Noninvasive blood test may accurately predict rejection after heart transplant
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Heart transplant is the definitive treatment option for patients with advanced HF, yet allograft rejection and injury remain impediments to posttransplant survival despite continued advances in posttransplant outcomes.
Endomyocardial biopsy and histopathology remain the principal surveillance tools for rejection after heart transplant since they were developed decades ago. However, endomyocardial biopsy is invasive and expensive, and histopathology reads are prone to interobserver variability, according to Michael Olymbios, MD, medical director of heart transplantation for Natera Inc.
Olymbios and colleagues recently conducted a clinical validation study to demonstrate that a donor-derived cell-free DNA blood test, Prospera Heart (Natera), is associated with acute organ rejection and could reduce the frequency of endomyocardial biopsy. Their findings were published in the Journal of Heart and Lung Transplantation.
Healio spoke with Olymbios about some of the drawbacks of endomyocardial biopsy, how donor-derived cell-free DNA can predict acute rejection and a new study designed to show the accuracy of a noninvasive blood test for transplant rejection.
Healio: What are some of the downsides of endomyocardial biopsy? Why is there a need for a noninvasive option?
Olymbios: The endomyocardial biopsy has been the standard of care for rejection surveillance in heart transplant almost since the beginning of heart transplant itself. It came about because there were really no noninvasively assessed biomarkers, until donor-derived cell-free DNA, for assessing heart allograft health. An ideal screening test is usually noninvasive, inexpensive and reproducible. Endomyocardial biopsy is invasive; it requires you to go in through the venous system and take “bites” out of the interventricular septum, the heart muscle itself, which are examined by a pathologist. It is not without complications. In fact, although serious complications are rare, repeat biopsy over time does damage to the tricuspid valve. This can require surgical repair. Even beyond the complications with the procedure itself, the histologic interpretation of the sample is somewhat subjective; there is a great deal of interobserver variability. All of this created a strong unmet need for a noninvasively assessed biomarker for allograft health.
Healio: Can you briefly describe the methods used for this study? Did anything about the findings surprise you, and why?
Olymbios: This was a study with adult heart transplant recipients in the United States, where a biopsy was paired with a Prospera blood draw to compare the findings of the two. As others have shown, there is a strong association between elevations in donor-derived cell-free DNA and biopsy-proven rejection. Additional interesting findings in this study were that Prospera was elevated even in the absence of biopsy-proven rejection. This suggests that molecular tools are more sensitive in detecting allographic injury and rejection. That alludes back to early work conducted at Stanford University and more recent work done by the NIH Genomic Research Alliance for Transplantation, showing donor-derived cell-free DNA rises up to 3 months before a patient has biopsy-proven rejection. In addition to being a dependable, noninvasively assessed marker, it is also, potentially, an early marker of rejection.
Healio: What are the next steps and what might this mean for transplant surgeons and cardiologists?
Olymbios: Currently, we are planning a randomized controlled trial comparing the approach of using Prospera surveillance with endomyocardial biopsy surveillance, to show that you can in fact do away with surveillance biopsies and it is safe and effective to do so. We expect to begin enrolling participants in January 2023. This trial is needed. For some time, the transplant field has known that endomyocardial biopsy is a less-than-ideal gold standard. Although the proof of concept has been attained through these observational studies for cell-free DNA, clinical utility studies have yet to be conducted.
Healio: What more do we need to learn from the upcoming research?
Olymbios: The key finding from the randomized trial will be that you can do away with the surveillance biopsy and use donor-derived cell-free DNA to determine whether a biopsy is necessary and that this approach is safe and effective. One of the benefits of a trial is we can demonstrate that a lot of what we call “rejection by biopsy” does not, in fact, need treatment. There is also variability in who gets treated and who does not. Some patients will have a very aggressive pathologist who calls a lot of biopsies “rejection,” whereas others have a less aggressive pathologist. These two patients ultimately have the same findings. That potentially means we overtreat some patients with heart transplants. Through this study, we will see those patients who did not have a surveillance biopsy and a low Prospera result will not get treated. We hope to show that they have equivalent outcomes.
One of the next steps is guiding treatment with molecular diagnostic tools.
Healio: What are the take-home messages of this study?
Olymbios: There is strong association between biopsy-proven rejection or graft dysfunction and elevated levels of donor-derived cell-free DNA; however, there were limitations to pathology. Those limitations have, to some extent, slowed our ability to develop newer tests like this one, because our reference standard, the gold standard, is flawed. It has taken the field a while to grapple with that, but we are moving in the right direction.
We are conducting another study, known as the heart trifecta study, using the molecular microscope developed at the University of Alberta, looking at intragraft gene expression profiling to define rejection. We have published findings on a similar study in kidney transplantation and the concordance between Prospera and the molecular landscape is far greater than with traditional histopathology.
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