Adequate CD4+ T Cell Reconstitution Prior to Onset of Agvhd Grade II-IV Protects Against Transplantation Related Mortality

Background Graft-versus-Host-Disease (GvHD) is a major cause of morbidity and mortality after allogeneic hematopoietic (stem) cell transplantation (HCT). Studies evaluating the relation between immune reconstitution (IR) and GvHD are largely lacking. We previously showed that successful CD4+ IR strongly predicts event-free survival chances (JACI 2018, Blood 2018). Therefore, we were interested in relating IR to acute and chronic GvHD after HCT. Methods Pediatric patients receiving their first allogeneic HCT between 2004 and 2018 were included. Blood samples and outcome data were collected and registered prospectively. Our main outcomes of interest were 5-year overall survival (OS) and non-relapse mortality (NRM) probabilities, stratified for aGvHD (grade II-IV) and for the presence or absence of adequate CD4+ IR (twice >50*106 CD4+CD3+ cells/L) prior to aGvHD onset. Other outcomes of interest were IR of T-cells, B-cells, NK-cells, monocytes, neutrophils, reticulocytes, and basophils, in patients with or without grade II-IV aGvHD or cGvHD. We applied a time-to-event multivariate Log-rank test to evaluate aGvHD-related survival. IR data were analyzed as continuous variables using multivariate linear-mixed-effects-regression modelling. HCT-source; cord blood transplantation, and bone marrow or peripheral blood transplantation, was analyzed as covariate. Results 391 pediatric patients were included; 97 (24.8%) had moderate-severe aGvHD (grade II-IV) and 42 (10.7%) had cGvHD (limited-extensive). Adequate early CD4+ IR before diagnosis of aGvHD grade II-IV was associated with reduced mortality compared to no CD4 +IR; OS was 77% versus 48% (p Interpretation Adequate CD4+ IR prior to aGvHD onset protects against aGvHD-related mortality after HCT. Either regulatory T-cell development or a lower risk of infection may be possible explanations. A specific delay in B-cell recovery after HCT provides an interesting clinical indicator for cGvHD, which demands further research. Our findings provide insight in the importance of monitoring the immune system after HCT to better understand the biology and determine strategies to prevent and treat GvHD.