Rituximab Retreatment after Disease Progression Is Comparable to Rituximab Maintenance Therapy in Patients with Low-Tumor Burden Follicular Lymphoma
In a randomized clinical trial, patients with low–tumor burden follicular lymphoma whose cancer responded to initial treatment with rituximab (Rituxan®) experienced similar disease control regardless of whether they subsequently received maintenance therapy with rituximab or were retreated with rituximab only when there was evidence of disease progression.
The median time until patients stopped responding to rituximab (time to treatment failure) was similar in the two treatment groups.
Journal of Clinical Oncology, August 25, 2014. (See the journal abstract.)
Follicular lymphoma is one of the most common types of B-cell non-Hodgkin lymphoma. This type of lymphoma typically progresses slowly and causes few symptoms. Although follicular lymphoma is usually diagnosed at an advanced stage, median survival ranges from 8 to 15 years after diagnosis.
Several treatment approaches are available for patients with asymptomatic low–tumor burden follicular lymphoma. One option is to defer immediate treatment and undergo observation or watchful waiting. Treatment is initiated when the patient begins to experience symptoms or other signs of disease progression.
Another option is treatment with rituximab, a monoclonal antibody that binds to a protein called CD20 on B-cells and kills cancer cells. Rituximab is often used as part of induction therapy for follicular lymphoma and, for patients who have responded to induction therapy, can be used as maintenance therapy—continued treatment at regular intervals to keep the cancer in remission. Studies have not established, however, the optimal dosing schedule of rituximab in patients with low–tumor burden follicular lymphoma.
The Rituximab Extended Schedule or Re-Treatment Trial (RESORT), conducted at many cancer centers in the United States, enrolled 545 patients with slow-developing, or indolent, lymphoma who had not undergone previous treatment for their disease. The reported results are only for the 408 patients in the trial with follicular lymphoma.
Patients in the trial received four once-weekly doses of rituximab as induction therapy. The 289 patients who had a partial or complete response to induction therapy with rituximab alone were randomly assigned to receive maintenance rituximab once every 3 months or to receive retreatment with rituximab once there was evidence that their cancer had recurred or was progressing.
The primary endpoint of the trial was the length of time until treatment failed. The secondary endpoints of the trial included the length of time to the receipt of cytotoxic therapy (e.g., chemotherapy, radiation therapy, or radioimmunotherapy), side effects, and health-related quality of life.
Although they were not pre-specified endpoints, the trial investigators also reported how much rituximab patients took and overall survival.
RESORT was conducted by the Eastern Cooperative Oncology Group with funding from the National Cancer Institute. Brad S. Kahl, M.D., of the University of Wisconsin School of Medicine and Public Health, led the trial.
The difference in time to treatment failure between the treatment groups was not statistically significant. After a median follow up of 4.5 years, the estimated median time to treatment failure was 4.3 years for patients in the maintenance rituximab group and 3.9 years for patients in the rituximab retreatment group. And at 3 years of follow up, 61 percent of patients in the retreatment group and 64 percent of patients in the maintenance group had experienced a treatment failure event.
At 3 years of follow up, 95 percent of patients in the maintenance group and 84 percent of patients in the retreatment group had not begun treatment with cytotoxic therapy—a statistically significant difference.
Health-related quality of life did not differ between the groups at any time point during the trial.
Patients in the maintenance group received substantially more rituximab than patients in the retreatment group: The median number of rituximab doses, including induction therapy, was 18 for patients in the maintenance group and 4 for patients in the retreatment group.
Serious side effects (grades 3, 4, or 5) were infrequent in both groups, and both treatment strategies were well tolerated. Second cancers were reported in 14 patients in the maintenance group and 16 patients in the retreatment group, with no obvious trend toward any specific second cancer in either group. One patient in the maintenance rituximab group died after developing progressive multifocal leukoencephalopathy.
Deaths were rare, with 11 in the retreatment group and 13 in the maintenance group. Overall survival was 94 percent in both groups.
Two years of maintenance therapy with rituximab in patients with follicular lymphoma "has increasingly been used in [clinical] practice" since 2011, when the Primary Ritxumab and Maintenance (PRIMA) trial showed that this approach improves progression-free survival compared with observation, said Mark Roschewski, M.D., of NCI’s Center for Cancer Research. (Patients in the PRIMA trial, however, had high–tumor burden follicular lymphoma).
However, in clinical practice, maintenance therapy with rituximab typically follows induction therapy with rituximab plus chemotherapy, as was done in the PRIMA trial, not induction therapy with rituximab alone, as was done in RESORT.
As a consequence of these differences in induction therapy, Dr. Roschewski noted, RESORT "does not directly address the question of maintenance [therapy]" as it is most often used in clinical practice today to treat follicular lymphoma.
The study authors also noted that "the excellent outcomes" for patients assigned to the retreatment group was due in part to the fact that, as a result of the trial’s design, only patients who responded to induction therapy with rituximab were eligible for assignment to retreatment. "Nevertheless, for patients responding to rituximab induction, the [retreatment] strategy is highly likely to result in avoidance of chemotherapy or radiation therapy for many years."
The RESORT results could be far-reaching, the authors noted. "Given the widespread use of [maintenance rituximab], the resource use implications are large," they wrote.
Dr. Roschewski agreed. "I find it highly relevant that there was no benefit to planned maintenance," he said. Although, he added, further studies may identify "a subset of patients who do benefit from planned maintenance."
In an accompanying editorial, Jonathan W. Friedberg, M.D., of the Wilmot Cancer Institute at the University of Rochester, called RESORT a "practice-changing study." Maintenance rituximab, he wrote, "should no longer be given to newly diagnosed patients with low–tumor burden follicular lymphoma responding to single-agent rituximab induction, given that a retreatment rituximab strategy has equivalent outcomes."