# Combination of Metronomic Chemotherapy and Rituximab in Frail and Elderly Patients with Relapsed/Refractory Follicular Lymphoma and Ineligible for Lenalidomide Treatment: A Retrospective Analysis

## TL;DR

This study explores a low-toxicity oral chemotherapy regimen for elderly or frail patients with difficult-to-treat lymphoma who cannot tolerate standard treatments.

## Contribution

The study introduces R-DEVEC-light as a feasible, low-toxicity treatment option for frail patients with relapsed/refractory follicular lymphoma.

## Key findings

- 84% of patients achieved remission with R-DEVEC-light, including 46% complete remission.
- The regimen showed a 42% progression-free survival rate after 27 months of follow-up.
- DEVEC-light had improved tolerability with manageable side effects and rare treatment discontinuations.

## Abstract

Relapsed or refractory follicular lymphoma (rrFL) is challenging to treat, especially in elderly and frail patients who often cannot tolerate therapies such as standard-dose immuno-chemotherapy, lenalidomide-based regimens, or CAR-T cell therapies. This study evaluates the metronomic, all-oral R-DEVEC or R-DEVEC-light regimen as a feasible, low-toxicity alternative for this vulnerable population. We aim to retrospectively assess the regimen’s real-world activity and safety in patients who discontinued or were ineligible for lenalidomide therapy. R-DEVEC-light show high response rates, manageable toxicity, and prolonged remissions, suggesting that metronomic chemotherapy may stabilize disease without compromising sensitivity to future treatments. If validated in larger studies, this approach could meaningfully expand treatment options for frail rrFL patients, offering a cost-effective, home-based therapy that fills an important gap in the current therapeutic landscape.

Background/Objectives: Relapsed or refractory follicular lymphoma (rrFL) remains difficult to treat in elderly or frail patients who cannot tolerate standard-dose immuno-chemotherapy as well as novel therapies. Metronomic chemotherapy (mCHEMO) may offer sustained antitumor activity with reduced toxicity. This study assessed the clinical activity and safety of R-DEVEC or R-DEVEC-light in rrFL patients following lenalidomide discontinuation or ineligibility. Methods: Data from the ReLLi Lymphoma Registry (2013–2025) were retrospectively analyzed. Eligible patients had rrFL after ≥1 prior therapy and initiated mCHEMO at least six months before data cutoff. Thirteen patients received DEVEC or the etoposide-free DEVEC-light regimen; all but one also received rituximab. Responders received maintenance vinorelbine, low-dose prednisone, and rituximab, followed by vinorelbine-only maintenance until progression or intolerance. Responses were assessed by CT after cycle two and PET/CT at completion of six induction cycles. Results: median age was 77 years (range 58–92); most patients were frail and had advanced disease. At the end of induction, 84% achieved remission (46% CR, 38% PR), with three PR converting to CR during maintenance. After a median follow-up of 27 months, the PFS was 42% (95CI 15–69%) and the OS 73% (95CI 47–100%). A transformation occurred in one patient; the main toxicity was grade 3 neutropenia (31%). DEVEC-light showed improved tolerability versus full DEVEC, with manageable infections and rare discontinuations. Conclusions: Metronomic R-DEVEC-light is a feasible and effective disease-controlling strategy for frail, heavily pretreated rrFL patients who do not tolerate lenalidomide and are excluded from modern therapies. This schedule warrants further prospective evaluation and exploration in combination with targeted agents.