Prevalence of Clinical Events Following High Donor Derived Cell Free DNA in the Absence of Rejection in Heart Transplant Recipients

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Purpose Donor-derived cell free DNA (dd-cfDNA) is a noninvasive biomarker used to assess graft injury following heart transplant (HTx). While the relationship between increased levels of dd-cfDNA and acute cellular rejection (ACR) and antibody mediated rejection (AMR) has been well studied, less is known about the frequency of other processes that damage the allograft following an elevated dd-cfDNA measurement. The goal of this analysis was to assess the prevalence of clinical events following a high dd-cfDNA measurement in the absence of rejection. Methods This retrospective study included 223 HTx recipients from the Donor-Derived Cell-Free DNA-Outcomes AlloMap Registry (D-OAR) with elevated dd-cfDNA (AlloSure®), defined as a level ≥0.20% that did not occur within 14 days of biopsy proven ACR (grade ≥2R) or AMR (pAMR≥1). Clinical events included the presence of donor specific antibodies (DSA), cardiac allograft vasculopathy (CAV; ISHLT grade ≥1), graft dysfunction [left ventricular ejection fraction (LVEF) ≤45% or a proportional decrease in LVEF ≥25% from the first D-OAR study visit], ACR, AMR and death. Clinical data were collected for 180 days following the first elevated dd-cfDNA. Allosensitization was defined as a pre-transplant panel reactive antibody ≥10%. Results The study consisted of 68% men and 71% Caucasians (mean ± SD age at HTx 52 ± 14 years), with non-ischemic cardiomyopathy (46%) representing the primary reason for HTx. The median time post-HTx to the first non-rejection elevated dd-cfDNA was 241 days (IQR 154-362). Fifty-seven of the 223 patients (26%), of whom 6 were allosensitized, experienced 70 clinical events in the 180 days post-elevated dd-cfDNA. The presence of at least one DSA (n=36) was the most common clinical event, of which 28/36 (78%) were de novo DSA. Graft dysfunction (n=14), CAV (n=9), AMR (n=5), death (n=4), and ACR (n=2) were the next most common. Median time (IQR) from elevated dd-cfDNA to these events was as follows: DSA, 37 days (15-104); graft dysfunction, 22 days (0-77); AMR, 70 days (42-91); and death, 100 days (75-124). Conclusion Elevated dd-cfDNA levels in the absence of allograft rejection appeared to precede the development of clinically relevant events within the next 6 months. Further studies are needed to determine whether elevated dd-cfDNA should trigger a change in clinical management. Donor-derived cell free DNA (dd-cfDNA) is a noninvasive biomarker used to assess graft injury following heart transplant (HTx). While the relationship between increased levels of dd-cfDNA and acute cellular rejection (ACR) and antibody mediated rejection (AMR) has been well studied, less is known about the frequency of other processes that damage the allograft following an elevated dd-cfDNA measurement. The goal of this analysis was to assess the prevalence of clinical events following a high dd-cfDNA measurement in the absence of rejection. This retrospective study included 223 HTx recipients from the Donor-Derived Cell-Free DNA-Outcomes AlloMap Registry (D-OAR) with elevated dd-cfDNA (AlloSure®), defined as a level ≥0.20% that did not occur within 14 days of biopsy proven ACR (grade ≥2R) or AMR (pAMR≥1). Clinical events included the presence of donor specific antibodies (DSA), cardiac allograft vasculopathy (CAV; ISHLT grade ≥1), graft dysfunction [left ventricular ejection fraction (LVEF) ≤45% or a proportional decrease in LVEF ≥25% from the first D-OAR study visit], ACR, AMR and death. Clinical data were collected for 180 days following the first elevated dd-cfDNA. Allosensitization was defined as a pre-transplant panel reactive antibody ≥10%. The study consisted of 68% men and 71% Caucasians (mean ± SD age at HTx 52 ± 14 years), with non-ischemic cardiomyopathy (46%) representing the primary reason for HTx. The median time post-HTx to the first non-rejection elevated dd-cfDNA was 241 days (IQR 154-362). Fifty-seven of the 223 patients (26%), of whom 6 were allosensitized, experienced 70 clinical events in the 180 days post-elevated dd-cfDNA. The presence of at least one DSA (n=36) was the most common clinical event, of which 28/36 (78%) were de novo DSA. Graft dysfunction (n=14), CAV (n=9), AMR (n=5), death (n=4), and ACR (n=2) were the next most common. Median time (IQR) from elevated dd-cfDNA to these events was as follows: DSA, 37 days (15-104); graft dysfunction, 22 days (0-77); AMR, 70 days (42-91); and death, 100 days (75-124). Elevated dd-cfDNA levels in the absence of allograft rejection appeared to precede the development of clinically relevant events within the next 6 months. Further studies are needed to determine whether elevated dd-cfDNA should trigger a change in clinical management.