This study will be conducted in two phases:

Phase I:

To find a safe dose of vorinostat to be used in combination with R-CHOP (vorinostat-RCHOP).

Phase II:

To estimate the 2-year progression-free survival rate in patients with newly diagnosed diffuse large B-cell lymphoma (DLBCL) treated with vorinostat and R-CHOP therapy (vorinostat-R-CHOP).

To estimate the response rate (complete and partial) and 2-year overall survival rate.

To evaluate the toxicity of vorinostat-R-CHOP in patients with newly diagnosed DLBCL.

To assess whether pre-treatment acetylation status of histones, expression of MHC Class II genes, and/or percentage of CD8+ tumor infiltrating lymphocytes (TIL) correlate with progression-free survival.

To explore whether treatment with vorinostat-R-CHOP increases histone acetylation, alters expression of MHC class II proteins, or alters percentage of T-cell subsets (CD8+, CD4+, FOXP3+) or infiltrating macrophages.

To explore whether histone acetylation status of tumor tissues correlates with MHC class II expression of peripheral blood B cells and lymphocyte subsets.

To explore whether the change in systemic levels of immune cytokines with vorinostat-RCHOP correlates with lymphoma symptoms, response, progression-free or overall survival.