Abstract Background: In Hodgkin lymphoma (HL) the malignant Hodgkin Reed-Sternberg (HRS) cells comprise only a small fraction of the total cellular tumor population, which orchestrate an inflammatory microenvironment of reactive cells that propagate a permissive milieu for HL growth. This HL-mediated immune suppression may have effects that extend beyond the tumor microenvironment. Previously we have shown that the circulating T cells of HL patients show high expression of the receptor programmed death-1 (PD-1). Here wecharacterize the systemic immune profile of 20 HL patients with newly diagnosed (ND) or relapsed (R) disease. Methods: Informed consent obtained from patients with ND (n = 14) or R (n = 6) HL treated since January of 2013. Blood samples were drawn pre-treatment, and at sequential time-points during therapy. Cryopreserved PBMCs were thawed then evaluated with multi-color flow cytometry. Cells were stained with fixable viability dye (eBioscence); then stained with fluorescent-conjugated antibodies. For intracellular staining, cells were fixed and permeabilized using FOXP3 staining kit (eBioscience) then stained with intracellular antibodies. Stained cells were analyzed using LSRII flow cytometer (BD Bioscience) and FlowJo software (Tree Star). The following anti-human antibodies were used: CD3, CD4, CD8, CD25, CD160, CD45RO, CD27, HLA-DR, PD-1,FOXP3 and Helios, (Biolegend). Singlet lymphocytes were gated based on forward and side scatter properties. Dead cells were excluded based on viability dye. Patient samples were compared to normal controls matched for age and sex (n = 20). Results: The median HL patient age was 38 (range: 20-90 years). Twelve of the HL subjects were male and 8 were female. All but 1 ND patient were treated with upfront ABVD. Two out of 6 R patients had prior stem cell transplant (SCT), but were not on immunosuppression. Thirteen patients (12 ND, 1 R) responded to therapy (11 CR and 2 PR); 4 patients (1 ND, 3 R) progressed on therapy or had stable disease, 2 patients do not have disease status confirmed. HL patients displayed distinct circulating immune profile compared to normal age matched controls, with increased circulating CD4 and CD8 effector cells and a decrease in CD8 central memory cells. The proportion of CD4 or CD8 effector memory T cells expressing CD160+ and PD1+ CD4 effector memory cells, were also highly significantly increased in HL patients. In contrast, a decreased percent of bona fide CD4+ regulatory T cell subset (Foxp3+Helios) was found in HL patients. Together these findings suggest that the systemic immune profile in HL patients is perturbed towards severe chronic activation/exhaustion of T cells. Conclusion: HL patients have evidence of chronic activation/exhaustion in their central memory T cells, suggesting that ineffective immune clearance of the HRS cells may be a systemic phenomenon. This underscores the rationale for immune targeted therapy in HL patients. Citation Format: Catherine S. Diefenbach, Bruce Raphael, Kenneth Hymes, Michael Grossbard, Tibor Moskovits, David Kaminetzky, Meghan Mcshea, Peter Martin, Jia Ruan, Lina Kozhaya, Maryam Bonakdar, Cem Abidoglu, John Leonard, Derya Unutmaz. Hodgkin lymphoma patients demonstrate evidence of chronic activation/exhaustion in circulating T cell subsets. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4895.