ABSTRACT: Impressive gains in progression-free survival must be weighed against scant evidence of an improvement in overall survival and some noteworthy risks.
CHICAGO—Ongoing trials are still clarifying the optimal approach to management after induction therapy for non-Hodgkin’s follicular lymphoma. In the meantime, patients and physicians are left to ponder whether maintenance rituximab (Rituxan) should be used routinely in all cases. Leading researchers in hematology debated this topic in an education session at ASCO 2008.
Speaking in support of routine rituximab maintenance, John F. Seymour, MBBS, PhD, of the Peter MacCallum Cancer Centre, Victoria, Australia, noted that despite dramatic improvements in the treatment of follicular lymphoma, patients continue to have relapses, and disseminated disease is incurable.
“Each episode of development of active disease and resumption of therapy impairs the quality of life of our patients, and delaying or avoiding that is beneficial for their enjoyment of life,” he asserted. Moreover, with each subsequent treatment of similar intensity, the duration and quality of remission decrease.
Maintenance therapy should keep disease in remission, improve the quality of remissions, and delay time to next therapy, Dr. Seymour said.
“Ideally, if we can achieve it, the most robust endpoint is that of an improvement of overall survival, and, pleasingly, there are a number of well-designed trials that show that in a number of contexts, we can actually achieve that with maintenance rituximab,” he commented.
Dr. Seymour first discussed the SAKK 35/98 trial, in which patients with untreated or relapsed/refractory follicular lymphoma received four doses of rituximab, and those with at least stable disease were randomized to observation or maintenance rituximab (Ghielmini M et al: Blood 103:4416-4423, 2004).
Median event-free survival was significantly better—almost doubled—with rituximab maintenance (23.2 vs 11.8 months), he noted. Furthermore, post hoc analyses showed trends toward longer durations of response in both the treatment-nave and pretreated subgroups.
In the ECOG 1496 trial, patients with untreated NHL who had at least stable disease after chemotherapy were randomized to rituximab maintenance or observation (Hochster HS et al: ASH 2005, abstract 349).
Median progression-free survival in the follicular lymphoma subgroup was significantly and dramatically better with maintenance (5 years vs 15 months), Dr. Seymour pointed out.
“To my surprise, overall survival, even in the follicular lymphoma subgroup, was also improved in this group who received maintenance rituximab,” he added, with a 4-year rate of 88% vs 72% (P = 0.03), albeit with 1-sided statistical testing.
A third randomized trial, conducted by the Minnie Pearl Cancer Research Network, compared maintenance rituximab vs re-treatment with rituximab at the time of progression in patients who had relapsed/refractory NHL after prior chemotherapy, received rituximab, and had at last stable disease (Hainsworth JD et al: J Clin Oncol 23:1088-1095, 2005).
In the follicular lymphoma group, median progression-free survival was significantly better with the maintenance therapy approach (33 vs 13 months), Dr. Seymour said.
In the EORTC 20981 trial, patients with follicular lymphoma in first or second relapse were randomized to CHOP vs R-CHOP, and those experiencing a partial or complete remission were further randomized to rituximab maintenance or observation (van Oers MH et al: Blood 108:3296-3301, 2006).
Again, progression-free survival was significantly better, by about 3 years, with rituximab maintenance (51.5 vs 14.9 months). Moreover, the findings were similar regardless of the initial treatment (CHOP vs R-CHOP) and initial extent of remission (complete vs partial).
The 3-year rate of overall survival was significantly better with maintenance in the entire study population (85% vs 77%) but not within the initial treatment subgroups (CHOP and R-CHOP) individually.
Dr. Seymour pointed out that with the exception of higher rates of grade 3-4 neutropenia and a modest increase in infections with maintenance, rates of adverse events did not differ.
In a fifth trial, the German Low-Grade Lymphoma Study Group (GLSG) trial, patients with advanced, relapsed/refractory follicular or mantle cell lymphoma were randomized to FCM (fludarabine, cyclophosphamide, mitoxantrone) with or without rituximab, and those with a partial or complete remission were further randomized to maintenance rituximab or observation (Forstpointner R et al: Blood 108:4003-4008, 2005).
The median duration of response was significantly better with maintenance in the population overall (not reached vs 17 months), as well as in the subset with follicular lymphoma who received R-FCM (not reached vs 26 months). In this trial, the only adverse event that was more common with rituximab was grade 3-4 neutropenia.