Relapse of acute lymphoblastic leukemia (ALL) remains a leading cause of mortality in childhood cancer. IntReALL 2020 will conduct randomized and historically controlled trials in children with relapsed B-cell precursor (BCP) ALL with the aim to replace toxic chemotherapy with better tolerated and more efficacious immunotherapeutic drugs. In standard risk (SR) patients, the CD22 directed antibody-drug conjugate inotuzumab ozogamicin (InO) will be randomly compared with standard of care (SOC) ALL-R3 induction. All patients will receive one SOC consolidation- and one Blina course, compared to historical controls. SR patients with MRD good response will receive 2 additional Blina courses replacing chemotherapy randomly compared with SOC. Patients with high-risk relapse will receive induction investigating InO versus ALL-R3 in an industry-sponsored trial, followed by IntReALL consolidation and allogeneic HSCT. Patients with isolated extramedullary (IEM) relapse are treated based on ALL-REZ BFM 2002 backbone. IntReALL 2020 will establish a federated relapsed/refractory leukaemia board generating personalized recommendations based on clinical, molecular-genetic and drug response profiling data. Patients with very-high risk disease will receive experimental/personalized therapies, including a trial investigating CD19-directed chimeric receptor antigen (CAR) T-cells produced in academic institutions. Other CAR T-cells trials as well as an induction trial for T-ALL relapse will be developed. Documentation and monitoring of the trials and the individualized treatment will be realized using the MARVIN database. Comprehensive statistical and data management activities will warrant the accuracy and interpretability of the data. IntReALL 2020 involves representatives from participating pharmaceutical companies and EMA as well as patient/parent advocates to discuss strategies for developing new drugs within academic trials warranting a benefit for all patients on the results. “This action is part of the Cancer Mission cluster of projects on ‘Diagnosis and treatment’.”