Prognostic Value of cMYC Gene Abnormalities in Diffuse Large B Cell Lymphoma Treated with Chemo-Immunotherapy

Abstract 2664

Diffuse large B cell lymphoma (DLBCL) is a heterogeneous group of aggressive lymphomas. Despite improvements in diagnostic and therapeutic procedures, DLBCL still represents a significant cause of morbidity and mortality. Two molecularly defined types of DLBCL have been recently described: the germinal center B-cell (GCB) and the activated B-cell (ABC) subtype. GCB type DLBCL has been shown to have a better OS and PFS than ABC-type in multiple series of DLBCL patients treated with chemoimmunotherapy. The processes involved in lymphomagenesis in both subtypes are not fully understood, but deregulated expression of various proto-oncogenes is observed, often as the result of chromosomal translocations leading to constitutive gene expression. The specific role of the cMYC gene abnormalities in the pathogenesis of these lymphomas is still a matter of debate. To address this question, the status of the cMYC gene was analyzed by interphase fluorescence in situ hybridization (FISH) using a break apart probe, in TMA arranged tissue samples from 241 patients with de novo DLBCL treated with chemoimmunotherapy (R-CHOP and R-CHOP-like regimens). cMYC was rearranged in 15 cases out of 166 evaluable (9.26%). We did not find differences in the incidence of cMYC rearrangements between GCB and ABC-DLBCL subtypes (9/74 GCB and 6/82 ABC type) as classified according to extended immunohistochemical algorithms (Choi et al in Cancer Res. 2009). In our series, patients with DLBCL and cMYC rearrangements presented more frequently extranodal disease (p=0.007), higher IPI (p=0.037) and tended to have less than 60 years (p=0.053). cMYC gains were observed in 33 cases (21.85%). In the univariate analysis, cMYC abnormalities (gains and rearrangements) had no impact on the clinical outcome in the ABC subtype. However, whilst the cMYC gains did not identify a risk group in terms of OS or PFS the presence of cMYC rearrangements showed a significantly inferior progression-free survival (PFS) in the GCB-type group (p<0.006). However, the multivariate analysis showed that the only independent adverse predictors in these series of DLBCL cases were the presence of a high International Prognostic Index score (p=0.0028; RR=2.59 95% CI 1,34–4,99) and the ABC phenotype (p=0.0182; RR=2.16 95% CI 1,1–4,21). In summary, although cMYC rearrangements apparently do not provide additional prognostic information to the IPI score and/or GC-ABC classification in the whole DLBCL population, it identifies a subgroup of GCB-type DLBCL with very poor outcome.