Treatment Patterns and Outcomes of Patients with Relapsed or Refractory Follicular Lymphoma Treated in 3rd Line and Beyond: A Multicenter Cohort Study from the French Hemsys Tumor Board Database
Authors: Manson Guillaume , Broussais Florence , Dumartin Laurent , codet De Boisse Guillaume , Houot Roch 
Published: December 2024

Introduction
Follicular lymphoma (FL) is the most common subtype of indolent non-Hodgkin lymphoma. Despite high initial response rates to front-line treatment, FL remains incurable with standard therapies. The majority of FL patients experience multiple relapses over their lifetime with shorter disease-free periods after each new line, especially for those with early progression and histological transformation. Here we aimed to describe real-world treatment patterns and efficacy for patients with relapsed or refractory (R/R) follicular lymphoma receiving three or more lines of systemic therapy.
Methods
This multicenter cohort study utilizes the HemSys database, a tumor board software deployed across 14 sites in a regional network in France. HemSys collects real-world patient disease characteristics and therapeutic sequences. Best response assessments were secondary evaluated after data extraction from longitudinal tumor board discussions. Eligible patients were at least 18 years old, had non-transformed grade 1-3a FL, and were receiving systemic therapy in the third line and/or beyond (3rd L+). From a cohort of 963 patients diagnosed with FL between 2010 and 2023, we identified 691 who received a first line of treatment, and 109 who were receiving systemic therapy in 3rd L+.
Results
Among 109 3rd L+ patients, the median age at tumor board presentation for 3rd line was 68.5 years (45-90), with a male predominance (58.2%).
A period of Watch and Wait occurred in 14 (12.8%) patients between diagnosis and initiation of the first line. First-line treatment primarily included anti-CD20 + CHOP regimens (64.2%), anti-CD20 + other agent (19.3%), rituximab monotherapy (12.8%). and radiotherapy or clinical trial inclusion (2.7%). Maintenance therapy was stopped during the COVID-19 pandemic. The POD24 after the 1° line was estimated at 48.62%.
In the third line, common treatments included anti CD20-bendamustine (17.4%), anti CD20-lenalidomide (17.4%), and CAR T-cells (5.5%). Of the patients receiving third-line therapy, 71 (65.1%) were previously exposed to rituximab alone or in combination with other agents, and among these, 27 (38%) had treatment initiated within 24 months following the third line initiation. Additionally, a significant proportion of patients (64%) who had progressed on previous lines remained rituximab-refractory.
The median intervals between treatment lines (TTNT) were 5.26 years between 1st and 3rd line, and 2 years between 2nd and 3rd line. The documented transformation rate from first to third line included was 14.7% . For the fourth line, out of 60 patients that received treatment, anti CD20-lenalidomide (20%) and anti CD20-bendamustine (13.3%) were the most common, and CAR-T cells were used in 4 (6.67%) patients. Fifth-line treatments, received by 29 patients, primarily included anti CD20-lenalidomide (34.5%) and anti CD20-inhibitor of PI3 kinase (13.79%). Notably, the response to treatment induction also declined progressively, with fewer complete responses (69% after 1st line, 23% after 3rd line) and increased progression rates (12% after 1st line induction to 20% after 3rd line). Visualization of treatment transitions across different lines of therapy will be presented on a Sankey Plot.
Conclusion
The treatment of R/R FL heavily relies on anti CD-20, rituximab or obinutuzumab, often in combination with chemotherapy, in first and second lines. Many patients required further treatment within 24 months, reflecting the aggressive nature of the disease in this selected population. Despite refractory status, rituximab remained central. The median TTNT from third to fourth line of just over one year underscores the rapid progression and limited durability of current treatments in this cohort, mainly representing patterns before bispecific and CAR-T cells implementation. The study reveals diverse treatment patterns and generally poor outcomes in 3rd line, highlighting the need for novel therapeutic options and personalized therapy.