Older Patients with Mantle-Cell Lymphoma

The long-term prognosis for older patients with mantle-cell lymphoma is poor. Only a minority of patients have a complete remission, and relapse or progression usually occurs within 2 to 3 years, resulting in an overall survival of <5 years.

This trial [N Engl J Med. 2012;367(6):520-531] was a double-randomized intergroup trial that aimed to find a more effective induction therapy for the condition. The investigators compared the rates of response to an induction regimen consisting of fludarabine, cyclophosphamide, and rituximab (R-FC) and an induction regimen with R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone). Also, the authors studied the duration of remission; patients who had a response were randomly assigned to maintenance therapy with rituximab or interferon alfa.

Eligible patients had newly diagnosed, histologically confirmed mantle-cell lymphoma, Ann Arbor stage II to IV, were ≥66 years of age or were 60 to 65 years of age if they were ineligible for high-dose treatment, and had an Eastern Cooperative Oncology Group performance status of 2 or less (with 0 indicating asymptomatic, 1 symptomatic but ambulatory, and 2 symptomatic and in bed less than half the day).

The primary prespecified end point for the comparison of the induction regimens was the rate of complete remission. The primary prespecified end point for the comparison of maintenance regimens was the duration of remission, which was calculated as the interval from the last day of induction therapy until progression or death from any cause. Secondary end points were the overall response rate, the time to treatment failure (defined as stable disease, relapse, progression, or death) from the start of induction therapy, overall survival, and toxic effects.

A total of 560 patients from 8 countries were enrolled in the trial between January 2004 and October 2010 and randomly assigned to chemotherapy with R-CHOP or R-FC; 532 of those patients were included in the intention-to-treat analysis and 485 were included in the primary analysis. Median age was 70 years.

The rate of complete remissions at the end of induction therapy was not significantly higher after R-FC (98 of 246 patients [40%]) than after R-CHOP (81 of 239 [34%]). The overall response rate was lower after R-FC than after R-CHOP, but the difference was not significant (192 of 246 patients [78%] and 206 of 239 [86%], respectively). Complete-remission rates, including unconfirmed complete remission, were also similar (53% and 49%, respectively). The rate of progression was higher during R-FC than during R-CHOP (14% vs 5%).

Overall survival was significantly shorter after R-FC than after R-CHOP (survival rate at 4 years, 47% vs 62%; P=.005; hazard ratio for death, 1.50; 95% confidence interval [CI], 1.13 to 1.99). Of the 560 patients, 115 of 280 patients in the R-FC group and 84 of 280 in the R-CHOP group died (199 total). Causes of death were mainly related to progression of lymphoma.

Hematologic toxic effects occurred more frequently in the R-FC group than in the R-CHOP group. Grade 1 or 2 constipation and neuropathy were more frequent among patients who received R-CHOP than among those who received R-FC. Grade 3 or 4 infections were balanced between the R-FC and R-CHOP groups, occurring in 17% and 14% of patients, respectively, but there was a trend toward a higher frequency of febrile neutropenia among patients who received R-CHOP than among those who received R-FC (17% vs 11%).

A total of 316 patients were randomly assigned to rituximab or interferon alfa, of whom 274 were included in the primary analysis (143 in the rituximab group and 131 in the interferon alfa group). The remission duration was significantly longer in the rituximab group than in the interferon alfa group, with a 45% reduction in the risk of progression or death according to the primary analysis (hazard ratio, 0.55; 95% CI, 0.36 to 0.87; P=.01).

At 4 years, 58% of the patients who received rituximab were still in remission (50 events) versus 29% of those who received interferon alfa (71 events).