Phase I study of taxol in refractory acute myelogenous leukemias using a weekly schedule.

Taxol is an antineoplastic drug which targets microtu-bules and which has significant clinical activity in ovarian and breast cancer, and also in lymphomas and non-small-cell lung cancer [1]. In the early clinical trials, a high incidence of acute reactions (bronchospasm, hypotension and arrhythmias) was observed due to the vehicle Cremophor [2]. For later clinical trials, taxol was administered with antiallergic premedication. In these trials, neutropenia was observed as dose-limiting toxicity. In addition, a sensory neuropathy, nausea, myalgias, mucositis and alope-cia were common. For phase II studies in solid tumors, 210 mg/m 2 as a 6-hour infusion and 250 mg/m 2 as a 24-hour infusion were recommended [1]. In refractory ovar-ian cancer, taxol could be safely administered at up to 250 mg/m 2 with G-CSF support; in this study, sensory neuropathy was the major dose-limiting toxicity [3]. In vitro, several human leukemic cell lines were found to be sensitive to taxol [5]. Taxol induces apoptosis in sensitive myeloid leukemia cell lines [5, 6]. In a phase I study, taxol was used in refractory acute leukemias. At doses of 390 mg/m 2 , repeated once every 3 weeks, severe mucositis was observed [7]. At this dose, a clearance of leukemic blasts from blood and bone marrow was observed in 2/6 patients. By analogy to vincristine, another agent targeting microtubules, we hypothesized that weekly administration of a lower dose repeated 3 times might lead to reduced side effects and enhanced antileukemic activity. We therefore designed a phase I study, in which taxol was administered to patients with relapsed or refractory acute myelogenous leukemia (AML) starting with a dose of 80 mg/m 2 repeated in 3 weekly intervals. Adults (aged 116 years) were eligible for this phase I study if they had relapsed AML or were not in complete remission (CR) after at least 2 courses of induction treatment. In addition, the likelihood of remission with standard salvage regimes (high-dose cytosine-arabinoside) had to be !40% as judged by a duration of first remission of less than 1 year and having received at least one prior salvage regimen. Other eligibility criteria were: serum cre-atinine and bilirubin each !1.6 mg/ml; Zubrod performance status !3; no prior cisplatin, or taxotere; no major cardiac history; at least 2 weeks from last prior therapy and full recovery from any toxic effects. Taxol was supplied by the Division of Cancer Treatment of the National Cancer Institute, Bethesda, Md. The probability …