Integration of Gene Mutations in Risk Prognostication for Watch-and-Wait Follicular Lymphoma Patients Initiating First-Line Treatment

Introduction

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.

Methods

A retrospective analysis was conducted on 214 FL patients managed with W&W between 2016 and 2023. Among all, 184 patients underwent targeted sequencing. The median follow-up was 30.4 months (IQR 21.4-41.9, range 6.4-95.8). A clinic-genetic model was developed using the multivariate Cox proportional hazards method.

Results

The clinic-genetic model incorporated two clinical factors (bone marrow involvement and elevated β2-MG) and three gene mutations (KMT2D, EP300, and TP53). Each factor was assigned one point based on its relative importance, as indicated by the z-Wald values from the Cox model. The total score for each patient was calculated as the sum of these points. Since this model includes two clinical factors overlapping with those in PRIMA-PI, along with three additional gene mutations, we termed it m3-PRIMA-PI. Patients were stratified into three risk groups based on their scores: low (score 0-1, n=127, 69.0%), intermediate (score 2, n=40, 21.7%), and high (score 3-5, n=17, 9.2%). The 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 two 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).

Conclusion

Integration of genetic mutations with clinical risk factors presents a promising tool for risk stratification in W&W FL patients.

No relevant conflicts of interest to declare.