Asparaginase-Based Treatment Modifications and Their Effect on Pediatric Acute Lymphoblastic Leukemia Outcomes: A...

Asparaginase is essential in acute lymphoblastic leukemia (ALL) therapy, but toxicity frequently necessitates formulation switching or discontinuation. This study evaluates real-world patterns of asparaginase use and the frequency and causes of formulation switching, and it assesses the impact of formulation switching and incomplete dosing on survival outcomes.

We conducted a retrospective single-center study of 313 children with ALL treated according to Berlin-Frankfurt-Munster-based protocols between January 2009 and January 2024. Three asparaginase preparations were used: native Escherichia coli L-asparaginase, pegylated E. coli asparaginase, and Erwinia chrysanthemi asparaginase. We evaluated formulation changes or discontinuation, their causes, and their impact on event-free survival (EFS), overall survival (OS), and cumulative incidence of relapse (CIR). To avoid reverse causation, patients unable to complete asparaginase because of an early event (induction death or refractory disease) were analyzed separately. The remaining patients were grouped as having received standard complete treatment, drug shortage or toxicityrelated formulation switch with preserved dose, or drug shortage or toxicity-related discontinuation with incomplete dose.

The median age of the patients was 6.9 years, 58.1% were male, and 86.6% had B-cell ALL while 13.4% had T-cell ALL. Asparaginase formulation change occurred for 78 patients (24.9%), increasing across risk groups (standard: 4.0%, intermediate: 15.4%, high: 42.9%), most often due to hypersensitivity (64 patients, 20.4%). After a median follow-up of 5.2 years, 5-year OS and EFS for the whole cohort were 87.4% and 81.6%, respectively. Among 302 evaluable patients, 5-year EFS was 83.1% in the standard complete treatment group, 93.8% in the formulation-switch group, and 69.1% in the incomplete treatment group (p=0.027 for three-group comparison); the corresponding 5-year CIR rates were 13.3%, 2.2%, and 15.9%. Formulation switch with preserved dose was not associated with inferior EFS (adjusted hazard ratio [HR]: 0.23, 95% confidence interval [CI]: 0.07-0.77), and discontinuation showed a numerically lower EFS that was not statistically significant (HR: 1.03, 95% CI: 0.36-2.91).

Formulation switching with preserved total cumulative exposure did not compromise outcomes, supporting the safety of substituting alternative preparations to maintain asparaginase exposure. Incomplete treatment showed a nonsignificant trend toward inferior EFS that warrants confirmation in larger cohorts. Ensuring access to alternative asparaginase formulations is critical, particularly where drug supply is constrained.