Previously, the phase 3 REMoDL-B trial showed no effect of adding bortezomib to rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone (R-CHOP) in patients with diffuse large B-cell lymphoma (DLBCL). However, after 5 years of follow-up, this study does suggest a benefit from the addition of bortezomib in patients with activated B-cell (ABC) and molecular high-grade (MHG) DLBCL. These findings were recently published in the Journal of Clinical Oncology.
Molecular heterogeneity is a recognised feature of diffuse large B-cell lymphoma (DLBCL), with varying outcomes across different karyotypic, genomic, and transcriptomic subtypes. The REMoDL-B trial compared rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone (R-CHOP) vs. R-CHOP plus bortezomib (RB-CHOP) in patients with newly diagnosed DLBCL stratified by molecular subtype. After a median follow-up of 30 months, no differences were found in progression-free survival (PFS) between the two treatment arms (HR[95%CI]: 0.86[0.65-1.13]). However, a subsequent subgroup analysis showed a trend towards a therapeutic benefit from bortezomib in patients with a more aggressive DLBCL subtype (molecular high-grade [MHG]) (PFS[95%CI]: 0.58[0.31-1.07). After 5 years of follow-up, this article updates the trial results of all patients whose lymphomas were successfully classified by gene expression profile (GEP).
REMoDL-B was an open-label phase 3 adaptive trial performed in centres in the United Kingdom and Switzerland. Eligible patients had untreated DLBCL, adequate biopsies for GEP and were fit enough to receive full-dose chemotherapy. All patients received R-CHOP for one cycle and were randomly assigned to R-CHOP (n=407) or RB-CHOP (n=394) for cycles 2-6. Whole-genome GEP was performed on mRNA extracted from diagnostic tissue. Biopsies were categorised as activated B-cell (ABC), germinal centre B-cell (GCB), MHG or unclassifiable. The primary endpoint of the trial was PFS.
The R and RB-CHOP treatment arms included a total of 240 and 229 patients with GCB subtype, 125 and 124 patients with ABC subtype, and 42 and 41 patients with MHG subtype, respectively. After a median follow-up of 64 months, there was no overall benefit of bortezomib on PFS (HR:0.81; P=0.085) or OS (HR: 0.86; p=0.32). However, an OS advantage from the addition of bortezomib was observed in the ABC subgroup (5-year OS rates: 80.4% vs. 67.4%; HR[95%CI]: 0.58[0.35-0.95]; p=0.032). Additionally, also patients with MHG DLBCL who received RB-CHOP had a significantly longer PFS compared with R-CHOP (5-year PFS rates: 54.9% vs. 29.3%, respectively; HR[95%CI]: 0.46[0.26-0.84]). Of note, the proportion of patients with MHG lymphoma is relatively small (approximately 10%), limiting the ability to detect important differences in OS. In the GCB subgroup, no differences were seen between both treatment arms. Regarding safety, the addition of bortezomib was well-tolerated and no new safety signals were reported.
This study confirms that different molecular subtypes of DLBCL exhibit different responses to bortezomib when given in combination with R-CHOP. With mature follow-up, this study suggests a benefit from the addition of bortezomib to R-CHOP for ABC and MHG subtypes of DLBCL.
Davies AJ, Barrans S, Stanton L, et al. Differential Efficacy From the Addition of Bortezomib to R-CHOP in Diffuse Large B-Cell Lymphoma According to the Molecular Subgroup in the REMoDL-B Study With a 5-Year Follow-Up. J Clin Oncol. 2023; 27;JCO2300033.