Obesity, Rather Than High Body Surface Area Alone, Predicts Clinically Significant Asparaginase Toxicity During Induction Therapy for Acute Lymphoblastic Leukemia

[Posted 28/Jul/2026]

AUDIENCE: Hematology, Oncology

KEY FINDINGS: This large multicenter analysis demonstrates that obesity-not elevated BSA alone-is the principal patient-related risk factor for clinically significant asparaginase toxicity during induction therapy for ALL. The greatest excess risk occurred in patients with both obesity and high BSA, particularly for hepatic toxicity and thromboembolic events, while pancreatitis risk was unaffected. Older age independently increased toxicity risk, especially hyperbilirubinemia. Notably, induction-phase AAT did not compromise early treatment response, as measured by EOI MRD. These findings suggest that obesity should be prioritized when identifying patients for enhanced toxicity surveillance and future preventive strategies, whereas high BSA in the absence of obesity does not appear to justify dose modification based solely on body size.

BACKGROUND: Asparaginase remains a cornerstone of induction therapy for acute lymphoblastic leukemia (ALL), but treatment-limiting toxicities frequently interrupt therapy and may compromise long-term outcomes. Previous studies have produced conflicting evidence regarding whether older age, obesity, or high body surface area (BSA) independently increase the risk of asparaginase-associated toxicities (AAT). This large Children’s Oncology Group analysis evaluated the relative contributions of these risk factors and examined whether induction-phase AAT affected early treatment response measured by end-of-induction (EOI) minimal residual disease (MRD).

DETAILS: This retrospective analysis included 4,925 patients aged 1-30 years enrolled in the Children’s Oncology Group trials AALL0232 and AALL0434. All patients received a single induction dose of pegaspargase 2500 IU/m² without dose capping. Investigators assessed grade >=3 hyperbilirubinemia, grade >=4 alanine aminotransferase (ALT) elevation, grade >=2 thromboembolism, and grade >=3 acute pancreatitis. Multivariable analyses evaluated the independent effects of age, obesity, and BSA, while EOI MRD positivity (>=0.01%) was analyzed to determine whether AAT adversely influenced early leukemia response. Among 4,925 patients, 290 (6%) experienced at least one clinically significant AAT during induction. Toxicity rates increased with advancing age and obesity. After adjustment for confounding variables, obesity independently increased the likelihood of AAT (OR 2.5; 95% CI 1.88-3.24), whereas high BSA alone was not an independent predictor. Patients with both obesity and high BSA had the greatest risk of overall AAT (OR 3.3; 95% CI 2.22-4.77), while high BSA without obesity was not associated with increased risk (OR 1.4; 95% CI 0.94-2.04). Older patients (>=10 years) demonstrated more than a twofold increase in AAT risk compared with younger children.

Obesity combined with high BSA significantly increased the risk of hyperbilirubinemia (OR 3.5; 95% CI 2.2-5.7), severe ALT elevation (OR 3.3; 95% CI 1.7-6.6), and thromboembolism (OR 3.1; 95% CI 1.5-6.5). Acute pancreatitis showed no significant association with obesity or BSA. Importantly, development of AAT did not increase the likelihood of EOI MRD positivity (36.6% vs 33.5%; Ps= .318), suggesting that induction toxicities did not adversely affect early disease response.

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Source: Orgel, E., Maese, L. D., Devidas, M., et al. Toxicity From Asparaginase During Acute Lymphoblastic Leukemia Induction: A Report From the Children's Oncology Group. Blood Advances. 2026; 10(14):4923-4930. Published: July 28, 2026. DOI: 10.1182/bloodadvances.2026019870