Early CD4+ T Cell Reconstruction As Predictor for Outcomes after Allogeneic Hematopoietic Cell Transplantation in Pediatric and Young Adult Patients: A Validation Cohort Analyses

Abstract

BackgroundAn association between early CD4+ recovery and survival after T-replete allogeneic Hematopoietic Cell Transplantation (HCT) in pediatric and young adult patients was previously reported (Admiraal et al, JACI 2017). However, validation in a separate cohort and in patients undergoing ex vivo T cell depleted (TCD) HCT is lacking. Therefore, we studied the relation between CD4+ T cell immune reconstitution (IR) and clinical outcomes, in a setting where a majority of patients received a TCD HCT.MethodsWe performed a retrospective analysis of data on children and young adults receiving their 1st allo-HCT for any indication between Jan-2008 and Dec-2017. The main goal was to relate CD4 IR (measured every 2-4 wks), within 100 days after HCT to the outcomes of interest. The main outcome of interest was overall survival (OS). Other outcomes of interest were non-relapse mortality (NRM), event-free survival (EFS), relapse and acute graft-versus-host-disease (aGvHD) grade 2-4. CD4 IR was defined according to previous studies, as having more than 50 CD4+ T cells/uL at 2 consecutive measurements within 100 days. Cox-proportional hazard and Fine and Gray competing risk models were used (R version 1.2.1335)Findings315 patients (220 Malignant, 95 non-malignant indications) were included, with a median age of 10.4 years (IQR 5.0–16.5yr). 66.0% (208/315) of the patients received a TCD graft, 12.7% (40/315) received cord blood, and 21.2% (67/315) T-replete bone marrow. The CI of CD4+ IR at 100 days was 66.7%. Incidence of achieving CD4 IR after TCD was lower compared to other cell sources, 54.7% vs 90.0% after cord blood and 89.6% after T-replete bone marrow (HR 0.47, P<0.001). The other multivariate predictors for CD4+ IR were age (continuous; 0.97, p=0.002) and mismatch MUD (HR 0.5, p=0.005). No impact of CD4+ IR on relapse or aGvHD grade 2-4 was found. Absence of CD4 IR was found to be a predictor for inferior OS (HR: 2.35, 95% CI 1.46-3.79, P<0.001; Fig 1A), and EFS (HR: 1.80, 95% CI 1.20–2.69, P=0.004) and increased NRM (HR: 6.58, 95% CI 2.82–15.38, P < 0.001; Fig 1B).InterpretationWe confirmed, in a separate HCT cohort, that early CD4 IR is a strong predictor for outcomes. Early CD4+ IR is an excellent biomarker for outcomes after HCT and should therefore be considered as a standard outcome measure. Finding strategies to better predict CD4+ T cell recovery after HCT may influence outcomes/survival in the future. An association between early CD4+ recovery and survival after T-replete allogeneic Hematopoietic Cell Transplantation (HCT) in pediatric and young adult patients was previously reported (Admiraal et al, JACI 2017). However, validation in a separate cohort and in patients undergoing ex vivo T cell depleted (TCD) HCT is lacking. Therefore, we studied the relation between CD4+ T cell immune reconstitution (IR) and clinical outcomes, in a setting where a majority of patients received a TCD HCT. We performed a retrospective analysis of data on children and young adults receiving their 1st allo-HCT for any indication between Jan-2008 and Dec-2017. The main goal was to relate CD4 IR (measured every 2-4 wks), within 100 days after HCT to the outcomes of interest. The main outcome of interest was overall survival (OS). Other outcomes of interest were non-relapse mortality (NRM), event-free survival (EFS), relapse and acute graft-versus-host-disease (aGvHD) grade 2-4. CD4 IR was defined according to previous studies, as having more than 50 CD4+ T cells/uL at 2 consecutive measurements within 100 days. Cox-proportional hazard and Fine and Gray competing risk models were used (R version 1.2.1335) 315 patients (220 Malignant, 95 non-malignant indications) were included, with a median age of 10.4 years (IQR 5.0–16.5yr). 66.0% (208/315) of the patients received a TCD graft, 12.7% (40/315) received cord blood, and 21.2% (67/315) T-replete bone marrow. The CI of CD4+ IR at 100 days was 66.7%. Incidence of achieving CD4 IR after TCD was lower compared to other cell sources, 54.7% vs 90.0% after cord blood and 89.6% after T-replete bone marrow (HR 0.47, P<0.001). The other multivariate predictors for CD4+ IR were age (continuous; 0.97, p=0.002) and mismatch MUD (HR 0.5, p=0.005). No impact of CD4+ IR on relapse or aGvHD grade 2-4 was found. Absence of CD4 IR was found to be a predictor for inferior OS (HR: 2.35, 95% CI 1.46-3.79, P<0.001; Fig 1A), and EFS (HR: 1.80, 95% CI 1.20–2.69, P=0.004) and increased NRM (HR: 6.58, 95% CI 2.82–15.38, P < 0.001; Fig 1B). We confirmed, in a separate HCT cohort, that early CD4 IR is a strong predictor for outcomes. Early CD4+ IR is an excellent biomarker for outcomes after HCT and should therefore be considered as a standard outcome measure. Finding strategies to better predict CD4+ T cell recovery after HCT may influence outcomes/survival in the future. Figure 1.Figure 1 View Large Image Figure ViewerDownload Hi-res image Download (PPT)