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

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...

Full description

Saved in:
Bibliographic Details
Published in:Blood 2008-01, Vol.111 (2), p.566-573
Main Authors: Fox, Elizabeth, Razzouk, Bassem I., Widemann, Brigitte C., Xiao, Shaun, O'Brien, Michelle, Goodspeed, Wendy, Reaman, Gregory H., Blaney, Susan M., Murgo, Anthony J., Balis, Frank M., Adamson, Peter C.
Format: Article
Language:English
Subjects:
Abdominal Pain - chemically induced
Abdominal Pain - drug therapy
Adolescent
Adult
Antineoplastic Agents - adverse effects
Antineoplastic Agents - pharmacokinetics
Arsenic Trioxide
Arsenicals - adverse effects
Arsenicals - pharmacokinetics
Biological and medical sciences
Child
Child, Preschool
Clinical Trials and Observations
Constipation - chemically induced
Constipation - drug therapy
Dermatitis - drug therapy
Dermatitis - etiology
Dose-Response Relationship, Drug
Female
Headache - chemically induced
Headache - drug therapy
Hematologic and hematopoietic diseases
Humans
Hyperglycemia - chemically induced
Hyperglycemia - drug therapy
Infusions, Intravenous
Leukemia, Promyelocytic, Acute - complications
Leukemia, Promyelocytic, Acute - drug therapy
Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis
Lymphoma - complications
Lymphoma - drug therapy
Male
Medical sciences
Nausea - chemically induced
Nausea - drug therapy
Oxides - adverse effects
Oxides - pharmacokinetics
Pancreatitis - chemically induced
Pancreatitis - drug therapy
Pneumonia - chemically induced
Pneumonia - drug therapy
Recurrence
Time Factors
Vomiting - chemically induced
Vomiting - drug therapy
Water-Electrolyte Balance - drug effects
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary: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.
ISSN:0006-4971
1528-0020
DOI:10.1182/blood-2007-08-107839