Background/Objectives: This study aimed to determine whether interim PET/CT (iPET) scans could identify follicular lymphoma (FL) patients at high risk of relapse following first-line therapy. Methods: A total of 117 FL patients who underwent iPET scans were included, with responses interpreted using the Deauville score (DS). Progression-free survival (PFS) was evaluated over a median follow-up of 34 months. Results: Overall, 34% of patients were classified as iPET (+), with significantly worse estimated 5-year PFS compared to iPET (−) patients (34% vs. 76%, hazard ratio 4.3, p < 0.001). Multivariate analysis confirmed iPET (+) as an independent predictor of PFS. Conclusions: Interim PET results are significant predictors of PFS in FL first-line therapy and could inform response-adapted treatment strategies.

Background/Objectives: This study aimed to determine whether interim PET/CT (iP-ET) scans could identify follicular lymphoma (FL) patients at high risk of relapse fol-lowing first-line therapy. Additionally, the potential of cell-free DNA (cfDNA) analysis to complement iPET in predicting outcomes was explored. Methods: A total of 121 FL patients who underwent iPET scans were included, with responses interpreted using the Deauville score (DS). Progression-free survival (PFS) was evaluated over a median follow-up of 34 months. Interim cfDNA data were analyzed for 14 patients to assess its potential for detecting false-positive PET results. Results: Overall, 34% of patients were classified as iPET(+), with significantly worse estimated 5-year PFS compared to iPET(-) patients (29% vs. 72%, hazard ratio 4.31, p < 0.001). Multivariate analysis confirmed iPET(+) as an independent predictor of PFS. Rituximab maintenance was predictive of reduced progression within the iPET(+) group but not among iPET(-) patients. cfDNA analysis identified two false-positive iPET cases and showed potential to identify pa-tients with complete response at risk of early progression. Conclusions: Interim PET results are significant predictors of PFS in FL first-line therapy and could inform re-sponse-adapted treatment strategies. cfDNA analysis has the potential to complement PET/CT by improving specificity and identifying patients at risk of early progression, offering a more precise approach to managing FL.