Integrative Study of a High-Grade B-Cell Lymphoma Cohort of 45 Patients: A Single Institution Real Life Study
Authors: Roulin Louise , Poullot Elsa , Blanc-Durand Paul , Robe Cyrielle , Lemonnier Francois , Le Bras Fabien , Gounot Romain , Belhadj Karim , Dupuis Jehan , Hammoud Mohammad , El Gnaoui Taoufik , Mule Sebastien , Copie Bergman Christiane , Molina Thierry , Delfau Larue Marie Helene , Itti Emmanuel , Gaulard Philippe , Haioun Corinne 
Published: November 2021

Abstract
Background :
High grade B cell lymphoma (HGBL) either Not Otherwise Specified (NOS) or either Double Hit (DH MYC/BCL2 or DH MYC/BCL6) or Triple Hit (TH) have been considered as separate entities from Diffuse Large B-Cell Lymphoma (DLBCL) NOS in the 2016 WHO classification. Until now, treatment of these particularly aggressive histological sybtypes remains unclear and most of patients (pts) still have a poor outcome because of chemoresistance or early relapse. Except IPI score, prognosis factors are not completely clarified. Since few years, treatment with Chimeric Antigen Receptor T (CAR-T) cells has changed the prognosis of relapsed refractory DLBCL and could represent a promising therapeutic approach - early in the course of the disease - to improve survival of HGBL. The aim of the present study is to describe a « real life » cohort of pts treated in our institution and to evaluate the prognostic impact of clinical, histological, genetic and imaging characteristics and treatment.
Methods :
We collected data of 45 pts diagnosed between January 2009 and October 2020. BCL2, BCL6 and MYC break were analyzed by Interphase Fluorescence In Situ Hybridization (FISH) with break-apart probes. When MYC was rearranged, MYC partner gene was analyzed with double fusion probes (MYC/IgH, MYC/IgL, MYC/IgK). Total metabolic tumor volume (TMTV) was calculated using fully automatic segmentation of lymphoma lesions by an artificial intelligence (P. Blanc-Durand, Eur J Nucl Med Mol Imaging, 2021).
All pts were treated with rituximab R-CHOP/CHOP-like regimens. Treatment was reinforced (intensive regimen) with high dose methotrexate (14 pts treated with RCOPADM and one with R-ACVBP) when they were considered fit enough. Autologous stem cell transplantation at 1st relapse was performed in 3 pts and 5 pts were treated with CAR-T cells at 2 nd relapse.
Results :
Baseline characteristics were as follows: median age 60 y (28-80), IPI 3-5 : n=33 (73%), CNS localization : n=8/42 (19%), bone marrow involvement : n=10/34 (22%).
Twenty-seven pts were DH lymphoma (MYC/BCL2: 18; MYC/BCL6: 9), 8 patients were TH-lymphoma and 10 were HGBL-NOS.
MYC rearrangement was detected in 40 cases with an immunoglobulin partner gene (IgH, IgL or IgK) in 14 (52%) of 27 evaluable cases.
TMTV was calculated for 29 pts with a median TMTV of 1019 ml (2-4536 ml). Fifteen pts were treated with an intensive regimen. With a median follow-up of alive pts of 17 months, 2-y progression-free survival (PFS) and overall survival (OS) were 42% [26.4 ; 56.8] and 62% [43.7 ; 75.5] respectively.
PFS and OS were significantly affected by IPI 3-5 (PFS: p= 0.006, HR=3.37 ; OS: p= 0.01, HR=3.71) and CNS involvement (PFS : p=0.006, HR=6.93 ; OS: p=0.006, HR=7.44). TMTV&gt;1000ml (PFS: p=0.051, HR 2.99 ; OS: p=0.033, HR=4.13) was associated with a significantly inferior OS.
Prognosis of HGBL DH/TH and HGBL-NOS was similar (PFS: p= 0.89, HR=0.93 ; OS: p=0.64, HR=1.32). Immunoglobulin as MYC partner gene had no significant impact on prognosis (PFS: p=0.47, HR=1.48 ; OS: p=0.32, HR=1.73). Intensive regimens did not improve significantly prognosis (PFS: p=0.26, HR=1.71 ; OS: p=0.08, HR=2.86).
Conclusion:
This monocentric study confirms previous reports on the poor prognosis of HGBL (DH/TH and NOS) especially for patients for both high IPI or high TMTV and in case of initial CNS involvement.
We confirm that intensive regimen don't improve prognosis supporting the need of alternative strategies incorporating bispecific monoclonal antibodies or consolidative CAR-T cells in very high risk pts.

Disclosures
Roulin: Janssen: Other: Travel and meetings. Lemonnier: Institut Roche: Research Funding; Gilead: Other: travel grant. Le Bras: Novartis: Honoraria; Takeda: Honoraria, Research Funding; Kite Gilead: Honoraria; Celgene BMS: Research Funding. Gaulard: Innate Pharma: Research Funding; Sanofi: Research Funding; Alderaan: Research Funding; Gilead: Consultancy; Takeda: Consultancy, Honoraria. Haioun: Miltenyi: Honoraria, Research Funding; Gilead: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; F. Hoffmann-La Roche Ltd: Honoraria, Research Funding; Servier: Honoraria, Research Funding; Takeda: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Amgen: Honoraria, Research Funding.