Rituximab maintenance treatment of relapsed/resistant follicular non-Hodgkin's lymphoma: long-term outcome of the EORTC 20981 phase III randomized intergroup study

Abstract

Purpose: In 2006, we published the results of the European Organisation for Research and Treatment of Cancer phase III trial EORTC 20981 on the role of rituximab in remission induction and maintenance treatment of relapsed/resistant follicular lymphoma (FL). At that time, the median follow-up for the maintenance phase was 33 months. Now, we report the long-term outcome of maintenance treatment, with a median follow-up of 6 years.

Patients and methods: Overall, 465 patients were randomly assigned to induction with either six cycles of cyclophosphamide, doxorubicin, vincristine, prednisone (CHOP) or rituximab plus CHOP (R-CHOP). Those in complete remission or partial remission after induction (n = 334) were randomly assigned to maintenance treatment with rituximab (375 mg/m(2) intravenously once every 3 months) or observation.

Results: Rituximab maintenance significantly improved progression-free survival (PFS) compared with observation (median, 3.7 years v 1.3 years; P < .001; hazard ratio [HR], 0.55), both after CHOP induction (P < .001; HR, 0.37) and R-CHOP (P = .003; HR, 0.69). The 5-year overall survival (OS) was 74% in the rituximab maintenance arm, and it was 64% in the observation arm (P = .07). After progression, a rituximab-containing salvage therapy was given to 59% of patients treated with CHOP followed by observation, compared with 26% after R-CHOP followed by rituximab maintenance. Rituximab maintenance was associated with a significant increase in grades 3 to 4 infections: 9.7% v 2.4% (P = .01).

Conclusion: With long-term follow-up, we confirm the superior PFS with rituximab maintenance in relapsed/resistant FL. The improvement of OS did not reach statistical significance, possibly because of the unbalanced use of rituximab in post-protocol salvage treatment.

Fig 1.

CONSORT diagram of (A) all randomly allocated patients and (B) those randomly assigned to maintenance. CHOP, cyclophosphamide, doxorubicin, vincristine, prednisone; R-CHOP, rituximab plus CHOP; CR, complete remission; PR, partial remission; PD, progressive disease.

Fig 2.

Effect of rituximab maintenance treatment on progression-free survival (PFS). Kaplan-Meier plot of PFS from second random assignment after rituximab maintenance therapy (n = 167) and observation (n = 167). Rituximab maintenance, median 3.7 years; observation, median 1.3 years. HR, hazard ratio.

Fig 3.

Effect of rituximab maintenance treatment on progression-free survival (PFS) after remission induction with either cyclophosphamide, doxorubicin, vincristine, prednisone (CHOP) or rituximab plus CHOP (R-CHOP). Kaplan-Meier plots of PFS and overall survival from second random assignment. (A) PFS after CHOP remission induction (n = 145). Rituximab maintenance, median 3.1 years; observation, median 1.0 year. (B) PFS after R-CHOP remission induction (n = 189). Rituximab maintenance, median 4.4 years; observation, median 1.9 years. HR, hazard ratio; O, observed; N, number.

Fig 4.

Effect of rituximab maintenance treatment on progression-free survival (PFS) in patients in partial remission (PR) or complete remission (CR) after remission induction treatment. Kaplan-Meier plots of PFS and overall survival from second random assignment. (A) PFS in patients with PR (n = 237). Rituximab maintenance, median 3.4 years; observation, median 1.3 years. (B) PFS in patients with CR (n = 97). Rituximab maintenance, median 4.4 years; observation, median 1.2 years. HR, hazard ratio; O, observed; N, number.

Fig 5.

Effect of rituximab maintenance treatment on overall survival. Kaplan-Meier plot of overall survival from second random assignment after rituximab maintenance therapy (n = 167) and observation (n = 167). Rituximab maintenance, 74.3% at 5 years; observation, 64.7% at 5 years. HR, hazard ratio.