Prognostic Implications and Characteristics of Low dd-cfDNA Results in Heart Transplant Patients with Biopsy Proven Rejection

Abstract

<h3>Purpose</h3> Donor-derived cell-free DNA (dd-cfDNA) has emerged as an important noninvasive marker of heart transplant allograft injury. The characteristics and prognostic implications of low level dd-cfDNA in patients with histological evidence of acute rejection is not known. Although considered the gold standard, endomyocardial biopsy is limited to focal tissue sampling and is subject to interobserver variability in its interpretation. <h3>Methods</h3> Patients enrolled in the Surveillance HeartCare Outcomes Registry (SHORE) with biopsy proven acute cellular rejection (ACR) and antibody mediated rejection (AMR) who had low levels of dd-cfDNA (<0.15%) were evaluated. A targeted amplification, next generation-sequencing assay (AlloSure®; CareDx, Inc.) was used to detect dd-cfDNA. <h3>Results</h3> The SHORE registry had 2029 patients in total. Patients with ACR 1R were excluded. Only those patients who had a dd-cfDNA level within 30 days of biopsy (mean 2.7 days) were included. 61 patients (male 78%, median age 48 years) had low dd-cfDNA and endomyocardial biopsy evidence of ACR ≥2R and/or AMR ≥1R. Mean duration of the biopsy from the time of transplant was 196.31 days (IQR 88-257 days). ACR was seen in 36 patients (35=2R, 1=3R) and AMR was seen in 27 patients (21=pAMR 1(H+), 6=pAMR2). 2 patients had both ACR and AMR. The mean ejection fraction (EF) at the time of the rejection was mostly preserved (ACR 2R=EF 62.8±5.6%,ACR 3R=EF 47.5%, and AMR 1=EF 60.9±6%, AMR 2=EF 61±4.7%). 2 patients (3.3%) died 330±31days after the initial diagnosis of rejection. None of the patients developed graft dysfunction at one year follow up. One patient developed coronary artery vasculopathy and 7 patients developed <i>de novo</i> DSA. <h3>Conclusion</h3> Patients with low dd-cfDNA and biopsy-confirmed rejection typically had lower grades of rejection and maintained preserved left ventricular function on echocardiography. There was no immediate death after rejection or graft dysfunction. In this preliminary analysis, low dd-cfDNA despite biopsy evidence of rejection appears to have favorable prognosis. Discordance between light-based histology and molecular histology has shown better correlation with dd-cfDNA levels, and so consideration of dd-cfDNA in treatment and immunosuppression management requires ongoing evaluation.