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

Abstract

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/microliter pre-treatment (range 142-1865) to a median of 198/microliter (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.

• Authors: M Lazzarino, E Orlandi, F Baldanti, M Furione, G Pagnucco, C Astori, L Arcaini, A Viglio, M Paulli, G Gerna, C Bernasconi
• Journal: British journal of haematology (Br J Haematol) Vol. 107 Issue 4 Pg. 877-82 (Dec 1999) ISSN: 0007-1048 [Print] England
• PMID: 10606897 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents, Hormonal
• Immunosuppressive Agents
• Dexamethasone
• Cyclophosphamide
• Vidarabine
• fludarabine

Topics

• Adult
• Aged
• Antineoplastic Agents, Hormonal (adverse effects)
• Antineoplastic Combined Chemotherapy Protocols (adverse effects)
• Cell Transformation, Viral
• Cyclophosphamide (adverse effects)
• Dexamethasone (adverse effects)
• Epstein-Barr Virus Infections (chemically induced)
• Humans
• Immunosuppression Therapy (adverse effects)
• Immunosuppressive Agents (adverse effects)
• Leukemia, Lymphocytic, Chronic, B-Cell (drug therapy)
• Lymphoma, Non-Hodgkin (drug therapy)
• Middle Aged
• Opportunistic Infections (complications)
• Vidarabine (adverse effects, analogs & derivatives)
• Virus Activation (drug effects)