Immunotherapy May be Preferable to Chemotherapy As Second-Line Treatment for POD24 Follicular Lymphoma (FL) Patients
Authors: Serna Ángel , Bosch Marc , Navarro Garces Victor , Lopez Pereira Patricia , Quintela David , Sancho Juan-Manuel , Sáez Marín Adolfo Jesús , Jiménez Ubieto Ana , López Alberto , Cordoba Raul , Cerdá Maria , De La Cruz Beatriz , Romero Samuel , Ferrero Ainara , Cerecedo Tomas Garcia , Villalobos Teresa , Rivero Andrea , García Cristina , Niebla Ana Marín , Iacoboni Gloria , Bosch Francesc , Costa Pau Abrisqueta 
Published: December 2024

Introduction
Early progression of FL after first-line treatment is associated with poor outcomes, especially for patients (pts) who progress within 24 months of initial therapy (POD24). However, second-line treatment strategies for these early relapsing pts are not well established, leading to heterogeneous management across centers. In the real-world setting, it remains unclear whether novel therapies improve outcomes compared to chemotherapy (CT)-based regimens.
The aim of our study was to analyze treatment patterns in this setting and compare outcomes for pts who received CT versus immunotherapy (IT) approaches.
Methods
We conducted a retrospective analysis of pts diagnosed with FL grade 1-3a POD24, treated with upfront (CT) in 11 centers from January 2015 to June 2023. Pts who received single-agent monoclonal antibodies or radiotherapy as first-line treatment were excluded from the analysis. Pts were categorized into 2 groups according to the second-line regimen: the CT group, which included those who received bendamustine-based regimens or other CT combinations, and the IT group, which included those who received monoclonal antibodies with lenalidomide and/or CD20xCD3 bispecific antibodies. Outcomes of interest were overall and complete response rate (ORR/CRR), duration of response (DOR), progression free survival (PFS) and overall survival (OS) using the Kaplan Meier method and the Cox model.
Results
Among 110 POD24 FL pts, 86 received CT and 24 received IT as second line treatment. Median age for the overall cohort was 56 years, with no differences according to subsequent therapy (58 vs 53 years, p=0.9). Fifty-eight pts (53%) were female and 101 (95%) presented an advanced stage disease. Most of the pts in the CT and IT groups had an intermediate and high-risk FLIPI score at diagnosis (91% vs 88%, p=0.80) and at time of first relapse (85% vs 91%, p=0.13), respectively.
Distribution of first-line treatment was well balanced between both groups. CHOP-based regimens were administered to 94% of pts in the CT group and 92% of pts in the IT group. Also, bendamustine-based regimens were administered to 6% in the CT group and 8% of pts in the IT group. In terms of response to frontline therapy, 28 pts (25%) attained a CR, 53 pts (48%) a partial response (PR) and 29 pts (27%) experienced a progressive disease (PD) as their best response. No differences according to response to first-line treatment were found between both groups. Maintenance treatment was administered in a total of 75 pts (68%), with lower use in the CT vs IT group (54 pts [63%] vs 21 pts [88%], p=0.03).
Second-line treatment in the CT group included bendamustine-based regimens (n=37, 43%), R-ESHAP (n=33, 38%), gemcitabine-based (n=4, 5%), and other regimens (n=12, 14%). The IT cohort comprised pts treated with lenalidomide in combination with monoclonal antibodies (n=8, 33%), bispecific antibodies (n=15, 63%) and idelalisib (n=1, 4%). For the full set of pts, best response included CR in 53 pts (48%), PR in 21 pts (19%) and PD in 36 pts (33%). There were no significant differences in terms of ORR (67% vs 71%, p=0.67) or CRR (47% vs 54%, p=0.51) between the CT and IT groups. Autologous stem cell transplantation (ASCT) was performed in 27 pts (25%) (31% for the CT and 4% for the IT, p=0.01).
The median follow-up from diagnosis of the overall cohort was 39 months: 50 months for the CT group and 23 months for the IT group. The median DOR for pts receiving CT was 16 months (95% CI: 10-25), whereas it was not reached for pts receiving IT (HR: 0.37, CI 95% 0.11-1.19; p=0.09). The median PFS for pts receiving CT was 14 months (95% CI: 8.8-18), compared to 22 months (95% CI: 15 - NA) for those receiving IT (HR: 0.5, CI 95% 0.25-1.01; p=0.05). The median OS for pts receiving either CT or IT as salvage therapy was not reached, but a trend towards better survival for the IT group was observed (HR: 0.23, CI 95% 0.03-1.7; p=0.15).
Conclusions
Treatment approaches for POD24 FL are heterogeneous across centers. In our study a prolonged PFS and DOR is observed in the group of patients receiving immunotherapy as salvage treatment, with a trend towards better OS. Novel agents such as lenalidomide and bispecific antibodies alone or in combination seem to improve the outcomes in this POD24 FL population.