Improving R-CHOP in diffuse large B-cell lymphoma is still a challenge (2019)

Since the introduction of rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone (R-CHOP) as the gold standard for the treatment of diffuse large B-cell lymphoma, clinical investigators have constantly tried to improve its effectiveness by adding new drugs and proposing combinations (ie, R-CHOP plus drug X).1Di Rocco A De Angelis F Ansuinelli M Foà R Martelli M Is now the time for molecular driven therapy for diffuse large B-cell lymphoma?.Expert Rev Hematol. 2017; 10: 761-774Google Scholar This strategy is justified by the great biological heterogeneity of diffuse large B-cell lymphomas, suggesting that R-CHOP cannot be a universal treatment but can instead provide a rational basis for personalised therapy. As such, for the past decade molecular classification on the basis of the distinction between germinal centre B-cell-like and activated B-cell-like subtypes has largely dominated the debate and focused efforts in terms of targeted therapy and biomarker research.2Lenz G Staudt LM Aggressive lymphomas.N Engl J Med. 2010; 362: 1417-1429Google Scholar To show the potential of such a strategy, biologically relevant, reliable, reproducible biomarkers and a corresponding effective molecule that are likely to improve the efficacy of the R-CHOP regimen need to be identified. The prospective multicentre phase 3 REMoDL-B trial, reported in The Lancet Oncology by Andrew Davies and colleagues,3Davies A Cummin TE Barrans S et al.Gene-expression profiling of bortezomib added to standard chemoimmunotherapy for diffuse large B-cell lymphoma (REMoDL-B): an open-label, randomised, phase 3 trial.Lancet Oncol. 2019; (published online April 1.)http://dx.doi.org/10.1016/S1470-2045(18)30935-5Google Scholar shows that real-time characterisation of diffuse large B-cell lymphoma is feasible by use of molecular biology with RNA extracted from formalin-fixed paraffin-embedded (FFPE) samples and cDNA-mediated annealing, selection, extension, and ligation techniques.3Davies A Cummin TE Barrans S et al.Gene-expression profiling of bortezomib added to standard chemoimmunotherapy for diffuse large B-cell lymphoma (REMoDL-B): an open-label, randomised, phase 3 trial.Lancet Oncol. 2019; (published online April 1.)http://dx.doi.org/10.1016/S1470-2045(18)30935-5Google Scholar Among the 1128 eligible patients in this trial, 918 (81%) were effectively classified according to their cell of origin (244 [27%] activated B cell, 475 [52%] germinal centre B cell, and 199 [22%] unclassified). Phenotyped patients were subsequently randomly assigned (1:1) after the first R-CHOP cycle to receive either R-CHOP or R-CHOP with bortezomib (RB-CHOP). The primary outcome analysis showed that the addition of bortezomib does not provide any benefit in terms of progression-free survival in the overall population (30-month progression-free survival 70·1% [95% CI 65·0–74·7] with R-CHOP vs 74·3% [69·3–78·7] with RB-CHOP; adjusted hazard ratio 0·84, 95% CI 0·64–1·11; p=0·23), with the same conclusion drawn in the secondary outcome analyses in the germinal centre B-cell, activated B-cell, and unclassified subgroups. These results support those of a randomised phase 2 trial by Leonard and colleagues.4Leonard JP Kolibaba KS Reeves JA et al.Randomized phase II study of R-CHOP with or without bortezomib in previously untreated patients with non-germinal center B-cell-like diffuse large B-cell lymphoma.J Clin Oncol. 2017; 35: 3538-3546Google Scholar However, Davis and colleagues point out a potential benefit of the combination for patients with double-hit lymphoma or dual-expressor lymphoma (ie, MYC and BCL2), although this benefit was not significant. The results show that despite overexpression of the nuclear factor (NF)-κB pathway and activating mutations of this pathway in activated B-cell diffuse large B-cell lymphoma, the addition of bortezomib—a proteasome and NF-κB pathway inhibitor—does not provide any benefit over R-CHOP.3Davies A Cummin TE Barrans S et al.Gene-expression profiling of bortezomib added to standard chemoimmunotherapy for diffuse large B-cell lymphoma (REMoDL-B): an open-label, randomised, phase 3 trial.Lancet Oncol. 2019; (published online April 1.)http://dx.doi.org/10.1016/S1470-2045(18)30935-5Google Scholar How can these ultimately disappointing results be explained? A relative under-representation of the activated B-cell subtype as compared with previous cohort studies in diffuse large B-cell lymphoma,5Staiger AM Ziepert M Horn H et al.Clinical impact of the cell-of-origin classification and the MYC/BCL2 dual expresser status in diffuse large B-cell lymphoma treated within prospective clinical trials of the German high-grade non-Hodgkin's lymphoma study group.J Clin Oncol. 2017; 35: 2515-2526Google Scholar substantially older patients in the activated B-cell subgroup, and the use of bortezomib only from the second cycle onwards, with a relatively low dose, might all have affected the efficacy outcome of the addition of bortezomib. These results also suggest that the dichotomy of the germinal centre B-cell and activated B-cell subtypes of diffuse large B-cell lymphoma is probably too simplistic or reductive. A phase 3 randomised study (Phoenix)6Younes A Sehn LH Johnson P et al.A global, randomized, placebo-controlled, phase 3 study of ibrutinib plus rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (RCHOP) in patients with previously untreated non-germinal center B-cell-like (GCB) diffuse large B-cell lymphoma (DLBCL).Blood. 2018; 132 (asbtr).: 784Google Scholar that specifically targeted the activated B-cell subtype did not clearly show the value of adding ibrutinib (an inhibitor of Bruton's tyrosine kinase) to R-CHOP in this setting. However, the toxicity of this combination in patients aged 60 years and older is probably partly responsible for the negative conclusion since a benefit in overall survival and progression-free survival was observed for patients younger than 60 years.6Younes A Sehn LH Johnson P et al.A global, randomized, placebo-controlled, phase 3 study of ibrutinib plus rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (RCHOP) in patients with previously untreated non-germinal center B-cell-like (GCB) diffuse large B-cell lymphoma (DLBCL).Blood. 2018; 132 (asbtr).: 784Google Scholar The prognostic effect of the cell-of-origin classification also remains uncertain and has been questioned in two prospective trials.5Staiger AM Ziepert M Horn H et al.Clinical impact of the cell-of-origin classification and the MYC/BCL2 dual expresser status in diffuse large B-cell lymphoma treated within prospective clinical trials of the German high-grade non-Hodgkin's lymphoma study group.J Clin Oncol. 2017; 35: 2515-2526Google Scholar Data from the CAVALLI phase 2 trial7Morschhauser F Feugier P Flinn IW et al.Venetoclax plus rituximab, cyclophosphamide, doxorubicin, vincristine and prednisolone (R-CHOP) improves outcomes in bcl2-positive first-line diffuse large B-cell lymphoma (DLBCL): first safety, efficacy and biomarker analyses from the phase II CAVALLI Study.Blood. 2018; 132 (abstr).: 782Google Scholar showed a benefit in adding the BH3 (BCL2 homology 3) mimetic venetoclax to R-CHOP in patients positive for BCL2, irrespective of whether they had the germinal centre or non-germinal centre B cell subtype of disease, suggesting that a single biomarker (BCL2 expression quantified by immunohistochemistry) might be more relevant than cell-of-origin molecular determination for patient selection.7Morschhauser F Feugier P Flinn IW et al.Venetoclax plus rituximab, cyclophosphamide, doxorubicin, vincristine and prednisolone (R-CHOP) improves outcomes in bcl2-positive first-line diffuse large B-cell lymphoma (DLBCL): first safety, efficacy and biomarker analyses from the phase II CAVALLI Study.Blood. 2018; 132 (abstr).: 782Google Scholar New classifications that integrate next-generation sequencing, fluorescence in-situ hybridisation, or copy number variation data are now available and might offer other therapeutic or predictive opportunities.8Chapuy B Stewart C Dunford AJ et al.Molecular subtypes of diffuse large B cell lymphoma are associated with distinct pathogenic mechanisms and outcomes.Nat Med. 2018; 24: 679-690Google Scholar, 9Schmitz R Wright GW Huang DW et al.Genetics and pathogenesis of diffuse large B-cell lymphoma.N Engl J Med. 2018; 378: 1396-1407Google Scholar, 10Reddy A Zhang J Davis NS et al.Genetic and functional drivers of diffuse large B cell lymphoma.Cell. 2017; 171: 481-494Google Scholar However, these models are complex, partially overlapping, and relatively difficult to test in a randomised clinical trial or apply in daily practice. The selection of diffuse large B-cell lymphoma patients on the basis of biological markers before the first treatment therefore remains a crucial challenge. I have received personal fees from Roche, Celgene, Janssen, Gilead, Amgen, and Servier. Gene-expression profiling of bortezomib added to standard chemoimmunotherapy for diffuse large B-cell lymphoma (REMoDL-B): an open-label, randomised, phase 3 trialThis 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. Full-Text PDF Open Access