Dasatinib crosses the blood-brain barrier and is an efficient therapy for central nervous system Philadelphia chromosome-positive leukemia.

Abstract:

: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 dasa-tinib (a dual-specific SRC/BCR-ABL kinase inhibitor) were compared in a preclinical 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 dasa-tinib 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).

journal_name

Blood

journal_title

Blood

authors

Porkka K,Koskenvesa P,Lundán T,Rimpiläinen J,Mustjoki S,Smykla R,Wild R,Luo R,Arnan M,Brethon B,Eccersley L,Hjorth-Hansen H,Höglund M,Klamova H,Knutsen H,Parikh S,Raffoux E,Gruber F,Brito-Babapulle F,Dombret H,Dua

doi

10.1182/blood-2008-02-140665

subject

Has Abstract

pub_date

2008-08-15 00:00:00

pages

1005-12

issue

4

eissn

0006-4971

issn

1528-0020

pii

blood-2008-02-140665

journal_volume

112

pub_type

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