Early findings after integration of donor‐derived cell‐free DNA into clinical care following pediatric heart transplantation

Abstract

Background: Endomyocardial biopsy (EMB) is costly and discomforting yet remains a key component of surveillance after pediatric heart transplantation (HT). Donorderived cell-free DNA (dd-cfDNA) has been histologically validated with high negative predictive value, offering an alternative to surveillance EMB (sEMB). Methods:We implemented an alternative surveillance protocol using commercially available dd-cfDNA assays in place of sEMB after pediatric HT. Recipients ≧7 months post-HT with reassuring clinical assessment were referred for dd-cfDNA. When not elevated above the manufacturers' threshold, sEMB was deferred. Subsequent clinical status and results of follow-up EMB were analyzed.Results: Over 17 months, 58 recipients [34% female, median age at HT 3.1 years (IQR 0.6-10.6)] had dd-cfDNA assessed per protocol. Median age was 14.8 years (8.4-18.3) and time from HT 6.0 years (2.2-11.2). Forty-seven (81%) had non-elevated dd-cfDNA and 11 (19%) were elevated. During a median of 8.7 months (4.2-15), all are alive without allograft loss/new dysfunction. Among those with non-elevated dd-cfDNA, 24 (51%) had subsequent sEMB at 12.1 months (6.9-12.9) with 23 showing no acute rejection (AR): grade 0R/pAMR0 (n = 16); 1R(1A)/pAMR0 (n = 7). One had AR (grade 2R(3A)/pAMR0) on follow-up sEMB after decreased immunosuppression following a diagnosis of PTLD. All 11 with elevated dd-cfDNA had reflex EMB at 19 days with AR in 4: grade 1R(1B-2)/pAMR0 (n = 3); 1R(1B)/pAMR2 (n = 1).

Rejection surveillance in pediatric heart transplant recipients: Critical reflection on the role of frequent and long‐term routine surveillance endomyocardial biopsies and comprehensive review of non‐invasive rejection screening tools

“…Feingold et al recently published their work on early, clinical use of dd‐cfDNA as an alternative surveillance protocol in place of RSB 113 . In this new protocol, pediatric HT recipients over 7‐month post‐HT with reassuring clinical assessment received dd‐cfDNA with reflex EMB when elevated above the manufacturer's threshold.…”

The methylome and cell-free DNA: current applications in medicine and pediatric disease

“…With time, using this marker will likely result in a decreased need for surveillance allograft biopsies and lead to increased selectivity in deciding which patients require for-cause allograft biopsies. 76 – 78 Clinically available testing currently exists and modifications to current methods allow for exploiting single-nucleotide polymorphisms to identify ddcfDNA without knowing donor genotype. 79 Despite the ability to recognize the source of cfDNA in the case of cancer or transplant rejection, the clinical applications of cfDNA are still limited.…”

A Review of Biomarkers of Cardiac Allograft Rejection: Toward an Integrated Diagnosis of Rejection

“…The 2022 updated guidelines from the International Society for Heart and Lung Transplantation (ISHLT) support the use of dd-cfDNA as a valid non-invasive biomarker to rule out rejection. As a result, some centers, mostly from North America, have adopted dd-cfDNA for rejection surveillance and to reduce the number of EMB during the period of 3 months to 1 year post-transplantation [ 34 ]. However, the clinical application of dd-cfDNA is still limited by costs and availability of platforms, particularly outside the US [ 32 , 33 ].…”