AALL1721/Cassiopeia trial design. AALL1721/Cassiopeia is a phase 2, single-arm, international multicenter trial of tisagenlecleucel in children and young adults with persistent MRD. Patients age 1 to 25 years diagnosed with CD19-expressing National Cancer Institute (NCI) HR (age 10 years or older or presenting with a white blood cell count ≥50 × 10^9/L) B-ALL are eligible in first remission after induction/protocol IA and consolidation/protocol IB chemotherapy if MRD is detected by central multiparameter flow cytometry at ≥0.01%. Leukapheresis can occur after induction, if EOI MRD ≥1%, or after consolidation, once a patient has a qualifying MRD result. Enrolled patients proceed to the next phase of standard-of-care therapy, interim maintenance (IM), during the period of tisagenlecleucel manufacture. After stopping IM chemotherapy, patients will receive a lymphodepleting chemotherapy regimen of fludarabine and cyclophosphamide followed by a single infusion of tisagenlecleucel. After infusion, no further cancer-directed chemotherapy (including intrathecal chemotherapy) will be administered per protocol. HD-MTX, high-dose methotrexate; tisa, tisagenlecleucel.