Aggressive B-cell lymphomas are a heterogeneous group of mature B-cell neoplasms with morphological similarities, but phenotypic and genetic differences. This thesis investigated the aggressive lymphomas from bench-to-bedside aiming to enhance insight into its pathobiology, to investigate mechanisms underlying therapy resistance, and to explore novel treatment combinations. We focused on the role of MYC gene rearrangements, impact of DNA mutations, and altered protein expression. We observed that MYC rearrangements functioned as drivers of transformation in one third of cases in transformed follicular lymphoma. Next, we described loss of human leukocyte antigen (HLA) DM with loss of antigen expression by HLA class II as a novel mechanism of immune escape in Hodgkin lymphoma and diffuse large B-cell lymphoma (DLBCL). Mutational analysis of paired DLBCL tumor samples indicated variable mutational heterogeneity at relapse, with PIM1 and SOCS1 potentially related to resistance. Focusing on treatment, we observed that necrosis as assessed by 18F-FDG PET-scans was associated with metabolic active DLBCL irrespectively of MYC rearrangements and this might identify patients at increased risk of relapse. The combination of the JAK2 inhibitor ruxolitinib and the checkpoint inhibitor pembrolizumab showed a remarkable response in a patient with a primary chemo- and radiotherapy refractory primary mediastinal B-cell lymphoma. Finally, we studied the treatment outcomes of patient groups with rare poor risk lymphoma (relapsed stage I DLBCL and central nervous system DLBCL). The results and considerations from this thesis form the basis for ongoing Dutch HOVON trials, in several of which the PhD candidate plays a central role.
|Kwalificatie||Doctor of Philosophy|
|Datum van toekenning||16-okt-2019|
|Plaats van publicatie||[Groningen]|
|Status||Published - 2019|