Progression of follicular lymphoma (FL) or transformation (tFL) within 24 months of immunochemotherapy (ICT) represent high-risk defining events (HRDE) with poor overall survival (OS). We examined baseline clinical characteristics, imaging and outcomes for patients experiencing HRDE in an international retrospective cohort of newly diagnosed FL patients requiring ICT. We defined HRDE groups as: relapse or progression of FL within 24 months (FL24); Early TFL (transformation <24 months of ICT); Late TFL (transformation >24 months of ICT). 433 patients were categorised: reference FL n=352 (no HRDE), FL24 n=43, Early TFL n=29, or Late TFL n=9. Chemotherapy regimens included bendamustine (63%), CHOP (27%) or CVP (10%); 85% received rituximab/15% obinutuzumab and 48% received maintenance therapy. Compared to the reference FL group, OS from HRDE was inferior for FL24 (HR 3.93, 95% CI 2.14-7.23), Early TFL (HR 8.16, 95% CI 4.38-15.2) and Late TFL (HR 8.23, 95% CI 3.18-21.25). OS from HRDE was inferior for Early TFL compared to FL24 (HR 2.08, 95% CI 1.02-4.21). In multivariable analysis, baseline performance status, elevated lactate dehydrogenase, elevated beta-2-microglobulin and grade 3A were associated with Early TFL. Clinical characteristics were not able to differentiate Early TFL from FL24. Standardised uptake value max was higher in Early TFL but not FL24 compared to reference FL. Early TFL and FL24 represent different HRDEs in FL after ICT and are associated with inferior OS. Distinguishing between early TFL and FL24 is important for biomarker development, management and to develop and interpret clinical trials in this area of unmet need.
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