Prognostic Impact of Germinal Center (GC)/ Activated B-Cell (ABC) Classification Analysed by Immunochemistry, FISH Analysis and GEP, In Relapsed/Refractory Diffuse Large B-Cell Lymphoma (DLBCL): The Bio-CORAL Study

Cell of origin (COO) has a major prognostic impact in DLBCL. However this impact has never been analysed in the context of relapsed/refractory DLBCL. The purpose of this study was to evaluate the prognostic value of COO immunohistochemical markers and BCL2, BCL6 and c-MYC translocations in a well-defined cohort of patients included in the CORAL trial¹.

Enrolled patients had CD20+ DLBCL in first relapse or refractory after upfront therapy. Treatment was randomized to either R-ICE (rituximab, ifosfamide, etoposide, carboplatin) or R-DHAP (rituximab, dexamethasone, aracytine, cisplatin). Responding patients had high-dose chemotherapy and ASCT. Paraffin-embedded tumor samples of 249 patients were analysed by immunochemistry for CD10/MME, BCL6, MUM1/IRF4, FOXP1, BCL2 expression and for BCL2, BCL6 and c-MYC breakpoints by FISH, and were categorized according to different COO algorythms^2-5. Primary biopsy at diagnosis and relapse biopsy were available for 189 and 147 patients respectively, including 87 matched pairs.

With a median follow-up at 27 months, there was no significant difference between R-ICE and R-DHAP for 2-year progression-free survival (PFS) (56.7%+/−5% vs 60%+/−5%, p=0.24) or overall survival (OS) (46%+/−5% vs 60%+/−5%, p=0.24). We confirmed that early relapse, prior rituximab exposure and secondary aaIPI had adverse prognostic value. In univariate analysis, absence of bcl6 expression, non-GC phenotype², ABC phenotype⁴, at diagnosis were associated with an unfavourable PFS (p=0.038, p=0.0044, p=0.044, respectively), whereas only non-GC phenotype² was associated to a worse OS (p=0.027). At relapse, expression of Foxp1 and bcl2, c-MYC breakpoint, ABC phenotype⁴, immunoFISH index⁵ was associated with an unfavourable PFS (p=0.02, p=0.027, p=0.03, p=0.032, p=0.02, respectively), and c-MYC breakpoint was associated with a worse OS (p=0.01). Tumor immunophenotype and FISH analysis at diagnosis and at relapse were statistically concordant in matched pairs (Wilcoxon's test between 0.42 and 1). In the whole group, only c-MYC breakpoint present in 13% of the patients was correlated with worse PFS (p= 0.02) and OS (p =0.04). Statistical interaction were found between GC/non-GC classification² and the treatment R-ICE vs R-DHAP. Patients with GC B-cell like DLBCL subtype treated with R-DHAP have a better 2-year PFS (64% +/−7%) than those with GC B-cell like DLBCL treated with R-ICE (42% +/−7%), and the patients with ABC B-cell like DLBCL treated either with R-DHAP (35%+/−7%) or R-ICE (45%+/−7%) (p= 0.04). In multivariate analysis, only GC/non-GC phenotype² interaction with the treatment, FOXP1 expression, prior rituximab exposure, secondary aaIIPI, time to relapse were statistically significant. Preliminary results of gene expression profiling seem to confirm these data and are currently under validation.

COO remains a major factor in relapsed patients with a better response to R-DHAP salvage chemotherapy in GC-B DLBCL, underlying the importance of molecular DLBCL subtyping. Treatment of ABC subtype is still unsatisfactory.

1. Gisselbrecht C, et J Clin Oncol. 2010.

2. Hans CP, et al.Blood. 2004;103:275-282.

3. Muris JJ, et al. J Pathol. 2006;208:714-723.

4. Nyman H, et al. Mod Pathol. 2009;22:1094-1101.

5. Copie-Bergman C, et al. J Clin Oncol. 2009;27:5573-5579.

Schmitz:Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Gisselbrecht:Roche: Research Funding.