Abstract
Chronic lymphocytic leukemia (CLL) is a lymphoproliferative disorder (LPD) derived from mature B-cells with heterogeneous outcomes. High-grade lymphoma can arise from CLL in 3-10% of cases, a process known as Richter’s transformation (RT). The majority of RT results in high grade B-cell lymphomas, though rarely transformation to Hodgkin lymphoma (HL) has been reported. Epstein Barr virus (EBV) viremia can arise in patients with CLL secondary to immunosuppression and can lead to an EBV driven LPD. In patients with CLL, this has been seen with fludarabine based treatments but has been reported with alemtuzumab. HL is also been associated with EBV virus in tumor cells but cases of HL and EBV viremia have not been reported. We report the first two cases in the English literature of CLL with EBV viremia and HL.
A 66 year old male was diagnosed with a RAI stage I, del13q14, Zap-70 (-), IgvH mutated, CD38 (+) CLL in 2004. Worsening thrombocytopenia resulted in the initiation of treatment in April 2012 using Ofatumumab and high dose methylprednisolone followed by lenalidomide maintenance therapy (HiLOG clinical trial). The patient responded to induction therapy and was continued on lenalidomide maintenance for 12 cycles. In May of 2013 the patient developed progressive fevers, chills, cough, weakness, weight loss, and hypercalcemia. Evaluation revealed an EBV viremia with whole blood PCR titers of 484,550 copies/mL. Bone marrow biopsy was consistent with CLL and full body PET CT scan showed diffuse lymphadenopathy with max SUV of 30.7 and splenomegaly. Biopsy of a left external iliac node showed large atypical lymphoid cells that were surrounded by small lymphocytes. The large atypical lymphoid cells were CD30 (+), EBV (+), Pax-5 (+), CD 20 (-), CD15 (-), CD5 (-), and CD3 (-) confirming HL. The patient has currently received 4 weekly treatments with rituximab for EBV driven LPD and one cycle of Adriamycin, bleomycin, vinblastine, and dexamethasone (ABVD) for HL with resolution of symptoms and a whole blood EBV PCR to <500 copies/mL.
A 68 year old male was diagnosed in England with an unknown stage del13q and IgVH unmutated CLL in 2002. He was started on treatment with 5 cycles of fludarabine, cyclophosphamide, rituximab in 2011 and achieved a complete response. His post therapy course was complicated with infection resulting in septic shock with renal failure resulting in dialysis. He stabilized but continued to have hypogammaglobulenemia and required intravenous immunoglobulin (IVIG) replacement. In April of 2013 he developed fevers to 104F, night sweats, weight loss and, fatigue. PET CT scan showed diffuse adenopathy with max SUV of 22.5, and bone marrow biopsy showed 60% CLL and a component of large cells that were CD 30 (+), CD15 (+), Mum1 (+), and EBER-ISH (+). The patient’s whole blood EBV PCR was 276,600 copies/mL. Based on the clinical picture the patient was diagnosed with an EBV positive HL, EBV viremia, and chronic CLL. He has completed 4 weekly treatments with rituximab for EBV driven LPD and cycle 1 of ABVD for HL with resolution of symptoms and a whole blood EBV PCR of <500 copies/mL.
Although EBV viremia has been reported in CLL and EBV staining can be positive in HL, these two cases are the first to report CLL with EBV viremia and EBV positive HL. The high EBV viral load likely provided a base for an EBV driven LPD, in these cases HL. In patients with constitutional symptoms who have stable CLL disease burden, the clinician should screen for RT and EBV viremia. When a concurrent process is found, as in our cases, treatment against both the EBV driven LPD and HL should be initiated. Further research is needed to establish a biological relationship between EBV viremia and HL in patients with CLL.
No relevant conflicts of interest to declare.
Author notes
Asterisk with author names denotes non-ASH members.
