Hematologic diseases have seen significant therapeutic advancements in recent years, particularly through the development of small-molecule targeted therapies, allogeneic hematopoietic cell transplantation (allo-HCT), and cellular therapies such as chimeric antigen receptor T-cell (CAR-T) therapy. HCT, however, remains the only potentially curative option for many hematologic conditions, including both malignant disorders and non-malignant disorders [1,2]. Nevertheless, transplant-related complications—most notably graft-versus-host disease (GVHD), infections, and disease relapse—remain substantial barriers to success [2].

Immune reconstitution (IR) following HCT is a critical determinant of post-transplant outcomes. In hematologic malignancies, IR plays a central role in balancing the beneficial effects of graft-versus-leukemia (GVL) activity and infection prevention against the risk of GVHD. Optimizing IR is thus fundamental to improving long-term outcomes after allo-HCT. Strategies aimed at reducing GVHD risk and impacting IR include: in vivo T-cell depletion (TCD) with serotherapy, e.g., antithymocyte globulin (ATG) [[3], [4], [5], [6], [7]]; post-transplant cyclophosphamide (PTCy) [[8], [9], [10], [11], [12], [13]]; and ex vivo TCD [14,15]. ATG is associated with impaired CD4+ T-cell reconstitution and reduced event-free survival (EFS) [6], while PTCy-based GVHD prophylaxis delays CD4+ T-cell recovery and increases the risk of infection and Cytomegalovirus (CMV) reactivation [8].

Compared to patients undergoing HCT, the dynamics of IR following cellular therapy, including CAR-T, are less well understood. Studying IR after CAR-T therapy and its clinical implications thus remains an active area of investigation [[16], [17], [18], [19], [20], [21], [22], [23], [24], [25]]. Notably, CD19 CAR-T therapy induces B-cell aplasia in up to 98 % of patients within 2 weeks post-infusion, with effects that may persist for months or even years [18,19]. On-target off-tumor effects—such as delayed reconstitution of CD4+ T cells or natural killer (NK) cells and immune effector cell-associated hematotoxicity—are commonly observed across CAR-T platforms, underscoring the need for long-term immune monitoring and prophylactic strategies.

IR is a dynamic, sequential process influenced by a range of factors, including donor-recipient human leukocyte antigen (HLA) matching, graft source, conditioning regimen, GVHD prophylaxis and treatment, donor age, and infection history [26]. To improve patient survival, we need a comprehensive understanding of IR dynamics following allo-HCT and CAR-T therapy and their associations with clinical outcomes. In thiswe summarize current understanding of IR kinetics, approaches for its evaluation and quantification, and the effects of various transplantation strategies. We also discuss strategies to enhance IR recovery, monitoring and outcomes after allo-HCT and cellular therapy.