L-asparaginase is a cornerstone enzymatic drug that is indispensable in the treatment of pediatric and adult acute lymphoblastic leukemia/lymphoma. Unfortunately, in 30% of asparaginase-treated patients, immune reactions are observed that result in a complete loss of enzyme anti-cancer activity. Administration of these asparaginases is also associated with a number of adverse side-effects (hepatotoxicity, pancreatitis, coagulopathy, neurotoxicity) due to their  glutaminase co-activity, and which limit further administration with a significant influence on relapse-free survival. Therefore, there is a great and urgent need for less toxic and less immunogenic asparaginase variants.