Journal Article

Gene-expression profiling of bortezomib added to standard chemoimmunotherapy for diffuse large B-cell lymphoma (REMoDL-B): an open-label, randomised, phase 3 trial

Clipson, Alexandra, Tooze, Reuben, Caddy, Josh, Stephens, Richard, Westhead, David R, Davies, Andrew, Mamot, Christoph, Barrans, Sharon, Kazmi-Stokes, Shamim, Cummin, Thomas E, Cucco, Francesco, Griffiths, Gareth, Sha, Chulin, Fields, Paul, Johnson, Peter W M, Burton, Catherine, Maishman, Tom, Care, Matthew A, McMillan, Andrew, Du, Ming-Qing, Pocock, Christopher, Collins, Graham P, Stanton, Louise, Novak, Urban

2019

Overview

Biologically distinct subtypes of diffuse large B-cell lymphoma can be identified using gene-expression analysis to determine their cell of origin, corresponding to germinal centre or activated B cell. We aimed to investigate whether adding bortezomib to standard therapy could improve outcomes in patients with these subtypes. In a randomised evaluation of molecular guided therapy for diffuse large B-cell lymphoma with bortezomib (REMoDL-B), an open-label, adaptive, randomised controlled, phase 3 superiority trial, participants were recruited from 107 cancer centres in the UK (n=94) and Switzerland (n=13). Eligible patients had previously untreated, histologically confirmed diffuse large B-cell lymphoma with sufficient diagnostic material from initial biopsies for gene-expression profiling and pathology review; were aged 18 years or older; had ECOG performance status of 2 or less; had bulky stage I or stage II–IV disease requiring full-course chemotherapy; had measurable disease; and had cardiac, lung, renal, and liver function sufficient to tolerate chemotherapy. Patients initially received one 21-day cycle of standard rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone (R-CHOP; rituximab 375 mg/m2, cyclophosphamide 750 mg/m2, doxorubicin 50 mg/m2, and vincristine 1·4 mg/m2 [to a maximum of 2 mg total dose] intravenously on day 1 of the cycle, and prednisolone 100 mg orally once daily on days 1–5). During this time, we did gene-expression profiling using whole genome cDNA-mediated annealing, selection, extension, and ligation assay of tissue from routine diagnostic biopsy samples to determine the cell-of-origin subtype of each participant (germinal centre B cell, activated B cell, or unclassified). Patients were then centrally randomly assigned (1:1) via a web-based system, with block randomisation stratified by international prognostic index score and cell-of-origin subtype, to continue R-CHOP alone (R-CHOP group; control), or with bortezomib (RB-CHOP group; experimental; 1·3 mg/m2 intravenously or 1·6 mg/m2 subcutaneously) on days 1 and 8 for cycles two to six. If RNA extracted from the diagnostic tissues was of insufficient quality or quantity, participants were given R-CHOP as per the control group. The primary endpoint was 30-month progression-free survival, for the germinal centre and activated B-cell population. The primary analysis was on the modified intention-to-treat population of activated and germinal centre B-cell population. Safety was assessed in all participants who were given at least one dose of study drug. We report the progression-free survival and safety outcomes for patients in the follow-up phase after the required number of events occurred. This study was registered at ClinicalTrials.gov, number NCT01324596, and recruitment and treatment has completed for all participants, with long-term follow-up ongoing. Between June 2, 2011, and June 10, 2015, 1128 eligible patients were registered, of whom 918 (81%) were randomly assigned to receive treatment (n=459 to R-CHOP, n=459 to RB-CHOP), comprising 244 (26·6%) with activated B-cell disease, 475 (51·7%) with germinal centre B cell disease, and 199 (21·7%) with unclassified disease. At a median follow-up of 29·7 months (95% CI 29·0–32·0), we saw no evidence for a difference in progression-free survival in the combined germinal centre and activated B-cell population between R-CHOP and RB-CHOP (30-month progression-free survival 70·1%, 95% CI 65·0–74·7 vs 74·3%, 69·3–78·7; hazard ratio 0·86, 95% CI 0·65–1·13; p=0·28). The most common grade 3 or worse adverse event was haematological toxicity, reported in 178 (39·8%) of 447 patients given R-CHOP and 187 (42·1%) of 444 given RB-CHOP. However, RB-CHOP was not associated with increased haematological toxicity and 398 [87·1%] of 459 participants assigned to receive RB-CHOP completed six cycles of treatment. Grade 3 or worse neuropathy occurred in 17 (3·8%) patients given RB-CHOP versus eight (1·8%) given R-CHOP. Serious adverse events occurred in 190 (42·5%) patients given R-CHOP, including five treatment-related deaths, and 223 (50·2%) given RB-CHOP, including four treatment-related deaths. This is the first large-scale study in diffuse large B-cell lymphoma to use real-time molecular characterisation for prospective stratification, randomisation, and subsequent analysis of biologically distinct subgroups of patients. The addition of bortezomib did not improve progression-free survival. Janssen-Cilag, Bloodwise, and Cancer Research UK.

• Publisher: Elsevier Ltd,Elsevier Limited,Lancet Pub. Group
• Subject: Adult / Aged / Aged, 80 and over / Antineoplastic Combined Chemotherapy Protocols - administration & dosage / Antineoplastic Combined Chemotherapy Protocols - adverse effects / B-cell lymphoma / Biomarkers, Tumor - genetics / Biopsy / Bortezomib / Bortezomib - administration & dosage / Bortezomib - adverse effects / Chemotherapy / Coronary artery disease / Cyclophosphamide / Cyclophosphamide - administration & dosage / Cyclophosphamide - adverse effects / Disease Progression / Doxorubicin / Doxorubicin - administration & dosage / Doxorubicin - adverse effects / Female / Gene expression / Gene Expression Profiling / Genomes / Heart diseases / Humans / Immunotherapy / Inhibitor drugs / Lung diseases / Lymphocytes B / Lymphoma / Lymphoma, Large B-Cell, Diffuse - drug therapy / Lymphoma, Large B-Cell, Diffuse - genetics / Lymphoma, Large B-Cell, Diffuse - immunology / Lymphoma, Large B-Cell, Diffuse - mortality / Male / Medical prognosis / Medical research / Middle Aged / Monoclonal antibodies / Mutation / Neuropathy / Neutropenia / Prednisolone / Prednisone - administration & dosage / Prednisone - adverse effects / Progression-Free Survival / Proteasome Inhibitors - administration & dosage / Proteasome Inhibitors - adverse effects / Renal function / Ribonucleic acid / Rituximab / Rituximab - administration & dosage / Rituximab - adverse effects / RNA / Sepsis / Switzerland / Targeted cancer therapy / Time Factors / Toxicity / Transcriptome / United Kingdom / Vincristine / Vincristine - administration & dosage / Vincristine - adverse effects / Young Adult