Dasatinib is an orally available tyrosine kinase inhibitor with low nanomolar activity against SRC family kinases, BCR-ABL, c-KIT, EPHA2, and the PDGF-β receptor. Dasatinib was found to have selective activity in several tumor models in the Pediatric Preclinical Testing Program. PATIENTS AND METHODS: A phase I study of dasatinib in pediatric patients with refractory solid tumors or imatinib-refractory, Philadelphia chromosome-positive leukemia was performed. Dose levels of 50, 65, 85, and 110 mg/m²/dose, administered orally twice daily for 28 days, with courses repeated without interruption, were studied. Pharmacokinetic studies were performed with the initial dose. RESULTS: A total of 39 patients (solid tumors, n = 28; chronic myeloid leukemia [CML], n = 9; acute lymphoblastic leukemia, n = 2) were enrolled. No dose-limiting toxicities (DLTs) were observed at the 50, 65, and 85 mg/m² dose levels. At 110 mg/m², two of six patients experienced DLT including grade 2 diarrhea and headache. In children with leukemia, grade 4 hypokalemia (50 mg/m²), grade 3 diarrhea (85 mg/m²), and grade 2 creatinine elevation (50 mg/m²) were observed. DLT in later courses included pleural effusions, hemangiomatosis, and GI hemorrhage. There were three complete cytogenetic responses, three partial cytogenetic responses, and two partial/minimal cytogenetic responses observed in evaluable patients with CML. CONCLUSION: Overall, drug disposition and tolerability of dasatinib were similar to those observed in adult patients.

Source: Pediatric phase I trial and pharmacokinetic study of dasatinib: a report from the children's oncology group phase I consortium. Aplenc R, Blaney SM, Strauss LC, Balis FM, Shusterman S, Ingle AM, Agrawal S, Sun J, Wright JJ, Adamson PC.MSCE, The Children's Hospital of Philadelphia, Pediatric Oncology/Stem Cell Transplant, Philadelphia, PA 19104-4318, USA. raplenc@mail.med.upenn.edu. J Clin Oncol. 2011 Mar 1;29(7):839-44. Epub 2011 Jan 24. PMID: 21263099

Suttorp M et al., Division of Pediatric Hematology-Oncology-Blood and Marrow Transplantation, University Hospital Carl Gustav Carus, Dresden, Germany. 2011 American Society for Blood and Marrow Transplantation.

In this article, the discussion is on the relative merit of the 2 therapeutic approaches and recommend that all children and adolescents with CML-CP should initially be treated with imatinib and maintained with TKI therapy indefinitely if there is a good response.

"Distinct Impact of Imatinib on Growth at Prepubertal and Pubertal Ages of Children with CML", Haruko Shim et al. Journal of Pediatrics, Published online 18 May 2011. doi:10.1016/j.jpeds.2011.03.046

Study: Objective: To determine the extent of growth impairment resulting from imatinib treatment in children with chronic myeloid leukemia (CML). Study design Clinical records of 48 chronic-phase CML children administered imatinib as the first-line therapy between 2001 and 2006 were analyzed retrospectively. Cumulative change in height was assessed using the height height-SDS and converted height data from age- and sex-adjusted Japanese norms. Results: A decrease in height-SDS was observed in 72.9% of children, with a median maximum reduction in height-SDS of 0.61 during imatinib treatment. Median follow-up time was 34 months (range, 10-88 months). Growth impairment was seen predominantly in children who started imatinib at a prepubertal age compared with those who started at pubertal age. Growth velocity tended to recuperate in prepubertal children with growth impairment, as they reached pubertal age, suggesting that imatinib had little impact on growth during puberty. Conclusions: Growth impairment was a major adverse effect of long-term imatinib treatment in children with CML. We report the distinct inhibitory effect of imatinib on growth in prepubertal and pubertal children with CML. We should be aware of growth deceleration in children, especially in young children given imatinib before puberty and subjected to prolonged exposure. Download full scientific article here (paid) ; see also Yahoo-Article as of 2 June 2011