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.