Combination of fludarabine and arabinosylcytosine for treatment of chronic lymphocytic leukemia: clinical efficacy and modulation of arabinosylcytosine pharmacology

Previous studies have demonstrated that treatment with fludarabine 4 h prior to arabinosylcytosine (ara-C) potentiates the accumulation of the active triphosphate of ara-C (ara-CTP) in leukemic lymphocytes. The clinical efficacy of this combination was evaluated in 15 patients with chronic lymphocytic leukemia (CLL) that was advanced in their disease (median Rai stage, IV) and refractory to treatment with fludarabine. Patients received 0.5 g/m² ara-C infused i.v. over 2 h followed at 20 h by a 30-min infusion of 30 mg/m² fludarabine. At 24 h, an identical dose of ara-C was infused. To intensify the therapy and to determine the duration of fludarabine potentiation of ara-CTP accumulation, six additional patients with Rai stage III or IV CLL were treated with an amended 2-week protocol. On week 1, 30 mg/m² fludarabine was infused over 30 min, followed 4 h later by a 2-h infusion of 0.5 g/m² ara-C; on week 2, the fludarabine dose was followed 4 h later by a 4-h infusion of ara-C (1.0 g/m²). In all, 1 partial remission and 7 minor responses in 1 or more disease sites were observed in the 21 patients. The major treatment-related toxic effects were myelosuppression and infection. Comparison of the ara-CTP accumulation area under the concentration-time curve (AUC) in circulating CLL cells of patients on the amended protocol demonstrated a significant (P=0.001) 1.6-fold (range, 1.4-to 2.0-fold) increase after fludarabine administration. Although the initial rates of ara-CTP accumulation were similar for the 2-h and 4-h infusions, ara-CTP accumulation continued for up to 4 h in four of five patients who received the longer infusion. The activity of the fludarabine and ara-C combination is being evaluated in in vitro model systems and in phase II clinical trials in combination with other drugs.