The Combination of High Total Metabolic Tumor Volume and Poor ECOG Performance Status Defines Ultra-High Risk Diffuse Large B-Cell Lymphoma. Validation across Multiple Cohorts of Large Clinical Trials and in Real World

Background. R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) is currently considered as the standard of care for patients with newly diagnosed diffuse large B-cell lymphoma (DLBCL). However, three-year progression-free survival (PFS) and overall survival (OS) rates remain at 60% and 70%, respectively. We recently reported a new tool to help the early identification of ultra-high risk DLBCL patients1. This tool was identified in a cohort of 301 patients included in the REMARC study, responders to R-CHOP, and was based on a combination of 2 factors at baseline: 1/ total metabolic tumor volume (TMTV) above 220cm3 measured on baseline 18FDG-PET and 2/ elevated ECOG PS ≥2. Here, we validated this combination in multiple cohorts including two large clinical trials and in real world. Methods: We evaluated the combination TMTV-PS in a series of 2306 patients with DLBCL including patients treated in clinical trials in Europe and the United States; PETAL (n= 510) and GOYA (n=1315) and 481 patients treated in Real world (RW) across multiple centers in Europe (France, Poland, Portugal, UK). All patients were treated with a combination of immuno-chemotherapy with curative intent (Rituximab (R) or Obinutuzumab (0)-CHOP (R-CHOP n= 70%%, O-CHOP n= 29 %, and intensified regimen n=1%). Patients in PETAL were treated by a PET-guided strategy. Associations of TMTV and ECOG PS at baseline were explored with the International Prognostic Index (IPI) and outcome. Results. For the PETAL, GOYA, and RW series, the median age was 62 (18-80), 62 (18-86), and 65 (17-92), and 55%, 58%, 60%, were > 60y respectively. ECOG PS>2 was present in 11%, 12%, 23% of the patients; IPI 3-5 in 38%, 44%, 51%; TMTV>220 in 45%, 61%, 44%, respectively. The combination of TMTV>220cm3 and ECOG PS>2 defined in PETAL, GOYA, and RW, patients with no risk factor representing 53%, 37% and 49% of the patients, one risk factor (either TMTV> 220cm3 or ECOG PS>2) representing 38%, 53.5%, 35% of the patients, and two risk factors representing 9%, 10%, and 16%, respectively. Patients with 2 risk factors had a significantly worse PFS than patients with 0 or 1 risk factor in the PETAL, GOYA and RW series, HR=3.32 (95% CL: 2.0-5.5); HR=2.68 (95% CL: 2.0-3.6), HR=4.06 (95% CL : 2.7-6.1), respectively. Overall survival was also significantly worse in patients with 2 risk factors than patients with 0 or 1 risk factor, HR=3.85 (95% CL: 2.2-6.8); HR=3.16 (95% CL: 2.2-4.5), HR=5.23 (95% CL: 3.4-