R-CHOP Versus R-FC Followed by Maintenance with Rituximab Versus Interferon-Alfa: Outcome of the First Randomized Trial for Elderly Patients with Mantle Cell Lymphoma

The prognosis of elderly patients with mantle cell lymphoma (MCL) is poor. Despite R-CHOP, only low rates of complete remissions (CR) are obtained and almost all patients relapse. Median overall survival (OS) used to be far below 5 years. Within the European MCL Network we performed a randomized intergroup trial to investigate both whether a fludarabine-containing induction regimen could improve the CR-rate, and whether maintenance with rituximab could prolong remission duration.

Patients with stage II-IV MCL >60 yrs not eligible for high-dose therapy were randomized between either 8 × R-CHOP-21 (day 1: rituximab 375 mg/m², cyclophosphamide 750 mg/m², doxorubicin 50 mg/m², vincristine 1.4 mg/m², max 2 mg and day 1–5 prednisone 100 mg) or 6 × R-FC-28 (rituximab 375 mg/m² day 1, fludarabine 30 mg/m² + cyclophosphamide 250 mg/m², both iv day 1–3). Responding (CR, CRu, PR) patients underwent a second randomization between maintenance with rituximab one dose every 2 months or interferon-alfa (IFN; regular IFN weekly 3×3 MIU or pegylated IFN 1×1 μg/kg), both given until progression.

First randomisation for induction therapy - R-CHOP vs R-FC: Between Jan 2004 and Oct 2010, 560 patients were entered; 457 were evaluable for response to induction. Median age was 70 yrs, 70% male, 83% stage IV, 41% intermediate and 50% high-risk MIPI. Whereas CR rates after R-FC and R-CHOP were similar (38 vs 34% CR, 52 vs 50% CR/CRu, respectively), the overall response rate was lower after R-FC (78% vs 87%; p=0.0508). Progressive disease was more frequent during R-FC (15% vs 5%). Of note, median OS was significantly inferior after R-FC (40 vs 64 months; p=0.0072). More patients died after initial progression (14% vs 4%) or in first remission (11% vs 3%) in the R-FC arm compared to R-CHOP. Hematologic grade 3–4 toxicities were more frequent during R-FC, especially thrombocytopenia (40% vs 17%). Non-hematologic grade 3–4 toxicity was rare (below 7% each), except neutropenic fever (12% R-FC; 18% R-CHOP) and infections (16% R-FC; 14% R-CHOP).

Second randomisation for maintenance therapy - Interferon-alpha vs Rituximab: From the responding patients, 310 underwent the second randomization. Sixty-one percent of patients had a CR/CRu upon induction therapy. Fifty-eight percent had received R-CHOP induction. Rituximab maintenance almost doubled the remission duration compared with IFN (at 4-yrs 57% vs 26% in remission; HR 0.54, 0.35–0.87; p=0.0109). Overall survival did not differ between both maintenance arms (p=0.17). However, the subcohort of R-CHOP-treated patients showed a significant advantage after rituximab maintenance (4-yr OS 87% vs 57% after IFN; p=0.0061). Hematologic grade 3–4 toxicity was higher in the IFN arm (leukocytopenia 33% vs 16%; thrombocytopenia 15% vs 6%); non-hematologic grade 3–4 toxicity was rare, except for infections (8% IFN; 7% rituximab). R-FC followed by rituximab resulted in the highest infection rate (CTC grades 1–4: 50%), whereas all other combinations (R-CHOP followed by rituximab or IFN, and R-FC followed by IFN) ranged between 25–35%. Patients in CR/CRu or PR after induction who did not receive any maintenance for various reasons, mainly based upon patient's decisions or ongoing cytopenia after induction (n = 104), had a poor outcome (median remission duration 18 months).

Induction therapy with R-FC is discouraged for elderly patients with MCL, whereas R-CHOP induction followed by rituximab maintenance should be considered the new standard for elderly MCL patients, to which new regimens need to be compared.

Off Label Use: rituximab maintenance for mantle cell lymphoma. Geisler:Roche: Consultancy, Research Funding; Celgene: Consultancy; GSK: Consultancy. Tilly:Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees. Hiddemann:Roche Pharma: Honoraria, Research Funding. Dreyling:Roche: Research Funding, Scientific advisory board, Speakers Bureau.