TY - JOUR
T1 - Phase 1 trial and pharmacokinetic study of arsenic trioxide in children and adolescents with refractory or relapsed acute leukemia, including acute promyelocytic leukemia or lymphoma
AU - Fox, Elizabeth
AU - Razzouk, Bassem I.
AU - Widemann, Brigitte C.
AU - Xiao, Shaun
AU - O'Brien, Michelle
AU - Goodspeed, Wendy
AU - Reaman, Gregory H.
AU - Blaney, Susan M.
AU - Murgo, Anthony J.
AU - Balis, Frank M.
AU - Adamson, Peter C.
PY - 2008/1/15
Y1 - 2008/1/15
N2 - Arsenic trioxide (ATO) induces remission in 85% of adults with refractory acute promyelocytic leukemia (APL). We conducted a phase 1 trial of ATO in children (median age 13 y, range, 2-19) with refractory leukemia. ATO was administered intravenously over 2 hours, 5 d/wk for 20 doses/cycle. Patients with APL (n = 13) received 0.15 mg/kg per day, and patients with other types of leukemia received 0.15 mg/kg per day (n = 2) or 0.2 mg/kg per day (n = 4). Nineteen of the 24 enrolled patients were fully evaluable for toxicity. At 0.15 mg/kg per day, 2 of 15 patients experienced dose-limiting corrected QT interval (QTc) prolongation, pneumonitis, or neuropathic pain. At 0.2 mg/kg per day, 2 of 4 patients had dose-limiting QTc prolongation or pancreatitis. Non-dose-limiting toxicities included elevated serum transaminases, nausea, vomiting, abdominal pain, constipation, electrolyte imbalance, hyperglycemia, dermatitis, and headache. At 0.15 mg/kg per day, the median (range) plasma arsenic maximum concentration (Cmax) was 0.28 μM (0.11-0.37 μM) and at 0.2 mg/kg per day, Cmax was 0.40 and 0.46 μM; area under the concentration times time curve (AUC0-24) was 2.50 μM-hr (1.28-3.85 μM-hr) and 4.37 μM-hr and 4.69 μM-hr, respectively. Morphologic complete response (CR) was achieved in 85% of patients with APL; no responses were observed in non-APL patients. ATO is well-tolerated in children at the recommended dose of 0.15 mg/kg per day. The response rate in children with relapsed APL is similar to the response rate in adults. This trial was registered as #NCT00020111 at www.ClinicalTrials.gov.
AB - Arsenic trioxide (ATO) induces remission in 85% of adults with refractory acute promyelocytic leukemia (APL). We conducted a phase 1 trial of ATO in children (median age 13 y, range, 2-19) with refractory leukemia. ATO was administered intravenously over 2 hours, 5 d/wk for 20 doses/cycle. Patients with APL (n = 13) received 0.15 mg/kg per day, and patients with other types of leukemia received 0.15 mg/kg per day (n = 2) or 0.2 mg/kg per day (n = 4). Nineteen of the 24 enrolled patients were fully evaluable for toxicity. At 0.15 mg/kg per day, 2 of 15 patients experienced dose-limiting corrected QT interval (QTc) prolongation, pneumonitis, or neuropathic pain. At 0.2 mg/kg per day, 2 of 4 patients had dose-limiting QTc prolongation or pancreatitis. Non-dose-limiting toxicities included elevated serum transaminases, nausea, vomiting, abdominal pain, constipation, electrolyte imbalance, hyperglycemia, dermatitis, and headache. At 0.15 mg/kg per day, the median (range) plasma arsenic maximum concentration (Cmax) was 0.28 μM (0.11-0.37 μM) and at 0.2 mg/kg per day, Cmax was 0.40 and 0.46 μM; area under the concentration times time curve (AUC0-24) was 2.50 μM-hr (1.28-3.85 μM-hr) and 4.37 μM-hr and 4.69 μM-hr, respectively. Morphologic complete response (CR) was achieved in 85% of patients with APL; no responses were observed in non-APL patients. ATO is well-tolerated in children at the recommended dose of 0.15 mg/kg per day. The response rate in children with relapsed APL is similar to the response rate in adults. This trial was registered as #NCT00020111 at www.ClinicalTrials.gov.
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U2 - 10.1182/blood-2007-08-107839
DO - 10.1182/blood-2007-08-107839
M3 - Article
C2 - 17959855
AN - SCOPUS:38349129611
SN - 0006-4971
VL - 111
SP - 566
EP - 573
JO - Blood
JF - Blood
IS - 2
ER -