Donor lymphocyte infusion as immune modulation after pediatric allogeneic transplantation

Relapse remains a leading cause of failure after allogeneic hematopoietic cell transplantation for pediatric hematologic malignancies. Donor lymphocyte infusion (DLI) offers a uniquely accessible and scalable form of nonengineered adoptive cellular therapy. Although historically viewed as salvage therapy, emerging data support a paradigm shift toward using DLI as strategic immune modulation rather than rescue. This review synthesizes the biological rationale and clinical evidence for DLI in children, integrating the adult data when necessary to define translatable principles. Across platforms, outcomes rely on timing, disease burden, and the immune context. We highlight the superiority of prophylactic and preemptive DLI over therapeutic use and review contemporary structured approaches relying on treatment initiation at low and safe doses and escalation based on strict tolerance and monitoring criteria. Special consideration is given to haploidentical transplantation and mechanisms of immune escape such as HLA loss that limit T-cell-based interventions. Furthermore, we examine emerging combinations, including DLI with blinatumomab in B-cell acute lymphoblastic leukemia and hypomethylating agents in myeloid malignancies. Finally, we discuss T-cell subset manipulation to mitigate graft-versus-host disease while preserving the graft-versus-leukemia effects. All these data support a modern framework for pediatric DLI that prioritizes early, biology-informed interventions and rational combinations, underscoring the urgent need for pediatric-specific prospective studies.