Can a blood test monitor lymphoma?

Disease monitoring biomarkers are parameters that reflect the progress of a disease. Ideally, a successful lymphoma biomarker would be inexpensive, easy to measure, non-invasive, highly specific and sensitive, as well as accurate and reproducible. Unsurprisingly, establishing a lymphoma biomarker is not easy. Indeed, very few successful disease monitoring biomarkers have been incorporated into wide clinical practice for any disease in the last decade. For lymphoma, clinicians currently assess treatment response via computed tomography (CT) or positron emission tomography (PET) scan. Although often effective, these methods have their limitations. CT is able to identify anatomic abnormalities but cannot differentiate between tumor tissue and residual fibrosis. Although PET scans can make this differentiation, it can also be difficult to interpret, as it is positive in patients with inflammation, infection, and other co-existing malignancies [1]. Furthermore, both methods are expensive and not always readily available when required, especially in rural or third-world settings. In Australia, government funding is restricted to pre-therapy and posttherapy assessment except in the context of a clinical trial. Thus, an accurate and specific blood disease response biomarker would be of great assistance in therapeutic decision-making. Epstein–Barr virus (EBV) is associated with a number of malignancies including a variety of B, T, and NK (natural killer) cell lymphomas [2]. The presence of the virus within the malignant cell means that EBV has the potential to be a highly specific biomarker. Several groups have clearly demonstrated that there is elevated cell-free, tumor-derived DNA in the plasma and serum of cancer patients [3–5]. The release of cell-free tumor-specific DNA into the peripheral blood exposes the possibility of a blood biomarker that could reflect tumor load. In accordance with this theory, several groups have shown that serum/plasma EBV DNA is increased in the peripheral blood of patients with a variety of EBVassociated diseases, including Hodgkin lymphoma (HL), post-transplant lymphoproliferative disorder (PTLD), extra-nodal NK–T cell lymphoma (ENKTL), and nasopharyngeal carcinoma (NPC) [6–9]. In contrast, results from cell-associated EBV can be misleading, particularly in the context of the B-cell depleting-agent rituximab [10]. It is yet to be established how the EBV DNA load changes during the course of treatment. Serial monitoring of EBV DNA load throughout treatment of different EBVassociated diseases is required to determine how the viral load evolves during treatment and in response to treatment, and to define a relationship between disease response and viral load. The biology of EBV DNA in the peripheral blood is still a matter of debate; however, work from our group and others has shown that the presence of the virus is not from viral reactivation [6,7,11,12]. Figure 1 illustrates the potential sources of cell-free and cell-associated EBV DNA in the peripheral blood of patients with lymphoma. Sources of cellassociated EBV DNA include benign latently infected B-cells or neoplastic cells that have migrated into the peripheral blood. Cell-free EBV DNA presumably arises from necrotic or apoptotic infected benign and neoplastic cells in the peripheral blood or