Bridging the Gap: Clinical Predictors and Immune Recovery as Determinants of Hematopoietic Cell Transplant Success

Outcomes after pediatric allogeneic hematopoietic cell transplantation (allo-HCT) have improved substantially over recent decades due to advances in donor selection, conditioning regimens, supportive care, and graft-versus-host disease (GVHD) management. Clinical predictors remain essential for pre-transplant risk stratification, but do not fully explain individual patient trajectories, motivating the incorporation of biological markers such as immune reconstitution for personalized care.
In a cohort of patients with Fanconi anemia transplanted between 2007 and 2020, we demonstrated excellent survival (5-year overall survival 83.2%, event-free survival 74%), with older age, HLA mismatch, and transplant era predicting outcomes. Ex vivo T cell depletion showed borderline negative associations with survival and increased graft failure, underscoring the need to evaluate graft manipulation strategies comprehensively. In a separate analysis of second HCT with cord blood grafts for post-transplant relapse, we found encouraging outcomes despite advanced disease, with universal engraftment, low relapse incidence, and decreasing treatment-related mortality over time, supporting cord blood as a viable salvage option.
In a multi-institutional cohort of 503 patients transplanted between 2008 and 2019, we demonstrated that achieving CD4 counts above 50 cells/µL and B cell counts above 25 cells/µL before day 100 powerfully predicts transplant outcomes. Combined CD4 and B cell recovery was associated with substantially reduced non-relapse mortality (NRM), lower rates of acute and chronic GVHD, and reduced relapse risk in patients with AML. These markers are readily available through standardized clinical assays, supporting near-term implementation for risk stratification, if confirmed in other cohorts. In CD34-selected ex vivo T cell depleted transplants, B cell recovery showed no significant association with NRM, highlighting that immune reconstitution findings should not be generalized across different transplant platforms without platform-specific validation.
Clinical predictors enable pre-transplant planning, while immune reconstitution markers provide dynamic post-transplant risk information reflecting how the chosen strategy performs biologically in the individual patient. This integrated approach can guide targeted interventions: patients with delayed CD4 and B cell recovery may benefit from intensified surveillance or immunosuppression modulation, while those with rapid recovery might tolerate earlier tapering of agents for infection and GVHD prophylaxis. We also discuss that high pre-transplant anti-thymocyte globulin (ATG) exposure prevents GVHD even when post-transplant levels are minimal, suggesting immunomodulation of antigen-presenting cells as a key mechanism beyond simple T cell depletion.
Variability in immune monitoring practices across centers remains a critical barrier to progress. The IMPACT consortium — comprising six pediatric transplant centers across Europe and the United States — enables standardized immune and microbiota profiling, improving harmonization and increasing statistical power for discovery and validation studies.
This thesis demonstrates that optimizing outcomes in pediatric and young adult allo-HCT requires integrating clinical and biological predictors. Early immune reconstitution, particularly combined CD4 and B cell recovery, serves as a powerful dynamic biomarker predicting infection risk, NRM, GVHD, and relapse. Moving forward, the field must prioritize harmonized monitoring protocols, prospective validation of immune-guided interventions, and collaborative efforts through consortia like IMPACT to transform immune reconstitution from descriptive observation into an actionable tool for precision transplantation.