Clinico‐biological features, treatment and survival of 457 patients with histological Grades 3A and 1–2 follicular lymphoma mostly treated with immunochemotherapy

Follicular lymphoma (FL) is a non-Hodgkin lymphoma (NHL) of follicle centre B-cells that grow in a follicular pattern. The 2008 World Health Organization (WHO) classification (Swerdlow et al, 2008) divides FL into three major grades: Grade 1 and 2 [<15 centroblasts/high-power field (HPF)] and Grade 3 (>15 centroblasts/HPF). FL Grade 3 is also divided into two types, 3A and 3B; Grade 3A is classified as a preserved maturation of the centrocytes. However, the prognostic value of this grading system remains controversial. Grade 3B FL is currently considered a distinct entity and managed as diffuse large B-cell lymphoma (Horn et al, 2011). It is well known that Grade 1–2, representing 75–90% of all FL cases, has an indolent evolution with a pattern of frequent relapses and is incurable with conventional therapy. However, Grade 3A FL is not yet well defined, with some characteristics of near aggressive lymphoma and others that are almost low-grade (Shustik et al, 2011; Vaidyanathan & Czuczman, 2014). The present study aimed to evaluate initial clinical and biological features, response and outcome of a large cohort of FL Grade 3A and 1–2 patients, most of whom had been treated with immunochemotherapy. Four hundred and fifty-seven patients diagnosed with FL were selected. Primary cutaneous and Grade 3B FL were excluded. In the overall cohort, median follow-up for surviving patients was 5 08 years, with a 10-year overall survival (OS) of 69% [95% confidence interval (CI): 63–75%] and 10-year progression-free survival (PFS) of 38% (95% CI: 32– 44%). Histological grade was based on the current WHO classification, assessed in all patients, and central histological review. Univariate and multivariate analysis was evaluated according to the histological grade, with all main clinical and histological data, prognostic factors, treatment strategies and response. Tumour response was assessed using International Working Group criteria for NHL (Cheson et al, 1999). The main clinical characteristics are summarized in Table I. Comparing the most important clinical differences between Grade 3A and Grade 1–2 FL, less extra nodal involvement was observed in Grade 3A patients, principally due to less bone marrow involvement in this group (Grade 3A, 35%; Grade 1–2, 54%, P = 0 003). This proportion is lower than previously described (Wahlin et al, 2012). Histological analysis did not identify significant differences between BCL2 and CD10 in both groups: 91% and 90% in Grade 3A; 95% and 92% in Grade 1–2, respectively. BCL6 expression was lower in Grade 3A patients: 77/77 (100%) and 54 out of 72 (75%) (P < 0 0001). This data was not previously described; however, this finding did not impact outcome. Ki67 index >50% was evident in Grade 3A compared with Grade 1–2 FL patients: 33/56 (59%) vs. 7/63 (11%) (P < 0 0001). Expression of Ki67 index >50% defined a small group (N = 39) in our cohort with a median survival of 1 5 years (0 7–2 3), regardless of histological subtype. Treatment was heterogeneous in both groups (Table I). Patients with FL Grade 3A were more frequently treated with anthracyclines and rituximab, and received less fludarabine, A trend towards a high complete response rate was observed in the Grade 3A FL group (Table SI). In univariate and multivariate analysis, the most important variables predicting response in FL Grade 3A patients was the FL International Prognostic Index (FLIPI) score (P = 0 009) and, included FLIPI score (P < 0 0001) and b2microglobulin (P = 0 041) for the Grade 1–2 group (Table SII). No significant differences in outcome (PFS and OS) were observed between Grades 1–2 and 3A (Fig 1). Of 270 patients that achieved CR, 121 relapsed: 21 (35%) FL Grade 3A patients and 100 (46%) FL Grade 1–2 patients (P = 0 126). At the time of this analysis, 24 (27 3%) and 91 (24 7%) FL Grade 3A and 1–2 patients, respectively, had died, mostly due to lymphoma progression. As expected, FLIPI score still remained an important prognostic factor for OS in both groups (Grade 3A, P = 0 050; Grade 1–2, P = 0 045). Univariate and Cox multivariate analysis of survival in both groups is shown in Table SIII. In our series, 95% and 70% of the Grade 3A and Grade 1–2 patients, respectively, received upfront anthracyclines (P < 0 0001). When only patients treated with anthracyclines were analysed, no differences in terms of OS and PFS were observed between the Grade 3A and Grade 1–2 cohorts (Fig S1), or when analysed for each particular group (Table SIII), and was in agreement with previous reports (Chau et al, 2003; Ganti et al, 2006). This report describes the largest number of FL patients treated with immunochemotherapy published to date. Upfront and cumulative rituximab treatment in Grade 3A and 1–2 FL patients were: 68% vs. 47% and 77% vs. 63%, respectively (P < 0 0001 and P = 0 032). OS probabilities were identical in Grades 1–2 and 3A patients treated with upfront and cumulative rituximab (Fig S2 and S3), and were the same in terms of PFS in upfront rituximab patients (Fig S2). However, PFS showed a non-significant trend for