B- Cell Chronic Lymphocytic Leukaemia Complicated by Aggressive T-Cell Lymphoma: Clinical and Molecular Analysis of a Rare Variant of Richter’s Syndrome.
Authors: Skoulidis Ferdinandos , Boyd Kevin , Cunningham David , Wotherspoon Andrew , Gonzalez David , Catovsky Daniel , Morgan Gareth , Matutes Estella , Dearden Claire 
Published: April 2020

Abstract
Richter’s syndrome denotes the development of higher grade lymphoma on the background of B-CLL. We report the clinical and molecular features of two rare cases of T-cell lymphoma occuring in this setting. A 69 year old man was referred in 1999 with a 2 year history of stage B Binet B -CLL.Treatment with chlorambucil and prednisolone was commenced in 2002 for progressive disease with complete response after 12 cycles. He relapsed 10 months later and was treated with fludarabine. Despite clinical response after 5 cycles, in April 2005 he developed hepatorenal failure and died. Post mortem liver biopsy showed portal tract infiltration by rapidly proliferating large pleomorphic cells with irregular nuclei, that stained for CD3, CD4, CD7, CD25, CD30 and were negative for CD20, CD79a, CD10, CD8, bcl-2,bcl-6. p53 was not overexpressed. Staining for EBV latent membrane protein (EBV LMP-1) was negative. Appearances were those of peripheral T-cell lymphoma. Clonality studies using standard, PCR based methodology were performed. A B-cell clone was detected in the bone marrow sample from 1999 relating to the B-CLL cells, however analysis of TCR β and γ chain gene rearrangement also revealed a clonal T-cell population. TCR gene rearrangement analysis of the liver biopsy specimen showed a T-cell clone, different from the one in the bone marrow. Finally, a B-cell clone was noted in the liver biopsy specimen, with a distinct pattern of IgH and Igκ gene rearrangements. The second case, a 66 year old man, was diagnosed in March 2003 with Binet stage A B-CLL. In June 2004 he was treated with chlorambucil for progressive disease. This was changed after 3 cycles to cyclophosphamide, vincristine and prednisolone for 2 cycles, with the additon of rituximab for a further 2 cycles due to lack of response. At that point he was referred to our hospital and underwent excision biopsy of a cervical lymph node. This revealed effacement of the nodal architecture by a diffuse population of rapidly proliferating large cells with markedly pleomorphic nuclei. The cells stained for CD2, CD3, CD4, CD30 and were negative for CD20, CD8, CD5, CD7 and ALK1. Staining for EBV LMP-1 and EBER RNA ISH were negative. Appearances were consistent with peripheral T-cell lymphoma. He was treated with six cycles of prednisolone, cyclophosphamide, etoposide, gemcitabine, bleomycin, vincristine and methotrexate with initial response and disease stabilisation, however a month later he relapsed and failed to respond to gemcitabine, cisplatin and methylprednisolone. In July 2005 he developed worsening liver impairment due to lymphomatous liver infiltration and died. Clonality studies confirmed the presence of the same T-cell clone on the lymph node and liver biopsy specimens. In conclusion, we present two cases of aggressive T-cell lymphoma complicating the course of B-CLL and report the presence of additional clonal B- and T -cell populations in one of them. We suggest that the immunosuppression and chronic immune dysregulation associated with CLL create a favourable environment for oligoclonal T-cell proliferation and the development, through acquisition of further genetic changes, of T- as well as B-cell neoplasms. The immunosuppressive and mutagenic effect of treatment with alkylating agents and purine nucleoside analogs may add to this risk.