Addition of Bortezomib to R-CHOP in DLBCL Subtypes Identified With Gene-Expression Profiling
In the phase III REMoDL-B trial reported in The Lancet Oncology, Davies et al found that the addition of bortezomib to standard R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone) did not improve progression-free survival subtypes of diffuse large B-cell lymphoma (DLBCL) identified with gene-expression profiling.
Prior studies suggested that the addition of bortezomib to chemoimmunotherapy improved progression-free survival in patients with the activated B-cell subtype vs those with the germinal center B-cell subtype.
Study Details
In the open-label multicenter trial, 918 previously untreated patients enrolled between June 2011 and June 2015 were treated with one 21-day cycle of standard R-CHOP. During this initial treatment, gene-expression profiling using routine diagnostic biopsy samples was performed to determine the cell-of-origin subtype of each patient (ie, germinal center B-cell, activated B-cell, or unclassified). Patients were then randomly assigned, with stratification for international prognostic index score and cell-of-origin subtype, to continue R-CHOP alone for 5 additional cycles (n = 459) or to receive bortezomib plus R-CHOP for 5 cycles (RB-CHOP; n = 459). Overall, 244 patients (26.6%) had activated B-cell disease, 475 (51.7%) had germinal center B-cell disease, and 199 (21.7%) had unclassified disease.
The primary endpoint was 30-month progression-free survival in the combined germinal center B-cell and activated B-cell populations.
Progression-Free Survival
Median follow-up was 29.7 months. Progression-free survival at 30 months in the combined germinal center and activated B-cell population was 74.3% in the RB-CHOP group vs 70.1% in the R-CHOP group (hazard ratio [HR] = 0.86, P = .28). The addition of bortezomib did not significantly improve progression-free survival in the activated B-cell subgroup (adjusted HR = 0.78, P = .27), the germinal center B-cell subgroup (adjusted HR = 0.85, P = .35), or the unclassifiable subgroup (adjusted HR = 1.29, P = .34).
Adverse Events
The most common grade ≥ 3 adverse events were hematologic events, occurring in 42.1% of the RB-CHOP group vs 39.8% of the R-CHOP group. Neuropathy of any grade occurred in 56.8% vs 41.6% of patients, but grade ≥ 3 neuropathy was observed in only 3.8% vs 1.8% of patients. Serious adverse events occurred in 50.2% vs 42.5% of patients, including 4 vs 5 treatment-related deaths.
The investigators concluded, “This is the first large-scale study in diffuse large B-cell lymphoma to use real-time molecular characterization for prospective stratification, randomization, and subsequent analysis of biologically distinct subgroups of patients. The addition of bortezomib did not improve progression-free survival.”
Peter W.M. Johnson, FMedSci, of the Cancer Research UK Centre, University of Southampton, is the corresponding author for The Lancet Oncology article.
Disclosure: The study was funded by Janssen-Cilag, Bloodwise, and Cancer Research UK. The study authors’ full disclosures can be found at thelancet.com.
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