Imatinib mesylate (STI571) for treatment of children with Philadelphia chromosome-positive leukemia

To determine the optimal dose, dose-limiting toxicities, and pharmacokinetics of imatinib mesylate in children with refractory or recurrent Philadelphia chromosome-positive (Ph+) leukemias. Oral imatinib mesylate was administered daily at dose levels ranging from 260-570 mg/m2 in consecutive 28-day courses of therapy. Serial blood samples for plasma pharmacokinetic studies were collected on days 1 and 8 of course 1. Thirty-one patients between 3-20 years of age with refractory Ph+ leukemias received 479 courses (median 6, range 1-46) of imatinib. The most common toxicities associated with imatinib administration, which occurred in < 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 twelve CML patients evaluable for cytogenetic response, 10 had a complete response and 1 had a partial response. Among ten ALL patients evaluable for morphologic response, seven achieved an M1 and one achieved an M2 bone marrow. Pharmacokinetic analyses revealed that there was marked interpatient variability in the pharmacokinetic parameters. Daily oral imatinib mesylate is well tolerated in children with Ph+ leukemias 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.