• This trial evaluated frontline VR-CAP and R-CHOP therapy for patients with centrally confirmed non-GCB DLBCL.

  • There was no significant improvement in response rates or long-term outcomes with VR-CAP vs R-CHOP in previously untreated non-GCB DLBCL.

This phase 2 study evaluated whether substituting bortezomib for vincristine in frontline rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) therapy could improve efficacy in non-germinal center B-cell-like diffuse large B-cell lymphoma (non-GCB DLBCL), centrally confirmed by immunohistochemistry (Hans method). In total, 164 patients were randomized 1:1 to receive six 21-day cycles of rituximab 375 mg/m2, cyclophosphamide 750 mg/m2, and doxorubicin 50 mg/m2, all IV day 1, prednisone 100 mg/m2 orally days 1-5, plus either bortezomib 1.3 mg/m2 IV days 1, 4, 8, 11 (rituximab, cyclophosphamide, doxorubicin, and prednisone with bortezomib [VR-CAP]; n = 84) or vincristine 1.4 mg/m2 (maximum 2 mg) IV day 1 (R-CHOP; n = 80). There were no significant differences between VR-CAP and R-CHOP in complete response rate (64.5%, 66.2%; odds ratio [OR], 0.91; P = .80), overall response rate (93.4%, 98.6%; OR, 0.21; P = .11), progression-free survival (hazard ratio [HR], 1.12; P = .76), or overall survival (HR, 0.89; P = .75). Rates of grade ≥3 adverse events (AEs; 88%, 89%), serious AEs (38%, 34%), discontinuations due to AEs (7%, 3%), and deaths due to AEs (2%, 5%) were similar with VR-CAP and R-CHOP. Grade ≥3 peripheral neuropathy rates were 6% and 3%, respectively. VR-CAP did not improve efficacy vs R-CHOP in non-GCB DLBCL. This trial was registered at www.clinicaltrials.gov as #NCT01040871.

Diffuse large B-cell lymphoma (DLBCL) accounts for 25% to 35% of all new non-Hodgkin lymphoma diagnoses globally each year.1,2  Gene expression profiling (GEP) has identified at least 3 molecularly distinct DLBCL subtypes based on differential expression of genes involved in B-cell development,3-10  including activated B-cell-like (ABC), germinal center B-cell-like (GCB), and unclassified subtypes. GCB and non-GCB DLBCL subtypes can also be distinguished using immunohistochemistry (IHC) algorithms based on expression of markers including CD10, BCL6, and MUM-1; these algorithms have demonstrated 71% to 93% concordance with GEP.11-13 

Clinical outcomes differ considerably between GCB and non-GCB DLBCL,6,8,14-16  with overall survival (OS) significantly inferior in non-GCB patients (5-year OS rates: 16%-64% vs 59%-76% GCB).3,7,17  Standard frontline treatment of DLBCL is rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP)18,19 ; however, outcomes with R-CHOP are inferior in non-GCB vs GCB DLBCL.4,13,20-23  More efficacious therapies targeting the molecular basis of non-GCB DLBCL are required.

The nuclear factor-κB (NF-κB) pathway is constitutively activated in non-GCB DLBCL,3,4,24-27  and represents a target for therapeutic intervention. The proteasome inhibitor bortezomib is a potent inhibitor of the transcriptional activity and nuclear translocation of NF-ĸB28-32 ; as such, bortezomib may have specific utility in non-GCB DLBCL. Bortezomib plus chemotherapy has demonstrated substantial activity in patients with previously untreated and relapsed DLBCL,14,33,34  potentially overcoming the negative prognosis associated with non-GCB vs GCB disease.14,33  Bortezomib plus R-CHOP appears to produce clinical benefit in non-GCB DLBCL.33  However, due to overlapping toxicity between bortezomib and vincristine, a higher-than-expected rate of dose-limiting neurotoxicity has been observed with this combination.35  In newly diagnosed mantle cell lymphoma (MCL), substitution of vincristine by bortezomib in the rituximab, cyclophosphamide, doxorubicin, and prednisone with bortezomib (VR-CAP) regimen has resulted in superior efficacy vs R-CHOP, while avoiding excessive neurotoxicity,36  and VR-CAP has recently been approved for MCL by the US Food and Drug Administration (FDA).37 

LYM-2034 was a multinational, randomized phase 2 study designed to evaluate VR-CAP vs R-CHOP in patients with previously untreated non-GCB DLBCL, as classified by central review using the Hans algorithm.12  Here, we report efficacy and safety results after 24.9 months’ median follow-up from randomization.

Patients

Adults with previously untreated, de novo CD20+ non-GCB DLBCL, histologically confirmed by IHC at a central laboratory, were eligible. Other inclusion criteria were: stage II-IV disease (American Joint Committee on Cancer NHL Staging System) or stage I primary mediastinal (thymic) DLBCL; Eastern Cooperative Oncology Group (ECOG) performance status ≤2; at least 1 measurable site of disease per Revised Response Criteria for Malignant Lymphoma38 ; absolute neutrophil count ≥1500 cells per μL; platelets ≥100 × 109 cells per L (or ≥50 × 109 cells per L in the case of thrombocytopenia due to bone marrow infiltration); alanine aminotransferase and aspartate aminotransferase levels ≤3 × upper limit of normal (ULN); total bilirubin <2 mg/dL; and serum creatinine <1.5 × ULN or creatinine clearance ≥50 mL per minute.

Key exclusion criteria were: diagnosis of transformed lymphoma (follicular, T-cell, or Hodgkin lymphoma) or central nervous system lymphoma; previous chemotherapy or extended radiotherapy for lymphoma; grade ≥2 peripheral neuropathy; and uncontrolled or severe cardiovascular disease.

Study design and treatment

This randomized, open-label, phase 2 study was conducted at 57 centers in 18 countries worldwide between January 2010 and December 2011. Independent ethics committees or institutional review boards in the participating centers approved the study, which was conducted in accordance with the Declaration of Helsinki and Good Clinical Practice guidelines. Patients provided written informed consent.

During screening, patients were required to submit tumor biopsies for DLBCL subtyping. Formalin-fixed, paraffin-embedded (FFPE) tumor tissue blocks were shipped to a central laboratory (PhenoPath Laboratories, Seattle, WA) for subtyping by IHC using the Hans method.12  The average turnaround time for central review from shipment to diagnosis was 5 days. Postrandomization GEP confirmation of DLBCL subtype was performed in a subset of patients. Patients with centrally confirmed non-GCB DLBCL by IHC were randomized to receive up to six 21-day cycles of VR-CAP or R-CHOP. Based on the importance of International Prognostic Index (IPI) score for tumor response and outcomes in DLBCL,39  randomization was stratified by IPI score (low [0 or 1] vs low-intermediate [2] vs high-intermediate [3] vs high [4 or 5] risk). Treatment comprised rituximab 375 mg/m2, cyclophosphamide 750 mg/m2, doxorubicin 50 mg/m2, all IV on day 1, and prednisone 100 mg/m2 orally (PO) on days 1 to 5, plus either bortezomib 1.3 mg/m2 IV on days 1, 4, 8, 11 (VR-CAP) of each cycle or vincristine 1.4 mg/m2 (maximum 2 mg) IV on day 1 (R-CHOP).

Bortezomib dose reduction was permitted for: grade ≥3 neutropenia with fever; grade 4 neutropenia lasting >7 days; platelets <10 × 109 cells per L; or any grade ≥3 nonhematologic toxicity, excluding neuropathy, considered by the investigator to be bortezomib-related. Bortezomib dose reductions were required for grade 2/3 peripheral sensory neuropathy, and bortezomib was discontinued for grade 4 peripheral sensory neuropathy. Dose adjustments for rituximab, cyclophosphamide, doxorubicin, and vincristine were made per the relevant prescribing information and current clinical practice. Concomitant medications, including growth factors, for conditions other than DLBCL were permitted, as were all supportive therapies other than anticancer treatments. Short-course steroid treatment (prednisone or equivalent; maximum 10 days, not exceeding 100 mg per day) was permitted for advanced disease in patients who had entered screening and were awaiting randomization. Radiotherapy was prohibited.

Treatment was discontinued for progressive disease (PD) or relapse, unacceptable toxicity, >3-week delay in treatment due to insufficient recovery from toxicity or patient withdrawal. Short-term follow-up visits to assess disease progression were required if treatment was discontinued before PD; these visits were completed every 6 weeks for 18 weeks, and then every 8 weeks thereafter until PD. During short-term follow-up, patients were evaluated by physical examination and laboratory tests only. At any visit, if there was clinical evidence for, or suspicion of, PD, then a computed tomography (CT) and positron emission tomography (PET) scan were performed at the investigator’s discretion to document progression. All patients underwent long-term survival follow-up after documented PD or at the start of alternate antineoplastic therapy. Long-term follow-up visits were completed every 12 weeks until death.

Objectives

The primary objective was to determine the complete response (CR) rate with VR-CAP and R-CHOP. Secondary objectives were to determine: overall response rate (ORR; CR plus partial response [PR] rate), duration of response (DOR), time to next lymphoma therapy (TTNT), 1- and 2-year progression-free survival (PFS) and OS rates, safety of VR-CAP and R-CHOP, and concordance between IHC and GEP for non-GCB DLBCL subtyping.

GEP confirmation of DLBCL subtype

RNA samples extracted from FFPE tumor tissue provided to the central laboratory for IHC confirmation of non-GCB DLBCL subtype were also evaluated by GEP using quantitative reverse transcription–polymerase chain reaction (RT-PCR). Tumor RNA was evaluated using the SensationPlus FFPE reagent kit prior to GEP as described previously.40  GeneChip Human Genome U133 Plus 2.0 Arrays were used for RNA profiling.

Assessments

Response and PD were assessed by CT and whole body 18Ffluorodeoxyglucose (FDG)-PET scan at the end of cycles 3 and 6, and thereafter as clinically indicated, according to the Revised Response Criteria for Malignant Lymphoma.38  PET review relied on standard visual assessment.41  A positive scan was defined as focal or diffuse FDG uptake above background in a location incompatible with normal anatomy or physiology, without a specific standardized uptake value cutoff. PET-negative status was required for an overall response assessment of CR by combined CT + PET scan; patients with PET-non-negative status were assigned an overall response assessment of PR. All efficacy assessments were centrally reviewed by an Independent Radiology Review Committee (IRC). Adverse events (AEs) were graded per National Cancer Institute–Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 4.0.42 

Statistical analyses

Assuming CR rates of 70% and 60% for VR-CAP and R-CHOP, respectively, and using Simon randomized phase 2 design43  with 1 preplanned interim futility analysis, a sample size of 75 evaluable patients per arm provided ≥85% probability of observing a better or equal CR rate with VR-CAP than with R-CHOP. This sample size would achieve 78% power if the CR rate was 80% with VR-CAP vs 60% with R-CHOP, using a likelihood ratio test with a 2-sided alpha of 0.05. Assuming that 10% of patients would be response-inevaluable, a sample size of 164 patients (82 per arm) with IHC-confirmed non-GCB DLBCL was planned, requiring screening of ∼364 patients based on the assumption that the non-GCB subtype constitutes ∼45% of all DLBCL.

The cutoff date for the primary end point (CR rate) was June 6, 2012, and the study completion date was June 6, 2013. The intent-to-treat population included all randomized patients. The safety population included all patients who had received at least 1 dose of study drug. The response-evaluable population included all randomized patients who had received at least 1 dose of study drug, had at least 1 measurable lesion at baseline, and had at least 1 postbaseline response assessment. The stratified Cochran-Mantel-Haenszel test was used for between-arm comparisons of response rates in the response-evaluable population. Kaplan-Meier methodology was used for time-to-event analyses (1- and 2-year PFS, OS, and TTNT rates). TTNT was measured from randomization to the start of new treatment; death due to PD prior to subsequent treatment was considered an event. Hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated based on a Cox regression model, with stratified log-rank test used for between-arm comparisons.

Patients

In total, 364 patients consented to DLBCL subtype screening and tumor samples from 342 patients were subtyped by IHC; 194 patients with non-GCB DLBCL were identified and of these, 26 did not meet the inclusion criteria and 4 were excluded for other reasons. Thus, 164 patients were randomized to VR-CAP (n = 84) or R-CHOP (n = 80). Figure 1 summarizes patient flow through the study.

Figure 1

CONSORT diagram of patient flow through study. ITT, intent-to-treat.

Figure 1

CONSORT diagram of patient flow through study. ITT, intent-to-treat.

Close modal

Patient demographics and baseline disease characteristics were similar between the 2 arms, with a slight male preponderance in the R-CHOP group that was not statistically significant (Table 1). Median age was 59.0 years (range, 20-84), with 52 (32%) patients aged >65 years.

Table 1

Patient demographics and baseline disease characteristics (intent-to-treat population)

ParameterVR-CAP, n = 84R-CHOP, n = 80
n%n%
Age, y   
 Median 59.5 58.5 
 Range 20-84 23-83 
 Age >65 y 26 31 26 33 
Gender     
 Male 41 49 47 59 
Race     
 White 64 76 52 65 
 Asian 15 18 14 18 
 Other 14 18 
ECOG performance status     
 0/1 73 87 64 80 
 2 11 13 16 20 
IPI*     
 Low (0 or 1) 21 25 20 25 
 Low-intermediate (2) 20 24 19 24 
 High-intermediate (3) 27 32 26 33 
 High (4 or 5) 16 19 15 19 
Disease stage at study entry     
 I/II 23 27 18 22 
 III/IV 61 73 62 78 
Symptomatic disease 54 64 57 71 
ParameterVR-CAP, n = 84R-CHOP, n = 80
n%n%
Age, y   
 Median 59.5 58.5 
 Range 20-84 23-83 
 Age >65 y 26 31 26 33 
Gender     
 Male 41 49 47 59 
Race     
 White 64 76 52 65 
 Asian 15 18 14 18 
 Other 14 18 
ECOG performance status     
 0/1 73 87 64 80 
 2 11 13 16 20 
IPI*     
 Low (0 or 1) 21 25 20 25 
 Low-intermediate (2) 20 24 19 24 
 High-intermediate (3) 27 32 26 33 
 High (4 or 5) 16 19 15 19 
Disease stage at study entry     
 I/II 23 27 18 22 
 III/IV 61 73 62 78 
Symptomatic disease 54 64 57 71 

ECOG, Eastern Cooperative Oncology Group; IPI, International Prognostic Index.

*

Percentages may not equal 100% due to rounding.

Treatment exposure

Of 164 randomized patients, 2 in the VR-CAP arm and 1 in the R-CHOP arm did not receive any study drug; 161 patients were therefore included in the safety population. Treatment exposure is summarized in Table 2. Seventy-one (87%) and 73 (92%) patients completed 6 cycles of treatment in the VR-CAP and R-CHOP arms, respectively. The remaining 11 (13%) and 6 (8%) patients, respectively, discontinued treatment before completing 6 cycles; reasons for discontinuation are noted in Figure 1. Mean relative dose intensity was similar between the 2 regimens for common drugs. However, the rate of dose reduction for bortezomib in the VR-CAP arm (37%) was greater than that for vincristine in the R-CHOP arm (5%).

Table 2

Summary of treatment exposure (safety population)

ParameterVR-CAP, n = 82R-CHOP, n = 79
Completed 6 cycles of treatment, n (%) 71 (87) 73 (92) 
Overall treatment duration in wk, median (range) 16.7 (1-27) 16.0 (1-21) 
Median doses received, n   
 Rituximab 
 Doxorubicin 
 Cyclophosphamide 
 Prednisone 30 30 
 Bortezomib/vincristine 22 
Patients receiving 6 cycles, n (%)   
 Rituximab 72 (88) 73 (92) 
 Doxorubicin 70 (85) 73 (92) 
 Cyclophosphamide 70 (85) 73 (92) 
 Prednisone 72 (88) 73 (92) 
 Bortezomib/vincristine 67 (82) 72 (91) 
Relative dose intensity, mean (SD)   
 Rituximab 1.00 (0.006) 1.00 (0.009) 
 Doxorubicin 0.96 (0.080) 0.97 (0.082) 
 Cyclophosphamide 0.96 (0.080) 0.97 (0.056) 
 Prednisone 0.99 (0.079) 0.96 (0.101) 
 Bortezomib/vincristine* 0.85 (0.140) 0.79 (0.102) 
Dose or schedule modified, n (%) 70 (85) 38 (48) 
 Any dose reduction 46 (56) 23 (29) 
 Dose bortezomib/vincristine withheld, n (%) 63 (77) 3 (4) 
 Dose of bortezomib/vincristine reduced, n (%) 30 (37) 4 (5) 
ParameterVR-CAP, n = 82R-CHOP, n = 79
Completed 6 cycles of treatment, n (%) 71 (87) 73 (92) 
Overall treatment duration in wk, median (range) 16.7 (1-27) 16.0 (1-21) 
Median doses received, n   
 Rituximab 
 Doxorubicin 
 Cyclophosphamide 
 Prednisone 30 30 
 Bortezomib/vincristine 22 
Patients receiving 6 cycles, n (%)   
 Rituximab 72 (88) 73 (92) 
 Doxorubicin 70 (85) 73 (92) 
 Cyclophosphamide 70 (85) 73 (92) 
 Prednisone 72 (88) 73 (92) 
 Bortezomib/vincristine 67 (82) 72 (91) 
Relative dose intensity, mean (SD)   
 Rituximab 1.00 (0.006) 1.00 (0.009) 
 Doxorubicin 0.96 (0.080) 0.97 (0.082) 
 Cyclophosphamide 0.96 (0.080) 0.97 (0.056) 
 Prednisone 0.99 (0.079) 0.96 (0.101) 
 Bortezomib/vincristine* 0.85 (0.140) 0.79 (0.102) 
Dose or schedule modified, n (%) 70 (85) 38 (48) 
 Any dose reduction 46 (56) 23 (29) 
 Dose bortezomib/vincristine withheld, n (%) 63 (77) 3 (4) 
 Dose of bortezomib/vincristine reduced, n (%) 30 (37) 4 (5) 

SD, standard deviation.

*

The dose of vincristine was capped at 2 mg.

Proportion of patients with ≥1 dose of bortezomib (VR-CAP arm) or vincristine (R-CHOP arm) withheld or reduced.

Efficacy

A total of 150 patients were evaluable for response (VR-CAP, n = 76; R-CHOP, n = 74). Reasons for exclusion from the response-evaluable population are noted in Figure 1. Based on IRC assessment, there was no statistically significant difference between VR-CAP and R-CHOP for the primary end point, CR rate (64.5% vs 66.2%; odds ratio [OR], 0.91; P = .80), or for the secondary end point, ORR (93.4% vs 98.6%; OR, 0.21; P = .11) (Table 3). In both arms, median time to response was 2.1 months. There were no statistically significant differences between VR-CAP and R-CHOP with regard to durable (lasting ≥6 months) CR rate (61.8% vs 56.8%; OR, 1.25; P = .52) or durable CR/PR rate (75.0% vs 78.4%; OR, 0.84; P = .65) (Table 3). Fourteen (18.4%) and 15 (20.3%) patients had a DOR of <6 months in the VR-CAP and R-CHOP arms, respectively; of these patients, 7 and 11, respectively, were censored without PD. Subgroup analyses demonstrated no statistically significant differences between VR-CAP and R-CHOP in CR rate or ORR by baseline IPI score (supplemental Table 1, see supplemental Data available at the Blood Web site).

Table 3

Best ORR and durable response rates per Independent Radiology Review Committee assessment (response-evaluable population)

Response rate% (90% CI)Odds ratio* (95% CI)P
VR-CAP, n = 76R-CHOP, n = 74
CR 64.5 (55.4-73.5) 66.2 (57.1-75.3) 0.91 (0.46-1.81) .80 
PR 28.9 32.4 – – 
ORR (CR + PR) 93.4 (88.7-98.1) 98.6 (96.4-100.0) 0.21 (0.03-1.76) .11 
Durable CR 61.8 (52.6-71.0) 56.8 (47.3-66.3) 1.25 (0.64-2.42) .52 
Durable CR/PR 75.0 (66.8-83.2) 78.4 (70.5-86.3) 0.84 (0.39-1.79) .65 
Response rate% (90% CI)Odds ratio* (95% CI)P
VR-CAP, n = 76R-CHOP, n = 74
CR 64.5 (55.4-73.5) 66.2 (57.1-75.3) 0.91 (0.46-1.81) .80 
PR 28.9 32.4 – – 
ORR (CR + PR) 93.4 (88.7-98.1) 98.6 (96.4-100.0) 0.21 (0.03-1.76) .11 
Durable CR 61.8 (52.6-71.0) 56.8 (47.3-66.3) 1.25 (0.64-2.42) .52 
Durable CR/PR 75.0 (66.8-83.2) 78.4 (70.5-86.3) 0.84 (0.39-1.79) .65 
*

R-CHOP vs VR-CAP; an odds ratio of >1 is in favor of VR-CAP.

Generalized Cochran-Mantel-Haenszel test for general association (stratified by International Prognostic Index score).

Durable response defined as CR or PR lasting ≥6 months.

Median follow-up among all patients was 24.9 months (range, 0-40) (VR-CAP, 23.8 months [range, 0-40]; R-CHOP, 26.0 months [range, 0-37]). Median PFS, OS, and TTNT in the ITT population were not estimable due to insufficient events. For VR-CAP and R-CHOP, respectively, there were 18 (21%) and 16 (20%) PD/death events, 15 (18%) and 16 (20%) deaths, and 25 (30%) and 20 (25%) new treatments or deaths due to PD events. Kaplan-Meier analyses of PFS and OS are shown in Figure 2. For VR-CAP and R-CHOP, respectively, 2-year PFS rates were 76.2% and 77.1%, 2-year OS rates were 80.1% and 79.0%, and 2-year TTNT rates were 69.3% and 71.8% (Table 4). There were no significant between-arm differences in PFS (HR, 1.12; P = .76), OS (HR, 0.89; P = .75), or TTNT rates (HR, 1.25; P = .49). Two-year PFS and OS rates appeared more favorable in patients with lower vs higher baseline IPI score; however, there were no overt between-arm differences (supplemental Table 2). Two-year PFS and OS rates appeared higher in patients with PET-negative vs PET-non-negative status (overall CR vs PR by combined CT + PET assessment) (supplemental Table 3), an observation that was more notable in the VR-CAP arm; however, these results should be interpreted cautiously due to the low number of events.

Figure 2

Kaplan-Meier analysis of survival outcomes. (A) PFS and (B) OS by treatment arm.

Figure 2

Kaplan-Meier analysis of survival outcomes. (A) PFS and (B) OS by treatment arm.

Close modal
Table 4

One- and 2-year rates of PFS, OS, and patients remaining treatment-free (intent-to-treat population)

Outcome% (95% CI)Hazard ratio* (95% CI)P
VR-CAP, n = 84R-CHOP, n = 80
PFS rate     
 1-y 80.0 (69.0-87.5) 82.3 (71.4-89.3) 1.12 (0.57-2.20) .76 
 2-y 76.2 (64.2-84.7) 77.1 (65.1-85.4) 
OS rate     
 1-y 91.2 (82.3-95.7) 85.9 (76.0-92.0) 0.89 (0.44-1.81) .75 
 2-y 80.1 (69.0-87.5) 79.0 (67.9-86.6) 
Treatment-free rate§     
 1-y 70.6 (59.2-79.4) 78.4 (67.2-86.2) 1.25 (0.69-2.24) .49 
 2-y 69.3 (57.8-78.3) 71.8 (59.6-80.9) 
Outcome% (95% CI)Hazard ratio* (95% CI)P
VR-CAP, n = 84R-CHOP, n = 80
PFS rate     
 1-y 80.0 (69.0-87.5) 82.3 (71.4-89.3) 1.12 (0.57-2.20) .76 
 2-y 76.2 (64.2-84.7) 77.1 (65.1-85.4) 
OS rate     
 1-y 91.2 (82.3-95.7) 85.9 (76.0-92.0) 0.89 (0.44-1.81) .75 
 2-y 80.1 (69.0-87.5) 79.0 (67.9-86.6) 
Treatment-free rate§     
 1-y 70.6 (59.2-79.4) 78.4 (67.2-86.2) 1.25 (0.69-2.24) .49 
 2-y 69.3 (57.8-78.3) 71.8 (59.6-80.9) 
*

R-CHOP vs VR-CAP; a HR of <1 indicates an advantage for VR-CAP.

Based on the log-rank test (stratified by International Prognostic Index score).

PFS rate by Independent Radiology Review Committee assessment.

§

Patients who had not received subsequent lymphoma therapy or had not died due to progressive disease.

Twenty-three (27%) patients in the VR-CAP arm and 19 (24%) in the R-CHOP arm received subsequent treatment. The most common agents received as subsequent therapy (VR-CAP vs R-CHOP) were rituximab (17% vs 11%), cytarabine (17% vs 10%), etoposide (16% vs 10%), dexamethasone (13% vs 6%), and cisplatin (12% vs 6%). Nine patients in the VR-CAP arm and 4 in the R-CHOP arm went on to receive high-dose therapy and autologous stem cell transplantation (HDT-ASCT) during subsequent therapy. For VR-CAP, details on CD34+ stem cell collection were available for 7 patients. After mobilization with G-CSF (n = 4) or chemotherapy (n = 3), CD34+ stem cell collection was successful in all 7 patients with a median yield of 6 × 106 cells/kg.

Concordance between IHC and GEP for non-GCB subtype classification

GEP confirmation of DLBCL subtype was performed in 103 patients randomized after IHC subtyping (VR-CAP, n = 53; R-CHOP, n = 50); in this population, the CR rate was 62.3% for VR-CAP (33 of 53) and 62.0% for R-CHOP (31 of 50). Ninety-one patients (n = 45 and n = 46, respectively) were confirmed to be non-GCB by GEP (88.3% concordance); in this population, the CR rate was 60.0% for VR-CAP (27 of 45) and 60.9% for R-CHOP (28 of 46). There were no significant between-arm differences in PFS (HR, 0.91; P = .84) or OS (HR, 1.08; P = .87) in patients with GEP-confirmed non-GCB DLBCL (supplemental Table 4).

Safety

VR-CAP and R-CHOP had similar overall safety profiles (supplemental Table 5). Rates of all-grade AEs (99% vs 100%), grade ≥3 AEs (88% vs 89%), serious AEs (SAEs) (38% vs 34%), treatment discontinuation due to AEs (7% vs 3%), and on-study deaths due to AEs (2% vs 5%) were similar for VR-CAP and R-CHOP. Table 5 summarizes the most common AEs in both treatment arms.

Table 5

Most common treatment-emergent AEs of any grade (≥15% of patients in either arm) and grade ≥3 (≥5% in either arm; safety population)

Treatment-emergent AEsVR-CAP, n = 82R-CHOP, n = 79
n%n%
Any grade     
 Any AE 81 99 79 100 
 Neutropenia 65 79 66 84 
 Thrombocytopenia 40 49 
 Diarrhea 26 32 11 14 
 PN NEC 26 32 17 22 
 Vomiting 25 31 11 14 
 Constipation 24 29 25 32 
 Nausea 22 27 20 25 
 Pyrexia 22 27 18 23 
 Fatigue 21 26 11 14 
 Anemia 19 23 17 22 
 Leukopenia 19 23 24 30 
 Cough 14 17 11 14 
 Peripheral edema 14 17 
 Decreased appetite 13 16 
 Paresthesia 12 15 10 13 
 Asthenia 10 12 14 18 
 Febrile neutropenia 16 20 
Grade ≥3     
 Any AE 72 88 70 89 
 Neutropenia 64 78 64 81 
 Thrombocytopenia 30 37 
 Leukopenia 18 22 18 23 
 Febrile neutropenia 16 20 
 Hyperglycemia 
 PN NEC 
 Anemia 
 Diarrhea 
 Pneumonia 
 Vomiting 
Treatment-emergent AEsVR-CAP, n = 82R-CHOP, n = 79
n%n%
Any grade     
 Any AE 81 99 79 100 
 Neutropenia 65 79 66 84 
 Thrombocytopenia 40 49 
 Diarrhea 26 32 11 14 
 PN NEC 26 32 17 22 
 Vomiting 25 31 11 14 
 Constipation 24 29 25 32 
 Nausea 22 27 20 25 
 Pyrexia 22 27 18 23 
 Fatigue 21 26 11 14 
 Anemia 19 23 17 22 
 Leukopenia 19 23 24 30 
 Cough 14 17 11 14 
 Peripheral edema 14 17 
 Decreased appetite 13 16 
 Paresthesia 12 15 10 13 
 Asthenia 10 12 14 18 
 Febrile neutropenia 16 20 
Grade ≥3     
 Any AE 72 88 70 89 
 Neutropenia 64 78 64 81 
 Thrombocytopenia 30 37 
 Leukopenia 18 22 18 23 
 Febrile neutropenia 16 20 
 Hyperglycemia 
 PN NEC 
 Anemia 
 Diarrhea 
 Pneumonia 
 Vomiting 

PN NEC, peripheral neuropathy not elsewhere classified, including peripheral sensory neuropathy, neuropathy peripheral, peripheral sensorimotor neuropathy, and peripheral motor neuropathy.

Focusing on the most common grade ≥3 AEs, VR-CAP was associated with neutropenia (78%), thrombocytopenia (37%), and leukopenia (22%), whereas with R-CHOP they were neutropenia (81%), leukopenia (23%), and febrile neutropenia (20%). Grade ≥3 AEs occurring with a ≥5% difference between VR-CAP and R-CHOP were thrombocytopenia (37% vs 3%), febrile neutropenia (9% vs 20%), and hyperglycemia (6% vs 0%) (Table 5). Grade ≥3 peripheral neuropathy not elsewhere classified (PN NEC) occurred in 5 (6%) and 2 (3%) patients in the VR-CAP and R-CHOP arms, respectively.

SAEs occurring in ≥5% of patients in either arm were febrile neutropenia (9% each), neutropenia (5% vs 6%), pyrexia (6% vs 0%), and pneumonia (5% vs 4%). The most common AEs (>2% of patients in either arm) leading to dose reduction were neutropenia (21%), thrombocytopenia (11%), peripheral sensory neuropathy (10%), neuralgia (9%), and febrile neutropenia (6%) with VR-CAP, and neutropenia (14%), febrile neutropenia (4%), and hypertension (3%) with R-CHOP. The only AEs leading to discontinuation in >1 patient were PN NEC and neutropenia (each n = 2, all VR-CAP).

Fifteen (18%) VR-CAP and 16 (20%) R-CHOP patients had died at data cutoff. There were 2 (2%) on-study deaths due to treatment-emergent AEs in the VR-CAP arm (cardiac arrest, upper gastrointestinal hemorrhage; each n = 1) and 3 (4%) in the R-CHOP arm (cardiac arrest, septic shock, and respiratory failure, each n = 1).

In this phase 2 randomized study, substituting bortezomib for vincristine in the standard R-CHOP regimen did not lead to a significant improvement in CR rate (primary end point), ORR, or durable response rate in patients with previously untreated, IHC-confirmed non-GCB DLBCL. In addition, 2-year PFS, TTNT, and OS rates did not differ significantly between the arms. Subsequent therapies were generally similar between the 2 treatment groups. Few patients received HDT-ASCT following VR-CAP or R-CHOP, reflecting common treatment practice for previously untreated DLBCL.18,19  At the time of this final analysis, PFS and OS data had not reached full maturity; however, findings from a recent report44  indicate that 2-year PFS is a good surrogate marker for long-term outcomes in DLBCL, and therefore more extended follow-up is unlikely to reveal a survival benefit for VR-CAP. The lack of efficacy improvement with VR-CAP in non-GCB DLBCL is in contrast with recent observations from a phase 3 study in newly diagnosed MCL, in which VR-CAP produced superior PFS, CR rates, time to progression, and TTNT as compared with R-CHOP.36 

The outcomes observed with R-CHOP administered as six 21-day cycles (per common treatment practice at the time of study design: now increasingly administered as eight 21-day cycles or six 14-day cycles)45-47  were largely consistent with previous studies of DLBCL.4,13,20,45  The median age of patients in the present study was 59.0 years, somewhat lower than that of newly diagnosed DLBCL patients typically observed in epidemiological studies,48,49  but consistent with data from previous clinical trials.11,45,50,51 

To our knowledge, this is the first reported study to prospectively randomize patients with non-GCB DLBCL confirmed centrally prior to treatment. Only patients with non-GCB DLBCL classified by the Hans IHC method12  were randomized to VR-CAP or R-CHOP therapy. The confirmation of non-GCB diagnosis prior to randomization requires 2 considerations in the interpretation of the data. First, the concern for a delay in treatment caused by the central review procedure (only 5 days on average) may have excluded patients with the worst disease prognosis from being considered for participation in the trial, which may explain the relatively good outcomes in both arms of the study. Second, the IHC DLBCL subtype classification method was well accepted at the time of initiation of this study, but has subsequently become subject to discussion. For example, Gutiérrez-García et al demonstrated a correlation between the Hans and other algorithms and GEP, but found a higher percentage of misclassified GCB cases compared with non-GCB cases.52  The alternative IHC algorithms developed by Choi et al11  and Meyer et al (Tally method)13  have classified DLBCL subtype more reliably than other algorithms, including the Hans method.12  The Tally algorithm in particular, which tallies antibody results without order precedence, has demonstrated the best concordance with GEP (93%), while maintaining prognostic significance.13  For the present trial, development of the protocol preceded the Choi and Meyer publications, hence the rationale for using the globally available Hans IHC method for DLBCL classification. A recent metaanalysis of studies on GEP or IHC classification in DLBCL and impact on PFS and OS suggests superiority of GEP.53  However, in the present study, non-GCB subtype classified by IHC was subsequently confirmed by GEP in a representative subset of the total patient population. This demonstrated that the Hans IHC algorithm had 88.3% concordance with GEP in identifying the non-GCB subtype, and also showed that both methods were equally effective in predicting CR. It is therefore unlikely that DLBCL misclassification had a major impact on the results of this study.

Interestingly, some major clinical trials45,54,55  and registry studies56  evaluating R-CHOP treatment in patients with DLBCL have not confirmed the worse prognosis of the non-GCB phenotype when classified by the Hans IHC method. Differences in response have, however, been reported with the addition of etoposide to treatment.15,55,57,58 

It is possible that the lack of difference in efficacy between VR-CAP and R-CHOP could be explained by limited differential efficacy with the addition of bortezomib or vincristine to the R-CHP base in frontline DLBCL. Genetic analyses have shown that DLBCL is characterized by a number of recurrent mutations along the B-cell receptor activation pathway (eg, in MyD88 or CARD11) leading to constitutive activation of NF-κB.59,60  Although inhibition of NF-κB signaling is among the mechanisms of action of bortezomib,28-32  not all compounds that inhibit the different steps of signal transduction pathways provide an equivalent clinical effect. Recent studies of ibrutinib, which inhibits upstream Bruton tyrosine kinase, have demonstrated proof-of-principle in a subset of patients with non-GCB DLBCL,61,62  whereas a phase 3 trial of enzastaurin, an inhibitor of the intermediate signal transducer PKC-β, failed to show clinical benefit in DLBCL, despite a strong association between high PKC-β expression and adverse prognosis.63-69  Thus, although bortezomib-mediated inhibition of key B-cell activation molecules underlying non-GCB DLBCL biology may have sound scientific basis, bortezomib may not be sufficiently active in the current dose, schedule, and combination for the treatment of non-GCB disease. Of note, recent in vitro data have demonstrated an unexpected role for bromodomain extraterminal domain proteins in regulating IκB kinase activity70  in DLBCL, suggesting that mere inhibition of NF-κB alone may be insufficient to kill lymphoma cells.71 

An alternative explanation for bortezomib not being sufficiently active is that the NF-ĸB signature alone is not responsible for the adverse prognosis of non-GCB DLBCL, but instead enriches for a subpopulation that owes its adverse prognosis to another molecular mechanism. Besides the upregulated genes in non-GCB DLBCL, including BCL2, c-FLIP, and cyclin D2, thought to be driven by constitutive activation of NF-ĸB,24,72  other genes are dysregulated73,74  but their contribution at the protein level to the inferior prognosis of non-GCB patients is unclear. In recent years, attention has focused on identifying additional molecular markers that are predictive of outcomes in DLBCL. B-cell lymphoma patients with translocation of both MYC and BCL2 (“double-hit” lymphomas) have very poor prognosis.75-79  This dual translocation is observed in ∼5% of DLBCL cases.80  Overexpression of both MYC and BCL2 protein by IHC, with or without corresponding gene rearrangement, is also observed in approximately one-third of DLBCL cases,80,81  and is associated with poor prognosis.80-83  In a cohort of nearly 900 de novo DLBCL patients treated with R-CHOP, MYC/BCL2 coexpression was associated with an aggressive clinical course and poor prognosis, irrespective of DLBCL subclass, but occurred significantly more commonly in the ABC (non-GCB) than GCB subtype.81  MYC/BCL2 coexpression by IHC may, therefore, be a better prognostic factor in DLBCL than non-GCB subtype; however, other data argue against this.45  Evaluation of MYC/BCL2 coexpression in the present dataset may provide further insight into our results; however, such analyses were precluded by lack of sample availability.

VR-CAP and R-CHOP showed similar safety profiles, with similar rates of all-grade AEs, grade ≥3 AEs, SAEs, discontinuations due to AEs, and on-study deaths. However, grade ≥3 febrile neutropenia rates were lower, and grade ≥3 thrombocytopenia rates were higher, with VR-CAP, likely reflecting the different regimen components. Rates of dose reduction were numerically higher for bortezomib in VR-CAP than for vincristine in R-CHOP, an observation that may be influenced by asymmetry in potential dose administrations between the arms. Higher rates of grade ≥3 thrombocytopenia and dose modifications with VR-CAP were also observed in a recent phase 3 study in newly diagnosed MCL.36  Although any-grade PN NEC rates appeared higher with VR-CAP vs R-CHOP, rates of grade ≥3 PN NEC and discontinuations due to PN NEC were similar between arms. In this study, bortezomib replaced vincristine rather than being added to R-CHOP, due to concerns over potential overlapping neurotoxicity with the 2 agents.35  Since commencement of LYM-2034, other reports have suggested that bortezomib plus R-CHOP is tolerable (with acceptable and manageable neurotoxicity) in DLBCL patients, albeit using 2 doses of bortezomib 1.3 mg/m2 per cycle (days 1, 4) rather than the 4 used here.33,84  This modified schedule is being assessed in a randomized, US-based phase 2 study in previously untreated non-GCB DLBCL (NCT00931918).

In summary, VR-CAP does not improve CR rate, ORR, 2-year PFS rate, or 2-year OS rate in patients with IHC-confirmed non-GCB DLBCL when compared with the current standard of care, R-CHOP. This study highlights the need for better identification of markers of poor prognosis in DLBCL and of markers for patients who could achieve better outcomes with bortezomib-based therapy vs standard R-CHOP.

Presented in poster format at the 12th International Conference on Malignant Lymphoma, Lugano, Switzerland, June 9-22, 2013.

The online version of this article contains a data supplement.

The publication costs of this article were defrayed in part by page charge payment. Therefore, and solely to indicate this fact, this article is hereby marked “advertisement” in accordance with 18 USC section 1734.

The authors thank all patients who participated and their families, as well as the investigators and staff at all LYM-2034 clinical sites for their valuable contribution to this study. They acknowledge Emma Landers of FireKite, an Ashfield company, part of UDG Healthcare plc, for writing support during the development of this manuscript, which was funded by Millennium Pharmaceuticals, Inc. and Janssen Global Services, LLC.

This work was supported by Janssen Research & Development, LLC.

Contribution: F.O undertook provision of study materials and patients; F.O., O.S., E.O., H.-S.E., M.S.T., J.R., V.P., D.R., S.C., H.v.d.V., and B.F. were responsible for collection and assembly of data; F.O., D.R., S.C., E.Z., C.E., and B.F. were responsible for data analysis and interpretation; D.R., H.v.d.V., and A.R. were responsible for the conception and design of the study; and all authors were involved with the writing of the manuscript and the final approval of the manuscript to be published.

Conflict-of-interest disclosure: F.O., O.S., E.O., H.-S.E., V.P., and B.F. declare no competing financial interests; M.S.T. has received honoraria (Amgen), holds a consultant or advisory role (Amgen, Affymetrix, Janssen), and has received travel and/or accommodation expenses (Amgen, Roche); J.R. holds a consulting or advisory role (Roche); D.R. is under employment (Janssen), holds equity ownership (Johnson & Johnson) and patents, loyalties, or other intellectual property (Janssen), and has received travel and/or accommodation expenses (Janssen); S.C. and H.v.d.V. are under employment (Janssen), hold equity ownership (Johnson & Johnson), and have received research funding (Janssen) and travel and/or accommodation expenses (Janssen); E.Z., C.E., and A.R. are under employment (Janssen) and hold equity ownership (Johnson & Johnson).

The current affiliation for H.v.d.V. is Millennium Pharmaceuticals, Inc, Cambridge, MA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited.

Correspondence: Fritz Offner, Department of Hematology, University Hospital Ghent, De Pintelaan 185, 9000 Ghent, Belgium; e-mail: [email protected].

1
Cultrera
 
JL
Dalia
 
SM
Diffuse large B-cell lymphoma: current strategies and future directions.
Cancer Contr
2012
, vol. 
19
 
3
(pg. 
204
-
213
)
2
Fayad
 
L
Younes
 
A
Novel treatment strategies for aggressive non-Hodgkin’s lymphoma.
Expert Opin Pharmacother
2006
, vol. 
7
 
6
(pg. 
733
-
748
)
3
Alizadeh
 
AA
Eisen
 
MB
Davis
 
RE
et al. 
Distinct types of diffuse large B-cell lymphoma identified by gene expression profiling.
Nature
2000
, vol. 
403
 
6769
(pg. 
503
-
511
)
4
Lenz
 
G
Wright
 
G
Dave
 
SS
et al. 
Lymphoma/Leukemia Molecular Profiling Project
Stromal gene signatures in large-B-cell lymphomas.
N Engl J Med
2008
, vol. 
359
 
22
(pg. 
2313
-
2323
)
5
Lossos
 
IS
Molecular pathogenesis of diffuse large B-cell lymphoma.
J Clin Oncol
2005
, vol. 
23
 
26
(pg. 
6351
-
6357
)
6
Nedomova
 
R
Papajik
 
T
Prochazka
 
V
Indrak
 
K
Jarosova
 
M
Cytogenetics and molecular cytogenetics in diffuse large B-cell lymphoma (DLBCL).
Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub
2013
, vol. 
157
 
3
(pg. 
239
-
247
)
7
Rosenwald
 
A
Wright
 
G
Chan
 
WC
et al. 
Lymphoma/Leukemia Molecular Profiling Project
The use of molecular profiling to predict survival after chemotherapy for diffuse large-B-cell lymphoma.
N Engl J Med
2002
, vol. 
346
 
25
(pg. 
1937
-
1947
)
8
Bea
 
S
Zettl
 
A
Wright
 
G
et al. 
Lymphoma/Leukemia Molecular Profiling Project
Diffuse large B-cell lymphoma subgroups have distinct genetic profiles that influence tumor biology and improve gene-expression-based survival prediction.
Blood
2005
, vol. 
106
 
9
(pg. 
3183
-
3190
)
9
Shipp
 
MA
Ross
 
KN
Tamayo
 
P
et al. 
Diffuse large B-cell lymphoma outcome prediction by gene-expression profiling and supervised machine learning.
Nat Med
2002
, vol. 
8
 
1
(pg. 
68
-
74
)
10
Wright
 
G
Tan
 
B
Rosenwald
 
A
Hurt
 
EH
Wiestner
 
A
Staudt
 
LM
A gene expression-based method to diagnose clinically distinct subgroups of diffuse large B cell lymphoma.
Proc Natl Acad Sci USA
2003
, vol. 
100
 
17
(pg. 
9991
-
9996
)
11
Choi
 
WW
Weisenburger
 
DD
Greiner
 
TC
et al. 
A new immunostain algorithm classifies diffuse large B-cell lymphoma into molecular subtypes with high accuracy.
Clin Cancer Res
2009
, vol. 
15
 
17
(pg. 
5494
-
5502
)
12
Hans
 
CP
Weisenburger
 
DD
Greiner
 
TC
et al. 
Confirmation of the molecular classification of diffuse large B-cell lymphoma by immunohistochemistry using a tissue microarray.
Blood
2004
, vol. 
103
 
1
(pg. 
275
-
282
)
13
Meyer
 
PN
Fu
 
K
Greiner
 
TC
et al. 
Immunohistochemical methods for predicting cell of origin and survival in patients with diffuse large B-cell lymphoma treated with rituximab.
J Clin Oncol
2011
, vol. 
29
 
2
(pg. 
200
-
207
)
14
Dunleavy
 
K
Pittaluga
 
S
Czuczman
 
MS
et al. 
Differential efficacy of bortezomib plus chemotherapy within molecular subtypes of diffuse large B-cell lymphoma.
Blood
2009
, vol. 
113
 
24
(pg. 
6069
-
6076
)
15
Thieblemont
 
C
Briere
 
J
Mounier
 
N
et al. 
The germinal center/activated B-cell subclassification has a prognostic impact for response to salvage therapy in relapsed/refractory diffuse large B-cell lymphoma: a bio-CORAL study.
J Clin Oncol
2011
, vol. 
29
 
31
(pg. 
4079
-
4087
)
16
Young
 
RM
Staudt
 
LM
Targeting pathological B cell receptor signalling in lymphoid malignancies.
Nat Rev Drug Discov
2013
, vol. 
12
 
3
(pg. 
229
-
243
)
17
Rosenwald
 
A
Wright
 
G
Leroy
 
K
et al. 
Molecular diagnosis of primary mediastinal B cell lymphoma identifies a clinically favorable subgroup of diffuse large B cell lymphoma related to Hodgkin lymphoma.
J Exp Med
2003
, vol. 
198
 
6
(pg. 
851
-
862
)
18
National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines in Clinical Oncology (NCCN Guidelines): Non-Hodgkin’s Lymphomas. Version 4.2014. Fort Washington, PA: NCCN; 2014
19
Ghielmini
 
M
Vitolo
 
U
Kimby
 
E
et al. 
Panel Members of the 1st ESMO Consensus Conference on Malignant Lymphoma
ESMO Guidelines consensus conference on malignant lymphoma 2011 part 1: diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL) and chronic lymphocytic leukemia (CLL).
Ann Oncol
2013
, vol. 
24
 
3
(pg. 
561
-
576
)
20
Fu
 
K
Weisenburger
 
DD
Choi
 
WW
et al. 
Addition of rituximab to standard chemotherapy improves the survival of both the germinal center B-cell-like and non-germinal center B-cell-like subtypes of diffuse large B-cell lymphoma.
J Clin Oncol
2008
, vol. 
26
 
28
(pg. 
4587
-
4594
)
21
Malumbres
 
R
Chen
 
J
Tibshirani
 
R
et al. 
Paraffin-based 6-gene model predicts outcome in diffuse large B-cell lymphoma patients treated with R-CHOP.
Blood
2008
, vol. 
111
 
12
(pg. 
5509
-
5514
)
22
Natkunam
 
Y
Farinha
 
P
Hsi
 
ED
et al. 
LMO2 protein expression predicts survival in patients with diffuse large B-cell lymphoma treated with anthracycline-based chemotherapy with and without rituximab.
J Clin Oncol
2008
, vol. 
26
 
3
(pg. 
447
-
454
)
23
Rimsza
 
LM
Leblanc
 
ML
Unger
 
JM
et al. 
Gene expression predicts overall survival in paraffin-embedded tissues of diffuse large B-cell lymphoma treated with R-CHOP.
Blood
2008
, vol. 
112
 
8
(pg. 
3425
-
3433
)
24
Davis
 
RE
Brown
 
KD
Siebenlist
 
U
Staudt
 
LM
Constitutive nuclear factor kappaB activity is required for survival of activated B cell-like diffuse large B cell lymphoma cells.
J Exp Med
2001
, vol. 
194
 
12
(pg. 
1861
-
1874
)
25
Hailfinger
 
S
Lenz
 
G
Ngo
 
V
et al. 
Essential role of MALT1 protease activity in activated B cell-like diffuse large B-cell lymphoma [published correction appears in Proc Natl Acad Sci USA. 2013;110(7):2677].
Proc Natl Acad Sci USA
2009
, vol. 
106
 
47
(pg. 
19946
-
19951
)
26
Lam
 
LT
Wright
 
G
Davis
 
RE
et al. 
Cooperative signaling through the signal transducer and activator of transcription 3 and nuclear factor-kappaB pathways in subtypes of diffuse large B-cell lymphoma.
Blood
2008
, vol. 
111
 
7
(pg. 
3701
-
3713
)
27
Ngo
 
VN
Davis
 
RE
Lamy
 
L
et al. 
A loss-of-function RNA interference screen for molecular targets in cancer.
Nature
2006
, vol. 
441
 
7089
(pg. 
106
-
110
)
28
Allen
 
C
Saigal
 
K
Nottingham
 
L
Arun
 
P
Chen
 
Z
Van Waes
 
C
Bortezomib-induced apoptosis with limited clinical response is accompanied by inhibition of canonical but not alternative nuclear factor-kappaB subunits in head and neck cancer.
Clin Cancer Res
2008
, vol. 
14
 
13
(pg. 
4175
-
4185
)
29
Ayala
 
G
Yan
 
J
Li
 
R
et al. 
Bortezomib-mediated inhibition of steroid receptor coactivator-3 degradation leads to activated Akt.
Clin Cancer Res
2008
, vol. 
14
 
22
(pg. 
7511
-
7518
)
30
Cusack
 
JC
Liu
 
R
Houston
 
M
et al. 
Enhanced chemosensitivity to CPT-11 with proteasome inhibitor PS-341: implications for systemic nuclear factor-kappaB inhibition.
Cancer Res
2001
, vol. 
61
 
9
(pg. 
3535
-
3540
)
31
Hideshima
 
T
Chauhan
 
D
Richardson
 
P
et al. 
NF-kappa B as a therapeutic target in multiple myeloma.
J Biol Chem
2002
, vol. 
277
 
19
(pg. 
16639
-
16647
)
32
Bu
 
R
Hussain
 
AR
Al-Obaisi
 
KA
Ahmed
 
M
Uddin
 
S
Al-Kuraya
 
KS
Bortezomib inhibits proteasomal degradation of IκBα and induces mitochondrial dependent apoptosis in activated B-cell diffuse large B-cell lymphoma.
Leuk Lymphoma
2014
, vol. 
55
 
2
(pg. 
415
-
424
)
33
Ruan
 
J
Martin
 
P
Furman
 
RR
et al. 
Bortezomib plus CHOP-rituximab for previously untreated diffuse large B-cell lymphoma and mantle cell lymphoma.
J Clin Oncol
2011
, vol. 
29
 
6
(pg. 
690
-
697
)
34
Elstrom
 
RL
Andemariam
 
B
Martin
 
P
et al. 
Bortezomib in combination with rituximab, dexamethasone, ifosfamide, cisplatin and etoposide chemoimmunotherapy in patients with relapsed and primary refractory diffuse large B-cell lymphoma.
Leuk Lymphoma
2012
, vol. 
53
 
8
(pg. 
1469
-
1473
)
35
Mounier
 
N
Ribrag
 
V
Haioun
 
C
et al. 
All B lymphoma subtypes do not share similar outcome after frontline R-CHOP plus bortezomib treatment: A randomized phase 2 trial from the Groupe d’etude des lymphomes de l’adulte (GELA).
Ann Oncol
2008
, vol. 
19
 
Suppl 4
pg. 
Abstract 135
 
36
Robak
 
T
Huang
 
H
Jin
 
J
et al. 
LYM-3002 Investigators
Bortezomib-based therapy for newly diagnosed mantle-cell lymphoma.
N Engl J Med
2015
, vol. 
372
 
10
(pg. 
944
-
953
)
37
Millennium Pharmaceuticals, Inc. VELCADE (bortezomib) for injection. For subcutaneous or intravenous use (October 2014, Revision 17). Cambridge, MA: Millennium Pharmaceuticals; 2014
38
Cheson
 
BD
Pfistner
 
B
Juweid
 
ME
et al. 
International Harmonization Project on Lymphoma
Revised response criteria for malignant lymphoma.
J Clin Oncol
2007
, vol. 
25
 
5
(pg. 
579
-
586
)
39
A predictive model for aggressive non-Hodgkin’s lymphoma. The International Non-Hodgkin’s Lymphoma Prognostic Factors Project.
N Engl J Med
1993
, vol. 
329
 
14
(pg. 
987
-
994
)
40
Chen
 
J
Guo
 
L
Peiffer
 
DA
et al. 
Genomic profiling of 766 cancer-related genes in archived esophageal normal and carcinoma tissues.
Int J Cancer
2008
, vol. 
122
 
10
(pg. 
2249
-
2254
)
41
Juweid
 
ME
Stroobants
 
S
Hoekstra
 
OS
et al. 
Imaging Subcommittee of International Harmonization Project in Lymphoma
Use of positron emission tomography for response assessment of lymphoma: consensus of the Imaging Subcommittee of International Harmonization Project in Lymphoma.
J Clin Oncol
2007
, vol. 
25
 
5
(pg. 
571
-
578
)
42
National Cancer Institute Common Terminology Criteria for Adverse Events v4.03. Bethesda, MD: National Cancer Institute; 2010
43
Simon
 
R
Wittes
 
RE
Ellenberg
 
SS
Randomized phase II clinical trials.
Cancer Treat Rep
1985
, vol. 
69
 
12
(pg. 
1375
-
1381
)
44
Maurer
 
MJ
Ghesquières
 
H
Jais
 
JP
et al. 
Event-free survival at 24 months is a robust end point for disease-related outcome in diffuse large B-cell lymphoma treated with immunochemotherapy.
J Clin Oncol
2014
, vol. 
32
 
10
(pg. 
1066
-
1073
)
45
Cunningham
 
D
Hawkes
 
EA
Jack
 
A
et al. 
Rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisolone in patients with newly diagnosed diffuse large B-cell non-Hodgkin lymphoma: a phase 3 comparison of dose intensification with 14-day versus 21-day cycles.
Lancet
2013
, vol. 
381
 
9880
(pg. 
1817
-
1826
)
46
Delarue
 
R
Tilly
 
H
Mounier
 
N
et al. 
Dose-dense rituximab-CHOP compared with standard rituximab-CHOP in elderly patients with diffuse large B-cell lymphoma (the LNH03-6B study): a randomised phase 3 trial.
Lancet Oncol
2013
, vol. 
14
 
6
(pg. 
525
-
533
)
47
Pfreundschuh
 
M
Schubert
 
J
Ziepert
 
M
et al. 
German High-Grade Non-Hodgkin Lymphoma Study Group (DSHNHL)
Six versus eight cycles of bi-weekly CHOP-14 with or without rituximab in elderly patients with aggressive CD20+ B-cell lymphomas: a randomised controlled trial (RICOVER-60).
Lancet Oncol
2008
, vol. 
9
 
2
(pg. 
105
-
116
)
48
Martelli
 
M
Ferreri
 
AJ
Agostinelli
 
C
Di Rocco
 
A
Pfreundschuh
 
M
Pileri
 
SA
Diffuse large B-cell lymphoma.
Crit Rev Oncol Hematol
2013
, vol. 
87
 
2
(pg. 
146
-
171
)
49
Smith
 
A
Howell
 
D
Patmore
 
R
Jack
 
A
Roman
 
E
Incidence of haematological malignancy by sub-type: a report from the Haematological Malignancy Research Network.
Br J Cancer
2011
, vol. 
105
 
11
(pg. 
1684
-
1692
)
50
Coutinho
 
R
Clear
 
AJ
Owen
 
A
et al. 
Poor concordance among nine immunohistochemistry classifiers of cell-of-origin for diffuse large B-cell lymphoma: implications for therapeutic strategies.
Clin Cancer Res
2013
, vol. 
19
 
24
(pg. 
6686
-
6695
)
51
Seymour
 
JF
Pfreundschuh
 
M
Trnĕný
 
M
et al. 
MAIN Study Investigators
R-CHOP with or without bevacizumab in patients with previously untreated diffuse large B-cell lymphoma: final MAIN study outcomes.
Haematologica
2014
, vol. 
99
 
8
(pg. 
1343
-
1349
)
52
Gutiérrez-García
 
G
Cardesa-Salzmann
 
T
Climent
 
F
et al. 
Grup per l’Estudi dels Limfomes de Catalunya I Balears (GELCAB)
Gene-expression profiling and not immunophenotypic algorithms predicts prognosis in patients with diffuse large B-cell lymphoma treated with immunochemotherapy.
Blood
2011
, vol. 
117
 
18
(pg. 
4836
-
4843
)
53
Read
 
JA
Koff
 
JL
Nastoupil
 
LJ
Williams
 
JN
Cohen
 
JB
Flowers
 
CR
Evaluating cell-of-origin subtype methods for predicting diffuse large B-cell lymphoma survival: a meta-analysis of gene expression profiling and immunohistochemistry algorithms.
Clin Lymphoma Myeloma Leuk
2014
, vol. 
14
 
6
(pg. 
460
-
467.e2
)
54
Copie-Bergman
 
C
Gaulard
 
P
Leroy
 
K
et al. 
Immuno-fluorescence in situ hybridization index predicts survival in patients with diffuse large B-cell lymphoma treated with R-CHOP: a GELA study.
J Clin Oncol
2009
, vol. 
27
 
33
(pg. 
5573
-
5579
)
55
Molina
 
TJ
Canioni
 
D
Copie-Bergman
 
C
et al. 
Young patients with non-germinal center B-cell-like diffuse large B-cell lymphoma benefit from intensified chemotherapy with ACVBP plus rituximab compared with CHOP plus rituximab: analysis of data from the Groupe d’Etudes des Lymphomes de l’Adulte/lymphoma study association phase III trial LNH 03-2B.
J Clin Oncol
2014
, vol. 
32
 
35
(pg. 
3996
-
4003
)
56
Gang
 
AO
Pedersen
 
MO
Knudsen
 
H
et al. 
Cell of origin predicts outcome to treatment with etoposide-containing chemotherapy in young patients with high-risk diffuse large B-cell lymphoma.
Leuk Lymphoma
2015
, vol. 
56
 
7
(pg. 
2039
-
2046
)
57
Wilson
 
WH
Dunleavy
 
K
Pittaluga
 
S
et al. 
Phase II study of dose-adjusted EPOCH and rituximab in untreated diffuse large B-cell lymphoma with analysis of germinal center and post-germinal center biomarkers.
J Clin Oncol
2008
, vol. 
26
 
16
(pg. 
2717
-
2724
)
58
Cuccuini
 
W
Briere
 
J
Mounier
 
N
et al. 
MYC+ diffuse large B-cell lymphoma is not salvaged by classical R-ICE or R-DHAP followed by BEAM plus autologous stem cell transplantation.
Blood
2012
, vol. 
119
 
20
(pg. 
4619
-
4624
)
59
Lenz
 
G
Davis
 
RE
Ngo
 
VN
et al. 
Oncogenic CARD11 mutations in human diffuse large B cell lymphoma.
Science
2008
, vol. 
319
 
5870
(pg. 
1676
-
1679
)
60
Young
 
RM
Shaffer
 
AL
Phelan
 
JD
Staudt
 
LM
B-cell receptor signaling in diffuse large B-cell lymphoma.
Semin Hematol
2015
, vol. 
52
 
2
(pg. 
77
-
85
)
61
Wilson
 
WH
Gerecitano
 
GF
Goy
 
A
et al. 
 
The Bruton’s tyrosine kinase (BTK) inhibitor, Ibrutinib (PCI-32765), has preferential activity in the ABC subtype of relapsed/refractory de novo diffuse large B-cell lymphoma (DLBCL): interim results of a multicenter, open-label, phase 2 study [abstract]. Blood. 2012;120(21). Abstract 686
62
Younes
 
A
Thieblemont
 
C
Morschhauser
 
F
et al. 
Combination of ibrutinib with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) for treatment-naive patients with CD20-positive B-cell non-Hodgkin lymphoma: a non-randomised, phase 1b study.
Lancet Oncol
2014
, vol. 
15
 
9
(pg. 
1019
-
1026
)
63
Chaiwatanatorn
 
K
Stamaratis
 
G
Opeskin
 
K
Firkin
 
F
Nandurkar
 
H
Protein kinase C-beta II expression in diffuse large B-cell lymphoma predicts for inferior outcome of anthracycline-based chemotherapy with and without rituximab.
Leuk Lymphoma
2009
, vol. 
50
 
10
(pg. 
1666
-
1675
)
64
Crump
 
M
Leppa
 
S
Fayad
 
L
et al. 
 
A phase III study of enzastaurin in patients with high-risk diffuse large B cell lymphoma following response to primary treatment: The Prelude Trial [abstract]. Blood. 2013;122(21). Abstract 371
65
Espinosa
 
I
Briones
 
J
Bordes
 
R
et al. 
Membrane PKC-beta 2 protein expression predicts for poor response to chemotherapy and survival in patients with diffuse large B-cell lymphoma.
Ann Hematol
2006
, vol. 
85
 
9
(pg. 
597
-
603
)
66
Hans
 
CP
Weisenburger
 
DD
Greiner
 
TC
et al. 
Expression of PKC-beta or cyclin D2 predicts for inferior survival in diffuse large B-cell lymphoma.
Mod Pathol
2005
, vol. 
18
 
10
(pg. 
1377
-
1384
)
67
Li
 
S
Phong
 
M
Lahn
 
M
et al. 
Retrospective analysis of protein kinase C-beta (PKC-beta) expression in lymphoid malignancies and its association with survival in diffuse large B-cell lymphomas.
Biol Direct
2007
, vol. 
2
 pg. 
8
 
68
Riihijärvi
 
S
Koivula
 
S
Nyman
 
H
Rydström
 
K
Jerkeman
 
M
Leppä
 
S
Prognostic impact of protein kinase C beta II expression in R-CHOP-treated diffuse large B-cell lymphoma patients.
Mod Pathol
2010
, vol. 
23
 
5
(pg. 
686
-
693
)
69
Schaffel
 
R
Morais
 
JC
Biasoli
 
I
et al. 
PKC-beta II expression has prognostic impact in nodal diffuse large B-cell lymphoma.
Mod Pathol
2007
, vol. 
20
 
3
(pg. 
326
-
330
)
70
Hinz
 
M
Scheidereit
 
C
The IκB kinase complex in NF-κB regulation and beyond.
EMBO Rep
2014
, vol. 
15
 
1
(pg. 
46
-
61
)
71
Ceribelli
 
M
Kelly
 
PN
Shaffer
 
AL
et al. 
Blockade of oncogenic IκB kinase activity in diffuse large B-cell lymphoma by bromodomain and extraterminal domain protein inhibitors.
Proc Natl Acad Sci USA
2014
, vol. 
111
 
31
(pg. 
11365
-
11370
)
72
Steinhardt
 
JJ
Gartenhaus
 
RB
Promising personalized therapeutic options for diffuse large B-cell lymphoma subtypes with oncogene addictions.
Clin Cancer Res
2012
, vol. 
18
 
17
(pg. 
4538
-
4548
)
73
Compagno
 
M
Lim
 
WK
Grunn
 
A
et al. 
Mutations of multiple genes cause deregulation of NF-kappaB in diffuse large B-cell lymphoma.
Nature
2009
, vol. 
459
 
7247
(pg. 
717
-
721
)
74
Lim
 
KH
Yang
 
Y
Staudt
 
LM
Pathogenetic importance and therapeutic implications of NF-κB in lymphoid malignancies.
Immunol Rev
2012
, vol. 
246
 
1
(pg. 
359
-
378
)
75
Aukema
 
SM
Siebert
 
R
Schuuring
 
E
et al. 
Double-hit B-cell lymphomas.
Blood
2011
, vol. 
117
 
8
(pg. 
2319
-
2331
)
76
Snuderl
 
M
Kolman
 
OK
Chen
 
YB
et al. 
B-cell lymphomas with concurrent IGH-BCL2 and MYC rearrangements are aggressive neoplasms with clinical and pathologic features distinct from Burkitt lymphoma and diffuse large B-cell lymphoma.
Am J Surg Pathol
2010
, vol. 
34
 
3
(pg. 
327
-
340
)
77
Tomita
 
N
BCL2 and MYC dual-hit lymphoma/leukemia.
J Clin Exp Hematop
2011
, vol. 
51
 
1
(pg. 
7
-
12
)
78
Lin
 
P
Medeiros
 
LJ
High-grade B-cell lymphoma/leukemia associated with t(14;18) and 8q24/MYC rearrangement: a neoplasm of germinal center immunophenotype with poor prognosis.
Haematologica
2007
, vol. 
92
 
10
(pg. 
1297
-
1301
)
79
Li
 
S
Lin
 
P
Fayad
 
LE
et al. 
B-cell lymphomas with MYC/8q24 rearrangements and IGH@BCL2/t(14;18)(q32;q21): an aggressive disease with heterogeneous histology, germinal center B-cell immunophenotype and poor outcome.
Mod Pathol
2012
, vol. 
25
 
1
(pg. 
145
-
156
)
80
Green
 
TM
Young
 
KH
Visco
 
C
et al. 
Immunohistochemical double-hit score is a strong predictor of outcome in patients with diffuse large B-cell lymphoma treated with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone.
J Clin Oncol
2012
, vol. 
30
 
28
(pg. 
3460
-
3467
)
81
Hu
 
S
Xu-Monette
 
ZY
Tzankov
 
A
et al. 
MYC/BCL2 protein coexpression contributes to the inferior survival of activated B-cell subtype of diffuse large B-cell lymphoma and demonstrates high-risk gene expression signatures: a report from The International DLBCL Rituximab-CHOP Consortium Program.
Blood
2013
, vol. 
121
 
20
(pg. 
4021
-
4031
)
82
Johnson
 
NA
Slack
 
GW
Savage
 
KJ
et al. 
Concurrent expression of MYC and BCL2 in diffuse large B-cell lymphoma treated with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone.
J Clin Oncol
2012
, vol. 
30
 
28
(pg. 
3452
-
3459
)
83
Valera
 
A
López-Guillermo
 
A
Cardesa-Salzmann
 
T
et al. 
Grup per l’Estudi dels Limfomes de Catalunya i Balears (GELCAB)
MYC protein expression and genetic alterations have prognostic impact in patients with diffuse large B-cell lymphoma treated with immunochemotherapy.
Haematologica
2013
, vol. 
98
 
10
(pg. 
1554
-
1562
)
84
Furman
 
RR
Martin
 
P
Ruan
 
J
et al. 
Phase 1 trial of bortezomib plus R-CHOP in previously untreated patients with aggressive non-Hodgkin lymphoma.
Cancer
2010
, vol. 
116
 
23
(pg. 
5432
-
5439
)

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