OBJECTIVES: At present, reinfusions of chimeric antigen receptor (CAR)-T cell have exhibited limited efficacy, while their efficacy on extramedullary relapse remains to be further elucidated in B-cell acute lymphoblastic leukemia (B-ALL). Although combination with IL-15 demonstrated the potential to enhance antitumor activity of CAR-T, the efficacy of this approach remains to be validated clinically. METHODS: We reported a patient with B-ALL with extramedullary relapse after allogeneic stem cell transplantation and who was resistant to chemotherapy and radiotherapy. In total, he received four treatments with CAR-T cells repeatedly under the status of disease progression. RESULTS: First, the patient received autologous murine CAR19-CD28-CD3ζ-T cells and achieved full resolution of extramedullary leukemia lasting 8 months. After systemic disease relapse, he received autologous humanized CAR22-41BB-CD3ζ-tEGFR-T cells and achieved complete remission (CR) with incomplete blood count recovery (CRi) with minimal residual disease (MRD) negativity in the bone marrow and shrinkage of extramedullary leukemia. Over 2 months later, he experienced a relapse of the systemic disease and he received autologous murine CAR19-41BB-CD3ζ-mIL15-T cells and achieved CRi lasting 5 months with the strongest expansion and persistence of CAR. Finally, on relapse of CD19 medullary disease, he received allogeneic humanized CAR22-41BB-CD3ζ-tEGFR-T cells but only achieved a transient decrease in the number of blasts. No CAR-T-cell-related encephalopathy syndrome was observed, and all side effects were manageable. CONCLUSION: Our report hints the feasibility and safety of CD19 CAR-T cell expressing membrane-bound IL-15 for patient with B-ALL even if relapsed after multiple CAR-T-cell therapies.