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Follicular lymphoma (FL) usually follows an indolent course and responds well to initial treatment. Overall survival (OS) has improved after the introduction of rituximab, yet most patients experience multiple relapses and die from lymphoma. For some patients, relapses are associated with transformation to aggressive disease with histological features of diffuse large B-cell lymphoma (DLBCL) and markedly inferior OS. There is no robust method for assessment of transformation risk at FL diagnosis. Prospective identification of high transformation risk would enable selection of patients for future treatments aiming to postpone or prevent transformation. We present a novel clinico-molecular predictor of transformation risk in rituximab-treated FL, based on a gene expression score capturing deregulation of the nuclear factor-kappa B (NF-kB) pathway. Few gene expression signatures have been associated with transformation risk in FL, and none have been tested in patients treated with rituximab. In Gentles et al., an expression signature composed of modules of embryonic stem cell genes was associated with transformation risk. Brodtkorb et al. found six gene expression signatures capturing deregulation of the NF-kB pathway and predicting transformation in the pre-rituximab era. NF-kB signaling is implicated in the pathogenesis of multiple B-cell lymphomas, including DLBCL. We used a novel cohort of 82 FL patients receiving firstline rituximab to investigate and further develop the expression-based transformation predictors described in Brodtkorb et al. The patients participated in two prospective randomized trials testing first-line rituximab with or without interferon-a. Gene expression and copy number profiles were obtained from 92 FL biopsies from these patients (Online Supplementary Methods). Biopsies were obtained prior to first-line treatment for FL and prior to any transformation event. Table 1 summarizes patients' clinical characteristics. All patients needed treatment at inclusion due to symptomatic FL. The proportion of patients in the Follicular Lymphoma International Prognostic Index (FLIPI) risk groups was representative for FL patients in general. Most patients were included at diagnosis of FL; a minority had been observed without treatment (Online Supplementary Figure S1). Median follow-up time from diagnosis of FL was 10.3 years (range: 0.5-26.0 years). By the end of follow up, 24 patients (29%) had not received new treatment and 21 of these were still alive. Overall survival at ten years was 77% [95% confidence interval (CI): 66-85%] (Figure 1A). The average annual transformation rate was 2.3% for the first ten years, and 21 patients (26%) were diagnosed with histological transformation to DLBCL (Figure 1B). No additional patients fulfilled the clinical criteria for transformation, reflecting a high biopsy frequency at relapse in the participating study centers. Overall survival at ten years after transformation was 35% (95%CI: 13-60%) (Figure 1C). To explore the robustness of the six NF-kB deregulation signatures, we compared those in the current cohort and a previously published cohort consisting of 75 FL biopsies from 44 patients treated with traditional chemotherapy (Online Supplementary Methods, Online Supplementary Tables S1 and S2, and Online Supplementary Figures S2-S4). For completeness, we considered all 14 deregulation signatures involving downstream targets of the NF-kB pathway described in Brodtkorb et al. A score is calculated for each signature and biopsy by averaging the expression values of the genes in the signature. The scores were highly consistent across the patient cohorts, suggesting that they represent robust molecular traits of FL (Online Supplementary Table S1 and Online Supplementary Figures S2-S4). Among these, the BTK score measured in pre-treatment FL biopsies was associated with transformation in the rituximab-treated cohort (Student t-test, P=0.039) (Online Supplementary Table S3), validating the previous findings in the pre-rituximab era. A binary BTK score found by thresholding the score on its median was associated with transformation (Fisher's exact test, P=0.022) (Online Supplementary Figure S5), also after adjustment for FLIPI (Logistic regression, P=0.019). Among patients with high BTK score, the median time from detecting a high score to transformation was 51 months (range: 7-185 months); a similar result was found in the chemotherapy-treated cohort (Online Supplementary Figure S6). The binary BTK score was associated with time to transformation (Log rank test, P=0.035) and time to new treatment (Log rank test, P=0.050) (Figure 1D and E). It was also correlated to the expression of the MKI67 gene, suggesting an association to increased proliferation in FL (Online Supplementary Figure S7). Follicular Lymphoma International Prognostic Index risk groups (low, intermediate, high) were associated with time to transformation (Log rank test, P=0.041), but not with time to new treatment (Online Supplementary Figure S8A and B). The binary BTK score and FLIPI were associated with time to transformation in a bivariate linear model [Cox's proportional hazards model, P=0.029; Hazard Ratio (HR) 3.18, 95%CI: 1.15-8.74, and P=0.021, HR 1.76, 95%CI: 1.11-2.78, respectively]. Considering all combinations of FLIPI (low, intermediate or high) and the

A clinico-molecular predictor identifies follicular lymphoma patients at risk of early transformation after first-line immunotherapy