Background: The AYA population is usually defined as pts aged 16 to 39 years. NCCN guidelines recommend that AYA patients with acute lymphoblastic leukemia (ALL) be treated with ‘pediatric-inspired’ protocols that includeL-asparaginase (L-ASP) as an integral component of their multiagent chemotherapy regimen. Hypersensitivity reaction is the most common toxicity associated with L-ASP treatment, occurring in 10%–30% of pts treated with E coli–derived L-ASP, necessitating its discontinuation. In those pts, it is recommended that L-ASP derived from Erwinia chrysanthemi (Erw) be initiated since it is immunologically distinct from E coli–derived L-ASP. Methods: A large compassionate-use trial in pts with ALL or lymphoblastic lymphoma who developed a hypersensitivity reaction (ie, grade ≥2) to an E coli–derived L-ASP was conducted to evaluate the safety of Erw. Pts were excluded if they had a history of pancreatitis, previous allergic reaction to Erw, or were pregnant. Adverse events (AEs) and/or case report forms were completed for 940 pts. The Erw safety information for the full study population was previously reported. Here, we report a safety analysis of pts aged ≥16 years with the majority being AYA (94%), a population in which little Erw safety information has been presented. Results: In this compassionate-use trial, 156 pts were aged ≥16 years. These pts were primarily male (67.9%), had nonrelapsed disease (70.5%), B-lineage ALL (71.2%), and received intramuscular Erw (85.9%). 71.8% completed their planned Erw course. Reasons for discontinuation included allergic reaction (3.2%), other AEs (9.6%), other reasons (6.4%), and unknown reasons (9%). Hypersensitivity occurred in 20 (12.8%); hyperglycemia, 9 (5.8%); pancreatitis, 6 (3.8%); thrombosis, 5 (3.2%); bleeding, 1 (1%). Grade 3/4 AEs with a >5% incidence included hyperglycemia (5.8%). There were 10 deaths: 4 disease progression, 3 infection, 1 coma, 1 renal impairment, 1 unknown. Conclusions: The safety profile of Erw in pts ≥16 years was consistent with the profile in the entire study population. This compassionate-use trial permitted the completion of L-ASP in 71.8% of AYA and adult pts. Clinical trial information: NCT00693602.