Rituximab Combined with Chemotherapy and Interferon in Follicular Lymphoma Patients: Final Analysis of the GELA-GOELAMS FL2000 Study with a 5-Year Follow-Up.

Background. The FL2000 study evaluated the combination of the anti-CD20 monoclonal antibody rituximab with chemotherapy plus interferon in the first line treatment of follicular lymphoma patients.

Methods. Untreated follicular lymphoma patients (n=359) presenting with a high tumor burden were randomly assigned to receive either 12 courses of the chemotherapy regimen CHVP (cyclophosphamide, adriamycin, etoposide and prednisolone) plus interferon-α2a (CHVP+I arm) over 18 months or 6 courses of the same chemotherapy regimen combined with 6 infusions of 375 mg/m² of rituximab and interferon for the same time period (R-CHVP+I arm). The primary endpoint of the study was event free survival and all results are shown as intent to treat.

Results. Six months after treatment initiation, 156 out of 183 (85%) and 164 out of 175 (94%) patients had a response to therapy in the CHVP+I and R-CHVP+I study arm, respectively (P=.009). At the end of the 18 months treatment period, 59% and 75% of the patients were respectively in CR or CRu in the CHVP+I and R-CHVP+I arm (P<.05). After a median follow-up of five years, event-free survival (EFS) estimates were respectively 37% [95% C.I. 29 – 44] and 53% [95% C.I. 45 – 60] in the CHVP+I and R-CHVP+I arm (P=.0004). Response duration in CR/CRu or PR patients at the end of the 18 months treatment was also improved in the R-CHVP+I arm (P=.012). 5-year overall survival (OS) estimates were not statistically different in the CHVP+I (79%) [95% C.I. 72 – 84]) and R-CHVP+I (84% [95% C.I. 78 – 84]) arms. The Follicular Lymphoma International Prognostic Index (FLIPI) score allowed separation of the whole study population into 3 different risk categories with significantly different outcome for each group both for 5 year EFS and OS (P<.0001, respectively each). In a multivariate regression analysis, event free survival was significantly influenced by both the FLIPI score (HR=2.08; 95% C.I. [1.6 – 2.8]) and the treatment arm (HR=0.59; 95% C.I. [0.44 – 0.78]). In an exploratory analysis considering the 187 patients with a low/intermediate (<3) FLIPI score, the outcome according to each treatment arm was not statistically different while the benefit of the rituximab combination was highly significant in term of EFS (P=.0002) and OS (P=.025) in the 162 patients with a high (≥3) FLIPI score.

Conclusions. These results extend our previous interim analyses and confirm that with a five year follow-up, the combination of rituximab with CHVP+I provides superior disease control in follicular lymphoma patients despite a shorter duration of chemotherapy. However, this combination appears to benefit essentially to high risk patients for whom overall survival is also significantly improved.