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

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 immune reconstitution (IR; CD4 ⁺ IR) predicts survival after HCT. Here, we studied the relation between CD4 ⁺ IR and survival in patients developing aGVHD. Pediatric patients undergoing first allogeneic HCT at University Medical Center Utrecht (UMC)/Princess Máxima Center (PMC) or Memorial Sloan Kettering Cancer Center (MSK) were included. Primary outcomes were nonrelapse mortality (NRM) and overall survival (OS), stratified for aGVHD and CD4 ⁺ IR, defined as ≥50 CD4 ⁺ T cells per μL within 100 days after HCT or before aGVHD onset. Multivariate and time-to-event Cox proportional hazards models were applied, and 591 patients (UMC/PMC, n = 276; MSK, n = 315) were included. NRM in patients with grade 3 to 4 aGVHD with or without CD4 ⁺ IR within 100 days after HCT was 30% vs 80% (P = .02) at UMC/PMC and 5% vs 67% (P = .02) at MSK. This was associated with lower OS without CD4 ⁺ IR (UMC/PMC, 61% vs 20%; P = .04; MSK, 75% vs 33%; P =. 12). Inadequate CD4 ⁺ IR before aGVHD onset was associated with significantly higher NRM (74% vs 12%; P < .001) and inferior OS (24% vs 78%; P < .001). In this retrospective analysis, we demonstrate that early CD4 ⁺ IR, a simple and robust marker predictive of outcomes after HCT, is associated with survival after moderate to severe aGVHD. This association must be confirmed prospectively but suggests strategies to improve T-cell recovery after HCT may influence survival in patients developing aGVHD. Key Points: • Early CD4 ⁺ IR predicts OS and NRM after moderate to severe aGVHD. • Approaches to augment early and predictable CD4 ⁺ IR could improve survival in patients developing aGVHD.