Less Is More: Rituximab Retreatment Tops Maintenance for Follicular Lymphoma

ATLANTA — Patients with newly diagnosed low-burden follicular lymphoma (FL) in remission avoided chemotherapy significantly longer if they received maintenance rituximab (Rituxan) instead of retreatment at progression, but they did not live any longer, according to updated results from a randomized trial.

After a median follow-up of 8.7 years, 83% of patients randomized to maintenance therapy had yet to receive any chemotherapy as compared with 63% of the retreatment group. Two-thirds of the maintenance group maintained their initial remission at 10 years, as compared with 30% of the retreatment group.

However, 10-year overall survival (OS) was 83%-84% in both groups, and transformation risk and incidence of second malignancies did not differ between the two groups. Although the trial met the primary endpoint of delaying the time to first cytotoxic therapy, the cumulative data make a case for a retreatment strategy for patients with low-tumor-burden FL, said Brad Kahl, MD, of Washington University in St. Louis, at the American Society of Hematology meeting.

“Obviously, this trial was really asking a bold question with indefinite maintenance, and we obviously wanted to watch the safety very carefully,” he said. “There was no increased risk of second cancers and we did not see any worrisome decline in immunoglobulin levels. Perhaps most importantly, with 10 years of follow-up, there is no overall survival benefit for prolonged maintenance in this population. The fact remains that four times less drug was utilized with the retreatment strategy.”

“Given the totality of the data, our conclusion is that a rituximab retreatment strategy is a highly effective strategy and remains our recommended approach for this patient population,” he stated.

During a discussion that followed his presentation, Kahl continued to state the case for a retreatment strategy. “With COVID, and obviously more severe COVID infections in B-cell-depleted patients and the inability to respond to vaccination, I would actually argue that maintenance is a questionable practice in 2021 in follicular lymphoma.”

The findings came from long-term follow-up in the RESORT randomized trial, which evaluated two different rituximab strategies in patients with low-burden FL and in remission (partial or complete) after an initial course of the drug. The primary analysis, reported in 2014, showed that maintenance therapy prolonged the time to initiation of chemotherapy but that the retreatment strategy provided similar disease control with substantially less rituximab. Patients in the maintenance strategy had received a median of 18 doses of rituximab as compared with four in the treatment group.

At the same time, an international team of investigators conducted a trial comparing watchful waiting (which was standard practice for patients with low-burden disease), rituximab induction therapy, and induction followed by maintenance therapy. Significantly more patients in the two rituximab arms avoided chemotherapy at 3 years, leading the investigators to conclude that single-agent rituximab should be considered an option for untreated low-burden FL. Of note, almost half the patients in the watchful waiting arm had not initiated treatment for FL after 3 years.

The trial began with 408 patients with newly diagnosed low-tumor-burden FL, all of whom received four weekly doses of rituximab, followed by response assessment 3 months later. Patients who attained a complete or partial response (n=299) were randomized to receive maintenance rituximab once every 3 months or no additional treatment until disease progression (retreatment group). At progression, patients in the retreatment group restarted the treatment strategy with four doses of rituximab.

Kahl reported updated findings after a median follow-up of 12.1 years. The objectives of the update were to examine the time to first cytotoxic therapy, duration of response (DOR), OS, and risk of leukemic transformation.

The new analysis showed that the difference in freedom from cytotoxic therapy increased over time in favor of the maintenance arm: 89% vs 79% at 3 years, 84% vs 71% at 5 years, and 83% vs 63% at 7 years. The difference represented a hazard ratio of 2.37 (95% CI 1.5-3.76, P=0.0001).

The median DOR to induction rituximab was 3.2 years. The proportion of patients still in response at follow-up increased in favor of the maintenance arm: 73% vs 45% at 5 years, 71% vs 37% at 7 years, and 66% vs 30% at 10 years.

The key outcomes of OS, transformation risk, and second malignancy did not differ between treatment strategies.

Providing context for the findings, Kahl emphasized that 30% of patients in the retreatment arm remained in remission at 10 years after a single dose of rituximab and that almost two-thirds of patients in the retreatment arm had avoided chemotherapy after a median follow-up of 8.7 years.

During the discussion, Kahl pointed out that the results apply only to patients with low-tumor-burden FL.

The update confirmed the original analysis, which favored the retreatment strategy, said Jeremy Abramson, MD, of Mass General Cancer Center in Boston.

“As when initially reported, the totality of these data continue to support a retreatment strategy rather than maintenance rituximab when treating low tumor burden follicular lymphoma with rituximab monotherapy,” Abramson told MedPage Today via email. “It is important to emphasize that low tumor burden follicular lymphoma can usually be followed with surveillance alone rather than active therapy, and a surveillance approach is certainly preferred over rituximab for low tumor burden disease without indications for therapy in order to maintain robust immunity in the context of an ongoing global pandemic.”