Hypersensitivity reactions (HSRs) may occur in patients receiving asparaginase for acute lymphoblastic leukemia/lymphoblastic lymphoma and this may prevent treatment completion and lead to inferior clinical outcomes. Patients with grade 2-4 HSRs to an Escherichia coli ( E. coli)-derived asparaginase are recommended to switch to an Erwinia-derived asparaginase. In this case report, a pediatric patient with T-cell acute lymphoblastic leukemia experienced HSRs to both E. coli-derived calaspargase pegol and recombinant Erwinia asparaginase JZP458. After an unsuccessful desensitization for calaspargase pegol, we developed a novel intramuscular desensitization protocol for JZP458, which was successful in delivering all scheduled asparaginase doses and maintaining asparaginase activity.