<jats:title>Summary</jats:title><jats:p>Asparaginase is an essential drug for acute lymphoblastic leukaemia (ALL) treatment, but has several side effects, and its discontinuation often compromises patient outcomes. In the prospective Japan Association of Childhood Leukaemia Study ALL‐02 protocol, two major changes were made: (1) additional chemotherapies to compensate for the reduction of treatment intensity when asparaginase was discontinued and (2) more intensive concomitant corticosteroid administration, relative to our previous ALL‐97 protocol. In ALL‐02 study, 1192 patients were included and L‐asparaginase was discontinued for 88 (7.4%). Discontinuation due to allergy was markedly decreased relative to the ALL‐97 protocol (2.3% vs 15.4%). Event‐free survival (EFS) among patients with T‐ALL was compromised when L‐asparaginase was discontinued, as well as among patients with high‐risk B‐cell ALL, especially when discontinued before maintenance therapy. Moreover, multivariate analysis identified discontinuation of L‐asparaginase as an independent poor prognostic factor for EFS. In the current study, additional chemotherapies failed to fully compensate for L‐asparaginase discontinuation, illustrating the difficulty of replacing asparaginase with other classes of drugs, although this study was not designed to evaluate the effect of these modifications. Concomitant intensive corticosteroid treatment may help to reduce allergy to asparaginase. These results will assist in further optimization of asparaginase use.</jats:p>