Key points: 

This report focuses on updates in follicular lymphoma (FL) biology, first-line treatment, the role of progression of disease in 24 months, clinical trial design, and redefining cure in FL.

●      FL  is an indolent B-cell non-Hodgkin lymphoma, in which most patients harbor the t(14;18) chromosomal translocation,  resulting in overexpression of the B-cell lymphoma 2 protein.

●      Recurrent mutations in epigenetic modifier genes, such as those encoding for acetyltransferases (eg, CREBBP) and methyltransferases (eg, KMT2D and EZH2), have emerged as genetic hallmarks of the disease, occurring early in the common mutated precursor cell, preceding its final clonal expansion into FL or transformed FL.

●      FL is a heterogeneous disease composed of distinct genomic, transcriptomic, and immunologic subtypes that are still being defined.

●      Multiple clinical and clinicogenetic risk scores (Follicular Lymphoma International Prognostic Index [FLIPI], FLIPI-2, m7FLIPI, PRIMA-PI, others)  have been developed to identify patients at low and high risk. However, these scores were developed in historical cohorts and do not perform as well for patients receiving current standard treatments. Furthermore, they do not guide treatment decisions.

●      Prospective trials have even shown that watchful waiting can be used for ≥10 years for a small subset of patients, suggesting that some patients require minimal therapy.

●      Outcomes with current frontline therapies are variable, with some patients achieving a functional cure (with ongoing remissions beyond 15 years) and others experiencing primary refractory disease or transformation.  FL has historically been considered an incurable disease. With more effective therapies, the authors advocate changing the terminology.

○      A subset of patients (20%-40%) have disease control lasting ≥10 years with rituximab treatment alone.

○      ~20% of patients will have progression of disease within 24 months after initial chemoimmunotherapy (CIT), including some with transformed disease. Such patients are poorly served by initial treatment and would benefit from alternative frontline treatments.

○      Frontline CIT is associated with infections, hematologic side effects, and secondary malignancies. Growing evidence suggests that bendamustine-based therapy may have increased long-term risks compared to other frontline approaches.

■      Maintenance rituximab for 2 years after CIT induction extends progression-free survival (PFS) but does not improve overall survival.

●      Bispecific antibodies (BsAbs) targeting CD3×CD20 (mosunetuzumab and epcoritamab) are approved by the US FDA for patients with multiple relapsed FL.  BsAbs have demonstrated high response rates (overall response rate, 78%-96%) and durable remissions (PFS, 15-24 months) in phase 2 trials among patients who had received ≥2 prior lines of therapy.

○      In addition, phase 2 trials have demonstrated encouraging results with BsAbs as initial therapy, either as monotherapy or in combination with lenalidomide.

●      See Table 2 in original paper for Ongoing phase 3 clinical trials with BsAbs in frontline FL.

●      Efforts are underway to develop surrogate end points that can identify a winning treatment regimen more rapidly. Complete response rate at 30 months has been established as a surrogate end point for PFS in first-line FL therapy based on a large analysis of 13 randomized trials of induction and maintenance therapy in FL.