Donor Clonal Hematopoiesis and Recipient Outcomes After Transplantation

Area of Science:

• Hematology
• Oncology
• Immunology

Background:

• Clonal hematopoiesis (CH) is the presence of somatic mutations in hematopoietic stem cells, increasing with age.
• CH can be transmitted during allogeneic hematopoietic cell transplantation (HCT).
• The clinical significance of donor CH in HCT recipients remains controversial.

Purpose of the Study:

• To investigate the impact of donor CH on recipient outcomes after allogeneic HCT.
• To assess the effect of donor CH on graft alloimmune function.
• To evaluate the risk of leukemic transformation in recipients of grafts from donors with CH.

Main Methods:

• Targeted error-corrected sequencing of 1,727 donors aged 40+.
• Assessment of donor CH effects on recipient clinical outcomes, including survival and relapse.
• Measurement of long-term engraftment of donor clones and cytokine levels in recipients.

Main Results:

• CH was found in 22.5% of donors, with DNMT3A and TET2 mutations being most common.
• Donor DNMT3A-CH with variant allele fraction ≥ 0.01 was linked to improved recipient overall and progression-free survival.
• Donor DNMT3A-CH was associated with reduced relapse, increased chronic graft-versus-host disease, and higher IL-12p70 levels.

Conclusions:

• Donor CH significantly impacts HCT recipient outcomes, influencing survival, relapse, and graft alloimmune function.
• Donor DNMT3A-CH is associated with improved survival due to reduced relapse and augmented inflammatory cytokines.
• Donor cell leukemia risk is linked to specific mutations (TP53, splicing factors) or germline predispositions (DDX41).