Hematopoietic Stem Cell Transplantation (HSCT) is a curative therapy for many hematologic disorders, but relapse and complications like Graft-versus-Host Disease (GVHD) remain challenges. Cellular therapies, including Donor Lymphocyte Infusions (DLI), CAR T-cells, Virus-Specific T-cells (VSTs), and Mesenchymal Stromal Cells (MSCs), offer potential solutions. However, the optimal timing for initiating these therapies remains unclear, because early use may increase risks like GVHD or toxicity and the delayed use may compromise efficacy, which creates an uncertain scenario and often impacts decision-making.

To systematically review the literature on clinical outcomes associated with the timing of cellular therapy after HSCT, identifying optimal windows for intervention, associated risks, and evidence gaps that may guide future protocols.

A systematic review was conducted using PubMed, Scopus, and Embase for studies from 2018-2024. Search terms included “hematopoietic stem cell transplantation,” “cellular therapy,” “CAR T”, “immune reconstitution,” and “timing.” Clinical trials, cohort studies, and case series reporting on cellular therapy timing post-HSCT and outcomes (relapse, survival, GVHD) were included. PRISMA guidelines were followed. Data extracted involved patient population, transplant type, therapy timing, outcomes, and limitations.

The timing of cellular therapy administration following hematopoietic stem cell transplantation (HSCT) is a critical determinant of clinical outcomes, with a clear trend favoring early intervention. Prophylactic or pre-emptive strategies in states of low disease or viral burden demonstrated superior efficacy. For instance, prophylactic donor lymphocyte infusion (DLI) in high-risk AML (median 190 days post-HSCT) improved overall survival (OS) and relapse-free survival (RFS), though this benefit was counterbalanced by an increased risk of Graft-versus-Host Disease (GVHD). Similarly, virus-specific T-cells (VSTs) used early (e.g., median 36 days post-HSCT) were highly effective in managing viral infections with minimal GVHD risk. In contrast, therapeutic DLI for overt relapse showed limited efficacy, primarily in CML, reinforcing the value of early use. mesenchymal stromal cells (MSCs) also exhibited context-dependent benefits, with prophylactic administration reducing GVHD incidence, while therapeutic infusions treated refractory cases. The application of CAR T-cells post-HSCT presents a unique challenge, where the interval from transplant appears to impact cell quality rather than just treatment opportunity. While the optimal timing window remains undefined, a longer interval between HSCT and CAR-T infusion (median 5.2 years) correlated with significantly shorter progression-free survival (PFS) in myeloma (9.5 vs. 21 months), likely due to reduced T-cell fitness, though OS and toxicity were unaffected. Key risks associated with post-HSCT cellular therapies include GVHD for allogeneic products like DLI and CAR-T cells (7-12% incidence), alongside CAR-T specific toxicities like CRS and ICANS. In conclusion, while early, pre-emptive cellular therapy is a promising strategy, its implementation requires careful balancing of efficacy against risks like GVHD. Significant evidence gaps persist, including a lack of randomized trials comparing timing strategies, undefined optimal intervals for CAR T-cell therapy, and a need for biomarkers to guide personalized timing.