Five-Year Survival Results from the Remodl-B Trial (ISRCTN 51837425) Show Improved Outcomes in Diffuse Large B-Cell Lymphoma Molecular Subgroups from the Addition of Bortezomib to R-CHOP Chemoimmunotherapy

Introduction: The REMoDL-B trial compared R-CHOP versus R-CHOP + bortezomib (RB-CHOP) in patients with diffuse large B-cell lymphoma (DLBCL) stratified by cell of origin (COO) determined by gene expression profile (GEP). The primary analysis of the trial at a median follow-up of 30 months found no overall difference in progression free (PFS) or overall survival (OS) by treatment arm. Retrospective analysis using a gene expression based classifier identified a molecular high grade group (MHG) with distinct molecular features. We present an update of this analysis and the trial final results for patients with lymphomas of activated B-cell (ABC), germinal-centre B-cell (GCB) or MHG type.

Methods: REMoDL-B was an open label randomised phase 3 adaptive trial with patients recruited from UK and Switzerland. Eligible patients had untreated, histologically confirmed DLBCL stage I-IV, were >18 year old, ECOG performance status≤2, and had cardiac, lung, renal, and liver function sufficient to tolerate full dose chemotherapy. Patients with sufficient material from initial biopsies for GEP were randomised between R-CHOP or RB-CHOP from cycle 2, stratified by international prognostic index (IPI) and COO. COO classification was performed in the trial with the DLBCL automatic classifier in time for randomisation and reassessed retrospectively adding in the MHG classifier. Time to event analyses were performed using the Kaplan-Meier method and cox regression modelling. REMoDL-B was coordinated by the Southampton Clinical Trials Unit and funded by a grant from Janssen-Cilag and endorsed by Cancer Research UK after independent peer review (C328/A12128).

Results: 801 of the 1,077 patients registered were identified as ABC, GCB or MHG type in the final analysis. 128 were unclassified and in 148 the diagnostic biopsy sample was insufficient. Median age was 65 (range 20-86) and 67% were stage III/IV, 48% had abnormal LDH, 29% had bulk, 17% had high IPI and 30% high intermediate IPI, 31% ABC, 59% GCB and 10% MHG. At a median follow up of 64 months in those still alive, there was no overall benefit of bortezomib on PFS or OS (5-year PFS of 64% in R-CHOP and 70% in RB-CHOP HR, 0.81 p=0.085, 5-year OS of 76% vs 79% HR, 0.86; p=0.32). Improved PFS and OS with RB-CHOP was however seen in ABC patients; 5-year PFS of 54% with R-CHOP vs 69% with RB-CHOP (Figure 1); 5-year OS of 67% in the R-CHOP arm vs 80% in the RB-CHOP arm: OS HR 0.58; (95% CI, 0.35 to 0.95) p=0.032. PFS was significantly improved in MHG patients: 5-year PFS 29% with R-CHOP vs 55% with RB-CHOP: HR 0.46 (95% CI 0.26-0.84) p=0.011 (Figure 2). 5-year OS was 48% vs 60% HR, 0.62; 95% (CI, 0.32 to 1.20) p=0.156. Outcomes by LymphGen classification will be presented. Adverse events were similar to those reported previously, with the most common grade 3 or worse being haematological toxicity, reported in 38% R-CHOP patients and 42% RB-CHOP patients.

Conclusions: Gene expression profiling can identify subtypes of DLBCL which may benefit from the addition of bortezomib to R-CHOP in initial therapy, specifically, ABC and MHG types.