Donor Derived Cell Free DNA Levels are Predictive of Clinical Events in Stable Heart Transplant Recipients

Abstract

Elevated donor derived-cell free DNA (dd-cfDNA) level is a reliable marker of heart transplant (HT) rejection. There is inter- and intra-patient variation in dd-cfDNA levels of unclear clinical significance at times when patients are not experiencing rejection. We used data from the Donor-Derived Cell-Free DNA-Outcomes AlloMap Registry (D-OAR). Standard deviation (SD) and area under the curve (AUC) of dd-cfDNA levels were determined for each subject with censoring of levels after a clinical endpoint. The primary outcome was a composite of all-cause mortality, graft dysfunction (LVEF < 40%, or a 25% decrease in LVEF), rejection, or cardiac allograft vasculopathy (CAV). All-cause mortality and graft dysfunction was a secondary endpoint. Thresholds of SD and AUC were determined with receiver operator curves. Multivariate Cox proportional hazards models were adjusted for recipient age, race, and sex; donor sex; and donor/recipient CMV serostatus. D-OAR includes 740 HT recipients with 2447 dd-cfDNA measurements. Median time post transplant to enrollment was 169 days; median age was 57 years; 26% were female; 70% were Caucasian; and 17% were Black. There were no sex or race differences in dd-cfDNA SD or AUC. There were 134 occurrences of the primary outcome. SD was significantly elevated in subjects with the individual endpoints of rejection, graft dysfunction, and CAV, and AUC was significantly elevated in subjects with rejection. For occurrence of the primary outcome, multivariate Cox proportional hazards models demonstrated no difference between high and low SD groups; however, there was a HR of 0.52 (95% CI 0.30-0.92, p-value 0.03) for being below the AUC threshold. For the secondary endpoint, there was a HR of 0.17 (95% CI 0.04-0.66, p-value 0.01) for being below the SD threshold, but no AUC relationship. During presumed times of stability, dd-cfDNA SD and AUC may have clinical utility in identifying patients in high risk groups for adverse clinical events.