Impact of graft sources on immune reconstitution and survival outcomes following allogeneic stem cell transplantation

Abstract

We evaluated the kinetics of immune reconstitution (IR) after allogeneic hematopoietic cell transplantation (HSCT) and analyzed the clinical effect of IR on posttransplant outcomes. Absolute lymphocyte and its subset counts were measured using flow cytometry on days 28, 100, 180, 365, and 730 after transplantation in 358 adult patients who underwent HSCT between 2009 and 2017. On day 100 after HSCT, 310 surviving patients were analyzed. Bone marrow transplantation (BMT), peripheral blood stem cell transplantation (PBSCT), and cord blood transplantation (CBT) were performed in 119, 55, and 136 patients, respectively. Mature B-cell and differentiated natural killer (NK) cell subset counts significantly increased after CBT. The 2-year overall survival (OS), nonrelapse mortality (NRM), cumulative incidence of relapse, and chronic GVHD in BMT, PBSCT, and CBT were 62%, 67%, and 76% (P = .021); 17%, 17%, and 13% (P = .82); 33%, 40%, and 27% (P = .063); and 43%, 45%, and 28% (P = .025), respectively. Multivariate analysis showed that higher CD16+CD57- NK cell counts correlated with lower disease relapse, whereas higher CD20+ B-cell counts correlated with lower NRM. OS-favoring factors were higher CD16+CD57- NK cell count (hazard ratio, 0.36; 95% confidence interval, 0.22-0.60; P < .001) and CD20+ B-cell count (hazard ratio, 0.53; 95% confidence interval, 0.30-0.93; P < .001) and lower Disease Risk/HCT-Specific Comorbidity index score. Collective contribution of graft source-specific and event-related immune reconstitution might yield better posttransplant outcomes in CBT.

Graphical abstract

Figure 1.

Visual overview of posttransplant IR in terms of time and graft source. Comprehensive IR data are summarized in supplemental Table 2. (A-B) ALC and CD20⁺ B- cell, CD4⁺CD45RA⁺ T-cell, and NK-cell counts (expressed as CD3⁻CD56⁺ and CD16⁺CD57⁻) were significantly higher during the early phase in all UCB recipients (all P < .001). In contrast to NK cells, the observation of CD8⁺ T-cell recovery was delayed in UCB recipients compared with that in BM and PBSC recipients. However, CD4⁺ T-cell expansion was temporally confirmed in memory T-cell and effector T-cell subsets in UCB recipients, and the overall difference in graft source–related IR gradually decreased over time.

Figure 2.

Contribution of immune cell subsets to posttransplant outcomes. (A) Forest plot of multivariate analysis results for posttransplant outcomes. (B) Heat map showing similarity in immune cells confirmed after posttransplant events (sorted hierarchically by HR). These results revealed that each lymphocyte type is predictive of specific posttransplant events.

Figure 3.

Expansion of key cell subsets; namely, CD20⁺B cells, CD8⁺CD11b⁻T cells, and CD16⁺CD57⁻NK cells, significantly positively affected 2-year OS. There were no significant differences in CIR or proportions of high vs low cell counts for CD20⁺ B cell and CD8⁺CD11b- T cell subsets. NRM benefits were found to be lower (range, 17%-21%) in patients with early IR of these cells. CIR was confirmed to be approximately 26% lower in patients with early IR of CD16⁺CD57⁻ NK cells.

Figure 4.

Survival curves after allogeneic HSCT. (A) OS and DFS were significantly better with rapid NK cell recovery. (B) Early IR of CD20⁺ B cells yielded longer OS and NRM even in patients with higher HCT-CI (≥3).

Figure 5.

Effect of graft source on the following outcomes after allogeneic HSCT. OS (A), CI-NRM (B), CI-relapse (C), acute grade 2 to 4 GVHD (D) and grade 3 to 4 GVHD (E), and chronic GVHD (F). Graft source–related outcomes were confirmed for OS, cumulative incidence of acute GVHD (≥grade 3), and chronic GVHD. Our data demonstrated rapid graft-related IR and revealed the clinical effects of posttransplant outcomes using lymphocyte subset analysis on day 100 after allogeneic HSCT. These results suggest that a specific IR profile after CBT yields superior posttransplant outcomes.