Children's Oncology Group AALL1331 utilized an intensive chemotherapy induction (Block 1) based on UK ALLR3 induction for children, adolescents, and young adults with acute lymphoblastic leukemia in first relapse, followed by risk-stratified therapy. High/intermediate risk patients were subsequently randomized to receive 2 blocks of chemotherapy or 2 blocks of blinatumomab followed by hematopoietic stem cell transplant. Low risk patients were randomized to chemotherapy or chemotherapy cycles intercalated with three blinatumomab blocks. Patients who had an early treatment failure were eligible to receive blinatumomab for up to 2 salvage cycles. We reviewed Block 1 responses, risk stratification, randomization rates, adverse events (AE), and event-free survival and overall survival for all enrolled patients. AALL1331 enrolled 661 patients: 24 died during Block 1 and 42 experienced early treatment failure. Overall, 531/661 (80.3%) attained complete remission with 586 risk-assigned and only 471 were randomized. Of 532 patients with marrow involvement, 290 (54.5%) were minimal residual disease positive (≥0.01%) after Block 1. Grade 3/4/5 AE occurred in Block 1 in 44.9, 24.1, and 3.6% patients respectively, with febrile neutropenia, infections, and sepsis most frequent. Notably, 190 enrolled patients (28.7%) did not proceed with post-induction therapy, including 115 (17.4%) risk stratified but not randomized. These patients had dismal survival. More effective and less toxic reinduction strategies are needed for B-ALL in first relapse. Trial Registration Number: NCT02101853.