Age-Related Immune Cell Dynamics Influences Outcomes after Allogeneic Hematopoietic Cell Transplantation

Allogeneic hematopoietic cell transplantation (HCT) holds a pivotal place in the setting of therapeutic algorithms for hematological disorders. Its therapeutic index is principally related to the immunogenic graft-versus-leukemia (GvL) effect that, together with an efficient immune reconstitution ensures the success of the procedure, contributing to disease control and immune competence. Factors influencing recipient immune recovery have been largely investigated across multiple cohorts issuing heterogenous results. Differences in outcomes in adult and pediatric populations suggest an age-related contribution to post-transplant immune reconstitution, however it is unclear how this parameter may affect the dynamics of single immune cells.

Here we conducted a monocentric prospective study questioning on the modifications of immune cell recovery in a cohort of 176 patients (58 children and 118 adults) with hematological disorders receiving a HCT between 2015 and 2020 and followed at our institution. Complete flow-based immune reconstitution data on T-CD4, T-CD8, NK and B cell populations were collected at defined time-points (+1, 3, 6 and 12 months post-HCT).

After ascertaining the dynamics in adult and pediatric populations of each cell component, the effect of a set of baseline clinico-biological variables on late (>6 months) reconstitution for each cell population was tested through univariable and multivariable linear or logistic regression models.

First, we analyzed the linear relationship existing between recipient and donor age and each cell compartment. Interestingly, while donor age did not impact on any of the parameters in study, CD4- T (Adj R² 0.4, p=5.7x 10^-15) and, in minor part, B cell post-transplant increments (Adj R² 0.05, p=0.004) were inversely correlated with recipient age, which instead did not influence CD8-T nor NK cell reconstitution. Results of stepwise multivariable analyses showed that CD8-T cell reconstitution was positively impacted by recipient positive CMV serostatus (p=0.00009) while donor CMV serostatus positively influenced CD4-T cell recovery (p=0.017). This effect was likely dependent from the expansion of CMV related T cell clonotypes in case of previous CMV immunity. The inverse correlation between CD4-T cells and recipient age was confirmed in multivariable analysis (p=0.0148). Donor EBV positive serostatus resulted instead to be a negative predictor of B cell recovery (p=0.0442). Interestingly none of the parameters analyzed influenced NK cell recovery. The impact on age mirrored a different kinetics of immune reconstitution in adult and pediatric patients (<18 years). Therefore, while early after HCT immune cell composition was similar in the two groups, with NK cells representing the largest component, followed by CD8-T and CD4-T, and minimal B cell contribution, in later phases we assisted to a faster expansion of CD4-T arm in children whereas CD8-T remained the major contributor of the immune recovery processes in adults still one year after transplant. B cell reconstitution was also faster in children, with a better immunoglobulin levels recuperation (measured on IgM to avoid bias of prophylactic IgG infusions) despite no differences in post-transplant pre-emptive rituximab utilization. When looking at different outcomes of pediatric and adult patients, both overall and event free survival were significantly higher in children (p=0.00062 and p=0.0062). While no difference in acute grade III-IV GvHD, adults experienced a significantly higher cumulative incidence (CI) of chronic GvHD (p=0.0258) and of specific infections, including EBV (p=0.031) and fungi (p=0.007). Although CI of relapse was not different, children experienced later relapses as compared to adults (median of 294 vs. 139 days, p=0.039), indicating a better disease control at least at early post-transplant stages.

Here, starting from immune reconstitution data prospectively collected for patients transplanted at our institution, we dissected the effect of age on post-transplant immune cells. A faster CD4-T and B cell recovery in children may be the driver of a better immune competence underpinning superior outcomes in pediatric populations. If age-related thymus involution may reflect suboptimal CD4-T cell differentiation in adults, younger donor selection does not seem to improve recipient post-transplant immune reconstitution.

Feugier:AstraZeneca, Janssen, Abbvie, Beigene, Gilead: Membership on an entity's Board of Directors or advisory committees, Other: Congress Invitations.