The clinical efficacy of purine analogues first became apparent in the late 1980s, and a progressive shift toward their use in first-line therapy has occurred. Fludarabine (Schering AG/Berlex’s Fludara) is approved for the treatment of chronic lymphocytic leukemia in patients who have failed prior therapy, but physicians report this agent forms the basis of first-line regimens in patients with a good performance status. Fludarabine is the leading cytotoxic agent throughout our study period in terms of market share.
Mechanism Of Action
Fludarabine is a purine analogue and is metabolized rapidly to F-Ara-ATP, which restricts DNA synthesis by inhibition of DNA polymerases and prevents elongation of DNA strands through direct incorporation into the DNA molecule.
Three large-scale, randomized trials have investigated single-agent fludarabine in previously untreated chronic lymphocytic leukemia patients. A three-arm study compared fludarabine (25 mg/m2 on days 1-5, every 28 days), chlorambucil (40 mg/m2 every 28 days), and a fludarabine (20 mg/m2 on days 1-5 every 28 days)/chlorambucil (20 mg/m2 every 28 days) combination in untreated patients with intermediate- and high-risk disease.
The overall response rate was markedly improved in patients receiving fludarabine compared with chlorambucil (63% versus 37%). Complete and partial responses were 20% and 43%, respectively, in the fludarabine arm compared with 4% and 33%, respectively, in the chlorambucil arm. The median duration of response was 25 and 14 months, and median survival was 66 months and 56 months in patients receiving fludarabine versus chlorambucil, respectively.
However, a significantly higher incidence of grade 3 and 4 toxicities, specifically neutropenia and infection rate, was observed in patients receiving fludarabine compared with chlorambucil. The combination of fludarabine and chlorambucil produced response rates similar to those of fludarabine alone but with greater toxicity. Despite the improved response rates, at a median follow-up of five years, overall survival was not significantly different between the three arms of the study.
The response rates for single-agent fludarabine in untreated patients are in agreement with results gained from two other large-scale trials.
The dose and schedule of chlorambucil in the Rai study have been criticized as not optimal, yet a study in which high-dose chlorambucil (15 mg daily for up to six months) was administered produced a median survival of 68 months, which is not significantly different from the 56 months achieved in the three-arm study. A more recent study compared high-dose chlorambucil (10 mg/m2 daily for 18 weeks) with fludarabine and found complete remissions (CRs) of 47% versus 33%, respectively, and partial remissions (PRs) of 41% versus 42%. Hematological toxicity was significantly higher in the chlorambucil arm, and infections were more common in the fludarabine arm. Survival data are not yet available.
In addition to its efficacy as a first-line agent, fludarabine works in the second-line setting, following failure with alkylating and/or anthracycline agents. More than 15 studies including a total of 1,400 patients have published results showing a wide range of response rates due to the heterogeneity of patient characteristics. Overall response rates are approximately 40%, including 10% CR and 20% nodular PR (nPR).
The major limitation of fludarabine is the high level of myelotoxicity, resulting in an increased infection rate. Elderly patients and those with a poor performance status are often unable to cope with these adverse side effects and are therefore limited to chlorambucil therapy.