In a study reported in the Journal of Clinical Oncology, Gibson et al identified significant associations of donor clonal hematopoiesis with outcomes in patients undergoing allogeneic hematopoietic stem cell transplantation (HCT).
As stated by the investigators, “Clonal hematopoiesis can be transmitted from a donor to a recipient during allogeneic HCT. Exclusion of candidate donors with clonal hematopoiesis is controversial since its impact on recipient outcomes and graft alloimmune function is uncertain.”
Study Details
Targeted error-corrected sequencing was performed on samples from 1,727 donors aged ≥ 40 years from cohorts at Dana-Farber Cancer Institute and Johns Hopkins University, with the effect of donor clonal hematopoiesis on recipient clinical outcomes being analyzed. Long-term engraftment of donor clones and cytokine levels after transplantation were assessed in subgroups of recipients.
Key Findings
Clonal hematopoiesis was present in 22.5% of donors, with DNMT3A (14.6%) and TET2 (5.2%) mutations being the most common.
In multivariate analysis including recipient and donor age, donor-recipient sex mismatch, HCT-specific comorbidity index score, conditioning intensity, donor type, disease category, and disease risk index classification, recipients of donor clonal hematopoiesis with variant allele frequency (VAF) ≥ 0.01, but not smaller clones, had improved progression-free survival (hazard ratio [HR] = 0.79, P = .011) vs recipients with donors with no clonal hematopoiesis.
Among donor clonal hematopoiesis types, only donor DNMT3A-clonal hematopoiesis was significantly associated with outcomes. In multivariate analysis, DNMT3A-clonal hematopoiesis with VAF ≥ 0.01 was associated with improved recipient overall survival (HR = 0.79, P = .042) and progression-free survival (HR = 0.72, P = .003) vs recipients with donors who did not have clonal hematopoiesis with VAF ≥ 0.01. In patients receiving calcineurin-based graft-vs-host disease prophylaxis, donor DNMT3A-clonal hematopoiesis was associated with reduced relapse (subdistribution HR = 0.59, P = .014), increased chronic graft-vs-host disease (subdistribution HR = 1.36, P = .042), and higher interleukin-12p70 levels in recipients.
Overall, 85% of 102 donor clones examined exhibited long-term engraftment in recipients, including clones with VAF < 0.01.
No recipient of sole DNMT3A- or TET2-clonal hematopoiesis developed donor cell leukemia. Donor cell leukemia developed in seven of eight cases involving donor clonal hematopoiesis with rare TP53 or splicing factor mutations or donors carrying germline DDX41 mutations.
The investigators concluded, “Donor clonal hematopoiesis 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-clonal hematopoiesis is associated with improved recipient survival because of reduced relapse risk and with an augmented network of inflammatory cytokines in recipients. Risk of [donor cell leukemia] in allogeneic hematopoietic cell transplantation is driven by somatic myelodysplastic syndrome–associated mutations or germline predisposition in donors.”
R. Coleman Lindsley, MD, PhD, of Dana-Farber Cancer Institute, is the corresponding author for the Journal of Clinical Oncology article.
Disclosure: The study was supported by grants from the National Institutes of Health, Damon Runyon Cancer Research Foundation, Alan and Lisa Dynner Fund, and others. For full disclosures of the study authors, visit ascopubs.org.
