Fludarabine

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Abstract
Fludarabine is an antineoplastic agent which has been studied in patients with a variety of lymphoproliferative malignancies. Clinical evidence from comparative studies in chronic lymphocytic leukaemia (CLL) suggests that fludarabine is at least as effective as CAP (cyclophosphamide, doxorubicin and prednisone) or CHOP (cyclophosphamide, vincristine, doxorubicin and prednisone) in previously treated or chemotherapy-naive patients and significantly more effective than chlorambucil in terms of response rate and duration and survival in chemotherapy-naive patients. Promising results have also been reported with fludarabine-based combination therapy in the treatment of patients with CLL. In addition, sequential therapy with fludarabine and cytarabine has demonstrated good efficacy in the treatment of acute leukaemias, as has fludarabine monotherapy and combination therapy in low grade non-Hodgkin’s lymphoma. A favourable cytoreductive response has been reported in patients with lymphoplasmacytoid lymphoma and in a smaller number of patients with cutaneous T cell lymphomas, CLL of T cell origin or prolymphocytic leukaemia. Recent data also support the use of fludarabine, either as a component of a nonmyeloablative conditioning regimen or in the attainment of minimal residual disease, in patients undergoing peripheral blood stem cell or bone marrow transplantation. The tolerability profile of fludarabine is similar to that of CAP, with the most common adverse events being granulocytopenia, thrombocytopenia, anaemia and infection. Alopecia and nausea/vomiting appear to be less frequent with fludarabine therapy than with CAP although the development of immune cytopenias is more frequent with fludarabine. Severe neurotoxicity has been reported with fludarabine but this is mostly confined to the use of high doses. Clinical experience therefore indicates that fludarabine is an effective and generally well-tolerated antineoplastic agent for the second-line treatment of advanced CLL. Recent data from comparative studies also support the earlier use of fludarabine in the treatment of chemotherapy-naive patients with CLL. Furthermore, results of available studies are increasingly highlighting an important future role for fludarabine in the treatment of acute leukaemias and low grade NHL and possibly other lymphoproliferative disorders, particularly when used as a component of combination chemotherapy. Postulated mechanisms for the antitumour activity of fludarabine include termination of DNA and RNA synthesis by incorporation of the active metabolite F-ara-A (9-β-D-arabino-furanosyl-2-fluoroadenine) triphosphate (F-ara-ATP) into elongating nucleic acid chains, inhibition of DNA and RNA polymerases, DNA primase, DNA ligase and ribonucleotide reductase and potentiation of deoxycytidine kinase activity. Both in vitro and in vivo studies have highlighted apoptosis as an additional important mode of fludarabine-induced cell death. However, the relative importance of inhibition of DNA and RNA synthesis in the induction of the apoptotic process by fludarabine has not been fully elucidated. In vitro, fludarabine demonstrated concentration-and time-dependent cytotoxicity against human leukaemia cell lines. Fludarabine has been shown to potentiate the activity of a number of antitumour agents in vitro including cytarabine, cisplatin, mitoxantrone and gallium nitrate. Fludarabine has in vivo antitumour activity against a wide range of murine tumour models and has been shown to induce radiosensitisation in the Meth-a fibrosarcoma, SA-NH sarcoma and MCA-K and MCA-4 murine mammary carcinoma models. The mechanism of fludarabine-induced radiosensitisation appears to involve the elimination of cells in S-phase by apoptosis and synchronisation of the remaining cells to a more radiosensitive cell cycle phase. Fludarabine also reduced the number of lymphocytes able to proliferate and trigger rejection in mice after total body irradiation, suggesting a possible future immunosuppressant role for fludarabine in bone marrow transplantation conditioning. Within 5 minutes of intravenous administration, the prodrug fludarabine undergoes complete dephosphorylation to F-ara-A. The plasma pharmacokinetics of F-ara-A appear to be linear with no accumulation following repeated daily administration. In adults, volume of distribution at steady state and plasma clearance were up to ≈10-fold greater than the corresponding values in children, and wide interstudy differences in the area under the plasma concentration-time curve were reported at each fludarabine dosage level studied. A predominantly biphasic decline in plasma F-ara-A concentrations has been reported with distribution and terminal elimination half-lives of 0.9 to 1.7 hours and 6.9 to 33.5 hours, respectively. However, a triphasic decline in plasma F-ara-A concentrations which included an initial distribution phase of 5 to 9 minutes has also been reported. Peak intracellular levels of the active metabolite of fludarabine, F-ara-ATP, have been reported within 3 to 4 hours after termination of fludarabine infusion. Renal mechanisms play an important role in the elimination of fludarabine with a reported correlation between increased serum creatinine and blood urea nitrogen levels and decreased F-ara-A elimination. In addition, fludarabine-associated neutropenia appears to be more severe in patients with a creatinine clearance 2 /day for 5 days repeated every 3 to 5 weeks) in noncomparative studies, objective response rates of 12 to 94% have been reported in previously...