The sequential administration of
fludarabine followed by
cytosine arabinoside (
ara-C) has demonstrated significant synergistic effects against the CEM human leukemic cell line. This in vitro synergism was investigated in a Phase I trial in pediatric patients with relapsed acute
leukemia. The optimum concentrations of 9-beta-D-arabinofuranosyl
2-fluoroadenine and
ara-C necessary to achieve significant drug synergism from in vitro studies were between 10 and 20 microM.
Fludarabine was infused at a dose to attain a target plasma concentration of 10 microM for 48 h, followed by a continuous infusion of escalated
ara-C doses to maintain plasma
ara-C concentrations of 10, 12.5, 15, or 17.5 microM for 72 h. Thirteen patients with
acute lymphocytic leukemia and 18 with
acute myelocytic leukemia were entered into the study, 30 of whom were clinically evaluable for toxicity. Pharmacokinetic and pharmacodynamic studies were performed on specimens from 20 patients. The optimal 9-beta-D-arabinofuranosyl
2-fluoroadenine and
ara-C concentrations in plasma were easily achieved after continuous infusion regimens of both drugs. Cellular
ara-CTP is augmented 5-8-fold in leukemic cells from patients receiving
fludarabine phosphate treatment followed by
ara-C. The maximum tolerated plasma concentrations for this combination regimen was 10 microM
fludarabine for 48 h followed by 72 h of 15 microM
ara-C, which were achieved at dose level 3. A significant number of responses were also seen. Nine of 18 evaluable patients (50%) with
acute myelocytic leukemia achieved complete or partial responses, and 3 of 9 evaluable patients with
acute lymphocytic leukemia achieved complete or partial responses.
Fludarabine and
ara-C successfully eradicated
bone marrow disease in 16 of 27 patients (59%), 23 patients of which had been treated previously with high-dose
ara-C. These results verified the synergistic effect
fludarabine exhibited in augmenting
ara-CTP concentrations in patients' leukemic blasts, thus improving the clinical response in relapsed pediatric
leukemias.