Imatinib mesylate (STI571) for treatment of children with Philadelphia chromosome-positive leukemia: results from a Children's Oncology Group phase 1 study

• Published in: Blood Vol. 104; no. 9; pp. 2655 - 2660
• Main Authors: Champagne, Martin A., Capdeville, Renaud, Krailo, Mark, Qu, Wenchun, Peng, Bin, Rosamilia, Marianne, Therrien, Martine, Zoellner, Ulrike, Blaney, Susan M., Bernstein, Mark
• Format: Journal Article
• Language: English
• Published: Washington, DC Elsevier Inc 01.11.2004; The Americain Society of Hematology
• Subjects: Adolescent; Adult; Antineoplastic agents; Benzamides; Biological and medical sciences; Chemotherapy; Child; Child, Preschool; Dose-Response Relationship, Drug; Hematologic and hematopoietic diseases; Humans; Imatinib Mesylate; Infant; Leukemia - drug therapy; Leukemia - genetics; Leukemia - mortality; Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis; Medical sciences; Pharmacokinetics; Pharmacology. Drug treatments; Philadelphia Chromosome; Piperazines - administration & dosage; Piperazines - blood; Piperazines - toxicity; Pyrimidines - administration & dosage; Pyrimidines - blood; Pyrimidines - toxicity; Salvage Therapy; Survival Analysis; Treatment Outcome; Chromosomal aberration; Antineoplastic agent; Relapse; Toxicity; Myeloproliferative syndrome; Abnormal chromosome C9; Lymphoproliferative syndrome; Chronic myelocytic leukemia; Abnormal chromosome G22; Acute lymphocytic leukemia; Child; Protein-tyrosine kinase; Human; Imatinib; Treatment resistance; Enzyme; Transferases; Acute; Oral administration; Enzyme inhibitor; Malignant hemopathy; Philadelphia chromosome; Chronic; Treatment; Phase I trial; Abnormal chromosome; Daily dose; Pharmacokinetics
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2003-09-3032

The purpose of this study was to determine dose-limiting toxicities and pharmacokinetics of imatinib in children with refractory or recurrent Philadelphia chromosome-positive (Ph+) leukemias. Oral imatinib was administered daily at dose levels ranging from 260 to 570 mg/m2. Plasma pharmacokinetic studies were performed on days 1 and 8 of course 1. There were 31 children who received 479 courses of imatinib. The most common toxicities encountered, which occurred in less than 5% of courses, were grade 1 or 2 nausea, vomiting, fatigue, diarrhea, and reversible increases in serum transaminases. One patient at the 440-mg/m2 dose level had dose-limiting weight gain. There were no other first-course dose-limiting toxicities. A maximum tolerated dosage was not defined. Among 12 chronic myeloid leukemia (CML) patients evaluable for cytogenetic response, 10 had a complete response and 1 had a partial response. Among 10 acute lymphoblastic leukemia (ALL) patients evaluable for morphologic response, 7 achieved an M1 and 1 achieved an M2 bone marrow. We observed marked interpatient variability in the pharmacokinetic parameters. In conclusion, we found that daily oral imatinib is well tolerated in children at doses ranging from 260 to 570 mg/m2. Doses of 260 and 340 mg/m2 provide systemic exposures similar to those of adults who are treated with daily doses of 400 and 600 mg, respectively. (Blood. 2004;104:2655-2660)