Fludarabine plus cyclophosphamide combination: a new standard for first-line therapy in chronic lymphocytic leukaemiaa

Phase III studies have demonstrated that the purine analogue fludarabine is an effective first-line agent in the primary treatment of B-cell chronic lymphocytic leukaemia (CLL) with superior efficacy to chlorambucil. However, although fludarabine improves responses, including an improvement in progression-free survival (PFS) in some studies, this remains sub-optimal. Thus, combination treatment with fludarabine has been considered. Both fludarabine and the alkylating agent cyclophosphamide are dose-dependently cytotoxic, and the extent of apoptosis when they are combined is more than the additive effect for each individual agent. Such increased apoptosis may be due to a synergistic effect between alkylation by cyclophosphamide and inhibition of DNA repair by fludarabine. Phase II studies in first-line CLL have shown that the efficacy of fludarabine plus cyclophosphamide (FC) is promising, with response rates often exceeding 90%. Data from Phase III studies have demonstrated that FC induces significantly higher response rates than fludarabine monotherapy across all patient age groups, including relatively young patients. PFS was also significantly longer with FC than with fludarabine monotherapy. Fludarabine is available in either intravenous or oral formulations and both appear to be similarly effective.