Dasatinib crosses the blood-brain barrier and is an efficient therapy for central nervous system philadelphia chromosome positive leukemia
Blood , Volume 112 - Issue 4 p. 1005- 1012
Although imatinib, a BCR-ABL tyrosine kinase inhibitor, is used to treat acute Philadelphia chromosome-positive (Ph+) leukemia, it does not prevent central nervous system (CNS) relapses resulting from poor drug penetration through the blood-brain barrier. Imatinib and dasatinib (a dual-specific SRC/BCR-ABL kinase inhibitor) were compared in a pre-clinical mouse model of intracranial Ph+ leukemia. Clinical dasatinib treatment in patients with CNS Ph+ leukemia was assessed. In preclinical studies, dasatinib increased survival, whereas imatinib failed to inhibit intracranial tumor growth. Stabilization and regression of CNS disease were achieved with continued dasatinib administration. The drug also demonstrated substantial activity in 11 adult and pediatric patients with CNS Ph+ leukemia. Eleven evaluable patients had clinically significant, long-lasting responses, which were complete in 7 patients. In 3 additional patients, isolated CNS relapse occurred during dasatinib therapy; and in 2 of them, it was caused by expansion of a BCR-ABL-mutated dasatinib-resistant clone, implying selection pressure exerted by the compound in the CNS. Dasatinib has promising therapeutic potential in managing intracranial leukemic disease and substantial clinical activity in patients who experience CNS relapse while on imatinib therapy. This study is registered at ClinicalTrials. gov as CA180006 (#NCT00108719) and CA180015 (#NCT00110097).
|BCR ABL protein, Philadelphia 1 chromosome, adolescent, adult, aged, animal, antineoplastic activity, article, blood brain barrier, cell proliferation, central nervous system, central nervous system tumor, child, chromosome analysis, chronic myeloid leukemia, clinical trial, dasatinib, disease model, drug blood level, drug effect, drug efficacy, drug monitoring, drug penetration, drug screening, female, gene mutation, human, imatinib, leukemia, lymphatic leukemia, male, metabolism, middle aged, mouse, priority journal, puncture, pyrimidine derivative, remission, survival rate, thiazole derivative, treatment outcome, tumor volume|
|Organisation||Erasmus MC: University Medical Center Rotterdam|
Porkka, K, Koskenvesa, P, Lundan, T, Rimpiläinen, J, Mustjoki, S, Smykla, R, … Lee, F.Y.F. (2008). Dasatinib crosses the blood-brain barrier and is an efficient therapy for central nervous system philadelphia chromosome positive leukemia. Blood, 112(4), 1005–1012. doi:10.1182/blood-2008-02-140665