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Published on: September 6, 2017
Clinical Utility of Combined Donor-Derived Cell-Free DNA and Peripheral Gene-Expression-Profiling in Heart Transplant
Cathrine M Moeller1,2, Andrea Fernandez Valledor1,3, Daniel Oren1
1Division of Cardiology, Department of Medicine, Columbia University Irving Medical Center, New York, New York, USA.
Insights
Combining donor-derived cell-free DNA (dd-cfDNA) and gene expression profiling (GEP) in heart transplant recipients identifies high-risk patients. Positive results for both dd-cfDNA and GEP significantly increase mortality risk.
Area of Science:
- Cardiology
- Transplant Medicine
- Molecular Diagnostics
Background:
- Donor-derived cell-free DNA (dd-cfDNA) and peripheral gene-expression profiling (pGEP) are emerging tools for monitoring heart transplant (HT) recipients for rejection.
- Assessing the combined utility of these non-invasive biomarkers is crucial for improving patient outcomes.
Purpose of the Study:
- To evaluate the combined diagnostic and prognostic value of dd-cfDNA (AlloSure) and pGEP (AlloMap) in heart transplant recipients.
- To correlate combined biomarker results with endomyocardial biopsy (EMB) findings and patient mortality.
Main Methods:
- A retrospective analysis of 2388 paired dd-cfDNA/GEP samples from 257 HT recipients between 2019 and 2023.
- Rejection was defined by EMB (ISHLT grade ≥ 1R/1B/pAMR > 0) within 30 days of sampling.
- Positive dd-cfDNA was defined as ≥0.12%, and positive GEP as >30 (within 5 months post-transplant) or >34 (thereafter).
Main Results:
- Of 2388 samples, 6.6% were positive for both dd-cfDNA and GEP ((+)dd-cfDNA/(+)GEP).
- The (+)dd-cfDNA/(+)GEP group showed the highest rejection rates (15.1%) and a 6.1-fold increased risk of mortality compared to the negative concordant group.
- Discordant results also showed elevated mortality risks, with (+)dd-cfDNA/(-)GEP having a 5.6-fold increased risk.
Conclusions:
- Combined dd-cfDNA and GEP testing can identify heart transplant recipients at higher risk for rejection and mortality.
- The (+)dd-cfDNA/(+)GEP group exhibits significantly increased mortality risk, highlighting the prognostic value of combined biomarker assessment.
- These non-invasive markers aid in risk stratification and potentially guide clinical management decisions in heart transplant recipients.
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.
