Early CD4+ T-Cell Reconstitution Is an Excellent Predictor for Survival and Non-Relapse Mortality in Pediatric and Young Adult Patients Who Develop Moderate to Severe Acute Graft-Versus-Host-Disease; A Dual Center Validation

Abstract

Background Acute Graft-versus-Host-Disease (aGvHD) is a major cause of morbidity and mortality after allogeneic hematopoietic (stem) cell transplantation (HCT). Studies evaluating the relation between immune reconstitution (IR) and aGvHD are largely lacking. We previously showed that successful CD4+ IR strongly predicts non-relapse mortality (NRM) and survival after HCT. We hypothesized that adequate CD4+ IR may influence outcomes in patients who develop aGvHD, because (CD4+) T regulatory (Tregs) play a crucial role in tolerance. Therefore, we studied the relation between CD4+ IR after HCT and outcomes (survival, NRM) in patients who developed moderate to severe aGvHD, in 2 separate pediatric / young adult cohorts. Methods Patients receiving their first allogeneic HCT at the UMC Utrecht / Princess Maxima Center (UMC/PMC; 2004 and 2018) and at Memorial Sloan Kettering Cancer Center (MSK; 2008 – 2018), New York were included. No restrictions applied in terms of donor source, indication, conditioning, age. CD4+ IR was measured every 2-4 weeks. The main outcomes of interest were 5-year overall survival (OS) and 5-year NRM, stratified for aGvHD 2-4 and adequate CD4+ IR (twice >50*106 CD4+/uL) prior to aGvHD onset. Fine and Gray competing risk models and cox-proportional hazard models were used. Results 591 patients (276 UMC/PMC; 315 MSK) were included (table 1); median age at UMC/PMC was 7.06 years (range 0.16-22.74) and at MSK 10.4 years (range 0.1-35.6). At UMC/PMC 73 (26.4%) and at MSK 70 (22.2%) patients developed aGvHD 2-4, while 29 (10.5%) and 32 (10.2%) developed aGvHD 3-4. At UMC/PMC 35% (26/73) developed aGvHD in the presence of CD4+ IR and at MSK 64% (45/70). The 5-yr OS for patients without aGvHD at UMC/PMC and MSK was 75% and 72%, resp. The only multivariate predictor for OS and NRM in patients with aGvHD 2-4 was CD4+ IR. In both cohorts, CD4+ IR before onset of aGvHD 2-4 was associated with higher 5-yrs OS compared to those who developed aGvHD 2-4 without CD4+ IR; 77% vs 48%, p Interpretation In 2 separate cohorts adequate ‘CD4+ IR prior to onset aGvHD' was found to be a simple and robust predictor for survival and NRM. These findings provide insight in the importance of adequate IR for HCT patients to survive moderate to severe aGvHD. Finding strategies to better predict CD4+ T cell recovery after HCT may influence survival chances.