Complex interaction affecting risk of treatment failure for patients with newly diagnosed Hodgkin lymphoma. Green arrows show how the malignant Hodgkin Reed-Sternberg cells interact with preexisting host factors, including cancer predisposition, pharmacogenetics, and acquired organ dysfunction, each of which may enhance malignant cell survival or interfere with effective treatment delivery. In addition, the Hodgkin Reed-Sternberg cells manipulate cells in their microenvironment, inducing release of growth-enhancing and immune-suppressing cytokines. Treatment (red arrows) reduces the risk of treatment failure by exerting direct cytotoxicity on the Hodgkin Reed-Sternberg cells, by interrupting the stimulation of tumor cell growth encouraged by microenvironmental cells, and by restoring an effective immune response. Treatment effectiveness is modulated (orange arrow) by host factors, with some (eg, good performance status, young age) increasing host tolerance for higher dose treatment and therefore effectiveness, and others (eg, organ dysfunction, coincident HIV infection) diminishing treatment effectiveness.