Plasma Cell-Free RNA Captures Immune Dynamics and Predicts GVHD after Hematopoietic Stem Cell Transplantation

Despite long-standing success of hematopoietic stem cell transplantation (HSCT) in the treatment of blood cancers and severe immune disorders, monitoring post-transplant complications remains challenging, in part because of the limited availability of informative molecular tests. Here, we evaluated the utility of cell-free RNA (cfRNA) in plasma as an analyte to monitor HSCT recipients and predict immune-related complications. We used RNA-sequencing to profile cfRNA in 549 plasma samples collected at predetermined time points from allogeneic HSCT recipients at two transplant centers. We found that cfRNA temporal profiles in recipients with a complication-free course follow a relatively uniform trajectory, whereas recipients who experience complications exhibit divergent trajectories. cfRNA patterns also differed greatly from circulating cell counts, providing complementary information on cell expansion and turnover. We also used cfRNA profiles at early time points to train machine learning models for the early prediction of acute GVHD, chronic and late acute GVHD, and the outcome of immunosuppression taper. We discovered shared signatures that achieved good performance across different scenarios in both cohorts. Overall, our findings provide support for the use of plasma cfRNA profiling to monitor immune related complications of HSCT.