Rituximab Maintenance Improves Overall Survival in Follicular Lymphoma

Nick Mulcahy

May 21, 2009

May 21, 2009 — In patients with follicular lymphoma, rituximab (Rituxan, Genentech; MabThera, Roche) maintenance therapy significantly improves overall survival, compared with observation or treatment with the drug at the time of disease progression, according to a new meta-analysis.

The study was undertaken because of inconsistent data on rituximab and overall survival in this setting, write the authors of the meta-analysis, which was published online April 15 in the Cochrane Database of Systematic Reviews.

Follicular lymphoma is a B-cell non-Hodgkin's lymphoma that is typically indolent or slow-growing.

"Rituximab maintenance therapy should be added to the standard therapy of patients with relapsed or refractory follicular lymphoma following a successful induction treatment," advise the authors, led by Liat Vidal, MD, from the Department of Internal Medicine at the Rabin Medical Center in Petah-Tiqva, Israel.

The meta-analysis is largely the same as that published earlier this year by Dr. Vidal and others in the Journal of the National Cancer Institute (2009:101:248-255), which was reported by Medscape Oncology at the time.

In the analysis of 5 randomized trials with 985 patients, those treated with rituximab maintenance therapy had significantly better overall survival than those randomized to observation or to treatment with rituximab at progression (hazard ratio [HR], 0.60; 95% confidence interval [CI], 0.45 - 0.79). The median follow-up in the studies ranged from 26 to 41 months.

However, the analysis found that the drug is associated with a higher rate of adverse events, particularly infections. The analysis also left important clinical questions about rituximab unanswered, such as the type of patients that benefit most and the optimal schedule and duration of treatment.

The authors also offered a considerable caveat about their findings: 3 of the 5 trials were terminated earlier than planned after meeting criteria set for stopping the trials. This may have skewed the findings of the meta-analysis, they suggest. "Statistical theories and the results of a systematic review of randomized trials stopped early for apparent benefit suggest that stopping trials early systematically overestimates treatment effects," they write.

Not included in the meta-analysis were 4 randomized trials currently underway, add the authors.

They also note that the practice of rituximab maintenance therapy is not currently recommended in major guidelines, such as those of the National Comprehensive Cancer Network.

Secondary Outcomes

Follicular lymphoma accounts for 15% to 30% of newly diagnosed lymphomas, according to the authors, and is characterized by slow growth, high initial response rate, but relapsing and progressive disease.

Most patients present with advanced disease and, indeed, in the 4 trials in the meta-analysis with disease-stage data, 85% to100% of the patients were stage III/IV.

In addition to the primary outcome of overall survival, the study authors examined secondary outcomes, including event-free survival and progression-free survival in the 5 studies (Blood. 2006;108:4003-4008; Blood. 2004;103:4416-4423; J Clin Oncol. 2005;23:1088-1095; J Clin Oncol. 2007;25[18S]:8004; Ann Hematol. 2002;81:553-557).

Patients treated with rituximab maintenance therapy had significantly better event-free survival than those randomized to observation (HR, 0.46; 95% CI, 0.37 - 0.57), and significantly better progression-free survival (HR, 0.53, 95% CI 0.42 - 0.66).

Differences in Scheduling, Induction Therapy

In a subgroup analysis of maintenance schedules, the authors found that there was no statistically significant effect of the rituximab schedule — either as 4 weekly infusions every 6 months or as a single infusion every 2 to 3 months — on the outcomes.

However, despite the survival benefit of rituximab maintenance therapy, compared with observation, no benefit was seen in the 1 study in which rituximab maintenance and rituximab at progression were compared.

"The optimal timing and schedule of rituximab in follicular lymphoma is still unclear," conclude the authors.

One of the limitations of the analysis is the fact that the 5 studies had different induction therapies. Because the trials were conducted before rituximab was considered part of standard induction therapy for patients with follicular lymphoma, some of the patients did not receive rituximab as part of their induction regimen, note the authors. Nevertheless, the inclusion of rituximab as part of the induction protocol did not significantly change the outcomes, they say.

Despite the variations in induction therapy and the differences in maintenance schedules, "the trials tended to have the same effect," observe the authors, adding that this supports the "robustness" of their results.

Adverse Events

The rate of grade 3/4 adverse events was reported in 2 of the 5 trials, and was higher with rituximab maintenance therapy than with observation (relative risk [RR], 1.52; 95% CI, 1.00 - 2.30).

Patients in the rituximab-maintenance group had significantly more infection-related adverse effects than those in the observation group (RR, 1.99; 95% CI, 1.21 - 3.27). Furthermore, the risk was increased for severe infectious adverse events (RR, 2.90; 95% CI, 1.24 - 6.76). According to the results of 1 study, the infections were mostly of the ear, nose, and throat. Hospitalization was required for all patients with grade 3/4 infections of these types.

The researchers have disclosed no relevant financial relationships.

Cochrane Database Syst Rev. 2009;2:CD006552. Abstract

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