Potential utility of ctDNA to detect false positive PET/CT in the evaluation of lymphoma response

BackgroundPET/CT remains a powerful tool for staging, restaging, and response to treatment of B lymphoma, but it has some limitations such as radioactivity, interpreter variability, and an unacceptable false-positive rate.MethodsThis study investigates the use of ultrasensitive ctDNA-NGS to detect minimal residual disease (MRD) in patients with follicular lymphoma (FL) after first line immunochemotherapy (IQT) (n=45) or CAR-T cell (N=11), primary mediastinal lymphoma (PMBL) (n=11) or large B cell lymphoma (LBCL) after first line IQT (n=14), who do not reach a complete response (CR). Lymph node tumors from 81 patients were analyzed using a custom NGS panel targeting the 56 most relevant mutated genes in B-cell lymphomas. Following identification of 5-8 somatic mutations per patient, plasma ctDNA was tracked by an ultra-sensitive and personalized NGS test to monitor MRD. All patients had treatment response assessment by PET/CT scans at end of treatment and/or after 4 cycles of treatment.ResultsAmong the 81 patients, 25 (31%) had positive PET/CT scans (DS4-DS5). Of these 25 patients, the personalized ctDNA-NGS test confirmed positive MRD in 14 (56%). Interestingly, all patients with positive results from both tests progressed within 7 months. The remaining 11 patients had negative MRD result by ctDNA-NGS despite positive PET/CT scans. Surprisingly, 91% of these patients did not progress within the next 25 months. The single patient who progressed, despite initial negative ctDNA result, showed a positive result in a subsequent ctDNA sample collected 5 months before progression. These findings suggest that PET/CT may have yielded false-positive MRD results in 40% (10/25) of the initially positive patients.ConclusionsThis study demonstrates the potential of ctDNA-NGS as a non-invasive tool for assessing treatment response and monitoring MRD in B lymphoma patients. Our personalized, ultra-sensitive ctDNA assay identified a significant proportion of false-positive results from PET/CT scans. These findings suggest that combining ctDNA-NGS with PET/CT in clinical practice could improve patient management by refining response assessment.Legal entity responsible for the studyA. Martín-Muñoz.FundingInstituto de Salud Carlos III.DisclosureAll authors have declared no conflicts of interest.