CXCR4-targeted Imaging in DLBCL: A Prospective Head-to-head Comparison of 68Ga-Pentixafor and 18F-FDG PET/CT.

Background: While 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography/computed tomography (PET/CT) remains the gold standard for staging diffuse large B-cell lymphoma (DLBCL), it is limited by nonspecific uptake and physiological artifacts. This study explores the potential of the novel C-X-C chemokine receptor type 4 (CXCR4)-targeted tracer 68Ga-Pentixafor as a complementary receptor-specific imaging modality. Methods: In this prospective single-center study, 27 treatment-naïve patients with histopathologically confirmed DLBCL underwent 68Ga-Pentixafor and 18F-FDG PET/CT within a 2-week interval. Lesion detection, Lugano staging concordance, and maximum standardized uptake value (SUVmax) were assessed and compared using Cohen's kappa for agreement and paired t-tests for quantitative variables. Results: 68Ga-Pentixafor PET/CT showed near-perfect agreement with 18F-FDG PET/CT for extranodal lesion detection (κ =0.926, P < 0.001). For nodal lesions, substantial agreement was observed (κ =0.804, P < 0.0001). Lugano staging results were consistent between both modalities in 92.6% of cases (25/27), with only two instances of discordance. Importantly, 68Ga-Pentixafor detected biopsy-confirmed bone marrow involvement in four cases missed by 18F-FDG. Although 18F-FDG showed higher SUVmax values for nodal lesions (15.2 ± 7.6 vs. 8.4 ± 4.2; P < 0.001), there was no significant difference in uptake for extranodal sites. Subgroup analysis indicated a nonsignificant trend toward higher CXCR4 expression in the nongerminal center B-cell (non-GCB) subtype compared to the GCB subtype (P = 0.665). Notably, gastrointestinal artifacts associated with metformin use were absent on 68Ga-Pentixafor scans. Conclusion: This first-of-its-kind study in a uniform cohort of newly diagnosed DLBCL patients demonstrates that 68Ga-Pentixafor PET/CT shows high concordance with 18F-FDG PET/CT, with superior detection in the bone marrow and reduced physiological background. Its receptor-specific targeting of CXCR4 facilitates accurate disease assessment and provides a noninvasive approach to evaluate therapeutic targets, supporting its potential role in personalized CXCR4-directed theranostic strategies.