CLINICAL AND LABORATORY STUDIES OF 2-CHLORODEOXYADENOSINE+ -CYTOSINE-ARABINOSIDE FOR RELAPSED OR REFRACTORY ACUTE MYELOGENOUS LEUKEMIA IN ADULTS/

Previous studies in pediatric patients with acute myelogenous leukemia (AML) have suggested that 2-chlorodeoxyadenosine (2CdA) is an effecti ve therapeutic agent. Santana et al (J Clin Oncol 1992; 10: 364-370) r eported a CR rate of 8/17 (95% CI 23-72%) in children with relapsed AM L and a median first CR of 21 months. The activity of 2CdA in adults w ith relapsed or refractory leukemia was therefore investigated in a ph ase study. In the phase II study, based on biochemical modulation rati onale, 2CdA was combined with Ara-C for adults with relapsed AML to te st the effectiveness of this combination therapy. In the phase I study 27 patients (25 AML and two MDS) with a median first CR duration of 2 1 weeks, received 2CdA at doses ranging from 5 to 13 mg/m(2)/day by co ntinuous infusion (CI) for 7 days. In vitro and ex vivo pharmacologic studies performed to determine the effect of pretreatment with 2CdA on Ara-CTP accumulation in leukemic blasts demonstrated a 50-65% increas e in the rate of Ara-CTP accumulation. Based on this biochemical modul ation, 2CdA (12 mg/m(2)/day x 5 days by CI) was combined with Ara-C (1 g/m(2)/day over 2 h) in a phase II study. Seventeen patients (15 AML, two MDS) with relapsed AML (median Ist CR of 19 weeks) were treated. In the phase I study two patients died before the day 14 marrow (ED). Marrow hypoplasia developed in 16 of the remaining 25. Leukemic regrow th occurred in nine after a median hypoplastic period of 2 weeks (rang e 1-3 weeks). The other seven patients died with aplastic marrows, med ian duration of hypoplasia was 2 weeks, range 1-4 weeks. None achieved CR and the median survival was 10.5 weeks. Toxicity generally was mil d except for three late occurring cases of grade III or IV renal dysfu nction and two cases of tumor lysis syndrome. The MTD was 10.8 mg/m(2) /day x 7 days. In the phase II study two patients, both with AML, achi eved CR (95% CI 1-33%). In both cases leukemia relapsed after 10 weeks and 17 weeks. There was one ED. Most (11/16) cleared their marrow alt hough leukemic infiltrate regrew in six cases. Toxicity was generally mild, with two episodes of grade 2 GI bleeding, one episode of severe renal dysfunction and one case of grade 2 CNS toxicity. We conclude th at as a single agent 2CdA at the MTD is a cytoreductive agent but is n ot sufficient to achieve CR in adults with relapsed AML. While combina tion of Ara-C with 2CdA increases the Ara-CTP uptake in these heavily treated patients this regimen does not appear to be an improvement ove r existing modalities.