Donor Clonal Hematopoiesis and Recipient Outcomes After Transplantation

Abstract

PURPOSE Clonal hematopoiesis (CH) can be transmitted from a donor to a 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. PATIENTS AND METHODS We performed targeted error-corrected sequencing on samples from 1,727 donors age 40 years 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 a variant allele fraction < 0.01. DNMT3A-CH with a variant allele fraction ≥ 0.01, but not smaller clones, was associated with improved recipient overall (hazard ratio [HR], 0.79; P = .042) and progression-free survival (HR, 0.72; P = .003) after adjustment for significant clinical variables. In patients who received calcineurin-based graft-versus-host disease prophylaxis, donor DNMT3A-CH was associated with reduced relapse (subdistribution HR, 0.59; P = .014), increased chronic graft-versus-host disease (subdistribution HR, 1.36; P = .042), and higher interleukin-12p70 levels in recipients. No recipient of sole DNMT3A or TET2-CH developed donor cell leukemia (DCL). In seven of eight 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 because of reduced relapse risk and with an augmented network of inflammatory cytokines in recipients. Risk of DCL in allogeneic hematopoietic cell transplantation is driven by somatic myelodysplastic syndrome–associated mutations or germline predisposition in donors.

Measures of Clonal Hematopoiesis: Are We Missing Something?

“…Rather, these studies rely on the detection of one or a few clones with somatic mutations above a critical threshold for detection. Depending on the sensitivity of the applied sequencing technique, this threshold can vary from 2%, or 0.5%, or anything in between ( 19 , 20 , 31 ). Consequently, we also introduced a threshold for detection into the model, and defined the CH index ( I CH ) as the fraction of all blood cells, which carry a genetic mark with a frequency above this minimal threshold.…”

Clonal Hematopoiesis and the Risk of Hematologic Malignancies after Curative Therapies for Sickle Cell Disease

“…The number of somatic mutations increases with age, and CH appears to be a common age-related condition. While CH is exceedingly rare in people under the age of 40 years, its prevalence increases with each decade of life, reaching nearly 40% in individuals 60 years and older [ 51 ]. However, the prevalence of CH greatly depends on the characteristics of the molecular assays applied to detect somatic mutations.…”

“…Donor-cell leukemia developed only in recipients whose donors had multiple mutations, mutations in spliceosome machinery, TP53 , or germline DDX41 mutation. Interestingly, none of the recipients whose donors had sole DNMT3A or TET2 mutations developed DCL [ 51 ].…”

The Reconstitution Dynamics of Cultivated Hematopoietic Stem Cells and Progenitors Is Independent of Age

“…Fortunately, with the emergence of less toxic, particularly, reduced-intensity conditioning regimens (RICs), the application of HSCTs as a potential treatment option for increasingly older patients has been reevaluated over the last decades [ 9 , 10 , 11 ]. Despite ongoing efforts to evaluate the risk associated with donor clonal hematopoiesis [ 12 , 13 ], the questions remain of how the dynamics of hematopoietic recovery after HSCT are affected by the age of the donor or of the recipient and of how this process might be accelerated in order to alleviate infections in the early post-transplant phase.…”