Using combined molecular testing to monitor heart transplant patients for allograft injury is better than using either test alone and could support remote testing in post-transplant care, according to new data published May 15 in the Journal of Heart and Lung Transplantation (JHLT).
The study presented a first report on the Surveillance HeartCare Outcomes Registry (SHORE), a prospective, multicenter, observational registry of patients receiving gene-expression profiling (GEP) and donor derived-cell free DNA (dd-cfDNA) testing for allograft rejection surveillance. SHORE was designed to evaluate the utility of combined molecular testing for acute cellular rejection (ACR) surveillance.
Authors from Stanford University in Stanford, CA, Baylor University Medical Center in Dallas, St. Luke's Health System in Kansas City, MO, and others assert that a rational approach to molecular testing for heart transplant surveillance testing has emerged from their findings. If the results bear out, some heart transplant patients may be able to receive post-transplant care without traveling to a transplant center and undergo fewer invasive biopsies.
SHORE follows heart transplant patients in the U.S. who received noninvasive molecular testing with GEP (AlloMap, CareDx) and dd-cfDNA (AlloSure, CareDx). The commercially available GEP assay measures immune activation via peripheral blood mRNA rejection-associated transcripts, whereas dd-cfDNA captures active allograft injury by assessing levels of circulating cfDNA released from injured myocardium.
For the article in JHLT, Dr. Kiran Khush and colleagues noted that the GEP assay used in this study was developed and validated to screen for ACR, but not for antibody-mediated rejection (AMR). The authors also noted that when assessed individually, both GEP and dd-cfDNA testing have limitations and therefore should be used in a dual approach. The study confirmed the hypothesis that the two tests are complementary, according to the authors.
Patients were followed through five years post-transplant. A point Khush and colleagues made is that biopsies were most commonly performed in the first three months post-transplant, with a gradual reduction in frequency up to one year post-transplant. While 21.3% of patients had ACR, it was only present in 2.7% of all biopsies performed over the course of the study, most frequently occurring within the first 30 days post-transplant. Those with negative GEP and negative dd-cfDNA testing were less likely to have a subsequent biopsy.
"Over time, centers performed fewer biopsies in both the first and second year after transplant in response to dd-cfDNA/GEP results in which one or both tests were negative," the authors noted. "An overall reduction in biopsies with the use of dual molecular testing has also been observed in three recent North American single center studies."
"Overall, both molecular tests results appeared to have a considerable impact on the decision to proceed with follow-up biopsies or to prompt a subsequent molecular test to assess for changes," wrote the authors. "We note the overall reduction in biopsies over time may not be entirely attributed to molecular testing; however, over time, dual negative testing was followed with fewer biopsies and dual positive testing with more biopsies."
While results from the SHORE registry could be encouraging for the two CareDx tests that were used, the authors cited limitations with the study, including there could be differences in how the molecular test results were interpreted. They also added that several other clinical events can occur post-transplant, including graft dysfunction, de novo donor-specific antibody development, cardiac allograft vasculopathy, cytomegalovirus infection, malignancy, renal dysfunction, and all-cause mortality.
However, most biopsies in the first two years post-transplant are performed as surveillance for ACR, the authors said. "Given the low incidence of ACR and the validity of dual molecular testing, we have shown that most routine, surveillance biopsies can be safely eliminated when one or both molecular tests are negative," Khush and colleagues said. "These results should also provide the clinical confidence to end the practice of simultaneous biopsy and noninvasive testing, particularly as centers adopt this approach to rejection surveillance.
"In addition to minimizing patient risk, discomfort, and anxiety, remote testing may decrease the burden of time and cost on patients and their caregivers through remote testing. Enabling routine rejection surveillance without requiring travel to the transplant center may also improve the access to and equity of post-transplant care."
Future SHORE publications will assess the relationship between noninvasive testing, AMR, and clinical outcomes following heart transplantation.
