A SPECTRUM OF CAUSES OF MOLECULAR INJURY IS DETECTED BY DONOR-DERIVED CELL-FREE DNA AFTER LUNG TRANSPLANT: PRELIMINARY EXPERIENCE

ABSTRACT

SESSION TITLE Lung Transplantation New Issues in 2022 SESSION TYPE Rapid Fire Original Inv PRESENTED ON 10/19/2022 1115 am - 1215 pm PURPOSE: Donor-derived cell-free DNA (dd-cfDNA) is a promising plasma analyte for surveillance of rejection and lung transplant (LT) injury. Herein we report our preliminary real-world experiences in concert with standard of practice (SOP) assessments. METHODS: We performed a prospective, cross-sectional, cohort study of a clinically available dd-cfDNA test (the Prospera™ test, Natera, Inc.) combined with SOP clinical assessments − spirometry, fiberoptic bronchoscopy (FOB), donor-specific HLA antibodies (DSA). Single LT dd-cfDNA results were corrected (2X) for lung mass before analysis. Clinical-pathologic cohorts were assigned based on ISHLT guidelines for acute cellular rejection (ACR), uncomplicated chronic lung allograft dysfunction (U-CLAD), and either CoVid-19 or Non-CoVid-19 allograft infection. We also compared median dd-cfDNA fractions between patients experiencing allograft dysfunction (AD) (defined by ΔFEV1≥ -10%) vs stability (STA) and stratified by DSA status. Groups were analyzed by Mann-Whitney (p<0.05) and data expressed as median with 25-75% interquartile range (IQR). RESULTS: A total of 54 plasma samples from 42 unique LT recipients (Single=6, Double=36) were collected at Spectrum Health between November 2021 and February 2022. Primary diagnoses included chronic obstructive pulmonary disease (n=7), interstitial lung disease (n=31), CoVid-19 related ARDS (n=2), CF (n=1) and PAH (n=1). Matching histopathology was available for 68% of dd-cfDNA samples. dd-cfDNA fraction trended 2-fold higher in patient with ACR (1.59%, IQR 0.09-3.57;n=3) and U-CLAD (1.88%, IQR 0.88-3.32;n=4) than STA (0.86%, IQR 0.21-1.62;n=14) patients. Patients with CoVid-19 had significantly higher dd-cfDNA fraction (6.91%, IQR 2.41-9.77;n=4) than both STA (p=0.035) and NON-CoVid-19 infection cohorts (p=0.049). Although no antibody-mediated rejection (AMR) events were observed, dd-cfDNA fraction was significantly elevated in DSA(+) patients (2.75%, IQR 1.72-6.25;n=8, class I (4) and II (4)) vs DSA(-) (1.035%, 0.04-1.64;n=46) cohorts (p=0.011). A trend was noted with elevated dd-cfDNA with AD (1.58%, IQR 0.74-3.62;n=17) vs AS (1.05%, 0.66-1.79;n=37) (p=0.29). CONCLUSIONS: Our preliminary experience is consistent with prior studies, suggesting elevated dd-cfDNA fraction during LT allograft rejection and specific types of infection, in particular, CoVid-19. Of interest, dd-cfDNA detected potential occult molecular injury associated with anti-HLA DSA. CLINICAL IMPLICATIONS dd-cfDNA fraction assessment after LT represents a valuable clinical tool for clinical surveillance of organ transplant health. DISCLOSURES Employee relationship with Veracyte, Inc Please note 2 years by Sangeeta Bhorade, value=Salary Removed 04/03/2022 by Sangeeta Bhorade Employee relationship with Natera Inc Please note 2/22/22- present Added 04/03/2022 by Sangeeta Bhorade, value=Salary Employee relationship with Natera Please note 05/2021-present Added 04/04/2022 by Kathryn Crabtree, value=Salary research relationship with United Therapeutics Please note 2016- ongoing by Reda Girgis, value=Grant/Research research relationship with Pfizer Please note 2014-2020 by Reda Girgis, value=Grant/Research Speaker/Speaker's Bureau relationship with Boehringher Ingelheim Please note 2016-ongoing by Reda Girgis, value=Honoraria Speaker/Speaker's Bureau relationship with Genentech Please note 2016-ongoing by Reda Girgis, value=Honoraria no disclosure on file for Cameron Lawson;No relevant relationships by Edward Murphy Employee relationship with Natera, Inc. Please note 2020- present by David Ross, value=Salary