Improving R-CHOP in diffuse large B-cell lymphoma is still a challenge
Mené au Royaume-Uni et en Suisse sur 918 patients atteints d'un lymphome diffus à grandes cellules B, cet essai de phase III évalue l'efficacité, du point de vue de la survie sans progression, et la toxicité de l'ajout du bortézomib à une chimio-immunothérapie de type R-CHOP, selon le sous-type de la maladie (GC ou ABC) déterminé grâce à l'analyse des profils d'expression génique (durée médiane de suivi : 29,7 mois)
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).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.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,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.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. 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 (...)
The Lancet Oncology , commentaire en libre accès, 2018