Nuances in the interpretation and utility of donor-derived cell-free DNA in lung transplantation following allogeneic hematopoietic stem cell transplantation – Case report

Respiratory complications following allogeneic HSCT can lead to severe morbidity and mortality. Lung transplantation (LT) is a potential treatment for select patients with late-onset non-infectious pulmonary complications post-HSCT. Donor-derived cell-free DNA (dd-cfDNA) is a noninvasive biomarker for monitoring the health of allografts following LT. However, its utility in a multi-genome setting of LT after HSCT has not yet been clinically validated. Here we describe a case of a 75-year-old, male patient who underwent single-lung transplantation for BOS related to chronic GVHD and presented with persistently elevated dd-cfDNA levels. In a surveillance biopsy, the patient was diagnosed with mild acute cellular rejection at three months. The patient's lung function remained stable, and the reported dd-cfDNA levels decreased after the rejection episode but remained elevated above levels that would be considered quiescent for LT alone. In this unique setting, as 3 different genomes contributed to the dd-cfDNA% reported value, valuable insight was obtained by performing further analysis to separate the specific SNPs to identify the contribution of recipient, lung-donor, and HSCT-donor cfDNA. This study highlights the potential utility of dd-cfDNA in the multi-genome setting of lung transplant post-HSCT, nuances that need to be considered while interpreting the results, and its value in monitoring lung rejection. •Respiratory complications post-allogeneic hematopoietic stem cell transplantation are frequent and can result in significant morbidity and mortality.•Lung transplantation is considered for patients with pulmonary complications post-HSCT.•dd-cfDNA is a useful biomarker for monitoring lung allograft injury and reducing protocol biopsies in lung transplantation.•Applying dd-cfDNA in combined HSCT and lung transplantation presents unique challenges for interpreting results.•By distinguishing cfDNA from HSCT donor, recipient, and lung allograft, the changes in lung cfDNA were linked to rejection.•Close surveillance after lung transplantation is crucial for preventing, identifying, and treating complications.