SAN DIEGO, CA—A study of two different strategies for managing patients with asymptomatic low-tumor-burden (LTB) follicular lymphoma (FL) found retreatment with rituximab at disease progression is as effective in managing the disease as ongoing maintenance therapy, results of RESORT, a Phase 3 Eastern Cooperative Oncology Group (ECOG) study, reported at the 53rd American Society of Hematology Annual Meeting and Exposition.
Optimal management for LTB FL is unclear. Historically, patients with LTB FL, defined as small tumor size, limited lymph node involvement, limited or no symptoms and other factors have been observed rather than treated. This “watch and wait” strategy, with initiation of chemotherapy upon development of high tumor burden, is considered a reasonable standard; in most cases, time to first cytotoxic therapy (TTCT) is generally deferred for approximately 3 years following diagnosis.
To date, three randomized controlled trials have failed to show an overall survival (OS) advantage for immediate chemotherapy vs watch and wait. However, a recent study found that rituximab monotherapy was superior to watch and wait for the endpoint of TTCT. In the US, 15% to 20% of patients with FL receive monotherapy as their initial treatment.
In the RESORT trial, Brad S. Kahl, MD, of the University of Wisconsin, Madison, Wisconsin, and ECOG colleagues investigated the hypothesis that, after initial rituximab therapy, an extended scheduled dosing (maintenance rituximab) will prolong disease control compared to retreatment dosing administered upon disease progression (rituximab retreatment). Dr. Kahl noted that patients with previously untreated LTB FL represents an ideal population in which to test this hypothesis because it is reasonably homogenous.
The primary endpoint, time to treatment failure (TTTF), was classified as disease progression within six months of the last rituximab dosage, no response to rituximab retreatment, initiation of alternative therapy, or the inability to complete protocol therapy. Secondary study objectives included TTCT, quality of life (QOL), and toxicities. The QOL analysis investigated whether there was a psychological benefit to being maintained in remission. Four QOL tools—FACT-G total score, FACT-G emotional well being, impact of event scale, and HADS Anxiety—were administered at randomization, 13, 26, 52, 104, 156, and 208 weeks post-randomization and at treatment failure.
No prior lymphoma therapy was allowed. Patients were assessed every three months, with restaging CT scans every six months. The study had 81% power to detect a 36% reduction in the TTTF hazard rate favoring maintenance rituximab treatment. Two stratification factors were included: age (<60 vs ≥60 years) and time from diagnosis (< one year vs ≥1 year).
The study was activated November 2003 and closed September 2008. A total of 545 patients were enrolled, 384 (71%) had FL histology; 161 non-FL patients will be analyzed and reported separately, Dr. Kahl said. Baseline characteristics, including median age (59.5 years in the rituximab retreatment group vs 58.9 years in the maintenance rituximab arm), performance status, and Follicular Lymphoma International Prognostic Index (FLIPI) risk categorization, were well matched between the two arms.
The 384 patients with LTB FL received rituximab 375mg/m2 weekly for four weeks as induction therapy. Complete response or partial response was achieved in 274 patients (71%); 140 were then randomized to rituximab maintenance (single dose rituximab every 12 weeks) and 134 to rituximab retreatment at disease progression (rituximab weekly for 4 weeks). Therapy was continued until treatment failure occurred.
The primary endpoint, TTTF, was 3.9 years for patients receiving maintenance rituximab treatment versus 3.6 years for patients receiving rituximab retreatment (HR 1.05; 95% CI: 0.74–1.48; P=0.80). Median follow-up for time to event data was 3.8 years (P=0.80). Ninety-five percent of patients receiving maintenance rituximab vs 86% of patients receiving rituximab retreatment stayed free of cytotoxic therapy at three years (HR 2.5 [95% CI: 1.08, 5.77]; P=0.03).
A total of 65 patients in the rituximab retreatment arm and 69 in the rituximab maintenance arm had treatment failures. This included no response in 18 patients in the rituximab retreatment group vs none in the maintenance rituximab arm and a time to progression of less than six months in 11 and 25 patients, respectively. A number of patients withdrew from the study: 16 in the rituximab retreatment arm and 26 in the maintenance rituximab arm. Dr. Kahl said many of these withdrawals were due to changes in insurance and, when the data were analyzed without such patients, no difference was observed.
The mean number of rituximab doses per patient (including the 4 induction doses) was 15.8 for the maintenance rituximab treatment arm (range 5–31) and 4.5 for the rituximab retreatment arm (range 4–16).
Grade 3/4 hematologic and non-hematologic toxicities occurred in <5% of patients. Other toxicities included second malignancies (nine in the rituximab retreatment arm and seven in the rituximab maintenance arm), one progressive multifocal leukoencephalopathy in the maintenance rituximab arm, and 22 deaths, ten in the rituximab retreatment arm and 12 in the maintenance rituximab arm. No significant difference was observed in health related QOL and anxiety between the two treatment groups at 12 months post-randomization.
Dr. Kahl said that rituximab retreatment was as effective as maintenance rituximab for TTTF and, although maintenance rituximab was superior to rituximab retreatment for TTCT, it was at a cost of 3.5 times more rituximab administered. Both strategies appeared to delay time to chemotherapy compared to historical controls.
Given the excellent outcomes with rituximab retreatment—86% of patients were chemotherapy free at three years—and given the fewer AE failures, lack of difference in QOL, and fewer doses required (and therefore less costly), rituximab retreatment is the recommended strategy if opting for rituximab monotherapy in the LTB FL patient population, Dr.Kahl concluded.
Future directions include following this cohort for the endpoints of OS and risk for transformation; an in-depth QOL analysis that includes patient coping style; and biomarker analysis. Also to be determined is whether response to induction therapy differed between those newly diagnosed with LTB FL compared with patients who entered the study under the watch and wait strategy.