Rate of Transformation and Secondary Malignancies in Follicular Lymphoma Patients Treated with First-Line Bendamustine Rituximab and Rituximab Maintenance

INTRODUCTION: Bendamustine-rituximab (BR) has exhibited improved outcomes in first-line therapy for Follicular Lymphoma (FL). Nevertheless, concerns regarding secondary malignancies and the transformation into aggressive lymphoma have arisen. Therefore, we aim to assess the outcomes in long-term follow-up of a cohort of FL patients treated within a tertiary care cancer centre. METHODS: Using the prospectively populated Lymphoma Data Base at the Princess Margaret Cancer Centre, we evaluated the outcomes of FL patients intended to be treated with 6 cycles of BR and 2 years of rituximab maintenance as frontline therapy between 2013 and 2022. RESULTS:137 patients were identified: at diagnosis, median age was 60 years (range 31-86), 61% had stage IV disease, 49% had elevated LDH, and 56% had high FLIPI; 126 (92%) completed 6 cycles of BR treatment, and 115 (84%) commenced rituximab maintenance (RM). At a median follow-up of 6.3 years (IQR 4.0-8.6), 5-year Progression-Free Survival (PFS), Duration of Response (DOR), and Overall Survival (OS) were 65% (95% CI, 60%–74%),72% (64–81%), and 85% (79%–92%), respectively. Disease progression occurred in 44 patients (32%), with 25 (18%) progressing within 24 months (POD24). A biopsy was performed at first progression in 42 patients (95%): 26 (62%), showed transformation to diffuse large B-cell lymphoma (DLBCL, 20/42 [48%]) or, high-grade B-cell lymphoma with CMYC +BCL2 rearrangements (6/42, 14%). Among the POD24 patients, transformation was seen in 22/25 (88%). POD24 and elevated LDH at relapse were significant predictors of transformation in univariate analysis (OR 188.4 [95% CI 35.46, -], p < .001 and OR 9.58 [95% CI 2.3-51.64], p=0.004). In multivariate analysis, for transformation risk, elevated LDH at relapse was the only factor that remained significant (OR 7.64 [95% CI,1.58,36.78], p=0.11). The median time to transformation was 10 months (IQR 5-30), and the 5-year cumulative risk of transformation was 18% [95% CI: 12.1,25.4%]. Fourteen patients (10%) underwent ASCT: in 11 (79%), the indication was tFL (10 patients as a consolidation after second-line treatment, one as third line), and in 3, relapse of FL. Furthermore, 7 (5%) patients underwent CART therapy as third line of treatment or afterward, 6 (86%) with a tFL , and one (14%) for FL. The 12-month OS after ASCT was 69.2% [95% CI: 48.2, 99.5%], and after CART was 57.1% [95% CI: 30.1, 100%]. Excluding transformation and nonmelanoma skin cancer, 17 (12.4%) patients experienced a secondary malignancy during the follow-up. Given the bias of malignancies that may be present at diagnosis, we excluded the malignancies diagnosed within the 6 months from the BR, the second malignancies were found in 14 patients (10.2%). The 5-year cumulative risk of secondary malignancies among patients was 9% [95% CI: 4.14,14%]. The median time from BR to second malignancy was 23 months (IQR 7.5-74.5). The incidence rate of secondary malignancies among patients was 22.3 per 1,000 person-year. CONCLUSION: These single-centre data are consistent with prospective clinical trial results in FL, with BR followed by RM offering prolonged 5-year PFS. However, we observed a notably higher rate of transformation to aggressive lymphomas compared to clinical trials, where rates of biopsy at progression are much lower. This observation underscores the need for biopsies at early progression/relapse, and has implications for trials designed to address markers of poor outcome (positive end of treatment PET scan or MRD), as tFL rates are underestimated when biopsies are not mandated by trial protocols. The elevated risk of secondary malignancies warrants further investigation through population-based studies.