Changes in asparaginase exposure and toxicity profiles in obese pediatric acute lymphoblastic leukemia patients

Pegaspargase is an important component in the treatment of acute lymphoblastic leukemia (ALL) but is associated with several toxicities including pancreatitis, hepatotoxicity, and thrombosis which can lead to discontinuation and delays in other chemotherapy.¹ In pediatric and adult patients, obesity has been identified as a risk factor for pegaspargase-associated toxicity.^2,3 In addition to obesity, age >10 years was also identified as a risk factor for toxicity in pediatric patients.² T o mitigate concerns over toxicity, studies have capped pegaspargase doses at 3,750 IU.⁴ In the St. Jude Children’s Research Hospital Total XVI trial, a randomized study of pegaspargase doses 2,500 IU/m² versus 3,500 IU/m², higher doses did not increase rates of missed doses or frequency of pancreatitis, thrombosis, osteonecrosis, or hepatotoxicity.⁵ This suggested that higher asparaginase doses can be given to pediatric patients without increasing risk of toxicity. To explore the rationale behind capping doses, we retrospectively evaluated whether obesity impacted pegaspargase pharmacokinetics, probability of asparaginase-related toxicities, or treatment efficacy (measured by minimal residual disease [MRD] at day 15, MRD at the end of induction [EOI], and event-free survival [EFS]) within the Total XVI study population during induction and continuation. Our findings demonstrate that pegaspargase clearance was significantly decreased in obese individuals relative to non-obese individuals (5.3%; P=0.006). However, pegaspargase exposure, frequency of toxicities, and treatment efficacy were not different between obese and non-obese individuals.

Children (N=598) with newly diagnosed ALL were enrolled in St Jude Children’s Research Hospital Total XVI protocol study from September 2007 to March 2017 (ClinicalTrials. gov identifier: NCT00549848). Approved by the institutional review board, consent was obtained from patients and parents/guardians in accordance with the Declaration of Helsinki. Details of this trial have been previously described.⁶ Patients less than 2 years old were excluded from this retrospective analysis. Chi-square and exact tests were used to compare the frequency of obese patients by toxicity. Simple and multiple logistic regression models controlling for body mass index (BMI), final risk, age at diagnosis, randomization arm, and immunophenotype were estimated to determine the odds of toxicity given BMI at the beginning of induction or continuation. Toxicities were prospectively graded based on Common Terminology Criteria for Adverse Events, version 3. We subdivided age at 9 years old when evaluating osteonecrosis because individuals 9 years old and older were prospectively screened with magnetic resonance imaging. Pegaspargase activity data from 564 of 598 patients enrolled in the Total XVI study were available and used to determine individual asparaginase pharmacokinetic parameter estimates.⁵ The population pharmacokinetics were summarized previously.⁵

A summary of patients’ characteristics stratified by obesity status is shown in Table 1. There were significant differences in age and final risk classification, with a higher percentage of overweight and obese individuals among the older patients (≥10 years old) and those classified as standard or high risk. During induction therapy, clearance of the first pegaspargase dose did not differ based on obesity status (309.4 vs. 303.1 vs. 299.6 vs. 307.1 mL/day/m² in normal weight, obese, overweight, and underweight individuals, respectively; P>0.1). Additionally, the estimated day 14 asparaginase activity did not differ based on obesity status (1.06 vs. 1.1 vs. 1.1 vs. 1.1 IU/ mL in normal weight, obese, overweight, and underweight individuals, respectively; P>0.1).

During re-induction therapy asparaginase pharmacokinetics were determined at weeks 7 and 17 of continuation. After controlling for various covariates (therapy timepoint, asparaginase dosage, age, antibody status, adverse events to asparaginase, randomization arm, and final risk) pegaspargase clearance was significantly lower in obese (220.7 vs. 233.8 mL/day/m² or 5.3%; P=0.006) and overweight (222.5 vs. 233.8 ml/day/m² or 4.5%; P=0.005) patients compared to the normal weight group (Table 2). However, pegaspargase exposure was not significantly different in either obese or overweight groups compared to the normal weight group (asparaginase day 14 activity: 1.08 vs. 1.12 vs. 1.13 IU/mL in normal weight, obese, and overweight individuals, respectively; P>0.1 and asparaginase area under the curve: 23.5 vs. 23.8 vs. 24.4 IU day/mL in normal weight, obese, and overweight individuals, respectively; P>0.08).

We did not observe differences in pancreatitis (grade ≥2) relative to BMI classification (Table 3). Specifically, in multivariable analysis, when controlling for risk classification, randomization arm, age and BMI classification, only risk classification was associated with significantly higher odds of pancreatitis (standard/high risk vs. low risk odds ratio [OR]=5.55; P=0.0088). No differences were observed in hyperbilirubinemia rates (grade ≥3 or ≥4) during remission induction or continuation therapy relative to BMI classification (Table 3). Additionally, there were no significant differences in rates of high alanine aminotransferase (grade ≥3) in remission induction while there was a significantly higher rate in overweight and obese individuals (P=0.042) (Table 3) during continuation. In multivariable analysis, only age ≥10 years was significantly associated with grade ≥4 hyperbilirubinemia during continuation (OR=46.6; P=0.0049). BMI classification was not significantly associated with increased odds of hyperbilirubinemia or high alanine aminotransferase levels when controlling for risk group, randomization arm, and age. During continuation therapy, the rate of osteonecrosis did not differ significantly between overweight or obese individuals and normal individuals: 13 of 202 (6.4%) versus 21 of 336 (6.3%), respectively (P=0.93) (Table 3). The odds of osteonecrosis (grade ≥2) were higher in standard/high-risk individuals than in low-risk ones (OR=4.971; P=0.0011) and individuals ≥9 years old compared to those <9 years old (OR=16.5; P<0.0001). However, controlling for these factors, BMI classification was not significantly associated with osteonecrosis.

Table 1.Patients’ characteristics, subdivided by body mass index classification.

Rate of grade ≥3 thrombosis did not differ significantly by obesity status during either remission induction or continuation therapy (Table 3). Instead, thrombosis (grade ≥3) was more common in T-cell ALL than in B-cell ALL during remission induction (OR=3.438; P=0.0239) and in individuals ≥10 years old than in those <10 years old during continuation therapy (OR=6.461; P<0.0001). However, controlling for these factors, BMI classification was not significantly associated with thrombosis.

We observed that the cumulative frequency of pegaspargase doses and the percentage of protocol-defined pegaspargase doses given were not significantly different between obese and normal weight individuals (P=0.11 and P=0.59, respectively). A higher percentage of individuals ≥10 years old were MRD positive at day 15 (25.8% vs. 8.9%; P=0.022) and at the EOI (17.6% vs. 10.4%; P=0.022) as compared to those <10 years old. Controlling for age, obesity status was not associated with differences in either day 15 or EOI MRD status.

Table 2.Mixed effects model of the effect of body mass index on asparaginase clearance (mL/day/m²) during re-induction therapy, accounting for covariates.

The 10-year EFS rate was higher in individuals <10 years old than in those older (10-year EFS: 92.8%, 95% confidence interval [95% CI]: 89.6%-95.1% vs. 79.1% [95% CI: 71.9%-84.7%], respectively; P<0.0001) and in low-risk individuals compared to standard/high-risk ones (10-year EFS: 96.7% [95% CI: 93.4%-98.3%] vs. 82.7% [95% CI: 77.8%-86.6%]; P<0.0001). However, EFS was not significantly different based on obesity status when controlling for age and risk status.

This study revealed a significant decrease in pegaspargase clearance in obese individuals compared to non-obese individuals (5.3%). We are unable to determine a reason to explain this difference in clearance for obese individuals. This alteration in pharmacokinetics did not result in a clinically significant increase in pegaspargase exposure, efficacy or toxicity, as evidenced by the similar activity and absence of a rise in pegaspargase-related toxicities in the obese group. Additionally, obesity status was not associated with a difference in day 15 MRD, EOI MRD, or EFS.

Asparaginase-related toxicities can potentially delay or truncate asparaginase therapy, which has been linked to lower EFS rates.^1,7 Our previous analysis demonstrated no disparity in the number of pegaspargase doses or treatment outcomes between those receiving 2,500 vs. 3,500 IU/m².⁵,⁶ In our current analysis we have also shown no decline in cumulative asparaginase dosing or EFS in obese individuals compared to their normal weight counterparts.

Several adult studies have shown a higher BMI associated with hyperbilirubinemia, more missed treatment, and lower rates of complete remission.³,⁹ Additionally, in adults, a dose-dependent relationship has been found between pegaspargase dose and rates of grade ≥3 toxicities, particularly in individuals with a BMI ≥25 kg/m² receiving pegaspargase doses >1,000 IU/m² compared to those receiving doses <1,000 IU/m².¹⁰

Several pediatric studies have also reported higher rates of hyperbilirubinemia, pancreatitis, and thrombosis in obese compared to non-obese pediatric patients, although in most cases, this observation was based on the overall rates of toxicities rather than specifically related to asparaginase treatment.^2,8,11,12 It has also been shown that pediatric patients who received more than 3,750 IU of pegaspargase (with 16.7% being obese) had higher incidences of venous thromboembolism, pancreatitis, and hyperglycemia.¹³ However, Kloos et al. found no statistically significant correlation between pancreatitis, central neurotoxicity, thrombosis, triglyceride levels and asparaginase levels.¹⁴ Dharia et al. reported a higher odds ratio of pancreatitis, thrombosis and hyperbilirubinemia with pegaspargase in overweight or obese patients, although this was not statistically significant, aligning with our results.¹⁵

Table 3.Asparaginase toxicities by body mass index category.

Based on results of this study in patients receiving treatment on the Total XVI protocol, we do not recommend capping pegaspargase dose. Instead, we advocate monitoring both asparaginase activity and related toxicities and considering adjustments of dose and/or schedule if either the predicted activity at day 14 falls outside a predefined range (e.g., 0.1-1 IU/mL) or if toxicities are observed.

In conclusion, our previous study showed no difference in toxicity between pegaspargase doses of 2,500 and 3,500 IU/ m² and the current study showed no difference in toxicity or efficacy based on obesity status. Therefore, our study does not support capping asparaginase doses in treatment regimens similar to our Total XVI protocol.

Footnotes

• Received April 30, 2024
• Accepted February 3, 2025

Correspondence

H.D. SWANSON - hope.swanson@stjude.org

Disclosures

SEK has received consulting fees from Jazz and Servier and St. Jude Children’s Research Hospital receives investigator-initiated research funding from Servier Pharmaceuticals. HDS has received consulting fees from Jazz Pharmaceuticals. The other authors have no conflicts of interest to disclose.

Contributions

Funding

This research was supported by National Institutes of Health grants NIH NCI P30 CA 21765, R01 CA 142665, and K08 CA 250418, as well as investigator-initiated research funding from Servier and ALSAC. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.