3 Background: Although EFS continues to improve for children and young adults with HR-ALL, central nervous system (CNS) disease has become an increasing site of treatment failure. AALL0232 was designed to test the safety and efficacy of interventions targeted to enhance CNS control including comparisons of HD-MTX versus Capizzi escalating methotrexate plus PEG asparaginase (C-MTX/ASNase) during interim maintenance-1 (IM-1) and dexamethasone (DEX) versus prednisone (PRED) during Induction. METHODS: AALL0232 was a Phase III, randomized trial for patients 1-30 years old with newly diagnosed NCI high risk B-precursor ALL that utilized a 2 x 2 factorial design with an augmented intensity Berlin-Frankfurt-Münster (BFM) backbone. Patients were randomized to receive DEX versus PRED during induction and HD-MTX (5gm/m(2) biweekly x 4) versus C-MTX/ASNase during IM-1. To date 2104/3156 AALL0232 patients have completed IM-1. RESULTS: Planned interim monitoring showed 5-year EFS for patients randomized to receive HD-MTX (N=1,209) was 82 + 3.4% versus 75.4 + 3.6% for the C-MTX/ASNase (N=1,217) regimen, p=0.006. Because this difference crossed a pre-defined boundary, enrollment was halted and patients were crossed over from C-MTX/ASNase to HD MTX when feasible. There were fewer marrow and CNS relapses in the HD-MTX versus C-MTX/ASNase arms (42 and 22 versus 68 and 32). The incidence of febrile neutropenia was lower with HD-MTX compared to the C-MTX; 5.2% vs 8.2%, respectively, p=0.005. There were no statistically significant differences in acute neurotoxicity, osteonecrosis, or other clinically relevant toxicities between the two regimens. CONCLUSIONS: HD-MTX administered in place of C-MTX, during the IM-1 phase of augmented BFM therapy is associated with superior EFS, with no increase in acute toxicity, in children and young adults with HR-ALL.