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
Authors: Thieblemont Catherine , Chartier Loïc , Dührsen Ulrich , Vitolo Umberto , Barrington Sally F , Vercellino Laetitia , Zaucha Jan , Patrocinio Carvalho Inês , Maria Gomes da Silva , Decazes Pierre , Viailly Pierre-Julien , Tilly Herve , Berriolo-Riedinger Alina , Casasnovas Rene-Olivier , Hüttmann Andreas , Ilyas Hajira , Mikhaeel George , Dunn Joel , Cottereau Anne Ségolène , Schmitz Christine , Paulson Joseph N. , Nielsen Tina G , Meignan Michel 
Published: February 2021

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 &gt; 60y respectively. ECOG PS&gt;2 was present in 11%, 12%, 23% of the patients; IPI 3-5 in 38%, 44%, 51%; TMTV&gt;220 in 45%, 61%, 44%, respectively. The combination of TMTV&gt;220cm3 and ECOG PS&gt;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&gt; 220cm3 or ECOG PS&gt;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: 3.4-8.1), respectively. The combination of TMTV-PS performed better than IPI with a positive C-Index for PFS and OS across all the series, PETAL, GOYA, and RW (figure 1)
Conclusion. The combination of TMTV and ECOG PS improves risk stratification for patients with DLBCL treated in frontline by standard treatment or intensified immuno-chemotherapy. This observation meets an unmet need for early and better identification of ultra-high risk DLBCL patients.

Disclosures
Thieblemont: Cellectis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Speakers Bureau; Hospira: Research Funding; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Bristol-Myers Squibb: Consultancy, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Incyte: Honoraria; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel support; Bayer: Honoraria; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Kite, a Gilead Company: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company). Dührsen:Gilead/Kite: Consultancy, Honoraria; Alexion: Honoraria; CPT: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Research Funding; Novartis: Consultancy, Honoraria; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Honoraria, Research Funding; Takeda: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria, Other: travel, accomodations, expenses; Janssen: Consultancy, Honoraria, Other: travel, accomodations, expenses. Vitolo:Roche: Honoraria, Other: travel, accomodations, expenses; Jansen: Honoraria. Zaucha:Cellgene: Other: travel, accomodations, expenses; Abbvie: Honoraria; Sandoz: Consultancy, Honoraria; Roche: Consultancy, Honoraria, Other: travel, accomodations, expenses; Takeda: Consultancy, Honoraria, Other: travel, accomodations, expenses; BMS: Consultancy; Novartis: Consultancy. Maria:Gilead: Consultancy, Other: travel, accomodations, expenses, Research Funding; Janssen: Consultancy, Other: travel, accomodations, expenses; MSD: Consultancy; BMS: Consultancy; Roche: Consultancy, Other: travel, accomodations, expenses; Abbvie: Consultancy, Other: travel, accomodations, expenses. Decazes:Bayer: Other: travel, accomodations, expenses. Tilly:BMS: Honoraria. Casasnovas:MSD: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; Takeda: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding; Gilead: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding; Roche: Consultancy, Honoraria, Other: travel, accomodations, expenses, Research Funding; Amgen: Consultancy, Honoraria. Hüttmann:University Hospital Essen, University of Duisburg-Essen, Essen, Germany: Current Employment; Lead Discovery Center GmbH: Consultancy; Gilead: Honoraria; Celgene: Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Seattle Genetics: Research Funding; Roche: Other: Travel expenses. Schmitz:Abbvie: Other: travel. Paulson:F. Hoffmann-La Roche Ltd.: Current Employment, Current equity holder in publicly-traded company. Nielsen:F. Hoffmann-La Roche: Current Employment, Current equity holder in publicly-traded company. Meignan:ROCHE: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company).