Cell-free DNA profiling informs all major complications of hematopoietic cell transplantation

Significance Hematopoietic cell transplantation is the gold standard treatment for many blood disorders, including blood cancers. Nonetheless, frequent post-transplant complications limit the long-term benefit of HCT. Here, we find that circulating cell-free DNA is a highly versatile analyte for mon...

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Bibliographic Details
Published in:Proceedings of the National Academy of Sciences - PNAS 2022-01, Vol.119 (4), p.1
Main Authors: Cheng, Alexandre Pellan, Cheng, Matthew Pellan, Loy, Conor James, Lenz, Joan Sesing, Chen, Kaiwen, Smalling, Sami, Burnham, Philip, Timblin, Kaitlyn Marie, Orejas, José Luis, Silverman, Emily, Polak, Paz, Marty, Francisco M, Ritz, Jerome, De Vlaminck, Iwijn
Format: Article
Language:English
Subjects:
Biological Sciences
Biomarkers
Bisulfite
Blood
Cancer
Cell-Free Nucleic Acids
Complications
Deoxyribonucleic acid
Disease Progression
DNA
DNA Fingerprinting
DNA Methylation
Failure analysis
Graft rejection
Graft versus host disease
Graft vs Host Disease - blood
Graft vs Host Disease - diagnosis
Graft vs Host Disease - etiology
Graft-versus-host reaction
Grafting
Grafts
Hematopoietic Stem Cell Transplantation - adverse effects
Hematopoietic Stem Cell Transplantation - methods
Humans
Infections
Liquid Biopsy - methods
Metagenomics
Monitoring
Organ Specificity - genetics
Physical Sciences
Postoperative Complications - blood
Postoperative Complications - diagnosis
Postoperative Complications - etiology
Recurrence
Remission
Telemedicine
Transplantation
Transplantation, Homologous
Tumors
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Summary:Significance Hematopoietic cell transplantation is the gold standard treatment for many blood disorders, including blood cancers. Nonetheless, frequent post-transplant complications limit the long-term benefit of HCT. Here, we find that circulating cell-free DNA is a highly versatile analyte for monitoring of the most important complications of HCT: Graft-Versus-Host Disease, infection, graft failure and disease relapse. We show that these different therapeutic complications can be informed from a single cell-free DNA sequencing assay followed by disease-specific bioinformatic analyses. This test requires only low coverage DNA sequencing and is compatible with small volumes of blood. Cell-free DNA may improve the care of allogeneic HCT recipients by enabling earlier detection and better prediction of the complex array of complications that occur after HCT. Allogeneic hematopoietic cell transplantation (HCT) provides effective treatment for hematologic malignancies and immune disorders. Monitoring of posttransplant complications is critical, yet current diagnostic options are limited. Here, we show that cell-free DNA (cfDNA) in blood is a 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 therapeutic complications are 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 infection, 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 timepoints before and after allogeneic HCT. We found that the abundance of solid-organ–derived cfDNA in the blood at 1 mo after HCT is predictive of acute GVHD (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 relapse and remission, and the fraction of tumor-specific cfDNA was informative of cancer relapse. This
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.2113476118