Follicular lymphoma is the most frequent low-grade lymphoma in western countries, accounting for 25% of all lymphoma cases (Tan & Horning, 2008). Although follicular lymphoma is generally considered a long lasting indolent disorder, survival duration is heterogeneous and precise prognostic evaluation in the Rituximab era is greatly needed (Johnston & Salles, 2008). The Follicular Lymphoma International Prognostic Index (FLIPI) was developed from the retrospective series of a collaborative international working party (Solal-Celigny et al, 2004) and was validated in independent series (Perea et al, 2005; Arcaini et al, 2006; Buske et al, 2006). The same working group recently proposed the Follicular Lymphoma International Prognostic Index 2 (FLIPI2), based on prospectively collected data: β2-microglobulin higher than the upper limit of normal, longest diameter of the largest involved node longer than 6 cm, bone marrow involvement, haemoglobin level lower than 120 g/l and age >60 years were independent predictive factors of progression-free survival (PFS). Using these variables, a prognostic model was devised to identify three groups with different risk levels (Federico et al, 2009). The present analysis aimed to validate the FLIPI2 prognostic score on a large cohort of patients with follicular lymphoma. Our study involved 498 patients consecutively diagnosed with follicular lymphoma between 1980 and 2008 in our Institution. In all cases the diagnosis was based on histological biopsy of pathological material. Diagnosis was made in line with the lymphoma classification in use at the time of diagnosis. 418 had all the parameters needed for FLIPI calculation. 280 patients had all the parameters needed for FLIPI2 calculation: of them 262 were diagnosed after 1995 and 190 were treated with Rituximab (101 received first-line treatment of Rituximab combined with chemotherapy). Continuous variables are summarized as median and range. Categorical variables are reported as count and relative frequency. Survival analysis was carried out using the Kaplan–Meier product-limit method. Overall survival (OS) and PFS was established according to Cheson’s criteria (Cheson et al, 2007). Gehan’s Wilcoxon test was used to compare survival rates in the different groups. To compare the performance of two predictors in terms of discriminatory power, the Harrell C statistics were used. The C statistic estimates the proportion of correct predictions, i.e. the proportion of all patient pairs in which the predictions and the outcome are concordant (Harrell et al, 1996). If the predicted survival time is greater for the patient who lived longer, the predictions for that pair are said to be concordant with the outcomes. The standard errors and the 95% Confidence Intervals of C statistics were empirically computed with 1000 bootstrap samples. The clinical features of the 498 patients with follicular lymphoma are given in Table SI. After a median follow-up of 4·7 years (range 1–21), 142 patients had died. For the entire series median OS was 12·6 years and the 3- and 5-year OS rates were 91% and 79%, respectively. Median PFS was 3·7 years and the 5- and 10-year PFS survivals rates were 60% and 44%, respectively (Fig SI). Using the FLIPI score, 210 patients (50%) were in the low risk group, 131 patients (31%) in the low-intermediate and 77 patients (19%) in the high risk group. With the FLIPI2 score, 58 patients (21%) of patients were in the low risk group, 166 patients (59%) in the low-intermediate and 56 patients (20%) in the high risk group (Table I). Distribution of FLIPI2 categories according to FLIPI are reported in Table SII. According to FLIPI, the 3-year PFS was 74% for the low risk group, 54% for the intermediate risk and 39% for the high risk group (P = 0·001). Median PFS was 6·8 years for the low risk group, 3·1 years for that of intermediate risk and 2·1 for the high risk group (P = 0·009) (Fig SII). 3-year OS was 98% for the low risk group, 95% for the intermediate risk and 89% for the high risk group (P = 0·009) (Fig SIII). Using FLIPI2, the 3-year PFS was 77% for patients classified as low risk, 61% for intermediate risk, and 39% for the high risk group (P = 0·001). Median PFS was not reached by the low risk group, and was 3·3 years for the intermediate risk and 2·4 years for the high risk group (P = 0·009) (Fig 1). The 3-year OS was 98% for the low risk group, 95% for the intermediate risk, and 89% for the high risk group (P = 0·009) (Fig SIV). PFS was also different in 3 FLIPI2 risk categories in patients treated with Rituximab (P = 0·009). Progression-free survival according to FLIPI2 in 280 patients with follicular lymphoma. Considering low risk FLIPI patients, PFS was statistically shorter for patients with a high β2-microglobulin level (Fig SV). FLIPI2 was also able to identify three risk categories with statistically different PFS in 139 patients of the FLIPI low risk category (Fig SVI). Applying Harrell C statistics to each parameter of two prognostic scores, FLIPI2 produced a more discriminating index compared to FLIPI (Table SIII). Follicular B-cell lymphoma is an indolent disease with a relatively long life expectancy. However, survival duration is quite heterogeneous, with a subset of patients experiencing a poorer outcome. Prognostic assessment at diagnosis is, therefore, an important part of the initial evaluation of follicular lymphoma patients as it allows a rational selection of patients that may benefit from more intensified treatments. In this report we have compared two prognostic indexes for follicular lymphoma (i.e. FLIPI and FLIPI2) in an attempt to determine the value of each of the models. The calculation of the OS and PFS rates according to the FLIPI and FLIPI2 scores strongly corroborate in an independent series of the two scores in detecting risk groups of follicular lymphoma patients. In our analysis, FLIPI2 was found to be somewhat superior to FLIPI: the parameters included in FLIPI2 showed the best performance with Harrell C statistics compared to the parameters of the FLIPI score. Interestingly, FLIPI2 was also able to stratify patients with good prognosis into three risk categories. In conclusion, this study showed in an independent series that the FLIPI2 score is a reproducible prognostic index of clinical utility for the initial prognostic assessment of patients with follicular lymphoma. We would like to thank professor Massimo Federico for helpful discussion. Fig SI. Overall survival and progression free survival of 498 patients with follicular lymphoma. Fig SII. Progression-free survival according to FLIPI in 418 patients with follicular lymphoma. Fig SIII. Overall survival according to FLIPI in 418 patients with follicular lymphoma. Fig SIV. Overall survival according to FLIPI2 in 280 patients with follicular lymphoma. Fig SV. Progression-free survival for FLIPI good risk patients (n = 152) according to b2-microglobulin level. Fig SVI. Progression-free survival for FLIPI low risk patients (n = 139) according to FLIPI2 risk categories. Table SI. Clinical features of 498 patients with follicular lymphoma. Table SII. Distribution of FLIPI and FLIPI2 in 279 patients with both indexes FLIPI and FLIPI2. Table SIII. Performances of FLIPI and FLIPI2 using Harrell C statistics. Please note: Wiley-Blackwell are not responsible for the content or functionality of any supporting materials supplied by the authors. Any queries (other than missing material) should be directed to the corresponding author for the article. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.
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