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<0.001; Figure 1A) and NRM 17% versus 35% (p=0.005; Figure 2A), respectively. For grade III-IV differences were even more striking; OS was 78% in patients with CD4+ IR prior to grade III-IV aGvHD onset and only 24% in patients without CD4+ IR (p<0.001, Figure 1B), and NRM was 22% versus 74% (p<0.001; Figure 2B), respectively. Innate immune cell reconstitution was similar in patients with or without acute or chronic GvHD. At diagnosis, patients with grade II-IV aGvHD had drastically lower B-cell counts compared to control patients (p<0.001). We also observed delayed recovery of B-cell subsets prior to cGvHD, both with and without (both p=0.001) prior steroid-treated aGvHD, compared to controls (Figure 2). 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. [ABSTRACT FROM AUTHOR]