Integration of gene mutations in risk prognostication for watch‐and‐wait follicular lymphoma patients initiating first‐line treatment

Follicular lymphoma (FL) patients with low tumor burden at diagnosis frequently undergo the watch-and-wait (W&W) strategy. The study aimed to facilitate risk assessment in predicting the time to lymphoma treatment (TLT) for W&W patients through an integrated analysis of clinical factors and genetic mutations. A retrospective study was conducted on 214 FL patients managed with W&W between 2016 and 2023. Among them, 184 patients underwent targeted sequencing. The median follow-up was 30.4 months (IQR 21.4-41.9, range 6.4-95.8). A clinico-genetic model m3-PRIMA-PI was developed using the multivariate Cox proportional hazards method, incorporating two clinical parameters (bone marrow involvement and elevated β2-MG) and three gene mutations (<i>KMT2D</i>, <i>EP300</i>, and <i>TP53</i>). Patients were categorized into low (69.0%), intermediate (21.7%), and high (9.2%) risk groups. Probabilities of treatment initiation at one year were 11.0% (95% CI, 5.2%-16.5%), 26.0% (95% CI, 10.7%-38.7%), and 54.3% (95% CI, 22.3%-73.1%); and at 2 years were 29.4% (95% CI, 20.2%-37.5%), 49.8% (95% CI, 31.1%-63.4%), and 93.5% (95% CI, 56.7%-99.0%), respectively. The predictive performance for TLT was superior with m3-PRIMA-PI, achieving a C-index of 0.66 (95% CI, 0.63-0.69), compared to established indexes like FLIPI (C-index 0.59, 95% CI, 0.56-0.62) and FLIPI2 (C-index 0.59, 95% CI, 0.55-0.61). The above results were further validated in an independent external cohort. The m3-PRIMA-PI may provide a promising tool for risk stratification in W&W FL patients.