Real-world Outcomes of Diffuse Large B-cell Lymphoma Treated with frontline R-CHOP(-like) regimens in an Asian Multi-ethnic Population

Real-world Outcomes of Diffuse Large B-cell Lymphoma Treated with frontline R-CHOP(-like) regimens in an Asian Multi-ethnic Population | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Real-world Outcomes of Diffuse Large B-cell Lymphoma Treated with frontline R-CHOP(-like) regimens in an Asian Multi-ethnic Population Ryan Lim, Jing Yuan Tan, Ya Hwee Tan, Zane En Qi Heng, Lawrence Cheng Kiat Ng, and 4 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4855200/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 15 Nov, 2024 Read the published version in Annals of Hematology → Version 1 posted 13 You are reading this latest preprint version Abstract Background Recent breakthrough advances in the treatment of DLBCL, such as the antibody-drug conjugate Polatuzumab vedotin, have yielded clinical survival benefit over R-CHOP for the first time in 20 years since the advent of the Rituximab era. We thus examine the outcomes of standard immunochemotherapy for DLBCL in our multi-ethnic Asian population, so as to determine the real-world clinical need to adopt new therapeutics in this disease entity. Methods We conducted a retrospective study involving patients (n = 1071) diagnosed with DLBCL at the National Cancer Centre Singapore from 2010–2022, and treated with first-line rituximab-based regimens. The median follow-up duration was 48 months. Survival analyses were performed using the Kaplan-Meier method and multivariate Cox proportional models. Results The cohort consisted of 590 male and 481 female patients with a median age of 63.8 years (range, 19.3–93.6). Most were stage III-IV at diagnosis (60.9%) and of non-germinal center B-cell like (non-GCB) subtype by Han’s criteria (56.5%). The vast majority received R-CHOP(-like) regimens (n = 997, 93.1%), including EPOCH-R (n = 95), achieving a 5-year progression-free survival (PFS) and overall survival (OS) of 64.5% and 74.7% respectively. Male sex ( p = 0.0294), age > 60 years ( p < 0.0001), poor ECOG scores ( 2 – 4 ) ( p < 0.0001), advanced stage (III-IV) ( p < 0.0001), presence of B-symptoms ( p = 0.0305), raised LDH ( p = 0.0161) were independent predictors of OS, 4 of which are risk factors in the International Prognostic Index (IPI). In the intermediate to high-risk subgroup (IPI scores 2–5; n = 752), the 5-year PFS and OS were only 59.0% and 69.8% respectively. EBV status, as was high-risk lymphoma ( MYC and/or BCL2 / BCL6 rearrangements), were not significantly associated with survival outcomes. EPOCH-R was used more frequently than R-CHOP in patients with MYC rearrangements (n = 82, p < 0.0001), including those with MYC/BCL2 double-hit genetics (n = 31, p < 0.0001). Notably, neither regimen significantly affected survival outcomes, both in MYC -rearranged (PFS: HR 0.60, p = 0.1704; OS: HR 0.49, p = 0.0852), and in MYC/BCL2 double-hit DLBCL (PFS: HR 1.30, p = 0.6433; OS: HR 1.02, p = 0.9803). Conclusion Our study demonstrates that our local population has similar clinicopathological and prognostic characteristics of DLBCL as compared to global findings. It also highlights the limitations of R-CHOP(-like) regimens in contemporary DLBCL management and therefore an ongoing need for improved therapeutic strategies. Polatuzumab vedotin CAR-T cells cell-of-origin double-hit bispecific antibody Figures Figure 1 Figure 2 Figure 3 INTRODUCTION Diffuse Large B-Cell Lymphoma (DLBCL) is the most common type of Non-Hodgkin’s Lymphoma (NHL). It is very aggressive but responds favourably to chemotherapy. Rituximab, Cyclophosphamide, Doxorubicin, Vincristine and prednisolone (R-CHOP) has been the standard of care treatment regimen for DLBCL 1 since the early 2000s. As compared to CHOP therapy, R-CHOP provided significantly higher rates of complete response (CR) and longer overall survival (OS) durations in both the elderly population 2 and younger patients 3 . The MabThera International Trial (MInT) Group showed that 6 cycles of R-CHOP therapy improved 6-year event-free survival (EFS) to 74.3% as compared to 55.8% for the CHOP group and 6-year OS to 90.1% from 80.0% 4 . Following the inclusion of anti-CD20 monoclonal antibody Rituximab to first-line therapy in DLBCL, there has been limited success in attempts made to improve upon this treatment regimen, with candidate drugs often failing to show benefit in phase III trials or causing an unacceptable increase in toxicity. Dose-intensified Rituximab, Doxorubicin, Cyclophosphamide, Vindesine, Bleomycin and Prednisolone (R-ACVBP) was shown to improve PFS and OS in patients aged 15–59 years, but was eventually not prescribed widely due to its high incidence of haematological toxic effects and limited applicability. 5 Other treatment options such as consolidation therapy with high-dose chemotherapy and autologous stem cell transplantation (ASCT) improved treatment response and progression-free survival (PFS), but did not result in prolonged OS 6,7 . Consequently, the survival outcomes in DLBCL improved only modestly during the rituximab era, demonstrating the limited efficacy of those novel therapeutics over the current standard of care 8 . Polatuzumab vedotin is an antibody-drug conjugate (ADC) directed at CD79b, a part of the heterodimeric signalling component of B-cell NHLs. It demonstrated good efficacy against NHL and DLBCL in initial in vivo and early clinical trials 9,10 . In 2023, a double-blind, placebo-controlled phase 3 trial showed that Polatuzumab vedotin in combination with Rituximab, Cyclophosphamide, Doxorubicin and Prednisolone (pola-R-CHP) improved PFS in the overall cohort over R-CHOP in patients with previously untreated intermediate- to high-risk DLBCL (IPI 2–5) 11 . Even though the OS data was considered to be immature and did not differ between both arms, the significant survival benefit from PFS prolongation paired with its acceptable side-effect profile and reasonable cost earned Polatuzumab vedotin health regulatory approvals in the UK 12 , US 13 and Singapore 14 for use in previously untreated DLBCL with International Prognostic Index (IPI) of 2–5. In Singapore, a country with a diverse multi-ethnic population, the first-line treatment for DLBCL is that of six 21-day cycles of R-CHOP immunochemotherapy 15 , in line with global guidelines 16 . The efficacy of R-CHOP over CHOP in our patient population is supported by the last large-scale Singapore DLBCL study done in 2008 showing a significantly higher 2-year survival of R-CHOP compared to CHOP alone (85.6% vs 64.7%) 17 . Given this recent breakthrough of Polatuzumab vedotin in the treatment of previously untreated DLBCL, we sought to review the current efficacy of the current standard-of-care treatment regimens for DLBCL in Singapore. Through this, we confirm the unmet clinical need of novel effective therapeutics in the treatment of DLBCL in our local population in a real-world setting. PATIENTS AND METHODS Study cohort Patients who were diagnosed with diffuse large B-cell lymphoma (DLBCL) and seen at the National Cancer Centre Singapore and Singapore General Hospital between 2010 and 2022 were retrospectively analysed. A total of 1071 patients who were treated with rituximab-based immunochemotherapy regimens were included in the final analysis. The median follow-up duration for this group of patients was 48 months. Relevant demographical and clinicopathological information were collected and summarised for the analysis. Demographical information available included sex, age and ethnicity. Clinical characteristics of each patient including B-symptoms, Eastern Cooperative Oncology Group (ECOG) performance status, disease stage, number of extranodal site involvement, chemotherapeutic regimen used and survival outcomes were included in the study. Finally, pathological information such as immunohistochemical markers (BCL2, BCL6, CD10, MUM1, MYC), gene rearrangements ( BCL2 , BCL6 , MYC ), and DLBCL cell-of-origin by Han’s algorithm 18 were included in the analysis. All data was obtained at the time of diagnosis or subsequent follow-up. The research study was carried out with approval from the SingHealth Centralised Institutional Review Board. Informed consent for the use of biospecimens was obtained in accordance with the Declaration of Helsinki and all methods were carried out in accordance with relevant guidelines and regulations. All data was obtained at the time of diagnosis or subsequent follow-up. Participants and/or their legal guardians provided informed consent for their data to be used in this research. The datasets created and analysed during this study are available from the corresponding authors upon reasonable request. Statistical Analysis The outcomes of interest in this study are progression-free survival (PFS) and overall survival (OS). PFS was defined as the time elapsed between the date of diagnosis to the date of relapse, progression, or death from any cause. OS was calculated from the date of diagnosis up to the date of death from any cause, or was censored at the date of last follow-up for survivors. For each individual clinicopathological parameter, Kaplan-Meier survival curves were plotted to estimate survival. The log-rank test was then used to determine hazard ratio (HR), the corresponding 95% confidence intervals of mortality and the p-values for each individual clinicopathological parameter. Parameters found to be significant on univariate analysis using a two-sided test with significance level of 0.05 were identified. These parameters were then used in the generation of Multivariate Cox regression models via a backwards procedure to test for independence of significant parameters for PFS and OS. MYC rearrangement and double-hit DLBCL were tested for association with choice of chemoimmunotherapy regimen with the chi-squared test. Kaplan-Meier survival curves were then plotted for R-CHOP vs EPOCH-R in patients with MYC rearrangement and double-hit DLBCL. All tests were performed using MedCalc statistical Software for Windows version 19.0.4 (MedCalc Software, Ostend, Belgium). RESULTS Patient demographics and clinicopathological characteristics The overall cohort consisted of 590 male and 481 female patients with a median age of 63.8 years (range, 19.3–93.6). Most were stage III-IV (60.9%) and of non-germinal center B-cell like (non-GCB) subtype by Han’s criteria (56.5%). Clinical and demographic characteristics of the whole study cohort are summarised in Table 1 . Table 1 Clinical and pathological characteristics of the overall cohort, n = 1071 Characteristic n (%) Total 1071 (100%) Sex Male 590 (55.1%) Female 481 (44.9%) Age ≤ 60 415 (38.7%) > 60 656 (61.3%) Ethnicity Chinese 766 (71.5%) Malay 177 (16.5%) Indian 39 (3.6%) Others 83 (8.3%) ECOG performance status 0–1 1002 (93.6%) 2–4 69 (6.4%) Stage I-II 416 (39.1%) III-IV 649 (60.9%) B-Symptoms Present 315 (29.4%) Absent 756 (70.6%) LDH Raised 830 (77.5%) Not raised 241 (22.5%) Extranodal sites >1 284 (26.5%) ≤1 787 (73.5%) IPI 0–1 255 (23.8%) 2 343 (32.0%) 3 301 (28.1%) 4–5 172 (16.1%) Cell of Origin GCB 423 (43.5%) Non-GCB 549 (56.5%) HIV status Positive 20 (1.9%) Negative 1009 (98.1%) HBsAg Positive 78 (7.8%) Negative 919 (92.2%) Anti-HBc Total Positive 320 (31.9%) Negative 683 (68.1%) HCV status Positive 20 (1.9%) Negative 1011 (98.1%) MYC/BCL2 double expressor Yes 157 (40.6%) No 230 (59.4%) MYC rearrangement Present 86 (19.6%) Absent 353 (80.4%) Both MYC and BCL2 rearrangement Present 32 (7.2%) Absent 412 (92.8%) Both MYC and BCL6 rearrangement Present 18 (4.1%) Absent 424 (95.9%) EBER Positive 32 (6.3%) Negative 476 (93.7%) *Missing data: Stage (n = 6), COO (n = 99), HIV status (n = 42), HBsAg (n = 74), Anti-HBc Total (n = 68), HCV status (n = 40), MYC/BCL2 double expressor (n = 684), MYC rearrangement (n = 632), MYC/BCL2 rearrangement (n = 627), MYC/BCL6 rearrangement (n = 629), EBER status (n = 563) The vast majority of the patient cohort received R-CHOP(-like) regimens (n = 997, 93.1%), including MR-CHOP (n = 78) and EPOCH-R (n = 95). This sub-cohort consisted of 544 males and 453 females, of which most were also stage III/IV (60.6%) and of non-germinal center B-cell like (non-GCB) subtype by Han’s criteria (56.1%). Clinical and demographic characteristics of the sub-cohort that received R-CHOP(-like) regimens are summarised in Table 2 . Table 2 Clinical and pathological characteristics of patients treated with R-CHOP(-like) regimens, n = 997 Characteristic n (%) Total 997 (100%) Sex Male 544 (54.6%) Female 453 (45.4%) Age < 60 597 (59.9%) ≥ 60 400 (40.1%) Ethnicity Chinese 719 (72.1%) Malay 159 (15.9%) Indian 36 (3.6%) Others 83 (8.3%) ECOG performance status 0–1 938 (94.1%) 2–4 59 (5.9%) Stage I-II 391 (39.4%) III-IV 602 (60.6%) B-Symptoms Present 292 (29.3%) Absent 705 (70.7%) LDH Raised 771 (77.3%) Not raised 226 (22.7%) Extranodal sites >1 262 (26.3%) ≤1 735 (73.7%) IPI 0–1 245 (24.6%) 2 319 (32.0%) 3 279 (28.0%) 4–5 154 (15.4%) Cell of Origin GCB 398 (43.9%) Non-GCB 509 (56.1%) HIV status Positive 19 (2.0%) Negative 940 (98.0%) HBsAg Positive 76 (8.2%) Negative 853 (91.8%) Anti-HBc Total Positive 306 (32.7%) Negative 630 (67.3%) HCV status Positive 20 (2.1%) Negative 942 (97.9%) MYC/BCL2 double expressor Yes 146 (40.4%) No 215 (59.6%) MYC rearrangement Present 82 (19.9%) Absent 330 (80.1%) Both MYC and BCL2 rearrangement Present 31 (7.4%) Absent 386 (92.6%) Both MYC and BCL6 rearrangement Present 17 (4.1%) Absent 398 (95.9%) EBER Positive 30 (6.4%) Negative 439 (93.6%) *Missing data: Stage (n = 4), COO (n = 90), HIV status (n = 38), HBsAg (n = 68), Anti-HBc Total (n = 61), HCV status (n = 35), MYC/BCL2 double expressor (n = 636), MYC rearrangement (n = 585), MYC/BCL2 rearrangement (n = 580), MYC/BCL6 rearrangement (n = 582), EBER status (n = 528) Molecular pathological characteristics For the overall patient cohort, fluorescence in-situ hybridization in a subgroup with available data revealed that MYC rearrangement was present in 86/439 (19.6%) cases, double-hit DLBCL with both MYC and BCL2 rearrangement was found in 32/444 (7.2%) cases and double-hit DLBCL with both MYC and BCL6 rearrangement was detected in 18/444 (4.1%) cases. MYC/BCL2 double expressor status was present in 157/387 (40.6%) cases. In another subgroup with available data, Epstein-Barr virus was positive in 32/508 (6.3%) cases. Survival analyses The patient sub-cohort that received R-CHOP(-like) regimens achieved a 5-year progression-free survival (PFS) and overall survival (OS) of 64.5% and 74.7% respectively (Fig. 1 ). At the point of data analysis, 274 patients (27.5%) had died. Further analysis will be performed in this sub-cohort of patients treated with R-CHOP(-like) regimens. Univariate analysis for OS revealed that male sex (HR 1.39, 95% CI 1.13–1.70, p = 0.0020), age > 60 (HR 1.53, 95% CI 1.24–1.89, p = 0.0001), ECOG performance status ≥ 2 (HR 3.90, 95% CI 2.36–6.42, p = < 0.0001), Stage III or IV (HR 2.33, 95% CI 1.89–2.87, p = < 0.0001), presence of B-symptoms (HR 1.51, 95% CI 1.20–1.91, p = 0.0004), raised LDH (HR 1.62, 95% CI 1.28–2.07, p = 0.0001), non-GCB cell of origin by Han’s algorithm (HR 1.40, 95% CI 1.12–1.74, p = 0.0029) and MYC/BCL2 double expressor status (HR 1.62, 95% CI 1.15–2.29, p = 0.0059) were all predictors for worse PFS (Table 3 ). Table 3 Univariable analysis for OS and PFS for patients treated with R-CHOP(-like) regimens, n = 997 Overall survival Progression-free survival Characteristic HR 95% CI p -value HR 95% CI p -value Sex (Male vs Female) 1.38 1.09–1.75 0.0084 1.39 1.13–1.70 0.0020 Age (> 60 vs ≤ 60) 2.11 1.66–2.69 < 0.0001 1.53 1.24–1.89 0.0001 ECOG Performance Status (2–4 vs 0–1) 4.73 2.68–8.34 < 0.0001 3.90 2.36–6.42 < 0.0001 Stage (III-IV vs I-II) 2.15 1.69–2.74 < 0.0001 2.33 1.89–2.87 < 0.0001 B-Symptoms (Present vs Absent) 1.67 1.28–2.17 0.0001 1.51 1.20–1.91 0.0004 LDH (Raised vs Not Raised) 1.87 1.42–2.46 1 vs ≤ 1) 1.87 1.41–2.47 < 0.0001 1.62 1.27–2.07 0.0001 IPI Risk Groups < 0.0001 < 0.0001 Cell Of Origin (Non-GCB vs GCB) 1.31 1.02–1.69 0.0328 1.40 1.12–1.74 0.0029 HIVs status (Positive vs Negative) 1.11 0.47–2.59 0.8134 0.99 0.47–2.98 0.9787 HBsAg (Positive vs Negative) 1.28 0.81–2.01 0.2896 1.11 0.75–1.65 0.5883 Anti-HBc Total (Positive vs Negative) 1.21 0.93–1.57 0.1513 1.10 0.88–1.39 0.3774 HCV Status (Positive vs Negative) 0.87 0.38–1.99 0.7434 0.93 0.45–1.91 0.8376 MYC/BCL2 Double Expressor (Yes vs No) 1.43 0.97–2.11 0.0714 1.62 1.15–2.29 0.0059 MYC Rearrangement (Present vs Absent) 1.16 0.72–1.85 0.5425 1.10 0.73–1.66 0.6500 Both MYC and BCL2 Rearrangement (Present vs Absent) 0.94 0.47–1.90 0.8681 1.35 0.71–2.54 0.3611 Both MYC and BCL6 Rearrangement (Present vs Absent) 1.43 0.51–4.03 0.4970 1.45 0.60–3.49 0.4078 EBER (Positive vs Negative) 0.65 0.32–1.30 0.2228 0.91 0.49–1.68 0.7627 For OS, male sex (HR 1.38, 95% CI 1.09–1.75, p = 0.0084), age > 60 (HR 2.11, 95% CI 1.66–2.69, p = < 0.0001), ECOG performance status ≥ 2 (HR 4.73, 95% CI 2.68–8.34, p = < 0.0001), Stage III or IV (HR 2.15, 95% CI 1.69–2.74, p = < 0.0001), presence of B-symptoms (HR 1.67, 95% CI 1.28–2.17, p = 0.0001), raised LDH (HR 1.87, 95% CI 1.42–2.46, p = < 0.0001), presence of extranodal sites (HR 1.87, 95% CI 1.41–2.47, p = < 0.0001) and non-GCB cell of origin by Han’s algorithm (HR 1.40, 95% CI 1.12–1.74, p = 0.0029) were all predictive of poorer outcomes on univariate analysis (Table 3 ). Following multivariate analysis of significant clinicopathological parameters, male sex (HR 1.33, 95% CI 1.03–1.73, p = 0.0294), age > 60 (HR 2.35, 95% CI 1.76–3.12, p < 0.0001), ECOG performance status ≥ 3 (HR 2.27, 95% CI 1.53–3.36, p < 0.0001), Stage III-IV (HR 1.92, 95% CI 1.42–2.59, p < 0.0001), presence of B-symptoms (HR 1.34, 95% CI 1.03–1.76, p = 0.0305) and raised LDH (HR 1.58, 95% CI 1.09–2.31, p = 0.0161) were independently prognostic for worse OS (Table 4 ). Table 4 Multivariable analysis for OS and PFS for patients treated with R-CHOP(-like) regimens, n = 997 Overall survival Progression-free survival Parameter HR 95% CI p -value HR 95% CI p -value Sex Female 1 1.03–1.73 0.0294 1 1.16–2.38 0.0051 Male 1.33 1.67 Age ≤ 60 1 1.76–3.12 60 2.35 1.95 ECOG Performance Status 0–1 1 1.53–3.36 < 0.0001 1 1.22–3.21 0.0054 2–4 2.27 1.98 Stage I-II 1 1.42–2.59 < 0.0001 1 1.28–2.87 0.0015 III-IV 1.92 1.92 B-Symptoms Absent 1 1.03–1.76 0.0305 1 0.99–2.06 0.0574 Present 1.34 1.43 LDH Not Raised 1 1.09–2.31 0.0161 - - - Raised 1.58 MYC/BCL2 Double Expressor Absent - - - 1 1.02–2.03 0.0404 Present 1.43 In the intermediate to high-risk subgroup (IPI scores 2–5; n = 752), the 5-year OS and PFS were only 69.8% and 58.0%, respectively (Fig. 1 ). EBV status, MYC and/or BCL2 rearrangements were not significantly associated with survival outcomes. MYC rearrangement and Double-hit DLBCL For patients treated with R-CHOP(-like) regimens, EPOCH-R was used more frequently than R-CHOP in patients with MYC rearrangements (n = 82, p < 0.0001), including those with MYC/BCL2 double-hit genetics (n = 31, p < 0.0001). Patients with MYC rearrangements achieved a 5-year OS of 70.7%, while those with both MYC and BCL2 rearrangements achieved a 5-year OS of 76.6% (Fig. 2 ). Notably, neither immunochemotherapy regimen significantly affected survival outcomes, both in MYC -rearranged (PFS: HR 0.60, p = 0.1704; OS: HR 0.49, p = 0.0852), and in MYC/BCL2 double-hit DLBCL (PFS: HR 1.30, p = 0.6433; OS: HR 1.02, p = 0.9803) (Fig. 3 ). DISCUSSION Our study is the largest clinical study investigating the treatment outcomes of DLBCL with standard R-CHOP(-like) immunochemotherapy regimens in Singapore to date. Survival outcomes in our study cohort are largely similar to existing major trial data for DLBCL treated with R-CHOP(-like) immunochemotherapy regimens. The LNH-98.5 trial reported a 10-year PFS of 36.5% in R-CHOP treated DLBCL 19 , while a retrospective Sweden study showed a 5-year OS of 65.3% in curative-intent DLBCL patients 20 . Our study also is in keeping with current consensus that up to 40% patients relapse or are refractory to first-line therapy 21 . Current literature is still unclear on the optimal immunochemotherapy regimen for double-expressor and high-grade DLBCLs with MYC translocations or double-hit/triple-hit genetics. While Dodero et al. suggest that EPOCH-R over RCHOP significantly improves 2-year PFS in younger DLBCL patents < 65 years 22 , the landmark Phase III Alliance/CALGB 50303 study revealed that EPOCH-R had higher toxicity and did not improve either OR or PFS as compared to R-CHOP 23 . A systemic review and meta-analysis in 2015 found that EPOCH-R first-line treatment significantly reduced progression risk as compared to R-CHOP in double-hit lymphomas 24 , while a later prospective study showed that EPOCH-R yielded a good 48-month event-free survival (EFS) of 71.6% and OS of 70.7% 25 . However, a recent large retrospective study showed that there was no difference in 4-year OS between R-CHOP and EPOCH-R treated high-grade DLBCLs 26 . In our study, intensification of treatment regimen with EPOCH-R in MYC rearranged or double hit ( MYC/BCL2 ) DLBCL did not significantly change treatment outcomes. However, this finding is limited by the relatively small number of such patients in our study and lack of both R-CHOP and EPOCH-R dosing information. Overall results suggest the potential survival benefit of EPOCH-R over R-CHOP in double-hit and high-grade DLBCLs remains controversial and to be further resolved. Due to the high rate of relapsed/refractory DLBCLs after first-line chemoimmunotherapy and the mediocre outcomes of regimen intensification in high risk DLBCLs, novel therapeutics for all DLBCL entities are sorely warranted. The main limitation of our study is its retrospective design and its resultant lack of specific clinicopathological information and loss to follow up of some cases. However, our study involves the largest cohort of DLBCLs treated with R-CHOP(-like) regimens to date in Singapore with comprehensive coverage of both demographical and clinicopathological factors in survival outcome analysis. In conclusion, our study showcases the real-world outcomes of DLBCL treated with frontline R-CHOP(-like) regimens in an Asian multi-ethnic population, which is similar to global outcomes. We thus highlight the crucial need for improved therapeutic strategies for DLBCL, especially for high-risk cases. Declarations COMPETING FINANCIAL INTERESTS STATEMENT All authors declare no competing financial interests. Author Contribution RML and JYC analysed the data and drafted the manuscript; JYT, YHT, ZEH, LCN, FLL, YTG, STL obtained patient data; RML and JYC designed the study, interpreted the results, and revised the manuscript; and all authors read and approved the final version of the manuscript. ACKNOWLEDGEMENTS This work was supported by the Tanoto Foundation Professorship in Medical Oncology, New Century Foundation Limited, Ling Foundation, Singapore Ministry of Health’s National Medical Research Council Research Transition Award (TA21jun-0005), Large Collaborative Grant (OFLCG18May-0028), and TETRAD II Collaborative Centre Grant (CG21APR2002) as well as the SingHealth Duke-NUS AM/ACP-Designated Philanthropic Fund Grant Award (08/FY2023/EX/27-A65). We would like to thank all subjects who have participated in this study. 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Leukemia 2015 29:7 . ;29(7):1578–1586. 10.1038/leu.2015.48 Tilly H, Morschhauser F, Sehn LH et al (2022) Polatuzumab Vedotin in Previously Untreated Diffuse Large B-Cell Lymphoma. N Engl J Med 386(4):351–363. 10.1056/NEJMOA2115304/SUPPL_FILE . /NEJMOA2115304_DATA-SHARING.PDF Overview | Polatuzumab vedotin in combination for untreated diffuse large B-cell lymphoma | Guidance | NICE FDA approves polatuzumab vedotin-piiq for previously untreated diffuse large B-cell lymphoma, not otherwise specified, and high-grade B-cell lymphoma | FDA. Accessed May 22 (2024) https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-polatuzumab-vedotin-piiq-previously-untreated-diffuse-large-b-cell-lymphoma-not Driving Better Decision-Making in Healthcare Polatuzumab vedotin for previously untreated diffuse large B-cell lymphoma Technology Guidance from the MOH Drug Advisory Committee Guidance Recommendations Technology Guidance. Published online 2024. Chan JY, Somasundaram N, Grigoropoulos N et al (2023) Evolving therapeutic landscape of diffuse large B-cell lymphoma: challenges and aspirations. Discover Oncol 14(1). 10.1007/S12672-023-00754-8 Tan D, Chan JY, Wudhikarn K et al (2024) Unmet needs in the first-line treatment of diffuse large B-cell lymphoma: Expert recommendations from the Asia-Pacific region with a focus on the challenging subtypes. Clin Lymphoma Myeloma Leuk Published online May 20. 10.1016/J.CLML.2024.05.013 Ngo L, Hee SW, Lim LC et al (2008) Prognostic factors in patients with diffuse large B cell lymphoma: Before and after the introduction of rituximab. Leuk Lymphoma 49(3):462–469. 10.1080/10428190701809156 Hans CP, Weisenburger DD, Greiner TC et al (2004) Confirmation of the molecular classification of diffuse large B-cell lymphoma by immunohistochemistry using a tissue microarray. Blood 103(1):275–282. 10.1182/BLOOD-2003-05-1545 Coiffier B, Thieblemont C, Van Den Neste E et al (2010) Long-term outcome of patients in the LNH-98.5 trial, the first randomized study comparing rituximab-CHOP to standard CHOP chemotherapy in DLBCL patients: a study by the Groupe d’Etudes des Lymphomes de l’Adulte. Blood 116(12):2040. 10.1182/BLOOD-2010-03-276246 Harrysson S, Eloranta S, Ekberg S et al (2021) Incidence of relapsed/refractory diffuse large B-cell lymphoma (DLBCL) including CNS relapse in a population-based cohort of 4243 patients in Sweden. Blood Cancer J 11(1):9. 10.1038/S41408-020-00403-1 Coiffier B, Sarkozy C (2016) Diffuse large B-cell lymphoma: R-CHOP failure—what to do? Hematology: Am Soc Hematol Educ Program 2016(1):366. 10.1182/ASHEDUCATION-2016.1.366 Dodero A, Guidetti A, Tucci A et al (2019) Dose-adjusted EPOCH plus rituximab improves the clinical outcome of young patients affected by double expressor diffuse large B-cell lymphoma. Leukemia 2019 33:4 . ;33(4):1047–1051. 10.1038/s41375-018-0320-9 Bartlett NL, Wilson WH, Jung SH, Dose-Adjusted EPOCH-R, Compared With et al (2019) R-CHOP as Frontline Therapy for Diffuse Large B-Cell Lymphoma: Clinical Outcomes of the Phase III Intergroup Trial Alliance/CALGB 50303. J Clin Oncol 37(21):1790–1799. 10.1200/JCO.18.01994 Howlett C, Snedecor SJ, Landsburg DJ et al (2015) Front-line, dose-escalated immunochemotherapy is associated with a significant progression-free survival advantage in patients with double-hit lymphomas: a systematic review and meta-analysis. Br J Haematol 170(4):504–514. 10.1111/BJH.13463 Dunleavy K, Fanale MA, Abramson JS et al (2018) A Prospective Multicenter Phase 2 Study of Dose-Adjusted-EPOCH-R in Untreated MYC-Rearranged Aggressive B-cell Lymphoma. Lancet Haematol 5(12):e609. 10.1016/S2352-3026(18)30177-7 Magnusson T, Narkhede M, Mehta A et al (2021) No difference in overall survival between R-CHOP and R-EPOCH among patients with advanced stage MYC-rearranged, double hit, or triple hit diffuse large B-cell lymphoma. Abstract #S224. Presented at the EHA2021 Virtual Congress, June 9–17 Additional Declarations No competing interests reported. Cite Share Download PDF Status: Published Journal Publication published 15 Nov, 2024 Read the published version in Annals of Hematology → Version 1 posted Editorial decision: Revision requested 30 Aug, 2024 Reviews received at journal 20 Aug, 2024 Reviews received at journal 18 Aug, 2024 Reviews received at journal 13 Aug, 2024 Reviewers agreed at journal 12 Aug, 2024 Reviewers agreed at journal 12 Aug, 2024 Reviewers agreed at journal 10 Aug, 2024 Reviewers agreed at journal 10 Aug, 2024 Reviewers agreed at journal 10 Aug, 2024 Reviewers invited by journal 10 Aug, 2024 Editor assigned by journal 06 Aug, 2024 Submission checks completed at journal 06 Aug, 2024 First submitted to journal 03 Aug, 2024 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-4855200","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":342791515,"identity":"1afaf3ef-9dd3-43b6-b55b-fbc0a0ba4347","order_by":0,"name":"Ryan Lim","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA70lEQVRIiWNgGAWjYNCCAgkGeWbmg4/BHGbmBiK0GEgwGLa3JRsDWUAtjERpAeIzZ8ykISwCWsxnJD97wGBgEc04I8esuqDiTzR/O1DLj4ptOLXI3EgzNwA6LLddIq3s9owzBrkzDjM2MPacuY1Ti4REgpkESEvjjORtt3nbDHIbgFqYGdvwaUn/BtbScCPBrBikZT5hLTkQWxrOHDFjBmnZQFALz5sysJaNwECW5jljnLsRqOUgXr+wp2+TYKioy50PjMrPPBVyufPOHz744EcFbi0MAgkMzH/QBQ/gVg8E/PilR8EoGAWjYBQwMAAAy/tTAi/I2gIAAAAASUVORK5CYII=","orcid":"","institution":"National Cancer Centre Singapore","correspondingAuthor":true,"prefix":"","firstName":"Ryan","middleName":"","lastName":"Lim","suffix":""},{"id":342791516,"identity":"73c37802-809e-47a0-912d-7d06b26cf3fa","order_by":1,"name":"Jing Yuan Tan","email":"","orcid":"","institution":"Singapore General Hospital","correspondingAuthor":false,"prefix":"","firstName":"Jing","middleName":"Yuan","lastName":"Tan","suffix":""},{"id":342791517,"identity":"10133fc1-2a7c-4f61-8b68-e693445f3c8a","order_by":2,"name":"Ya Hwee Tan","email":"","orcid":"","institution":"National Cancer Centre Singapore","correspondingAuthor":false,"prefix":"","firstName":"Ya","middleName":"Hwee","lastName":"Tan","suffix":""},{"id":342791518,"identity":"0138b856-d7a0-4080-97cb-16dedb1fd5b9","order_by":3,"name":"Zane En Qi Heng","email":"","orcid":"","institution":"National University of Singapore","correspondingAuthor":false,"prefix":"","firstName":"Zane","middleName":"En Qi","lastName":"Heng","suffix":""},{"id":342791519,"identity":"8c336a3c-c3ab-4b4c-b6a8-cbccd3d67fb0","order_by":4,"name":"Lawrence Cheng Kiat Ng","email":"","orcid":"","institution":"Singapore General Hospital","correspondingAuthor":false,"prefix":"","firstName":"Lawrence","middleName":"Cheng Kiat","lastName":"Ng","suffix":""},{"id":342791520,"identity":"fd5fe8eb-18e8-4cb9-9ccc-31d1483b1193","order_by":5,"name":"Francesca Lorraine Wei Inng Lim","email":"","orcid":"","institution":"Singapore General Hospital","correspondingAuthor":false,"prefix":"","firstName":"Francesca","middleName":"Lorraine Wei Inng","lastName":"Lim","suffix":""},{"id":342791521,"identity":"96614a5c-23d4-4ce2-a2c9-5bfad35f44ea","order_by":6,"name":"Yeow Tee Goh","email":"","orcid":"","institution":"Singapore General Hospital","correspondingAuthor":false,"prefix":"","firstName":"Yeow","middleName":"Tee","lastName":"Goh","suffix":""},{"id":342791522,"identity":"d887472e-cc73-4c76-a7bb-f673edf33ae0","order_by":7,"name":"Soon Thye Lim","email":"","orcid":"","institution":"National Cancer Centre Singapore","correspondingAuthor":false,"prefix":"","firstName":"Soon","middleName":"Thye","lastName":"Lim","suffix":""},{"id":342791523,"identity":"fe5cc351-4f30-49b6-b342-59ddf4abf37e","order_by":8,"name":"Jason Yongsheng Chan","email":"","orcid":"","institution":"National Cancer Centre Singapore","correspondingAuthor":false,"prefix":"","firstName":"Jason","middleName":"Yongsheng","lastName":"Chan","suffix":""}],"badges":[],"createdAt":"2024-08-04 03:23:42","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-4855200/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-4855200/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1007/s00277-024-06067-2","type":"published","date":"2024-11-15T15:57:52+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":64277944,"identity":"87f355bb-4333-4eba-a98c-b2535e2adfa6","added_by":"auto","created_at":"2024-09-11 07:01:01","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":498599,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eSurvival outcomes for RCHOP and EPOCH-R treated cohort. a) OS and b) PFS in overall cohort. c) OS and d) PFS in intermediate to high-risk sub-cohort (IPI scores 2-5).\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"Figure1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-4855200/v1/a63c8555ae19668cccc5306c.jpg"},{"id":64277942,"identity":"8196b620-16a2-4d76-9eb9-5ef0eb34bbd7","added_by":"auto","created_at":"2024-09-11 07:01:01","extension":"jpg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":244229,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eSurvival outcomes represented by OS in a) \u003c/strong\u003e\u003cem\u003e\u003cstrong\u003eMYC\u003c/strong\u003e\u003c/em\u003e\u003cstrong\u003ere-rearranged and b) \u003c/strong\u003e\u003cem\u003e\u003cstrong\u003eMYC/BCL2\u003c/strong\u003e\u003c/em\u003e\u003cstrong\u003e double-hit DLBCL.\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"Figure2.jpg","url":"https://assets-eu.researchsquare.com/files/rs-4855200/v1/cdd89167618a31ada38cef15.jpg"},{"id":64277945,"identity":"1db4d6f2-7433-4a79-a4c8-911f944f4dce","added_by":"auto","created_at":"2024-09-11 07:01:01","extension":"jpg","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":260162,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eKaplan-Meier Survival Analysis. There was no statistically significant difference in OS between R-CHOP vs EPOCH-R in (a) \u003c/strong\u003e\u003cem\u003e\u003cstrong\u003eMYC\u003c/strong\u003e\u003c/em\u003e\u003cstrong\u003e re-arranged and b) \u003c/strong\u003e\u003cem\u003e\u003cstrong\u003eMYC/BCL2\u003c/strong\u003e\u003c/em\u003e\u003cstrong\u003edouble-hit DLBCL.\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"Figure3.jpg","url":"https://assets-eu.researchsquare.com/files/rs-4855200/v1/0a44ec92e4738b05eed3a7c7.jpg"},{"id":69284790,"identity":"2277b59f-4be7-473b-9737-72c22dbd07bb","added_by":"auto","created_at":"2024-11-18 19:22:35","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":2383365,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4855200/v1/5096c394-f0f4-4d66-be25-16e0fef7e504.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Real-world Outcomes of Diffuse Large B-cell Lymphoma Treated with frontline R-CHOP(-like) regimens in an Asian Multi-ethnic Population","fulltext":[{"header":"INTRODUCTION","content":"\u003cp\u003eDiffuse Large B-Cell Lymphoma (DLBCL) is the most common type of Non-Hodgkin\u0026rsquo;s Lymphoma (NHL). It is very aggressive but responds favourably to chemotherapy. Rituximab, Cyclophosphamide, Doxorubicin, Vincristine and prednisolone (R-CHOP) has been the standard of care treatment regimen for DLBCL\u003csup\u003e1\u003c/sup\u003e since the early 2000s. As compared to CHOP therapy, R-CHOP provided significantly higher rates of complete response (CR) and longer overall survival (OS) durations in both the elderly population\u003csup\u003e2\u003c/sup\u003e and younger patients\u003csup\u003e3\u003c/sup\u003e. The MabThera International Trial (MInT) Group showed that 6 cycles of R-CHOP therapy improved 6-year event-free survival (EFS) to 74.3% as compared to 55.8% for the CHOP group and 6-year OS to 90.1% from 80.0%\u003csup\u003e4\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eFollowing the inclusion of anti-CD20 monoclonal antibody Rituximab to first-line therapy in DLBCL, there has been limited success in attempts made to improve upon this treatment regimen, with candidate drugs often failing to show benefit in phase III trials or causing an unacceptable increase in toxicity. Dose-intensified Rituximab, Doxorubicin, Cyclophosphamide, Vindesine, Bleomycin and Prednisolone (R-ACVBP) was shown to improve PFS and OS in patients aged 15\u0026ndash;59 years, but was eventually not prescribed widely due to its high incidence of haematological toxic effects and limited applicability.\u003csup\u003e5\u003c/sup\u003e Other treatment options such as consolidation therapy with high-dose chemotherapy and autologous stem cell transplantation (ASCT) improved treatment response and progression-free survival (PFS), but did not result in prolonged OS\u003csup\u003e6,7\u003c/sup\u003e. Consequently, the survival outcomes in DLBCL improved only modestly during the rituximab era, demonstrating the limited efficacy of those novel therapeutics over the current standard of care\u003csup\u003e8\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003ePolatuzumab vedotin is an antibody-drug conjugate (ADC) directed at CD79b, a part of the heterodimeric signalling component of B-cell NHLs. It demonstrated good efficacy against NHL and DLBCL in initial in vivo and early clinical trials\u003csup\u003e9,10\u003c/sup\u003e. In 2023, a double-blind, placebo-controlled phase 3 trial showed that Polatuzumab vedotin in combination with Rituximab, Cyclophosphamide, Doxorubicin and Prednisolone (pola-R-CHP) improved PFS in the overall cohort over R-CHOP in patients with previously untreated intermediate- to high-risk DLBCL (IPI 2\u0026ndash;5)\u003csup\u003e11\u003c/sup\u003e. Even though the OS data was considered to be immature and did not differ between both arms, the significant survival benefit from PFS prolongation paired with its acceptable side-effect profile and reasonable cost earned Polatuzumab vedotin health regulatory approvals in the UK\u003csup\u003e12\u003c/sup\u003e, US\u003csup\u003e13\u003c/sup\u003e and Singapore\u003csup\u003e14\u003c/sup\u003e for use in previously untreated DLBCL with International Prognostic Index (IPI) of 2\u0026ndash;5.\u003c/p\u003e \u003cp\u003eIn Singapore, a country with a diverse multi-ethnic population, the first-line treatment for DLBCL is that of six 21-day cycles of R-CHOP immunochemotherapy\u003csup\u003e15\u003c/sup\u003e, in line with global guidelines\u003csup\u003e16\u003c/sup\u003e. The efficacy of R-CHOP over CHOP in our patient population is supported by the last large-scale Singapore DLBCL study done in 2008 showing a significantly higher 2-year survival of R-CHOP compared to CHOP alone (85.6% vs 64.7%)\u003csup\u003e17\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003e Given this recent breakthrough of Polatuzumab vedotin in the treatment of previously untreated DLBCL, we sought to review the current efficacy of the current standard-of-care treatment regimens for DLBCL in Singapore. Through this, we confirm the unmet clinical need of novel effective therapeutics in the treatment of DLBCL in our local population in a real-world setting.\u003c/p\u003e"},{"header":"PATIENTS AND METHODS","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eStudy cohort\u003c/h2\u003e \u003cp\u003ePatients who were diagnosed with diffuse large B-cell lymphoma (DLBCL) and seen at the National Cancer Centre Singapore and Singapore General Hospital between 2010 and 2022 were retrospectively analysed. A total of 1071 patients who were treated with rituximab-based immunochemotherapy regimens were included in the final analysis. The median follow-up duration for this group of patients was 48 months.\u003c/p\u003e \u003cp\u003eRelevant demographical and clinicopathological information were collected and summarised for the analysis. Demographical information available included sex, age and ethnicity. Clinical characteristics of each patient including B-symptoms, Eastern Cooperative Oncology Group (ECOG) performance status, disease stage, number of extranodal site involvement, chemotherapeutic regimen used and survival outcomes were included in the study. Finally, pathological information such as immunohistochemical markers (BCL2, BCL6, CD10, MUM1, MYC), gene rearrangements (\u003cem\u003eBCL2\u003c/em\u003e, \u003cem\u003eBCL6\u003c/em\u003e, \u003cem\u003eMYC\u003c/em\u003e), and DLBCL cell-of-origin by Han\u0026rsquo;s algorithm\u003csup\u003e18\u003c/sup\u003e were included in the analysis. All data was obtained at the time of diagnosis or subsequent follow-up.\u003c/p\u003e \u003cp\u003e The research study was carried out with approval from the SingHealth Centralised Institutional Review Board. Informed consent for the use of biospecimens was obtained in accordance with the Declaration of Helsinki and all methods were carried out in accordance with relevant guidelines and regulations. All data was obtained at the time of diagnosis or subsequent follow-up. Participants and/or their legal guardians provided informed consent for their data to be used in this research. The datasets created and analysed during this study are available from the corresponding authors upon reasonable request.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003eStatistical Analysis\u003c/h2\u003e \u003cp\u003eThe outcomes of interest in this study are progression-free survival (PFS) and overall survival (OS). PFS was defined as the time elapsed between the date of diagnosis to the date of relapse, progression, or death from any cause. OS was calculated from the date of diagnosis up to the date of death from any cause, or was censored at the date of last follow-up for survivors. For each individual clinicopathological parameter, Kaplan-Meier survival curves were plotted to estimate survival. The log-rank test was then used to determine hazard ratio (HR), the corresponding 95% confidence intervals of mortality and the p-values for each individual clinicopathological parameter. Parameters found to be significant on univariate analysis using a two-sided test with significance level of 0.05 were identified. These parameters were then used in the generation of Multivariate Cox regression models via a backwards procedure to test for independence of significant parameters for PFS and OS.\u003c/p\u003e \u003cp\u003e \u003cem\u003eMYC\u003c/em\u003e rearrangement and double-hit DLBCL were tested for association with choice of chemoimmunotherapy regimen with the chi-squared test. Kaplan-Meier survival curves were then plotted for R-CHOP vs EPOCH-R in patients with \u003cem\u003eMYC\u003c/em\u003e rearrangement and double-hit DLBCL. All tests were performed using MedCalc statistical Software for Windows version 19.0.4 (MedCalc Software, Ostend, Belgium).\u003c/p\u003e \u003c/div\u003e"},{"header":"RESULTS","content":"\u003cdiv id=\"Sec6\" class=\"Section2\"\u003e \u003ch2\u003ePatient demographics and clinicopathological characteristics\u003c/h2\u003e \u003cp\u003eThe overall cohort consisted of 590 male and 481 female patients with a median age of 63.8 years (range, 19.3\u0026ndash;93.6). Most were stage III-IV (60.9%) and of non-germinal center B-cell like (non-GCB) subtype by Han\u0026rsquo;s criteria (56.5%). Clinical and demographic characteristics of the whole study cohort are summarised in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eClinical and pathological characteristics of the overall cohort, n\u0026thinsp;=\u0026thinsp;1071\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"3\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCharacteristic\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003en (%)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"1\" nameend=\"c3\" namest=\"c3\"\u003e\u0026nbsp;\u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eTotal\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1071 (100%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"1\" nameend=\"c3\" namest=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003eSex\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"1\" nameend=\"c3\" namest=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eMale\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e590 (55.1%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"1\" nameend=\"c3\" namest=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eFemale\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e481 (44.9%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"1\" nameend=\"c3\" namest=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003eAge\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"1\" nameend=\"c3\" namest=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003e\u0026le; 60\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e415 (38.7%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"1\" nameend=\"c3\" namest=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003e\u0026gt; 60\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e656 (61.3%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"1\" nameend=\"c3\" namest=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003eEthnicity\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"1\" nameend=\"c3\" namest=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eChinese\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e766 (71.5%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"1\" nameend=\"c3\" namest=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eMalay\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e177 (16.5%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"1\" nameend=\"c3\" namest=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eIndian\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e39 (3.6%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"1\" nameend=\"c3\" namest=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eOthers\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e83 (8.3%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"1\" nameend=\"c3\" namest=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003eECOG performance status\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"1\" nameend=\"c3\" namest=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003e0\u0026ndash;1\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1002 (93.6%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"1\" nameend=\"c3\" namest=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003e2\u0026ndash;4\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e69 (6.4%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"1\" nameend=\"c3\" namest=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003eStage\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"1\" nameend=\"c3\" namest=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eI-II\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e416 (39.1%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"1\" nameend=\"c3\" namest=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eIII-IV\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e649 (60.9%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"1\" nameend=\"c3\" namest=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003eB-Symptoms\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"1\" nameend=\"c3\" namest=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003ePresent\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e315 (29.4%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"1\" nameend=\"c3\" namest=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eAbsent\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e756 (70.6%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"1\" nameend=\"c3\" namest=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003eLDH\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"1\" nameend=\"c3\" namest=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eRaised\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e830 (77.5%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"1\" nameend=\"c3\" namest=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eNot raised\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e241 (22.5%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"1\" nameend=\"c3\" namest=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003eExtranodal sites\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"1\" nameend=\"c3\" namest=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003e\u0026gt;1\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e284 (26.5%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"1\" nameend=\"c3\" namest=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003e\u0026le;1\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e787 (73.5%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"1\" nameend=\"c3\" namest=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003eIPI\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"1\" nameend=\"c3\" namest=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003e0\u0026ndash;1\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e255 (23.8%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"1\" nameend=\"c3\" namest=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003e2\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e343 (32.0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"1\" nameend=\"c3\" namest=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003e3\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e301 (28.1%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"1\" nameend=\"c3\" namest=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003e4\u0026ndash;5\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e172 (16.1%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"1\" nameend=\"c3\" namest=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003eCell of Origin\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"1\" nameend=\"c3\" namest=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eGCB\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e423 (43.5%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"1\" nameend=\"c3\" namest=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eNon-GCB\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e549 (56.5%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"1\" nameend=\"c3\" namest=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003eHIV status\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"1\" nameend=\"c3\" namest=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003ePositive\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e20 (1.9%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"1\" nameend=\"c3\" namest=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eNegative\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1009 (98.1%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"1\" nameend=\"c3\" namest=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c3\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003eHBsAg\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003ePositive\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e78 (7.8%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003eNegative\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e919 (92.2%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c3\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003eAnti-HBc Total\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003ePositive\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e320 (31.9%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003eNegative\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e683 (68.1%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c3\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003eHCV status\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003ePositive\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e20 (1.9%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003eNegative\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1011 (98.1%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c3\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003eMYC/BCL2 double expressor\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003eYes\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e157 (40.6%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003eNo\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e230 (59.4%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c3\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003eMYC\u003c/b\u003e \u003cb\u003erearrangement\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003ePresent\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e86 (19.6%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003eAbsent\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e353 (80.4%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c3\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003eBoth MYC and BCL2 rearrangement\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003ePresent\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e32 (7.2%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003eAbsent\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e412 (92.8%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c3\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003eBoth MYC and BCL6 rearrangement\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003ePresent\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e18 (4.1%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003eAbsent\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e424 (95.9%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c3\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003eEBER\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003ePositive\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e32 (6.3%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003eNegative\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e476 (93.7%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"3\"\u003e*Missing data: Stage (n\u0026thinsp;=\u0026thinsp;6), COO (n\u0026thinsp;=\u0026thinsp;99), HIV status (n\u0026thinsp;=\u0026thinsp;42), HBsAg (n\u0026thinsp;=\u0026thinsp;74), Anti-HBc Total (n\u0026thinsp;=\u0026thinsp;68), HCV status (n\u0026thinsp;=\u0026thinsp;40), MYC/BCL2 double expressor (n\u0026thinsp;=\u0026thinsp;684), MYC rearrangement (n\u0026thinsp;=\u0026thinsp;632), MYC/BCL2 rearrangement (n\u0026thinsp;=\u0026thinsp;627), MYC/BCL6 rearrangement (n\u0026thinsp;=\u0026thinsp;629), EBER status (n\u0026thinsp;=\u0026thinsp;563)\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eThe vast majority of the patient cohort received R-CHOP(-like) regimens (n\u0026thinsp;=\u0026thinsp;997, 93.1%), including MR-CHOP (n\u0026thinsp;=\u0026thinsp;78) and EPOCH-R (n\u0026thinsp;=\u0026thinsp;95). This sub-cohort consisted of 544 males and 453 females, of which most were also stage III/IV (60.6%) and of non-germinal center B-cell like (non-GCB) subtype by Han\u0026rsquo;s criteria (56.1%). Clinical and demographic characteristics of the sub-cohort that received R-CHOP(-like) regimens are summarised in Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eClinical and pathological characteristics of patients treated with R-CHOP(-like) regimens, n\u0026thinsp;=\u0026thinsp;997\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"3\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCharacteristic\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003en (%)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"1\" nameend=\"c3\" namest=\"c3\"\u003e\u0026nbsp;\u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eTotal\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e997 (100%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"1\" nameend=\"c3\" namest=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003eSex\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"1\" nameend=\"c3\" namest=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eMale\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e544 (54.6%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"1\" nameend=\"c3\" namest=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eFemale\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e453 (45.4%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"1\" nameend=\"c3\" namest=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003eAge\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"1\" nameend=\"c3\" namest=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003e\u0026lt; 60\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e597 (59.9%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"1\" nameend=\"c3\" namest=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003e\u0026ge; 60\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e400 (40.1%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"1\" nameend=\"c3\" namest=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003eEthnicity\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"1\" nameend=\"c3\" namest=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eChinese\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e719 (72.1%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"1\" nameend=\"c3\" namest=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eMalay\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e159 (15.9%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"1\" nameend=\"c3\" namest=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eIndian\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e36 (3.6%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"1\" nameend=\"c3\" namest=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eOthers\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e83 (8.3%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"1\" nameend=\"c3\" namest=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003eECOG performance status\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"1\" nameend=\"c3\" namest=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003e0\u0026ndash;1\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e938 (94.1%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"1\" nameend=\"c3\" namest=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003e2\u0026ndash;4\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e59 (5.9%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"1\" nameend=\"c3\" namest=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003eStage\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"1\" nameend=\"c3\" namest=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eI-II\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e391 (39.4%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"1\" nameend=\"c3\" namest=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eIII-IV\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e602 (60.6%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"1\" nameend=\"c3\" namest=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003eB-Symptoms\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"1\" nameend=\"c3\" namest=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003ePresent\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e292 (29.3%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"1\" nameend=\"c3\" namest=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eAbsent\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e705 (70.7%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"1\" nameend=\"c3\" namest=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003eLDH\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"1\" nameend=\"c3\" namest=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eRaised\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e771 (77.3%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"1\" nameend=\"c3\" namest=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eNot raised\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e226 (22.7%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"1\" nameend=\"c3\" namest=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003eExtranodal sites\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"1\" nameend=\"c3\" namest=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003e\u0026gt;1\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e262 (26.3%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"1\" nameend=\"c3\" namest=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003e\u0026le;1\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e735 (73.7%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"1\" nameend=\"c3\" namest=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003eIPI\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"1\" nameend=\"c3\" namest=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003e0\u0026ndash;1\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e245 (24.6%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"1\" nameend=\"c3\" namest=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003e2\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e319 (32.0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"1\" nameend=\"c3\" namest=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003e3\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e279 (28.0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"1\" nameend=\"c3\" namest=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003e4\u0026ndash;5\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e154 (15.4%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"1\" nameend=\"c3\" namest=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003eCell of Origin\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"1\" nameend=\"c3\" namest=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eGCB\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e398 (43.9%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"1\" nameend=\"c3\" namest=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eNon-GCB\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e509 (56.1%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"1\" nameend=\"c3\" namest=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003eHIV status\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"1\" nameend=\"c3\" namest=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003ePositive\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e19 (2.0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"1\" nameend=\"c3\" namest=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eNegative\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e940 (98.0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"1\" nameend=\"c3\" namest=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c3\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003eHBsAg\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003ePositive\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e76 (8.2%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003eNegative\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e853 (91.8%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c3\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003eAnti-HBc Total\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003ePositive\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e306 (32.7%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003eNegative\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e630 (67.3%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c3\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003eHCV status\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003ePositive\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e20 (2.1%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003eNegative\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e942 (97.9%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c3\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003eMYC/BCL2 double expressor\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003eYes\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e146 (40.4%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003eNo\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e215 (59.6%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c3\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003eMYC\u003c/b\u003e \u003cb\u003erearrangement\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003ePresent\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e82 (19.9%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003eAbsent\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e330 (80.1%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c3\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003eBoth MYC and BCL2 rearrangement\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003ePresent\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e31 (7.4%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003eAbsent\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e386 (92.6%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c3\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003eBoth MYC and BCL6 rearrangement\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003ePresent\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e17 (4.1%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003eAbsent\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e398 (95.9%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c3\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003eEBER\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003ePositive\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e30 (6.4%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003eNegative\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e439 (93.6%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"3\"\u003e*Missing data: Stage (n\u0026thinsp;=\u0026thinsp;4), COO (n\u0026thinsp;=\u0026thinsp;90), HIV status (n\u0026thinsp;=\u0026thinsp;38), HBsAg (n\u0026thinsp;=\u0026thinsp;68), Anti-HBc Total (n\u0026thinsp;=\u0026thinsp;61), HCV status (n\u0026thinsp;=\u0026thinsp;35), MYC/BCL2 double expressor (n\u0026thinsp;=\u0026thinsp;636), MYC rearrangement (n\u0026thinsp;=\u0026thinsp;585), MYC/BCL2 rearrangement (n\u0026thinsp;=\u0026thinsp;580), MYC/BCL6 rearrangement (n\u0026thinsp;=\u0026thinsp;582), EBER status (n\u0026thinsp;=\u0026thinsp;528)\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec7\" class=\"Section2\"\u003e \u003ch2\u003eMolecular pathological characteristics\u003c/h2\u003e \u003cp\u003eFor the overall patient cohort, fluorescence in-situ hybridization in a subgroup with available data revealed that \u003cem\u003eMYC\u003c/em\u003e rearrangement was present in 86/439 (19.6%) cases, double-hit DLBCL with both \u003cem\u003eMYC\u003c/em\u003e and \u003cem\u003eBCL2\u003c/em\u003e rearrangement was found in 32/444 (7.2%) cases and double-hit DLBCL with both \u003cem\u003eMYC\u003c/em\u003e and \u003cem\u003eBCL6\u003c/em\u003e rearrangement was detected in 18/444 (4.1%) cases. MYC/BCL2 double expressor status was present in 157/387 (40.6%) cases. In another subgroup with available data, Epstein-Barr virus was positive in 32/508 (6.3%) cases.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003eSurvival analyses\u003c/h2\u003e \u003cp\u003eThe patient sub-cohort that received R-CHOP(-like) regimens achieved a 5-year progression-free survival (PFS) and overall survival (OS) of 64.5% and 74.7% respectively (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). At the point of data analysis, 274 patients (27.5%) had died. Further analysis will be performed in this sub-cohort of patients treated with R-CHOP(-like) regimens.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eUnivariate analysis for OS revealed that male sex (HR 1.39, 95% CI 1.13\u0026ndash;1.70, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.0020), age\u0026thinsp;\u0026gt;\u0026thinsp;60 (HR 1.53, 95% CI 1.24\u0026ndash;1.89, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.0001), ECOG performance status\u0026thinsp;\u0026ge;\u0026thinsp;2 (HR 3.90, 95% CI 2.36\u0026ndash;6.42, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;\u0026lt;\u0026thinsp;0.0001), Stage III or IV (HR 2.33, 95% CI 1.89\u0026ndash;2.87, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;\u0026lt;\u0026thinsp;0.0001), presence of B-symptoms (HR 1.51, 95% CI 1.20\u0026ndash;1.91, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.0004), raised LDH (HR 1.62, 95% CI 1.28\u0026ndash;2.07, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.0001), non-GCB cell of origin by Han\u0026rsquo;s algorithm (HR 1.40, 95% CI 1.12\u0026ndash;1.74, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.0029) and MYC/BCL2 double expressor status (HR 1.62, 95% CI 1.15\u0026ndash;2.29, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.0059) were all predictors for worse PFS (Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab3\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eUnivariable analysis for OS and PFS for patients treated with R-CHOP(-like) regimens, n\u0026thinsp;=\u0026thinsp;997\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"7\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colspan=\"3\" nameend=\"c4\" namest=\"c2\"\u003e \u003cp\u003eOverall survival\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"3\" nameend=\"c7\" namest=\"c5\"\u003e \u003cp\u003eProgression-free survival\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCharacteristic\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eHR\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003e95% CI\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cem\u003ep\u003c/em\u003e-value\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eHR\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003e95% CI\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c7\"\u003e \u003cp\u003e\u003cem\u003ep\u003c/em\u003e-value\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eSex \u003c/b\u003e\u003c/p\u003e \u003cp\u003e\u003cb\u003e(Male vs Female)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.38\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1.09\u0026ndash;1.75\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003e0.0084\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1.39\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e1.13\u0026ndash;1.70\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e\u003cb\u003e0.0020\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eAge\u003c/b\u003e\u003c/p\u003e \u003cp\u003e\u003cb\u003e(\u0026gt;\u0026thinsp;60 vs\u0026thinsp;\u0026le;\u0026thinsp;60)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2.11\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1.66\u0026ndash;2.69\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003e\u0026lt;\u0026thinsp;0.0001\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1.53\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e1.24\u0026ndash;1.89\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e\u003cb\u003e0.0001\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eECOG Performance Status\u003c/b\u003e\u003c/p\u003e \u003cp\u003e\u003cb\u003e(2\u0026ndash;4 vs 0\u0026ndash;1)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e4.73\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2.68\u0026ndash;8.34\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003e\u0026lt;\u0026thinsp;0.0001\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e3.90\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e2.36\u0026ndash;6.42\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e\u003cb\u003e\u0026lt;\u0026thinsp;0.0001\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eStage\u003c/b\u003e\u003c/p\u003e \u003cp\u003e\u003cb\u003e(III-IV vs I-II)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2.15\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1.69\u0026ndash;2.74\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003e\u0026lt;\u0026thinsp;0.0001\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e2.33\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e1.89\u0026ndash;2.87\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e\u003cb\u003e\u0026lt;\u0026thinsp;0.0001\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eB-Symptoms\u003c/b\u003e\u003c/p\u003e \u003cp\u003e\u003cb\u003e(Present vs Absent)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.67\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1.28\u0026ndash;2.17\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003e0.0001\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1.51\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e1.20\u0026ndash;1.91\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e\u003cb\u003e0.0004\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eLDH\u003c/b\u003e\u003c/p\u003e \u003cp\u003e\u003cb\u003e(Raised vs Not Raised)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.87\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1.42\u0026ndash;2.46\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003e\u0026lt;\u0026thinsp;0.0001\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1.62\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e1.28\u0026ndash;2.07\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e\u003cb\u003e0.0001\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eExtranodal sites\u003c/b\u003e\u003c/p\u003e \u003cp\u003e\u003cb\u003e(\u0026gt;\u0026thinsp;1 vs\u0026thinsp;\u0026le;\u0026thinsp;1)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.87\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1.41\u0026ndash;2.47\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003e\u0026lt;\u0026thinsp;0.0001\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1.62\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e1.27\u0026ndash;2.07\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e\u003cb\u003e0.0001\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eIPI Risk Groups\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003e\u0026lt;\u0026thinsp;0.0001\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e\u003cb\u003e\u0026lt;\u0026thinsp;0.0001\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eCell Of Origin\u003c/b\u003e\u003c/p\u003e \u003cp\u003e\u003cb\u003e(Non-GCB vs GCB)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.31\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1.02\u0026ndash;1.69\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003e0.0328\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1.40\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e1.12\u0026ndash;1.74\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e\u003cb\u003e0.0029\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eHIVs status\u003c/b\u003e\u003c/p\u003e \u003cp\u003e\u003cb\u003e(Positive vs Negative)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.11\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.47\u0026ndash;2.59\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.8134\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.99\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.47\u0026ndash;2.98\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.9787\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eHBsAg\u003c/b\u003e\u003c/p\u003e \u003cp\u003e\u003cb\u003e(Positive vs Negative)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.28\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.81\u0026ndash;2.01\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.2896\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1.11\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.75\u0026ndash;1.65\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.5883\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eAnti-HBc Total\u003c/b\u003e\u003c/p\u003e \u003cp\u003e\u003cb\u003e(Positive vs Negative)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.21\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.93\u0026ndash;1.57\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.1513\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1.10\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.88\u0026ndash;1.39\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.3774\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eHCV Status\u003c/b\u003e\u003c/p\u003e \u003cp\u003e\u003cb\u003e(Positive vs Negative)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.87\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.38\u0026ndash;1.99\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.7434\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.93\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.45\u0026ndash;1.91\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.8376\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eMYC/BCL2 Double Expressor\u003c/b\u003e\u003c/p\u003e \u003cp\u003e\u003cb\u003e(Yes vs No)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.43\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.97\u0026ndash;2.11\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.0714\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1.62\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e1.15\u0026ndash;2.29\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e\u003cb\u003e0.0059\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eMYC\u003c/b\u003e \u003cb\u003eRearrangement\u003c/b\u003e\u003c/p\u003e \u003cp\u003e\u003cb\u003e(Present vs Absent)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.16\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.72\u0026ndash;1.85\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.5425\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1.10\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.73\u0026ndash;1.66\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.6500\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eBoth\u003c/b\u003e \u003cb\u003eMYC\u003c/b\u003e \u003cb\u003eand\u003c/b\u003e \u003cb\u003eBCL2\u003c/b\u003e \u003cb\u003eRearrangement (Present vs Absent)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.94\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.47\u0026ndash;1.90\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.8681\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1.35\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.71\u0026ndash;2.54\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.3611\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eBoth\u003c/b\u003e \u003cb\u003eMYC\u003c/b\u003e \u003cb\u003eand\u003c/b\u003e \u003cb\u003eBCL6\u003c/b\u003e \u003cb\u003eRearrangement (Present vs Absent)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.43\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.51\u0026ndash;4.03\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.4970\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1.45\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.60\u0026ndash;3.49\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.4078\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eEBER\u003c/b\u003e\u003c/p\u003e \u003cp\u003e\u003cb\u003e(Positive vs Negative)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.65\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.32\u0026ndash;1.30\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.2228\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.91\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.49\u0026ndash;1.68\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.7627\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eFor OS, male sex (HR 1.38, 95% CI 1.09\u0026ndash;1.75, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.0084), age\u0026thinsp;\u0026gt;\u0026thinsp;60 (HR 2.11, 95% CI 1.66\u0026ndash;2.69, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;\u0026lt;\u0026thinsp;0.0001), ECOG performance status\u0026thinsp;\u0026ge;\u0026thinsp;2 (HR 4.73, 95% CI 2.68\u0026ndash;8.34, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;\u0026lt;\u0026thinsp;0.0001), Stage III or IV (HR 2.15, 95% CI 1.69\u0026ndash;2.74, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;\u0026lt;\u0026thinsp;0.0001), presence of B-symptoms (HR 1.67, 95% CI 1.28\u0026ndash;2.17, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.0001), raised LDH (HR 1.87, 95% CI 1.42\u0026ndash;2.46, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;\u0026lt;\u0026thinsp;0.0001), presence of extranodal sites (HR 1.87, 95% CI 1.41\u0026ndash;2.47, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;\u0026lt;\u0026thinsp;0.0001) and non-GCB cell of origin by Han\u0026rsquo;s algorithm (HR 1.40, 95% CI 1.12\u0026ndash;1.74, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.0029) were all predictive of poorer outcomes on univariate analysis (Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eFollowing multivariate analysis of significant clinicopathological parameters, male sex (HR 1.33, 95% CI 1.03\u0026ndash;1.73, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.0294), age\u0026thinsp;\u0026gt;\u0026thinsp;60 (HR 2.35, 95% CI 1.76\u0026ndash;3.12, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.0001), ECOG performance status\u0026thinsp;\u0026ge;\u0026thinsp;3 (HR 2.27, 95% CI 1.53\u0026ndash;3.36, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.0001), Stage III-IV (HR 1.92, 95% CI 1.42\u0026ndash;2.59, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.0001), presence of B-symptoms (HR 1.34, 95% CI 1.03\u0026ndash;1.76, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.0305) and raised LDH (HR 1.58, 95% CI 1.09\u0026ndash;2.31, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.0161) were independently prognostic for worse OS (Table\u0026nbsp;\u003cspan refid=\"Tab4\" class=\"InternalRef\"\u003e4\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab4\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 4\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eMultivariable analysis for OS and PFS for patients treated with R-CHOP(-like) regimens, n\u0026thinsp;=\u0026thinsp;997\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"7\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colspan=\"3\" nameend=\"c4\" namest=\"c2\"\u003e \u003cp\u003eOverall survival\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"3\" nameend=\"c7\" namest=\"c5\"\u003e \u003cp\u003eProgression-free survival\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eParameter\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eHR\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003e95% CI\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cem\u003ep\u003c/em\u003e-value\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eHR\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003e95% CI\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c7\"\u003e \u003cp\u003e\u003cem\u003ep\u003c/em\u003e-value\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003ctr\u003e \u003cth align=\"left\" colspan=\"5\" nameend=\"c5\" namest=\"c1\"\u003e \u003cp\u003e\u003cem\u003eSex\u003c/em\u003e\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eFemale\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003e1.03\u0026ndash;1.73\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003e\u003cb\u003e0.0294\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003e1.16\u0026ndash;2.38\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003e\u003cb\u003e0.0051\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eMale\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.33\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1.67\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"5\" nameend=\"c5\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003eAge\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003e\u0026le; 60\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003e1.76\u0026ndash;3.12\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003e\u003cb\u003e\u0026lt;\u0026thinsp;0.0001\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003e1.33\u0026ndash;2.84\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003e\u003cb\u003e0.0006\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003e\u0026gt; 60\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2.35\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1.95\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"5\" nameend=\"c5\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003eECOG Performance Status\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003e0\u0026ndash;1\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003e1.53\u0026ndash;3.36\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003e\u003cb\u003e\u0026lt;\u0026thinsp;0.0001\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003e1.22\u0026ndash;3.21\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003e\u003cb\u003e0.0054\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003e2\u0026ndash;4\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2.27\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1.98\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eStage\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eI-II\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1.42\u0026ndash;2.59\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003e\u0026lt;\u0026thinsp;0.0001\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e1.28\u0026ndash;2.87\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e\u003cb\u003e0.0015\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eIII-IV\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.92\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1.92\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eB-Symptoms\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eAbsent\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1.03\u0026ndash;1.76\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003e0.0305\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.99\u0026ndash;2.06\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.0574\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003ePresent\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.34\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1.43\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eLDH\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eNot Raised\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1.09\u0026ndash;2.31\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003e0.0161\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eRaised\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.58\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eMYC/BCL2 Double Expressor\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eAbsent\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e1.02\u0026ndash;2.03\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e\u003cb\u003e0.0404\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003ePresent\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1.43\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eIn the intermediate to high-risk subgroup (IPI scores 2\u0026ndash;5; n\u0026thinsp;=\u0026thinsp;752), the 5-year OS and PFS were only 69.8% and 58.0%, respectively (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). EBV status, \u003cem\u003eMYC\u003c/em\u003e and/or \u003cem\u003eBCL2\u003c/em\u003e rearrangements were not significantly associated with survival outcomes.\u003c/p\u003e \u003cp\u003e \u003cb\u003eMYC\u003c/b\u003e \u003cb\u003erearrangement and Double-hit DLBCL\u003c/b\u003e\u003c/p\u003e \u003cp\u003eFor patients treated with R-CHOP(-like) regimens, EPOCH-R was used more frequently than R-CHOP in patients with \u003cem\u003eMYC\u003c/em\u003e rearrangements (n\u0026thinsp;=\u0026thinsp;82, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.0001), including those with \u003cem\u003eMYC/BCL2\u003c/em\u003e double-hit genetics (n\u0026thinsp;=\u0026thinsp;31, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.0001). Patients with \u003cem\u003eMYC\u003c/em\u003e rearrangements achieved a 5-year OS of 70.7%, while those with both \u003cem\u003eMYC\u003c/em\u003e and \u003cem\u003eBCL2\u003c/em\u003e rearrangements achieved a 5-year OS of 76.6% (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eNotably, neither immunochemotherapy regimen significantly affected survival outcomes, both in \u003cem\u003eMYC\u003c/em\u003e-rearranged (PFS: HR 0.60, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.1704; OS: HR 0.49, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.0852), and in \u003cem\u003eMYC/BCL2\u003c/em\u003e double-hit DLBCL (PFS: HR 1.30, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.6433; OS: HR 1.02, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.9803) (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e"},{"header":"DISCUSSION","content":"\u003cp\u003eOur study is the largest clinical study investigating the treatment outcomes of DLBCL with standard R-CHOP(-like) immunochemotherapy regimens in Singapore to date. Survival outcomes in our study cohort are largely similar to existing major trial data for DLBCL treated with R-CHOP(-like) immunochemotherapy regimens. The LNH-98.5 trial reported a 10-year PFS of 36.5% in R-CHOP treated DLBCL\u003csup\u003e19\u003c/sup\u003e, while a retrospective Sweden study showed a 5-year OS of 65.3% in curative-intent DLBCL patients\u003csup\u003e20\u003c/sup\u003e. Our study also is in keeping with current consensus that up to 40% patients relapse or are refractory to first-line therapy\u003csup\u003e21\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eCurrent literature is still unclear on the optimal immunochemotherapy regimen for double-expressor and high-grade DLBCLs with \u003cem\u003eMYC\u003c/em\u003e translocations or double-hit/triple-hit genetics. While Dodero et al. suggest that EPOCH-R over RCHOP significantly improves 2-year PFS in younger DLBCL patents\u0026thinsp;\u0026lt;\u0026thinsp;65 years\u003csup\u003e22\u003c/sup\u003e, the landmark Phase III Alliance/CALGB 50303 study revealed that EPOCH-R had higher toxicity and did not improve either OR or PFS as compared to R-CHOP\u003csup\u003e23\u003c/sup\u003e. A systemic review and meta-analysis in 2015 found that EPOCH-R first-line treatment significantly reduced progression risk as compared to R-CHOP in double-hit lymphomas\u003csup\u003e24\u003c/sup\u003e, while a later prospective study showed that EPOCH-R yielded a good 48-month event-free survival (EFS) of 71.6% and OS of 70.7%\u003csup\u003e25\u003c/sup\u003e. However, a recent large retrospective study showed that there was no difference in 4-year OS between R-CHOP and EPOCH-R treated high-grade DLBCLs\u003csup\u003e26\u003c/sup\u003e. In our study, intensification of treatment regimen with EPOCH-R in \u003cem\u003eMYC\u003c/em\u003e rearranged or double hit (\u003cem\u003eMYC/BCL2\u003c/em\u003e) DLBCL did not significantly change treatment outcomes. However, this finding is limited by the relatively small number of such patients in our study and lack of both R-CHOP and EPOCH-R dosing information. Overall results suggest the potential survival benefit of EPOCH-R over R-CHOP in double-hit and high-grade DLBCLs remains controversial and to be further resolved. Due to the high rate of relapsed/refractory DLBCLs after first-line chemoimmunotherapy and the mediocre outcomes of regimen intensification in high risk DLBCLs, novel therapeutics for all DLBCL entities are sorely warranted.\u003c/p\u003e \u003cp\u003eThe main limitation of our study is its retrospective design and its resultant lack of specific clinicopathological information and loss to follow up of some cases. However, our study involves the largest cohort of DLBCLs treated with R-CHOP(-like) regimens to date in Singapore with comprehensive coverage of both demographical and clinicopathological factors in survival outcome analysis.\u003c/p\u003e \u003cp\u003eIn conclusion, our study showcases the real-world outcomes of DLBCL treated with frontline R-CHOP(-like) regimens in an Asian multi-ethnic population, which is similar to global outcomes. We thus highlight the crucial need for improved therapeutic strategies for DLBCL, especially for high-risk cases.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e \u003ch2\u003eCOMPETING FINANCIAL INTERESTS STATEMENT\u003c/h2\u003e \u003cp\u003eAll authors declare no competing financial interests.\u003c/p\u003e \u003c/p\u003e\u003ch2\u003eAuthor Contribution\u003c/h2\u003e\u003cp\u003eRML and JYC analysed the data and drafted the manuscript; JYT, YHT, ZEH, LCN, FLL, YTG, STL obtained patient data; RML and JYC designed the study, interpreted the results, and revised the manuscript; and all authors read and approved the final version of the manuscript.\u003c/p\u003e\u003ch2\u003eACKNOWLEDGEMENTS\u003c/h2\u003e \u003cp\u003eThis work was supported by the Tanoto Foundation Professorship in Medical Oncology, New Century Foundation Limited, Ling Foundation, Singapore Ministry of Health\u0026rsquo;s National Medical Research Council Research Transition Award (TA21jun-0005), Large Collaborative Grant (OFLCG18May-0028), and TETRAD II Collaborative Centre Grant (CG21APR2002) as well as the SingHealth Duke-NUS AM/ACP-Designated Philanthropic Fund Grant Award (08/FY2023/EX/27-A65). We would like to thank all subjects who have participated in this study.\u003c/p\u003e\u003ch2\u003eData Availability\u003c/h2\u003e\u003cp\u003eThe datasets created and analysed during this study are available from the corresponding authors upon reasonable request.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eSehn LH, Donaldson J, Chhanabhai M et al (2005) Introduction of combined CHOP plus rituximab therapy dramatically improved outcome of diffuse large B-cell lymphoma in British Columbia. 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Lancet Haematol 5(12):e609. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1016/S2352-3026(18)30177-7\u003c/span\u003e\u003cspan address=\"10.1016/S2352-3026(18)30177-7\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMagnusson T, Narkhede M, Mehta A et al (2021) No difference in overall survival between R-CHOP and R-EPOCH among patients with advanced stage MYC-rearranged, double hit, or triple hit diffuse large B-cell lymphoma. Abstract #S224. Presented at the EHA2021 Virtual Congress, June 9\u0026ndash;17\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"annals-of-hematology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"aohe","sideBox":"Learn more about [Annals of Hematology](http://link.springer.com/journal/277)","snPcode":"277","submissionUrl":"https://submission.nature.com/new-submission/277/3","title":"Annals of Hematology","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"Polatuzumab vedotin, CAR-T cells, cell-of-origin, double-hit, bispecific antibody","lastPublishedDoi":"10.21203/rs.3.rs-4855200/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4855200/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e \u003cp\u003eRecent breakthrough advances in the treatment of DLBCL, such as the antibody-drug conjugate Polatuzumab vedotin, have yielded clinical survival benefit over R-CHOP for the first time in 20 years since the advent of the Rituximab era. We thus examine the outcomes of standard immunochemotherapy for DLBCL in our multi-ethnic Asian population, so as to determine the real-world clinical need to adopt new therapeutics in this disease entity.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003eWe conducted a retrospective study involving patients (n\u0026thinsp;=\u0026thinsp;1071) diagnosed with DLBCL at the National Cancer Centre Singapore from 2010\u0026ndash;2022, and treated with first-line rituximab-based regimens. The median follow-up duration was 48 months. Survival analyses were performed using the Kaplan-Meier method and multivariate Cox proportional models.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eThe cohort consisted of 590 male and 481 female patients with a median age of 63.8 years (range, 19.3\u0026ndash;93.6). Most were stage III-IV at diagnosis (60.9%) and of non-germinal center B-cell like (non-GCB) subtype by Han\u0026rsquo;s criteria (56.5%). The vast majority received R-CHOP(-like) regimens (n\u0026thinsp;=\u0026thinsp;997, 93.1%), including EPOCH-R (n\u0026thinsp;=\u0026thinsp;95), achieving a 5-year progression-free survival (PFS) and overall survival (OS) of 64.5% and 74.7% respectively. Male sex (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.0294), age\u0026thinsp;\u0026gt;\u0026thinsp;60 years (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.0001), poor ECOG scores (\u003cspan additionalcitationids=\"CR3\" citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e) (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.0001), advanced stage (III-IV) (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.0001), presence of B-symptoms (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.0305), raised LDH (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.0161) were independent predictors of OS, 4 of which are risk factors in the International Prognostic Index (IPI). In the intermediate to high-risk subgroup (IPI scores 2\u0026ndash;5; n\u0026thinsp;=\u0026thinsp;752), the 5-year PFS and OS were only 59.0% and 69.8% respectively. EBV status, as was high-risk lymphoma (\u003cem\u003eMYC\u003c/em\u003e and/or \u003cem\u003eBCL2\u003c/em\u003e/\u003cem\u003eBCL6\u003c/em\u003e rearrangements), were not significantly associated with survival outcomes. EPOCH-R was used more frequently than R-CHOP in patients with \u003cem\u003eMYC\u003c/em\u003e rearrangements (n\u0026thinsp;=\u0026thinsp;82, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.0001), including those with \u003cem\u003eMYC/BCL2\u003c/em\u003e double-hit genetics (n\u0026thinsp;=\u0026thinsp;31, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.0001). Notably, neither regimen significantly affected survival outcomes, both in \u003cem\u003eMYC\u003c/em\u003e-rearranged (PFS: HR 0.60, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.1704; OS: HR 0.49, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.0852), and in \u003cem\u003eMYC/BCL2\u003c/em\u003e double-hit DLBCL (PFS: HR 1.30, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.6433; OS: HR 1.02, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.9803).\u003c/p\u003e\u003ch2\u003eConclusion\u003c/h2\u003e \u003cp\u003eOur study demonstrates that our local population has similar clinicopathological and prognostic characteristics of DLBCL as compared to global findings. It also highlights the limitations of R-CHOP(-like) regimens in contemporary DLBCL management and therefore an ongoing need for improved therapeutic strategies.\u003c/p\u003e","manuscriptTitle":"Real-world Outcomes of Diffuse Large B-cell Lymphoma Treated with frontline R-CHOP(-like) regimens in an Asian Multi-ethnic Population","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-09-11 07:00:56","doi":"10.21203/rs.3.rs-4855200/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2024-08-30T07:33:36+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2024-08-20T16:24:40+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2024-08-18T12:03:02+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2024-08-13T10:31:46+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"226598923937245136129826156439224253310","date":"2024-08-12T09:56:56+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"65700664267645098620746623102169554817","date":"2024-08-12T08:02:00+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"76541820999075292454477603741072558934","date":"2024-08-10T12:35:40+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"56065740199347000506032082009733594824","date":"2024-08-10T10:30:50+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"127132836513312430971617507400824467007","date":"2024-08-10T10:21:31+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2024-08-10T07:36:12+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2024-08-06T05:25:41+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2024-08-06T05:24:30+00:00","index":"","fulltext":""},{"type":"submitted","content":"Annals of Hematology","date":"2024-08-04T03:22:24+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"annals-of-hematology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"aohe","sideBox":"Learn more about [Annals of Hematology](http://link.springer.com/journal/277)","snPcode":"277","submissionUrl":"https://submission.nature.com/new-submission/277/3","title":"Annals of Hematology","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"685469a9-a52b-4b11-898e-e3c507c80c4d","owner":[],"postedDate":"September 11th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2024-11-18T19:16:00+00:00","versionOfRecord":{"articleIdentity":"rs-4855200","link":"https://doi.org/10.1007/s00277-024-06067-2","journal":{"identity":"annals-of-hematology","isVorOnly":false,"title":"Annals of Hematology"},"publishedOn":"2024-11-15 15:57:52","publishedOnDateReadable":"November 15th, 2024"},"versionCreatedAt":"2024-09-11 07:00:56","video":"","vorDoi":"10.1007/s00277-024-06067-2","vorDoiUrl":"https://doi.org/10.1007/s00277-024-06067-2","workflowStages":[]},"version":"v1","identity":"rs-4855200","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4855200","identity":"rs-4855200","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}