Transplantation and old stem cell age independently increase the risk of clonal hematopoiesis in long-term survivors of pediatric HCT

In pediatric hematopoietic cell transplantation (HCT) recipients, transplanted donor cells may need to function far beyond normal human lifespan. Here, we investigated the risk of clonal hematopoiesis (CH) in 144 pediatric long-term HCT survivors, compared to 115 healthy controls. CH was detected in 16% of HCT survivors, at variant allele frequencies (VAFs) of 0.01-0.31. Mutations were predominantly in DNMT3A (80%) and TET2 (20%). Older stem cell age and the HCT procedure independently increased the risk of CH (odds ratios 1.07 per year increase (p<0.001) and 2.61 for HCT (p=0.02)), indicating both aging- and transplantation-induced effects. Large clones (VAF >0.10) were found exclusively in HCT recipients. Notably, CH was also detected within 15 years after cord blood HCT. Inflammatory processes around graft infusion were associated with CH presence. Future studies are required to track the evolution of post-transplant CH and its impact on future cardiovascular disease, second malignancies and overall survival. Significance statementAs the number of long-term HCT survivors continues to increase, so does the population at risk of long-term effects. We demonstrate that pediatric HCT survivors are at increased risk of clonal hematopoiesis compared to the general population. Given the young age of these recipients, our data emphasize the need for prospective studies to assess the potential health consequences of post-transplant CH.