The immunosuppression and potential for EBV reactivation of fludarabine combined with cyclophosphamide and dexamethasone in patients with lymphoproliferative disorders

Fludarabine is effective in chronic lymphocytic leukaemia (CLL) and low-gra de non-Hodgltin's lymphoma (NHL). A major side-effect of this purine analog ue is immunosuppression which may favour opportunistic infections. Addition ally, impairment of immunosurveillance might promote Epstein-Barr virus (EB V) reactivation and possibly favour transformation to high-grade malignancy . The aim of this study was to evaluate the immunosuppression-related effec ts of the fludarabine-based combination Flucyd in advanced low-grade NHL or CLL by serially monitoring T-lymphocyte subsets, opportunistic infections, EBV-reactivation, and histologic transformation. 24 patients with advanced NHL (n=21) or CLL (n=3) received fludarabine 25 mg/m(2)/d+cyclophosphamide 350 mg/m(2)/ d + dexamethasone 20 mg/d in 3 d courses for a maximum of six courses. The overall response rate was 79% (eight CR, 11 PR, five failures ); 11 patients relapsed or progressed between 3 and 19 months from response , and eight are in CR or PR at 3-27 months. The CD4(+) lymphocyte counts de creased significantly during therapy from a median of 484/mu l pre-treatmen t (range 142-1865) to a median of 198/mu l (71-367). In 19 responders monit ored off therapy every 3 months until relapse/progression, CD4(+) counts we re persistently low with minimal recovery over time. During treatment, 16 i nfections occurred in 11/24 patients. No delayed opportunistic infections o ccurred in responders while off therapy. The circulating EBV DNA load seria lly measured in 19 patients by a quantitative PCR assay showed an increase in four patients during treatment. A lymph node biopsy performed in two of these was PCR positive for EBV DNA, whereas LMP1 and EBERs were negative. S ix NHL patients evolved into high-grade B-cell NHL. In conclusion fludarabi ne combined with cyclophosphamide and dexamethasone is an effective therapy for recurrent indolent lymphoma. This combination produces prolonged T-lym phocytopenia and has the potential to reactivate a latent EBV infection, T- cell dysfunction, however, is not associated with higher incidence of clini cal opportunistic infections and does not adversely influence clinical outc ome.