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‐grade non‐Hodgkin's lymphoma (NHL). A major side‐effect of this purine analogue is immunosuppression which may favour opportunistic infections. Additionally, impairment of immunosurveillance might promote Epstein‐Barr virus (EBV) reactivation and possibly favour transformation to high‐grade malignancy. The aim of this study was to evaluate the immunosuppression‐related effects 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/m2/d + cyclophosphamide 350 mg/m2/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 decreased significantly during therapy from a median of 484/μl pre‐treatment (range 142–1865) to a median of 198/μl (71–367). In 19 responders monitored off therapy every 3 months until relapse/progression, CD4+ counts were persistently low with minimal recovery over time. During treatment, 16 infections occurred in 11/24 patients. No delayed opportunistic infections occurred in responders while off therapy. The circulating EBV DNA load serially 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. Six NHL patients evolved into high‐grade B‐cell NHL. In conclusion, fludarabine combined with cyclophosphamide and dexamethasone is an effective therapy for recurrent indolent lymphoma. This combination produces prolonged T‐lymphocytopenia and has the potential to reactivate a latent EBV infection. T‐cell dysfunction, however, is not associated with higher incidence of clinical opportunistic infections and does not adversely influence clinical outcome.