Donor clonal hematopoiesis and recipient outcomes after transplantation

Background Clonal hematopoiesis (CH) can be transmitted from donor to recipient during allogeneic hematopoietic cell transplantation. Exclusion of candidate donors with CH is controversial since its impact on recipient outcomes and graft alloimmune function is uncertain. Methods We performed targeted error-corrected sequencing on samples from 1727 donors aged 40 or older and assessed the effect of donor CH on recipient clinical outcomes. We measured long-term engraftment of 102 donor clones and cytokine levels in 256 recipients at 3 and 12 months after transplant. Results CH was present in 22.5% of donors, with DNMT3A (14.6%) and TET2 (5.2%) mutations being most common; 85% of donor clones showed long-term engraftment in recipients after transplantation, including clones with variant allele fraction (VAF)<0.01. DNMT3A-CH with VAF≥0.01, but not smaller clones, was associated with improved recipient overall (HR 0.79, P=0.042) and progression-free survival (HR 0.72, P=0.003) after adjustment for significant clinical variables. In patients who received calcineurin-based GVHD prophylaxis, donor DNMT3A-CH was associated with reduced relapse (sHR 0.59, P=0.014), increased chronic GVHD (sHR 1.36, P=0.042), and higher IL-12p70 levels in recipients. No recipient of sole DNMT3A or TET2-CH developed donor cell leukemia (DCL). In 7 of 8 cases, DCL evolved from donor CH with rare TP53 or splicing factor mutations or from donors carrying germline DDX41 mutations. Conclusion Donor CH is closely associated with clinical outcomes in transplant recipients, with differential impact on graft alloimmune function and potential for leukemic transformation related to mutated gene and somatic clonal abundance. Donor DNMT3A-CH is associated with improved recipient survival due to reduced relapse risk, and with an augmented network of inflammatory cytokines in recipients. Risk of DCL in allogeneic transplantation is driven by pre-existing somatic MDS-associated mutations or germline predisposition in donors.