Cell-free DNA Tissues-of-Origin Profiling to Predict Graft versus Host Disease and Detect Infection after Hematopoietic Cell Transplantation

Cheng, A. P.; Cheng, M. P.; Lenz, J. S.; Chen, K.; Burnham, P.; Timblin, K. M.; Orejas, J. L.; Silverman, E.; Marty, F. M.; Ritz, J.; De Vlaminck, I.

doi:10.1101/2020.04.25.061580

bioRxiv · 10.1101/2020.04.25.061580

Cell-free DNA Tissues-of-Origin Profiling to Predict Graft versus Host Disease and Detect Infection after Hematopoietic Cell Transplantation

Cheng, A. P.·Cheng, M. P.·Lenz, J. S.·Chen, K.·Burnham, P.·Timblin, K. M.·Orejas, J. L.·Silverman, E.·Marty, F. M.·Ritz, J.·De Vlaminck, I.

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Abstract

Allogeneic hematopoietic cell transplantation (HCT) provides effective treatment for hematologic malignancies and immune disorders. Monitoring of post-transplant complications is critical, yet current diagnostic options are limited. Here, we show that cell-free DNA (cfDNA) in blood is a highly versatile analyte for monitoring of the most important complications that occur after HCT: graft-versus-host disease (GVHD), a frequent immune complication of HCT; infection; relapse of underlying disease; and graft failure. We demonstrate that these different therapeutic complications can be informed from a single assay, low-coverage bisulfite sequencing of cfDNA, followed by disease-specific bioinformatic analyses. To inform GVHD, we profile cfDNA methylation marks to trace the cfDNA tissues-of-origin and to quantify tissue-specific injury. To inform on infections, we implement metagenomic cfDNA profiling. To inform cancer relapse, we implement analyses of tumor-specific genomic aberrations. Finally, to detect graft failure we quantify the proportion of donor and recipient specific cfDNA. We applied this assay to 170 plasma samples collected from 27 HCT recipients at predetermined time points before and after allogeneic HCT. We found that the abundance of solid-organ derived cfDNA in the blood at one-month after HCT is an early predictor of acute graft-versus-host disease (area under the curve, 0.88). Metagenomic profiling of cfDNA revealed the frequent occurrence of viral reactivation in this patient population. The fraction of donor specific cfDNA was indicative of cell chimerism, relapse and remission, and the fraction of tumor specific cfDNA was informative of cancer relapse. This proof-of-principle study shows that cfDNA has the potential to improve the care of allogeneic HCT recipients by enabling earlier detection and better prediction of the complex array of complications that occur after HCT.

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Cheng, A. P., Cheng, M. P., Lenz, J. S., Chen, K., Burnham, P., Timblin, K. M., Orejas, J. L., Silverman, E., Marty, F. M., Ritz, J., De Vlaminck, I.. 2020-04-29. Cell-free DNA Tissues-of-Origin Profiling to Predict Graft versus Host Disease and Detect Infection after Hematopoietic Cell Transplantation. https://doi.org/10.1101/2020.04.25.061580

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