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

Abstract

Background: Biologically distinct sub-types of diffuse large B-cell lymphoma (DLBCL) can be identified using gene expression analysis to determine their cell of origin (COO), corresponding to germinal centre (GCB) or activated B‐cells (ABC). This study investigated whether adding bortezomib(B) to standard therapy could improve outcomes in these subtypes.

Methods: The REMoDL-B trial is an open-label adaptive two-stage randomised controlled trial at 107 centres in the United Kingdom and Switzerland. Eligible patients (pts) had previously untreated, histologically confirmed DLBCL with sufficient diagnostic material for gene expression profiling and pathology review; age 18 years or older; Eastern Cooperative Oncology Group performance status of ≤2; bulky stage I or stage II-IV requiring full course chemotherapy; measurable disease, and cardiac, lung, renal and liver function sufficient to tolerate chemotherapy. Pts initially received 1 cycle of standard R‐CHOP. During this time, gene expression profiling by whole genome cDNA-mediated annealing, selection, extension and ligation assay was performed on routine diagnostic biopsy material. Patients were then centrally assigned (1:1) via a web-based system, with block randomisation stratified by international prognostic index and COO subtype to continue R‐CHOP +/‐ bortezomib (1.3 mg/m2 IV or 1.6 mg/m2 SC) days 1+8 for cycles 2‐6. The primary endpoint was 30 month progression‐free survival (PFS) for the GCB + ABC population. The primary analysis was intention-to-treat. The safety population consisted of all participants who received at least one dose of study drug. The study was registered at ClinicalTrials.gov: NCT01324596. We report the PFS and safety outcomes for patients in the follow-up phase after the required number of events occurred. Recruitment and treatment has completed for all participants, with long-term follow-up continuing

Findings: Between June 2011 and June 2015, 1128 eligible pts were registered and a total of 918 randomised. There was no evidence for a difference in PFS in the combined GCB + ABC population between R‐CHOP (N=361)and RB‐CHOP (N=358) (30 month PFS: 70.6% vs 75.2% respectively) adjusted HR = 0.82, 95% CI 0.63 - 1.08; P=0.16. The most common Grade ≥3 adverse event experienced was haematological toxicity, with 178 (39.8%) and 187 (42.1%) of pts receiving R-CHOP and RB-CHOP experienced, respectively. However, RB‐CHOP was not associated with increased haematological toxicity and 87% of pts completed 6 cycles; Grade ≥3 neuropathy occurred in 3.8% RB‐CHOP vs 1.8% R‐CHOP pts. Serious adverse events occurred in 190 (42.5%) and 223 (50.2%) of pts, including 5 and 4 treatment-related deaths in pts receiving R-CHOP and RB-CHOP, respectively.

Interpretation: This is the first large-scale study in DLBCL to use real-time molecular characterisation for prospective stratification and randomisation, and subsequent analysis of biologically distinct subgroups. The addition of bortezomib did not improve outcomes in the ABC subgroup as expected, but proteosome inhibition could be investigated as a possible means to improve the treatment of cytogenetic 'double-hit' DLBCL.

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

More information

Identifiers

ORCID for Andrew Davies: orcid.org/0000-0002-7517-6938

ORCID for Louise Stanton: orcid.org/0000-0001-8181-840X

ORCID for Gareth Griffiths: orcid.org/0000-0002-9579-8021

ORCID for Peter Johnson: orcid.org/0000-0003-2306-4974

Catalogue record

Export record

Altmetrics