Frontline treatment of follicular lymphoma: what will it take to change current practice?

Follicular lymphoma is the most common subtype of indolent lymphoma. Despite multiple trials over the past decades showing improved progression-free survival with new first-line therapeutic strategies, such as anti-CD20 maintenance therapy and new glycoengineered anti-CD20 antibodies, no standardized approach has been widely adopted in routine clinical practice. Several factors may explain this, including the increased incidence of infectious adverse events associated with these therapies, particularly during the COVID-19 pandemic, and the lack of overall survival benefit despite long-term follow-up. A consensus has emerged acknowledging the high prognostic variability of follicular lymphoma, which complicates the adoption of a one-size-fits-all first-line treatment strategy. A plethora of prognostic scores (Follicular Lymphoma International Prognostic Index [FLIPI], FLIPI2, PRIMA-Prognostic Index, m7-FLIPI, FLEX [Follicular Lymphoma Evaluation Index], 23-gene score, etc) has been proposed but none can reliably identify the ∼20% of patients who will die within 10 years of first-line immunochemotherapy and for whom a critical medical need remains despite recent therapeutic improvements. Consequently, current prognostic models mainly serve as tools to cross-compare and stratify clinical trials. In this review, we highlight current and future strategies aimed at reshaping frontline treatment paradigms to improve outcomes, including tailored approaches based on risk- or response-adapted designs, development of new predictive, rather than prognostic, tools, approaches to reduce adverse events to enhance health-related quality of life, and the potential use of T-cell-engaging therapies to improve survival in the highest risk patients.