TNF Polymorphisms Independently Predict Outcome in Patients with B-Cell Non-Hodgkin's Lymphoma

Objectives: Tumour Necrosis Factor a (TNF alpha) and Lymphotoxin alpha (LT alpha) have been implicated in the pathogenesis of lymphoproliferative disorders. Patients with B-cell non-Hodgkin's lymphoma (NHL) often have high serum levels of TNF which may be associated with a poor outcome. TNF alpha and LTa polymorphisms are known to influence expression of these cytokines and may explain the variable response to therapy. Patients and Methods: In patients with NHL, serum levels of TNF alpha and LT alpha were measured. DNA was typed using allele specific PCR and restriction fragment length polymorphism for the -308 TNF alpha and + 252 LT alpha polymorphisms and comparison was made with clinical outcome. Results: The presence of high producing alleles was significantly associated with high serum levels of TNF alpha and LT alpha. The presence of 2 or more high producing alleles was significantly associated with more advanced disease at presentation (stage III and IV), p=0.024, a higher International Prognostic Index (IPI) score, p=0.038, failure to achieve a complete remission (CR) after 1st line therapy (88% vs 33%, p=0.01) and shorter progression free survival (PFS) (median 24 months compared with 78 months, p=0.001). Multivariate analysis confirmed that TNF high-risk haplotype (HRH) was an independent prognostic factor for PFS. Conclusions: These results demonstrate that TNF polymorphisms are independent prognostic factors in NHL. Further study is required to further define the importance of TNF polymorphisms within different lymphoma subtypes and with different therapeutic approaches.