ALBERT

Description: Introduction. Diffuse large B-cell lymphoma (DLBCL) represents the largest entity of non-Hodgkin lymphoma. In spite of a remarkable improvement in the treatment of DLBCL patients, considerable proportion of the patients fail to cure. 18F-FDG PET/CT is routinely performed for staging and monitoring of DLBCL. Metabolic heterogeneity (MH) calculated using the PET images potentially reflects heterogeneities of glucose metabolism, blood flow, fibrosis, and hypoxia. While high MH at diagnosis predicts poor prognosis of primary mediastinal large B-cell lymphoma (PMBCL) and other malignancies (Ceriani L, Blood. 2018), the prognostic significance of MH in newly diagnosed DLBCL remains to be clarified. Recently, we reported that high total metabolic tumor volume (TMTV) 150cm3 or more predicts poor prognosis of newly diagnosed DLBCL after R-CHOP-like treatment (Senjo H, Cancer Med. 2019). In the current study, we explored the impact of MH in baseline PET-CT on prognosis of newly diagnosed DLBCL and also tested if MH could be correlated with TMTV in baseline PET-CT. Methods. We retrospectively evaluated the impacts of MH at diagnosis on overall survival (OS) and event free survival (EFS) in 86 patients with newly diagnosed DLBCL treated with R-CHOP-like regimens at Sapporo Hokuyu Hospital (training cohort). MH was determined using the area under curve of cumulative standardized uptake value-volume histogram (AUC-CSH) method, as previously described (Ceriani L, Blood. 2018). In patients with multiple lesions of lymphoma, the lesion with the highest TMTV was selected for MH evaluation. The results were verified in the independent validation cohort of 64 patients treated at Aiiku Hospital. 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 value of AUC-CSH as 0.481 for separating patients with EFS failure at 24 months, and therefore we defined AUC-CSH 〈 0.481 and ≥ 0.481 as MH high and MH low, respectively. In the training cohort (n=86), there was no significant difference in the patient characteristics between the MH low and high groups except the significantly higher incidence of bone marrow involvement in the MH low group compared to the MH high group (23.3% vs 0%, P=0.00108). Importantly, both OS and EFS were significantly lower in patients with high MH than in those with low MH [5-year OS (5-yr OS); 89.5% vs 61.2%, P=0.0122, 5-year EFS (5-yr EFS); 73.1% vs 51.1%, P=0.0327] (Figure A). In a univariate analysis, TMTV ≥150cm3 and high MH were associated with poor 5-yr OS and EFS. Pearson's correlation tests demonstrated no correlation between MH and TMTV [R2=0.137 P=0.208] (Figure B). A multivariate analysis that included MH and all factors in NCCN-IPI; age, LDH, clinical stage, ECOG PS and major organ involvement, demonstrated that age 〉 70 and high MH were independently associated with poor 5-yr OS (age; HR, 6.03; 95% CI, 1.63 to 22.3, P=0.00699, MH; HR, 5.68; 95% CI, 1.46 to 22.1, P=0.0121). We performed an additional multivariate analysis including both MH and TMTV. We found that both MH and TMTV persisted as independent prognostic factors in this multivariate analysis (MH; HR, 7.20; 95% CI, 1.49 to 34.7, P=0.014, TMTV; HR, 29.60; 95% CI, 2.93 to 300.0, P=0.00411; log-rank, Table). Combined with TMTV, MH stratified patients into three distinguishable prognostic groups; MH low/TMTV low with 5-yr OS 94.7% and 5-yr EFS 87.9%, MH low/TMTV high or MH high/TMTV low with 5-yr OS 77.7% and 5-yr EFS 61.0%, and MH high/TMTV high with 5-yr OS 45.7% and 5-yr EFS 31.5% (Figure C). In the validation cohort (n=64), we confirmed high MH predicted worse prognosis [5-yr OS; 68.6% vs 37.1%, P = 0.0254, 5-yr EFS; 57.3% vs 32.6%, P=0.0375] (Figure D). MH was not correlated with TMTV in the validation cohort either, and a combination of MH and TMTV again stratified the patients into three distinctive prognostic groups (Figures E and F). In the univariate analysis, MH was again associated with poor 5-yr OS and EFS. In the multivariate analysis, MH was associated with poor 5-yr OS. Altogether, we validated that prognostic values of MH in the patients with newly diagnosed DLBCL. Conclusion. High MH predicts worse prognosis in the patients with newly diagnosed DLBCL independently of NCCN-IPI and was not correlated with TMTV. Baseline MH is a novel prognostic biomarker in DLBCL. Figure Disclosures Teshima: Novartis: Honoraria, Research Funding.

Description: Background. Diffuse large B-cell lymphoma (DLBCL) is the most frequent subtype of non-Hodgkin lymphoma. High total metabolic tumor volume (TMTV) or total lesion glycolysis (TLG) calculated using 18F-FDG PET/CT images at diagnosis predicts poor prognosis of patients with DLBCL. However, high cost and poor access to the imaging facilities hamper wider use of 18F-FDG PET/CT. Methods. In order to explore a surrogate marker for TMTV/TLG, we evaluated the correlations between the serum levels of soluble interleukin-2 receptor (sIL-2R) and TMTV/TLG in 64 patients with DLBCL, and the results were verified in an independent validation cohort of 86 patients. The study procedures were in accordance with the Helsinki Declaration and institutional ethical guidelines, conducted under the auspices of the institutional ethics committee, and approved by the institutional review boards. Results. In the training cohort(n=64), OS and EFS were significantly lower in patients with TMTV≥150cm3 than in those with less than 150cm3 [5-year OS; 84.0% vs 29.1%, P=0.000194, 5-year EFS; 71.4% vs 28.7%, P=0.000384]. We also found that TLG≥1500cm3 at diagnosis predicted significantly inferior OS and EFS[5-year OS; 84.0% vs 31.7%; P=0.000477, 5-year EFS; 70.2% vs 30.6%, P=0.00107].Pearson's correlation tests demonstrated highly significant positive correlations between sIL-2R and TMTV[R2=0.490; P=0.00004] and between sIL-2R and TLG[R2=0.543; P=0.00000357]. Serum sIL-2R≥1300 U/ml was a strong prognostic factor both for worse OS and EFS[5-year OS; 85.2% vs 25.9%, P=0.000035, 5-year EFS; 72.0% vs 26.8%, P=0.000076].In a univariate analysis, B symptom, LDH, sIL-2R, TMTV and TLG were associated with poor 5-year OS; and B symptom, LDH, PS, sIL-2R, TMTV and TLG were identified as poor prognostic factors for 5-year EFS. We performed multivariate analysis that included sIL-2R and all factors in NCCN-IPI; age, LDH, clinical stage, ECOG PS and major organ involvement. In this multivariate analysis, age and sIL-2R were independently associated with poor 5-year OS(age; HR, 4.44; 95% CI, 1.05 to 18.7, P=0.0424, sIL-2R; HR, 4.45; 95% CI, 1.04 to 19.1, P=0.0444). Another multivariate analysis that included TMTV and all factors for NCCN-IPI demonstrated that TMTV was an only independent prognostic factor for 5-year OS(HR, 3.87; 95% CI, 1.08 to 13.8; log-rank, P=0.0373).Subgroup analyses included the patients with NCCN-IPI High-Int and High(n=49) demonstrated that the cut off value of TMTV 150cm3 stratified treatment outcomes in this poor prognostic group [5-year OS; 75.0% vs 27.7%, P=0.0355, 5-year EFS; 66.7% vs 29.7%, P=0.0493]. Similar results were obtained using the cut-off value of sIL-2R 1300U/mL [5-year OS; 75.0% vs 25.9%, P=0.0182, 5-year EFS; 58.3% vs 29.7%, P=0.0499]. In the validation cohort(n=86), Kaplan-Meier curves showed that OS and EFS in patients with TMTV≥150cm3 was again lower than in those with TMTV