RESPONSE ORIENTED MAINTENANCE THERAPY IN ADVANCED FOLLICULAR LYMPHOMA. RESULTS OF THE INTERIM ANALYSIS OF THE FOLL12 TRIAL CONDUCTED BY THE FONDAZIONE ITALIANA LINFOMI

Introduction: Rituximab maintenance after frontline R+chemo prolongs remissions and is a widely adopted treatment option for patients with follicular lymphoma (FL). Moreover, metabolic and molecular response assessed with FDG‐PET and MRD have been confirmed as strong predictors of patients’ survival thus suggesting the benefit of a response adapted maintenance strategy as post induction therapy. Methods: FOLL12 is a multicenter, randomized, phase III, non inferiority study comparing standard vs response adapted maintenance in patients with stage II‐IV, previously untreated, intermediate‐high risk FL according to FLIPI2, requiring therapeutic intervention. All patients received induction immunochemotherapy (ICT) with 6 cycles of R‐CHOP or 6 cycles of R‐bendamustine both followed by 2 additional doses of rituximab. After induction ICT, patients in the standard arm were treated with bimonthly rituximab doses for up to two years. Patients in the experimental arm were managed according to centrally reviewed metabolic and molecular response (i.e. Complete metabolic and molecular response: no therapy; Complete metabolic response without molecular response: 4 weekly rituximab doses; Lack of metabolic response (Deauville score 4‐5): radiommunotherapy with ibritumomab tiuxetan followed by standard rituximab maintenance). Primary study endpoint was 3 years progression free survival (PFS) by intention to treat. A sample size of 770 evaluable patients was planned assuming a reference of 3yr PFS at 70% with a non inferiority margin of 7% between arms. Results: A total of 790 eligible patients were randomized to standard (394 patients) or experimental (396 patients) arm. Groups were well balanced according to patient characteristics and response rates. At the end of induction therapy 88% of cases resulted PET‐ and 91% MRD‐. After a median follow‐up of 37 months (range 1‐71), the 3‐year overall survival (OS) and PFS were 96% and 76%, respectively. An interim analysis, planned at the occurrence of 70% events, was anticipated at the occurrence of 50% of events and submitted to the external data safety monitoring committee (DSMC). The analysis showed that response oriented experimental arm resulted significantly inferior to the standard maintenance arm in terms of PFS (estimated 3‐year PFS, 68% vs. 84%; hazard ratio for PFS, 2.05 [95% CI 1.50‐2.81; P < 0.0001]). The DSMC considered unlikely that longer follow‐up could modify the results and was favorable in publishing these data. Conclusions: In patients with intermediate‐high risk FL according to FLIPI2 and requiring systemic therapy, omission of R‐maintenance resulted in a significantly lower 3‐year PFS, despite the attainment of a post‐induction complete metabolic response.