EVALUATION OF CLINICOGENETIC RISK MODELS FOR OUTCOME OF FOLLICULAR LYMPHOMA PATIENTS IN THE PRIMA TRIAL

Abstract

Introduction: Composite scores integrating genes mutation status with the clinical predictor FLIPI have been recently proposed to improve risk stratification for follicular lymphoma (FL) patients. We evaluated the ability of m7‐FLIPI and POD24‐PI scores to predict progression free survival (PFS) in a large cohort of patients receiving first‐line immunochemotherapy, with or without rituximab maintenance. Methods: Tumour biopsies were obtained at FL diagnosis from 252 patients from the PRIMA study, either as FFPE tissues (n = 98) or fresh‐frozen tissues (n = 154). After DNA extraction, DNA‐targeted sequencing was performed using the Foundation One Heme™ panel. m7‐FLIPI and POD24‐PI models were applied as originally described. Results: The frequency of non‐silent mutations were similar to those previously reported: CREBBP = 75%, EZH2 = 28%, CARD1 = 19%, ARID1A = 19%, EP300 = 16%, FOXO1 = 16% and MEF2B = 12%. We first evaluated the prognostic value of each gene mutation status separately. While some mutations were associated with a longer (MEF2B, EZH2) or shorter (EP300, CREBBP) PFS as previously described, ARID1A or CARD11 mutations were not associated with patients outcome. Moreover, FOXO1 mutations were associated with a good outcome, in opposite to their prognostic weight in the m7‐FLIPI. The m7‐FLIPI and FLIPI scores classified 28% and 43% of patients as high‐risk, respectively. m7‐FLIPI correlated with PFS (p = 0·005; OR = 1.74, 95%CI: 1.00‐3.02), slightly outperforming the FLIPI (Figure Presented) (p = 0.01; OR = 1.63, 95%CI: 0.99‐2.70), but not the FLIPI‐2 (p < 0.0001, OR = 2.85, 95%CI: 1.62‐5.03) (Figure 1A‐B). A high m7‐FLIPI score was associated with a shorter PFS in patients randomized in the rituximab maintenance group of PRIMA (p = 0.001), but was not prognostic for patients in the observation group (Figure 1C‐D). Progression of the disease within 24 months after diagnosis (POD24) proved to be a strong predictor of overall survival, which led to the proposal of the POD24‐PI as a predictor of early progression. In our study, 56 patients (22%) progressed within 2 years. FOXO1 mutations were enriched in the group of patients who did not experience POD24 (19% vs 7%, p = 0.04). The m7‐FLIPI, POD24‐PI, FLIPI‐1 and FLIPI‐2 scores showed specificity of 77%, 72%, 62% and 76%, respectively, and sensitivity of 46%, 54%, 60% and 53%, respectively, to predict POD24. The m7‐FLIPI and FLIPI‐2 thus showed the highest specificities, reflecting the prediction of correctly classifying as “low‐risk” a patient, but the FLIPI‐1 had the highest sensitivity to predict the risk of progression at the critical 2‐year endpoint. Conclusions: We confirmed in a large cohort, using a clinically validated assay, the applicability of composite scores m7‐FLIPI and POD24‐PI. Nevertheless, these scores showed some limitations, and need further evaluation to better discriminate risk group categories identified with FLIPI‐1 or ‐2 in larger cohorts and in patients treated with other approaches.