A long-term follow-up analysis of a randomized phase III clinical trial has provided new insights into rituximab dosing strategies for patients with low-tumor burden follicular lymphoma. The study, known as the RESORT trial (E4402), compared two different approaches to rituximab administration in this patient population. Results of this extended follow-up were published in the Journal of Clinical Oncology on January 9, 2024.
The RESORT trial was conducted by the Eastern Cooperative Oncology Group (now part of ECOG-ACRIN) and funded by the National Cancer Institute. It was initially launched in 2003 to evaluate the optimal way to administer rituximab in patients with previously untreated, low-tumor burden follicular lymphoma.
Follicular lymphoma is typically an indolent form of non-Hodgkin lymphoma. Patients with low-tumor burden disease often have an excellent prognosis and may be managed initially with a watch-and-wait approach. However, some patients and clinicians prefer active treatment. Single-agent rituximab has emerged as an attractive option given its efficacy and favorable toxicity profile compared to chemotherapy regimens.
The primary goal of the RESORT study was to determine whether a prolonged maintenance rituximab strategy would be superior to a retreatment approach. The study enrolled 408 patients with previously untreated, low-tumor burden follicular lymphoma. All patients received an initial course of four weekly rituximab infusions. The 299 patients who had a response or stable disease after this induction were then randomized to one of two rituximab dosing strategies:
1) Maintenance rituximab (MR): Patients received a single dose of rituximab every 13 weeks until treatment failure.
2) Retreatment rituximab (RR): Patients were observed without further treatment until disease progression, at which point they received another 4-week course of rituximab. This retreatment approach could be repeated multiple times until treatment failure.
The primary endpoint of the study was time to treatment failure (TTF). Secondary endpoints included time to first cytotoxic therapy, duration of response, overall survival, toxicities, risk of second malignancies, risk of histologic transformation, and rituximab utilization.
Eligible patients had low-tumor burden follicular lymphoma as defined by the Groupe d'Etude des Lymphomes Folliculaires (GELF) criteria. Key inclusion criteria were: age ≥18 years, stage II-IV disease, WHO performance status 0-1, and no prior therapy for follicular lymphoma. Patients with large cell transformation or central nervous system involvement were excluded.
The demographic and disease characteristics were well-balanced between the two randomized arms. The median age was 59 years, with approximately 47% male patients. The majority had stage III-IV disease (94-99%) and low or intermediate risk disease by the Follicular Lymphoma International Prognostic Index (FLIPI) (60-61%). Most patients had grade 1-2 follicular lymphoma histology.
The initial results of the study, published in 2014, showed no significant difference between the maintenance and retreatment strategies for the primary endpoint of TTF. The current analysis provides long-term follow-up data on key secondary endpoints with a median follow-up of 12.1 years.
For the endpoint of freedom from first cytotoxic therapy (chemotherapy or radiation), the maintenance strategy showed clear superiority. At 7 years, 83% of patients in the maintenance arm remained free of cytotoxic therapy, compared to 63% in the retreatment arm (hazard ratio 2.37, 95% CI 1.5-3.8). This suggests that the maintenance approach was more effective at delaying the need for more intensive treatments.
The duration of response also favored the maintenance strategy. At 10 years, 66% of patients in the maintenance arm remained in their initial response, compared to only 30% in the retreatment arm. For patients in the retreatment arm who required subsequent courses of rituximab, the median duration of response declined with each retreatment - from 3.2 years after initial treatment to 2.1 years after first retreatment and 0.8 years after second retreatment.
Despite the advantages seen with maintenance rituximab for delaying progression and cytotoxic therapy, there was no difference in overall survival between the two arms. The 10-year overall survival rate was 83% with maintenance rituximab versus 84% with the retreatment approach.
As expected, patients assigned to maintenance rituximab received substantially more rituximab overall. The median number of rituximab doses was 18 (range 5-35) in the maintenance arm compared to 4 (range 4-16) in the retreatment arm. In the retreatment group, 55 patients received one retreatment course, 12 received two retreatments, and 4 received three retreatments.
The incidence of second malignancies was similar between arms, occurring in 17 maintenance patients and 19 retreatment patients. There were numerically fewer cases of histologic transformation to aggressive lymphoma in the maintenance arm (2 cases) compared to the retreatment arm (6 cases), but the study was not powered to detect a difference in this rare event.
This long-term analysis has some limitations. The database for the primary endpoint of time to treatment failure was locked in 2011 after initial results were communicated to investigators and patients. Therefore, this report focuses only on pre-specified secondary endpoints. Additionally, full protocol data collection ended in 2015, after which only key outcomes like disease progression, death, transformation and second malignancies were tracked.
The authors conclude that while maintenance rituximab showed benefits in delaying time to cytotoxic therapy and prolonging initial response duration, the lack of overall survival benefit does not support routine use of prolonged maintenance in this patient population. They suggest that a retreatment strategy remains preferable given the much lower overall rituximab exposure.
These findings have important clinical implications for the management of patients with low-tumor burden follicular lymphoma. The results reinforce that single-agent rituximab is an effective and well-tolerated initial therapy for many of these patients. However, they argue against the routine use of indefinite maintenance rituximab, which substantially increases drug exposure and healthcare utilization without improving long-term outcomes.
The lack of survival benefit with maintenance rituximab in this and other follicular lymphoma studies highlights the excellent outcomes achievable with sequential therapies in this indolent disease. It also emphasizes the need to consider quality of life and treatment burden when making management decisions.
The authors note that their study was completed prior to the COVID-19 pandemic. Recent evidence has shown that prolonged B-cell depletion from rituximab can increase the risk of severe COVID-19 and impair response to vaccination. This provides an additional rationale to avoid extended maintenance rituximab schedules when possible.
It is important to note that this study specifically evaluated indefinite maintenance rituximab (until treatment failure) versus retreatment. Other studies have shown potential benefits with shorter fixed-duration maintenance strategies. For example, a recent study by the Lymphoma Study Association found improved progression-free survival with a 9-month maintenance rituximab schedule compared to induction alone in low-tumor burden follicular lymphoma. However, this shorter maintenance approach also failed to improve overall survival or time to next therapy.
The optimal initial management for low-tumor burden follicular lymphoma remains somewhat controversial. Options include watch-and-wait, single-agent rituximab (with or without short-term maintenance), and radiation therapy for limited stage disease. The choice should be individualized based on patient preferences and disease characteristics.
Recent research has identified clinical and imaging factors that may help predict which patients are at higher risk of early progression and could benefit from more intensive initial therapy. These include elevated lactate dehydrogenase, more than four nodal areas of involvement, more than one extranodal site, and high baseline total metabolic tumor volume on PET imaging.
In conclusion, this long-term follow-up of the RESORT trial provides valuable data to guide rituximab use in low-tumor burden follicular lymphoma. While demonstrating some benefits with maintenance therapy, the results support a more conservative retreatment approach as the preferred strategy for most patients. The study highlights the excellent long-term outcomes achievable in this patient population and the need to balance disease control with quality of life and treatment burden. As always, management decisions should be individualized through shared decision-making between clinicians and patients.
References
Kahl BS, Jegede OA, Peterson C, et al. Long-Term Follow-Up of the RESORT Study (E4402): A Randomized Phase III Comparison of Two Different Rituximab Dosing Strategies for Low-Tumor Burden Follicular Lymphoma. J Clin Oncol. 2024;42(7):774-778. doi:10.1200/JCO.23.01912
