Reduced FDG Uptake in the Brain on Baseline 18FDG PET/CT Predicts Worse Prognosis of Newly Diagnosed Intravascular Large B-Cell Lymphoma and Advanced-Stage Diffuse Large B-Cell Lymphoma

[Introduction] Intravascular large B-cell lymphoma (IVLBCL) is a rare subtype of diffuse large B-cell lymphoma (DLBCL) with selective growth of lymphoma cells in the lumina of small vessels. Considerable proportion of IVLBCL patients fail to cure, but its prognostic factors have not been thoroughly established. Although the assessment of total tumor burden using metabolic tumor volume (TMTV) at diagnosis is a robust prognostic indicator in DLBCL, it is laborious and time-consuming to estimate TMTV in IVLBCL with disseminated lesions distributed throughout the body. In cases of high tumor burden in IVLBCL or advanced-stage DLBCL, we often observe significantly reduced physiological FDG uptake in the brain on baseline ¹⁸FDG-PET/CT, which is known as "steal phenomenon." However, there are no previous reports on the association between this phenomenon and prognosis in IVLBCL or advanced-stage DLBCL patients. In the current study, we explored the impact of reduced FDG uptake in the brain on baseline PET/CT on prognosis of newly diagnosed IVLBCL or advanced-stage DLBCL and tested if steal phenomenon could be correlated with TMTV in baseline PET/CT.[Methods] We retrospectively evaluated the impacts of reduced FDG uptake in the brain at diagnosis on overall survival (OS) and event free survival (EFS) in 50 patients with histopathologically proven newly diagnosed IVLBCL and 129 patients with newly diagnosed advanced-stage DLBCL treated with R-CHOP-like regimens at hospitals participating in the North Japan Hematology Study Group between January 2010 and February 2022. The study procedures were in accordance with the Helsinki Declaration and institutional ethical guidelines and were approved by the institutional review boards.[Results]ROC curve analysis determined the optimal cutoff values of FDG uptake in brain (BrainSUVmax) as 9.091 in IVLBCL and 9.189 in DLBCL patients, respectively. Therefore, we defined BrainSUVmax^high or BrainSUVmax^low using each cutoff values for each disease cohorts.In the IVLBCL cohort, 25 patients (50.0%) additionally received high-dose methotrexate (HD-MTX) during the initial therapy, and another half of patients did not. There was no significant difference in the patient characteristics between the BrainSUVmax^high or BrainSUVmax^low group including the proportion of patients older than 75 years, male sex, poor performance status (ECOG PS >1), elevated serum LDH, and extra-nodal lesions. Median follow-up duration for censored cases was 43.3 months (range, 4.63-127.1). Importantly, both OS and EFS were significantly higher in patients with BrainSUVmax^high than those with BrainSUVmax^low (2-year OS; 100.0% vs 68.6%, P=0.00116, 2-year EFS; 82.6% vs 49.7%, P=0.0116). Pearson’s correlation tests demonstrated negative correlation between TMTV and BrainSUVmax (R2= -0.315, P=0.0258). In a univariate analysis, high TMTV, no addition of HD-MTX, and BrainSUVmax^low were associated with poor 2-year OS and EFS. Multivariate analysis demonstrated that BrainSUVmax^low was independently associated with poor 2-year OS (HR, 12.3; 95% CI, 1.19 to 127.5, P=0.035).In advanced-stage DLBCL cohort, there was either no significant difference in the patient characteristics between the BrainSUVmax^high or BrainSUVmax^low group including the proportion of patients older than 75 years, male sex, poor performance status (>1), elevated serum LDH, and extra-nodal lesions. Median follow-up duration for censored cases was 38.9 months (range, 0.13-123.0). Again, both OS and EFS were significantly higher in patients with BrainSUVmax^high than those with BrainSUVmax^low [2-year OS; 84.0% vs 65.2%, P=0.00159, 2-year EFS; 67.5% vs 55.9%, P=0.0136]. BrainSUVmax was also negatively correlated with TMTV in DLBCL cohort (R2= -0.418, P<0.001). In the multivariate analysis including BrainSUVmax and all factors for NCCN-IPI, BrainSUVmax^low was independently associated with poor 2-year OS (HR, 1.81; 95% CI, 1.01 to 3.60, P=0.049). Subgroup analysis included patients with NCCN-IPI High-Int (n=58) demonstrated that BrainSUVmax further stratified treatment outcomes in this group (2-year OS; 89.5% vs 64.7%, high vs low, P=0.013).[Conclusion] Reduced FDG uptake in the brain at diagnosis represents a convenient surrogate marker to estimate metabolic tumor volume based on 18FDG PET/CT that can predict treatment outcomes of patients with newly diagnosed IVLBCL or advanced-stage DLBCL.