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On 19th May 2017, in the Journal of Clinical Oncology, Annette M. Staiger from the University of Tübingen, Tübingen, Germany, and colleagues published an article which aimed to assess the prognostic impact and interdependence of the Cell-of-Origin (COO) classification, Dual Expression (DE) of MYC and BCL2, and translocations in MYC, BCL2, and BCL6 in DLBCL patients enrolled in two prospectively randomized clinical trials1 (RICOVER-602 and R-MegaCHOEP3).
In the current analysis, formalin-fixed paraffin-embedded samples were reviewed by expert hemato-pathologists in accordance with the WHO 2008 classification.
COO classification was successfully obtained for 326/949 and 88/202 tumors in RICOVER-60 and R-MegaCHOEP, respectively. In RICOVER-60: ABC = 42% (137/326); GCB = 44% (142); unclassified = 14% (47). In R-MegaCHOEP: ABC = 27% (24/88); GCB = 60% (53); unclassified = 13% (11). The R-MegaCHOEP study enrolled significantly more GCB pts (69%; 53/77) vs. the RICOVER-60 study (51%; 149/279; P = 0.005). In RICOVER-60, more immunoblastic lymphomas were designated ABC (14/98; 14%) than GCB subtype (2/93; 2%; P = 0.002).
IHC
FISH
Survival
The authors stated that their paper is the first, to their knowledge, FFPE study on gene expression-based COO profiling of prospective, randomized trials. They concluded that COO profiling alone failed to identify prognostic subgroups. However, “MYC/BCL2 DE status was highly prognostic of poor survival.”
Purpose: To explore the prognostic impact and interdependence of the cell-of-origin (COO) classification, dual expression (DE) of MYC and BCL2 proteins, and MYC, BCL2, and BCL6 translocations in two prospectively randomized clinical trials of patients with diffuse large B-cell lymphoma (DLBCL).
Patients and Methods: Overall, 452 formalin-fixed paraffin-embedded samples from two prospective, randomized DLBCL trials (RICOVER-60, prospective, randomized study for patients > 60 years, all IPI groups; and R-MegaCHOEP, prospective, randomized study for patients ≤ 60 years with age-adjusted IPI 2,3) of the German High-Grade Non-Hodgkin Lymphoma Study Group were analyzed with the Lymph2Cx assay for COO classification, with immunohistochemistry for MYC and BCL2, and with fluorescent in situ hybridization for MYC, BCL2, and BCL6 rearrangements.
Results: COO classification was successful in 414 of 452 samples. No significant differences with respect to COO (activated B-cell [ABC]-like DLBCL v germinal center B-cell [GCB]-like DLBCL) were observed in event-free survival, progression-free survival, and overall survival in patients treated with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) in the RICOVER-60 trial. Also, no differences with respect to COO were observed in multivariable analyses adjusted for International Prognostic Index factors in event-free survival (hazard ratio [HR] of ABC-like disease v GCB-like disease, 1.0; 95% CI, 0.6 to 1.6; P = .93), progression-free survival (HR, 1.1; 95% CI, 0.6 to 1.8; P = .82), and overall survival (HR, 1.0; 95% CI, 0.6 to 1.8; P = .96). Similar results were observed in the R-MegaCHOEP trial. In patients treated with R-CHOP, DE status was associated with significantly inferior survival compared with nonDE within the GCB, but not within the ABC subgroup. DE status was associated with significantly inferior outcome compared with patients with ABC-like DLBCL without DE (5-year PFS rate, 39% [95% CI,19% to 59%] v 68% [95% CI, 52% to 85%]; P = .03) and compared with patients with GCB-like DLBCL without DE. When data from patients with nonDE were analyzed separately, the outcome of patients in the ABC subgroup was inferior to that of patients in the GCB subgroup (5-year PFS rate, 68% [95% CI, 52% to 85%] v 85% [95% CI, 74% to 96%]; P = .04).
Conclusion: COO profiling in two prospective randomized DLBCL trials failed to identify prognostic subgroups, whereas dual expression of MYC and BCL2 was predictive of poor survival. Evaluation of prognostic or predictive biomarkers in the management of DLBCL, such as the COO, within prospective clinical trials will be important in the future.
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