Abstract: Background Mantle cell lymphoma (MCL) is a lymphoproliferative disorder characterized by the t(11;14) balanced translocation, involving on chromosome 11 the gene encoding cyclin D1, CCND1. The enhancer of IGH, on chromosome 11, induces aberrant Cyclin D1 overexpression. A few reports have shown that the CCND1 oncogene locus is a recurrently amplified region in MCL. However, the prognostic value of this copy number abnormality (CNA) is not known. The incidence and clinical impact of CCND1 CNA were investigated on diagnostic samples from patients enrolled in the first-line randomized controlled trial LyMa (S. Le Gouill et al. NEJM 2017). Patients and methods A series of 100 lymph node biopsies performed at diagnosis for patients enrolled in the LyMa trial (n=299) was selected. After DNA extraction, CNAs were investigated in these samples using the innovative Oncoscan® SNP-array technique adapted to analyze highly degraded DNA extracted from formalin-fixed paraffin-embedded (FFPE) tissues. Ninety-four samples were informative for CNAs. CCND1 gains were controlled by fluorescence in situ hybridization on interphase nuclei, following standard procedures using LSI IGH/CCND1 XT Dual color, dual fusion translocation probes (Abbott Molecular, Des Plaines, IL). Progression-free and overall survivals were calculated from the date of inclusion until relapse/death or last news and death or last news respectively. Cumulative incidence of relapse (CIR) was estimated from the date of inclusion until the date of relapse or last news Results Amplifications of a large portion of 11q, beginning at the t(11;14) breakpoint, were observed with Oncoscan® in 7 patients. All these cases with a gain of 11q13-14 (CCND1) also had a gain of the 14q32 locus (IGH) suggesting amplification of the rearranged IGH-CCND1 region of t(11;14). This was confirmed by FISH analysis which disclosed three different configurations. The first was the classical CCND1-IGH rearrangement (CCND1 on normal chromosome 11, IGH on normal chromosome 14 and two fusion signals from the t(11;14)(CCND1-IGH)). The second configuration associated CCND1-IGH fusion signals and a gain of both CCND1 and IGH signals. The third configuration was a duplication of a CCND1-IGH fusion signals (3 signals). Both in SNP and in FISH, the amplification was always identified as sub-clonal, concerning only part of the cells. In some patients, different configurations coexisted. Compared to other patients of the series, those with amplification of IGH and CCND1 regions had a higher-risk bio-MIPI (11q13-14, p=0.015; 14q32, p=0.004). Patients with large gains at 11q13-14 (CCND1 N=7) had poorer median PFS (18 months vs not reached (NR); p=0.004), OS (35 months vs NR; p=0.01) and CIR (33 months vs not NR; p=0.004). The same was observed for patients with gains at 14q32 (IGH; N=8), with significantly different median PFS (23 months vs NR; p 〈 0.001), OS (38 months vs NR; p=0.001) and CIR (28 months vs NR; p 〈 0.001). Conclusion Gains of the IGH-CCND1 rearrangement or involved genes appear to be a potential new biomarker predictive of poor response to first line immunochemotherapy in young MCL patients. Disclosures Hermine: Novartis: Research Funding; Hybrigenics: Research Funding; AB Science: Consultancy, Equity Ownership, Honoraria, Research Funding; Erythec: Research Funding; Celgene Corporation: Research Funding.

Abstract: Mantle cell lymphoma (MCL) is a lymphoproliferative disorder characterized by the t(11;14)(q13;q32) CCND1/IGH translocation. This lymphoma is however extremely heterogeneous in terms of molecular alterations. Moreover, the course of the disease can vary greatly between indolent forms with slow progression and aggressive conditions rapidly pejorative. The identification of early markers allowing to predict individual patients outcome has however been unsuccessful so far. The LyMa trial treated homogeneously a cohort of young MCL patients. This appeared as a good opportunity to search for biomarkers of response to therapy. DNA extracted from diagnostic paraffin‐embedded lymph node biopsies from 100 patients with newly diagnosed MCL, homogeneously treated in this prospective clinical trial, were investigated for copy number alterations and copy neutral loss of heterozygosity using the Oncoscan SNP‐array scanning the whole genome. An independent confirmatory cohort was used to strengthen the possibly relevant anomalies observed. Here we describe the recurrent anomalies identified with this technique. Deletions of 17p( TP53 ) and 9p( CDKN2A ) were more frequent in refractory or early relapsing patients (10%), but had no significant impact in univariate analysis on progression‐free (PFS) or overall survival (OS). Regardless of the presence of TP53 or CDKN2A deletions, gains in 7p22 (8,5%) were associated with better PFS in univariate but not in multivariate analysis including MCL International Prognostic Index and treatment. Gains of 11q( CCDN1 ), suggesting gains of the CCND1/IGH fusion, were associated with worse OS and PFS in univariate and multivariate analyses. This worse prognosis impact was confirmed by FISH in an independent confirmatory cohort. This work, using a whole genome approach, confirms the broad genomic landscape of MCL and shows that gains of the CCND1/IGH fusion can be considered as a new prognostic structural variant. Genomic abnormalities of prognostic impact could be useful to strengthen or de‐escalate treatment schedules or choosing targeted therapies or CART‐cells.

Abstract: There is no consensus on the optimal systemic treatment of patients with extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue. The IELSG-19 phase III study, to our knowledge, was the first such study to address the question of first-line treatment in a randomized trial. Patients and Methods Eligible patients were initially randomly assigned (1:1 ratio) to receive either chlorambucil monotherapy (6 mg/m 2 /d orally on weeks 1 to 6, 9 to 10, 13 to 14, 17 to 18, and 21 to 22) or a combination of chlorambucil (same schedule as above) and rituximab (375 mg/m 2 intravenously on day 1 of weeks 1, 2, 3, 4, 9, 13, 17, and 21). After the planned enrollment of 252 patients, the protocol was amended to continue with a three-arm design (1:1:6 ratio), with a new arm that included rituximab alone (same schedule as the combination arm) and with a final sample size of 454 patients. The main end point was event-free survival (EFS). Analysis of chlorambucil versus the combination arm was performed and reported separately before any analysis of the third arm. Results At a median follow-up of 7.4 years, addition of rituximab to chlorambucil led to significantly better EFS (hazard ratio, 0.54; 95% CI, 0.38 to 0.77). EFS at 5 years was 51% (95% CI, 42 to 60) with chlorambucil alone, 50% (95% CI, 42 to 59) with rituximab alone, and 68% (95% CI, 60 to 76) with the combination ( P = .0009). Progression-free survival was also significantly better with the combination ( P = .0119). Five-year overall survival was approximately 90% in each arm. All treatments were well tolerated. No unexpected toxicities were recorded. Conclusion Rituximab in combination with chlorambucil demonstrated superior efficacy in mucosa-associated lymphoid tissue lymphoma; however, improvements in EFS and progression-free survival did not translate into longer overall survival.

Abstract: The standard treatment of patients with diffuse large B-cell lymphoma (DLBCL) is rituximab in combination with cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP). Lenalidomide, an immunomodulatory agent, has shown activity in DLBCL. This randomized phase III trial compared lenalidomide as maintenance therapy with placebo in elderly patients with DLBCL who achieved a complete response (CR) or partial response (PR) to R-CHOP induction. Methods Patients with previously untreated DLBCL or other aggressive B-cell lymphoma were 60 to 80 years old, had CR or PR after six or eight cycles of R-CHOP, and were randomly assigned to lenalidomide maintenance 25 mg/d or placebo for 21 days of every 28-day cycle for 24 months. The primary end point was progression-free survival (PFS). Results A total of 650 patients were randomly assigned. At the time of the primary analysis (December 2015), with a median follow-up of 39 months from random assignment, median PFS was not reached for lenalidomide maintenance versus 58.9 months for placebo (hazard ratio, 0.708; 95% CI, 0.537 to 0.933; P = .01). The result was consistent among analyzed subgroups (eg, male v female, age-adjusted International Prognostic Index 0 or 1 v 2 or 3, age younger than 70 v ≥ 70 years), response (PR v CR) after R-CHOP, and positron emission tomography status at assignment (negative v positive). With longer median follow-up of 52 months (October 2016), overall survival was similar between arms (hazard ratio, 1.218; 95% CI, 0.861 to 1.721; P = .26). Most common grade 3 or 4 adverse events associated with lenalidomide versus placebo maintenance were neutropenia (56% v 22%) and cutaneous reactions (5% v 1%), respectively. Conclusion Lenalidomide maintenance for 24 months after obtaining a CR or PR to R-CHOP significantly prolonged PFS in elderly patients with DLBCL.

Abstract: Chimeric antigen receptor-modified T (CAR T) cell therapy is a highly promising treatment for haematological malignancies but is frequently associated with cytokine release syndrome and neurotoxicity. Between July 2018 and July 2019, all patients treated with CD19-targeted CAR T-cell therapy for relapsing lymphoma were followed-up longitudinally to describe neurological symptoms and their evolution over time. Four different French centres participated and 84 patients (median age 59 years, 31% females) were included. Neurotoxicity, defined as the presence of at least one neurological symptom appearing after treatment infusion, was reported in 43% of the patients. The median time to onset was 7 days after infusion with a median duration of 6 days. More than half of the patients (64%) had grade 1–2 severity and 34% had grade 3–4. CRS was observed in 80% of all patients. The most frequent neurological symptoms were cognitive signs, being severe in 36%, and were equally distributed between language disorders and cognitive disorders without language impairment. Non-pyramidal motor disorders, severe in 11%, were reported in 42% of the patients. Elevation of C-reactive protein (CRP) within 4 days after treatment was significantly correlated with the occurrence of grade 3–4 neurotoxicity. Although sometimes severe, neurotoxicity was almost always reversible. The efficacy of steroids and antiepileptic drugs remains unproven in the management of neurotoxicity. Neurotoxicity associated with CAR T-cell therapies occurs in more than 40% of patients. The clinical pattern is heterogeneous but cognitive disorders (not limited to language disorders) and, to a minor degree, non-pyramidal motor disorders, appeared as a signature of severe neurotoxicity.

Abstract: Introduction : High total metabolic tumor volume (TMTV) measured on 18F-FDG PET/CT before R-CHOP has been shown to be significantly associated with worse progression-free survival (PFS) and overall survival (OS) in patients with diffuse large B-cell lymphoma (DLBCL; Cottereau et al. Clin Cancer Res. 2016;22:3801-9) . The REMARC study (NCT01122472) is an international, multicenter, double-blind, randomized phase III trial that assessed lenalidomide (LEN) maintenance therapy versus placebo (PBO) in 650 patients responding to R-CHOP. With a median follow-up of ~40 months, independent review demonstrated that 2 years of LEN maintenance therapy significantly improved progression-free survival (PFS); median was not reached in the LEN arm vs 58.9 months in the PBO arm (HR=0.71 [95% CI, 0.54-0.93]; p=0.0135; Thieblemont et al. J Clin Oncol. 2017;35:2473-81). Methods: For these analyses, patients enrolled in the REMARC trial who had baseline PET/CT before R-CHOP (not mandatory per study protocol) with available fused images and end of treatment PET/CT were included. Total metabolic tumor volume (TMTV, defined as the sum of the regions of the local tumors with FDG uptake) was measured on baseline PET/CT with the 41% SUVmax thresholding method using the free semiautomatic software Beth Israel Fiji20 (http://petctviewer.org). The optimal TMTV cut-off to PFS (per FDA censoring rule) and overall survival (OS) was determined by Receiver Operating Curve (ROC) curves and X-tile analyses. Survival was estimated using Kaplan Meier (KM) curves. Multivariable analysis were performed with descending Cox model including TMTV, IPIaa, treatment arm and PET/CT response evaluated by Deauville criteria. Analyses were performed on the evaluable population and separate arms Results: 228 of 650 REMARC patients had TMTV data available for analysis, including n=108 in the PBO arm and n=120 in the LEN arm. Clinical characteristics were similar to the overall population. The median baseline TMTV was 295 cm3 (Q1-Q3, 99-702). After a median follow-up of 51.6 mo, 4y-PFS was 73% and 4y-OS was 85%. The optimal TMTV cut-off determined by ROC was 300 cm3 for PFS and OS. Patients with TMTV 〉 300 vs ≤300 cm3 presented with worse ECOG performance status (ECOG ≥2: 19% vs 9%, p=0.034), higher Ann Arbor stage (stage III-IV: 95% vs 86%, p=0.042), more extra-nodal sites ( 〉 1: 65% vs 38%, p 〈 0.001), more frequently elevated LDH (76% vs 43%, p 〈 0.001), higher IPI (IPI 3-5: 87% vs 51%, p 〈 0.001), and higher aaIPI (aaIPI 2-3: 76% vs 34%, p 〈 0.001). In all evaluated patients, a significant impact of TMTV for cut-offs of 〉 300 vs ≤300 cm3 was observed for PFS (HR=2.09; 95% CI, 1.22-3.69) and OS (HR=2.99; 95% CI, 1.44-6.18). Patients with high TMTV 〉 300 cm3 vs low TMTV ≤300 cm3, respectively, had a 4-year PFS of 57% vs 73% and OS of 70% vs 88%. These results were more disparate when a higher TMTV cut-off of 〉 1000 was applied. In multivariate analysis, only TMTV maintained an independent prognostic value. The prognostic impact of TMTV 〉 300 vs ≤300 cm3 on PFS (HR=2.4; 95% CI, 1.1-5.22) and OS (HR=5.0; 95% CI, 1.4-17.) was maintained in the PBO arm (Figure 1A). In contrast, when the analysis was focused on patients in LEN arm, TMTV 〉 300 vs ≤300 cm3 lost its prognostic impact on PFS and OS. In the LEN arm, 4-year PFS and OS did not differ significantly between patients with high and low TMTV (Figure 1B). Conclusion: TMTV measured on baseline PET/CT is a strong prognosticator of outcome in DLBCL, even in patients in response after R-CHOP. High TMTV at baseline was significantly associated with worse PFS and OS in patients receiving PBO following a response to R-CHOP in the REMARC study. Interestingly, LEN maintenance reduces the negative impact of high baseline TMTV on survival in patients with DLBCL Disclosures Casasnovas: takeda: Consultancy; merck: Consultancy; MSD: Consultancy; Roche: Consultancy; Gilead Sciences: Research Funding; Roche: Honoraria; Takeda: Honoraria; Merck: Honoraria; Gilead Sciences: Honoraria; Janssen: Honoraria; Celgene: Honoraria; MSD: Honoraria; Roche: Research Funding; Gilead Sciences: Consultancy; Janssen: Consultancy. Tilly:Celgene: Membership on an entity's Board of Directors or advisory committees; BMS: Honoraria; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees; Astra-Zeneca: Membership on an entity's Board of Directors or advisory committees. Feugier:Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Ribrag:Infinity: Consultancy, Honoraria; Servier: Consultancy, Honoraria; Amgen: Research Funding; Roche: Honoraria, Other: travel; MSD: Honoraria; BMS: Consultancy, Honoraria, Other: travel; epizyme: Consultancy, Honoraria; NanoString Technologies: Consultancy, Honoraria; Gilead: Consultancy, Honoraria; argenX: Research Funding; pharmamar: Other: travel; Incyte Corporation: Consultancy. Macro:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Financial support for congress; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Financial support for congress; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Financial support for congress; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Financial support for congress. Morschhauser:Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Epizyme: Consultancy; Janssen: Other: Scientific Lectures; Roche: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees. Trotman:Janssen: Other: Unremunerated member of Ad Board, Research Funding; F. Hoffman-La Roche: Other: Travel to meeting, Unremunerated member of Ad Board, Research Funding; Takeda: Other: Unremunerated member of Ad Board; Celgene: Other: Unremunerated member of Ad Board, Research Funding; PCYC: Research Funding; Beigene: Research Funding. Godmer:CELGENE: Other: Invitation to congress. Salles:Servier: Honoraria; Novartis: Consultancy, Honoraria; Morphosys: Honoraria; Servier: Honoraria, Other: Advisory Board; Celgene: Honoraria, Other: Advisory Board, Research Funding; Acerta: Honoraria; Merck: Honoraria; Janssen: Honoraria, Other: Advisory Board; Pfizer: Honoraria; Epizyme: Honoraria; F. Hoffmann-La Roche Ltd: Consultancy, Honoraria, Research Funding; Gilead: Honoraria, Other: Advisory Board; BMS: Honoraria, Other: Advisory Board; Takeda: Honoraria; Amgen: Honoraria; Abbvie: Honoraria. Coiffier:CELGENE: Consultancy, Membership on an entity's Board of Directors or advisory committees; MUNDIPHARMA: Membership on an entity's Board of Directors or advisory committees; CELLTRION: Membership on an entity's Board of Directors or advisory committees; MORPHOSYS: Membership on an entity's Board of Directors or advisory committees; NOVARTIS: Membership on an entity's Board of Directors or advisory committees. Meignan:F. Hoffman-La Roche Ltd: Honoraria.

Abstract: Background. R-CHOP is the standard first-line treatment for elderly patients with diffuse large B-cell lymphoma (DLBCL). However 30% of patients will relapse and 70% of relapsed patients will die within 2 years of diagnosis. The REMARC study (clinicalTrials.gov NCT01122472) is an international, multicenter, double-blind, randomized, placebo controlled, phase III trial that assessed the benefit of lenalidomide (LEN) maintenance after response to R-CHOP in patients aged 60 to 80 years with untreated DLBCL, FL3b or transformed lymphoma. Patients achieving CR or PR at the end of 6 or 8 cycles of R-CHOP21 or R-CHOP14 were stratified by CR/PR status and country and randomized 1:1 to receive 2 years of LEN maintenance (25 mg/day for 21 of every 28 days) or placebo (PBO). The primary endpoint of the study was progression-free survival (PFS). Secondary endpoints were safety, PR to CR conversion rate, and overall survival (OS). Diagnosis was retrospectively centrally reviewed. In patients with adequate samples, GCB/nonGCB profile was assessed by the Hans algorithm and GCB/ABC/unclassified profile was assessed using NanoString gene expression profiling technology. Methods. From 05/2009 to 05/2014, 784 patients were enrolled either before R-CHOP (n= 437) or after completion of 6 or 8 cycles of R-CHOP (n= 347). At the end of R-CHOP therapy, 650 patients were randomized to maintenance, either in CR (n= 495) or in PR (n= 152). Central review found that 3 patients were randomized in SD or PD, all in LEN arm. At time of diagnosis, median age was 68 y (range 58-80), 43.5% were older than 70 y, and 56% were male. aaIPI was low in 38.5% and high in 57.5% of patients (missing data 4%). COO analyses are ongoing for both Hans algorithm and NanoString technology. Results. With a median follow-up of 40 months, median PFS (according to independent centralized radiology review) was not reached in the LEN group versus 68 months in the PBO group (hazard ratio favoring the LEN group, 0.708 (95% CI 0.537-0.932; p=0.0135))(See Figure). In the LEN group, 18 patients (21%) converted from PR to CR during maintenance compared to 13 patients (14%) in the PBO group. Immature overall survival data did not show any benefit for LEN arm, a lack of difference not attributable to an excess of lymphoma relapse, secondary cancer or safety problems in LEN arm. Deaths generally occurred off study drug (median time from last dose of study drug to death was 277 days (range 20, 1291) in LEN arm and 334 (41, 1594) in control arm. During maintenance, the most common observed grade 3 or 4 AEs were neutropenia (56% vs. 22%), rash (5% vs. 1%), infections (8% vs. 6%), and thrombocytopenia (2.5% vs. 0.6%) in LEN and PBO arms, respectively. Dose adjustments were necessary in 72% of the LEN patients and 42% of PBO patients. 59% of patients stopped LEN and 40% stopped PBO for toxicity (p 〈 0.001). Median number of cycles was 15 in LEN and 25 in PBO (p 〈 0.001). Secondary primary malignancies occurred in 33 patients receiving LEN and in 42 patients on PBO. Conclusion. This analysis of the REMARC study shows that 2 years of LEN maintenance in patients responding to R-CHOP significantly improved PFS (primary endpoint) without an early significant impact on OS. The COO analysis is currently ongoing. This is the first report finding that using an immunomodulatory agent as maintenance therapy prolongs PFS for patients with DLBCL after first line treatment with R-CHOP. Figure 1. Progression-free survival of elderly patients with diffuse large B-cell lymphoma in response to R-CHOP treated in maintenance with either lenalidomide or placebo Figure 1 Figure 1. Disclosures Thieblemont: Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Research Funding; Bayer healthcare: Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees. Gomez da Silva:Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; ROche: Consultancy, Membership on an entity's Board of Directors or advisory committees; takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bristol Meyer Squibb: Consultancy, Membership on an entity's Board of Directors or advisory committees. Morschhauser:Celgene: Consultancy, Honoraria; Roche: Consultancy, Honoraria; Gilead Sciences: Consultancy, Honoraria; Janssen: Honoraria; Servier: Consultancy, Honoraria. Haioun:Sandoz: Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees. Cabecadas:celgene: Consultancy, Honoraria. Salles:Gilead: Honoraria, Research Funding; Janssen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Mundipharma: Honoraria; Roche/Genentech: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria; Novartis: Consultancy, Honoraria. Coiffier:Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Mundipharma: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Astra-Zeneca: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Celltrion: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees.

Abstract: Early identification of ultra-risk diffuse large B-cell lymphoma (DLBCL) patients is needed to aid stratification to innovative treatment. Previous studies suggested high baseline total metabolic tumor volume (TMTV) negatively impacts survival of DLBCL patients. We analyzed the prognostic impact of TMTV and prognostic indices in DLBCL patients, aged 60 to 80 years, from the phase 3 REMARC study that randomized responding patients to R-CHOP (rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone) into maintenance lenalidomide or placebo. TMTV was computed on baseline positron emission tomography/computed tomography using the 41% maximum standardized uptake value method; the optimal TMTV cutoff for progression-free (PFS) and overall survival (OS) was determined and confirmed by a training validation method. There were 301 out of 650 evaluable patients, including 192 patients classified as germinal center B-cell–like (GCB)/non-GCB and MYC/BCL2 expressor. Median baseline TMTV was 238 cm3; optimal TMTV cutoff was 220 cm3. Patients with high vs low TMTV showed worse/higher Eastern Cooperative Oncology Group performance status (ECOG PS) ≥2, stage III or IV disease, & gt;1 extranodal site, elevated lactate dehydrogenase, International Prognostic Index (IPI) 3-5, and age-adjusted IPI 2-3. High vs low TMTV significantly impacted PFS and OS, independent of maintenance treatment. Although the GCB/non-GCB profile and MYC expression did not correlate with TMTV/survival, BCL2 & gt;70% impacted PFS and could be stratified by TMTV. Multivariate analysis identified baseline TMTV and ECOG PS as independently associated with PFS and OS. Even in responding patients, after R-CHOP, high baseline TMTV was a strong prognosticator of inferior PFS and OS. Moreover, TMTV combined with ECOG PS may identify an ultra-risk DLBCL population. This trial was registered at www.clinicaltrials.gov as #NCT01122472.