 6727.5 | .002** |
| Bilirubin (μmol/L) | 4.8 (19–44) | 9.5 (4.5–13.15) | 3.4 (2.3–5.1) | W = 2326.5 | .001** |
| Albumin (g/L) | 37 (34.5–39) | 37 (34–39) | 37 (15–39.7) | W = 17285 | .15 |
| GGT (U/L) | 33.8 (16.2–102.7) | 79 (27–204) | 25.5 (14.7–63.5) | W = 284 | .004** |
| Neutrophil count | 0.52 (0.17–1.3) | 0.56 (0.20–1.2) | 0.44 (0.13–1.39) | W = 8444 | .29 |
ALL = acute lymphocytic leukemia, ALT = alanine aminotransferase, AST = aspartate aminotransferase, BMI = body mass index, FISH = fluorescence in situ hybridization, GGT = gamma-glutamyl transferase, IQR = interquartile range, LBL = lymphoblastic lymphoma, MLL = mixed-lineage leukemia, PEG-ASP = pegasparaginase, SD = standard deviation, TKI = tyrosine kinase inhibitors.
Philadelphia chromosome status.
Fisher exact test.
Statistically significant.
3.2. Rate of PEG-ASP-induced hepatotoxicity
A total of 142 (38.6%, 95% CI = 33.9–43.8) of the 368 patients developed hepatotoxicity. Of the 328 pediatric patients, 118 (32.0%, 95% CI = 27.4–36.9) developed hepatotoxicity, and of the 41 adult patients, 25 (6.78%, 95% CI = 4.6–9.8) developed hepatotoxicity. Among the patients who developed hepatoxicity and in which ALT and AST levels increased, grade 1 hepatoxicity occurred in most (16%, n = 60), followed by grades 2 (5.96%, n = 22) and 3 (5.15%, n = 19). Grade 4 toxicity developed in 1 patient (0.27%). Grade 1 toxicity occurred in most of the patients who experienced bilirubinemia (10.84%; n = 40), while the remainder experienced grade 2 (5.15%; n = 19), 3 (4.34%; n = 16), and 4 (1.36%; n = 5) toxicity. The transaminitis and hyperbilirubinemia grades are presented in Tables 2 and 3, respectively.
Table 2.
Transaminitis grades.
| Grade | N | % |
|---|---|---|
| 1 | 60 | 16.26 |
| 2 | 22 | 5.96 |
| 3 | 19 | 5.15 |
| 4 | 1 | 0.27 |
| Not reported* | 40 | 28.1 |
| Total | 142 | 100 |
Transaminitis occurred, but transaminitis grading was not reported.
Table 3.
Hyperbilirubinemia grades.
| Grade | N | % |
|---|---|---|
| 1 | 40 | 10.84 |
| 2 | 19 | 5.15 |
| 3 | 16 | 4.34 |
| 4 | 5 | 1.36 |
| Not reported* | 62 | 7.59 |
| Total | 142 | 100 |
Hyperbilirubinemia occurred, but hyperbilirubinemia grading was not reported.
Of 142 cases of hepatotoxicity, 40 cases were associated with transaminitis, and 62 with hyperbilirubinemia; however, the corresponding CTCAE grades were not reported. A sensitivity analysis, assuming the worst-case scenario, reclassified all “not reported” cases as high-grade, resulting in a grade 3 to 4 toxicity. Under this assumption, transaminitis increases the proportion of severity (grade 3 + 4) from 14.1% to 42.3%, and hyperbilirubinemia increases from 14.8% to 58.5% (Table 4). Therefore, under extreme conditions, the burden of toxicity may be significantly underestimated in the original analysis, but overall trends remain consistent.
Table 4.
Summary table: sensitivity analysis comparison.
| Toxicity type | Scenario | Severe cases (grade 3 + 4) | Total patients | % Severe |
|---|---|---|---|---|
| Transaminitis | Original | 20 | 142 | 14.08% |
| Worst-case | 60 | 142 | 42.25% | |
| Hyperbilirubinemia | Original | 21 | 142 | 14.79% |
| Worst-case | 83 | 142 | 58.45% |
3.3. Risk factors associated with PEG-ASP-induced hepatotoxicity
Of all 19 variables assessed in the univariable analysis, including PEG-ASP dose (P = .007), CNS status (P = .03), the presence of hyperdiploidy (P = .03), and vincristine administration (P = .005) showed a significant association with the development of hepatotoxicity. Multivariate analysis confirmed baseline (pretreatment) liver parameters as significant identifiers of the risk factors for hepatotoxicity, distinct from posttreatment elevations that define the onset of toxicity. For each 1 U/L increase in baseline ALT, hepatotoxicity risk rose 51.2% (OR = 1.512, 95% CI = 1.198–1.909), while a 1 μmol/L bilirubin increase conferred 32.4% higher risk (OR = 1.324, 95% CI = 1.089–1.610). Critically, baseline LFTs reflect hepatic reserve rather than drug-induced injury, explaining their predictive value. Hyperdiploidy remained an independent measure (OR = 1.456, 95% CI = 1.112–1.907), potentially linked to metabolic vulnerabilities in hyperdiploid ALL. Dose-response analysis revealed a 42% increased risk per 500 IU/m2 PEG-ASP dose escalation (OR = 1.42, 95% CI = 1.18–1.71), confirming BSA-adjusted dosing is essential for hepatotoxicity risk stratification, as presented in Table 5.
Table 5.
Risk factors of PEG-ASP-induced hepatotoxicity.
| Variable | Odds ratio | 95% CI | P-value | |
|---|---|---|---|---|
| CNS status | 0.891 | 0.654 | 1.214 | 0.46 |
| Bilirubin | 1.324 | 1.089 | 1.610 | .005* |
| Hyperdiploidy | 1.456 | 1.112 | 1.907 | .006* |
| PEG-ASP dose | 1.421 | 1.180 | 1.710 | .007* |
| Vincristine administration | 1.398 | 1.087 | 1.798 | .009* |
| ALT | 1.512 | 1.198 | 1.909 | .001* |
| AST | 1.445 | 1.156 | 1.806 | .001* |
| GGT | 1.367 | 1.089 | 1.716 | .007* |
ALT = alanine aminotransferase, AST = aspartate aminotransferase, CI = confidence interval, CNS = central nervous system, GGT = gamma–glutamyl transferase, PEG-ASP = pegasparaginase.
Statistical significance.
4. Discussion
This study investigated the rate of PEG-ASP-related hepatotoxicity in adult and pediatric patients with ALL in a Saudi population. We found that PEG-ASP-induced hepatotoxicity is common and affects 38% of patients following the first dose. Grade 1 hepatotoxicity, including transaminitis and hyperbilirubinemia, was found to affect most patients, with a few incurring high-grade hepatotoxicity (grades 3 and 4). Our study identified PEG-ASP doses, the presence of hyperdiploidy, vincristine administration, and levels of ALT, AST, GGT, and bilirubin as risk factors for the development of hepatotoxicity.
The findings of this study supported previous studies that highlighted associations between PEG-ASP-induced hepatotoxicity and increased ALT, AST, bilirubin, and GGT levels. Most notable is a study by Patel et al[8] that showed similar hepatotoxicity and elevated liver enzymes, especially in adults receiving high doses of PEG-ASP. What makes our finding novel is that it utilizes a large, multicenter Saudi cohort, integrating pediatric and adult cases, exploring clinical and cytogenetic parameters. We also report on a novel association between hyperdiploidy and hepatotoxicity that has not been previously reported. Our findings will lay the foundation for population-specific risk stratification and the need to further investigate genetically related toxicity to PEG-ASP.
Previous studies have documented a diverse range of hepatotoxicity rates associated with PEG-ASP use in pediatric and adult patients. The hepatoxicity observed in adult patients treated with PEG has been observed to range from 8% to 60%.[5,10,14–19] Our study reported a lower rate (7.6%), which is attributable to the low number of adult patients in our study cohort. In pediatric patients, our study reported a rate of 35%, which aligns with the rate reported by a recent single-center study in Saudi Arabia (30.4%)[7] as well as a study based in the United States, whose authors reported that 27% of patients developed hepatotoxicity.[11]
In our study, compared to the patients who developed grade 1 hepatotoxicity (transaminase 16% and hyperbilirubinemia 10%), we observed a lower percentage of Grade 3 (5% transaminase and 4% hyperbilirubinemia) and Grade 4 hepatotoxicity (0.2% transaminase and 1.3% hyperbilirubinemia). This result contrasts with the findings of previous studies, which have reported higher percentages of Grades 3 and 4 hepatotoxicity.[18,20] For example, in a single-center, retrospective study conducted at the University of Chicago Medicine, the authors found that 71% of adult patients treated with a pediatric-inspired adult regimen developed grades 3 and 4 hepatoxicity upon treatment with PEG-ASP.[18] Similarly, another study based in the United States reported that 55% of patients older than 40 years developed grades 3 and 4 hepatotoxicity.[20]
While previous findings from North America and East Asia highlighted age, BMI, and baseline bilirubin as key parameters for PEG-ASP hepatotoxicity.[9,14,18] Our findings show both consistencies and disparities. Associations were observed between elevated baseline bilirubin and hepatotoxicity, which indicates a potential role as a risk stratifier. However, unlike other reports that show age and obesity to have a significant clinical outcome toxicity, which in this case we observed no significant association in the Saudi cohort. This may suggest population differences in age distribution, genetic markers, and treatment protocols. Notable in this study is that our cohort had relatively fewer adults and obese patients, potentially underpowering the significance of BMI-related effects. Factors such as nutritional differences, co-morbidities, and drug metabolism across the study population may suggest these variations.
The relevance of this study to the Middle Eastern context, where the paucity of data on chemotherapy toxicity presents a challenge, and the lack of access to intensive monitoring and genetic testing presents an opportunity for low-cost parameters such as baseline bilirubin to be used in dosing strategy and monitoring. Our findings also suggest the need to adopt risk-adapted regimens that may justify the need for closer monitoring of LFT and hepatoprotective strategies in high-risk patients who do not have access to second-line asparaginase alternatives.
Our study identified the PEG-ASP dose and bilirubin levels as significant measures in the development of PEG-ASP-induced hepatotoxicity. This result is consistent with findings observed in previous studies on the risk factors associated with PEG-ASP-induced hepatotoxicity. Earlier studies have identified dose and age as risk factors for hepatotoxicity. The large, retrospective GMALL study identified dose and age (>45 years; P = .005) as independent factors of hepatotoxicity.[9] Furthermore, the same study reported that an increased level of bilirubin during the induction phase was correlated with a delayed inferior prognosis.[9] Similar findings were observed in cases where high PEF-ASP doses (i.e., 2000 IU) were associated with hepatotoxicity in newly diagnosed adult patients.[9] A recent study by Baek et al found that applying a capped dosing strategy for PEG has resulted in a comparable or delayed onset of most toxicities compared with uncapped dosing.[21] These findings suggest that dose capping may be a promising area for future research to optimize dosing and reduce treatment-related toxicity.
Additional studies that have investigated the risk factors associated with hepatotoxicity in children and adolescent patients have identified obesity and older age (≥10 years) as significant risk of hepatotoxicity.[11] Hypofibrinogenemia has been reported as a pharmacodynamic marker of hepatotoxicity in adult patients,[18] and body surface area (>2 m2), albumin level (<3 mg/dL), and platelet count (<50K) have also been identified as risk factors for hepatotoxicity;[19] however, the difference in age (pediatric vs adult) and PEG-ASP dose used in these studies impedes a direct comparison with our study. Notably, our study identified a correlation between the presence of hyperdiploidy DNA and the risk of hepatotoxicity, which, to the best of our knowledge, has not yet been investigated in published studies.[7,11,18–20] Hyperdiploidy has been identified as the most common cytogenetic abnormality pattern in childhood ALL (OR = 1.456, 95% CI = 1.112–1.907) and has been found to exhibit particular sensitivity to asparaginase.[22] Although the association has not been highlighted in published studies, we hypothetically deduced that hyperdiploid leukemic cells may exhibit or lead to an increased demand for protein synthesis, which heightens stress response during asparagine depletion. Hyperdiploidy is also associated with the CREBBP mutation,[22] which affects histone acetylation and also affects hepatic metabolic pathways, which may render the liver more vulnerable to drug-induced injury. Furthermore, an increase in tumor burden and metabolism in hyperdiploid ALL may lead to the release of hepatotoxic cytokines or oxidative stress mediators during cell lysis. Therefore, further studies in pharmacogenomics may be warranted to explore these associations. In addition, further evidence has highlighted the role of genetic predisposition in relation to PEG-ASP–induced hepatotoxicity.[23,24] Variants in genes involved in drug metabolism, such as GSTT1, GSTM1, and UGT1A1, have been associated with a higher risk of PEG-ASP hepatoxicity.[25] Further studies, particularly within the Saudi population are needed to confirm these associations and support personalized therapy strategies.
It’s important to note that the safety profile of PEG-ASP continues to evolve following the transition to Calaspargase pegol (CalPEG-ASP) for patients under 21.5 years of age in the United States.[26] CalPEG-ASP is a newer PEGylated formulation with a longer half-life, allowing less frequent dosing while maintaining efficacy and safety outcomes comparable to PEG-ASP.[27,28] Preclinical data further demonstrate similar hepatic effects between both agents.[29] Future research should investigate whether CalPEG-ASP provides any advantage in reducing hepatotoxicity or improving tolerability among pediatric and adult patients in Saudi Arabia.
This study was the first to investigate the rate of PEG-ASP-induced hepatotoxicity in pediatric and adult patients with ALL among a Saudi population over 7 years. The key strength of this study is the data obtained from 2 sites over a long period of time to obtain a valid and broad overview of the scale of PEG-ASP-induced hepatotoxicity in a Saudi population. Our study investigated several risk factors that have not been studied previously (i.e., FISH abnormality, MLL rearrangement, and hypo-and hyperdiploidy). However, this study has a number of limitations that must also be considered when interpreting its findings. The retrospective nature of our study did not allow us to assess all possible factors and, therefore, relied on the patient records’ documentation quality.[20] Our study retrieved data over a seven-year period, during which other factors might have affected the rate of toxicity. While this was a two-center study, its findings may not be generalizable to patients across Saudi Arabia. This study assessed hepatotoxicity after receiving PEG-ASP during the induction phase and did not assess the risk of hepatotoxicity in the consolidation and maintenance phases. Furthermore, pooling subtypes such as T-ALL versus B-ALL and pediatric versus adult patients may mask differential effects. Subgroup analyses are recommended in future larger studies. Patients who died before hepatotoxicity were not included in the study which may introduce survival bias. This exclusion could lead to an underestimation of the actual rate of hepatotoxicity. The absence of toxicity grade documentation in a proportion of cases is a limitation. It may have led to an underestimation of severe hepatotoxicity rates and limited our ability to explore grade-specific predictors, which highlighted that future studies will need to consider the importance of consistent toxicity grading.
5. Conclusion
We found that PEG-ASP-induced hepatotoxicity is prevalent among Saudi patients with ALL, especially in patients with elevated baseline bilirubin, hyperdiploidy, and higher doses of PEG-ASP. It also indicates the need to incorporate regular baseline liver function evaluation and cytogenic risk profiling in future treatment plans to identify patients at risk. This study serves as baseline evidence for ongoing assessments of hepatotoxicity associated with PEG-ASP use in Saudi patients with ALL. Future studies should evaluate diverse cohorts, evaluate pharmacogenetics predictors (e.g., UGT1A1 polymorphisms), and identify hepatoprotective interventions to decrease PEG-ASP toxicity. This will also aid in developing of national clinical guidelines tailored to patients with ALL in Saudi Arabia.
Acknowledgments
The authors would like to thank Raghad Alrashidi, Raghad Almutairi and Areej Alhanaya for their assistance in data collection.
Author contributions
Conceptualization: Ghadah H. Alshehri, Nada Alsuhebany, Mira M. Alhumaid, Reema H. Alanazi, Amani A. Alsetri, Shaher Bahakeem, Alaa A. Alhubaishi, Abdullah M. Alrajhi.
Data curation: Nada Alsuhebany, Mira M. Alhumaid, Reema H. Alanazi, Amani A. Alsetri, Ghaliah A. Aldamegh, Dalal T. Alangari, Abdullah M. Alrajhi.
Formal analysis: Shaher Bahakeem.
Funding acquisition: Ghadah H. Alshehri.
Investigation: Ghadah H. Alshehri, Nada Alsuhebany, Mira M. Alhumaid, Reema H. Alanazi, Amani A. Alsetri, Ghaliah A. Aldamegh, Dalal T. Alangari, Salwa S. Zghebi, Abdullah M. Alrajhi.
Methodology: Ghadah H. Alshehri, Nada Alsuhebany, Mira M. Alhumaid, Reema H. Alanazi, Amani A. Alsetri, Ghaliah A. Aldamegh, Dalal T. Alangari, Abdullah M. Alrajhi.
Project administration: Ghadah H. Alshehri, Alaa A. Alhubaishi.
Supervision: Ghadah H. Alshehri, Alaa A. Alhubaishi, Abdullah M. Alrajhi.
Validation: Ghadah H. Alshehri, Alaa A. Alhubaishi, Salwa S. Zghebi, Abdullah M. Alrajhi.
Writing – original draft: Ghadah H. Alshehri, Nada Alsuhebany, Shaher Bahakeem, Salwa S. Zghebi, Abdullah M. Alrajhi.
Writing – review & editing: Ghadah H. Alshehri, Nada Alsuhebany, Mira M. Alhumaid, Reema H. Alanazi, Amani A. Alsetri, Shaher Bahakeem, Ghaliah A. Aldamegh, Dalal T. Alangari, Alaa A. Alhubaishi, Salwa S. Zghebi, Abdullah M. Alrajhi.
Supplementary Material
Abbreviations:
- ALL
- acute lymphocytic leukemia
- ALT
- alanine aminotransferase
- AST
- aspartate aminotransferase
- BMI
- body mass index
- BSA
- body surface area
- CalPEG-ASP
- calaspargase pegol
- CNS
- central nervous system
- CTCAE
- common terminology criteria for adverse events
- DNA
- deoxyribonucleic acid
- EQUATOR
- enhancing the quality and transparency of health research
- FDA
- U.S. Food and Drug Administration
- FISH
- fluorescence in situ hybridization
- GGT
- gamma–glutamyl transferase
- GMALL
- German Multicenter Study Group for Adult ALL
- GSTT1/ GSTM1
- glutathione S-transferase theta 1/mu 1
- LFT
- liver function test
- MLL
- mixed-lineage leukemia
- MNGHA
- Ministry of National Guard Health Affairs
- PEG-ASP
- pegasparaginase
- Ph+/Ph−
- Philadelphia chromosome positive/negative
- STROBE
- strengthening the reporting of observational studies in epidemiology
- UGT1A1
- uridine diphosphate glucuronosyltransferase 1A1
- ULN
- upper limit of normal.
The research was funded by the Princess Nourah bint Abdulrahman University Researchers Support Initiative (PNURSP2025R352), Princess Nourah bint Abdulrahman University, Riyadh, Saudi Arabia.
The authors have no conflicts of interest to disclose.
The data that support the findings of this study are available from a third party, but restrictions apply to the availability of these data, which were used under license for the current study, and so are not publicly available. Data are available from the authors upon reasonable request and with permission of the third party.
Supplemental Digital Content is available for this article.
How to cite this article: Alshehri GH, Alsuhebany N, Alhumaid MM, Alanazi RH, Alsetri AA, Bahakeem S, Aldamegh GA, Alangari DT, Alhubaishi AA, Zghebi SS, Alrajhi AM. Pegasparaginase-induced hepatotoxicity in patients with acute lymphocytic leukemia in the Saudi population: A retrospective cohort study. Medicine 2026;105:1(e46640).
The views expressed in this paper are those of the author(s) and not do not necessarily reflect those of the Saudi Food & Drug Authority or its stakeholders. Guaranteeing the accuracy and the validity of the data is the sole responsibility of the research team.
Contributor Information
Ghadah H. Alshehri, Email: ghalshehri@pnu.edu.sa.
Nada Alsuhebany, Email: nalsuhebany@gmail.com.
Mira M. Alhumaid, Email: miraalhumaid@gmail.com.
Reema H. Alanazi, Email: rhbalanazi@gmail.com.
Amani A. Alsetri, Email: amanialsetri@gmail.com.
Shaher Bahakeem, Email: shmbahakeem@gmail.com.
Ghaliah A. Aldamegh, Email: ghaliah789@gmail.com.
Dalal T. Alangari, Email: dalalalangari22@gmail.com.
Salwa S. Zghebi, Email: Salwa.zghebi@manchester.ac.uk.
Abdullah M. Alrajhi, Email: abdullahalrajhi335@gmail.com.
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