title: 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.affiliation: Institute of Haematology, University of Pavia, Division of Haematology, IRCCS Policlinico S. Matteo, Pavia, Italy. mlazzarino@smatteo.pv.it
authors.forename: M
authors.initials: M
authors.lastname: Lazzarino
authors.forename: E
authors.initials: E
authors.lastname: Orlandi
authors.forename: F
authors.initials: F
authors.lastname: Baldanti
authors.forename: M
authors.initials: M
authors.lastname: Furione
authors.forename: G
authors.initials: G
authors.lastname: Pagnucco
authors.forename: C
authors.initials: C
authors.lastname: Astori
authors.forename: L
authors.initials: L
authors.lastname: Arcaini
authors.forename: A
authors.initials: A
authors.lastname: Viglio
authors.forename: M
authors.initials: M
authors.lastname: Paulli
authors.forename: G
authors.initials: G
authors.lastname: Gerna
authors.forename: C
authors.initials: C
authors.lastname: Bernasconi
mesh_terms: D000328:Adult; D000368:Aged; D018931:Antineoplastic Agents, Hormonal / Q000009:adverse effects; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects*; D002472:Cell Transformation, Viral; D003520:Cyclophosphamide / Q000009:adverse effects; D003907:Dexamethasone / Q000009:adverse effects; D020031:Epstein-Barr Virus Infections / Q000139:chemically induced*; D006801:Humans; D007165:Immunosuppression Therapy / Q000009:adverse effects*; D007166:Immunosuppressive Agents / Q000009:adverse effects*; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000188:drug therapy; D008228:Lymphoma, Non-Hodgkin / Q000188:drug therapy; D008875:Middle Aged; D009894:Opportunistic Infections / Q000150:complications; D014740:Vidarabine / Q000009:adverse effects / Q000031:analogs & derivatives*; D014775:Virus Activation / Q000187:drug effects
chemical_list: D018931:Antineoplastic Agents, Hormonal; D007166:Immunosuppressive Agents; D003907:Dexamethasone; D003520:Cyclophosphamide; D014740:Vidarabine; C024352:fludarabine