Interaction between BCL2 and Interleukin-10 Gene Polymorphisms Alter Outcomes of Diffuse Large B-Cell Lymphoma following Rituximab Plus CHOP Chemotherapy

Purpose: Rituximab may overcome bcl-2-mediated chemoresistance through the inhibition of interleukin-10 (IL-10)-mediated loops, thus down-regulating bcl-2 expression. We examined the effects of genetic variation in BCL2/IL10 gene loops on treatment outcomes of diffuse large B-cell lymphoma when treated with either CHOP or rituximab plus CHOP (R-CHOP) chemotherapy. Experimental Design: Four genotypes were tested including BCL2 -938 C > A (rs2279115), +21 A > G (rs1801018), IL10 -819 T > C (rs1800871), and -592 A > C (rs1800872) in patients receiving either R-CHOP (n = 125) or CHOP (n = 110). Results: IL10 SNPs, -819 TT/TC or -592 AA/AC genotypes correlated with improved CHOP response rates (P = 0.04). Neither polymorphism separately influenced the failure-free survival (FFS) or overall survival in patients, but the IL10 haplotype was associated with treatment outcomes after R-CHOP for FFS (P = 0.03) or progression (P = 0.007), whereas the -938 AA BCL2 genotype significantly affected overall survival (P = 0.04). An interactive effect between BCL2 and IL10 SNPs was significant in the group with both -938 AA BCL2 genotype and 1 to 2 copies of CC IL10 haplotype. This group showed a better FFS (P = 0.01) and a lower probability of progression (P = 0.004) compared with other genotype groups when treated with R-CHOP chemotherapy. Conclusions: These data indicated that R-CHOP chemotherapy resistance in diffuse large B-cell lymphoma may involve interactions between the BCL2 and IL10 genes.