The POD24 challenge: where do we go from here for early progressors?

Follicular lymphoma is the most common indolent lymphoma, with a favorable prognosis and survival measured in decades. However, approximately 15% to 20% of patients encounter early disease progression, termed POD24, within 24 months from diagnosis or treatment initiation. Recognizing the correlation between POD24 and a heightened risk of lymphoma-related death has sparked intensive investigations into the clinical and biological determinants of POD24 and the development of innovative treatment strategies targeting this group. Research is also ongoing to understand the varying impact of POD24 based on different clinical contexts and the implications of early histologic transformation on POD24 prognosis. Recent investigations have uncovered potential new predictors of POD24, including genetic and nongenetic alterations as well as some conflicting F-fludeoxyglucose-positron emission tomography characteristics such as maximum standardized uptake value and total metabolic tumor volume. These developments, together with clinical predictors, have led to the emergence of several clinicopathologic tools to help identify at diagnosis patients who may be at higher risk for POD24. As these models are not routinely used, more work is needed to develop new risk-stratification strategies integrating clinical and molecular risk profiling that can be easily implemented in clinical practice to drive therapeutic choice. This review aims to delineate the modest but incremental progress achieved in our understanding of POD24, both clinically and biologically. Furthermore, we offer insights into the best practices to approach POD24 in the current era, aspiring to chart a new path forward to optimize patient outcomes.