BackgroundL‐Asparaginase is an integral component of standard chemotherapy regimens for the treatment of acute lymphoblastic leukemia (ALL). Clinical hypersensitivity, a common reason for treatment discontinuation, has been reported in 10–30% of patients receivingEscherichia coli‐derived asparaginase. After hypersensitivity,E. coli‐derived asparaginase should be discontinued and an alternative asparaginase preparation, such as asparaginaseErwinia chrysanthemi, may be initiated. We conducted a compassionate‐use study to collect additional safety information on asparaginaseErwinia chrysanthemiand to support FDA approval of the product.ProcedurePatients with ALL or lymphoblastic lymphoma (LBL; N = 1368) who developed a hypersensitivity reaction (grade ≥2) to anE. coli‐derived asparaginase participated in this trial. The recommended asparaginaseErwinia chrysanthemidose was 25,000 IU/m2three days per week (Monday/Wednesday/Friday) for two consecutive weeks for each missed pegylatedE. coli‐derived asparaginase dose and 25,000 IU/m2for each missed nonpegylated asparaginase dose for the completion of their planned asparaginase treatment.ResultsAdverse event reports and/or case report forms were completed for 940 patients. The most common adverse event (AE) was hypersensitivity (13.6%). Eighteen patients (1.9%) died during the study. Most patients (77.6%) completed their planned asparaginase treatment with asparaginaseErwinia chrysanthemi. There was no apparent difference in the incidence of the most commonly reported AEs with asparaginase treatment by age, administration, or disease state.ConclusionsThis study further established the safety profile of asparaginaseErwinia chrysanthemiin patients with ALL or LBL who had a hypersensitivity reaction to anE. coli‐derived asparaginase. Pediatr Blood Cancer 2014;61:1232–1238. © 2014 Wiley Periodicals, Inc.