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Rituximab plus polychemotherapy is the standard of care in diffuse large B-cell lymphoma (DLBCL). GAINED, a randomized phase 3 trial, compared obinutuzumab to rituximab. Transplant-eligible patients (18-60 years) with an untreated age-adjusted International Prognostic Index (aaIPI) score ≥1 DLBCL were randomized (1:1) between obinutuzumab or rituximab and stratified by aaIPI (1; 2-3) and chemotherapy regimen (doxorubicin, cyclophosphamide, prednisone plus vindesine, bleomycin [ACVBP] or vincristine [CHOP]). Consolidation treatment was determined according to response to interim positron emission tomography (PET). Responders after cycle 2 and 4 (PET2-/PET4-) received immunochemotherapy. Responders after only cycle 4 (PET2+/4-) received transplantation. The primary objective was an 8% improvement (hazard ratio [HR] = 0.73; 80% power; α risk, 2.5%; 1-sided) in 2-year event-free survival (EFS) in the obinutuzumab arm. From September 2012, 670 patients were enrolled (obinutuzumab, n = 336; rituximab, n = 334). A total of 383 (57.2%) were aaIPI 2-3, 339 (50.6%) received CHOP. Median follow-up was 38.7 months. The 2-year EFS was similar in both groups (59.8% vs 56.6%; P = .123; HR = 0.88). The 2-year PFS in the whole cohort was 83.1% (95% confidence interval, 80% to 85.8%). PET2-/4- and PET2+/4- had similar 2-year progression-free survival (PFS) and overall survival (OS): 89.9% vs 83.9% and 94.8% vs 92.8%. The 2-year PFS and OS for PET4+ patients were 62% and 83.1%. Grade 3-5 infections were more frequent in the obinutuzumab arm (21% vs 12%). Obinutuzumab is not superior to rituximab in aaIPI ≥1 DLBCL transplant-eligible patients. This trial was registered at www.clinicaltrials.gov as #NCT01659099., (© 2021 by The American Society of Hematology.)

Purpose: MYC rearrangement ( MYC -R) occurs in approximately 10% of diffuse large B-cell lymphomas (DLBCLs) and has been associated with poor prognosis in many studies. The impact of MYC- R on prognosis may be influenced by the MYC partner gene (immunoglobulin [IG] or a non-IG gene). We evaluated a large cohort of patients through the Lunenburg Lymphoma Biomarker Consortium to validate the prognostic significance of MYC-R (single-, double-, and triple-hit status) in DLBCL within the context of the MYC partner gene., Methods: The study cohort included patients with histologically confirmed DLBCL morphology derived from large prospective trials and patient registries in Europe and North America who were uniformly treated with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone therapy or the like. Fluorescence in situ hybridization for the MYC , BCL2 , BCL6 , and IG heavy and light chain loci was used, and results were correlated with clinical outcomes., Results: A total of 5,117 patients were identified of whom 2,383 (47%) had biopsy material available to assess for MYC -R. MYC -R was present in 264 (11%) of 2,383 patients and was associated with a significantly shorter progression-free and overall survival, with a strong time-dependent effect within the first 24 months after diagnosis. The adverse prognostic impact of MYC- R was only evident in patients with a concurrent rearrangement of BCL2 and/or BCL6 and an IG partner (hazard ratio, 2.4; 95% CI, 1.6 to 3.6; P < .001)., Conclusion: The negative prognostic impact of MYC -R in DLBCL is largely observed in patients with MYC double hit/triple-hit disease in which MYC is translocated to an IG partner, and this effect is restricted to the first 2 years after diagnosis. Our results suggest that diagnostic strategies should be adopted to identify this high-risk cohort, and risk-adjusted therapeutic approaches should be refined further.

Diffuse large B cell lymphoma (DLBCL) is a heterogeneous disease treated with anti-CD20-based immuno-chemotherapy (R-CHOP). We identified that low levels of GAPDH predict a poor response to R-CHOP treatment. Importantly, we demonstrated that GAPDH low lymphomas use OxPhos metabolism and rely on mTORC1 signaling and glutaminolysis. Consistently, disruptors of OxPhos metabolism (phenformin) or glutaminolysis (L-asparaginase) induce cytotoxic responses in GAPDH low B cells and improve GAPDH low B cell-lymphoma-bearing mice survival, while they are low or not efficient on GAPDH high B cell lymphomas. Ultimately, we selected four GAPDH low DLBCL patients, who were refractory to all anti-CD20-based therapies, and targeted DLBCL metabolism using L-asparaginase (K), mTOR inhibitor (T), and metformin (M) (called KTM therapy). Three out of the four patients presented a complete response upon one cycle of KTM. These findings establish that the GAPDH expression level predicts DLBCL patients' response to R-CHOP treatment and their sensitivity to specific metabolic inhibitors., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Background: Immunochemotherapy with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) is a standard front-line treatment for follicular lymphoma. The combination of lenalidomide and rituximab has shown high efficacy in relapsed or refractory and untreated follicular lymphoma. We aimed to evaluate the safety and activity of the combination of lenalidomide and R-CHOP (R2-CHOP) in previously untreated patients with high burden follicular lymphoma., Methods: This single-arm, open-label, multicentre, phase 2 trial was done in 16 hospitals in France, all of which were Lymphoma Study Association (LYSA) sites. Eligible patients were aged 18-70 years and had previously untreated CD20-positive follicular lymphoma of grade 1, 2, or 3a; at least one high tumour burden criterion according to Groupe d'Etude des Lymphomes Folliculaires criteria; an Eastern Cooperative Oncology Group performance status score of 2 or less; and a minimum life expectancy of more than 3 months. Patients received induction therapy with six cycles of R2-CHOP every 3 weeks (one cycle involved standard R-CHOP on days 1-5, and 25 mg oral lenalidomide per day on days 1-14), followed by two rituximab infusions at 3-week intervals. The total treatment schedule was 24 weeks. Patients who achieved a complete or partial response to induction therapy received maintenance therapy consisting of one rituximab infusion every 8 weeks for 2 years. The primary outcome was the proportion of patients who achieved a complete response (complete response and complete response unconfirmed), according to International Workshop to Standardize Response Criteria, at the end of induction treatment. Safety was assessed in all patients who completed treatment. This trial is registered with ClinicalTrials.gov, number NCT01393756, and is closed to accrual., Findings: Between Dec 21, 2010, and Jan 25, 2012, 80 patients were enrolled, and 68 (85%) completed six cycles of R2-CHOP. At the end of the induction phase, 59 patients achieved a complete response (74%, 95% CI 63-83). 55 patients achieved a complete response at 30 months from enrolment (69%, 57-78). The most frequent adverse event was grade 4 neutropenia in 52 (65%) patients. The most frequent non-haematological side-effects included grade 1-2 sensory neuropathy in 28 (35%) patients and grade 1-2 transient rash in 27 (34%) patients. Four patients died during the study period; none of these deaths were judged to be related to treatment., Interpretations: Lenalidomide in combination with R-CHOP had an acceptable safety profile and showed anti-cancer activity in patients with previously untreated high burden follicular lymphoma. A future comparative study showing evidence of a survival advantage would be necessary for this combination to be proposed as a treatment for follicular lymphoma., Funding: French Ministry of Health, Celgene Corporation, and Amgen France., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Background: Our aim was to evaluate whether the cell of origin (COO) as defined by the Hans algorithm and MYC/BCL2 coexpression, which are the two main biological risk factors in elderly patients treated with rituximab, cyclophosphamide, doxorubicin hydrochloride, vincristine, and prednisolone (R-CHOP), maintain their prognostic value in a large prospective clinical trial., Patients and Methods: We evaluated 285 paraffin-embedded samples from patients (60-80 years of age) enrolled in the Lymphoma Study Association trial LNH03-6B who were treated with R-CHOP. We correlated the COO defined by the transcriptome according to the Wright algorithm with that defined by the Hans algorithm in a subset of 62 tumors with available frozen tissue samples., Results: The non-germinal center B-cell-like phenotype according to the Hans algorithm and BCL2 expression (but not MYC and BCL2 coexpression) predicted worse progression-free survival [hazard ratio (HR)=1.78, P = 0.003 and HR = 1.79, P = 0.003, respectively] and overall survival (HR = 1.85, P = 0.005 and HR = 1.67, P = 0.02, respectively) independently of the International Prognostic Index. The correlation between the Hans algorithm and the Wright algorithm was 91%, with an almost perfect concordance according to a kappa test (0.81)., Conclusions: Our results suggest that immunohistochemically defined COO remains a useful tool for predicting prognosis in diffuse large B-cell lymphoma when performed under optimized standardized conditions and that BCL2 expression may help to identify elderly patients at risk for relapse and who could potentially respond to anti-BCL2 targeted agents. In this prospective phase III trial, the coexpression of MYC and BCL2 does not appear to predict worse survival., Clinical Trial Number: NCT00144755., (© The Author 2017. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Purpose: Next-generation sequencing (NGS) has detailed the genomic characterization of diffuse large B-cell lymphoma (DLBCL) by identifying recurrent somatic mutations. We set out to design a clinically feasible NGS panel focusing on genes whose mutations hold potential therapeutic impact. Furthermore, for the first time, we evaluated the prognostic value of these mutations in prospective clinical trials., Experimental Design: A Lymphopanel was designed to identify mutations in 34 genes, selected according to literature and a whole exome sequencing study of relapsed/refractory DLBCL patients. The tumor DNA of 215 patients with CD20(+)de novo DLBCL in the prospective, multicenter, and randomized LNH-03B LYSA clinical trials was sequenced to deep, uniform coverage with the Lymphopanel. Cell-of-origin molecular classification was obtained through gene expression profiling with HGU133+2.0 Affymetrix GeneChip arrays., Results: The Lymphopanel was informative for 96% of patients. A clear depiction of DLBCL subtype molecular heterogeneity was uncovered with the Lymphopanel, confirming that activated B-cell-like (ABC), germinal center B-cell like (GCB), and primary mediastinal B-cell lymphoma (PMBL) are frequently affected by mutations in NF-κB, epigenetic, and JAK-STAT pathways, respectively. Novel truncating immunity pathway, ITPKB, MFHAS1, and XPO1 mutations were identified as highly enriched in PMBL. Notably, TNFAIP3 and GNA13 mutations in ABC patients treated with R-CHOP were associated with significantly less favorable prognoses., Conclusions: This study demonstrates the contribution of NGS with a consensus gene panel to personalized therapy in DLBCL, highlighting the molecular heterogeneity of subtypes and identifying somatic mutations with therapeutic and prognostic impact. Clin Cancer Res; 22(12); 2919-28. ©2016 AACRSee related commentary by Lim and Elenitoba-Johnson, p. 2829., (©2016 American Association for Cancer Research.)

Diffuse large B-cell lymphoma (DLBCL) with MYC rearrangement (MYC-R) carries an unfavorable outcome. We explored the prognostic value of the MYC translocation partner gene in a series of MYC-R de novo DLBCL patients enrolled in first-line prospective clinical trials (Groupe d'Etudes des Lymphomes de l'Adulte/Lymphoma Study Association) and treated with rituximab-anthracycline-based chemotherapy. A total of 774 DLBCL cases characterized for cell of origin by the Hans classifier were analyzed using fluorescence in situ hybridization with BCL2, BCL6, MYC, immunoglobulin (IG)K, and IGL break-apart and IGH/MYC, IGK/MYC, and IGL/MYC fusion probes. MYC-R was observed in 51/574 (8.9%) evaluable DLBCL cases. MYC-R cases were predominantly of the germinal center B-cell-like subtype 37/51 (74%) with no distinctive morphologic and phenotypic features. Nineteen cases were MYC single-hit and 32 cases were MYC double-hit (MYC plus BCL2 and/or BCL6) DLBCL. MYC translocation partner was an IG gene in 24 cases (MYC-IG) and a non-IG gene (MYC-non-IG) in 26 of 50 evaluable cases. Noteworthy, MYC-IG patients had shorter overall survival (OS) (P = .0002) compared with MYC-negative patients, whereas no survival difference was observed between MYC-non-IG and MYC-negative patients. In multivariate analyses, MYC-IG predicted poor progression-free survival (P = .0051) and OS (P = .0006) independently from the International Prognostic Index and the Hans classifier. In conclusion, we show in this prospective randomized trial that the adverse prognostic impact of MYC-R is correlated to the MYC-IG translocation partner gene in DLBCL patients treated with immunochemotherapy. These results may have an important impact on the clinical management of DLBCL patients with MYC-R who should be routinely characterized according to MYC partner gene. These trials are individually registered at www.clinicaltrials.gov as #NCT00144807, #NCT01087424, #NCT00169143, #NCT00144755, #NCT00140660, #NCT00140595, and #NCT00135499., (© 2015 by The American Society of Hematology.)

Purpose: We performed a multistage genome-wide association study to identify inherited genetic variants that predict outcome in diffuse large B-cell lymphoma patients treated with immunochemotherapy., Methods: We conducted a meta-analysis of two genome-wide association study data sets, one from the LNH2003B trial (N = 540), a prospective clinical trial from the Lymphoma Study Association, and the other from the Molecular Epidemiology Resource study (N = 312), a prospective observational study from the University of Iowa-Mayo Clinic Lymphoma Specialized Program of Research Excellence. Top single nucleotide polymorphisms were then genotyped in independent cohorts of patients from the Specialized Program of Research Excellence (N = 391) and the Groupe Ouest-Est des Leucémies Aiguës et Maladies du Sang (GOELAMS) -075 randomized trial (N = 294). We calculated the hazard ratios (HRs) and 95% CIs for event-free survival (EFS) and overall survival (OS) using a log-additive genetic model with adjustment for age, sex, and age-adjusted International Prognostic Index., Results: In a meta-analysis of the four studies, the top loci for EFS were marked by rs7712513 at 5q23.2 (near SNX2 and SNCAIP; HR, 1.39; 95% CI, 1.23 to 1.57; P = 2.08 × 10(-7)), and rs7765004 at 6q21 (near MARCKS and HDAC2; HR, 1.38; 95% CI, 1.22 to 1.57; P = 7.09 × 10(-7)), although they did not reach conventional genome-wide significance (P = 5 × 10(-8)). Both rs7712513 (HR, 1.49; 95% CI, 1.29 to 1.72; P = 3.53 × 10(-8)) and rs7765004 (HR, 1.47; 95% CI, 1.27 to 1.71; P = 5.36 × 10(-7)) were also associated with OS. In exploratory analyses, a two-single nucleotide polymorphism risk score was highly predictive of EFS (P = 1.78 × 10(-12)) and was independent of treatment, IPI, and cell-of-origin classification., Conclusion: Our study provides encouraging evidence for associations between loci at 5q23.2 and 6q21 with EFS and OS in patients with diffuse large B-cell lymphoma treated with immunochemotherapy, suggesting novel biology and the potential contribution of host genetics to the prognosis of this aggressive malignancy., (© 2015 by American Society of Clinical Oncology.)

Purpose: To determine whether any tumor biomarkers could account for the survival advantage observed in the LNH 03-2B trial among patients with diffuse large B-cell lymphoma (DLBCL) and low-intermediate risk according to the International Prognostic Index when treated with dose-intensive rituximab, doxorubicin, cyclophosphamide, vindesine, bleomycin, and prednisone (R-ACVBP) compared with standard rituximab, doxorubicin, cyclophosphamide, vincristine, and prednisone (R-CHOP)., Patients and Methods: Using immunohistochemistry, expression of CD10, BCL6, MUM1, MYC, and BCL2 and coexpression of MYC/BCL2 were examined. The interaction effects between each biomarker and treatment arm on survival were studied in a restricted model and a full model incorporating clinical parameters., Results: Among the 379 patients analyzed in the trial, 229 tumors were evaluable for germinal center B-cell-like (GCB)/non-GCB subclassification according to the Hans algorithm. Among all the biomarkers, only the interaction between the Hans algorithm and the treatment arm was significant for progression-free survival (PFS) and overall survival (OS) in univariable (PFS, P = .04; OS, P = .01) and multivariable (PFS, P = .03; OS, P = .01) analyses. Non-GCB tumors predicted worse PFS (hazard ratio [HR], 3.21; 95% CI, 1.29 to 8.00; P = .01) and OS (HR, 6.09; 95% CI, 1.37 to 27.03; P = .02) among patients treated with R-CHOP compared with patients who received R-ACVBP, whereas there were no significant survival differences between these regimens among patients with GCB tumors., Conclusion: The survival benefit related to R-ACVBP over R-CHOP is at least partly linked to improved survival among patients with non-GCB DLBCL. Therefore, the Hans algorithm could be considered a theragnostic biomarker for selecting young patients with DLBCL who can benefit from an intensified R-ACVBP immunochemotherapy regimen., (© 2014 by American Society of Clinical Oncology.)

Background: Immunochemotherapy with rituximab and cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) has become the standard of care for elderly patients with diffuse large B-cell lymphoma. We aimed to ascertain if a dose-dense R-CHOP regimen administered every 2 weeks (R-CHOP14) was superior to the standard 3-week schedule (R-CHOP21)., Methods: We did a randomised phase 3 trial at 83 centres in four countries. 602 patients aged 60-80 years with untreated diffuse large B-cell lymphoma and at least one adverse prognostic factor (age-adjusted international prognostic index ≥ 1) were eligible for the study. We randomly allocated individuals to R-CHOP-ie, rituximab (375 mg/m(2)), cyclophosphamide (750 mg/m(2)), doxorubicin (50 mg/m(2)), vincristine (1.4 mg/m(2), up to 2 mg) all on day 1, and prednisone 40 mg/m(2) daily for 5 days-administered every 14 days (n=304) or every 21 days (n=298) for eight cycles. We did permuted-block randomisation (block size four, allocation ratio 1:1) stratified by centre and number of adverse prognostic factors. The primary endpoint was event-free survival. Our analysis was of the intention-to-treat population, and we present the final analysis. This study is registered with ClinicalTrials.gov, number NCT00144755., Findings: Two patients allocated R-CHOP21 were ineligible for the study and were excluded from analyses. After median follow-up of 56 months (IQR 27-60), 3-year event-free survival was 56% (95% CI 50-62) in the R-CHOP14 group and 60% (55-66) in the R-CHOP21 group (hazard ratio 1.04, 95% CI 0.82-1.31; p=0.7614). Grade 3-4 neutropenia occurred in 224 (74%) of 304 patients allocated R-CHOP14 and 189 (64%) of 296 assigned R-CHOP21, despite increased use of granulocyte colony-stimulating factor in the R-CHOP14 group compared with the R-CHOP21 group. 143 (47%) patients in the R-CHOP14 group received at least one red-blood-cell transfusion versus 93 (31%) in the R-CHOP21 group (p=0.0001). 35 (12%) patients allocated R-CHOP14 received at least one platelet transfusion versus 25 (8%) assigned R-CHOP21 (p=0.2156). 155 (51%) patients who were assigned R-CHOP14 had at least one serious adverse event compared with 140 (47%) who were allocated R-CHOP21., Interpretation: In elderly patients with untreated diffuse large B-cell lymphoma and at least one adverse prognostic factor, a 2-week dose-dense R-CHOP regimen did not improve efficacy compared with the 3-week standard schedule. The frequency of toxic side-effects was similar between regimens, but R-CHOP14 was associated with increased need for red-blood-cell transfusion., Funding: Groupe d'Etude des Lymphomes de l'Adulte (GELA), Amgen., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Background: The outcome of diffuse large B-cell lymphoma has been substantially improved by the addition of the anti-CD20 monoclonal antibody rituximab to chemotherapy regimens. We aimed to assess, in patients aged 18-59 years, the potential survival benefit provided by a dose-intensive immunochemotherapy regimen plus rituximab compared with standard treatment plus rituximab., Methods: We did an open-label randomised trial comparing dose-intensive rituximab, doxorubicin, cyclophosphamide, vindesine, bleomycin, and prednisone (R-ACVBP) with subsequent consolidation versus standard rituximab, doxorubicin, cyclophosphamide, vincristine, and prednisone (R-CHOP). Random assignment was done with a computer-assisted randomisation-allocation sequence with a block size of four. Patients were aged 18-59 years with untreated diffuse large B-cell lymphoma and an age-adjusted international prognostic index equal to 1. Our primary endpoint was event-free survival. Our analyses of efficacy and safety were of the intention-to-treat population. This study is registered with ClinicalTrials.gov, number NCT00140595., Findings: One patient withdrew consent before treatment and 54 did not complete treatment. After a median follow-up of 44 months, our 3-year estimate of event-free survival was 81% (95% CI 75-86) in the R-ACVBP group and 67% (59-73) in the R-CHOP group (hazard ratio [HR] 0·56, 95% CI 0·38-0·83; p=0·0035). 3-year estimates of progression-free survival (87% [95% CI, 81-91] vs 73% [66-79]; HR 0·48 [0·30-0·76]; p=0·0015) and overall survival (92% [87-95] vs 84% [77-89]; HR 0·44 [0·28-0·81]; p=0·0071) were also increased in the R-ACVBP group. 82 (42%) of 196 patients in the R-ACVBP group experienced a serious adverse event compared with 28 (15%) of 183 in the R-CHOP group. Grade 3-4 haematological toxic effects were more common in the R-ACVBP group, with a higher proportion of patients experiencing a febrile neutropenic episode (38% [75 of 196] vs 9% [16 of 183])., Interpretation: Compared with standard R-CHOP, intensified immunochemotherapy with R-ACVBP significantly improves survival of patients aged 18-59 years with diffuse large B-cell lymphoma with low-intermediate risk according to the International Prognostic Index. Haematological toxic effects of the intensive regimen were raised but manageable., Funding: Groupe d'Etudes des Lymphomes de l'Adulte and Amgen., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Genomic alterations play a crucial role in the development and progression of diffuse large B-cell lymphomas (DLBCLs). We determined gene copy number alterations (GCNAs) of TP53, CDKN2A, CDKN1B, BCL2, MYC, REL, and RB1 with a single polymerase chain reaction (PCR) assay (quantitative multiplex PCR of short fragments [QMPSF]) in a cohort of 114 patients with DLBCL to assess their prognostic value and relationship with the gene expression profile. Losses of TP53 and CDKN2A, observed in 8% and 35% of patients, respectively, were significantly associated with a shorter survival after rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) treatment, independently of the International Prognostic Index and of the cell of origin. Analysis of the 9p21 genomic region indicated that transcripts encoding p14ARF and p16INK4A were both disrupted in most patients with CDKN2A deletion. These patients predominantly had an activated B-cell profile and showed a specific gene expression signature, characterized by dysregulation of the RB/E2F pathway, activation of cellular metabolism, and decreased immune and inflammatory responses. These features may constitute the molecular basis sustaining the unfavorable outcome and chemoresistance of this DLBCL subgroup. Detection of TP53 and CDKN2A loss by QMPSF is a powerful tool that could be used for patient stratification in future clinical trials.

Purpose: To evaluate the prognostic value of cell of origin immunohistochemical markers and BCL2, BCL6, and c-MYC translocations in a homogeneous cohort of patients with diffuse large B-cell lymphoma (DLBCL) treated with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP)., Patients and Methods: Patients with CD20+ DLBCL were enrolled in the randomized LNH98-5 and 01-5B Groupe d'Etude des Lymphomes de l'Adulte trials. Paraffin-embedded tumor samples of 119 patients treated with R-CHOP were analyzed by immunohistochemistry for CD10, BCL6, MUM1/IRF4, LMO2, and forkhead box protein P1 (FOXP1) expression and for BCL2, BCL6, and c-MYC breakpoints by fluorescence in situ hybridization (FISH) on tissue microarray., Results: LMO2 expression and BCL2 breakpoint were associated with the germinal center (GC) subtype defined by Hans' algorithm, respectively (P < .0001; P = .0002) whereas FOXP1 expression and BCL6 breakpoint were associated with the non-germinal center (non-GC) subtype (P = .008 and P = .0001, respectively). The immunohistochemical markers analyzed independently, GC/non-GC phenotype and BCL2 breakpoint did not predict overall survival (OS). BCL6 breakpoint was significantly associated with an unfavorable impact on OS (P = .04). Interestingly, an immunoFISH index, defined by positivity for at least two of three non-GC markers (FOXP1, MUM1/IRF4, BCL6 breakpoint) was significantly associated with a shorter 5-year OS rate (44%; 95% CI, 28 to 60 v 78%; 95% CI, 59 to 89; P = .01) which was independent (P = .04) of the age-adjusted International Prognostic Index (P = .04) in multivariate analysis., Conclusion: Our study demonstrates that combining immunohistochemistry with FISH allows construction of an immunoFISH index that significantly predicts survival in elderly DLBCL patients treated with R-CHOP.

Gene expression profiles have been associated with clinical outcome in patients with diffuse large B-cell lymphoma (DLBCL) treated with anthracycline-containing chemotherapy. Using Affymetrix HU133A microarrays, we analyzed the lymphoma transcriptional profile of 30 patients treated with CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) and 23 patients treated with rituximab (R)-CHOP in the Groupe d'Etude des Lymphomes de l'Adulte clinical centers. We used this data set to select transcripts showing an association with progression-free survival in all patients or showing a differential effect in the two treatment groups. We performed real-time quantitative reverse transcription-PCR in the 23 R-CHOP samples of the screening set and an additional 44 R-CHOP samples set to evaluate the prognostic significance of these transcripts. In these 67 patients, the level of expression of 16 genes and the cell-of-origin classification were significantly associated with overall survival, independently of the International Prognostic Index. A multivariate model comprising four genes of the cell-of-origin signature (LMO2, MME, LPP and FOXP1) and two genes related to immune response, identified for their differential effects in R-CHOP patients (APOBEC3G and RAB33A), demonstrated a high predictive efficiency in this set of patients, suggesting that both features affect outcome in DLBCL patients receiving immunochemotherapy.

Purpose: Chemoradiotherapy has been considered standard treatment for patients with limited-stage aggressive lymphoma on the basis of trials conducted before the introduction of the International Prognostic Index. To evaluate this approach in elderly patients with low-risk localized lymphoma, we conducted a trial comparing chemoradiotherapy with chemotherapy alone., Patients and Methods: Previously untreated patients older than 60 years with localized stage I or II histologically aggressive lymphoma and no adverse prognostic factors of the International Prognostic Index were randomly assigned to receive either four cycles of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) plus involved-field radiotherapy (299 patients) or chemotherapy alone with four cycles of CHOP (277 patients)., Results: With a median follow-up time of 7 years, event-free and overall survival did not differ between the two treatment groups (P = .6 and P = .5, respectively). The 5-year estimates of event-free survival were 61% for patients receiving chemotherapy alone and 64% for patients receiving CHOP plus radiotherapy; the 5-year estimates of overall survival were 72% and 68%, respectively. In a multivariate analysis, overall survival was affected by stage II disease (P < .001) and male sex (P = .03)., Conclusion: In this large prospective study, CHOP plus radiotherapy did not provide any advantage over CHOP alone for the treatment of low-risk localized aggressive lymphoma in elderly patients.

We report the case of a patient treated with a combination of fludarabine and cyclophosphamide after suffering from B-cell chronic lymphocytic leukemia for 10 years. Three months after treatment, the patient presented with an unusual association, not previously reported in the literature: Richter syndrome (monotypic Epstein-Barr virus- negative large B-cell lymphoma) with the proliferation of Epstein-Barr virus-positive B cells secreting a polytypic immunoglobulin A. The Epstein-Barr virus-positive lymphoproliferation can be accounted for by the type of immunosuppression induced by the treatment.

Background: Chemoradiotherapy is standard treatment for localized aggressive lymphoma. To determine the optimal therapy for nonelderly persons with low-risk localized lymphoma, we conducted a randomized trial comparing chemoradiotherapy with chemotherapy alone., Methods: Previously untreated patients less than 61 years old with localized stage I or II aggressive lymphoma and no adverse prognostic factors according to the International Prognostic Index were randomly assigned to three cycles of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) plus involved-field radiotherapy (329 patients) or chemotherapy alone with dose-intensified doxorubicin, cyclophosphamide, vindesine, bleomycin, and prednisone (ACVBP) plus sequential consolidation (318 patients)., Results: With a median follow-up of 7.7 years, event-free and overall survival rates were significantly higher in the group given chemotherapy alone than in the group given CHOP plus radiotherapy (P<0.001 and P=0.001, respectively). The five-year estimates of event-free survival were 82 percent (95 percent confidence interval, 78 to 87 percent) for patients receiving chemotherapy alone and 74 percent (95 percent confidence interval, 69 to 78 percent) for those receiving chemoradiotherapy. The respective five-year estimates of overall survival were 90 percent (95 percent confidence interval, 87 to 93 percent) and 81 percent (95 percent confidence interval, 77 to 86 percent). In a multivariate analysis, event-free and overall survival rates were affected by treatment group, independently of tumor stage and the presence or absence of bulky disease., Conclusions: In patients under 61 years of age, chemotherapy with three cycles of ACVBP followed by sequential consolidation is superior to three cycles of CHOP plus radiotherapy for the treatment of low-risk localized lymphoma., (Copyright 2005 Massachusetts Medical Society.)

We conducted a randomized trial to compare the intensive conventional chemotherapy regimen ACVBP (doxorubicin, cyclophosphamide, vindesine, bleomycin, prednisone) with standard CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) in previously untreated patients with poor-risk aggressive lymphoma. Patients aged 61 to 69 years who had aggressive non-Hodgkin lymphoma with at least one prognostic factor of the age-adjusted international prognostic index (IPI) were included. ACVBP consisted of an induction phase of intensified chemotherapy and central nervous system (CNS) prophylaxis followed by a sequential consolidation phase. Of the 708 patients registered for the study, 635 were eligible. The rate of complete response was 58% in the ACVBP group and 56% in the CHOP group (P =.5). Treatment-related death occurred in 13% of the ACVBP group and 7% of the CHOP group (P =.014). At 5 years, the event-free survival was 39% in the ACVBP group and 29% in the CHOP group (P =.005). The overall survival was significantly longer for patients treated with ACVBP, at 5 years it was 46% compared with 38% for patients treated with CHOP (P =.036). CNS progressions or relapses were more frequent in the CHOP group (P =.004). Despite higher toxicity, the ACVBP regimen, used as first-line treatment for patients with poor-risk aggressive lymphoma, is superior to standard CHOP with regard to both event-free survival and overall survival.