Clinical Utility of Combined Donor-Derived Cell-Free DNA and Peripheral Gene-Expression-Profiling in Heart Transplant Recipients.
Academic Article
Overview
abstract
INTRODUCTION: Donor-derived-cell-free-DNA (dd-cfDNA) and peripheral-gene-expression-profiling (pGEP) are tools for monitoring heart transplant (HT) recipients for rejection. We aimed to assess the combined utility of dd-cfDNA/pGEP in HT recipients. METHODS: We evaluated HT recipients between 2019 and 2023 with a paired dd-cfDNA(AlloSure-AS)/GEP(AlloMap-AM) results (HeartCare-CareDx-CA-USA). Multi-organ-transplant recipients were excluded. Samples were assessed with endomyocardial biopsy <30 days from the day of sample drawn, with rejection defined as ISHLT grade ≥ 1R/1B/pAMR > 0. A positive GEP test score was defined as >30 within 5 months posttransplant and 34 thereafter; a positive dd-cfDNA result was ≥0.12%. Samples were categorized into four groups based on dd-cfDNA/GEP results. RESULTS: Of the 2388 samples (257 patients) included, 1437 samples (60.2%) were (-)dd-cfDNA/(-)GEP, 419 samples (17.5%) were (-)dd-cfDNA/(+)GEP, 375 samples (15.7%) were (+)dd-cfDNA/(-)GEP, and 157 samples (6.6%) were (+)dd-cfDNA/(+)GEP. The median age was 55 years and 27% were females. The median time from HT to sample was 10 months [IQR 5-18]. The median positive AS level was 0.22% [IQR 0.15-0.48]. Twenty-nine percent of the samples had correlated EMB results, mostly in the (+)dd-cfDNA/(+)GEP group (55%), followed by the discordant groups (+)dd-cfDNA/(-)GEP (49%) and (-)dd-cfDNA/(+)GEP (32%), and the (-)dd-cfDNA/(-)GEP group (20%; p < 0.001). Rejection occurred in 7.1% of samples, with the highest rates in the (+)dd-cfDNA/(+)GEP group (15.1%), followed by the (+)dd-cfDNA/(-)GEP (10.9%), (-)dd-cfDNA/(-)GEP (3.8%), and (-)dd-cfDNA/(+)GEP (3.7%) (p < 0.001) groups. The median follow-up time was 29 months [IQR 16-42]. The (+)dd-cfDNA/(+)GEP group demonstrated an increased risk of mortality (HR: 6.1, 95% CI [2.5-14.8]; p < 0.001) compared to (-)dd-cfDNA/(-)GEP group. Similarly the (+)dd-cfDNA/(-)GEP group demonstrated an almost 6-fold risk of mortality (HR: 5.6, 95% CI [1.8-17.5]; p = 0.003). CONCLUSIONS: Patients with (+)dd-cfDNA/(+)GEP result were more frequently biopsied and had higher rates of rejection. This group exhibited a six-fold increased risk of mortality and a seven-fold increased risk of mortality at dd-cfDNA thresholds of 0.12% and 0.20%, respectively, compared to the negative concordant group.
