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Formulating a novel prognostic index for diffuse large B-cell lymphoma: T cells break the SILence

For over 20 years, predicting outcome in diffuse large B-cell lymphoma (DLBCL) has relied on the International Prognostic Index (IPI) – a set of five clinical parameters associated with the overall and relapse-free survival. After the introduction of R-CHOP immunochemotherapy led to a marked improvement in outcomes, the IPI was recalibrated first by reclassification of risk groups (revised IPI), and then by a more granular categorization of age and lactate dehydrogenase levels (enhanced IPI).[1] These repeated observations were however unsuccessful in identifying the truly high-risk patient group experiencing early refractory or relapsing disease. The latter largely contribute to lymphoma-related mortality, but might well benefit from upfront therapeutic approaches other than standard R-CHOP. When applied to large-scale data, the revised IPI explains only 16% of the survival variation in DLBCL, while even more complex models only bring this value to <30%.[2] This poor performance results from lack of information regarding genetic diversity of DLBCL, which continues to be subcategorized into an ever increasing number of histologically or molecularly defined subtypes. The main line of research during the past decade revolved around gene expression profiling of DLBCL. It was found to encompass three main distinct entities: germinal center B-cell-like (GCB), activated B-cell-like (ABC), and primary mediastinal B-cell lymphoma. While this cell-of-origin classification had immense success in elucidating signaling pathways driving the pathophysiology of DLBCL, it still has not been clearly translated into clinical practice. So far, the only subgroup for which an alternative therapy has been widely accepted is the ‘double-hit lymphoma’ with concurrent rearrangements of the MYC and BLC2 (and/or BCL6) genes. Many centers treat this aggressive, high-grade malignancy, distinguished in the 2016 World Health Organization classification,[3] with the intensified, dose-adjusted EPOCH-R chemotherapy combination, even though high-level evidence for this strategy has not yet been established. Interestingly, alternative gene expression-based classifications of DLBCL have also emerged more recently, revealing the critical role of microenvironment in this disease. The Lymphoma/Leukemia Molecular Profiling project found that the cell-of-origin-based survival predictions can be significantly enhanced by incorporating additional genes, including the ‘MHC class II signature’ genes involved with antigen presentation and immune surveillance.[4] Furthermore, Monti et al. described a poor-prognosis DLBCL ‘host response’ cluster characterized by increased expression of T/NK cell receptors, macrophage/dendritic cell markers, and inflammatory mediators.[5] Another classification based on genes implicated in the immune cell infiltration, fibrosis, and angiogenesis can also predict survival among DLBCL patients treated with immunochemotherapy.[6] So far, these clues about the connection between immune microenvironment and prognosis have not led to any practical advances in the clinical management of DLBCL. In the article accompanying this commentary, Tomita et al. offer and validate a prognostic score which entirely removes patient-derived variables for the benefit of factors related to DLBCL biology: its extent (advanced stage), bulk and proliferative rate (lactate dehydrogenase), and interaction with the immune system (serum level of the soluble interleukin2 receptor alpha, sIL-2Ra).[7] While this SIL index only