NEW YORK – Donor-derived cell-free DNA (dd-cfDNA)-based liquid biopsies are beginning to change clinical practice in the heart transplant space and may be poised for stronger guideline recommendations in the near future.
Molecular diagnostics companies Natera and CareDx presented data from ongoing studies that support the clinical utility of their respective dd-cfDNA-based heart transplant monitoring tests at the annual meeting of the International Society for Heart and Lung Transplantation, held this week in Boston.
Natera presented findings from its ongoing DEFINE-HT, a prospective, multicenter clinical study assessing whether elevated dd-cfDNA levels, as measured by Prospera Heart with Donor Quantity Score (DQS), are associated with adverse patient outcomes. As of late last year, the study had amassed slightly over 1,100 samples from 110 participants, taken at enrollment and then serially over the course of the 12 months following their transplant. In particular, a key goal of the study was to determine whether dd-cfDNA, as measured by donor fraction and absolute quantity, improved prognostication of clinical outcomes one year following transplant.
DQS is a feature of Prospera Heart that normalizes sample measurements for background total cfDNA.
Sangeeta Bhorade, chief medical officer of organ health at Natera, explained that adding DQS to standard donor fraction measurements helps reduce confounding variables such as recipient cfDNA that could be shed into the bloodstream for a variety of reasons.
"If there's an ongoing infection or a malignancy or a type of surgery, or any other stress on the body, that could actually elevate the recipient cell-free DNA, which would make the fraction incorrect," Bhorade said.
Overall, the study found that using Prospera with DQS resulted in stronger correlations with clinical outcomes, as compared to donor fraction alone. Transplant recipients with elevated dd-cfDNA levels were at significantly greater risk for experiencing adverse events.
Furthermore, elevated levels of dd-cfDNA appeared to predict graft dysfunction more often than via endomyocardial biopsies (EMB), often predicting it in the absence of biopsy-positive rejection.
"It's a very rich dataset," said Palak Shah, director of the Inova Cardiovascular Genomics Center and the study's principal investigator.
Shah said that most studies looking for relationships between dd-cfDNA and transplant outcomes tend to be cross-sectional, which evaluate patients at fewer, and often single, time points.
In these studies, he explained "you don't really know what happens to the patient other than when the cell-free DNA was done and the biopsy was done, and I think that the ability to look at longitudinal outcomes in DEFINE-HT is one of the study's unique aspects."
In line with Natera's findings, researchers affiliated with CareDx showed data from the ongoing SHORE study demonstrating that its HeartCare product may be more predictive of clinical outcomes than EMBs. The company's findings further suggested that a dual-positive HeartCare result, indicating both elevated immune activity and organ damage, was prognostic of poor outcomes, including graft dysfunction, rejection, or death from rejection, even when the associated pathology review of a biopsy was negative.
"With the SHORE study, we're beginning to show that clinicians are informing treatment decisions as a result of testing, including a reduction in the use of steroids and biopsy procedures," said CareDx CEO John Hanna.
Steroids such as prednisone are commonly prescribed to transplant recipients as a way to help induce and maintain immunosuppression to prevent graft rejection. They come with significant side effects, however, making dose management a complicated but key part of overall patient care.
In another of the presentations based on SHORE data, investigators showed that positive HeartCare findings, particularly when both GEP and dd-cfDNA results were positive, were associated with less prednisone weaning. This happened even when EMB results were negative, suggesting that the results of these assays played a strong role in informing physicians' decisions.
Jeffrey Teuteberg, a professor of medicine at Stanford University and principal investigator of the SHORE study, said via email that his own clinical practice has changed as a result of the data he has been generating in the study.
"We converted nearly all of our routine rejection surveillance to noninvasive molecular testing," he said. "With this change, we have eliminated about 95 percent of our routine surveillance biopsies."
Steven Potter, professor of surgery and urology at Georgetown University School of Medicine and a practicing abdominal transplant surgeon who was not involved with either of the studies, largely echoed Teuteberg's remarks, saying that the use of molecular testing in the heart transplant space as well as in other organ transplant areas has become a critical component of the care of these patients.
"In heart transplantation, molecular testing has emerged as a standard of care that's essentially universally employed," he said. "And in the kidney transplant realm, it's emerged as a standard of care that is employed by a large majority of transplant centers in the surveillance of their kidney transplant patients."
With greater adoption of and trust in dd-cfDNA graft testing, CareDx, Natera, and other stakeholders anticipate stronger recommendations for such testing in future clinical guidelines.
"I think these data showing the combined results and the prognosis of outcomes will lead clinicians ultimately to recommend utilization of both tests, because knowing prognosis is everything," Hanna said. "It determines how aggressively or non-aggressively you treat."
Hanna added that presenting these data at conferences such as ISHLT is a key part of the process of changing clinical guidelines.
"Clinicians attending these conferences pay close attention to the studies and the publications, and ultimately they write the guidelines," he said.
Teuteberg noted that guidelines are often not updated regularly, making it incumbent on researchers and clinicians working in the field to push for changes that they think are merited.
"I suspect that when guidelines are updated, the use of noninvasive monitoring for rejection surveillance will have a much stronger recommendation," he said.
Potter noted that some professional transplant organizations have already made these kinds of strong recommendations.
"As the chair of the working group that developed those cell-free DNA guidelines for the American Society of Transplant Surgeons, we were unequivocal about the clinical utility [of these tests] in the guidance we provided," he said.
With data from these and other studies providing a firm base of evidence for the clinical value of cell-free DNA tests for solid organ transplantation, Potter said that he hopes future research will include cost-benefit analyses of molecular testing.
"Many transplant surgeons and physicians in this space are convinced that not only is there clinical utility to cell-free DNA testing, but that these tests may actually save payors money in the long term because of improved outcomes and fewer invasive tests like biopsies," he said. "However, at this point in time, we don't have the cost benefit data to really make a strong argument in that respect."