Phase 1 study of arsenic trioxide, high-dose cytarabine, and idarubicin to down-regulate constitutive signal transducer and activator of transcription 3 activity in patients aged <60 years with acute myeloid leukemia

Authors


  • The first author was the principal investigator of this protocol, oversaw patient accrual, contributed to the care of the patients, followed data collection, reviewed the data, and wrote the article The second author performed the statistical analyses. The third author constructed the database. The fourth author served as the research coordinator for this protocol. The fifth author reviewed the pathology specimens. The sixth and seventh authors reviewed all karyotype analyses. The eighth author oversaw the single nucleotide polymorphism analysis. The ninth author was the principal investigator on the high-dose cytarabine and idarubicin trials, served as a coinvestigator on this protocol, and contributed to the care of the patients. The 10th author contributed to the care of the patients. The 11th author was a senior coinvestigator on this protocol. All authors reviewed and approved the final article.

Abstract

BACKGROUND:

Constitutive activation of signal transducer and activator of transcription-3 (STAT3) was detected in blasts from approximately 50% of patients with acute myeloid leukemia (AML) and was correlated with an adverse outcome. In vitro treatment of AML blasts with arsenic trioxide (ATO) down-regulated STAT3 activity within 6 hours associated with a reduced viability within 48 hours.

METHODS:

A phase 1 clinical trial to evaluate the biologically effective dose and/or the maximally tolerated dose (MTD) of ATO in vivo in conjunction with high-dose cytarabine (Hidac) and idarubicin (Ida) in patients with AML aged <60 years was conducted. Data were compared with 117 historic AML patients who had received treatment with Hidac/Ida.

RESULTS:

In total, 61 patients were enrolled onto 11 different dose levels (from 0.01 to 0.65 mg/kg ideal body weight). The MTD was 0.5 mg/kg. Compared with historic controls, patients who received ATO/Hidac/Ida, although they had similar pretreatment characteristics, had better overall survival (P = .039).

CONCLUSIONS:

ATO priming may have improved the outcome of patients aged <60 years with AML who received Hidac/Ida. The current data suggested that ATO may enhance the effect of chemotherapy. The authors concluded that further studies of this novel combination are warranted. Cancer 2011;. © 2011 American Cancer Society.

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