Molecular Profiling and Disease Tracking of Post-transplant Lymphoproliferative Disorders using Cell-free DNA

Post-transplant lymphoproliferative disorder (PTLD) is a life-threatening complication of hematopoietic stem cell or solid organ transplantation. Current prognostic tools for PTLD lack sufficient precision in predicting treatment response. This prospective feasibility study (NTR7402) evaluates circulating tumor DNA (ctDNA) for risk stratification and treatment monitoring in PTLD. Plasma samples (n = 86) from 27 patients (13 EBV positive and 14 EBV negative) were analyzed using targeted 115-gene sequencing and low-coverage whole-genome sequencing at diagnosis, after rituximab and/or chemotherapy and at the end of treatment (EOT). At baseline, somatic single nucleotide variants were detected in all cases. Multi-nucleotide variants were mostly detected in the BCL6 super enhancer hypermutation region especially in EBV-negative cases. Copy number variants were detected in 13/27 cases. Elevated ctDNA at baseline indicated a poor outcome of rituximab monotherapy, and undetectable ctDNA at interim was correlated with better response. Seven cases showed complete undetectable ctDNA while PET/CT indicated active disease at interim; all seven patients reached complete metabolic response by EOT. We demonstrate that ctDNA could potentially be used for prognostication and disease monitoring in PTLD, outperforming PET/CT in 8 cases. This indicates that ctDNA monitoring can complement PET/CT to guide early escalation to chemotherapy in high-risk patients, though larger cohorts are needed to validate these findings.