No abstract

We evaluated the role of rituximab (R) both in remission induction and maintenance treatment of relapsed/resistant follicular lymphoma (FL). A total of 465 patients were randomized to induction with 6 cycles of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) (every 3 weeks) or R-CHOP (R: 375 mg/m 2 intravenously, day 1). Those in complete remission (CR) or partial remission (PR) were randomized to maintenance with R (375 mg/m 2 intravenously once every 3 months for a maximum of 2 years) or observation. R-CHOP induction yielded an increased overall response rate (CHOP, 72.3%; R-CHOP, 85.1%; P < .001) and CR rate (CHOP, 15.6%; R-CHOP, 29.5%; P < .001). Median progressionfree survival (PFS) from first randomization was 20.2 months after CHOP versus 33.1 months after R-CHOP (hazard ratio [HR], 0.65; P < .001). Rituximab maintenance yielded a median PFS from second randomization of 51.5 months versus 14.9 months with observation (HR, 0.40; P < .001). Improved PFS was found both after induction with CHOP (HR, 0.30; P < .001) and R-CHOP (HR, 0.54; P ‫؍‬ .004). R maintenance also improved overall survival from second randomization: 85% at 3 years versus 77% with observation (HR, 0.52; P ‫؍‬ .011). This is the first trial showing that in relapsed/ resistant FL rituximab maintenance considerably improves PFS not only after CHOP but also after R-CHOP induction. IntroductionFor patients with follicular lymphoma (FL) chemotherapy alone has not resulted in improved overall survival (OS) over the past 30 years. [1][2][3][4] Although in most patients complete remissions (CRs) or partial remissions (PRs) can be obtained with either single agents or combination chemotherapy, the clinical course is characterized by a high relapse rate. After relapse, both the response rate and relapse-free survival after subsequent salvage treatment regimens steadily decrease, resulting in a median survival of only 4 to 5 years after first relapse. [5][6][7][8] Therefore, new treatment modalities resulting in increased progression-free survival (PFS) and OS are urgently required. Optimal treatment of patients relapsed after 1 or 2 chemotherapy regimens is largely unknown.Rituximab (R) is a chimeric murine/human anti-CD20 monoclonal antibody capable of killing CD20 ϩ lymphoma cells. Effector mechanisms include complement-mediated cytotoxicity, antibodydependent cellular cytotoxicity, and possibly direct induction of apoptosis. 9,10 In the nonrandomized pivotal study in 166 relapsed low-grade lymphoma patients, monotherapy with rituximab resulted in a response rate of 48%, with a 6% complete remission (CR) rate and a median time to progression in responding patients of 13 months. 11 Toxicity was generally mild to moderate (grade 1 or 2) and occurred primarily with the first infusion. 11 In a subsequent small phase 2 study, the combination of R with cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) was shown to be safe and effective. 12 Treatment results in FL might not only be improved by more effective induction...

A B S T R A C T PurposeIn 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 MethodsOverall, 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 ϭ 334) were randomly assigned to maintenance treatment with rituximab (375 mg/m 2 intravenously once every 3 months) or observation. ResultsRituximab maintenance significantly improved progression-free survival (PFS) compared with observation (median, 3.7 years v 1.3 years; P Ͻ .001; hazard ratio [HR], 0.55), both after CHOP induction (P Ͻ .001; HR, 0.37) and R-CHOP (P ϭ .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 ϭ .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 ϭ .01). ConclusionWith 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.

Postinduction BCL2/IgH major break point status in BM/PB is not useful for decisions on subsequent therapy for patients with relapsed/resistant FL.