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 t he active triphosphate of ara-C (ara-CTP) in leukemic lymphocytes. The clinical efficacy of this combination was evaluated in 15 patients wi th chronic lymphocytic leukemia (CLL) that was advanced in their disea se (median Rai stage, IV) and refractory to treatment with fludarabine . Patients received 0.5 g/m(2) ara-C infused i.v. over 2 h followed at 20 h by a 30-min infusion of 30 mg/m(2) fludarabine. At 24 h, an iden tical dose of ara-C was infused. To intensify the therapy and to deter mine the duration of fludarabine potentiation of ara-CTP accumulation, six additional patients with Rai stage III or IV CLL were treated wit h an amended 2-week protocol. On week 1, 30 mg/m(2) fludarabine was in fused over 30 min, followed 4 h later by a 2-h infusion of 0.5 g/m(2) ara-C; on week 2, the fludarabine dose was followed 4 h later by a 4-h infusion of ara-C (1.0 g/m(2)). In all, 1 partial remission and 7 min or responses in 1 or more disease sites were observed in the 21 patien ts. The major treatment-related toxic effects were myelosuppression an d infection. Comparison of the ara-CTP accumulation area under the con centration-time curve (AUC) in circulating CLL cells of patients on th e amended protocol demonstrated a significant (P = 0.001) 1.6-fold (ra nge, 1.4- to 2.0-fold) increase after fludarabine administration. Alth ough 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 f our 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 othe r drugs.