Rituximab maintenance improves clinical outcome of relapsed/resistant follicular non-Hodgkin lymphoma in patients both with and without rituximab during induction: results of a prospective randomized phase 3 intergroup trial

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...

Rituximab maintenance improves overall survival in follicular lymphoma: A retrospective nationwide real‐world analysis from Taiwan Cancer Registry Database

“…First, we stratify the patients into 2 groups, the R‐maintenance and the observation groups, to investigate the clinical relevance of rituximab maintenance. The Japanese study is designed as a phase II single‐arm study and is aimed to show the safety of rituximab maintenance in Asian patients with indolent BCL 17. Our study further demonstrates the survival benefit of rituximab maintenance in FL and shows that patients with older age or stage IV disease exhibit a survival advantage when they receive rituximab maintenance.…”

“…The clinical benefit of rituximab maintenance in FL is equivocal according to previous studies 16, 17, 18, 19. Although PFS is improved in patients receiving rituximab maintenance, there is no difference in OS 16.…”

“…Although the study revealed longer progression‐free survival (PFS) in patients undergoing rituximab maintenance, no advantage for overall survival (OS) was demonstrated 16. Other studies also demonstrated only a progression‐free benefit of rituximab maintenance after re‐induction therapies in relapse FL 17, 18. Currently, no prospective randomized study has demonstrated the overall survival benefit of rituximab maintenance in the patients with FL.…”

“…Rituximab combined with cytotoxic chemotherapies is superior to chemotherapies alone, regardless of frontline treatments or in relapse and/or refractory FL 8, 9, 10, 12, 13, 14, 15. Several prospective trials tried to address the clinical benefits of rituximab maintenance in the patients with FL, but rituximab maintenance only improves progression‐free survival instead of overall survival 16, 17, 18, 19. The clinical benefit of rituximab maintenance is still uncertain.…”

Radioimmunotherapy for B-cell lymphoma: Y90 ibritumomab tiuxetan and I131 tositumomab

“…Efficacy following previous treatment with rituximab The use of rituximab in the treatment of follicular lymphomas has expanded considerably in recent years based on the results of a number of randomized studies (Hiddemann et al, 2005;Marcus et al, 2005;Forstpointner et al, 2006;van Oers et al, 2006). This begs the question, what is the efficacy of CD20 targeted RIT in patients that have recurred after exposure to rituximab?…”