A SWOT-Consensus for CAR-T in Follicular Lymphoma: Fine Tuning of Patient Journey and Selection
Authors: Marchetti Monia , Corradini Paolo , Arcaini Luca , Bramanti Stefania , Di Rocco Alice , Ladetto Marco , Luminari Stefano , Rigacci Luigi , Zinzani Pier Luigi 
Published: December 2024

BACKGROUND
Lymphoma is the primary cause of death for FL (follicular lymphoma) patients. Continuous therapy with targeted drugs yields only short-lasting responses in relapsed/refractory (R/R) FL patients, particularly in those with a high disease burden or those who relapse within 24 months of prior therapies. CAR-T therapies were approved for R/R FL after at least two prior therapies based on the prolonged remission reported in over 40% of patients. However, the expected progression-free survival (PFS) for third-line FL patients in real-life settings is 9-10 months. Recently, bispecific antibody (BiTE) therapies have also been approved in the same setting, but indirect comparisons indicate lower PFS and deep response rates compared to CAR-T therapies. Despite current NCCN guidelines favoring CAR-T therapies for R/R FL, several hurdles limit the timely access to CAR-T for many patients, adversely affecting FL patient survival.

AIMS AND METHODS
The present project aims to define the ideal patient flow that may optimize CAR-T therapeutic yield in FL, utilizing the GRADE framework. This framework suggests developing statements based on patient-intervention-comparator-outcome (PICO) questions. A Core Panel (CP) of eight national key opinion leaders formulated three questions to identify patients who should receive CAR-T therapy in the third line, as well as those in the first- and second-line who can undergo pre-assessment to optimize the eventual process to CAR-T.
The CP selected critical outcomes for each PICO question and identified the most relevant clinical factors to select patient subgroups, facilitating personalized decision-making. A SWOT analysis was conducted: Strengths and Weaknesses included clinical benefits and undesirable outcomes related to the intervention, while Opportunities and Threats addressed the non-clinical positive and negative consequences of the intervention. Based on the SWOT analysis, Good Practice Statements (GPS), Research Statements (RS), and Remarks (RK) were elaborated and approved by the CP. An External Panel of 12 senior hematologists validated the statements based on a median Likert score of ≥7 (scale 1-9).

RESULTS
A national panel of 20 hematologists developed 9 Good Practice Statements (GPS), 3 Research Statements (RS), and 9 Remarks (RK).
GPS 3.1 - In order to improve survival in patients who have failed two prior lines of therapy and exhibit refractory disease and/or early relapse, CAR-T therapy is strongly recommended, irrespective of prior ASCT and FLIPI score or metabolic tumor volume at relapse.
GPS 3.2 - Patients with late relapses require careful assessment of available therapeutic options (including watchful waiting), even if the above criteria apply.
GPS 3.3 - In order to prevent lymphocytoapheresis failure, patients who have received bendamustine within the last six months should be considered for treatments alternative to CAR-T.
GPS 2.1 - Preliminary assessment of CAR-T eligibility is recommended for FL patients who are refractory to frontline therapy, experience early relapse (POD24), or exhibit a high disease burden at relapse (GELF mass criteria or metabolic tumor burden), provided they do not have significant comorbidities.
GPS 2.2 - Potential candidates for subsequent CAR-T therapy should avoid second-line treatments that might negatively impact lymphocyte collection.
GPS 2.3 - Early assessment of response is recommended in FL patients who may be potential candidates for third-line CAR-T therapy (see GPS 2.1).
GPS 1.1 - In order to timely implement possible CAR-T therapy, hematology centers are recommended to establish a specific “CAR-T pathway” starting from diagnosis in younger FL patients and those with a high disease burden (FLIPI/m7FLIPI, metabolic tumor burden).
GPS 1.2 - A CAR-T focused choice of second-line treatment is recommended for patients diagnosed at a young age, with a high disease burden, or with a suboptimal response after frontline therapy (e.g., less than VGPR).

CONCLUSION
The journey of FL patients to CAR-T can be improved and optimized by incorporating specific recommendations into clinical practice. SWOT analysis can aid in developing clinical recommendations based on both clinical evidence and non-clinical outcomes.