Study Shows Efficacy for Incorporating Less Invasive, Blood Testing-Based Approach to Rejection Surveillance After Pediatric Heart Transplantation

Following heart transplantation, patients require routine, life-long surveillance using endomyocardial biopsy to assess or confirm histologic findings of acute rejection. While a current standard of care, endomyocardial biopsy is invasive (it requires general anesthesia for children and adolescents), costly, and of low-yield for detecting acute rejection when clinical examination and immunosuppressant drug levels are normal. Less invasive approaches to surveillance for acute rejection would benefit patients by possibly avoiding routine, repeat invasive biopsies, simplifying and speeding up the diagnostic routine while at the same time likely improving patient quality of life.  

New research from a multidisciplinary team of investigators at the Heart Institute at UPMC Children’s Hospital of Pittsburgh outlines their findings using donor-derived cell-free DNA (dd-cfDNA), a non-invasive, blood-based biomarker, in lieu of endomyocardial biopsy in a cohort of 58 pediatric heart transplant recipients at UPMC Children’s Hospital. This marks the first real-world clinical use data to emerge on the feasibility, reliability, and success of dd-cfDNA testing as part of routine care of pediatric patients following heart transplantation.

The study¹, published in August in the journal Pediatric Transplantation, was led by Brian Feingold MD, MS, FAHA, professor of pediatrics and clinical and translational science, and medical director of the Heart Failure and Transplantation Programs in the Heart Institute at UPMC Children’s.

“In 2021, we should not be using a 1980s approach to screen for rejection in our patients. While we can obtain useful clinical data from endomyocardial biopsy, its routine use for screening for rejection is an old paradigm. We can and must devise more robust and patient-friendly clinical diagnostic approaches for our heart transplant recipients. Our findings using dd-cfDNA at our institution provide crucial support for the field to continue these kinds of investigations,” says Dr. Feingold.

The care protocol that Dr. Feingold’s team implemented for the use of dd-cfDNA for surveillance included a gradual introduction of dd-cfDNA assessments in place of every other planned surveillance biopsy and only among patients greater than 7 months post-transplant whose health status and clinical presentation were deemed to be well (including stable echocardiogram results and no signs of acute rejection on their recent prior endomyocardial biopsies). These patients underwent dd-cfDNA analysis and were only referred for biopsy with an elevated dd-cfDNA.

Several findings from the analysis are noteworthy. 

• Of the 58 individuals monitored with dd-cfDNA, there were no mortalities or episodes of allograft dysfunction or loss over a median follow-up of 8.7 months. 
• Most individuals who were tested (81%) had non-elevated dd-cfDNA levels and consequently did not undergo the surveillance endomyocardial biopsy that they would have otherwise received. 
• Among 24 recipients who had a later surveillance biopsy, 23 (96%) showed no signs of acute rejection, while one patient showed acute rejection following a decrease in immunosuppression after a subsequent diagnosis of post-transplant lymphoproliferative disorder. 
• Of the 11 patients with elevated dd-cfDNA levels, all had subsequent biopsies, with 4 patients showing varying grades of acute rejection.

Based on this experience, Dr. Feingold’s team has recently revised its rejection surveillance protocol to utilize dd-cfDNA screening in combination with clinical assessment instead of surveillance biopsy for all routine rejection assessments after 3 months from transplantation. 

Additional research will be required to validate further the generalizability of the study's findings across institutions with varying rejection surveillance protocols and to assess or confirm other nonspecific clinical concerns that may indicate graft performance or signs of acute rejection. In addition, dd-cfDNA has shown promise to detect rejection not seen or not well seen on biopsy, and the team at Children's sees a signal for this as well. This is a particularly exciting finding because it may help unlock treatments for transplanted hearts that are at risk for chronic rejection, which leads to post-transplant heart failure and graft loss, usually over decades. 

“If we can reduce the number of biopsies needed while maintaining or improving upon surveillance approaches and transplant outcomes, or perhaps being able to identify signs of acute rejection before they become clinically recognizable by biopsy, this will undoubtedly benefit our patient population,” says Dr. Feingold. “We are continuing our studies of this approach to learn more and fill in the gaps in our evidence base.”

Learn more about Dr. Feingold and the pediatric heart transplantation program at UPMC Children’s Hospital of Pittsburgh.

Reference

1. Feingold B, Rose-Felker K, West SC, Zinn MD, Berman P, Moninger A, Huston A, Stinner B, Xu Q, Zeevi A, Miller SA. Early Findings After Integration of Donor-Derived Cell-Free DNA Into Clinical Care Following Pediatric Heart Transplantation. Pediatr Transplant. 2021; 00: e14124. Epub ahead of print.