CD4+ T-cell reconstitution predicts survival outcomes after acute graft-versus-host-disease: a dual-center validation

Abstract

Acute Graft-versus-Host-Disease (aGvHD) is a major cause of morbidity and mortality after allogeneic hematopoietic cell transplantation (HCT). We previously showed that early CD4+ T-cell reconstitution (CD4+IR) predicts survival after HCT. Here, we studied the relation between CD4+ IR and survival in patients who developed aGvHD. Pediatric patients receiving their first allogeneic HCT at the UMC Utrecht / Princess Máxima Center (UMC/PMC) or Memorial Sloan Kettering Cancer Center (MSK), were included. Primary outcomes were non-relapse mortality (NRM) and overall survival (OS), stratified for aGvHD and CD4+IR; defined as ³50 CD4+ T-cells/uL within 100 days after HCT, or prior to aGvHD onset. Multivariate and time-to-event Cox Proportional Hazard models were applied. 591 Patients (N= 276 UMC/PMC; N= 315 MSK) were included. NRM in patients with aGvHD grade III-IV with or without CD4+IR within 100 days after HCT was 30% vs 80% (p=0.02) at UMC/PMC and 5% vs 67% (p=0.02) at MSK. This associated with lower OS without CD4+IR; 61% vs. 20% (p=0.04) at UMC/PMC, and 75% vs. 33% (p=0.12) at MSK. Inadequate CD4+IR prior to aGvHD onset associates with significantly higher NRM; 74% vs 12% (p<0.001), and inferior OS; 24% vs 78% (p<0.001). In this retrospective analysis we demonstratethat early CD4+ IR, a simple and robust markerpredictive of outcomes after HCT,associates with survival after moderate to severe aGvHD.These associations need to be confirmed in a prospective manner but suggest that strategies to improve T-cell recovery after HCT may influence survival in patients developing aGvHD.

Immune Reconstitution After Allogeneic Haematopoietic Cell Transplantation: From Observational Studies to Targeted Interventions

“…The abundance of naïve T cells in the graft may influence the outcome of patients after allogeneic HCT as long as thymic function has not been restored. Although total numbers of CD4 + T cells have been shown to directly correlate with survival post GvHD ( 10 , 11 ), levels of naïve T cells have been identified as the most potent drivers of alloreactivity ( 12 ). In agreement, high levels of CD4 + naïve T cells (but not of CD8 + T cells) in allografts have been observed to correlate with an increased incidence of acute GvHD (aGvHD) post transplantation ( 13 ).…”

“…Moreover, as IR is age dependent, this and other reviews are hampered by the lack of data from a primarily paediatric setting ( 7 ). Table 1 provides published data on immune cell subsets in adaptive IR and their relation to aGvHD after HCT in paediatric and adult patients ( 10 , 11 , 17 – 19 , 49 , 98 , 100 – 110 ).…”

“…Koning et al reported a retrospective dual-centre study of CD4 + T-cell reconstitution in paediatric patients following HCT with an aim to identify predictors of survival outcomes after aGvHD ( 10 ). Achieving CD4 + T-cell IR within 100 days after HCT did not decrease the risk of developing aGvHD but was strongly predictive for better survival outcomes (non-relapse mortality and overall survival) after moderate-to-severe aGvHD.…”

Lymphoid and myeloid immune cell reconstitution after nicotinamide-expanded cord blood transplantation

“…We and others have recently shown that adequate CD4+ T-cell IR (CD4 + IR) is crucial for favorable survival outcomes [ 1 , 2 , 6 – 8 ]. Patients with adequate CD4 + IR (>50 × 10 6 CD4+ T-cells/L blood, within 100 days after HCT) had a lower risk of viral reactivation [ 1 ], virus-related morbidity and mortality [ 1 ], aGvHD-related mortality [ 27 ], and relapse-related mortality [ 6 , 8 ]. In addition, IR of other immune cell subsets, such as natural killer (NK)-cells [ 28 – 30 ], CD8+ T-cells [ 31 – 33 ], and B-cells [ 34 – 39 ], were also related to HCT outcome.…”

Combined Analysis of Early CD4+ T Cell Counts and CMV Serostatus May Improve CMV Risk Assessment after Allogeneic Hematopoietic Cell Transplantation

“…This association is based on the contribution of the helper T cell immunity in ensuring pathogen defence against CMV and other common viruses as well as its major role in the alloreactive eradication of residual malignant cells after HCT [ 13 ]. Despite the successful validation of these T helper cell cut-off levels in paediatric patients receiving T cell depletion with anti-thymocyte globulin (ATG) [ 14 ], in patients with graft-versus-host disease (GVHD) [ 15 ], and in HCT with different graft sources [ 16 ], their application in the context of CMV exposed patients is limited by the median onset of the first CMV reactivation episodes after HCT, which is as early as day+33 without prophylaxis [ 5 ]. We hypothesized that an unsupervised machine learning approach, namely a k -means data clustering, of CD4 + helper T cell counts at day+30 after HCT, combined with the R serostatus might identify early predictors of CMV-dependent clinical outcomes, and thus might improve the CMV-based risk assessment post-transplantation.…”