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 statement As 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.

DSN has stocks in Madrigal Pharmaceuticals. SN was advisor for Sobi. CAL is on a data and safety monitoring board for ExCellThera and was medical advisor for Sobi and Orchard Therapeutics.

This study was financially supported by a VENI grant of the Netherlands Organization for Scientific Research (NWO) (grant number VI.Veni.202.021 to MEB), a physician scientist grant of the European Hematology Association (to MEB), a John Hansen research grant from the DKMS and a KiKa project grant (project number 418). The KiKa project grant supported the salary of KFM. The funders had no role in the design, execution or writing of this work, nor in the decision to submit results.

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The ethics committee of the Princess Maxima Center for Pediatric Oncology (NedMec) gave ethical approval for this work.

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