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

Abstract

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/m(2). 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/m(2) 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/m(2). Doses of 260 and 340 mg/m(2) provide systemic exposures similar to those of adults who are treated with daily doses of 400 and 600 mg, respectively.

The tyrosine kinase c‐Abl promotes proliferation and is expressed in atypical teratoid and malignant rhabdoid tumors

“…[9][10][11][12][13][14][15][16] Imatinib, a tyrosine kinase inhibitor directed against c-Abl, c-Kit and platelet-derived growth factor (PDGF) receptor subtypes a and b, 17 reportedly is tolerated relatively well in children. 18,19 Because it has been demonstrated that imatinib inhibits proliferation of the rhabdoid tumor cell line BT12, 20 our objective was to investigate the expression and functional role of tyrosine kinases targeted by imatinib in rhabdoid tumors.…”

Imatinib mesylate is effective in children with chronic myelogenous leukemia in late chronic and advanced phase and in relapse after stem cell transplantation

“…9,10 The Children's Oncology Group conducted a phase 1 study testing imatinib mesylate in 31 children with Philadelphia (Ph) chromosomepositive leukemia suggesting efficacy of this drug in this age group. 11 Given these preliminary results, we performed a phase 2 study testing imatinib mesylate in children with either CML in advanced phase, refractory or intolerant to IFN therapy or relapsing after SCT.…”

Innovative approaches of targeted therapy for CML of childhood in combination with paediatric haematopoietic SCT

“…[25][26][27] The latter may be because of an inadequate reserve of normal stem cells, requiring treatment of neutropenia by G-CSF in some patients. Absorption and metabolism of IMA may be affected by other concomitant medications, and possible adverse effects of drug interactions must always be excluded first.…”

“…The results from small paediatric phase II trials, similar to those in adults indicated that, in CP most patients achieve normal blood counts within 3 months and that complete haematological and cytogenetic responses are achieved with a probability of 96 and 69%, respectively, after one year of treatment. [25][26][27] The drug is licensed since 2003 for use in children, but long-term experience with IMA in children of all age groups is still very limited and the durability of responses as well as longterm side effects of this drug remains to be determined.…”

“…24 The efficacy and side effects of this new drug have been evaluated in paediatrics in controlled phase I and phase II trials comprising less than 100 patients so far. [25][26][27] The starting dose in children should be near 300 mg/m 2 (260-340 mg/m 2 were identified as giving drug exposures similar to the 400-600 mg adult dosage levels) orally once daily. The results from small paediatric phase II trials, similar to those in adults indicated that, in CP most patients achieve normal blood counts within 3 months and that complete haematological and cytogenetic responses are achieved with a probability of 96 and 69%, respectively, after one year of treatment.…”