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Confounder Identification in Diffuse Large B-Cell Lymphoma: Findings from an Expert Panel of German and Austrian
Jan-Michel Heger1, Philipp Gödel1, Stefan Habringer2,3
1Department I of Internal Medicine, Center for Integrated Oncology Aachen Bonn Cologne Düsseldorf, University of Cologne, Medical Faculty and University Hospital Cologne, Cologne, Germany.
Introduction:
Robust confounder identification is essential for valid indirect treatment comparisons (ITCs), particularly in relapsed/refractory diffuse large B-cell lymphoma (R/R DLBCL), where treatment pathways are heterogeneous and comparative evidence between chimeric antigen receptor T-cell (CAR-T) therapies remains limited. This study aimed to validate clinically relevant prognostic factors and treatment-effect modifiers for comparative effectiveness analyses in DLBCL using a structured expert consensus approach.
Methods:
Candidate variables were identified through a prior systematic literature review and refined by clinical review. A panel of six experienced hematologists and oncologists from Germany and Austria participated in a two-round expert elicitation process. They assessed the importance of each variable as a prognostic factor and/or treatment-effect modifier using a three-point Likert scale. Variables were categorized into relevance tiers according to predefined consensus thresholds and subsequently allocated to specific clinical endpoints, including progression-free survival (PFS), overall survival (OS), response outcomes, and CAR-T-related toxicities.
Results:
Several variables achieved high consensus as prognostic factors. Tier A prognostic factors included ECOG performance status, age, disease histology, International Prognostic Index (IPI), disease stage, elevated lactate dehydrogenase (LDH), bulky disease, extranodal involvement, tumor burden, primary refractory disease, number of relapses, time to relapse, and prior lines of therapy. Unanimous agreement was observed for ECOG performance status, IPI, disease histology, disease stage, elevated LDH, and primary refractory disease as prognostic factors for survival outcomes. Compared with prognostic factors, substantially lower agreement was observed for treatment-effect modifiers, particularly for response-based outcomes. Tier A-effect modifiers included primary refractory disease, time to first relapse, best response to prior therapy, bridging therapy, CAR-T product type, and CAR-T-related response characteristics. Bridging therapy was the only modifier achieving unanimous agreement for complete and overall response rates. Tumor burden-related variables were considered important for both efficacy and toxicity outcomes, including cytokine release syndrome and immune effector cell-associated neurotoxicity syndrome.
Conclusions:
Clinicians demonstrated strong consensus regarding established prognostic factors related to disease aggressiveness, treatment resistance, patient fitness, and tumor burden in R/R DLBCL. Agreement on treatment-effect modifiers was more limited, reflecting the limited evidence currently available.
