Lenalidomide-Rituximab vs. Lenalidomide-Rituximab-Bendamustine in Relapsed/Refractory Follicular Lymphoma: A Phase II Showdown

Background

Follicular lymphoma (FL) is the most common indolent non-Hodgkin lymphoma, characterized by recurrent relapses and decreasing responsiveness to therapy over time. The advent of immunomodulatory drugs like lenalidomide, combined with anti-CD20 monoclonal antibodies (rituximab), has expanded treatment options for relapsed/refractory FL (R/R FL). The HOVON110/ReBeL study sought to evaluate whether adding bendamustine to the lenalidomide-rituximab (R2) backbone (forming R2B) could improve outcomes in this challenging patient population.

Study Design

This multinational, prospective, randomized, non-comparative phase II trial (NCT number not provided) enrolled 92 patients with R/R FL from December 2014 to July 2019. Patients were randomized 1:1 to receive either R2 (Arm A) or R2B (Arm B). Treatment continued until disease progression or unacceptable toxicity. Patients achieving partial or complete remission (PR/CR) on CT imaging received rituximab maintenance every 3 months for 2 years. The co-primary endpoints were investigator-assessed CR rates at end-of-induction (EOI) and severe toxicity rates.

Key Findings

The trial was stopped prematurely due to slow accrual. At EOI, CR rates were modest in both arms: 11.4% (95% CI 3.8–24.6%) for R2 and 15.2% (95% CI 6.3–28.9%) for R2B. With a median follow-up of 74 months, severe toxicity rates were 6.8% (Arm A) and 13.0% (Arm B), including two pneumonia-related deaths in Arm A. Grade 3-4 adverse events occurred in 43% (Arm A) and 66% (Arm B) of patients. The 60-month event-free survival (EFS) was 39.5% (Arm A) vs. 56.4% (Arm B), while overall survival (OS) reached 72.1% and 86.3%, respectively.

Expert Commentary

The study highlights the ongoing challenge of achieving durable responses in R/R FL. While R2B showed numerically superior EFS and OS, this came at the cost of increased toxicity—a critical consideration for this typically older patient population. The low CT-based CR rates despite good survival outcomes suggest that functional imaging (e.g., PET) might better capture treatment response in future studies.

Conclusion

Both R2 and R2B remain viable options for R/R FL, with R2B offering potentially better long-term disease control at the expense of higher toxicity. These findings underscore the need for personalized treatment approaches and novel therapeutic strategies in this disease setting.