Richter transformation driven by Epstein–Barr virus reactivation during therapy‐related immunosuppression in chronic lymphocytic leukaemia

Abstract

The increased risk of Richter transformation (RT) in patients with chronic lymphocytic leukaemia (CLL) due to Epstein-Barr virus (EBV) reactivation during immunosuppressive therapy with fludarabine other targeted agents remains controversial. Among 31 RT cases classified as diffuse large B-cell lymphoma (DLBCL), seven (23%) showed EBV expression. In contrast to EBV tumours, EBV DLBCLs derived predominantly from IGVH-hypermutated CLL, and they also showed CLL-unrelated IGVH sequences more frequently. Intriguingly, despite having different cellular origins, clonally related and unrelated EBV DLBCLs shared a previous history of immunosuppressive chemo-immunotherapy, a non-germinal centre DLBCL phenotype, EBV latency programme type II or III, and very short survival. These data suggested that EBV reactivation during therapy-related immunosuppression can transform either CLL cells or non-tumoural B lymphocytes into EBV DLBCL. To investigate this hypothesis, xenogeneic transplantation of blood cells from 31 patients with CLL and monoclonal B-cell lymphocytosis (MBL) was performed in Rag2 IL2γc mice. Remarkably, the recipients' impaired immunosurveillance favoured the spontaneous outgrowth of EBV B-cell clones from 95% of CLL and 64% of MBL patients samples, but not from healthy donors. Eventually, these cells generated monoclonal tumours (mostly CLL-unrelated but also CLL-related), recapitulating the principal features of EBV DLBCL in patients. Accordingly, clonally related and unrelated EBV DLBCL xenografts showed indistinguishable cellular, virological and molecular features, and synergistically responded to combined inhibition of EBV replication with ganciclovir and B-cell receptor signalling with ibrutinib in vivo. Our study underscores the risk of RT driven by EBV in CLL patients receiving immunosuppressive therapies, and provides the scientific rationale for testing ganciclovir and ibrutinib in EBV DLBCL. Copyright © 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

EBV Positive Diffuse Large B Cell Lymphoma and Chronic Lymphocytic Leukemia Patients Exhibit Increased Anti-dUTPase Antibodies

“…It is also well documented that a small percentage (10–15%) of patients with CLL will undergo histological transformation into an aggressive form of DLBCL [ 11 , 12 , 13 , 14 ] referred to as Ritchter syndrome (RS). Recently, it was reported that RS might occur following aggressive therapy during CLL that results in the reactivation of EBV [ 17 ]. Therefore, it is possible that the CLL patients tested in this study and the study by de Sanjose et al [ 58 ] represent two subgroups one in which EBV is a negative prognostic factor for patients with CLL and a second subgroup in which EBV contributes to RS transformation.…”

“…While several studies have implicated EBV in RS [ 15 , 16 ], a mechanistic relationship has not been determined. However, a recent study demonstrated that therapy related to immunosuppression in patients with CLL resulted in EBV reactivation, which drove RS and the formation of the ABC subtype DLBCL in some patients [ 17 ]. This study as well as a recent study of DLBCL [ 18 ] has suggested that products of lytic EBV may contribute to the development of these malignancies, but additional studies need to be performed.…”

Cytomegalovirus and Epstein-Barr Infections: Prevalence and Impact on Patients with Hematological Diseases

“…In RS, the large cells may represent a new neoplasm or they could emerge through the transformation of the original CLL clone, which might occur due to the EBV reactivation [ 105 ]. The association between EBV reactivation and the increased risk of RS development in CLL patients during immunosuppressive therapy was also reported [ 106 ]. The pathogenesis and course of CLL condition have been linked to EBV-induced STAT-5, which may be associated with the rise of the mortality rates among CLL carriers [ 107 ].…”

The involvement of microRNA in the pathogenesis of Richter syndrome

“…Moreover, it has recently been shown in an in vivo model that immunosuppressive therapy leads to the reactivation of Epstein-Barr virus in CLL xenografts, increasing the risk of DLBCL (Richter transformation). 53 The viral miRNA that correlate in our networks could be a marker of viral reactivation.…”