Treating Advanced Indolent Follicular Lymphoma Without Chemotherapy

About one-third of patients with symptomatic indolent lymphoma did not require new long-term therapy following the administration of first-line rituximab without chemotherapy, a new study in the Journal of Clinical Oncology found.

Patients with symptomatic indolent lymphoma are usually administered rituximab plus chemotherapy. However, the logistics of this approach-including the optimal timing, sequence, and choice of regimen-is contentious.

“In the current era, where substantial resources are being utilized to identify ‘chemotherapy-free’ options for treating advanced stage follicular lymphoma, the current study is a powerful reminder that one feasible option is simply not to give chemotherapy,” Brian K. Link, MD, a professor at the Carver College of Medicine at the University of Iowa, told Cancer Network.

The Nordic Lymphoma Group (NLG) conducted two randomized clinical trials to evaluate whether survival could be maintained without chemotherapy while decreasing short- and long-term effects, such as cardiotoxicity and second primary cancer.

NLG researchers randomized 439 patients with indolent B-cell lymphoma (84% with follicular lymphoma) to rituximab monotherapy or rituximab combined with interferon alfa-2a (IFNa-2a). Of note, interferon was used to sensitize B cells by enhancing CD20 expression and boosting antibody-dependent cellular toxicity.

Survival in both trials was sufficient to permit long-term follow-up to determine new therapy, transformation, late toxicity, and overall survival (OS)-although results favored combined therapy. This long-term follow-up also helped to elucidate the late effects of sole biologic therapy, and address concerns about undertreatment.

The researchers gathered cross-sectional follow-up data from 321 indolent lymphoma patients from the NLG trials. All subjects were administered first-line therapy with 1 or 2 cycles of 4 weekly infusions of rituximab 375 mg/m². A total of 148 patients were then randomized to receive IFNa-2a. The overall median follow-up was 9.8 years. Overall survival was the study’s primary endpoint, while the secondary endpoint was time to treatment failure.

At the conclusion of follow-up, 73% of patients survived, with a median follow-up of 10.6 years. In total, 36% of patients, including 38% with follicular lymphoma, did not require chemotherapy.

In follicular lymphoma patients who needed novel therapy within 24 months secondary to early disease progression, the 10-year survival rate was 59%, compared with 81% in patients with a longer remission. Notably, interferon did not enhance long-term outcomes.

Overall, the investigators diagnosed transformation in 20% of patients and 18% of patients with follicular lymphoma. They noted additional malignancy in 12% of patients. Few short- and long-term adverse events were recorded.

OS following a chemotherapy-free initial approach to treating indolent lymphoma was associated with a comparable OS to other first-line immunochemotherapy studies. 

“By acknowledging that the chemotherapy-free approach is still a matter of debate,” concluded the researchers, “the current study shows that a substantial proportion of patients do not need chemotherapy, even after a long follow-up time.”

Link agreed the research may have significant implications. “Although the study does not help us assess the option of watchful waiting, as all patients in the current analysis were treated with at least rituximab, the overall theme of the study is a poignant reminder that chemotherapy-or any therapy-given at [the] time of diagnosis simply because follicular lymphoma exists has never been demonstrated to confer superior survival when compared with a more conservative strategy, though there is increasing evidence that transformation rates may be modestly affected,” Link said.

Alison R. Sehgal, MD, a hematologist/oncologist at UPMC Hillman Cancer Center and an assistant professor at the University of Pittsburgh School of Medicine, helped put the future implications of the study into context.

“A recent clinical trial, the RELEVANCE trial, compared a chemotherapy free regimen of lenalidomide and rituximab to traditional rituximab and chemotherapy as initial therapy for follicular lymphoma. There was no difference in the complete response rate, progression free survival, or rates of withdrawal from therapy/toxicity,” Sehgal told Cancer Network.

“Understanding the context of this study, demonstrating the long-term results of initial rituximab-only therapy, needs to be evaluated in the context of the RELEVANCE study. Whether rituximab alone offers any overall survival benefit to the majority of patients with newly diagnosed indolent lymphoma compared to rituximab/chemotherapy remains to be seen. Moving forward, it would be helpful to identify in advance of therapy selection which patients could be managed with rituximab alone compared to those who may benefit from first-line chemoimmunotherapy.As yet, this group has not been clearly identified,” Sehgal added.

Indolent lymphoma refers to a group of slow-growth B-cell lymphomas. Although many treatment options for this cancer exist, and initial responses are good, patients typically experience several relapses.

With the advent of rituximab, the prognosis for patients with CD20+ lymphomas is markedly ameliorated. Nevertheless, not enough evidence supports the benefit of early treatment compared with watchful waiting.