DETECTION OF EPSTEIN-BARR-VIRUS IN TRANSFORMATIONS OF LOW-GRADE B-CELL LYMPHOMAS AFTER FLUDARABINE TREATMENT

Fludarabine is a highly effective chemotherapeutic agent for chronic l ymphocytic leukemia/small lymphocytic lymphoma and is also active in o ther B-cell lymphoproliferative disorders, Although highly efficacious in destroying the malignant B-cells, fludarabine also causes T-cell l ymphopenia and immunosuppression. We present five patients given fluda rabine for low-grade B-cell lymphoproliferative disorders who showed t ransformation of the primary neoplasm to a higher grade tumor. Immunoh istologic antibody studies were performed on paraffin-embedded tissue sections of the initial tissue (when available) and on the follow-up b iopsy specimens for CD20, CD3, CD45RO, CD43, CD30, CD15, and latent me mbrane protein (LMP-1) for Epstein-Barr virus (EBV), The initial diagn oses in these five patients included chronic lymphocytic leukemia/smal l lymphocytic lymphoma (three cases), follicle center lymphoma (one ca se), and Waldenstrom's macroglobulinemia (one case). All of the follow -up biopsy specimens showed scattered Hodgkin's-like cells, and two of the five also showed foci of large-cell transformation, The Hodgkin's -like cells showed CD30 immunoreactivity in four of the five cases and CD15 immunoreactivity in three of the five. Strong immunoreactivity o f the large, atypical, Hodgkin's-like cells for LMP-1 of EBV was noted in four cases; in the remaining case, this finding was equivocal, In situ hybridization for EBV-encoded RNA was positive in four of the fiv e cases. Molecular studies by polymerase chain reaction (PCR) showed t he presence of EBV in three of the five cases, PCR for detection of im munoglobulin heavy chain demonstrated identical monoclonal rearrangeme nts in the original lymphoma and transformation in one case with avail able material. The CD4 lymphocyte count in each patient was less than 550/mu L, indicating cellular dysfunction, Transformation of low-grade non-Hodgkin's lymphomas after fludarabine therapy might be associated with EBV and severe immunosuppression.