Impact of AMR Treatment: Responders vs Non-Responders Characteristics

Purpose Patients who fail to respond to initial pulmonary antibody-mediated rejection (AMR) treatment may benefit from second generation therapies. Unfortunately, current approaches identify non-responders late after irreversible allograft loss and chronic lung allograft dysfunction (CLAD) has developed. We hypothesize that responders and non-responders show distinct features. In this study, we compared responders and non-responders to identify distinctive features that can be used to recognize the non-responders early before CLAD develops. Methods A committee reviewed clinical data of a prospective cohort of 435 patients to adjudicate for AMR and CLAD. Patients were assigned as responders if they were alive and free from CLAD 1 year after AMR diagnosis, otherwise, AMR patients were categorized as non-responders. Donor-specific antibody (DSA) specificity, strength, lung histopathology, and magnitude of FEV1 decline at the time of AMR diagnosis, 30 days, and 90 days after diagnosis were compared between the groups. Then, we compared molecular biomarker of allograft injury: donor-derived cell-free DNA (%ddcfDNA) - focusing on baseline %ddcfDNA (average of the two lowest values from transplantation) and %ddcfDNA levels at AMR diagnosis. Results 49 (11.2%) subjects developed AMR including definite (N=1, 2%), probable (N=8, 16%), and possible (N=40, 82%). 73% of AMR patients developed CLAD within 1 year of AMR diagnosis (non-responders) and 27% were responders. Responders and non-responders show important differences at AMR diagnosis, including time from transplantation to AMR (median 107 IQR = 35-224 versus 302, IQR 130-555 days; p=0.002) and FEV1 decline at diagnosis from baseline (12.7% vs 29.0%, p=0.023). Time from transplantation to DSA development, DSA specificity and DSA clearance by 90-day of AMR diagnosis were similar (p>0.05) between the groups. %ddcfDNA rise at AMR diagnosis was higher than for no AMR controls (p Conclusion This study showed that responders and non-responders to AMR treatment have differences in the magnitude of FEV1 decline, time of AMR development, and %ddcfDNA. If validated in another cohort, these features can be used to identify and treat non-responders early to prevent CLAD, thus early death.