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- W2589676876 abstract "6538 Background: Constitutive signal transducer and activator of transcription (STAT) 3 activity has been shown to be present in acute myeloid leukemia (AML) cells from 50% of patients and to correlate with shorter disease-free survival. We hypothesized that down-regulating constitutive STAT3 activity might improve outcome. In the absence of a specific STAT3 inhibitor, we studied arsenic trioxide (ATO) in vitro and showed that ATO at a concentration of 0.91 μM achieved 50% down-regulation of constitutive STAT3 activity in AML cells within 6 hours. We then conducted a phase I clinical trial to determine the biologically effective dose (BED) and/or the maximally tolerated dose of ATO in vivo in conjunction with induction chemotherapy. Methods: Untreated AML patients younger than age 60 received a single one-hour ATO infusion in escalating doses in 3-patient cohorts prior to high-dose cytarabine [3 gm/m2 (1.5 mg/m2 for age ≥ 50) every 12 hrs x 12 doses] and idarubicin (12 mg/m2 x 3 doses). The BED was defined by a 50% reduction in constitutive STAT3 activity in leukemia cells in vivo as determined by western blotting. ATO doses ranged from 0.01 to 0.25 mg/kg, the latter equivalent to 4 μM, the effective concentration in patients with acute promyelocytic leukemia. Results: Twenty-seven patients (17:10 female:male) were accrued, including 2 with secondary AML. Median age was 46 (range 22–57) years, and median white blood cell count at diagnosis was 13.2 (range 1.6–95.1) x 109/L. Karyotype was favorable in 3, normal in 14 and unfavorable in 10. Eighteen patients achieved complete remission, 5 had refractory disease, 3 were unevaluable and 1 is too early to assess. The BED was achieved at 0.25 mg/kg without dose-limiting toxicity and we are currently accruing 7 more patients at this dose level to study apoptosis and gene expression profiling in pre- and post-ATO samples. Conclusions: ATO down-regulates constitutive STAT3 activity in vivo in clinically tolerable doses. Its impact on treatment outcome will be studied in future trials. No significant financial relationships to disclose." @default.
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- W2589676876 date "2005-06-01" @default.
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- W2589676876 title "Targeting signal transducer and activator of transcription 3 protein with arsenic trioxide: A phase I clinical trial" @default.
- W2589676876 doi "https://doi.org/10.1200/jco.2005.23.16_suppl.6538" @default.
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