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

Abstract

Background: 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.

Methods: 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.

Findings: 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.

Interpretation: 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.

Funding: Janssen-Cilag, Bloodwise, and Cancer Research UK.

Copyright © 2019 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.

Figures

Figure 1

Study profile ITT=intention-to-treat. R-CHOP=rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone. RB-CHOP=rituximab, bortezomib, cyclophosphamide, doxorubicin, vincristine, and prednisolone.

Figure 2

Progression-free survival in the m ITT population (A), activated B-cell subgroup (B), germinal centre B-cell subgroup (C), and unclassified group (D), by treatment Data are for the mITT population, which comprises germinal centre and activated B-cell ITT participants (n=719); activated B-cell subgroup (n=244); germinal centre B-cell subgroup (n=475); and unclassified subgroup (n=199); with estimated proportions of participants achieving progression-free survival at 12 months and 30 months. HR=hazard ratio. ITT=intention-to-treat. mITT=modified ITT. R-CHOP=rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone. RB-CHOP=rituximab, bortezomib, cyclophosphamide, doxorubicin, vincristine, and prednisolone.

Figure 3

Progression-free survival comparing double-hit lymphomas to non-rearranged cases (A) and double-expressor (high MYC and high BCL-2 mRNA) lymphomas to all other cases (B), by treatment group Data are progression-free survival and hazard ratio (HR), with non-DHL and non-DEL patients as reference categories. DEL=dual-expressor lymphoma. DHL=double-hit lymphoma. R-CHOP=rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone. RB-CHOP=rituximab, bortezomib, cyclophosphamide, doxorubicin, vincristine, and prednisolone.

Figure 4

Forest plot of hazard ratios based on progression free survival for participants at high risk and with different molecular subtypes of disease, by treatment group Data are for all randomised participants (ie, ITT population). Hazard ratios and p values are effect estimates from a multivariable model adjusted for IPI score. DEL=dual-expressor lymphoma. DHL=double-hit lymphoma. IPI=international prognostic index. ITT=intention-to-treat. R-CHOP=rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone. RB-CHOP=rituximab, bortezomib, cyclophosphamide, doxorubicin, vincristine, and prednisolone.