Posttransplant cells for the win? DLI and adoptive cell therapy to eradicate MRD

Relapse remains the leading cause of failure after allogeneic stem cell transplantation (allo-SCT) for hematologic malignancies. Donor lymphocyte infusion (DLI), the infusion of lymphocytes from the original stem cell donor, was introduced in the late 1980s as a strategy to prevent or treat relapse by augmenting the graft-versus-leukemia (GvL) effect. Over time, DLI has been used in various settings: initially as therapeutic DLI for overt relapse and later as preemptive DLI, administered in response to early signs of relapse, such as persistent or recurrent measurable residual disease (MRD), or as prophylactic DLI to mitigate high relapse risk before clinical relapse occurs (see Visual Abstract). However, questions remain regarding how, when, and in whom DLI is best deployed, reflecting ongoing controversy and heterogeneity in clinical practice. A recent survey of 165 European Society for Blood and Marrow Transplantation centers across 43 countries reported that DLI was used prophylactically for high-risk hematologic diseases in 43.8% of these centers. DLI was used preemptively for MRD positivity in 86.9% of centers and for mixed chimerism in 73.1%. Therapeutic DLI was administered for hematologic relapse in 73.1% of centers. Active graft-versus-host disease and active infections were considered absolute contraindications by 85.6% and 57.5% of the centers, respectively. This observed variability in center practices underscores the need to clarify the "who, when, and why" of posttransplant cellular interventions. In this review, we explore DLI strategies and the potential sequencing with novel targeted therapies across prophylactic, preemptive, and therapeutic applications, illustrated through case examples in patients with acute myeloid leukemia. We highlight findings from retrospective, as well as the scarce prospective studies and extend considerations to other indications, including chronic myeloid leukemia, myelofibrosis, and acute lymphoblastic leukemia. Additionally, we review emerging combination strategies with targeted therapies across different hematologic malignancies and adoptive cell therapies beyond conventional DLI.