Phase I evaluation of prolonged-infusion gemcitabine with fludarabine for relapsed or refractory acute myelogenous leukemia

Purpose: The purpose of this study was to determine the maximum tolerated duration of infusion of gemcitabine at 10 mg/m²/min in combination with fludarabine at 25 mg/m² daily for 5 days in the treatment of relapsed or refractory acute myelogenous leukemia. Experimental Design: Eighteen patients with relapsed or refractory acute myelogenous leukemia were enrolled. The median age was 54.5 years (range, 21-80 years). Patients received a 30-min infusion of fludarabine at 25 mg/m² daily for 5 days. i.v. gemcitabine was given as a single infusion at 10 mg/m²/min with the duration adjusted following a modified continuous reassessment method. Results: After 18 patients, the maximum recommended duration of infusion of gemcitabine in combination with fludarabine was selected as a 15-h infusion given at 10 mg/m²/min (9000 mg/m²). Severe stomatitis or esophagitis was the most common nonhematological dose-limiting toxicity. Myelosuppression was universal. Febrile neutropenia was common, and 3 of 18 (17%) patients developed bacteremia. Occasional nausea, vomiting, or diarrhea was also reported. There were three complete responses and two partial responses for an overall response rate of 28%. Conclusions: Prolonged-infusion gemcitabine at a fixed dose rate of 10 mg/m²/min for 15 h with 25 mg/m²/day fludarabine for 5 days is a tolerable induction regimen for relapsed or refractory leukemia. Stomatitis, esophagitis, febrile neutropenia, and myelosuppression should be anticipated; however, this regimen may be beneficial in patients with relapsed or refractory leukemia.