EBV Related Transformation Events in CLL.
Authors: Sayala Hazem A. , O’Connor Sheila J. , Jack Andrew S. , Patalappa Chetan , Hillmen Peter , Owen Roger G. 
Published: April 2020

Abstract
Less than 5% of patients with CLL undergo histological transformation to diffuse large B cell lymphoma (DLBL) while transformation to Classical Hodgkins lymphoma (CHL) is also recognised. It has been assumed that such events reflect genetic changes in the CLL clone but there is now emerging evidence to suggest that at least some transformation events may be Epstein Barr virus (EBV) related neoplasms not clonally related to CLL. In this analysis we have reviewed the clinical and laboratory features of 15 CLL patients with biopsy proven histological transformation to DLBL and 2 patients who developed CHL. Histological sections were assessed for the expression of a wide range of immunophenotypic markers as well as EBV latent membrane protein 1 (LMP-1). Of the 15 patients developing DLBL 5 appeared on phenotypic grounds to be related to the underlying CLL clone. In the remaining patients the tumour cells appeared phenotypically distinct as they lacked CD5 and CD23 and demonstrated expression of germinal centre markers in some instances. LMP1 positivity was demonstrable in 5 patients with DLBL (1 apparently related and 4 unrelated to the underlying CLL). Of the 2 patients who developed CHL 1 was associated with EBV and lacked CD20 expression.
The 6 patients with EBV+ tumours were heavily pretreated (median prior therapies 4, range 1–5) while the median time from original diagnosis to histological transformation was 74.5 months (range 17–114). Previous therapies included chlorambucil (n= 4), fludarabine monotherapy (n=3), FC (n=2), FCR (n=1 patient), high dose methyl prednisolone (n= 1) and alemtuzumab (n=2). 2 patient received only one line of therapy for CLL but one of these was heavily immunosuppressed with steroids and azathioprine for autoimmune neutropenia. 4 patients presented with nodal disease and 2 patients presented with extranodal disease (bone marrow and liver). The outcome of the EBV associated tumours in these patients was death in 2 patients (opportunistic infection and complications of intensive chemotherapy), remission with intensive combination chemotherapy in 2 patients one of whom died 10 months later of progressive CLL and spontaneous remission of nodal disease in 1 patient. 1 patient is still undergoing intensive chemotherapy and the outcome is not known yet. We would conclude that not all transformation events in CLL occur within the original clone. The majority appear to be clonally distinct and a significant proportion of these appear to be EBV associated. This presumably occurs as a result of both the underlying immune-deficiency seen in CLL as well the potent immunosuppressive agents given as therapy. This phenomenon may also be a feature of other B-cell disorders as we have recently seen a phenotypically and genotypically distinct EBV associated DLBL in a patient treated with chlorambucil, CHOP and FCR for mantle cell lymphoma. The natural history of these tumours remains uncertain at this stage but it is clear that at least a minority may resolve spontaneously. All biopsies demonstrating histological transformation in CLL patients should be assessed for the presence of EBV.