Biogeneric Native and Polyethylene Glycol–conjugated Escherichia coli Asparaginases for Treating Children with Acute Lymphoblastic Leukemia

BACKGROUND: Escherichia coli asparaginases (EcASNase) available for the treatment of children with acute lymphoblastic leukemia are largely of suboptimal quality in low-middle income countries and contribute to inferior outcomes. METHODS: The pharmacokinetics, activity, and immunogenicity of a native (EcASNase) and a PEGylated ASNase (PEG-EcASNase) were analyzed. Biogeneric EcASNase (10,000 IU/m2) was administered intramuscularly every 72 hours (cohort 1, 76 patients) or every 48 hours (cohort 2, 69 patients). Cohort 3 (176 patients) received a PEG-EcASNase biogeneric (1000 IU/m2) intramuscularly every 14 days. RESULTS: In cohort 1, 69% of trough induction samples were suboptimal (<100 IU/L). Cohort 2 achieved a median trough activity >600 IU/L during induction, with no suboptimal activity. The median trough activity during induction in cohort 3 was 467 IU/L, with suboptimal activity observed in 7%-16%. Patients receiving 1 induction PEG-EcASNase dose had 8-fold higher odds of suboptimal activity postinduction. Hypersensitivity was higher with EcASNase (12% versus 5%) and pancreatitis, more often with PEG-EcASNAse (5% versus 1%). Antidrug antibodies were strongly associated with silent inactivation and hypersensitivity (P < 0.0001). CONCLUSIONS: Pharmacological monitoring enabled optimization of EcASNase dosing, detection of silent PEG-EcASNase inactivation, and identification of induction dosing intensity as a determinant of sustained activity for generic ASNase products marketed in low-middle income countries.