R-CVP versus R-CHOP versus R-FM as first-line therapy for advanced-stage follicular lymphoma: Final results of FOLL05 trial from the Fondazione Italiana Linfomi (FIL).

8006 Background: The optimal chemotherapy regimen for patients with advanced, active follicular lymphoma (FL) has not been established yet. We conducted a randomized trial comparing R-CVP with R-CHOP and R-FM. Methods: Previously untreated patients with advanced FL were randomly assigned to receive 8 doses of rituximab associated to 8 cycles of CVP, or 6 cycles of CHOP or FM (fludarabine 25 mg/m2 day 1-3, mitoxantrone 10 mg/m2 day 1). No maintenance therapy was allowed. The principal study end point was Time to Treatment Failure (TTF). Events in TTF were failure of induction therapy, progressive or relapse disease and death from any causes. In order to show a hazard ratio between each experimental arms and standard arm of 0.53 we planned to accrue 534 patients (178 per arm) with 4 years of accrual and 1 year of follow-up. Statistical tests were two-sided with an alpha error of 0.05, adjusted by Bonferroni for multiple arm comparison, and power of 90%. Results: Between March 2006 and September 2010, 534 patients were enrolled; 30 were subsequently excluded due to violation of inclusion criteria. Median patient age was 56 years (range 30-75), 63% of patients had stage IV disease, 37% had 3-5 FLIPI and 27% 3-5 FLIPI2 scores. At the end of induction treatment the overall response rate (CR+ PR) for the whole group was 91% (p=0.247). After a median follow-up of 34 months 208 events for TTF were recorded; 3-year TTF was 46%, 64% and 61% for patients treated with R-CVP, R-CHOP and R-FM respectively (R-CHOP vs R-CVP p=0.007; R-FM vs R-CVP p=0.021; R-FM vs R-CHOP p=0.969). The 3-year overall survival rate (OS) was 98%, 95% and 93% for R-CVP, R-CHOP and R-FM group, respectively (P=NS). Patients treated with R-FM had a higher rate of g III-IV neutropenia (64% vs 28% R-CVP, p<0.001; and vs 50% R-CHOP, p=0.015). During follow-up second malignancies were registered as late events in 23 patients (2%, 3% and 8% in R-CVP, R-CHOP and R-FM, respectively). Conclusions: This trial showed that R-CVP was associated with an inferior 3-year TTF and PFS compared with R-FM and R-CHOP. OS was similar among study arms but R-FM showed a higher rate of secondary tumors.