Genetic Profiling in Diffuse Large B-Cell Lymphoma: The Promise and the Challenge.

Diffuse large B-cell lymphoma (DLBCL) is the most common non-Hodgkin lymphoma. Over the previous 2 decades, tremendous progress has been made in our understanding of the molecular pathogenesis of DLBCL. However, this biological understanding has not yet been translated into improved first-line therapy. A major barrier to the introduction of molecularly targeted therapy in DLBCL is the considerable molecular heterogeneity of this disease. Recent studies have tried to rationalize this heterogeneity by proposing new genetic subtypes of DLBCL. Although remarkable consensus exists over the broad nature of these genetic subtypes, important questions remain over precisely how, or even why, genetic subtyping might be incorporated into diagnostic laboratories. In this review, we compare the findings of the major genetic subtyping studies and discuss the implications this may have for diagnostic pathology services and the management of DLBCL.

Long-Term Ibrutinib Therapy Reverses CD8+ T Cell Exhaustion in B Cell Chronic Lymphocytic Leukaemia.

Chronic Lymphocytic Leukaemia (CLL) is associated with immune suppression and susceptibility to infection. CD8+ T cell numbers are increased and demonstrate elevated expression of PD-1 and impaired function. The mechanisms driving these features of exhaustion are uncertain but are likely to include chronic immune recognition of tumor and/or infectious agents. We investigated the number, phenotype and function of total and virus-specific CD8+ T cells in 65 patients with CLL and 14 patients undergoing long-term ibrutinib therapy (median 21 months). Ibrutinib substantially reduced the number of both CD3+ T cells and CD8+ T cells. Importantly, this was associated with a reduction in PD-1 expression on CD8+ T cells (median 28 vs. 24%; p = 0.042) and 3.5 fold increase in cytokine production following mitogen stimulation. The influence of ibrutinib on antigen-specific CD8+ T cell function was assessed by HLA-peptide tetramers and revealed increased IFNγ and TNFα cytokine responses following stimulation with CMV or EBV peptides together with a 55% reduction in the frequency of "inflated" virus-specific CD8+ T cells. These findings reveal that long-term ibrutinib therapy is associated with substantial reversal of T cell exhaustion in B-CLL and is likely to contribute to the reduced infection risk seen in association with this agent.