RESUMEN
Secondary central nervous system lymphoma (SCNSL) is a rare and difficult to treat type of Non-Hodgkin lymphoma characterized by systemic and central nervous system (CNS) disease manifestations. In this study, 124 patients with SCNSL intensively treated and with clinical long-term follow-up were included. Initial histopathology, as divided in low-grade, other aggressive, and diffuse large B-cell lymphoma (DLBCL), was of prognostic significance. Overall response to induction treatment was a prognostic factor with early responding DLBCL-SCNSL in comparison to those non-responding experiencing a significantly better progression-free survival (PFS) and overall survival (OS). However, the type of induction regime was not prognostic for survival. Following consolidating high-dose chemotherapy and autologous stem cell transplantation (HDT-ASCT), DLBCL-SCNSL patients had better median PFS and OS. The important role of HDT-ASCT was further highlighted by favorable responses and survival of patients not responding to induction therapy and by excellent results in patients with de novo DLBCL-SCNSL (65% long-term survival). SCNSL identified as a progression of disease within 6 months of initial systemic lymphoma presentation represented a previously not appreciated subgroup with particularly dismal outcome. This temporal stratification model of SCNSL diagnosis revealed CNS progression of disease within 6 months as a promising candidate prognosticator for future studies.
RESUMEN
Immune checkpoint inhibitor (ICI) therapy has shown a significant benefit in the treatment of a variety of cancer entities. However, immune-related adverse events (irAEs) occur frequently and can lead to ICI treatment termination. MicroRNA-146a (miR-146a) has regulatory functions in immune cells. We observed that mice lacking miR-146a developed markedly more severe irAEs compared with WT mice in several irAE target organs in 2 different murine models. miR-146a-/- mice exhibited increased T cell activation and effector function upon ICI treatment. Moreover, neutrophil numbers in the spleen and the inflamed intestine were highly increased in ICI-treated miR-146a-/- mice. Therapeutic administration of a miR-146a mimic reduced irAE severity. To validate our preclinical findings in patients, we analyzed the effect of a SNP in the MIR146A gene on irAE severity in 167 patients treated with ICIs. We found that the SNP rs2910164 leading to reduced miR-146a expression was associated with an increased risk of developing severe irAEs, reduced progression-free survival, and increased neutrophil counts both at baseline and during ICI therapy. In conclusion, we characterized miR-146a as a molecular target for preventing ICI-mediated autoimmune dysregulation. Furthermore, we identified the MIR146A SNP rs2910164 as a biomarker to predict severe irAE development in ICI-treated patients.